British Undergraduate Cardiovascular Journal, Volume 3, Autumn 2015

B|U|C|J British Undergraduate Cardiovascular Journal

Volume 3

Autumn 2015

HIGHLIGHTS Abstracts from the 3rd International Undergraduate Cardiovascular Conference 2015

Published by the British Undergraduate Cardiovascular Association Supporting the next generation in cardiovascular medicine

Editorial Team Lead Editor Sarah Ayton University of East Anglia (UEA)

Editor Dr Mahvesh Rana Javaid Barking, Havering & Redbridge NHS Trust

Editor Rafail Angelos Kotronias Keele University

Journal Design Emily Yeung University of Edinburgh Sarah Ayton University of East Anglia (UEA)

Editor Marilena Giannoudi Newcastle University

Abstract System Technical Support Dil Hussain & Shabir Islam British Cardiovascular Society

Reviewers Reviewer Professor Marcus Flather University of East Anglia (UEA)

Reviewer Dr Muhammad Rashid Mersey Deanery

Reviewer Dr Nicholas Gollop University of East Anglia (UEA)

Reviewer Dr Amr Gamal Freeman Hospital, Newcastle upon Tyne

Reviewer Dr Andrew Deaner Barking, Havering & Redbridge NHS Trust

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Contents

Foreword

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Reviews  The Diagnosis of Congenital Heart Disease: Focusing on the Use of Imaging Techniques

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 Alternatives to Heart Transplant for End Stage Heart Failure

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 The Role of Cell Transplantation in Left Ventricular Assist Devices: A Literature Review

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 Genetics of Cardiomyopathies

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 A Comparison of the Applications of High Dose and Normal Dose Statins for the Primary and Secondary Prevention of Cardiovascular Events

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 A Review to Determine the Effectiveness of Novel Oral Anticoagulants Compared to Warfarin at Decreasing All-cause Mortality in Patients with Atrial Fibrillation

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Educational Articles  Cardiac Causes of Syncope  Assessing a Chest Radiograph of a patient with Cardiovascular Disease Interview  Interview with Professor Gregory Lip Elective Report  What strategies are utilized in the prevention of rheumatic heart disease in the Pacific? A reflective report based on the Samoan National Health Service Supplement  Oral presentations

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 Poster presentations

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Foreword Welcome to the 3rd edition of the British Undergraduate Cardiovascular Journal (BUCJ). Following the success of the previous two editions, the third edition aims to continue to provide medical students and junior doctors interested in cardiovascular medicine with up-to-date reviews, as well as educational articles and reports.

The editorial team have worked hard with each of our writers and our review team of accomplished cardiologists to put together what we hope will be an informative and useful journal.

We hope that it is an enjoyable read.

Sarah Ayton Lead Editor BUCA Research Officer

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Rafail Angelos Kotronias Editor BUCA President

Marilena Giannoudi Editor BUCA Vice President

British Undergraduate Cardiovascular Journal

Dr Mahvesh Rana Javaid Editor BUCA Founder

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Review The Diagnosis of Congenital Heart Disease: Focusing on the Use of Imaging Techniques Hiral Jhala, Imperial College London

Introduction Congenital heart disease or defects (CHD) is defined as a structural abnormality of the heart or great vessels, usually of an idiopathic nature, which if untreated, leads to impaired cardiac function and hence life threatening complications. CHD can be classified as shown in Table 1.

those surviving into adulthood, is heart failure, which can be prevented with a diagnosis at an earlier stage, courtesy of non-invasive imaging techniques, such as foetal echocardiography. As well as being the sole method of accurately assessing cardiac anatomy, imaging has a significant role in monitoring disease progression.

Table 1 Classification of common congenital heart defects adapted from: https://myradnotes.wordpress.com/2008/page/10/

Non-Invasive Techniques Chest X-Ray A chest radiograph is used to determine the mediastinal contours, pericardial size and the orientation of the aorta and pulmonary vasculature relative to the heart [4]. Conditions such as dextrocardia (Figure 1), often suspected during routine auscultation, can be confirmed very obviously in this way.

High Flow

Low flow

CYANOTIC R  L SHUNTS: Truncus arteriosus (TA) Total anomalous pulmonary venous return (TAPVR) Transposition of the great arteries (TGA) (dTGA/l-TGA) Tricuspid atresia

ACYANOTIC L  R SHUNTS: Ventricular Septal Defect (VSD) Atrial Septal Defect (ASD) Atrioventricular Septal Defect (AVSD) Patent Ductus Arteriosus (PDA)* Patent Foramen Ovale (PFO)

Figure 1: Chest radiograph of patient with dextrocardia situs inversus. The apex of the heart is oriented to the right as opposed to the left.

R  L SHUNTS: Tetralogy of Fallot (TOF) Ebstein anomaly

VENTRICULAR ABNORMALITIES: Hypoplastic left heart syndrome Hypoplastic right heart syndrome Double inlet left ventricle Double outlet right ventricle Normal flow

OBSTRUCTIVE LESIONS: Coarctation of the aorta* Aortic Stenosis PA Stenosis Bicuspid aortic valve stenosis

*defect is in the vessel and not intrinsic to the heart itself.

CHD is the most common form of congenital abnormality occurring in 6-8 of 1000 live births [1,2], with a wide distribution. A large percentage of affected individuals survive into adulthood [3], therefore it is imperative that the defect is diagnosed as early as possible through imaging, as well as auscultation, pulse oximetry, assessment of venous pressure, and looking for features of cyanosis or failure to thrive. The main complication posing a huge mortality risk for

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Echocardiography The beating heart and blood flow can be assessed using 2D echocardiography (echo) and Doppler techniques respectively. There are various forms of echo: transthoracic echo (TTE), transoesophageal echo (TOE), Doppler, colour-Doppler, contrast and 3D. In the context of CHD, 2D TTE remains the gold standard as far as non-invasive imaging is concerned [5,6]. It is also the safest method, having no associated clinical risks.

High frequency sound waves emitted by a transducer bounce off structures in the heart, causing an echo, which is seen as a continuous moving pictures. Echo assesses the following parameters [7]: • Size of atria and ventricles, wall thickness and cavity volume.

• Thickness of the interventricular and interatrial septa • Motion, flexibility, thickness and structure of the valves.

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Review Echo allows a proper assessment of the valves including identifying specific abnormalities, such as the presence of active infective vegetations (Figure 2).

Hence it is the first line investigation for valvular disease [9]

Figure 4 Echocardiograph highlighting atrioventricular valve resulting from interventricular septum.

a common an absent

Figure 2: Echocardiograph showing a large vegetation on the tricuspid valve in a patient with infective endocarditis.

An apical view is particularly useful when determining septal defects (Figure 3-5).

Figure 5 Apex echocardiograph showing right ventricular hypertrophy

Figure 3: Parasternal long axis echocardiograph showing a ventricular septal defect.

Doppler is also used to assess haemodynamic function, and especially blood flow through the chambers, valves and great vessels. By measuring the velocities of blood flow without the need for invasive cardiac catheterisation, it’s possible to identify any abnormal relationships between the left and right sides of the heart. Valvular regurgitation is particularly well demonstrated as a jet flow, in Doppler imaging (Figure 6).

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Figure 6 Apex transthoracic echocardiograph with colour Doppler flow showing mitral regurgitation (arrow). Blue = blood flow away from probe; red =blood flow towards probe.

A jet flow can be seen through the mitral valve.

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Review TOE can also be used at a later stage [8], although less frequently, to obtain 3D images primarily of the valves, left atrium and left ventricles from the posterior aspect of the heart. However it is a more invasive and challenging procedure which comes with its limitations [9]. This requires anaesthesia or sedatives and its field of view is limited [9]. However it is the preferred method of diagnosing infective endocarditis [9] (Figure 7).

3D echo is a newer technique which provides a more accurate assessment of cardiac function than 2D echo.

Prenatal 2D echo is limited, in that it is dependent on the skill of the operator, and can only detect defects in high-risk pregnancies [6], because of which the detection rate varies between 31-96% [6].

Table 2 Advantages and limitations of 3D transthoracic echocardiography in congenital heart disease.

Advantages Produces easily interpretable, detailed, anatomical images of the beating heart Ability to measure depth (additional dimension, characteristic of 3D). This is essential with assessing the septa or atrioventricular junctions from a surgical point of view Allows a thorough understanding of abnormal relationships between adjoining structures, due to its high spatial resolution

Limitations Application in congenital disease requires specific training Difficult to image small children with the transducers currently available

Current 3D technology makes it challenging to assess tachycardia patients or those unwilling or unable to cooperate for respiratory manoeuvres

Cardiac MRI Cardiac magnetic resonance imaging (MRI) is used in conjunction with echocardiography and cardiac catheterisation to diagnose CHD most accurately. MRI exploits the differences in the magnetic properties of various tissue types, by applying a magnetic field coupled with radiowaves to create a cross sectional image of the patient’s body [11]. For this reason, it is used for tissue characterisation and looking at blood flow and mediastinal anatomy. Figure 8 shows the different views of a cardiac MRI.

Figure 7 Transoesophageal echocardiograph four chambered view showing infective endocarditis with multiple tricuspid valve vegetations (long arrow) and pacing leads (short arrow)

Table 2 [10] describes the advantages and disadvantages of 3D echo in the context of CHD.

Figure 8 Cardiac MRI in short axis, vertical long axis, 3 and 4 chambered views

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Review From different angles, MRI alone can be used to assess disease such as Tetralogy of Fallot (TOF) which consists of four lesions: a large VSD, pulmonary stenosis, right ventricular hypertrophy and an overriding aorta (Figures 9 and 10). MRI can accurately determine abnormalities in valve structure. Equally it can show abnormalities in the outflow tracts or aortic root. It is especially useful when identifying collateral vessels or when investigating TOF, coarctation of the aorta, and conditions affecting the pulmonary and systemic veins such as pulmonary vein stenosis or anomalous systemic vein connections.

Figure 9 Parasternal long axis MRI showing pulmonary atresia in a 55 year old female with untreated Tetralogy of Fallot. An overriding aorta (left) and ventricular septal defect (right) can be seen.

Image taken from Michael Puderbach et al. Circulation.

2004;110:e461-e462 – 4 chambered view of cardiac cine MRI over cardiac cycle.

Figure 10 Transverse MRI of an infant with Tetralogy of Fallot. Large VSD and right ventricular hypertrophy is seen (left) - the descending aorta is on the right, consistent with a right sided aortic arch. A large ascending aorta and presence of pulmonary atresia is shown (right). The oval shape of the descending aorta is secondary to large collateral vessels.

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MRI, which its high resolution and 3D imaging enables one to reconstruct data in any plane, which echo or catheterisation alone cannot offer [12]. MRI provides clinicians with detailed pictures of the any patient’s anatomical and physiological state post-surgery, based on which, a transfer to adult services can be made [12]. Cine imaging using fast gradient echo sequences can be viewed in long or short axis planes to evaluate the functioning of the myocardium and in particular, assessing the volumes of the ventricular cavities [12]. Its dynamic imaging enables visualisation of the motion of the valves and myocardium throughout the whole cardiac cycle, as well as of the outflow tracts and great vessels [12].

When imaging paediatric patients, if under the age of 7, sedation or general anaesthesia is required, both of which come with associated risks, including hypothermia in small infants [12], and therefore close monitoring is essential. Limited access to the ventilator and to the patient themselves, makes the process logistically challenging, however, if done using anaesthesia, it does provide the opportunity to carry out other procedures whilst the patient is sedated [12].

ECHO VS MRI The techniques with the greatest diagnostic value and hence predominantly used are echocardiography and MRI. Overall, MRI has been regarded as a more accurate diagnostic tool than echo. Chowdhury et al [13], found both a sensitivity and specificity greater than 92.3% (MRI) for measuring post-surgery biventricular ejection fraction and pulmonary regurgitant fraction in TOF. Moreover, Greenberg et al [14] describes MRI as being more sensitive when evaluating post-surgery branch pulmonary artery abnormalities in TOF. This is because MRI can image anatomical areas which are inaccessible in adults through echo, such as the aortic arch and pulmonary artery branches [15]. We can compare these techniques further by looking at their methodological and clinical strengths and weaknesses, demonstrated in Table 3 [9].

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Review Table 3 A comparison of the methodological and clinical strengths and limitations of echocardiography and MRI Methodolo gical strengths

Clinical strengths

Methodolo gical limitations

Clinical limitations

Echocardiography Real time, M-mode traces and 3D imaging Accurate velocity measurements of local structures Portable and suitable for use in operating theatres and during exercise No ionising radiation

Applicable in almost all cases: Valve disease, jet velocities, septal defects and vegetations Limited windows, angles and depth of access Cannot measure volumetric flow

Limited access to RV, pulmonary vasculature and aorta

MRI Versatile with excellent resolution Unrestricted access to structures Multi-slice cine coverage Assessment of biventricular function Accurate measurement of volumetric flow Enables tissue characterisation Dynamic angiography No ionising radiation Many applications: CoA, TOF, shunts, TGA and complex cases

Thick image slices Time consuming and expensive Requires significant training and expertise Contraindicated with pacemakers and ICDs Children need sedation/anaesthesia, which is risky in this group Unreliable when trying to exclude PFO, small ASD or mobile vegetations in endocarditis Unreliable for measuring tricuspid regurgitation jet velocity to estimate RV pressure

Computed Tomography (CT) Computed tomography (CT) uses X-rays to produce cross-sectional images of a patient’s body. It provides excellent spatial resolution, though with limited versatility, within a short acquisition period [16]. It is also used for patients with pacemakers or implantable cardioverter defibrillators (ICDs), where MRI cannot be used [9], and when assessing branch pulmonary arteries where echo has an inadequate acoustic window [16]. It is also most useful for visualising airway and anatomy, pulmonary venous anatomy, identifying MAPCAs (major aorto-pulmonary collateral arteries) (Figure 11) and to assess pulmonary atresia prior to cardiac catheterisation [12]. However, repeated doses are a concern for young patients due to the eventual accumulation of ionising radiation, therefore CT is used less frequently in CHD [9].

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Figure 11 Pediatric chest CT showing major aortopulmonary collateral arteries (MAPCAs)

Invasive Techniques Cardiac Catheterisation Cardiac catheterisation is the most frequently used invasive technique, done either by MRI guidance or with fluoroscopy. Insertion of a catheter into the femoral artery or vein and into the heart, allows proper assessment of the coronary circulation primarily to identify coronary artery disease secondary to CHD. MRI guidance allows more accurate imaging of soft tissue, with less exposure to radiation than fluoroscopy, and is therefore the preferred catheterisation method [17]. Wagner et al [18] describes how contrast enhanced magnetic resonance angiography (MRA) facilitates the evaluation of cavopulmonary morphology and function, through high spatial resolution.

The use of X-ray angiography (Figure 12) with a contrast such as gadolinium, enables complex modelling of structures by way of achieving isotropic 3D images [12].

As well as being a diagnostic technique, catheterisation can be used as a treatment method, for example to insert closure devices for septal defects such as PDA, ASD and VSD. It is also used in balloon dilatation procedures, and stenting such as in coarctation of the aorta (older children) or ductus arteriosus (infants). It may also be used in the embolization of collaterals occurring in pulmonary atresia with VSD [19]. Unlike the imaging techniques previously mentioned, catheterisation does involved exposure to ionising radiation, and paediatric patients require sedation or general anaesthesia. Bleeding or

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Review infection at the site of incision are the main risks associated with catheterisation.

Advances in interventional MR and new techniques such as 4D imaging have further enhanced our understanding of the cardiovascular system and in particular CHD [20]. The objective of current research is to be able to visualised metabolic processes in vivo at a cellular level and see their impact on cardiovascular remodelling and flow dynamic [20].

Conclusion The emergence of invasive and non-invasive imaging has revolutionised our ability to diagnose CHD in both paediatric and adult patients, with echocardiography and MRI being the most commonly used. These complimentary techniques, when used in conjunction with other routine investigations, allows us to make the most accurate diagnosis, and devise a subsequent treatment and care plan to ensure the best possible prognosis for each individual patient.

References

[6] Araujo Junior E, da Rocha LA, Nardozza LMM. Sonocubic fine: new three-dimensional ultrasound software to the screening of congenital heart diseases. Revista Brasileira de Cirurgia Cardiovascular. [Online] 2014 Jul-Sep; 29(3): 426– 431.

Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409063 [Accessed Tuesday 21st July 2015] [7] Murphy KF, Kotler MN, Reichek N, Perloff JK. Ultrasound in the diagnosis of congenital heart disease. Americal Heart Journal. [Online] 1975 May;89(5):638-56. Available from http://www.ncbi.nlm.nih.gov/pubmed/1091128 [Accessed Tuesday 21st July 2015] [8] Geibel A. Echocardiographic evaluation in unoperated congenital heart disease in adults. Herz. [Online] 1999 Jun;24(4):276-92.

Available from http://www.ncbi.nlm.nih.gov/pubmed/10444707 [Accessed Tuesday 21st July 2015] [9] Kilner PJ. Imaging congenital heart disease in adults. The British Journal of Radiology. [Online] 2011 Dec; 84(Spec Iss 3): S258–S268.

Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473918/ [Accessed Tuesday 21st July 2015]

[1] Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. [Online] 2007 Jan 16;115(2):163-72.

Available from http://www.ncbi.nlm.nih.gov/pubmed/17210844 [Accessed Monday 20th July 2015].

[10] Badano LP, Boccalini F, Muraru D, Dal Bianco L, Peluso D, Bellu R et al. Current Clinical Applications of Transthoracic Three-Dimensional Echocardiography.

Journal of Cardiovascular Ultrasound. [Online] 2012 Mar; 20(1): 1–22.

Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324722/ [Accessed Wednesday 22nd July 2015]

[2] Hoffman JI, Kaplan S. The Incidence of congenital heart disease. Journal of the American College of Cardiology.

[Online] 2002 Jun 19;39(12):1890-900. Available from http://www.ncbi.nlm.nih.gov/pubmed/12084585 [Accessed Monday 20th July 2015]

[11] Berger A. Magnetic resonance imaging. The British Medical Journal. [Online] 2002 Jan 5; 324(7328): 35. Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121941/ [Accessed Wednesday 22nd July 2015]

[3] Hoffman JI, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. American Heart Journal. [Online] 2004 Mar; 147(3):425-39.

Available from http://www.ncbi.nlm.nih.gov/pubmed/14999190 [Accessed Monday 20th July 2015]

[12] Ntsinjana HN, Hughes ML, Taylor AM. The Role of Cardiovascular Magnetic Resonance in Pediatric Congenital Heart Disease. Journal of Cardiovascular Magnetic Resonance. [Online] 2011; 13(1): 51. Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210092/ [Accessed Wednesday 22nd July 2015]

[4] Goel A, Gaillard F et al. Congenital Heart disease – chest x-ray approach.

[Online] Available from http://radiopaedia.org/articles/congenital-heart-diseasechest-x-ray-approach [Accessed Monday 20th July 2015] [5] Mertens L, Friedberg MK. The gold standard for noninvasive imaging in congenital heart disease: echocardiography. Current Opinion in Cardiology. [Online] 2009 Mar;24(2):119-24.

Available from http://www.ncbi.nlm.nih.gov/pubmed/19225295 [Accessed Tuesday 21st July 2015]

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[13] Chowdhury UK, Pradeep KK, Patel CD, Singh R, Kumar AS, Airan B et al. Noninvasive assessment of repaired tetralogy of Fallot by magnetic resonance imaging and dynamic radionuclide studies. The Annals of Thoracic Surgery. [Online] 2006 Apr;81(4):1436-42. Available from http://www.ncbi.nlm.nih.gov/pubmed/16564289 [Accessed Wednesday 22nd July 2015].

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Review [14] Greenberg SB, Crisci KL, Koenig P, Robinson B, Anisman P, Russo P. Magnetic resonance imaging compared with echocardiography in the evaluation of pulmonary artery abnormalities in children with tetralogy of Fallot following palliative and corrective surgery. Pediatric Radiology.

[Online] 1997 Dec;27(12):932-5.Available from http://www.ncbi.nlm.nih.gov/pubmed/9388286 [Accessed Wednesday 22nd July 2015] [15] Rebergen SA, de Roos A. Congenital heart disease.

Evaluation of anatomy and function by MRI. Herz. [Online] 2000 Jun;25(4):365-83.

Available from http://www.ncbi.nlm.nih.gov/pubmed/10948773 [Accessed Wednesday 22nd July 2015] [16] Kilner PJ. The Role of Cardiovascular Magnetic Resonance in Adults with Congenital Heart Disease. Progress in Cardiovascular Diseases. [Online] 2011 Nov-Dec; 54(3): 295–304.

Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245850/ [Accessed Thursday 23rd July 2015]

[18] Wagner M, Nguyen KL, Khan S, Mirsadraee S, Satou GM, Finn JP. Contrast-enhanced MR angiography of cavopulmonary connections in adult patients with congenital heart disease. Americal Journal of Roentgenology. [Online] 2012 Nov;199(5):W565-74. Available from http://www.ncbi.nlm.nih.gov/pubmed/23096200 [Accessed Friday 24th July 2015] [19] Andrews RE and Tulloh RMR. Interventional Cardiac Catheterisation in Congenital Heart Disease. Archives of Disease in Childhood. [Online] 2004;89:1168-1173. Available from: doi:10.1136/adc.2003.046532 [Accessed Friday 14th August 2015] [20] Valverde I, Hussain T, Razavi R. Novel Imaging Techniques for the Diagnosis and Treatment of Congenital Heart Defects. Future Cardiology. [Online] 2012;8(2):149152.

Available from http://www.medscape.com/viewarticle/760769_6.

[Accessed Friday 24th July 2015]

[17] Razavi R, Hill DL, Keevil SF, Miguel ME, Muthurangu V, Hegde S et al. Cardiac catheterisation guided by MRI in children and adults with congenital heart disease. Lancet.

[Online] 2003 Dec 6;362(9399):1877-82. Available from http://www.ncbi.nlm.nih.gov/pubmed/14667742/ [Accessed Thursday 23rd July 2015]

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Review Alternatives to Heart Transplant for End Stage Heart Failure Luke Williams, Imperial College London Introduction Heart failure (HF) is an important clinical syndrome associated with considerable morbidity and mortality.

It is estimated that the prevalence of HF in the UK in 2013 was 1.22% for males of all ages and 0.76% for females of all ages, with these figures rising to 7.84% and 5.89% in over 75s respectively (1). This is increasing year on year, in part due to better management of myocardial infarction and an ageing population. HF is a syndrome characterised by structural disease of the heart, such as left ventricular (LV) remodelling and symptoms associated with failure of the LV to maintain adequate cardiac output. HF can be classified from stage A to stage D according to ACC/AHA guidelines (2), with stage D also known as refractory or end stage heart failure (ESHF). This group of patients have advanced structural heart disease with an estimated 5 year mortality of 80% (3) and suffer daily symptoms, usually consisting of dyspnoea at rest, lethargy and oedema, despite maximal medical therapy. They also require frequent hospitalisation due to acute decompensation, often requiring intensive care. Causes of HF are many and the aim of treatment is initially to prevent progression to stage D by treating reversible causes, such as primary coronary intervention (PCI) for coronary artery disease (the most common cause of HF). Despite this a number of patients will develop ESHF, of which the only curative treatment is heart transplant. Unfortunately, demand for donor organs far outstrips supply, with 246 adult patients on the UK active heart transplant list on March 31st 2014, and a median wait time for non-urgent transplant of 592 days (95%CI: 468-716) (4). Sadly, many patients die on the list or are not eligible for transplant due to age or comorbidities. This means that there is an urgent need for alternative treatments, either as a bridge to transplant or as definitive therapy.

Novel devices and treatments have become available, expanding the possibilities for patients with ESHF. The purpose of this article is to review the current alternative options for patients with ESHF and look towards the future management of this important syndrome.

Medical Therapy By definition, all patients with ESHF should be on maximal medical therapy. However, it is worth reviewing the current best medical treatment as it is important to optimise patients for surgery and minimise symptoms. It also remains the only option for

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palliative patients. Medical therapies seek LV function and reduce LV wall stress. One of the most important groups of medications is diuretics, which treat symptomatic peripheral and pulmonary oedema, as well as reducing ventricular diastolic pressure (5).

Additionally, the potassium sparing diuretics spironolactone and eplenerone have been shown to reduce risk of death via their action on the ReninAngiotensin-Aldosterone System (RAAS) (6).

Inhibition of the RAAS improves mortality in HF and thus Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) also form an important part of the medical management of HF. ACEi have been shown to reduce remodelling of the heart through their action to counteract vasoconstriction via reduction of angiotensin II, as well as their inhibition of bradykinin breakdown (7). ARBs are thought to provide a more complete block of angiotensin II, but do not prevent breakdown of bradykinin. Although bradykinin has beneficial effects in terms of remodelling of the heart, it is sometimes useful not to potentiate its effects as some patients will develop chronic cough due to excess bradykinin with ACEi. Clinical trials have shown reduction in mortality with ARBs, but there is no added benefit with combination ACEi/ARB therapy and this results in higher rates of drug withdrawal, in part due to more adverse effects (7).

Beta-blockers are also used in HF and have a number of beneficial effects. Chiefly, heart rate reduction decreases myocardial oxygen demand and has been shown to reduce mortality. Caution must be taken when initiating beta-blocker therapy, however, due to the potential to worsen symptoms caused by reduction in LV systolic function. NICE therefore recommends a “start low and go slow� approach to initiation of betablockers in HF (7).

Digoxin has also been shown to reduce hospitalisation, but not mortality (8). It is particularly useful in patients with arrhythmias. In patients with acute decompensated HF, worsening LV function and low cardiac output, other inotropes such as Milrinone and Dobutamine can be used to support the heart by enhancing cardiac contractility.

The progression of HF is characterised by numerous acute decompensations requiring admission and concomitant gradual decline. Once a patient is on

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Review continuous inotrope therapy they are essentially palliative unless they receive a transplant or mechanical support device.

Mechanical Device Therapy Left Ventricular Assist Devices (LVADs) are pumps that maintain cardiac output for the LV. They can be extracorporeal, paracorporeal or intracorporeal.

Extracorporeal and paracorporeal devices are mostly used in the acute setting of cardiogenic shock to allow recovery or urgent transplant and as such are not an alternative to transplant. However, implantable intracorporeal devices have developed significantly in recent years from large, pulsatile devices prone to wear to smaller, continuous-flow and longer lasting devices. Modern devices have an outflow catheter in the LV apex connected to a pump implanted below the diaphragm, with a return catheter placed in the aorta.

Batteries and a controller are connected via external wires (9). This offers the potential for longer-term bridge to transplant or even destination therapy in patients who would otherwise require transplant and allows discharge from hospital with device in situ.

Currently criteria for LVADs are similar to those for heart transplant except that age is not considered to be a limiting factor (with the oldest reported recipient being 88) (10) Patients do, however, require anticoagulation. Furthermore, patients with refractory angina, refractory ventricular tachycardia and restrictive cardiomyopathies are considered inappropriate for an LVAD (10).

Outcomes with LVADs were analysed in a recent systematic review (11), with LVADs shown to improve survival and functional status, with 47% survival at 4 years in the only long term study. However, these devices are also associated with considerable risks, in particular bleeding, stroke and infection. At 1 year roughly 55% are re-hospitalised for any cause, with 10% having a stroke, 20% a serious device related infection, 5% a device malfunction due to clotting and 50% having a major bleed (weighted averages of analysed studies (11)). Furthermore, the LVAD is dependent on adequate flow through the pulmonary system and therefore requires a functioning right ventricle (RV), but RV function deteriorates to right HF in around 18% (10).

In the future the development of transcutaneous energy transfer may improve the portability and quality of life associated with these devices (12). There are also several intra-pericardial devices in development, which should help to establish LVAD as a definitive treatment, not just a bridge to transplant.

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Another option that has been explored as an alternative to transplant is a total artificial heart (TAH).

There is, however, only one device with FDA approval, and that only as a bridge to transplant. This has 2 ventricles and 4 valves and delivers blood in a pulsatile manner. Complications are similar to those with LVAD, but there is less outcome data, due to fewer centres offering this option. New devices are in development and have been implanted in the US under FDA Humanitarian device exemption, but it remains to be seen if TAH will offer any benefit over LVAD. Currently, it is only attempted in patients where LVAD is inappropriate due to RV failure, ventricular septal defect, restrictive cardiomyopathy, refractory ventricular tachycardia or LV thrombus (12).

Stem Cell Therapy Much hope and expectation has been pinned on stem cell research in many fields of medicine, with limited success to date. One area of investigation has been the use of stem cells to replace dead or dysfunctional myocytes in HF. Stem cells from various sources can be introduced into damaged areas of myocardium in the hope that they will differentiate into cardiac myocytes and replace lost or injured myocytes. A meta-analysis published this year (13) sought to evaluate the use of stem cells in this setting.

31 independent trials, incorporating 1521 patients were analysed and it was found that cell treatment reduces mortality and rehospitalisation significantly, as well as improving LV ejection fraction, symptoms, exercise capacity and quality of life. These are promising results, but are not yet enough to convert into clinical practise due to risk of bias and lack of large randomised controlled trials.

Much research has also been done into the potential for using stem cells to recellularise an extracellular matrix and hence create a bio-artificial heart. This is still very experimental, but a rat heart has been successfully recellularised with some contractile function, while porcine extracellular matrix recellularisation has also shown promise (14). These are a very long way from clinical practise, but they open the possibility of producing a new heart from the patient’s own stem cells in the future.

Palliative Care Finally, it is important to remember that all of the procedures discussed above, as well as heart transplantation itself, involve spending large amounts of time in hospital, undergoing serious and invasive medical procedures and are associated with high levels of risk of death, adverse events and failure. For many

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Review patients these risks and the short-term reduction in quality of life will outweigh the benefits. It is vital to discuss all of the options and the risks and benefits with each individual patient to help them come to an informed decision. The chronic gradual decline of HF, punctuated by acute decompensation and hospitalisation makes it difficult to know when to approach palliation as an option. However, patients may benefit from early intervention from specialised palliative care teams, allowing them to plan for the future and receive psychological and practical support.

Palliative care teams are best suited to manage symptoms at the end of life, including pain management, as well as providing psychological support for both the patient and family. Palliation has been shown to be of great benefit in a number of different situations, including ESHF (15). Even patients who opt for more radical therapies may benefit from palliative care involvement to plan for potential complications. The importance of this aspect of medicine with respect to HF was emphasised in the 2011 Canadian Heart Failure Management Guidelines (16).

Conclusion Heart transplant offers the only curative therapy for ESHF. However, due to a shortage of donors and strict exclusion criteria, this treatment is unfortunately not an option for most patients.

Great advances have been made in recent times with mechanical devices to assist LV function and reduce mortality. As these devices get smaller and more reliable it is likely that they will become a viable longterm alternative to heart transplantation.

Furthermore, stem cell therapies offer hope for regeneration of cardiac myocytes and LV function. It is vital to continue to explore alternative therapies to heart transplantation and improve the options we have. Nonetheless, as we strive to find alternative cures we must not forget that each patient is individual and for some radical therapy may not be appropriate.

The management of ESHF requires a large multidisciplinary team, including cardiologists, cardiac surgeons, anaesthetists, physiotherapists, occupational therapists and should also include a specialist palliative care team once ESHF is diagnosed.

References (1) Bhatnagar P, Wickramasinghe K, Williams J, Rayner M, Townsend N. The epidemiology of cardiovascular disease in the UK 2014. Heart (British Cardiac Society) 2015;101(15) 1182-1189.

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(2) Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/ AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. Journal of the American College of Cardiology 2001;38(7) 2101-2113.

(3) Dunlay SM, Pereira NL, Kushwaha SS. Contemporary strategies in the diagnosis and management of heart failure. Mayo Clinic proceedings 2014;89(5) 662-676.

(4) NHS Blood and Transplant. Annual Report on Cardiothoracic transplantation. Report for 2013/14. NHS England; 2014.

(5) Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. The Cochrane database of systematic reviews 2012;2 CD003838.

(6) Nicolini F, Gherli T. Alternatives to transplantation in the surgical therapy for heart failure. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2009;35(2) 214-228.

(7) Mancini GBJ, Howlett JG, Borer J, Liu PP, Mehra MR, Pfeffer M, et al. Pharmacologic Options for the Management of Systolic Heart Failure: Examining Underlying Mechanisms. Canadian Journal of Cardiology.

(8) Bozorgnia B, Mather PJ. Current Management of Heart Failure: When to Refer to Heart Failure Specialist and When Hospice is the Best Option. The Medical clinics of North America 2015;99(4) 863876.

(9) Kirkpatrick JN, Wieselthaler G, Strueber M, St John Sutton MG, Rame JE. Ventricular assist devices for treatment of acute heart failure and chronic heart failure. Heart (British Cardiac Society) 2015;101(14) 1091-1096.

(10) Mancini D, Colombo PC. Left Ventricular Assist Devices: A Rapidly Evolving Alternative to Transplant. Journal of the American College of Cardiology 2015;65(23) 2542-2555.

(11) McIlvennan CK, Magid KH, Ambardekar AV, Thompson JS, Matlock DD, Allen LA. Clinical outcomes after continuous-flow left ventricular assist device: a systematic review. Circulation.Heart failure 2014;7(6) 1003-1013.

(12) Milano CA, Simeone AA. Mechanical circulatory support: devices, outcomes and complications. Heart failure reviews 2013;18(1) 35-53.

(13) Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circulation research 2015;116(8) 1361-1377.

(14) Smit FE, Dohmen PM. Bio-artificial heart as ultimate treatment of end-stage heart failure. Medical science monitor basic research 2014;20 161-163.

(15) Fendler TJ, Swetz KM, Allen LA. Team-based Palliative and Endof-life Care for Heart Failure. Heart failure clinics 2015;11(3) 479-498.

(16) McKelvie RS, Moe GW, Cheung A, Costigan J, Ducharme A, Estrella-Holder E, et al. The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care. The Canadian journal of cardiology 2011;27(3) 319-338.

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Review The Role of Cell Transplantation in Left Ventricular Assist Devices: A Literature Review Chean Chung Shen, University of Liverpool Abstract Background & Aim: Cardiac transplantation has always been the ‘gold standard’ therapy of end-stage cardiac failure.

For some patients awaiting heart transplantation, mechanical circulatory support by left ventricular assist device (LVAD) is of great benefit. However, sufficient regeneration of cardiac muscle and adequate recovery of ventricular function are essential to allow LVAD explantation. Combining cell transplantation techniques with LVAD support might improve long term results. This review focuses on the clinical role of the aforementioned combination therapy among patients with end-stage heart failure.

Methods: PubMed, ScienceDirect and MEDLINE were searched for studies regarding the clinical outcomes of combining cell therapy with LVAD, in patients with cardiac failure. The search terms such as ‘LVAD’, ‘Left ventricular assist device’, ‘stem cell’, ‘bone marrow mononuclear cells’ and ‘left ventricular assist system’ were used.

Results: Nine studies were identified that evaluated the role of combination therapies of cell transplantation and the use of left ventricular assist device. Most were preliminary trials, case report or case series, with a total of 50 patients.

Primary end points of the studies were LVAD explantation, death, or cardiac transplantation. The safety, efficacy, and feasibility of the use of bone marrow mononuclear cell, autologous skeletal myoblasts, or allogenic mesenchymal precursor cells (MPCs), in combination with LVAD, were also reviewed.

Conclusion: More pilot studies that will then lead to an increase in randomised controlled trials examining the role of combination strategies of cell transplantation and LVAD support should be conducted in the future as previous studies have shown promising results.

Aim This structured review aims to summarise the available clinical evidence for the role of cell transplantation as an adjunctive therapy to left ventricular assist device (LVAD) support in patients with heart failure.

Introduction & Background Improvements in the management of acute myocardial infarction (MI), such as the use of antiplatelets and reperfusion therapy, has significantly improved survival rate. These developments, in combination with an ageing population have translated into an increase in the prevalence of end stage congestive cardiac failure (CCF), which affect 23 million patients worldwide (1, 2). CCF is associated with progressive cellular and structural changes, resulting in ventricular remodelling and diminished cardiac function (3). Currently, the only available therapy for CCF is heart transplantation. However, not every patient with CCF is a candidate for heart transplantation, and there is a lack of donors. This has encouraged experiments on regenerative therapies, such as mechanical circulatory support with a left ventricular assist device (LVAD) (4, 5).

Ventricular assisting devices (VADs) may be used in the short term, in patients recovering from MI or heart surgery, and in the long term in patients with advanced CCF and ischaemic cardiomyopathy. LVAD is one of the most common VADs and has well-documented

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benefits for survival and quality of life in patients with advanced CCF both as a bridge to cardiac transplantation and as a long-term destination therapy in patients who are not candidates for transplantation.

It can potentially be used as a bridge to recovery, as shown by its utility in improving myocardial function, and by salutary changes in ventricular structures, normalisation of extracellular matrix, myocyte contractile strength and circulating neurohormones (3, 6, 7, 8). According to a study by Jahanyar et al, LVADs can increase stem-cell factor (SCF), which is expressed throughout the myocardium and c-Kit, which was only found in myocardial mast cells. These changes coincide with an up-regulation of phenotypically altered mast cells post LVAD implantation, thus suggesting an involvement in reverse cardiac remodelling with LVAD support. However, this reverse remodelling is usually insufficient to allow recovery of cardiac function that would lead to the removal of the device (7,9). This has encouraged efforts to investigate adjunctive therapies to LVAD support, especially the use of stem cells, mesenchymal precursor cells (MPCs), and pharmacological or biological modifiers of SCF, as potential interventions to augment ventricular recovery (10).

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Review Cell transplantation is becoming a novel therapeutic approach for the treatment of CCF, with increasing evidence suggesting the improvement of myocardial function after cell transplantation. Various experimental studies have been conducted, involving the use of cardiac myocytes, fetal and neonatal cardiomyocytes, skeletal myoblasts, fibroblasts, and, embryonic and haematopoietic stem cells (11).

This structured review aims to summarise the available clinical evidence for the role of combining cell transplantation and LVAD support in patients with CCF.

Table 1: Bibliographic Search of PubMed, ScienceDirect and MEDLINE PubMed Keywords

Inclusion criteria

searches ‘Left ventricular assist

Humans, English Language, full

device’ AND ‘stem cell’

text available, excluding reviews

‘Left ventricular assist

Humans, English Language, full

devices’ AND ‘stem

text available, excluding reviews

Humans, English Language, full

device’ AND ‘stem cells’

text available, excluding reviews

Methods A literature search using PubMed, ScienceDirect and MEDLINE was conducted, and a manual search of the references of relevant articles. The search used and the number of search results are shown in Table 1.

‘Left ventricular assist

Humans, English Language, full

devices’ AND ‘stem cell’

text available, excluding reviews

‘LVAD’ AND ‘stem cell’

Humans, English Language, full

‘LVADs’ AND ‘stem

Humans, English Language, full

The search was limited to clinical trials, observational studies and randomised controlled trials that showed full texts, involved human participants, were in English, and were published in the past 10 years. The reference lists of the identified articles were reviewed for additional relevant publications. All reviews and meta-analyses were excluded. This yielded a total of nine articles for this review.

cells’

text available, excluding reviews

‘LVAD’ AND ‘stem cells’

Humans, English Language, full

Ascheim et al investigated the safety and efficacy of mesenchymal precursor cells (MPC) in myocardial recovery. A multicentre, double-blinded, shamprocedure controlled trial was undertaken, in which 30 patients were randomised (2:1) to receive either intramyocardial injection of 25 million MPCs or cryoprotective medium during LVAD implantation.

The safety end-points were incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction and immune sensitisation 90 days after randomisation. Key efficacy end-points were functional status and ventricular function while temporarily weaned from LVAD support. Patients were followed up until transplantation or 12 months after randomisation. During this follow up, no safety events were observed and successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days. The probability that MPCs

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4

4

cells’ ‘Left ventricular assist

Results Various cell populations and delivery strategies have been investigated for cardiac repair and regenerative capacity in the last decade. Table 2 summarises the results of clinical trials investigating the use of LVAD support and cell therapy.

Number of

4

4

4

text available, excluding reviews 1

4

text available, excluding reviews ‘LVADs’ AND ‘stem cell’

Humans, English Language, full

1

text available, excluding reviews ‘left ventricular assist

Humans, English Language, full

system’ AND ‘stem cell’

text available

‘Bone marrow’ AND

Humans, English Language, full

‘mononuclear cell’ AND

text available

7

6

‘left ventricular assist device’ ‘mechanical assist

Humans, English Language, full

system’ AND ‘stem cell’

text available

6

increased the likelihood of successful weaning was 93%, showing that there was a potential signal of its efficacy. At 90 days, three deaths occurred in the control group whereas none occurred in MPC patients.

Mean left ventricular ejection fraction (LVEF) was 24% in MPC group and 22.5% in control group. At 12 months, 30% of MPC treated patients and 40% of control patients were successfully temporarily weaned from LVAD support, and 6 deaths had occurred in MPC patients (12).

Nabil Dib et al evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass graft (CABG) and LVAD implantation.

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Review Table 2 Summary of the clinical trials investigating the use of LVAD support and cell therapy Study

Study type

Number of

Cell type

Aetiology of

patients Ascheim et

al12

Phase I, multi-center,

20

Clinical outcomes

cardiomyopathy Allogenic

Ischaemic and non-

Increased weaning

double blind, sham

mesenchymal

ischaemic

frequency and duration

procedure controlled

precursor cells (MPCs)

Ischaemic

4 Heart transplants, 3

trial Nabil Dib et al13

Phase I, non-

6

randomised, multi-

Autologous skeletal myoblasts

deaths

center Pagani et al14

Phase I

5

Autologous skeletal

Ischaemic

myoblasts

3 heart transplants, 1 destination therapy, 1 death

Fujita et

al15

Phase I

4

Autologous skeletal

Ischaemic

myoblasts and bone

1 LVAD explantation, 3 non-cardiac deaths

marrow cells Gojo et

al16

Case report

1

Autologous bone

Ischaemic

LVAD explantation

Dilated

LVAD explantation

Ischaemic

Death and sepsis

Ischaemic

1 improved perfusion, 1

marrow mononuclear cells (BMMNCs) Sawa et

al17

Case report

1

Autologous skeletal myoblast

Miyagawa et

Case report

1

al18 Anastasiadis et

Autologous skeletal myoblasts

Case series

2

Autologous BMMNCs

al19 Nasseri et al20

unknown Case series

10

Autologous BMMNCs

Ischaemic

1 LVAD explantation, 3 heart transplants, 2 deaths

This was a phase I, non-randomised, multicentre pilot study of 30 patients with history of ischaemic cardiomyopathy. 24 patients with a previous history of MI and LVEF<40% were enrolled in the CABG arm. Six patients undergoing LVAD implantation were enrolled into the second arm. Myoblasts were successfully transplanted into all patients without any significant adverse events. Follow-up positron emission tomography (PET) scans were used to show new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography was also used to measure the average change in LVEF at 1 year and 2 years. Four of six patients who underwent heart transplantation were histologically evaluated for engraftment of skeletal myoblasts within the infarcted myocardium.

The results of this study demonstrated the survival, feasibility, and safety of autologous myoblast transplantation and suggested that it could offer a potential therapeutic treatment for end-stage heart disease (13).

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Further to the aforementioned study, Pagani et al reported histological analysis of hearts from patients with end-stage heart disease who were transplanted with autologous skeletal myoblasts concurrent with LVAD implantation. Five patients with ischaemic cardiomyopathy, refractory heart failure and listed for heart transplantation underwent muscle biopsy from the quadriceps muscle. Myoblasts were isolated, grown and transplanted. Four patients underwent LVAD explant after 68, 91, 141, and 191 days of LVAD support respectively. One patient who was on LVAD support awaiting heart transplantation remained alive at the end of the study. Skeletal muscle cell survival and differentiation into mature cardiomyocytes were demonstrated in three of the four explanted hearts using an antibody against skeletal muscle specific myosin heavy chain. There was also an increase in small vessel formation at the site of surviving myotubes in one of the three patients. These results demonstrated the survival of autologous myoblast cell in the human heart and the feasibility of myoblast transplants for myocardial repair (14).

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Review Fujita et al evaluated the potential application of combination cell therapy of simultaneous injection of autologous bone marrow mononuclear cells (BMMNCs) and skeletal myoblasts in patients with severe ischemic cardiomyopathy who required LVAD implantation. Four patients who required LVAD implantation due to severe ischemic cardiomyopathy were studied. Skeletal myoblasts were obtained from the thigh and BMMNCs were collected and purified at the time of operation. These cells were then directly injected in a serial manner into damaged myocardium.

No major complications were observed. Two patients showed decreased brain natriuretic peptide (BNP) level and echocardiographic improvements in the transplanted areas as well as increased perfusion revealed by PET. One of these patients was successfully weaned from LVAD. Histological findings at autopsy of the other patient showed a small amount of skeletal muscle in the injected area. Only marginal improvements were observed in the other two patients. This study demonstrated that combined cell transplantation is feasible for patients with severe ischaemic cardiomyopathy and functional recovery is anticipated (15).

Gojo S et al described a case where BMMNCs were transplanted in a patient who sustained an acute MI, resulting in the use of an LVAD. The heart regained good function after cell transplantation, and the LVAD was explanted 6 weeks later. This suggested that this novel therapy could be an alternative to cardiac transplantation for severe ischemic heart failure (16).

Sawa et al also produced a case report, in which a 56 year old male who suffered from idiopathic dilated cardiomyopathy (DCM), received a transplant of autologous myoblast sheets manufactured in temperature-responsive culture dishes. After the treatment, his clinical condition improved markedly, and the LVAD was discontinued. Cardiac transplantation was avoided. These findings suggested that cellular therapy using myoblast sheets is promising for treating patients with end-stage DCM. It might be an effective alternative to cardiac transplantation in the near future (17).

Miyagawa et al described a case where combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells were introduced as a treatment for a patient suffering from severe heart failure caused by ischaemic cardiomyopathy who was managed with a LVAD. The patient showed signs of improved cardiac performance, angiogenesis and reduced fibrosis (18).

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Anastasiadis et al discussed about a hybrid approach of implanting autologous BMMNCs during LVAD implantation. They hypothesised that this may improve native cardiac function and enhances myocardial reperfusion in patients with end-stage ischaemic heart failure. This may eventually provide a realistic alternative to cardiac transplantation allowing scarce donor hearts to be used for more complex cardiac defects. This report also encouraged its hypothesis to be tested through further well-designed randomised controlled studies (19).

Nasseri et al tested the hypothesis that myocardial implantation of autologous BMMNCs increases the likelihood of successful weaning from LVAD support.

10 patients with deteriorating heart function receiving LVAD support and concomitant implantation of BMMNC were examined. The results of the study were: one late and one early death, one patient showed a significant improvement in LV functions, three patients underwent heart transplantation, four patients required LVAD support for more than one year without evidence of recovery. Only one patient was successfully weaned from LVAD support after 4 months, who then had stable LV function. This study concluded that in patients with end-stage cardiomyopathy, intramyocardial injection of BMMNCs does not increase the likelihood of successful weaning of LVAD support and this encouraged the exploration of other cell-based strategies (20). This finding was supported by a study by Stempien et al, which was conducted on patients with ischaemic cardiomyopathy, who were scheduled for a placement of LVAD as a bridge to transplantation. The patients underwent bone marrow aspiration a day before surgery. This study showed that CD34+ stem cells do not increase vascularity in the unloaded ischaemic ventricles, and suggested that more pre-clinical studies were needed before predicting results in human subjects with ischaemic cardiomyopathy and LVADs (21).

Discussion In the last decade, various cell populations and delivery strategies, such as the use of stem cells derived from bone marrow, blood, skeletal muscles, embryonic tissues and cardiac tissue, have been studied in patients with end stage CCF, ischaemic heart disease and severe cardiomyopathy, and they have been examined for cardiac regeneration (11). The role of cell transplantation in LVAD is still being investigated and there is still limited clinical data regarding the efficacy of cell therapy in patients who are on LVAD support due to CCF. Currently, the most clinical experience with cell therapy is with BMMNCs (11, 15, 19, 20).

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Review Understanding of the most effective cell therapy in cardiac regeneration is fundamental to improve its clinical success.

Several studies on the mechanical support of LVAD have shown that LVAD increases contractile properties of cardiac myocytes and beta-adrenergic hyperresponsiveness (8). The exact mechanism in which LVAD helps in the reversal of cardiac failure is still unclear. However, the effect of ventricular volume and pressure unloading and improved cytokine and neurohormonal activation are thought to induce reverse modelling (3,7). In mouse models, significant improvement in cell apoptosis/proliferation balance by ventricular unloading has been shown. However, all these beneficial effects on ventricular function deteriorate over time (22). This encouraged strategies of combining mechanical therapy with cell therapy.

In the studies reviewed a total of 50 patients who have been treated using a combination of mechanical LVAD support and cell therapy (12-20). Most patients suffered from severe cardiac failure secondary to ischaemic cardiomyopathy. The data is limited, due to the small sample size and most studies conducted were non-randomised. Additionally, most studies were either in the early phase of the trial or case reports. All studies used autologous cells, either bone marrow derived or skeletal myoblasts, except a phase I trial conducted by Ascheim et al (12, 23). Most of the phase I trials were conducted to evaluate the safety, feasibility and efficacy of combination strategies of LVAD support and cell transplantation. The measured effect used in the case reports and case series was mainly LVEF (23). Ascheim et al is the first and only randomised trial which shows encouraging results and positive outcomes (12, 23). However, there is a concern about safety regarding sensitisation (23). Overall, the studies show that the combination of LVAD support and cell transplantation is promising (7, 12-20).

Randomised multi-centre studies are warranted to obtain data regarding the use of this combination strategy.

Possible future applications The advancement of mechanical circulatory support using LVAD will help to uncover the optimal technology for quicker recovery of cardiac function and further reducing adverse cardiac events. LVAD may not only have a role as a bridge to transplantation or a destination therapy, but could potentially be a bridge to recovery. Advancements in LVADs may improve recovery, such as the use of pulsatile flow LVAD (24, 25). Additionally, more permanent LVADs will lead to further data regarding cardiac function recovery and adverse events. More preclinical studies

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also lead to a better understanding of the underlying molecular mechanism in cardiac muscle repair, regeneration and recovery. However, the limited number of patients involved in clinical trials makes moving forward towards clinical application more difficult and time-consuming (23). The development of other experimental regenerative therapies such as the use of growth factors, exosomes, gene therapy and biomaterials is intriguing, and this could be applied in combination with LVAD support. More combination strategies could also be experimented in the future to reduce adverse cardiac events and mortality, as well as to aid in the recovery of a failing heart (23).

Conclusion Pharmacological and surgical interventions have been used to treat CCF, with cardiac transplantation being the gold standard for patients with end stage heart failure. CCF is increasing in prevalence due to the ageing world population. Its mortality remains high, encouraging more pre-clinical and clinical studies of regenerative therapies which could improve cardiac muscle recovery and promote reverse remodelling.

Improvement in technology of mechanical circulatory support is crucial and recently, cell therapy for the treatment of heart disease has shown promising results. Combining the two could give positive outcomes and better sustained results. More testing on animal models is required and clinical research should be focused on randomised controlled trials in patients undergoing LVAD implantation.

References 1. Levy D, Kenchaiah S, Larson MG et al. Long term trends in the incidence of and survival with heart failure. New England Journal of Medicine.

(2002) 347(18):1397–402. doi:10.1056/NEJMoa020265.

2. De Jonge N, Vantrim pont PJ. Heart failure: chapter 8.

Treatment of end-stage heart failure. Neth Heart J (2004) 12(12):548–54.

3. Levin H, Oz M, Chen J et al. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation (1995) 91(11):2717–20. doi:10.1161/01. CIR.91.11.2717.

4 .De Jonge N, Kirkels JH, Klöpping C et al. Guidelines for heart transplantation. Neth Heart J (2008) 16(3):79–87. doi:10.1007/BF0308612.

5. Mason C, Dunnill P. A brief definition of regenerative medicine.

Regen Med (2008) 3:1–5. doi:10.2217/17460751.3.1..

6. Maybaum S, Kamalakannan G, Murthy S. Cardiac recovery during mechanical assist device support. Semin Thorac Cardiovasc Surg (2008) 20(3):234–46. doi:10.1053/j.semtcvs.2008.08.003.

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Review 7. Ibrahim M, Rao C, Athanasiou T, Yacoub MH, Terracciano CM. Mechanical unloading and cell therapy have a synergistic role in the recovery and regeneration of the failing heart. Eur J Cardiothorac Surg (2012) 42(2):312–8. doi:10.1093/ejcts/ezs067.

17. Sawa Y, Miyagawa S, Sakaguchi T et al. Tissue engineered myoblast sheets improved cardiac function sufficiently to discontinue LVAS in a patient with DCM: report of a case.

Surg Today (2012) 42(2):181–4. doi:10.1007/s00595-0110106-4.

8. Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation (1998) 97(23):2316–22. doi:10.1161/01.CIR.97.23.2316.

18. Miyagawa S, Matsumiya G, Funatsu T et al. Combined autologous cellular cardiomyoplasty using skeletal myoblasts and bone marrow cells for human ischemic cardiomyopathy with left ventricular assist system implantation: report of a case. Surg Today (2009) 39(2):133– 6. doi:10.1007/s00595-008-3803-x.

9. Jahanyar J, Youker KA, Torre-Amione G et al. Increased expression of stem cell factor and its receptor after left ventricular assist device support: a potential novel target for therapeutic interventions in heart failure. J Heart Lung Transplant.

2008 Jul;27(7):701-9. doi: 10.1016/j.healun.2008.03.021. Epub 2008 Jun 2.

10. Du Pré BC, Doevendans PA, Van Laake LW. Stem cells for cardiac repair: an introduction. J Geriatr Cardiol (2013) 10(2):186–97. doi:10.3969/j.issn.16715411.2013.02.003.

11. Segers VFM, Lee RT. Stem-cell therapy for cardiac disease.

Nature (2008) 451(7181):937–42. doi:10.1038/nature06800.

12. Ascheim DD, Gelijns AC, Goldstein D et al. Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary LVADs. Circulation (2014) 129:2287–96. doi:10.1161/CIRCULATIONAHA. 113.007412.

13. Dib N, Michler RE, Pagani FD et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation (2005) 112(12):1748–55. doi:10.1161/CIRCULATIONAHA.105.547810.

14. Pagani FD, DerSimonian H, Zawadzka A et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol (2003) 41(5):879–88. doi:10.1016/S0735-1097(03)00081-0 40.

15. Fujita T, Sakaguchi T, Miyagawa S et al. Clinical impact of combined transplantation of autologous skeletal myoblasts and bone marrow mononuclear cells in patients with severely deteriorated ischemic cardiomyopathy. Surg Today (2011) 41(8):1029–36. doi:10.1007/s00595-0104526-3.

16. Gojo S, Kyo S, Nishimura S et al. Cardiac resurrection after bone-marrow-derived mononuclear cell transplantation during leftventricular assist device support.

Ann Thorac Surg. 2007 Feb;83(2):661-2.

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19. Anastasiadis K, Antonitsis P, Argiriadou H et al. Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion. J Transl Med (2011) 9(1):12. doi:10.1186/ 1479-5876-9-12.

20. Nasseri BA, Kukucka M, Dandel M et al. Intramyocardial delivery of bone marrow mononuclear cells and mechanical assist deviceimplantation in patients with end-stage cardiomyopathy. Cell Transplant. 2007;16(9):941-9.

21. Stempien-Otero A, Helterline D, Plummer T et al.

Mechanisms of bone marrow-derived cell therapy in ischemic cardiomyopathy with left ventricular assist device bridge to transplant. J Am Coll Cardiol. 2015 Apr 14;65(14):1424-34. doi: 10.1016/j.jacc.2015.01.042.

22. Monreal G, Sherwood L C, Sobieski M A et al. Large animal models for left ventricular assist device research and development.

ASAIO J (2014) 60(1):2–8. doi:10.1097/MAT.0000000000000005 23. Tseng CSC, Faiz ZR, de Jonge N, and Steven AJC. Advanced strategies for end stage heart failure: combining regenerative approaches with LVAD, a new horizon?

Frontiers in Surgery.

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24. Cheng A, Williamitis CA, Slaughter MS. Comparison of continuous-flow and pulsatile-flow left ventricular assist devices: is there an advantage to pulsatility? Ann Cardiothorac Surg (2014) 3(6):573–81. doi:10.3978/j.issn.2225-319X. 2014.08.24.

25. Bartoli CR, Giridharan GA, Litwak KN et al. Hemodynamic responses to continuous versus pulsatile mechanical unloading of the failing left ventricle. ASAIO J (2010) 56(5):410–6. doi:10.1097/MAT.0b013e3181e7bf3c.

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Review Genetics of Cardiomyopathies Christian Eichhorn, Imperial College London Abstract: Cardiomyopathies represent a majority of cardiac diseases and can manifest at any age. The presentation, diagnosis and management of cardiomyopathies reflect significant clinical challenges, as there are limited treatment options and an extensive overlap between the different types of cardiomyopathies, while the physical and mental burden on individuals and their families can also vary greatly. More than two decades ago, genes have been discovered to be implicated in the pathogenesis of cardiomyopathies. Since then, a considerable body of work has led to advancement of our understanding of the diseases on a cellular, molecular and genetic level â&#x20AC;&#x201C; it has become clear that cardiomyopathies are influenced by a number of factors and genes, and will therefore express a great variety in clinical presentation as demonstrated by the patient body. Some of the most striking associations, for example, include the MYH7 and MYBPC3 gene in hypertrophic cardiomyopathy; additional evidence strongly associates desmosomal genes with arrhythmogenic right ventricular cardiomyopathy and more than 50 individual genes to be causative in dilated cardiomyopathy. Our insights have not yet produced novel treatments but clinicians are now able to steer their clinical focus more appropriately towards affected and potentially affected individuals, using genetic testing and novel classification criteria. This review aims to focus on the basic aspects and genetics of each type of cardiomyopathy and aims to outline the meaning of diagnosis and inheritance for patients and their family, as well as how consequences such as heart failure and sudden cardiac death surface and can be avoided.

Introduction Cardiomyopathies can be defined as a heterogeneous group of myocardial diseases that present with mechanical or electrical dysfunction characterised by abnormal myocardial structure in the absence of ischaemic heart disease or abnormal loading conditions (1,2). Cardiomyopathies often result in hypertrophied or dilated ventricles, mostly due to inherited genes but occasionally due to secondary systemic disorders (1). Inherited cardiomyopathies tend to emerge during or following adolescence but can occur at any age. Hypertrophic cardiomyopathy (HCM) is most prevalent at around 1:500 of the general population, followed by dilated cardiomyopathy (DCM; 1:2500) while restrictive cardiomyopathy (RCM; 1:1000-1:5000) and arrhythmogenic right ventricular cardiomyopathy (ARVC; 1:2000-1:5000) are the least common (3). Each type can present major clinical challenges, which have been documented clinically since the late 1950â&#x20AC;&#x2122;s; it was only in 1989 that the first HCM-causing gene was identified (4).

Classification Cardiomyopathies have been shown to express a vast genetic heterogeneity leading to heterogeneous phenotypes, enabling the medical profession to differentiate between various types of cardiomyopathies. Recently, experts have distanced themselves from simply classifying cardiomyopathies according to anatomy and physiology. In 2008, the European Society of Cardiology (ESC) proposed a new

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classification of familial/genetic and non-familial/nongenetic variants of each form of cardiomyopathy; this classification is particularly useful in clinical practice (5). In 2006, the American Heart Association (AHA) decided that cardiomyopathies shall be classified into primary (only affect the heart) and secondary (part of a multi-system disorder) cardiomyopathies; furthermore, the 2006 classification subdivides the primary cardiomyopathies into those that are genetic, mixed and acquired and including ion channelopathies (dysfunction of ion channels); (5,6). Most familial cardiomyopathies are monogenic disorders (controlled by a single gene).

Even though a classification of different forms of cardiomyopathies is possible, the genetic characteristics of different cardiomyopathies share several similarities.

Firstly, it is possible for different types of cardiomyopathies to originate from a mutation in the same gene, i.e. a different variant of the same gene will result in, for example, HCM, while another variant will result in RCM; however, one variant of one gene cannot cause two types of cardiomyopathies (7).

Multiple variants of a single disease-causing gene can be present in one case of cardiomyopathy.

Another similarity of cardiomyopathies is that each form can be caused by a multitude of different mutations in an abundant number of genes, some of which are frequent and some of which only run in a single family (7).

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Review One of the complexities among all types of cardiomyopathies is also that identical mutations can result in varying levels of phenotypic expressions and severities; this indicates that other factors, such as the environment, still have a considerable effect (7).

HCM-causing mutations are found in up to 60-70% of patients with HCM (3). So far, it has been found that 11 or more mutated genes of contractile sarcomeric proteins are the cause of HCM, with over 1400 variants of these mutated genes (16).

Contrary to popular belief, cardiomyopathies rarely progress and patients usually live a symptom-free life.

However, a minority of patients face detrimental consequences such as heart failure (HF) or sudden cardiac death (SCD); in fact, a significant number of SCD cases in young adults are due to HCM or ARVC (8,9).

The sarcomere represents the functional unit of striated muscle. The genes that are most commonly mutated are the MYH7 gene for the beta-myosin heavy chain and the MYBPC3 gene for myosin-binding protein C, both components of the sarcomeric thick filament and each making up a third of affected genes (3,17). Other causative genes (present in <5% of population) for proteins in the thick filament include the MYL2 and MYL3 genes for the regulatory and essential myosin light chain respectively (17). The causative genes in the thin filament, representative of less than 5% of cases, are the TNNT2 gene for troponin T and the TNNI3 gene for troponin I, as well as the ACTC1 gene for actin (17). Other genes, less commonly found in patients, may also affect the Z-disc (attached at lateral borders of the sarcomere and has multiple functions, for example: mechanical stability and intracellular signalling) and the intercalated disc (connects neighbouring sarcomeres) (17,18). Most mutations are single amino acid substitutions and affected proteins are then usually integrated into the sarcomere (3).

Genetics of Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is characterised by an increased ventricular wall thickness (usually left ventricle (LV)) in the absence of loading conditions and presence of myocyte disarray and cardiac fibrosis.

With a prevalence of approximately 1:500, HCM is the most commonly inherited cardiac disease, usually inherited as an autosomal dominant trait (10,11). Noninvasive cardiac imaging, such as echocardiography or cardiac magnetic resonance imaging, and electrocardiography are usually used in the diagnosis of HCM. HCM affects the relaxation of the heart and causes diastolic dysfunction, leading to HF symptoms; for a quarter of patients, the left ventricular outflow tract (LVOT) becomes obstructed which is correlated with adverse prognosis (12).

Symptomatic patients can suffer from a number of different manifestations, such as (1,13): - Fatigue and dyspnoea (due to impaired diastolic filling and cardiac output) - Chest pain (CP) (due to insufficient blood supply for increased demand) - Atrial fibrillation (AF); this may result in palpitations, pre-syncope and syncope - Sudden cardiac death (SCD) - Heart failure (HF) Out of these manifestations, the most significant clinical outcomes are HF and SCD; HCM is the most common cause of SCD in people aged less than 35 years, while overall annual HCM related mortality is at 0.5%, comparable to the annual mortality of the general population (13-15).

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Recent studies of the cohort of patients, which do not have HCM-causing mutations but still suffer from unexplained left ventricular hypertrophy (LVH), point to other mutations, which cause storage cardiomyopathies. Storage cardiomyopathies are distinct, as myocytes show different features such as accumulation of glycogen instead of myocyte disarray and fibrosis (17).

The study of how mutations in sarcomeric proteins affect contractile function has been at the focus of a number of in vivo and in vitro studies. Cardiovascular researchers now believe that for HCM, mutations in genes encoding the proteins tropomyosin, troponin T and troponin I increase Ca2+ sensitivity, while mutations affecting the protein myosin, and enhance this sensitivity further by promoting additional crossbridges between thick and thin filaments. This results in reduced regulation and increased Ca2+ levels during diastole (3). Furthermore, sarcomeric mutations enhance the energy requirements of myosin (3). A novel hypothesis also states that the ubiquitine proteasome complex is unable to degrade timely, causing HCM (19).

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Review Accordingly, this pathophysiology points to an increase in myofilament activation, myocyte hypercontractility and excessive energy use (3). These changes, combined with affected myocardial energetics and calcium handling, lead to the activation of signalling pathways, such as the calcineurin-NFAT signalling pathway (3,17). The effects of activating these signalling pathways are myocyte disarray, fibrosis and growth as well as reduced relaxation, most commonly resulting in LVH (3).

- Genetic disease: Roughly 20-35% of cases of DCM are familial; similar to HCM, DCM shows genetic heterogeneity and is mainly inherited via autosomal dominant inheritance. Xlinked autosomal recessive and mitochondrial inheritance has been observed in DCM but is less frequent (6). Idiopathic DCM cases, whose cause could not be determined, are increasingly found to include a genetic component as more than a third of these patients have affected family members (22).

In terms of electrophysiological manifestations, such as ventricular arrhythmias, which can be detrimental, several pathogenic pathways have been proposed; these, however, are still not fully validated. Myocyte disarray may cause electrical instability while the increased demand for oxygen may result in coronary microvascular dysfunction (20,21). The alterations in Ca2+ handling appear to play a significant role as well.

Unlike in HCM, where the heart requires increased pressures to fill (as it is hypertrophied and stiff, which causes shortness of breath), in DCM the heart is dilated and contracts less strongly. This often leads to a reduced ability of the heart to supply the bodyâ&#x20AC;&#x2122;s organs with blood and as a result of this, DCM leads much more commonly to HF. This can be explained genetically by the fact that the beta-myosin heavy chain mutations have the opposite effect in DCM: motor function is decreased (3). This contrasting phenotypic effect when compared to HCM also applies for other genes where, for example, the sensitivity of the thin-regulatory filaments for Ca2+ is encoded to be lower as well as the affinity of troponin for Ca2+ to be decreased (3). Furthermore, proteins of the Z-disc and Ca2+ re-uptake (SERCA) proteins can be affected by mutations (23).

Genetics of Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is pathologically characterised by an enlarged left ventricle, functionally by impaired systolic dysfunction (ejection fraction <50%; usually also diastolic dysfunction is present) and histologically by myocardial fibrosis (1,7,8). DCM is prevalent in about 1:2500 of the general population, normally manifesting between the ages of 20 and 60.

DCM is more common in black people and in men (1).

DCM patients may deteriorate abruptly when SCD, acute pulmonary oedema or emboli occur but otherwise, progression is gradual. As the left ventricle deteriorates more progressively, especially in cases of familial DCM, there is gradual advancement from no complaints to exertional dyspnoea, orthopnoea and fatigue (7).

These symptoms may progress to those of arrhythmia or mitral regurgitation (growth of the ventricle pulls leaflets of the valve apart). HF, SCD and cardioembolic events are the main causes of mortality in DCM (7).

DCM is the third most common cause of heart failure and is the main reason for cardiac transplantation (6).

In terms of specific genes, there are over 50 genes that have been identified to be causative in DCM (7).

Screening for up to 20 genes will result in finding pathogenic variants in only up to a third of patients and the most common genes are titin (TTN; up to 25% of cases), lamin A/C (LMNA), beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) (7,8).

Almost all genes lack genotype-phenotype correlations and many genes are only responsible for a small proportion of DCM cases, which is a difficulty when trying to define pathophysiologic pathways.

Mutated genes for proteins range from the membrane-scaffolding apparatus, the sarcomere, the nuclear envelope, the Ca2+-handling proteins, the transcription factors and

A rough division into DCM can be made: - Specific causes: - Ischaemia - Myocarditis (infection, autoimmune, toxic) - Metabolic insults (haemochromatosis, thyrotoxicosis - Nutritional deficiencies (thiamine, selenium, carnitine) - Toxins/drugs

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RNA splicing to the cell energy generating machinery as described by Watkins et al. (3). The altered proteins result in changes in myocyte structure and function, leading to a number of different heterogeneous pathways where adverse force transmission results in cellular injury, inflammation, collagen deposition, remodelling, dilatation, and systolic failure (2,3).

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Review Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a form of cardiomyopathy in which the myocardium of the right ventricle is replaced by fibrofatty tissue, with a predisposition to ventricular arrhythmias that can potentially prove fatal (1).

Other features include electrical abnormalities, normally preceding overt cardiomyopathy, as well as HF (10-20% of patients) and a predilection for SCD (2,7). Establishing a diagnosis is difficult because the right ventricle (RV) often becomes dilated and it has been growingly noted that the LV is also affected (24).

It is estimated that the prevalence of ARVC is between 1:2000 and 1:5000, with 40-50% being familial and an autosomal dominant inheritance pattern (1). It also affects men more often than women, especially in the age range of 15-35 years (25).

The proportion of carriers that express the phenotype is reduced in ARVC compared to other cardiomyopathies and the severity also varies greatly (8). Complexity is added by often more than one diseased gene, therefore increasingly pointing away from a monogenic classification of ARVC. Moreover, establishing a diagnosis is difficult because of the reduced penetrance and subtle signs and symptoms whose diagnostic criteria are not necessarily clear-cut and overlap with HCM and DCM an overlap that is also evident in terms of genetic features. As a result of this, progress in the identification of diseased genes in ARVC has been slower than in other forms of cardiomyopathy.

Nevertheless, it is now known that ARVC is a disease of the desmosome.

Desmosomes operate as strong intercellular connections that resist mechanical stresses, with the ability to vary their strength of adhesion in embryonic development; additionally, desmosomes also perform as signalling centres (26).

Five genes encoding for three categories of desmosomal structures have been found to be diseased in ARVC (3):   

Transmembrane proteins (desmoglein and desmocollin) Proteins anchored to intermediate filaments (desmoplakin) Proteins that bind desmosomes adhering to desmoplakin (plakoglobin and plakophilin which are part of the armadillo family of proteins)

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Mutations have been found in two more genes that do not encode for proteins of the desmosome (27,28):  

Transforming growth factor beta 3 Transmembrane protein 43

Defective desmosomes will lead to the adhesion in between cells to be weakened which may lead to cell detachment during mechanical stresses, followed by cell death. There have been indications of remodelling of gap junctions (responsible for cardiac conduction) and these defective gap junctions may therefore provide an explanation for electrocardiographic changes and ventricular arrhythmias (3,29).

Another effect of these mutations is that WNT/betacatenin is suppressed, which causes precursor cells of right ventricular myocytes to differentiate into adipocytes (3). Other pathways may be modified and contribute to the increased expression of lipidmetabolic pathways.

Table 1 Summary of the clinical features of HCM, DCM and ARVC together with a general overview of the genes that are affected

Clinical Features

Genes affected

HCM Fatigue, dyspnoea, CP, AF, SCD

Myosin genes, thick/thin filament genes, Z/intercalated disk genes

DCM Exertional dyspnoea, orthopnoea, fatigue, arrhythmias, HF, embolic events, SCD >50 different genes, screening for up to 20

ARVC Electrical abnormalities, HF, SCD, overt cardiomyopathy

Desmosomal genes

Other Cardiomyopathies Restrictive cardiomyopathy (RVC) can be can be defined as reduced diastolic function due to reduced ventricular compliance, while left ventricular noncompaction (LVNC) can be defined as a congenital systolic and diastolic dysfunction as well as a predilection to arrhythmias and cardio-embolic events with marked trabeculations and ventricular recesses (30-32). RVC and LVNC are rarer forms of cardiomyopathies that can be classified individually but have been identified to have extensive overlap with HCM and DCM (1). The exact prevalence of these forms of cardiomyopathy are not known and it is recognised that other family members that share specific mutations encoding for RVC or LVNC with a relative, may themselves express HCM phenotypes instead (2).

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Review For LVNC, the pathophysiological pathway and the clinical course remain unclear and therefore, a greater number of possibly affected genes have been proposed. However, it is believed that during the first 70 days of embryonic development of the heart, the trabeculations fail to ‘compact’ (1). The overlap with HCM and DCM requires thorough analysis of other family members for an accurate diagnosis; LVNC is more prevalent in first-degree relatives, with an inheritance pattern that can vary from autosomal dominant, X-linked to mitochondrial (1).

The genes that are affected include those of structural proteins and it is important to note that LVNC is also associated with other cardiac congenital conditions, such as a bicuspid aortic valve. Additionally, the Xlinked gene G4.5, which causes Barth syndrome - a genetic multi-system disorder exclusively present in males, and mitochondrial disorders – can cause LVNC. RCM is the rarest form of heart muscle disease (2). The aetiology in this case is not clear and the cases that are familial are characterised by mutations in the genes encoding sarcomeric proteins, leading to an increase in the calcium sensitivity, similar to HCM (2). This leads to enlarged atria and normal sized ventricles while patients are unable to increase their cardiac output (as their stroke volume is fixed) (1). Patients may then develop breathlessness, right heart failure and atrial arrhythmias and may possibly die from HF or ventricular arrhythmias (33).

Modifier Genes and Environment Modifier genes are genes that can impose an influence on the phenotype expressed by a primary mutation.

Modifier genes are not always inherited with the disease, which makes it difficult to identify them. A number of these modifier genes have been proposed as it is now generally accepted that the genotypephenotype correlation expresses plasticity (34). This variability in genotype-phenotype correlations, studied within and between families, is due to a number of factors ranging from the type and location of the primary mutation, the number of variants, modifier genes and the environment (3).

In terms of environmental factors, diet and fitness have been found to influence outcomes in patients with cardiomyopathies (30-32). Furthermore, mental stress is an environmental factor that can trigger arrhythmias, as well as exercise, which can be a precipitating factor for SCD (3). Therefore, it is recommended to exercise to a maximum of 85% of maximum heart rate in order to lower the risk of SCD.

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Figure 1: Illustrations of the different morphologies in cardiomyopathies. Source: Pamela A Harvey, Leslie A Leinwand The cell biology of disease: cellular mechanisms of cardiomyopathy. J. Cell Biol.: 2011, 194(3);355-65

Genetic Testing and Potential Therapies The general practitioner will often be the doctor who will encounter the patient, and perhaps even other family members, presenting with the signs and symptoms of cardiomyopathy. History and physical examination have been found to be poor predictors of disease and sudden cardiac death risk in young people.

It is therefore important to undergo evaluation by a specialist and use specialist diagnostic techniques (35).

These diagnostic techniques include an electrocardiogram, an echocardiograph and cardiac magnetic resonance imaging; it is important to conduct these investigations in order to differentiate, for example, HCM from athlete’s heart and exclude primary causes such as hypertension or amyloidosis (deposition of amyloid in the body), or coronary artery disease and alcoholism as causes of a dilated heart (3638).

As mentioned previously, pathogenic mutations are detectable in up to 60-70% of HCM patients, 40-50% of ARVC patients and about a third of DCM cases (3).

Because of this lack in testing sensitivity, genetic testing is only recommended after a clinical diagnosis can be made. In HCM, genetic testing provides an early intervention indication only for the troponin T mutation; this mutation, together with the LMNA mutation and possibly desmosome-associated and SCN5A mutations in DCM, are the only known mutations, which confer a predilection to SCD. These mutations may therefore indicate the need for prophylactic implantable cardioverter defibrillators (ICD), which are associated with a reduction in mortality from SCD (39-41).

Furthermore, in HCM, and even more so in ARVC, it has been found that the presence of multiple genetic variants increase the likelihood of penetrant disease; this indicates that the known 11 disease-causing genes in HCM and all 5 disease-causing genes in ARVC should be tested for (2,42).

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Review Genetic testing also provides another indication in that adverse outcome (death due to cardiovascular disease, stroke, HF) odds are increased in those patients that are genotype-positive compared to those that are genotype-negative (43).

Pathogenic mutations that are only present in a single family or a low number of patients may present a barrier to genetic testing, as it may be difficult to estimate the pathogenicity of these mutations. This is particularly evident in genetic testing for DCM-causing mutations of which over 40 are known, many of which run in a single family only.

However, the great benefit of genetic testing is the identification of pathogenic mutations in other family members, a process that is termed cascade testing.

Some of the benefits of cascade testing are: 

Anxiety, related to uncertainty of whether oneself is affected, may be reduced. 50% of firstdegree relatives of a cardiomyopathy patient (mostly autosomal dominant inheritance patterns) will be affected and most relatives prefer to know whether they are affected or not.

Furthermore, counselling may be offered to those that are affected by a pathogenic mutation.



Prevention of progression of disease or death via the use of prophylactic measures such as ICD or clinical follow-up in genotype or phenotype positive relatives may be realised. The only therapeutic intervention that is currently showing promising results is angiotensin-converting enzyme (ACE)-inhibitors in genotype-positive, phenotype-negative patients with Duchenne's muscular dystrophy for prevention or delay of DCM development and the use of ACE-inhibitors in asymptomatic LV dysfunction (2,44,45).



It is cost-effective because it is cheaper to treat and examine relatives prophylactically and exclude those relatives that are genotype and phenotype negative from further clinical visits.

The drawbacks of genetic testing mainly deal with the psychological influence that cascade testing has on children and adolescents (42). It is also quite possible that inappropriate or unnecessary measures are taken following genetic testing of the individual and cascade testing. Cascade testing, although cost-effective, still requires financial resources as well as manpower.

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Therapies that target the pathophysiologic processes in cardiomyopathies specifically and effectively are currently not available. The hope is that the incomplete penetrance, i.e. the fact that some carriers tolerate certain mutations better than others, will lead to novel therapies that may modify the progression of cardiomyopathies (3). It is also hoped that incomplete penetrance is due to subtle cellular perturbations that can be compensated for, as may be the case in patients with life-long asymptomatic disease (3,46).

In addition to that, novel therapies may aim to alter cellular variables before the abrupt advent of worsening symptoms in HCM and DCM (3). As mentioned previously, in some forms of cardiomyopathy, namely HCM (calcineurin-NFAT signalling pathway) and ARVC (WNT/beta-signalling), the different variant of genetic mutations result in the same final pathophysiologic pathway; these pathways may present therapeutic targets, enabling the doctor to use therapies that are effective against multiple types of cardiomyopathies at once.

In 2014, Sanofi and MyoKardia announced a groundbreaking collaboration that would see an investment of $200 million towards the advancement of targeted therapies for patients with genetic heart disease, mainly HCM and DCM (47). Following this, an announcement in March 2015 has been released by MyoKardia regarding a small selective allosteric modulator 0f cardiac myosin, called MYK-461, moving into phase 1 clinical trials; this will enable the assessment of safety, tolerability and effects of this orally administered drug, which aims to repair normal heart muscle contraction and relaxation and to prevent disease progression. This example reflects the analysis made by Ashrafian et al. in 2011, which concluded that the significant depth of insight into HCM allows for the possibility of targeted therapies in the “not too distant future” – but as with any medical therapy, it may take many years to move from bench to bedside (48).

Those patients that present with multiple genetic variants, environmental and modifying genetic factors pose the greatest problem as it will be harder to identify therapies for these patients.

In conclusion, it is evident that the genetics of cardiomyopathies has led to wide-ranging amounts of information about the pathophysiology of cardiomyopathy and may prove to provide novel clinical and therapeutic modalities that will be of use in a multi-disciplinary setting that attempts to provide the best care for the patient.

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Review References

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Review (27) Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, et al. Regulatory mutations in transforming growth factorbeta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovascular research 2005;65(2) 366-373.

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(29) Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, et al. Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 2004;1(1) 3-11.

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(38) Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the European Society of Cardiology Committee for Practice Guidelines. Journal of the American College of Cardiology 2003;42(9) 1687-1713.

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Review A Comparison of the Applications of High Dose and Normal Dose Statins for the Primary and Secondary Prevention of Cardiovascular Events Rabeet Khan & Christian Eichhorn, Imperial College London Abstract Cardiovascular disease is a frequent cause of mortality, especially in more economically developed countries where an increasingly elderly population has allowed non-communicable diseases to dominate. Statins have long been considered as an effective treatment for the prevention of both primary and secondary cardiovascular events; however, the relative benefit of using high dose statins as compared to low dose statins is still being appraised.

Although high dose statins are more effective than low dose statins at controlling cardiovascular disease, they are also associated with a higher side-effect risk. Therefore, the current recommended statin dosage depends upon the patientâ&#x20AC;&#x2122;s cardiovascular mortality risk and the risk to benefit ratio of the specific patient case. The aim of this paper is to review and evaluate the current knowledgebase of statin use in order to determine, which dosage is more clinically useful in preventing cardiovascular events.

Introduction Cardiovascular disease (CVD) is currently the leading cause of mortality in developed countries with a prevalence of 22% in men aged 70-79 years (1,2) and accounted for 30% of the 58 million deaths estimated worldwide in 2005(3). Due to the prevalence of CVD, there has been particular focus on prevention of CVD risk factors to minimize mortality and the cost to healthcare (4,5). Statins are more commonly known as HMG CoA reductase (HMGR) inhibitors (6) and their use in the prevention of CVD has become increasingly prevalent with prescriptions rising 5-fold in the UK between 2001 and 2011 (7). Statins are extensively used for cardiovascular disease (CVD) prevention due to their lipid lowering and endothelium protective functions. In addition to reducing cholesterol via inhibition of HMGR, statins are also actively involved in stabilizing atherosclerotic plaques, reducing vascular inflammation and maintaining endothelial homeostasis (6). Due to these effects, statin administration can effectively reduce the risk of CVD events such as coronary artery disease (CAD) by up to 15% (8). Statin use needs to be monitored carefully for optimal efficacy and safety and to minimize risks of potential side effects such as myopathy, rhabdomyolysis and increased transaminase levels (1).

However, the side effects of statins can vary depending on the specific statin being used. In general, statins are well tolerated but potential adverse effects associated with aggressive statin treatment such as muscle toxicity need to be kept under review(1). Therefore, there is ongoing research into whether high dose or normal dose statins should be used clinically; with a higher dose providing improved outcome at the expense of safety (9).

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This article will review the evidence for the efficacy and safety of high dose and normal dose statins in the treatment of CVD. Statin Pharmacology Statins have a variety of mechanisms that not only have cholesterol lowering effects but also other pleiotropic effects such as optimizing endothelial function and reducing vascular inflammation(6). The two main mechanisms of action of statins are: 1.The inhibition of HMGR 2.The inhibition of the formation of metabolic intermediates in the cholesterol biosynthesis pathway(6).

Statins are competitive inhibitors of HMGR and are capable of creating a hydrophobic binding pocket at the HMGR active site to which they can bind and induce an inhibitory effect (10). This inhibition prevents the substrate to product transition in the rate limiting reaction of the cholesterol biosynthesis pathway (6,10,11) leading to reduced cholesterol levels, which are directly correlated with reduced cardiovascular risk(7). This specifically refers to levels of LDLs (low density lipoproteins), which are atherogenic (12) as they deliver cholesterol to cells via the LDL receptor (13). Figure 1 shows a simplified version of the cholesterol biosynthesis pathway (14).

With regards to the second mechanism, statins can also inhibit the formation of isoprenoid intermediates that are synthesized further downstream in the cholesterol pathway (6). Isoprenoid intermediates are required for the post-translational modification of Rho-like GTPases e.g. Rac1 (which is responsible for endothelial cell migration and adhesion) (15), therefore inhibition of this pathway leads to Rac1 degradation (6,16,17).

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Review Rac1 degradation leads to reduced production of reactive oxygen species which confer cardiovascular protective effects on the body (16). Statins exert intra and extra-hepatic effects and differences in metabolism and tissue permeability (ability to enter hepatocytes) accounts for the variation in pleiotropic effects between statins (6).

HMG-CoA

Acetyl-CoA

HMG-CoA Reductase

Mevalonate

Isopentenyl-PP

Squalene

Geranyl-PP

Farnesyl-PP

Cholesterol

Figure 1 â&#x20AC;&#x201C; Flowchart showing the cholesterol biosynthesis pathway (14). The enzyme HMG-CoA reductase catalyzes the transition from HMG-CoA to Mevalonate.

Statin Therapy Recommendation According to the NICE guidelines, it is recommended that all patients should undergo a CVD risk assessment check before beginning statin therapy and that ideally, the modifiable risks should be dealt with using lifestyle changes such as dietary and exercise changes (18). If lifestyle changes are ineffective and a risk assessment shows that the benefits of statin therapy will outweigh the potential risks, then treatment may be commenced (18). For primary prevention, it is recommended that 20mg of atorvastatin be offered to patients with a CVD risk â&#x2030;Ľ10% over 10 years (18).

Statins are contraindicated in pregnant and breastfeeding women, heavy drinkers, previously statin induced hypersensitive patients and patients suffering from renal or liver disease(7). Statins have a range of side effects such as increased stroke risk and diabetes (7,21); these will be discussed further in the next section.

Comparison of High and Regular Dose Statin Use In order to determine the clinically optimum LDL values for patients with CVD, 5 major trials have been conducted to determine how differences in statin dose can affect the risk of cardiovascular events (9,22). A results summary of the key trials has been provided in table 1. Although these trials were not able to determine an optimum LDL value (as they used nontitrated doses of statins), they did reveal differences in the effects of high and regular dose statins on the body(9).

Relative to placebo, regular dose statins have a relative risk reduction of 23% for myocardial infarction (MI) (RR 0.77, NNT 4.35), and 17% for stroke (RR 0.83 NNT 5.88) (1,9,23). A meta-analysis (n>270,000) conducted to compare high and low dose statin efficacy has shown that high dose statins are even more effective than lower dose statins at reducing myocardial infarction and lead to a further MI and stroke risk reduction of 16% and 18% respectively (1,9,24). Therefore, it was concluded that intensive statin therapy was more effective than standard dose therapy at preventing these cardiovascular events and subsequently reducing CVD mortality (1,25). The reduced myocardial death risk may be attributed to the relative effectiveness of high dose statins in reversing atherosclerosis compared to lower doses(9). This was explored by the REVERSAL trial that randomized 654 patients with coronary artery disease (CAD) to daily 80mg atorvastatin or 40mg pravastatin therapy(9).

The patients were then assessed using ultrasound after 18 months to look for changes in LDL levels and atheroma volume (9).

A higher statin dose may be required if the patient requires secondary prevention post-myocardial infarction (MI) or for high-risk patients with a stable coronary syndrome (19,20). Current guidelines recommend the LDL levels of these patients to be lowered to <70mg/dl and therefore a greater atorvastatin dose of 80mg is required (1,7,18,19).

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Review Table 1: Summary of the Findings of Various Trials Comparing Efficacy of Intensive Vs. Standard Statin Therapy. Table contains data adapted from Cannon CP et al., REVERSAL, IDEAL Stoekenbroek report, SAGE and TNT trials (24-28).

Trial

No. of participants

Drugs prescribed

Outcome measure

Cannon CP et al.

4162

80mg atorvastatin daily or 40mg pravastatin daily.

REVERSAL

654

IDEAL trial Stoekenbroek RM et al. report

8888

SAGE

893

TNT (RCT)

10,001

Result

Conclusion

Myocardial infarction risk after 24 months, 95% CI.

16% coronary heart disease or myocardial infarction hazard ratio reduction in favour of atorvastatin.

80mg atorvastatin daily or 40mg pravastatin daily.

Percentage change in atheroma volume after 18 months, 95% CI.

80mg atorvastatin daily or 20mg simvastatin daily.

80mg atorvastatin daily or 40mg pravastatin daily.

Peripheral artery disease (PAD) incidence after 5 years, 95% CI. Low-density lipoprotein (LDL) reduction after 12 months, 95% Cl.

Coronary atherosclerosis volume increased with pravastatin (+2.7%) but was reduced by atorvastatin (-0.4%).

PAD incidence was 2.2% in atorvastatin group and 3.2% in the simvastatin group.

23% greater LDL lowering observed in atorvastatin group compared to the pravastatin group.

10mg or 80mg atorvastatin daily.

Major cardiovascular event risk reduction after 4.9 years, CI = 95%.

In patients who have recently had an acute coronary syndrome, intensive statin therapy is more protective from cardiovascular events than standard therapy.

In patients with coronary heart disease (CHD), intensive statin therapy is more effective at reducing atheroma progression than standard therapy.

High dose statin therapy is more effective at reducing risk of PAD than standard therapy.

In elderly patients, intensive therapy was more effective at reducing LDL and subsequent cardiovascular events than standard therapy.

Intensive statin therapy is significantly more clinically effective than standard therapy in treating CHD.

The LDL cholesterol was far lower in the atorvastatin group (LDL lowered to 79mg/dL) compared to the pravastatin group (LDL lowered to 110mg/dL) (9,26).

Furthermore, the atheroma volume was stabilized by atorvastatin therapy (- 0.4%) whereas it continued to increase (+2.7%) in patients on pravastatin demonstrating the relative beneficial effects of high dose statins (9,26).

Peripheral artery disease (PAD) has similar risk factors to CAD and is also a predictor of myocardial death and cardiovascular disease progression (27). The IDEAL trial focused on secondary CVD prevention and randomized 8888 post-MI patients to 80mg/day atorvastatin or 20-40mg/day simvastatin use in order to compare the incidence of PAD following high and low dose statin treatment (27). A report of the IDEAL trial showed that after a follow up of approximately 5 years, the incidence of PAD was 2.2% in the

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Compared with 10mg atorvastatin therapy, 80mg therapy showed a 22% relative risk reduction in major cardiovascular events.

atorvastatin group and 3.2% in the simvastatin group (HR=0.70, 95% CI 0.53 to 0.91; p=0.007) (27).

A posthoc analysis showed that the prevalence of major coronary events in PAD patients was 5.7% lower in the high dose atorvastatin group than in the regular dose simvastatin use although this was not statistically significant (HR=0.68, 95% CI 0.41 to 1.11; p=0.13) (27).

However, atorvastatin did successfully reduce further the overall number of cardiovascular and coronary events in these patients compared with simvastatin therapy indicating that high dose statin therapy is more efficacious than lower dose therapy at reducing the incidence of PAD (27). On another note, it can also be suggested that the difference observed is partially attributable to the increased effectiveness of atorvastatin compared to simvastatin and not completely due to differences in dosage. This could be a confounding variable.

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Review Since cardiovascular disease is particularly prevalent in the elderly(1), it is important to consider the uses of high and regular dose statins in this age group. The Study Assessing Goals in the Elderly (SAGE) that focused on elderly patients aged 65-85 years assigned high dose atorvastatin or low dose pravastatin therapy to 893 patients to observe differences in statin response (28). As before, patients on high dose atorvastatin therapy showed decreased LDL concentrations, total cholesterol and total triglycerides compared to patients on pravastatin therapy (28). The ambulatory myocardial ischaemia time in patients was significantly reduced in both groups confirming that statin therapy is effective in elderly patients (28,29). Similar results were reported by other studies and analysis showed no significant differences in statin effect with age. However, the main obstacle in achieving statin therapy success in the elderly is reduced adherence level (30-32). Patients aged over 75 years had a 19% lower treatment persistence with the largest decline occurring in the first 6 months of therapy (29,32).

Although high dose statins have the ability to reduce the risk of cardiovascular events (8,33), there is still some data suggesting that the difference in mortality between high and low dose statins is not significant (34). A review conducted by Therapeutics Initiative (which functions to provide evidence-based advice on drug therapy) looking at randomized control trials with nâ&#x2030;Ľ1000 and a follow up of 1 year showed that although high dose statins reduced non-fatal MI compared to normal doses, they failed to produce any significant difference in overall mortality (34). This was especially true in women where high dose statins increased total mortality when compared with regular doses (34).

Therefore, a letter containing critically appraised summary evidence by Therapeutics Initiative concluded that there is no overall clinical benefit of high statin doses over regular statin doses (34).

Despite the presence of some conflicting evidence, meta-analyses based on many studies have shown that high dose statin therapy overall is more effective at reducing cardiovascular disease risk factors than lower dose therapy(1,9). In terms of mortality, further reductions due to high dose therapy are only observed in high-risk patients in particular, therefore suggesting that high dose statins should only be used in patients at high risk of atherosclerosis(9). Differences in high and regular dose statin action could be due to differing mechanisms of action whereby regular dose statins selectively inhibit Rac1 and do not affect the Rho/Rhokinase pathway, which is in fact selectively inhibited by high dose statins (16,35,36).

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Safety Comparison of High and Low Dose Statin Use Although high dose statins appear to be more effective than regular dose statins, studies have shown that they are associated with an increased risk of side effects hence reducing their utility in clinical practice (1,37).

Most statins are usually associated with a low side effect risk but cerivastatin was withdrawn due to a very high fatal rhabdomyolysis risk at high doses (1,38).

Studies investigating side-effect profiles may have underestimated the adverse effect risk as they do not contain a clinically representative proportion of highrisk patients that are seen in modern everyday practice(1). Therefore, it is important to consider the potential risks of high dose statins when considering their use in patients.

Muscle toxicity is an occasional side effect of statins and leads to myopathy, rhabdomyolysis, myalgia or myositis (1,39,40). It is hypothesized that the cause of this toxicity is due to the lack of coenzyme Q10 that occurs as a result of HMGR inhibition(1). Coenzyme Q10 is naturally involved in the electron transport chain and therefore a lack of this coenzyme interferes with mitochondrial respiratory reactions such as oxidative phosphorylation (41,42). Compared with lower doses, high dose simvastatin therapy has an increased risk of myopathy, especially in older patients where there is reduced clearance of the drug from the plasma(1). Although the risk is only slightly higher with high dose therapy, it can increase further if the patient is taking other drugs that may interact with the statin, such as potent cytochrome P450 (CYP)3A4 inhibitors (1,43). This can occur in elderly patients who commonly suffer from co-morbidities (29).

Statins can also interfere with insulin secretion and sensitivity via multiple mechanisms and cause diabetes. The JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial showed that compared with the placebo group, patients in the 20mg/day Rosuvastatin group had a 26% higher incidence of diabetes (21,44,45).

Actions in the liver can result in liver enzyme increases with transaminase levels rising 3 fold more commonly in high dose statins compared with low doses(1).

However, this dose-dependent increase is usually asymptomatic and studies have failed to show any increases in liver damage incidence associated with high dose statin induced transaminase increase(1). The National Lipid Association Muscle Expert Panel recommend that liver enzyme concentrations should still be monitored to minimise the risk of hepatotoxicity(1).

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Review An important side effect to consider is the induction of cancer as a result of LDL lowering. An inverse relationship has been observed in clinical trials whereby the risk of developing cancer increases as the level of LDL lowering increases (46). A graph (R2=0.43, P=0.009) of cancer rate (per 100,000 person-years) against achieved LDL-C (mg/dL) showed that as the achieved LDL-C decreases from 140mg/dL to 90mg/dL, the cancer rate increases by 1000 per 100,000 person-years. However, the induction of cancer may be less frequent in clinical practice since the trials that observed this relationship were hypothesis-generating and exploratory (46).

Conclusion In conclusion, the current literature provides a large evidence base for the effectiveness of high dose statin therapy over regular doses in patients of all ages with CVD risk factors. Due to the side effects of statin use, high doses are best used in high-risk patients with established CAD as the benefit to risk ratio in these patients is favorable. However, in most patients, statin therapy is well tolerated and is therefore an effective treatment of CVD. Future research is required to determine the values of the exact LDL concentration targets needed in patients with different levels of risk in order to increase treatment efficiency and CVD prevention success.

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(39) Tomaszewski M, Stepien KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacological Reports :PR 2011;63(4): 859-866.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/22001973 [Accessed 22nd July 2015].

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Review A review to determine the effectiveness of Novel Oral Anticoagulants compared to warfarin at decreasing all-cause mortality in patients with Atrial Fibrillation Quinn L, Khaing P, Lee J, McWilliam S & Shaheen H, University of Birmingham Abstract Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with increased risk of stroke.

Anticoagulants are indicated to decrease the risk of stroke in patients with AF. Warfarin has previously formed the mainstay of treatment however the evidence base to support use of the Novel Oral Anticoagulants (NOACs) as an alternative to warfarin therapy is increasing.

Objective: To determine the difference in all-cause mortality between patients with AF receiving NOAC therapy compared to warfarin therapy.

Methods: Bibliographical databases (MEDLINE, EMBASE, PubMed and Cochrane library) were screened for guidelines, evidence summaries and systematic reviews. Eligibility criteria considered the patient cohort, interventions, comparator, outcomes, to include Relative Risk reduction or Odds ratio in all-cause mortality and results synthesised from Randomised Controlled Trials. Studies were appraised using the Critical Appraisal Skills Programme checklists. 34 full text articles were assessed for eligibility of which 14 were included in this review.

Results: Percentage all-cause mortality ranged from 4.5-7.7% in the NOAC group compared to 5.1-8.4% in the warfarin group. Treatment with NOACs, to include Apixaban, Rivaroxaban, Dabigatran etexilate and Edoxaban, resulted in a Relative Risk reduction ranging from 9 to 13%, depending on the meta-analysis, with reasonably narrow confidence intervals (95% CI 0.79-1.02). All systematic reviews, except 2, found this Relative Risk reduction to be statistically significant.

Conclusions: NOACs, as a class, decrease risk of all-cause mortality compared to warfarin. Applicability of the studies’ findings to the general target population is limited by differences in stroke risk, TTR in the warfarin control group and selection bias of the study participants. Nevertheless, NOACs should be considered as an alternative to warfarin as they decrease risk of all-cause mortality.

Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia [1] but prevalence is age-dependent affecting 0.7% of people aged 55-59 years and 18% of people over 85 years [2]. Furthermore, AF may be an incidental finding or symptomatic, presenting with dyspnoea or syncope [1]; It may also present with the consequence of stroke, as its presence increases the risk of stroke, by five times [3].

In patients with AF, their risk of stroke is assessed in order to determine their need for anticoagulation therapy. ‘The National Institute for Health and Care Excellence’ (NICE) guidelines recommend use of the CHA2DS2-VASc score to assess risk of stroke in patients with AF [1].

Presence of the following factors attains a score which is summed overall to produce the CHA2DS2-VASc score:  

Congestive Heart Failure=1 Hypertension=1

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     

Age>75=2 Age 65-74=1 Diabetes=1 Stroke/TIA/Thromboembolism=2 Vascular disease=1 Sex Female=1

The CHA2DS2-VASc score more effectively discriminates patients at low risk of stroke compared to its predecessor, the CHADS2 score [4]. Based on this score, anticoagulants are offered to patients with AF at increased risk of stroke [1]. However, the HASBLED score should also be undertaken to assess patients’ risk of bleeding. The HASBLED score gives a value of one to the presence of any of the following factors: Uncontrolled Hypertension systolic>160mmHg, Abnormal liver function, Abnormal renal function, Stroke, Bleeding, Labile International Normalised Ratio, Age>65 years, Anti-platelets/NSAIDs, Alcohol>8units/week. Benefits and risks of anticoagulant therapy must be considered but at large, patients at increased risk of bleeding do benefit from

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Review anticoagulants; they should, however, be monitored appropriately [1].

Warfarin, a vitamin K antagonist, has previously formed the mainstay of thrombo-prophylactic therapy. However, a multitude of problems exist with warfarin therapy, including the requirement for frequent monitoring of the International Normalised Ratio (INR-a measure of the patient’s prothrombin time compared with that of normal); the risk of overwarfarinisation and subsequent haemorrhage and interactions with foods and drugs. The plethora of problems associated with warfarinisation justifies the need for new anticoagulant agents [5]. The Novel Oral Anti-Coagulants (NOACs) include three licensed drugs in the UK: Dabigatran etexilate(a direct thrombin inhibitor), Rivaroxaban and Apixaban (both Factor Xa inhibitors). These agents aim to provide an alternative therapy for patients requiring thrombo-prophylactic therapy, including patients with AF, but determination of their efficacy compared to warfarin is ongoing [5].

Objective The aim of this review is to determine the difference in all-cause mortality with NOACs compared to warfarin in patients with AF. Methods Bibliographical databases were searched for guidelines, evidence summaries and systematic reviews: MEDLINE, EMBASE, Pubmed and the Cochrane Library were searched up to May 2015.

Search limitations applied were ‘English language’ and ‘review’. Guidelines and evidence summaries were considered eligible if they synthesised evidence from randomised controlled trials and were subsequently appraised using the AGREE 2 appraisal tool if eligible [6]. Systematic reviews were assessed for eligibility using the title and abstract to ensure their population, intervention, comparator and outcome matched our review, if they synthesised evidence from randomised controlled trials and performed a meta-analysis.

Eligible studies were appraised using the ‘Critical Appraisal Skills Programme’ (CASP) Systematic Review Checklist [7].

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Quality of each systematic review was graded using the ‘Assessing the methodological quality of systematic reviews’ (AMSTAR) [8] score which is a validated and reliable method assessing 11 domains including conflicts of interest, detailed and transparent methods and assessment for publication bias [9].

Clinical Trials.gov was also accessed to identify new or ongoing randomised controlled trials published since January 2015 [10].

The patient populations of the included studies were adults >18 years with non-valvular AF. The intervention was NOAC therapy; dabigatran etexilate or rivaroxaban or Apixaban, dose and frequency not specified but expected to be as indicated. The comparator was dose-adjusted warfarin. Study outcome was all-cause mortality as opposed to specific-cause mortality, for which any one specific cause can be interpreted very differently between studies.

Results The search strategy identified 4 guidelines and 2 evidence summaries which met our eligibility criteria.

Bibliographical database searches identified 31 systematic reviews of which 11 met review eligibility criteria. Since the most recent systematic review in December 2014, no newly published or ongoing randomised controlled trials were obtained from either the bibliographical databases or clinicaltrials.gov up until May 2015. A summary of the systematic review result can be found in Table 1.

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Review Table 1: Systematic Review Results Systematic review

Included studies

Bruins Slot KM, Berge E. [17]

Amadeus, Aristotle, Aristotle-J, Edoxaban Asia, Edoxaban US/Europe, ExploreXa, J-Rocket AF, Opal-1, Opal-2, Rocket

Factor Xa: 881/19630 (4.5%) VKA: 986/19294 (5.1%)

Results All-cause mortality NOAC vs VKA RR or OR, as reported CI 95% Factor Xa inhibitors vs warfarin OR 0.88 (0.81 to 0.97)

Salazar CA, del Aguila D, Cordova EG. [18]

Lip, NCT01136408, Olsson, Petro, Rely, Sportif II, Sportif III, Sportif V Aristotle, Rely, Rocket AF

DTI: 1080/16314 (6.6%) VKA: 691/10287 (6.7%)

DTI vs warfarin OR 0.91 (0..83 to 1.01)

NOACs: 1249/22257 (5.6%) Warfarin: 1406/22185 (6.3%)

NOACs vs warfarin RR 0.88 (0.82-0.95)

RELY, ROCKET-AF, ARISTOTLE

Unavailable

Apixaban/Rivaraoxaban/Dabigatran 110mg vs warfarin HR 0.90 (0.84-0.96) p=0.002

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. [22] Liu T, Korantzopoulos P, Li L, Li G. [23]

All-cause mortality deaths/total (percentage)

Apixaban/Rivaroxaban/Dabigatran 150mg vs warfarin HR 0.91 (0.85-0.97) p=0.004 Capodanno D, Capranzano P, Giacchi G, Calvi V, Tamburino C. [24] Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. [25]

RELY, ROCKET-AF, ARISTOTLE

NOACs: 1695/28292 (6%) Warfarin: 1406/22193 (6.3%)

NOACs vs warfarin OR 0.88 (0.82-0.95) p=0.0001

RELY, ROCKET-AF, ARISTOTLE

NOACs vs warfarin RR 0.88 (0.82 to 0.96)

Baker WL, Phung OJ. [26]

RELY, ROCKET-AF, ARISTOTLE

DTI: 438/6076 (7.2%) Warfarin: 487/6022 (8.1%) FXa: 811/16181 (5.0%) Warfarin: 919/16163 (5.7%) NOACs: 1249/22307 (5.6%) Warfarin: 1406/22228 (6.3%)

(PETRO-not for all cause mortality) For all-cause mortality RELY, ROCKET-AF, ARISTOTLE

NOACs: 602/7876 (7.6%) Warfarin: 658/7846 (8.4%)

NOACs vs warfarin OR 0.90 (0.79-1.02)

ROCKET-AF, RELY, ARISTOTLE

NOACs: 2069/28342 (7.3%) Warfarin: 1788/22236 (8.0%)

NOACs vs warfarin RR 0.91 (0.85-0.97) p=0.002

RELY, ROCKET-AF, ARISTOTLE, ENGAGE-AF TIMI 48

DTI: 3205/42 341 (7.7%) Warfarin: 2245/29 221 (7.7%)

RELY, WEITZ 0..3%, ARISTOTLE, JROCKET-AF 0.3%, ROCKET-AF

NOACs: 1715/30584 (5.6%) Warfarin: 1416/23531 (6.0%)

DTI vs warfarin RR 0.89 (0.85-0.94) p<0.0001 ARR 0.76% (0.39-1.13%) p<0.0001 NNT=132 NOACs vs warfarin RR=0.89 (0.83-0.96) p=0.001 NNT=244

Sardar P, Chatterjee S, Wu WC, Lichstein E, Ghosh J, Aikat S et al.

[27] Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, SuárezGea ML, VargasCastrillón E. [28] Liew A, O’Donnell M, Douketis J. [29]

Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. [31]

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NOACs vs warfarin RR 0.87 (0.80-0.97)

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Review Systematic reviews: A 2013 Cochrane review compared the efficacy and safety of long-term (>4weeks) Factor Xa inhibitor therapy (including Rivaroxaban and Apixaban) to doseadjusted warfarin in patients with AF, assessing a series of outcomes including all-cause mortality (although this was not the primary endpoint). The population had a mean CHADS2 score of 2.7(1.9-3.5) and mean age was 65-74 years with no upper limits.

Follow-up varied from 12 weeks to 1.9 years. The authors employed a thorough and complete search strategy; used bibliographic databases, screened reference lists, contacted authors where appropriate, searched for unpublished studies and translated papers into English.

The review considered 6 randomised controlled trials consisting of 38,924 participants in total, attaining a high quality grade score for methodology with no heterogeneity(I2=0.0%). The Cochrane handbook 2011 was used to assess for risk of study bias.

Generally, the included studies used allocation concealment, appropriate blinding and utilised intention to treat analyses. Moreover, there was no evidence of selective reporting. 5/6 of the individual studiesâ&#x20AC;&#x2122; results demonstrated that although the risk of all-cause mortality was decreased with NOACs compared to warfarin, the benefit of NOACs remained unclear as the Confidence Intervals(CI, given as 95%) crossed the line of no difference. One study in fact identified NOACs as increasing the risk of all-cause mortality, the reasoning for which was not clearly described. It was nevertheless appropriate to combine the study results as the findings were largely similar.

Overall, treatment with factor Xa inhibitors (largely Apixaban and Rivaroxaban) resulted in 45 deaths/1000 population as opposed to 51 deaths/1000 for warfarin.

The Odds Ratio (OR) was 0.88, hence a 12% decreased risk of death in patients taking Factor Xa inhibitors compared to warfarin; a statistically significant and precise result with a narrow CI (0.81-0.97)[17]. In this case, where events are rare, the OR is analogous to the RR. The OR is defined as the odds of an event occurring in the intervention group against the odds of that same event occurring in the control group [13].

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A 2014 Cochrane review similarly aimed to assess the efficacy, safety and all-cause mortality (secondary endpoint) of the alternative type of NOAC, direct thrombin inhibitors(DTIs), compared to warfarin in patients with AF. 8 randomised controlled trials with a total of 27,623 participants and three DTIs (dabigatran 110mg or 150mg, AZD0837, ximelagatran) were included. All important and relevant studies were included in the review. Although statistical heterogeneity was assessed as low, clinical heterogeneity was assessed as moderate due to variations in methodology and outcome definitions.

The eight randomised controlled trials each addressed the primary aim of this review, however their validity was questionable due to the variable use of intention to treat analysis, with four studies implementing per protocol analysis instead. Furthermore, 1 of the 8 studies (RE-LY [19]) produced 75% of the results weighting. The results from the individual studies were largely similar, revealing a decreased risk of death in patients receiving NOACs compared to warfarin, but results were imprecise due to large confidence intervals and not statistically significant as they each crossed the line of no difference. It was therefore appropriate to combine the results from individual studies. Three studies for dabigatran, three studies for AD0837 and two studies for ximelagatran were analysed separately to assess for efficacy of each DTI against warfarin revealing an OR of 0.9(CI=0.8-1.01), 0.42(CI=0.02-8.76) and 0.96(0.78-1.17) respectively, each eliciting large confidence intervals and uncertainty as to which treatment was more effective.

Combined analysis including all three DTIs against warfarin revealed an OR of 0.91(0.83-1.01) which also showed no statistical significance [18].

The same three randomised controlled trials (RELY [19], ROCKET-AF [20], ARISTOTLE [21]) which compared NOACs to warfarin in patients with AF featured in eight separate systematic reviews [22-29].

Adam [25] found a RR reduction with NOACs compared to warfarin of 0.88, with a narrow confidence interval (CI=0.82-0.96) that was statistically significant and achieved a high AMSTAR [8] score of 10/11. Similarly, Baker [26], Capodanno [24], Miller [12] and Outes [28]) identified a RR reduction of 0.85-0.91(combined CI=0.80-0.97), with each systematic review achieving an AMSTAR[8] score of 7/11 or above. Liu [23] assessed two intervention arms of Dabigatran at doses of 110mg and 150mg, which had a RR reduction of 0.9(CI=0.84-0.96) and 0.91(CI=0.85-0.97) compared to warfarin respectively.

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Review However, this systematic review attained an AMSTAR [8] score of only 5/11. Sardar [27] similarly found a RR reduction of 0.90 with NOACs compared to warfarin however this value was not statistically significant (CI=0.79-1.02).

A 2014 meta-analysis by Liew et al [29] found an 11% (CI=0.85-0.94, p<0.0001) statistically significant decreased risk of mortality in patients taking NOACs (Dabigatran/Rivaroxaban/Apixaban/edoxaban) compared to those receiving warfarin therapy.

Although the ENGAGE trial [30] of edoxaban did not find a statistically significant reduction in the Hazard Ratio (HR=0.92, CI=0.83-1.01, p=0.08) [29]. HR is generally equivalent to the Relative Risk and relates to survival over time [13]. The Number Needed to Treat (NNT) was 132 patients to achieve one less death, in patients taking NOACs compared to warfarin [29]. The NNT is the number of patients that need to receive the intervention to benefit or suffer one less event than the patients treated with the control [13].

In summary, the evidence largely demonstrates that NOACs (Apixaban/Rivaroxaban/Dabigatran) decrease RR of all-cause mortality in patients with AF and that this result is statistically significant.

Discussion This review has identified that there is a RR reduction in all-cause mortality with NOACs compared to warfarin in patients with AF. A likely explanation for this decrease is a reduction in the number of major adverse events, such as haemorrhagic stroke or fatal bleeding, in patients taking NOACs compared to warfarin [26].

Generally, the included systematic reviews included small numbers of randomised controlled trials and often did not include publication status as an inclusion criterion, as they failed to assess for risk of publication bias either through funnel plots or statistical tests.

Therefore, the risk of publication bias remains and presents a limiting factor [8]. Heterogeneity between studies was however low, which was partly ensured by assessment of a generalised outcome (all-cause mortality) that was consistently addressed between studies.

Furthermore, the pooled analyses consisted of different types of NOAC, analysing NOACs as a group rather than individual types of NOAC, which vary in their pharmacodynamics, pharmacokinetics and adverse events. Although it was considered reasonable

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to do this, as they act on the common coagulation pathway and no heterogeneity was present between studies, this nevertheless introduces bias. Future systematic reviews should seek to obtain randomised controlled trials that compare efficacy of individual NOACs against one another. This would facilitate meta-analyses, providing superior quality evidence to that identified by indirect comparison meta-analyses that assume similarity and consistency and hence inevitably introduce bias [31].

Applicability Moreover, the applicability of the studies included in this review is limited for several reasons. Firstly, the included systematic reviews ran for a limited time period ranging from 12 weeks to 3 years, rendering it difficult to assess long-term efficacy of NOACs compared to warfarin. This is particularly important as patients with AF warranting anticoagulation can expect lifelong treatment [1]. Therefore, long-term follow up studies, ideally of randomised controlled trials, should be performed to elicit long-term efficacy at 5 and 10 years although cohort studies may offer a more realistic alternative.

Secondly, patients recruited into the trial control groups will have introduced selection bias as they will more likely be optimally managed and less likely to have comorbidities/poly-pharmacy than the general population of warfarinised patients, again limiting the applicability of the study to the target population [22].

Another limitation relates to the CHADS2 or CHA2DS2-VASc scores of the included patient cohorts. The average CHADS2 in some randomised controlled trials was high, hence poorly representing patients at lower risk of stroke. Therefore, the review findings with regards to all-cause mortality in NOACs compared to warfarin must be cautiously applied to patients with a low CHADS2 score. Further research comparing all-cause mortality with NOACs against warfarin in patients with a low CHADS2 score is hence warranted in the form of randomised controlled trials.

Additionally, the included randomised controlled trials assessed CHADS2 in place of the recommended CHA2DS2-VASc score [1].

The Canadian Cardiovascular Society [14] recommend that NOACs mostly be prescribed in preference to warfarin for patients with AF, whereas NICE guidelines [1] recommend either/or. Our review focused on allcause mortality as one marker of drug efficacy and safety. Our review findings would recommend that

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Review NOACs mostly be used in preference to warfarin in patients with AF as they decrease all-cause mortality.

Similarly, although NICE guidelines [1] do not recommend edoxaban, pooled analyses demonstrated edoxaban decreased all-cause mortality compared to warfarin [29] and hence it would be reasonable to recommend edoxaban. However guidelines must consider several outcomes and balance the benefits, harms and costs of each when delivering recommendations for practice. Besides, uncertainties with regards to the practical use of NOACs need to be resolved, including 1) Management of bleeding episodes, 2) Antidotes for NOACs and 3) Whether patients should be switched from warfarin to NOACs [15].

Conclusion Our review has shown that NOACs, as a class, decrease all-cause mortality in patients with AF compared to warfarin. Despite the stated limitations, this is nevertheless an important consideration when prescribing anticoagulants at the individual practitioner level. However, it is also an important consideration at the policy level as decreased mortality will likely result in decreased resource-use and cost associated with management of major haemorrhagic episodes.

References [1] The National Institute for Health and Care Excellence.

Atrial fibrillation: the management of atrial fibrillation. June 2014. http://www.nice.org.uk/guidance/cg180/evidence/cg180atrial-fibrillation-update-full-guideline3 (last accessed 14th May 2015) [2] Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J. 2006;27:949-53 [3] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.

Stroke. 1991;22(8):983-8.

[4] Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011;342:d124.

[5] Joint Formulary Committee. British National Formulary.

69th ed. London: BMJ Group and Pharmaceutical Press; 2015 [6] Agree Trust. Appraisal of Guidelines for Research & Evaluation II. http://www.agreetrust.org/wpcontent/uploads/2013/10/AGREE-II-Users-Manual-and-23item-Instrument_2009_UPDATE_2013.pdf (last accessed 14th May 2015) [7] Critical Appraisal Skills Programme. CASP Checklists. http://www.casp-uk.net/#!casp-tools-checklists/c18f8 (last accessed 14th May 2015) [8] Assessing the Methodological Quality of Systematic Reviews.

Amstar Checklist. http://amstar.ca/Amstar_Checklist.php (last accessed 14th May 2015) [9] National Collaborating Centre for Methods and Tools.

AMSTAR: assessing methodological quality of systematic reviews. http://www.nccmt.ca/registry/view/eng/97.html (last accessed 14th May 2015) [10] U.S. National Institutes of Health. Clinical Trials.gov Homepage. https://clinicaltrials.gov/ (last accessed 14th May 2015) [11] The National Institute for Health and Care Excellence.

Clinical Knowledge Summary: Atrial Fibrillation. Revised March 2015. http://cks.nice.org.uk/atrial-fibrillation (last accessed 14th May 2015) [12] Steinberg BA, Piccini JP. Anticoagulation in atrial fibrillation.

BMJ. 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2116 (last accessed 14th May 2015) [13] BMJ Clinical Evidence. A glossary of EBM terms. http://clinicalevidence.bmj.com/x/set/static/ebm/toolbox/67 8178.html (last accessed 25th August 2015) [14] Canadian Cardiovascular Society. 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Canadian Journal of Cardiology 2014:30.

1114-30. http://www.onlinecjc.ca/article/S0828-282X(14)01249-5/pdf (last accessed 14th May 2015) [15] European Society of Cardiology. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation.

European Heart Journal. 2012; 33: 2719â&#x20AC;&#x201C;2747 [16] American College of Cardiology. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary.

J Am Coll Cardiol.

2014;64(21):2246-2280 [17] Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev. 2013; 8: CD008980

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Review [18] Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database Syst Rev. 2014; 3: CD009893 [19] Connolly SJ, Ezekowitz MD, Yusuf S et al: RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151 [20] Patel MR, Mahaffey KW, Garg J et al: ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891 [21] Granger CB, Alexander JH, McMurray JJ et al: ARISTOTLE committees and investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992 [22] Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012; 110(3): 453-460 [23] Liu T, Korantzopoulos P, Li L, Li G. Survival benefit of new anticoagulants compared with warfarin in patients with atrial fibrillation: a meta-analysis. Int J Cardiol 2012; 156(1): 96-97

[26] Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012; 5(5): 711-719 [27] Sardar P, Chatterjee S, Wu WC, Lichstein E, Ghosh J, Aikat S et al. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischaemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLoS One 2013; 8(10): e77694 [28] Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in patients with nonvalvular atrial fibrillation: a systematic review and metaanalysis of subgroups. Thrombosis 2013; 2013: 640723 [29] Liew A, O’Donnell M, Douketis J. Comparing mortality in patients with atrial fibrillation who are receiving a directacting oral anticoagulant or warfarin: a meta-analysis of randomised trials. J Thromb Haemost 2014; 12(9): 1419-1424.

[30] Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al: ENGAGE AF-TIMI 48 Investigators.

Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369(22): 2093-2104 [31] Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126(20): 2381-2391

[24] Capodanno D, Capranzano P, Giacchi G, Calvi V, Tamburino C. Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. Int J Cardiol 2013; 167(4): 1237-1241 [25] Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012; 157(11): 796-807

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Educational Article Cardiac Causes of Syncope Vignesh Dhileepan & Shruti Jayakumar, Kings College London Syncope (commonly known as ‘fainting’, ‘passing out’ or ‘blacking out’) is defined as “a transient loss of consciousness (TLOC) due to global cerebral hypoperfusion characterised by rapid onset, short duration and spontaneous complete recovery”.

Although it is caused by a variety of aetiologies, the eventual mechanism common to all causes of syncope is a transient reduction in blood pressure, distinguishing it from other causes of TLOC (1).

The causes of syncope are broadly divided into neurally mediated (reflex syncope), postural, arrhythmic and structural. The latter two constitute cardiac causes of syncope and are potentially lifethreatening.

Syncope

Neurally mediated (reflex)

Postural (orthostatic hypotension)

Arrhythmic

Structural

Vasovagal

Primary autonomic failure (e.g.

Parkinson’s disease)

Bradyarrhythmia (e.g. atrioventricular block)

Valvular disease (e.g. aortic stenosis)

Situational (e.g. post-micturition syncope)

Secondary autonomic failure (e.g. diabetes)

Tachyarrhythmia (e.g. ventricular tachycardia)

Cardiac masses (e.g. atrial myxoma)

Carotid sinus hypersensitivity

Drug-induced (e.g. antihypertensives)

Cardiomyopathy (e.g. obstructive hypertrophic cardiomyopathy)

Volume depletion (e.g. haemorrhage)

Pericardial disease

Non-cardiac (e.g. pulmonary embolism, aortic dissection)

Figure 1: Causes of syncope - adapted from "Guidelines for the diagnosis and management of syncope" (1)

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Educational Article Arrhythmic syncope Arrhythmias may cause a variety of symptoms including dizziness, palpitations, breathlessness, central chest pain, syncope and sudden cardiac death (SCD). The latter makes these patients a particularly high risk group and highlights the importance of eliciting a family history of SCD in all cases of syncope. Arrhythmias can be broadly classified as tachy- and brady-arrhythmias, of which bradyarrhythmias are more likely to cause symptoms (2). Syncope from arrhythmias is not solely determined by the arrhythmia itself, but also by other factors such as ventricular rate, left ventricular function, and the adequacy of vascular compensation (i.e. baroreceptor reflex) (1).

Bradyarrhythmias (<60bpm) may occur anywhere along the cardiac conduction pathway. They include sick sinus syndrome and atrioventricular (AV) block, of which Mobitz type II and 3rd degree AV block are the most closely associated with syncope.

Additionally, dysfunction of an already implanted pacemaker is an important cause of bradyarrhythmia.

The reduction in blood pressure is ultimately caused by long pauses (>3 seconds) between ventricular contraction.

These occur due to: 1. Failure of impulse initiation (sinus arrest) or impulse conduction to the ventricles (sinoatrial block, AV block), AND 2. Concomitant delay or failure of an ectopic escape mechanism.

Bradyarrhythmias also predispose to ventricular tachycardia due to prolonged repolarisation time (3).

Tachyarrhythmias (>100bpm) may be ventricular or supraventricular and an eventual drop in blood pressure may occur for various reasons, including insufficient ventricular filling, energetic failure during sustained tachycardia and reflex vasodilatation at onset. Supraventricular tachycardias (e.g. atrial fibrillation, atrial flutter, atrioventricular nodal re-entry tachycardia) are in fact a rare cause of syncope as most patients only experience palpitations. However, these may be the precipitant of a vasovagal syncope, or cause syncope when there is co-existing ventricular pathology, such as a non-compliant ventricle which cannot tolerate sustained tachycardia.(4) Ventricular

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tachycardia (VT) is most commonly encountered in patients with structural heart disease and so care must be taken to rule this out when ventricular tachycardia is the cause.

Distinguishing features: Features strongly suggesting an arrhythmia are the absence of a warning, onset while sitting or lying down and palpitations (5). A long QT interval on ECG suggests an arrhythmic cause of syncope as it can lead to a brief torsade de pointes. Another important ECG feature to look out for even when the patient is stable is a pre-exciting delta wave and short PR interval, suggesting the Wolff-Parkinson-White syndrome.

There are a number of methods available for long term ECG monitoring, from standard ambulatory Holter monitoring to external and implantable loop recorders, and these should be considered when there is a high pre-test probability of arrhythmic syncope.

The definitive diagnostic feature of arrhythmic syncope is a successfully captured association between the syncope and a documented arrhythmia (1)Management: Treatment is that of the primary arrhythmia. The definitive treatment of bradyarrhythmias is permanent pacemaker insertion, although in patients with sinoatrial nodal dysfunction there is no evidence that this prolongs survival (6). The definitive treatment of tachyarrhythmias is either catheter ablation (in the case of most supraventricular tachycardias) or an implantable cardioverter defibrillator (in the case of ventricular tachycardia or fibrillation). Drugs that are causing or exacerbating an arrhythmia, especially in those with long QT syndrome, should be stopped.

Structural In structural (mechanical) causes, syncope predominantly occurs due to a reduction in cardiac output from mechanical obstruction. However, like arrhythmias, this is in fact multifactorial and may also partly be due to orthostatic hypotension, reflex vasodilatation and/or primary arrhythmia (1).

Therefore, arrhythmic and structural causes of syncope should always be considered together and the diagnosis of one should prompt investigation for the other. In older patients, the most likely causes of exertional syncope are aortic stenosis, cardiac tumours and pericardial disease. This is often apparent due to

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Educational Article the presence of other symptoms such as reduced exercise tolerance, breathlessness and peripheral oedema. In young people, inherited causes are most likely, such as hypertrophic cardiomyopathy, familial dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Lastly, a common cause of syncope is ‘scar-related VT’ due to ischaemic fibrosis, which may be indicated by pathological qwaves (4).

References (1) Task Force for the Diagnosis and Management of Syncope, European Society of Cardiology (ESC), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA), Heart Rhythm Society (HRS), Moya A, et al.

Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009 Nov;30(21):2631-2671.

(2) Kumar P, Clark M. Essentials of Clinical Medicine. 5th edi.

China.Saunders Elsevier 2011:806.

Distinguishing features: Clinical features suggesting structural causes of syncope include onset upon exertion (suggesting left ventricular inflow/outflow tract obstruction) and history of ischaemic heart disease. Most structural causes of syncope can be picked up on ECG.

(4) Anderson J, O’Callaghan P. Cardiac syncope. Epilepsia 2012;53(s7):34-41.

Management: The presence of structural heart disease in any case of syncope, regardless of the exact cause, indicates a significantly increased risk of sudden cardiac death, and syncope may be viewed as an opportunity to prevent this.

Surgery should be carried out in those with outflow tract obstruction such as aortic stenosis and cardiac tumours. An implantable cardioverter defibrillator may need to be implanted in those with structural heart disease predisposing to arrhythmias, such as hypertrophic cardiomyopathy (1).

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(3) Rosso R, Adler A, Strasberg B, Guevara-Valdivia ME, Somani R, Baranchuk A, et al. Long QT syndrome complicating atrioventricular block: arrhythmogenic effects of cardiac memory. Circ Arrhythm Electrophysiol 2014 Dec;7(6):1129-1135.

(5) Farne H, Norris-Cervetto E, Warbrick-Smith J. Blackout.

Oxford cases in medicine and surgery. 1st ed. Oxford: Oxford University Press; 2010.

(6) Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013 Aug;34(29):2281-2329.

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Educational Article Assessing a Chest Radiograph of a patient with Cardiovascular Disease Victor Galusko, Cristina Cernei, Ryan Perkins & Steffan Jones, Swansea University R - ROTATION The Rotation is determined by the bony structures:

Introduction The chest radiograph (CXR) is one of the most requested initial clinical investigations. Just like any other investigation, it has its own advantages and disadvantages. It is routine to carry out a chest radiograph on every new admission, and will certainly be done if the patient presents with chest pain. This screening investigation is minimally invasive, quick, cheap and widely available in most hospitals, even when the patient is acutely unwell.

It is important to realise which conclusions can be drawn from this investigation and which signs may be evident, suggesting certain pathologies. The spectrum of pathologies that can be found is vast, and only the most important findings will be discussed in this review.

Overwhelming prominent pathology on a CXR may mask subtle changes. A systematic approach of assessing a chest radiograph of a patient with cardiovascular disease is therefore needed. The ‘DRipp SSS’ mnemonic can be used for the initial CXR assessment with a focus on adult pathology.

Initial Assessment of the Radiograph (DRipp):

D – DETAILS As with any radiograph the assessment should begin by checking the patient Details - the patient’s name, date of birth and the time at which the CXR was taken.

This is a vital first step to take to avoid incorrect inferences. Where possible, the most recent radiograph should be compared to previous ones to avoid diagnosing a normal anatomical variant as pathology.

• The spine should be straight and the clavicles equidistant medially from the spinous process between them.

• The thorax should also appear straight. Unless the patient’s history suggests structural abnormalities (either congenital or acquired), a malposition is indicative of how unwell the patient is.

I - INSPIRATION Good Inspiration allows for optimal visualization of the heart and its borders.

When assessing the contents of the thorax, at least 6 ½ ribs should be visible (i.e. the hemi-diaphragms lying below the 6th rib anteriorly).

PP – POSITION & PENETRATION Furthermore, it is important to determine the Position and Penetration of the film. In terms of position, the PA (postero-anterior) positioning is preferred to an AP (anterior-posterior) due to the falsely magnified anterior structures – particularly the heart - seen in the latter position. However, patients’ immobility and facilities such as portable X-ray machines means the radiograph will be quicker done in the AP position [2].

Finally, Penetration is important to detect low-density lesions [2, p.9]. If the vertebral bodies are clear through the cardiac shadow the film is over-penetrated and if they are not visible at all the film is underpenetrated and the lungs will also look falsely white.

SSS Site, Shape and Size are the three ‘S’s that are commonly applied to assess any skin lesion and can be applied to assess the well-known chest ‘lump’, the heart. We shall further review the three ‘S’s commencing with the heart’s position, the shape and finally the size and the relate pathologies of the heart and its surrounding vasculature.

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Educational Article Table 1 A non-exhaustive list of the pathologies that can cause enlargement of a specific part of the heart Region Dilated

Features on Chest X-ray

Possible Pathologies

Right Atrial Enlargement

Fullness at Right Heart Border

Right Ventricular Enlargement

Uplifting of Cardiac Apex

Left Atrial Enlargement

Double Density Sign (see Figure 3) Splaying of the tracheal carina (see Figure 4) Posterior prominence (with possible oesophageal compression) will be evident on a lateral CXR Prominent left cardiac border Cardiac Apex displaced laterally and downwards

Left Ventricular Enlargement

Aortic Arch Dilation

Prominent Aortic Arch

Pulmonary Artery Dilation

Prominent pulmonary arteries in hilar regions Possible â&#x20AC;&#x153;bat wingâ&#x20AC;? oedema (see Figure 4)

General Cardiomegaly

Atrial Septal Defect Pulmonary Embolism Tricuspid Regurgitation Atrial Septal Defect Pulmonary Embolism Pulmonary Stenosis Tricuspid Regurgitation Mitral Regurgitation Patent Ductus Arteriosus Ventricular Septal Defect

Aortic Regurgitation Aortic Stenosis Coarctation of the aorta Hypertension Mitral Regurgitation Patent Ductus Arteriosus Sickle Cell Disease Ventricular Septal Defect Aortic Dissection Atrial Septal Defect COPD Pulmonary Embolism Ventricular Septal Defect Acquired or Congenital Atrioventricular canal defect Cardiomyopathies COPD Heart Failure Pericardial Effusion (figure 3a and b)

S - SITE S - SHAPE The heart should be positioned in the left side of the thorax. In cases where the apex is positioned to the right the patient is said to have the condition called dextrocardia. This could be an isolated rotation of the heart or part of situs inversus (i.e. rare congenital condition in which the major organs are mirrored in the opposite side of the body) [7]. Both of these conditions can be asymptomatic, but in 5-10% are associated with congenital heart defects that may give rise to symptoms and clinical signs [5]. The heart may also lie in the midline, this is called mesocardia. Other cardiac malpositions have been reported [6] but are very rare, and will therefore not be discussed in this review.

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To assess the Shape of the heart, subtle enlargement of a single part may point towards specific pathologies and narrow down the differential diagnoses. Figure 1 has been labelled to highlight the different regions of the chest that can become enlarged or deviated. A bulge in the respective regions (Figure 1) can result from any one of the pathologies displayed in Table 1.

This list in non-exhaustive, and does not include infectious causes of cardiomegaly. Moreover, abnormalities in nearby structures, for example the thymus gland, can give a false sense of cardiomegaly.

It should be noted that hyperinflation of the chest (as occurs in COPD) may result in the stretching of the heart and may look almost elliptical.

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Educational Article

Figure 1: This figure demonstrates the regions of the heart and chest anatomy that can be seen on a chest radiograph.

The regions of the heart cannot be visualized directly as seen here (apart from the heartâ&#x20AC;&#x2122;s borders) but were filled in for a better appreciation of the rotation of the heart in the thorax. See table 1 for the pathologies that can result in the dilation of any of the following regions.

Figure 2: This is a normal CXR with the cardiac and thoracic diameters labelled. The equation below was used to calculate the CTr to be 0.47. Using a ruler to measure the lengths, you can attempt the calculation yourself. đ??śđ?&#x2018;&#x2021;đ?&#x2018;&#x; =

Maximum Heart Diameter (horizontally) đ?&#x2018;&#x20AC;đ?&#x2018;&#x17D;đ?&#x2018;Ľđ?&#x2018;&#x2013;đ?&#x2018;&#x161;đ?&#x2018;˘đ?&#x2018;&#x161; đ?&#x2018;&#x2021;â&#x201E;&#x17D;đ?&#x2018;&#x153;đ?&#x2018;&#x;đ?&#x2018;&#x17D;đ?&#x2018;Ľ đ??ˇđ?&#x2018;&#x2013;đ?&#x2018;&#x17D;đ?&#x2018;&#x161;đ?&#x2018;&#x2019;đ?&#x2018;Ąđ?&#x2018;&#x2019;đ?&#x2018;&#x; (â&#x201E;&#x17D;đ?&#x2018;&#x153;đ?&#x2018;&#x;đ?&#x2018;&#x2013;đ?&#x2018;§đ?&#x2018;&#x153;đ?&#x2018;&#x203A;đ?&#x2018;Ąđ?&#x2018;&#x17D;đ?&#x2018;&#x2122;đ?&#x2018;&#x2122;đ?&#x2018;Ś)

S- SIZE Related to the third S (size), an enlarged heart or cardiomegaly is one of the abnormalities most commonly seen on a chest radiograph. Cardiomegaly is classified by a cardiothoracic ratio (CTr) of >0.5 on a PA film. The CTr can be easily calculated on the PACS system using the measuring tools provided using the equation in Figure 2. However, it is a common sign which can be also be seen crudely by a doctor/ radiographer/ other trained healthcare professional looking at a CXR. A large ratio is most likely a sign of pathology, which may pertain to any of the structures within the pericardial sac. These include cardiac chambers, cardiac wall thickness, pericardial space and its possible contents (e.g. tumour, air, fluid) [4].

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Figure 3a: This image shows evidence of a pericardial effusion. Please note, there are numerous lines present that could deceivingly look like the pericardial effusion, even on a normal CXR.

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Figure 3b: This outlines the features on the radiograph for a pericardial effusion.

CXRs of Common Pathologies This section will discuss the commonly seen and the most important pathologies that can be seen on a CXR. One example mentioned above is that of left atrial enlargement, which commonly results from mitral stenosis (see Figure 4). The enlarging left atrium loses its normal concavity and becomes almost convex, and shifts the right heart border further to the right. As the atrium expands the carina, the bifurcation of the trachea becomes more splayed (>90o). As the left atrium grows it pushes into the adjacent lung and causing overlapping, resulting in the double density sign [2].

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Figure 4: This image shows an example of left atrial enlargement accompanied by a mid-diastolic murmur, it is suggestive of mitral stenosis that was later confirmed by echocardiography. Moreover, there is a â&#x20AC;&#x153;Bat Wingâ&#x20AC;?

Appearance consistent with pulmonary venous congestion.

Also some coincidental aortic knuckle calcification was detected.

Table 2

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Assessing the Vasculature (part of third S (size)) A brief assessment of the vasculature surrounding the heart may add to the clinical picture. It is important to look at the pulmonary hila as this may explain the initial patient complaint of shortness of breath that may be a consequence of the oedema. Dilated pulmonary vessels in this region can be a sign of pulmonary hypertension that can have a number of causes, some of which are life threatening. Figure 5 demonstrates marked right pulmonary artery dilation.

In pulmonary hypertension, the right side interlobar artery at the hilum, should be no more than 15 mm in diameter in women, and 16 mm in men [1]. A more subtle sign of pulmonary hypertension, both primary and secondary to heart failure, is the size of the vasculature.

Normally, due to gravity, the blood flow to the lung bases is greater than the blood flow to the apices, however in pulmonary hypertension the blood flow to the apices increases. This results in the dilation of the vessels in the lung apices, meaning that the calibre of the vessels increases (please note, not the number of vessels) causing an upper lobe diversion [2].

Figure 5: A CXR of a patient with a left sided pleural effusion and right pulmonary artery dilation in the hilum

Figure 6: This radiograph illustrates an upper lobe diversion (4). Also notice sternotomy sutures (1), AVR & MVR (2), Bat Wing appearance (3), and Aortic knuckle calcification (5).

Moreover, there is sometimes evidence of calcification (calcific atherosclerosis), however this is rarely seen on a radiograph. A CXR is therefore not diagnostic pulmonary hypertension but serves as a screening tool for further investigation.

Figure 5a: The radiograph shows pulmonary hypertension due to COPD. Notice the number of ribs visible – 10, a hyperinflated or ‘barrel’ chest, and reduced peripheral vascularity.

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As a consequence of pulmonary hypertension, the pressure imbalance will cause pulmonary oedema that will be visible as symmetrical shadowing on the lungs.

It will be especially widespread during acute episodes of worsening of heart failure, during these episodes the patient will be severely short of breath and will need prompt treatment.

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Educational Article Another sign of heart failure is the “Bat Wing” sign around the pulmonary hila. This is a description of oedema around the hila usually caused by a decrease in cardiac contractility [4].

More evanescent signs of heart failure, are Kerley B lines that are oedematous interlobular septa visible as lines just above the costophrenic angles [2].

Pulmonary oedema is a common clinical sign on a CXR and may not necessarily mean the presence of heart failure. Another condition from which it is important to differentiate it from is acute respiratory distress syndrome (ARDS), as the treatment will differ. Table 3 summarises the radiological findings that may be useful in distinguishing between the two conditions, although patient history may be more of an aid in this situation [2].

Table 3 Radiological signs of ARDS as compared to Heart Failure due to LVF [2] Characteristics Cardiothoracic ratio Opacification/white shadowing Upper lobe blood vessels size

ARDS Normal Peripheral

LVF >50% More central

Normal size

Increased width

Kerley B lines

Rare

More common

Radiological signs

At least 12h after symptoms onset

Before symptoms onset

Figure 6a: A CXR showing the “Bat Wing” sign and Kerley B lines of a patient with congestive heart failure. Note the patient has a right-sided pleural effusion and evidence of sternotomy and AVR. Aortic arch calcification is also present.

Figure 7a: This is a CXR of a patient presenting with chest pain. Aortic dissection of the ascending aorta is present, and shown by widening and displacement of the mediastinum towards the right side Figure 6b: Highlighting the features of CXR in Figure 6a

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Visualising the aorta, its course, and its size may aid to discern between the different causes of chest pain.

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In conclusion chest x-rays are a must for a number of patients on the initial arrival to hospital. It is of utmost importance that every clinician has a systematic approach to assess chest radiographs. This review suggested DRipp SSS as a starting point for medical students and new doctors. It aims to show a rounded understanding of the pathologies a chest radiograph could include but did not focus on congenital abnormalities. Further, it is important to interpret the radiographs in conjuncture with the patientâ&#x20AC;&#x2122;s presenting complaints and past medical history, as well as the clinical examination. It should also be noted that other modalities, such as CT and echocardiography, can be used in diagnosing cardiac abnormalities [4].

Figure 7b: Highlighting the important regions that should be assessed when handling a patient with chest pain

Finally, it is important to pick up early new changes such as Superior Vena Cava (SVC) dilatation and investigate it. Normally the SVC should be less than 23mm wide [2].

Causes for dilatation of the SVC involve malignancy 90% of the cases of which 75% are due to bronchopulmonary cancer mostly consisting of small cell cancers. Benign causes are rare usually due to a thrombus around a catheter [3]. A CT is the diagnosis modality of a dilated SVC [4].

References 1. Chang CH. The normal roentgenographic measurement of the right descending pulmonary artery in 1085 cases.

American Journal Roentgenology, Radium Therapy, and Nuclear Medicine [Internet].1962 [cited 2015 August 12]; 87:929-35. Available from: PubMed ID 138878070.

2. Corne J, Carroll M, Brown I, Delany D. Chest X-Ray Made Easy. 2nd ed. London: Elsevier Ltd; 2002.

3. Lacout A, Marcy PY, Thariat J, Lacombe P, Hajjam M. Radio-anatomy of the superior vena cava syndrome and therapeutic orientations. Journal de Radiologie Diagnostique et Intervetionnelle [internet]. 2012 [cited 2015 August 12]; 93(7-8): 601-610.

Available from: doi:10.1016/j/diii.2012.03.025 4. Longmore M, Wilkinson IB, Baldwin A, Wallin E. Oxford Handbook of Clinical Medicine. 9th ed. US: Oxford University press; 2014.

5. Oppido G, Napoleone CP, Martano S, Gargiulo G. Hypoplastic left heart syndrome in Situs inversus totalis.

European Journal of Cardiothoracic Surgery [internet]. 2004 [cited 2015 August 12]; 26(5):1052- 1054.

Figure 8: Displaying a dilated SVC

6. Perloff JK. The Cardiac Malpositions. American Journal of Cardiology [internet]. 2011 [cited 2015 August 12]; 108(9):1352-61.

Available from: doi:10.1016/j.amjcard.2011.06.055.

7. Ra-id Abdulla. Heart Diseases in Children: A Pediatricianâ&#x20AC;&#x2122;s Guide (Chapter 2). US:Springer; 2011.

All images were obtained from Morriston Hospital with the help of Mr Umair Aslam and Dr Joseph George.

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Interview Interview with Professor Gregory Lip Manasi Jyothish, University of Birmingham Question 1: You’re somebody who has had quite a prolific clinical and research career. Can you briefly tell us about your career trajectory up till date?

After medical school and core medical training in Glasgow, I developed an interest in cardiology. I always have had an interest in research and academia, and this led me to pursue an M.D. research programme. However it was perhaps being given the right opportunity and meeting the right mentors that made all the difference. If you have the right attitude, energy and enthusiasm - and you apply yourself - you will succeed.

Question 2: What was it that drew you to pursuing cardiology as your chosen speciality and how did you first develop your current research focus?

Cardiology brings together a lot of aspects I was interested in - translational science, epidemiology and physiology, as well as the clinical application. I was first and foremost a clinician and as a junior doctor you see a lot of clinical conundrums and problems that grab your attention.

My initial research focused on identifying biomarkers for patients with atrial fibrillation (AF) who are high risk for stroke. The field for biomarkers evolves very rapidly, and we all see that few of these biomarkers have come to clinical application, and most have a ‘rule out’ value rather than ‘rule in’. The practical aspect and clinical application is important. For example, when you see a patient in clinic, you need to risk stratify that patient for stroke on the spot and make a decision regarding their necessity for anticoagulation straight away. There isn’t time to decipher and ascertain whether they are positive for various biomarkers (which could take weeks). Also, there was no treatment indication for patients who were identified as being supposedly low risk for stroke. This is where the CHA2DS2VASc score comes in, which allows for simple decision making for risk stratification in AF and need for anticoagulation. This score allows for identification of patients who are identified as being low risk for stroke (score 0 in males, 1 in females), so their risk of stroke is <1% and antithrombotic therapy is not recommended. For all patients who have 1 or more risk factors for stroke, we can offer effective

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Figure 1 Professor Gregory Lip

stroke prevention, which is oral anticoagulation therapy.

To give you a second example, when you see a patient with AF for the first time, it is difficult to make a decision as to whether they need to be started on warfarin or one of the NOACs (non-Vitamin K antagonist oral anticoagulants, previously called new or novel oral anticoagulants) as often you don’t know how the patient will respond to warfarin. Some institutions are carrying out a ‘trial of warfarin’ to see if the patient can respond well to warfarin, as reflected

by TTR (Time in therapeutic range). However, the TTR for the first 6 months tends to be very poor, so for 6 months the patients are virtually unprotected and would be at risk of fatal and devastating strokes. So one of the strategies we devised is known as the ‘SAMe-TT2R2 score’.

This is a simple clinical prediction rule to aid in the decision making process to help choose patients that will do better on warfarin than the NOACs. In summary, clinical research allows us to come up with simple solutions for simple clinical questions that have the potential to alter everyday practice.

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Interview Question 3: 2014 was a milestone year for you, with being ranked as the worldâ&#x20AC;&#x2122;s leading expert in AF, what stimulated your interest in this condition?

AF is so common; all of us have met patients or friends and family members who suffer from this condition.

Of course sometimes you meet certain patients that can change your perception of life and your area of interest that you want to study.

For me, this was a 72 year old woman who was classified as low risk for stroke (e.g. using the old CHADS2 score) and was treated with aspirin. She suffered a severe stroke. She was my mother.

Question 4: The gulf between academic medicine and clinical medicine is problematic, so how important is it for doctors to engage in and have an appreciation of research today?

I think research is very important for medical careers despite whether you eventually end up as an academic/non-academic.

The clinical and the academic sides complement each other and clinical research helps us find answers for the common clinical questions that occur in everyday clinical practice.

Sadly, there is a perception that some training programmes are not very conducive to getting research done.

All of us never stop learning. I certainly learn a lot when supervising students/post grads.

Medicine is something that is a lifelong career that involves lifetime learning. One improves as a doctor by asking questions and more importantly by trying to find solutions for those questions. If we are all spoon-fed and are learning things by rote, medical knowledge would never have advanced.

Question 5: You are an Adjunct Professor in Cardiovascular Sciences at Aalborg University, Denmark, Visiting Professor of Cardiology at Belgrade University, Serbia and furthermore, an Honorary Professor in Geriatric Cardiology at the Chinese PLA Medical School, Beijing, China.

How does the health infrastructure and care differ in these countries from what we are experiencing here in England and what do we have to learn from the care delivered in these countries that we can implement to our healthcare system?

One example that we can learn from in the fields of research and academia is from Denmark.

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They have a very sophisticated healthcare system with a national registration system in which each citizen is coded and healthcare contact accounted for. This leads to a nationwide database that allows for clinical epidemiology studies to take place.

Another global collaboration has been establishing the Inter-AF collaboration which encompasses registries from the US, Europe, Brazil, China, Japan and Serbia.

It aims to carry out global inter-country comparisons of Atrial Fibrillation statistics, risk factors and management strategies. At an European level, I am chairman of the ESC Euro Observational Research Programme in AF (EORP-AF) which uses a large registry to make epidemiological studies of AF. The aim of this programme of registries is to provide a better understanding of medical practice, based on observational data collected with robust methodological procedures.

Of note, it is extremely gratifying and beneficial to have collaborations with people in various countries who have the same research interests with the ultimate aim of furthering medical knowledge and improving patient care.

Question 6: Half of your time is spent with clinical work and the other half of your time is spent with your research activities. Which one do you find most satisfying?

I have a clinical academic timetable and I must admit at times it feels like youâ&#x20AC;&#x2122;re trying to do two jobs at the same time. Both are extremely time consuming and busy jobs but they complement each other. I run the AF service, as well as the hypertension service. I also do coronary angioplasty and remain on call rota for primary angioplasty. My research allows me the opportunity to apply the research knowledge that gained to a clinical setting and this is very satisfying.

Question 7: According to you, what has been the most important cardiovascular breakthrough in the last 5 years?

A lot of examples spring to mind, certainly within the fields of stroke prevention and anticoagulation, the biggest breakthroughs have been in our handling of anticoagulation. Warfarin is a good drug that has been around for a very long time but there has been an increased awareness in the last 10 years or so about how we handle warfarin and more attention is being paid to TTR etc. as the realisation has come about that it is not just a matter of writing a prescription and

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Interview forgetting about it! Thus, although warfarin is a great drug it needs to be used carefully with attention to the quality of anticoagulation control.

Secondly, the NOACs - whilst they have a lot of advantages, it is important that they are used safely and correctly for the appropriate patients.

Question 8: According to you, what are the biggest cardiovascular problems that require more research input in today’s world?

There have been huge advances made in cardiovascular treatments. However, it is very important to implement strategies that can be applied to the wider population in a more effective manner.

For example, Asian patients behave differently on warfarin as they suffer from more strokes and more intracranial bleeds so there is quite a lot of research being undertaken right now to understand why this is the case.

So, although a lot has been achieved the next area requiring research would be how to implement strategies in a more efficient and effective manner to a wider, global population.

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Question 9: Cardiology is a notoriously competitive speciality to get into nowadays, what are the qualities you deem to be important to nurture in someone who aspires to be a cardiologist?

If cardiology is your designated area of clinical interest, it requires hard work, as is the case with most specialities, but it can be achieved.

With cardiology, you get the full range from basic science to clinical research, as well as the clinical application. The speciality requires hard work, dedication and a degree of persistence – also, a bit of innovation wouldn’t go amiss! If you have a philosophy of wanting to answer common clinical questions with the aim of improving patient care then you’ve probably got the full set of qualities needed to make it!

Birmingham is certainly on the map for certain aspects of cardiovascular disease, so if there are students out there who are interested in pursuing this as a speciality, then being in the right environment with the right supervisor or mentor will help.

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Elective Report What strategies are utilised in the prevention of rheumatic heart disease in the Pacific? A reflective report based on the Samoan National Health Service Hisham Omer, Birmingham University Background

Reflection

Rheumatic heart disease (RHD) is a major cause of morbidity and mortality in less developed nations (1).

With 15.6 million people worldwide currently affected by the disease and 233,000 deaths annually, this condition highlights a major issue for healthcare in developing countries (2).

I conducted my elective placement at Tupua Tamasese Meaole (TTM) Hospital in the Samoan capital (Apia) with the intention of working alongside healthcare staff in the management of patients with RF and RHD.

RHD occurs as a long-term consequence of rheumatic fever (RF), an inflammatory disease that typically occurs three to four weeks after infection with group A streptococci (GAS) (1). These infections occur mainly in children who present primarily with a sore throat (streptococcal pharyngitis). Persistent undertreatment of GAS infections and the resultant inflammatory response contributes to the development of valvular fibrosis. RHD then develops as result of this valvular damage and is characterised by heart failure years later (3). The diagnosis of RHD is often confirmed using echocardiography (echo).

Strategies for managing RHD are mainly focused on prevention. This can be divided into primary and secondary prophylaxis. Primary measures involve the adequate treatment of GAS infections to prevent the development of RF, whereas secondary measures aim to prevent recurrent attacks of RF and progression towards RHD (4). For secondary prevention intramuscular (IM) Benzylpenicillin is required.

In spite of the preventative options available, RF and RHD remains a major issue for Pacific Island states such as Samoa, particularly when patients require lifesaving cardiac surgery for significant valvular disease.

The Samoan National Health Service (NHS) lacks the expertise for valve replacement procedures and as such, patients are transferred to New Zealand for management under the governmentâ&#x20AC;&#x2122;s Overseas Treatment Scheme (OVT). Only about 25-30 patients require surgery annually, but this has a significant impact on the OVT budget requiring NZ$10 million per year (3).

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The majority of patients that I saw with RF/RHD had been diagnosed incidentally. The method of diagnosis for most elderly patients was auscultation with subsequent echo. However a number of younger patients were diagnosed during their school years using echo, reflecting the start of the school-based RF prevention programme in 2000 (3). It was interesting to compare the health status of patients who were diagnosed incidentally at a later age against those diagnosed at school. Unsurprisingly, very few of those with early diagnoses had severe heart failure, whereas the prognosis for the majority of those diagnosed late, was extremely poor. The difference in patient outcomes was marked and emphasised the importance of early identification and treatment.

Figure 1 Tupua tamasese meaole (TTM) II National and Teaching hospital

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Elective Report One notable case was an elderly female patient with known history of RHD who had previously undergone a valvuloplasty in New Zealand. It was fascinating to hear about the impact on the patient and the family regarding the stresses of care abroad. This case challenged my views concerning overseas treatment.

Previously, I was in favour of treatment abroad owing to the expertise available and the facilities present to deal with post-operative care. However, with greater consideration of the additional anxieties of transportation, accommodation and stay in a foreign land, I feel that that surgeries performed in Samoa by visiting cardiac surgeons would be more preferable.

Though statistics for operations performed in 2008 highlight the issues of surgery in Samoa, with 50% of the 14 cases developing complications and three deaths occurring (6), the complication rate could be reduced by risk stratification. This could involve performing the low risk procedures in Samoa, reserving higher risk cases for New Zealand. The most successful and cost-effective solution however, I feel, remains a strong prevention programme.

During my time at the RF centre I witnessed an interesting case involving a 13-year old boy who was referred to the centre following an echo in the community. The scan was conducted as part of a mobile clinic in Savaiâ&#x20AC;&#x2122;i, an outer Samoan village, where the child was found to have both aortic and mitral regurgitation. To be given such a diagnosis at an early age was something I felt was astonishing. Without treatment, the prospect of this child developing heart failure in the imminent future was unsettling. His management plan involved life-long treatment with IM Benzylpenicillin and referral to the cardiac surgeons in New Zealand for assessment with the potential of valve repair or replacement. This case was powerful in demonstrating the impact that RF/RHD can have on patients and families. Screening in the community can be difficult, as it requires multiple personnel with expertise to cover a wider range of villages, however, this case clearly demonstrated its benefits. Early diagnosis of RHD in this child allowed management plans to be put in place earlier, thus increasing the likelihood of positive outcomes.

Autumn 2015

Figure 2 Tower of TTM II National and Teaching hospital

A visiting group from the USA named Rheumatic Rescue joined TTM hospital during my final week. The group consisted of 40 volunteers including students, echo technicians and hospital physicians who conducted health promotion in schools and echo screening. Children aged 5-15 years old were targeted.

It was fascinating to learn about the methods utilised for health promotion. Puppet shows and songs were used to encourage children to inform parents if they developed sore throats. Such was the effectiveness of the health messages delivered that in follow up surveys, 80% of children stated they knew what the puppet show was about and 88% stated they would go to a doctor or a nurse for a sore throat. The simplicity and effectiveness of these methods were remarkable and highlighted that simple measures are often the most powerful. I, however, worry about the sustainability of such a programme. Without guidance for Samoan healthcare professionals, it is unlikely that such programmes will continue. This highlights the need for government expenditure on further training opportunities for the local workforce such as echo training.

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Elective Report References

Conclusion It is clear that RF/RHD is a pressing issue among Samoans. Though largely preventable, new cases of RF continue to emerge with high risk of progression towards RHD in adult life, thus conferring a substantial impact on individuals and families. In addition, the cost of managing RHD abroad through cardiac surgery is significant and largely unsustainable, draining a considerable amount from the health budget.

Prevention, therefore, is the main focus of the Samoan NHS. With more emphasis on health education, screening of high-risk populations and IM Benzylpenicillin prophylaxis, large steps may be made towards reducing the burden of RF/RHD.

1. Cardiovascular disease in less-developed countries Oxford Medicine [Internet]. [cited 2014 Dec 24]. Available from: http://oxfordmedicine.com/view/10.1093/med/97801996432 19.001.0001/med-9780199643219-chapter-014#med9780199643219-div1-1757 2. Rheumatic Heart Disease | World Heart Federation [Internet]. [cited 2014 Dec 24]. Available from: http://www.world-heart-federation.org/press/factsheets/rheumatic-heart-disease/ 3. Viali S. Rheumatic heart disease in Samoa and the Pacific Nations. J Prim Health Care [Internet]. 2014 Mar [cited 2014 Dec 24];6(1):84–5.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/24624418 4. WHO Model Prescribing Information: Drugs Used in the Treatment of Streptococcal Pharyngitis and Prevention of Rheumatic Fever [Internet]. [cited 2015 Jul 30]. Available from: http://apps.who.int/medicinedocs/en/p/printable.html 5. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis [Internet]. 2012 Nov 15 [cited 2015 Jul 9];55(10):1279–82.

Available from: http://cid.oxfordjournals.org/content/55/10/1279.long 6. Viali S, Saena P, Futi V. Rheumatic Fever Programme in Samoa. N Z Med J [Internet]. 2011 Feb 11 [cited 2014 Dec 24];124(1329):26–35.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/21475357

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Supplement ORAL PRESENTATIONS THE ROLE OF THE FRACTALKINE RECEPTOR IN MYOCARDIAL ISCHAEMIA AND REPERFUSION Giannoudi M, Bennaceur K, Spyridopoulos I Background: Gold-standard treatment for ST-elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PPCI) facilitating myocardial reperfusion. Following this procedure T cell count alternations have been noted, namely a decrease in T cell numbers until 90 minutes post-PPCI, followed by a subsequent increase.

Lymphopenia, post-PPCI is associated with increased mortality. Recently a relationship between lymphopenia, decreased T cells in particular, and expression of the Fractalkine receptor (CX3CR1) has been described. Differentiated T cells have been found to express this receptor. The process of cellular differentiation has been linked with senescence, which represents decreased proliferation but ongoing cytokine release capacity.

Aims: To confirm the presence of CX3CR1 on T cell subsets at 24 hours post-PPCI. To investigate the presence of cell surface receptors associated with senescence on CX3CR1 expressing cells.

Methods: Peripheral blood was withdrawn from STEMI patients (n=20) at 24 hours post-PPCI, and healthy control volunteers (n=10). Multi-colour flow cytometry determined absolute counts and percentages of T cell subpopulations and their CX3CR1 expression. Presence of cell surface markers of differentiation and senescence; CD27, CD57 and PD1 on T cells was also investigated.

Results: Differentiated, memory T cell subsets (TEM and TEMRA) expressed CX3CR1. More CD8+ than CD4+ T cells expressed CX3CR1. CX3CR1+ cells were positively correlated with the cell surface receptor CD57, a marker of cellular senescence, CD4+ (r=0.71, p<0.0001), CD8+(r=0.77, p<0.001).

Conclusion: Following ischaemia/reperfusion in STEMI patients, memory T cells express CX3CR1 and display an immunoscenescent phenotype with potential cytotoxic ability.

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Supplement SURGICAL RADIOFREQUENCY ABLATION FOR CONCOMITANT ATRIAL FIBRILLATION: 10YEAR SINGLE-CENTER RESULTS Huelin Alcubierre FJ, Lopez Ayala P, Carnero Alcazar M, Ramchandani B, Maroto Castellanos LC Background: Radiofrequency ablation for treatment of concomitant atrial fibrillation (AF) has replaced surgical incisions and should be performed whenever possible. However, its long-term effects are still unclear.

Aims: We sought to determine early and long-term clinical outcomes and recurrence of AF after bipolar radiofrequency surgical ablation.

Methods: We included all consecutive patients who underwent a surgical radiofrequency ablation of AF from February2004 to December-2014. Main end-points: mortality, major stroke and recurrence of AF, defined as episode of AF lasting >30 seconds 3 months after the procedure. Follow-up was performed with outpatient clinical visits and 24-hour Holter. Follow-up visits were scheduled at 30 days, 6 months and every year postoperatively.

Results: N=260. Population mean age: 64.5 (SD: 10.5). Logistic EuroSCORE: 5.9 (SD: 4.7). Concomitant procedures: mitral valve procedure in 177 (68%), within 216 (84%) valve surgeries done. Postoperative outcomes: mortality 3.5%, stroke 2.3%, pacemaker implantation 7%, major bleeding 6.6%, myocardial infarction 2.7%. A total of 77.8% patients were discharged in sinus rhythm. After 5-year of follow-up overall survival was 90.8%: Survival free from stroke and recurrence of AF was 96% and 59%, respectively. Multivariate Cox regression analysis revealed that AF duration >24 months (HR: 1.01, 95% CI: 1,006-1.014) and AF recurrence during the first 3 months (HR: 3, 95% CI: 1.8-4.8) were independent risk factors for AF late recurrence.

Conclusion: Radiofrequency ablation is a safe procedure for treatment of concomitant AF and effective at restoring sinus rhythm (60% at 5 years). AF duration and early recurrence are the principal risk factors associated with AF late recurrence.

ALGORITHM FOR ESTIMATING DIASTASIS FOR CARDIAC IMAGING Sri A, Vassiliou V Background: Novel cardiac magnetic resonance imaging (CMR) sequences, such as T1 mapping, require imaging during the diastasis. This is calculated at the time of the scan for each individual patient from the four chamber or short axis stack imaging of the left ventricle. However, it is an additional step of complexity, requiring extra time and prone to human error.

Aims: We investigated whether diastasis could be accurately estimated using the heart rate alone.

Method: Patients who underwent a clinical CMR were retrospectively selected and grouped by their mean heart rate (n=70, 10 patients per stepwise 10 heart beat groups). The diastasis was calculated manually using the formula ((time at beginning of diastolic stasis) + (time at end of diastolic stasis)/2). A formula for the line of best fit estimated diastasis on the basis of heart rate. This formula that calculated the diastasis value per heart group was estimated and validated against a separate cohort of patients (n=50).

Results: A good linear relationship was identified between diastolic pause and each heart rate group suggesting it is possible to estimate diastasis using the following equation: Diastolic pause= 633 -40.82*HR group, R2=0.82.

Applying this formula to a separate validation cohort showed that there was good correlation between the estimated and calculated diastasis value (R2=0.84).

Conclusion: It is possible to estimate accurately diastasis for patients undergoing imaging using the identified formula, saving time and avoiding potential introduction of error.

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Supplement IS THERE A LINK BETWEEN VENOUS THROMBOSIS AND ATHEROSCLEROSIS? Kingdon J, Phinikaridou A, Andia M, Patel AS, Modarai B, Botnar R, Smith A, Saha P Background: Epidemiological evidence suggests that deep vein thrombosis (DVT) is associated with an increased risk of myocardial infraction and stroke, which persists for over 20years. It is unclear, however, if a direct causal relationship exists between DVT and atherosclerosis and how this might occur. Inflammation is common to the pathogenesis of both conditions and may be the link between them.

Aim: To determine whether DVT accelerates plaque progression in an animal model of atherosclerosis.

Methods: Venous thrombosis or sham operation was surgically induced in the inferior vena cava of ApoE-/- mice fed a high fat western diet for 3 months. Plaque volume in the brachiocephalic artery (BCA) was measured using magnetic resonance imaging (MRI) at 28 days following thrombus induction. The aortic root was harvested for histological analysis of plaque size and structure. Blood, spleen and aorta (beyond the aortic root) were harvested for flow cytometric analysis of the inflammatory cell content.

Results: Plaque volume was 33% larger in mice with a DVT (2.4±0.15mm3 vs 1.8±0.11mm3 in sham controls, n=20/gp, P<0.01). This was associated with an increase in circulating ‘inflammatory’ monocytes, a reduction in splenic ‘inflammatory’ monocytes and an increase in macrophages in the aorta.

Conclusion: These results suggest that DVT directly accelerates the progression of atherosclerotic plaque in ApoE-/mice fed a high fat western diet. It appears that this relationship is associated with an increase in the recruitment of inflammatory monocytes. Future studies will focus on the effect of early venous thrombolysis on plaque progression.

EARLY SINGLE-CENTER EXPERIENCE WITH EDWARDS INTUITY BIOPROSTHESIS FOR THE TREATMENT OF SEVERE AORTIC STENOSIS

SUTURELESS

Lopez Ayala P, Huelin Alcubierre FJ, Garcia Bouza M, Maroto Castellanos LC, Carnero Alcazar M Background: Since the development of TAVI, prostheses have been implanted without surgical sutures. However, this implantation is not exempt of problems, paravalvular leakage being the most frequent one. Open surgical aortic valve replacement has the advantage of removing the diseased valve. In theory, combination of both techniques should bring advantages.

Aim: To evaluate the safety, hemodynamic performance and cardiovascular events of EDWARDS INTUITY sutureless bioprosthesis for the treatment of severe aortic stenosis.

Methods: A prospective descriptive study, in which all consecutive patients who underwent EDWARDS INTUITY (TM Edwards Lifesciences Corporation, Irvine, CA) sutureless bioprosthesis implantation between January-2013 and August-2014 in our center were included.

Results: N=24. Population mean age 72.6 (95% CI 65.4-79.1). Logistic EuroSCORE1, 10.5 (95% CI 9.4-12.6).

Implantation success was 96% (23/24). J-type ministernotomy was performed in 12 patients. Concomitant procedures were performed in 4 cases. Cardiopulmonary Bypass (CPB) and cross-clamp mean time were 52 minutes (95% CI 4462) and 38.4 minutes (95% CI 32-44), respectively. In-hospital mortality was 4.2% (n=1), not related to technique.

During follow-up, 2 patients died (8.7%). Mean transprosthetic gradient at discharge and at 1 year was 9.0mmHg and 7.3mmHg, respectively. No significant paravalvular leak was observed. One patient was re-operated due to postoperative bleeding and another patient required a definitive pacemaker.

Conclusions: Implantation of EDWARDS INTUITY sutureless bioprothesis is a safe procedure in the short and midterm, with shorter CPB and cross-clamp duration and enables a less invasive surgical approach than conventional midsternotomy. After a 1-year follow-up, hemodynamic performance was excellent.

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Supplement POSTER PRESENTATIONS INCREASING BURDEN OF PSYCHIATRIC COMORBIDITIES AMONGST PATIENTS WITH ISCHAEMIC HEART DISEASE Klimach S, Gollop ND Background: Psychiatric disorders commonly occur with significant medical conditions, including ischaemic heart disease (IHD). The mechanism(s), patterns and trends underlying this association are incompletely understood and poorly defined.

Aim: To identify patterns and trends in psychiatric co-morbidities among IHD patients in the North West of England.

Methods: Patients with a diagnosis of IHD were identified using an anonymised database of admissions collected from 7 hospitals between January 2000 and March 2013. Psychiatric co-morbidities within the cohort were identified and the data analysed investigating comorbidities, associations, length of stay and mortality.

Results: 88,714 patients were admitted with IHD during the study period with a mean age of 68.6 years and a male to female ratio of 1.3:1. Of which 9799 (11.05%) had a psychiactric comorbidity documented. The most prevalent psychiatric comorbidities were: dementia (4.1%), depression (2.9%), alcohol abuse/dependency (1.6%), and anxiety disorder (1.1%). The prevalence of psychiatric comorbidities increased from 7.1% in 2000 to 13.55% in 2013.

Conclusion: In this cohort 1 in 10 patients with IHD had a diagnosed psychiatric disorder. Furthermore a trend for increasing psychiatric comorbidity was identified. Clinicians should consider psychiatric comorbidities in patients with IHD to facilitate early identification and tailored holistic management. While the data presented does not imply causation or association we suggest that improving psychiatric management in this population could improve quality of life, management of IHD and engagement with IHD services and rehabilitation.

SIGNIFICANT LEFT MAIN STEM STENOSIS AND SURVIVAL IN PATIENTS WITH AORTIC STENOSIS UNDERGOING TAVI Selvendran SS, Aggarwal N, Vassiliou V Background and Aim: Percutaneous transcatheter aortic valve implantation (TAVI) is gaining significant popularity as an alternative to conventional aortic valve replacement surgery, especially in high-risk patients. We investigated the association between the presence of prognostic coronary artery disease, defined as left mainstem disease (LMS) >=50% and survival in patients undergoing TAVI for aortic stenosis (AS).

Methods: Between 2009-2013, consecutive patients with severe AS scheduled for TAVI underwent cardiovascular magnetic resonance (CMR) in a single institution. Data on patient demographics, biomarkers, coronary artery disease and CMR derived results were analysed to identify any associations with overall mortality. Follow-up was completed using electronic hospital records and data obtained from the Office of National Statistics.

Results: 75 patients (80+/-7years; 41 male) were followed for a median 50 (30, 56) months. During this period 28 patients died. On univariate analysis presence of LMS>=50%, low albumin, high right ventricular end-diastolic volume, hypertension and high body surface area were all associated with worse survival. On multivariable analysis only presence of LMS>=50% remained significantly associated with prognosis (HR=31.8, 95% CI:2.9-350.0). All three patients with LMS>=50% died, whereas only 25/72 (35%) with LMS<50% died.

Conclusions: In patients with AS undergoing TAVI, presence of LMS>=50% is independently associated with worse survival.

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Supplement EFFECTIVENESS OF POST-OPERATIVE METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS DECOLONISATION THERAPY IN REDUCING SURGICAL SITE INFECTIONS AFTER CORONARY ARTERY BYPASS GRAFTING Mogan YP, Ooi OC Background: Previous studies have shown that pre-operative MRSA colonisation carries high risk of Surgical Site Infection (SSI). Emphasis has been placed on pre-operative decolonisation therapy. However, little has been reported on benefits of empirical post-operative mupirocin in reducing SSI. Aim: To assess the impact of post-operative decolonisation using mupirocin on rate of SSI after Coronary Artery Bypass Grafting (CABG).

Methods: A retrospective single-centre cohort study looking at consecutive isolated CABG cases done at National University Hospital, Singapore from January 2011 to December 2014. Patients screened negative for MRSA in the immediate post-operative period were included (n=1011). All patients received daily routine chlorhexidine sponging.

The primary outcome measure was post-operative SSI, signified by a positive swab culture.

Results: In the test group, 118 (11.7%) patients received empirical decolonisation with mupirocin. 10 (8.47%) patients had a SSI, of which 2 (20%) were positive for MRSA at the surgical site.

In the control group, 78 (8.73%) patients had a SSI, of which 8 (10.3%) were positive for MRSA at the surgical site. Chisquare analysis showed no significant association between post-operative empirical decolonisation with mupirocin and SSI (p = 0.925) or MRSA infection at the surgical site (p=0.329).

Conclusion: Our study has shown that post-operative decolonisation with mupirocin did not confer any protective effect against post-CABG SSI. In fact, our results show that this therapeutic measure may promote MRSA resistance to mupirocin. With recent reports suggesting this possibility, it is important to place emphasis on other infection control measures in preventing cross-infection.

SYMPTOM DRIVEN INVESTIGATION FOR CARDIAC DISEASE IN YOUNG INDIVIDUALS: A COUNTER-INTUITIVE STRATEGY Hughes K Background: Sudden cardiac death (SCD) in the young is a devastating event and policy issue of increasing concern.

Currently, testing for cardiac conditions that may lead to SCD outside elite athletes is only indicated in the presence of abnormal history or physical examination. However, it is known that around 80% of SCD victims are asymptomatic prior to their death. This study aimed to assess the effectiveness of H+P in detecting potentially sinister cardiac disease in young individuals.

Methods: Between 2011-2012, 18,137 individuals aged 14-35 years underwent cardiovascular screening with a health questionnaire, physical examination (H+P) and ECG interpreted in line with the 2010 ESC recommendations.

Individuals requiring further evaluation were referred to secondary care. Outcomes from second-tier investigations were available in 75% of referred individuals.

Results: 2,786 (15%) athletes undergoing pre-participation screening and 15,351 (85%) apparently healthy nonathletes were evaluated. 98 (3.5%) athletes and 590 (3.8%) non-athletes required further investigation. The predominant reason for referral in both groups was an ECG abnormality. The prevalence of sinister cardiac diseases was similar in both groups (approx. 0.3%). An abnormality in H+P detected a sinister cardiac disease in only 1 of the 8 athletes (13%) and in 3 of the 26 (12%) non-athletes.

Conclusions: Our findings show that H+P is a very poor predictor of cardiac disease with a sensitivity of 12-13%. As an abnormal H+P is currently requisite for further investigation of cardiac disease, policy may need to change to improve the cost-effectiveness of detection of SCD-associated conditions and reduce SCD mortality irrespective of athletic status.

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Supplement GENETIC SCREENING OF GATA5 IN PATIENTS WITH BICUSPID AORTIC VALVE Solberg Y Background: Bicuspid aortic valve (BAV) is one of the most prevalent congenital heart defects and occurs in around 12% of all live births. It is associated with adverse cardiovascular outcomes and is accountable for more morbidity and mortality than all other congenital heart defects combined. BAV is highly heritable, however, the underlying pathophysiology is poorly understood. Animal models and genetic studies have attempted to identify a genetic pathway involved in the formation of BAV and a number of genes involved in the development of the heart, have been identified. These include: FBN1, TGFBR2, NOTCH1 and GATA5. Although only the NOTCH1 gene has been associated to cases, increasing evidence suggests that GATA5 is a potential gene candidate underlying this cardiac malformation.

Aim: The aim of this study was to establish whether genetic mutations in GATA5 are associated with the development of BAV. Methods: Thirty patients with BAV were included in the study. To determine the presence of any genetic mutations in the GATA5 gene, a twenty millilitres venous blood sample was collected from the patients, which was used for genomic DNA analysis.

Results: Out of the thirty patients, two mutations were identified in GATA5, one in exons-2 (c.56C>G, p.Ser19Trp) and the other one in exon-7 (c.1173G>T, p.Trp391Cys).

Conclusion: The study was able to establish an association of GATA5 with our cohort of isolated BAV cases. Our findings corroborate that GATA5 plays an essential part in vulvogenesis, as previously demonstrated in the GATA5 mouse model study

ELECTROCARDIOGRAPHICAL ASSESSMENT OF PATIENTS WITH BRUGADA SYNDROME Wasim S Background: The presence of Brugada Syndrome (BrS) predisposes patients to sudden arrhythmic death syndrome.

Diagnosis of this condition relies heavily on the electrocardiogram (ECG). Despite recent advances, no effective stratification technique to-date exists in identifying those at greater risk, with the only effective treatment being an Implantable Cardiovertor Defibrillator (ICD).

Methods: Continuous digital ECG parameters were analysed for 128 Brugada Syndrome patients, 69 male (mean age 44.9 ± 16.1) and 59 female (mean age 42.3 ± 16.0). Patients with positive ajmaline testing for BrS over a 10 year period were included. The ECG parameters were compared between the following subgroups: genetic linked BrS mutations (absent vs present), symptomatic patients (absent vs present) and sex (male vs female).

Results: Males have a higher J point elevation mean compared to females (p<0.001). A statistical difference also exists between the sexes with regard to QRS duration (p = 0.001), in addition to the duration of the Type 1 Brugada Syndrome pattern displayed (p<0.001). No difference between symptomatic and asymptomatic patients exists in regards to J point elevation. Patients with a BrS genetically linked mutation have on average higher mean values for their ECG parameters, although results are not statistically significant. Moreover, there is a positive association for the maximum QTc value in all patients P<0.005.

Conclusion: The results from this study are promising, showing potential for future eligibility criteria for ICD implantation in those at risk of BrS and Sudden Arrhythmic Death Syndrome. Future work must be undertaken to exactly quantify those in greater need of treatment.

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Supplement A RETROSPECTIVE STUDY OF THE EARLY OUTCOME OF CEREBROVASCULAR ACCIDENT IN REDO AORTIC VALVE REPLACEMENT: TAVI AND CONVENTIONAL AT KING'S COLLEGE HOSPITAL Singh K, Castle D, Deshpande R Background: Aortic stenosis is the most frequent valvular heart disease in Europe and North America with surgical aortic valve replacement (SAVR) being the definitive treatment. The need for redo aortic valve replacement has increased over the past decade due to the limited durability of prosthetic valves combined with an aging population.

These patients often have a higher risk for a second surgical procedure and so could benefit from valve-in-valve Transcatheter aortic valve replacement (ViV TAVI) instead.

Aims: To compare the 30 day outcome of cerebrovascular accident (CVA) in patients undergoing redo SAVR and ViV TAVI at Kingâ&#x20AC;&#x2122;s College Hospital.

Methods: Patients older than 70 years who underwent either redo SAVR or ViV TAVI were identified using the TAVI and cardiac surgery databases. All patients had 30 day follow up and the in-hospital and 30 day outcomes were compared.

Results: A total of 19 patients were identified with a mean age of 79.5 years. There was no 30 day mortality. 11% of redo SAVR patients and 20% of ViV TAVI patients had a CVA (P>0.05). Patients undergoing redo SAVR had a 26.3% longer hospital stay.

Conclusion: ViV TAVI is a good alternative for patients at a high risk from redo SAVR as the complications rate was comparable between the two groups. The increased incidence of CVA with ViV TAVI was not statistically significant.

More work is needed on the long term quality of life and durability of the valves between the two patient groups.

CLINICAL MARKERS OF CORRELATION BETWEEN AGEING AND HYPERTENSION Khoshimova N, Usmonova Z, Muinjanov B Background and Aims: Non-invasive measures of large artery structure and function -- such as aorto-femoral pulse wave velocity (PWV), arterial compliance (AC) and common carotid intima-media thickness (CCA IMT) -- can predict new CV events, independent traditional CV risk factors. However, neither their relations with aorta properties not the effects of aging and hypertension on those relations are yet clear.

Methods and Results: 40 subjects (18 M, 22 F; mean age 60+/-16 years, range 21-83 years) free of any acute CV event, valve disease or atrial fibrillation, were studied. Aortic IMT, diastolic diameter (D) and distensibility (Dist) were measured by transesophageal echocardiography at three different levels: ascending aorta (AA), distal aortic arch (Aarc) and descending aorta (DA). PWV was measured by Complior. AC was measured as the ratio of stroke volume to pulse pressure. CCA IMT was measured by ultrasonography in diastole. The Dist, IMT, and D of each aortic segment were introduced alternatively into the regression models.

Conclusions: Non-invasive measures of large artery structure and function are not equivalent with respect to their relations with aortic properties, so that AC seems to reflect proximal aorta function, PWV proximal aorta structure and distal aorta function, and CCA IMT distal aorta structure. Future studies are needed to confirm whether these relations identify a common pathogenetic mechanism, which may be the target for new therapeutic strategies.

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Supplement INCIDENCE OF VALVULAR HEART DISEASE AFTER TREATMENT OF PARKINSON`S DISEASE Muinjonov B Background: Recently, the increased prevalance of cardiac valvular disease in patients treated with Dopamine Agonists (DAs) for prolactinoma has raised concerns about the safety of this drug in patients with Parkinson`s disease.

Aim: The objective of this study was to define the actual effect of Parkinson`s disease treatment on cardiac tissue.

Methods: We evaluated 40 patients with Parkinson`s disease. All patients were treated with the ergot derivative dopamine agonists: cabergoline, levodopa and MAO-B inhibitors (selegiline (Eldepryl, Zelapar) and rasagiline (Azilect)). All patients were followed for a mean of 61 months. Pretreatment echocardiographic examination revealed valvular pathology only in 3 patients, which were excluded.

Results: Based on strikingly similar echocardiographic and histopathoogical features, we detected that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions.

Noninflammatory fibrotic degeneration of cardiac valves (multiple) was defined in 31 patients (p<0.001). . In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves.

Conclusion: These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome.

THERAPEUTIC APPLICATION OF POLYMERSOME NANOPARTICLES AS DELIVERY VEHICLES FOR CARDIOPROTECTIVE MOLECULES Radenkovic D, Davidson SM, Yellon DM Background: Coronary heart disease is the major cause of death around the world and novel therapeutic strategies are required to reduce the damage to the myocardium after an ischaemic episode. Polymersomes are synthetic amphiphilic nanoparticles, which received enormous attention in recent years due to their marvellous ability to act as various drug carriers.

Aims: The aim of this project was to test polymersomes in adult rat ventricular cardiomyocytes (ARVC) for the first time, by quantifying their uptake and carrying out toxicity experiments.

Methods: Two types of polymersomes were studied: poly 2-methacryloyloxy ethyl-phosphorylcholine-co-poly2diisopropylamino ethyl methacrylate (PMPC-PDPA) and poly oligo-ethylene glycol methacrylate (POEGMA-PDPA), tagged with different fluorescent dyes. Their uptake into ARVC was investigated using confocal microscopy. Toxicity was tested by measuring the survival of ARVC treated with polymersomes after 4h, 24h and 48h, by staining with a vital dye and imaging by fluorescent microscopy.

Results: PMPC-PDPA polymersomes were rapidly taken up into cardiomyocytes and localized intracellularly after 15 min at 37°C. In contrast, the fluorescence signal of POEGMA-PDPA polymersomes was only observed around the sarcolemma and they remained located at the cell membrane. Both polymersomes were found to be non-toxic for cardiomyocytes. Maximal increase in cell death occurred after 4h and reached 20%. However up to 40% cell death was seen with higher PMPC-PDPA polymersome concentrations.

Conclusion: PMPC-PDPA polymersomes have the potential to deliver cardioprotective miRNAs intracellularly. On the other hand, it may be possible to coat POEGMA-PDPA with cardioprotective ligands such as HSP70 or SDF-1Îą. Future experiments will investigate these possibilities.

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Supplement PREVALENCE AND LENGTH OF HOSPITAL STAY IN PATIENTS WITH AORTIC VALVE DISEASE IS LOWER AMONGST SOUTH ASIANS Klimach S, Gollop ND Background: Aortic Stenosis (AS) is the commonest valvular lesion among European and American populations with calcific AS present in 2-7% aged >65 and severe stenosis present in 3% of >75 year olds [1]. Ethnicity is thought to influence severity and progression of AS. There are limited studies investigating the prevalence and severity of AS among Asian patients.

Aim: To determine the prevalence and length of hospital stay (LOS) and its predictors among black and ethnic minority patients with AS in the North West of England.

Methods: Patients with a diagnosis of AS were identified using an anonymised database of admissions collected from 7 hospitals between January 2000 and March 2013. Ethnic minority groups were defined as South Asians, AfroCaribbean, Oriental and Mixed with Caucasian used as a reference. Multi-variant Logistic regression, with adjustment for age, gender, type of admission and comorbidities was performed. Data for prevalence and LOS was analysed.

Results: 4764 AS admissions occurred during the study period. Patients defined as ethnic minorities constituted 3.2%.

Patients of South Asian descent admitted with AS had significantly shorter adjusted LOS (P<0.05) and were significantly younger (mean age 56 vs 73 years). The prevalence of AS was also lower in this group.

Conclusion: Previous work has suggested that ethnic minorities receive less support upon discharge and may be discharged prematurely. Further research is needed to identify the cause(s) and potential solution(s) to this health inequality.

PROLONGED LENGTH OF HOSPITAL STAY IN FAR-EAST ASIAN AND AFRO-CARIBBEAN PATIENTS WITH CARDIOMYOPATHY Klimach S, Gollop ND Background: Cardiomyopathies are a heterogeneous group of disorders characterised by abnormal myocardial structure potentially leading to heart failure. Cardiomyopathies accounted for 8741 admissions in 2011/12, often with prolonged length of stay (LOS). The effect of ethnicity on LOS in patients with cardiomyopathy is unknown.

Aim: To determine the role of ethnicity in determining LOS in cardiomyopathic patients presenting to hospitals in the North West of England.

Methods: Cardiomyopathic patients were identified from a database of adult admissions across 7 hospitals between January 2000 and March 2013 using the Algorithm for Comorbidities Associations, Length of Stay and Mortality.

Logistic regression, with Caucasian as the reference group, was performed with adjustment for age, gender, comorbidities and admission type. Only non-identifiable patient data were obtained in accordance with local research ethical policy. Ethnic groups were defined as Caucasian, South Asian, Afro-Caribbean, Far-Eastern and Mixed.

Results: 1884 patients with cardiomyopathy were identified. Within the Caucasian group, the majority were male (70.1%) and was similar for other groups with the exception of ‘mixed ethnic’ (55.6% female). Patients from ‘mixed ethnic’ group appeared to present younger (mean age 44 vs 56.7years), have fewer co-morbidities (55.6 vs 66%) and present as emergencies (55.6 vs 78.8%), these differences did not affect LOS (7.16 vs 6.31 days). Far-East Asian and Afro-Caribbean ethnic groups had longer LOS after adjustment.

Conclusion: There is limited data to suggest why some groups had greater LOS. Prospective studies to identify causative factors and facilitate improved, tailored care are required.

Autumn 2015

British Undergraduate Cardiovascular Journal

66

Supplement DNACPR (DO NOT ATTEMPT CARDIO-PULMONARY MISUNDERSTOOD BY SOME HEALTHCARE PROVIDERS? Alshamkhani W, Gaqmage P, Pradhan M

RESUSCITATION)

TERM,

IS

IT

Background: A DNACPR order only applies to the decision to withhold CPR in the event of a cardiopulmonary arrest and should not impact other aspects of care. However, some believe that diagnostic tests, procedures and other important decisions in patients care should not be commenced when a patient is ‘DNACPR.’ This may be due to misunderstanding the scope of DNACPR orders by some providers. A survey was run to assess the understanding of the term DNACPR among health care professionals working at one of the York Teaching Hospitals.

Methods: Using a cross-sectional study model, a standard questionnaire was designed and 100 copies were distributed among health care professionals of the following grades: Consultants, SPR, SHO, FYT, and Nurses. Responses were collected on the same day. The results, then, were analysed on an excel spreadsheet.

Results: Correct responses: Consultants 8/14 (57%), SPR 5/13(38.46%), SHO 7/20 (35%), FYT 4/7(57.1%) and Nurses 19/46 (41.3%).

Outcome: Following the survey, health care providers were educated through seminars presented in the journal club, grand rounds, and wards. The same survey was repeated after 4 months. Results showed significant improvement among all grades: Consultants 9/11 (81.8%), SPR 7/13 (53%), SHO 8/16 (50%), FYT 17/20 (85%) and Nurses 24/40 (60%).

Conclusion: Patients with DNACPR often receive less care. It is commonly misinterpreted as not for medication or only for comfort care/ end of life care. There seems to be a significant degree of misunderstanding among all grades.

Continuous medical education about the meaning of DNACPR is crucial to achieving a better quality of patient care.

SPATIAL HETEROGENEITIES OF GAP JUNCTIONS EXIST WITHIN THE NATIVE, NONREMODELLED LEFT ATRIUM Eichhorn C, Chowdhury R, Debney MT, Qureshi NA, Roney CH, Peters NS, Ng FS Background: Recent clinical studies have shown that focal drivers contribute to maintaining atrial fibrillation (AF), also demonstrating that these drivers (rotors) prefer to anchor to specific sites in the left atrium (LA).

Aims: To assess our hypothesis of whether any regional heterogeneities in fibrosis and gap-junctional cell-to-cell coupling exist, and thus may contribute towards determining the location of these drivers in the LA, regional analysis of cardiac gap-junctions and fibrosis in the canine LA were performed.

Methods: Five explanted canine left atria were divided into nine equal areas (figure) and rapidly frozen.

Immunohistochemistry of connexin 40 and 43 were performed and the heterogeneity of connexin 40, the colocalisation of connexin 40 and 43 in intercalated disks, the size of en-face intercalated disks and the proportional occupation by connexin 43 of these en-face disks were calculated. Using autofluorescence, we analysed the total amount of fibrosis and the proportion of interstitial and scar fibrosis for each of the regions.

Results: Gap-junctional disk size was increased in the mid-posterior LA wall compared with other regions (p = 0.03; 1,2,3 — septal: mean = 47.57 ± 33.31 µm2; 4,5,6 — posterior: mean = 90.38 ± 87.69 µm2; 7,8,9 — anterior: mean = 87.30 ± 39.56µm2). No other regional differences were detected.

Conclusion: Immunohistochemistry showed detectable differences in the gap-junctional disk size between regions in the native, non-remodelled LA. Correlating structural data above with optical mapping data of AF in these preparations may help to find spatial structural heterogeneities that contribute in forming the drivers in AF.

Autumn 2015

British Undergraduate Cardiovascular Journal

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Supplement PREVALENCE AND TRENDS CARDIOMYOPATHY PATIENTS

OF

PSYCHIATRIC

CO-MORBIDITIES

AMONG

UK

Klimach S, Gollop ND Background: Psychiatric disorders commonly occur with significant medical conditions, including cardiomyopathies.

The cardiomyopathies are a heterogeneous group of disorders characterised by abnormal myocardial structure, often resulting in heart failure. A number of studies have identified increased levels of anxiety and depression in patients diagnosed with hypertrophic cardiomyopathy. However the patterns of psychiatric co-morbidity among the United Kingdom’s (UK) cardiomyopathic cohorts remains unknown.

Aim: To determine the patterns and trends in psychiatric co-morbidities among cardiomyopathic patients in the North West of England.

Methods: Cardiomyopathic patients were identified using an anonymised database of admissions collected from 7 hospitals between January 2000 and March 2013. Psychiatric co-morbidities within the cohort were identified and the data analysed investigating comorbidities, associations, length of stay and mortality.

Results: 1884 patients with cardiomyopathy were identified with a female to male ratio of 3.3:1. Mean age at diagnosis was 56.7 years, the majority being of Caucasian origin (83.3%). Of these 288 (15.3%) had a psychiatric condition during the period. Diagnoses included alcohol abuse (6.1%), depression (4.5%) and anxiety disorders (1.2%). The prevalence of psychiatric disorders among the cohort increased during the period from 12.9% for 2000-2002 to 19.01% for 20092013 with depression demonstrating the greatest individual increase (2.64% to 6.73%).

Conclusion: The prevalence of psychiatric co-morbidities among our cohort was lower than previously published.

However, we suggest psychiatric co-morbidities are significant risk factors for morbidity and mortality in cardiomyopathic patients, thus warrant lower thresholds of identification and treatment.

CAPILLAROSCOPIC INDICES IN YOUNG INDIVIDUALS WITH HIGH NORMAL ARTERIAL PRESSURE Koutsogiannis M, Nikolova J, Nikolova P Introduction: Microcirculation would be a focus of investigation in many cardiovascular disorders.

Background: Changes in microcirculation to be found out in high normal arterial pressure (HNAP).

Materials and methods: An inquiry was carried out among 116 students of medicine (60 men and 56 women) at age of 23 ± 1.3 years, registering the percentage of predisposing factors for hypertension. Anthropometric and arterial pressure (AP) value's measurements were carried out too. The followed up groups were two: control one with optimal AP (≤120 for systolic and ≤80 mm Hg for diastolic), and such with HNAP (130-139 for systolic and/or 85-89 mm Hg for diastolic one). AP values – systolic, diastolic and mean were registered according to the rules and monitored by CNAP monitor (Biopac Instruments, USA). The native capillaroscopy was carried out by capillaroscope JH1005, PRC. Arterial, venous and top loop's diameter, loop's length, arterial/venous diameter ratio and the number of abnormal capillaries were examined.

Results: 42.6% (75% men and 25% women) of all the investigated are with HNAP. The abnormal consumption of salt and fats in HNAP individuals is 79 %. Arterial venous ratio is reduced significantly in HNAP group - 0.53 ± 0.18 vs 0.68 ± 0.2 in the controls. The percentage of abnormal capillaries in HNAP group is increased compared to the controls (22.34 ± 13.07 vs 13.75 ± 9.8). The number of capillaries, functioning do not differ in both groups.

Conclusion: The microcirculatory changes in HNAP group at this age are rather functional, concerned probably with vessel spasm.

Autumn 2015

British Undergraduate Cardiovascular Journal

68

Supplement B-TYPE NATRIURETIC PEPTIDE IS AN INFORMATIVE TOOL IN THE EARLY MANAGEMENT OF ST ELEVATION ACUTE CORONARY SYNDROME Rakhimov K Background: In acute coronary syndrome patients, serial BNP measurements accurately predict the risk of death or congestive heart failure. However, the relationship of BNP to invasive or non-invasive strategy in ST elevation acute coronary syndrome (STE-ACS) patients remains unclear.

Methods: 59 STE-ACS patients presenting within 3 hours of symptom onset were included in the prospective study.

Patients underwent either Primary PCI (33 subjects) or Fibrinolysis (26 subjects). The primary end point was composite of death, shock, congestive heart failure, re-infarction up to 14 days. Baseline, Day 3 and Day 7 BNP were available for all patients. Statistical analysis was performed by means of T-test, chi-square test, Kaplan-Meier survival analysis, a p<0.05 was considered statistically significant.

Results: Increasing baseline BNP levels were associated with higher risk of primary end point (p<0.001). At 14 days, primary end point occurred in 9% patients who were assigned to Primary PCI and 19,2% in Fibrinolysis (relative risk in the Primary PCI group, 0,47; p=0.004). Median BNP level declined significantly after Primary PCI compared to Fibrinolysis (P<0.01) at Day 7.

Conclusion: Baseline and subsequent BNP explains lower event rates with Primary PCI in STE-ACS patients. Thus, BNP may be used as an informative tool in the early management of STE-ACS.

SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE: ARE PATIENTS BEING APPROPRIATELY MANAGED? Brito-Mutunayagam S, Armstrong K Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Despite this, recent data suggests that there is considerable underutilization of well-established cardio-protective medications for secondary prevention of CVD in this patient cohort.

Aims: To investigate adherence to The Renal Association recommendations for secondary prevention of CVD in CKD patients utilising aspirin, ACE inhibitors, beta-blockers and statins, unless contraindicated.

Methods: The clinic letters of 150 patients attending a general nephrology clinic over a 6 month period at Southampton Hospital were reviewed. Patients with CKD (any stage) were included if they had a previous cardiac event (described as acute coronary syndrome) that required hospitalisation and/or cardiac intervention. The electronic discharge summary post-cardiac event (time-point 1) and latest clinic letter at time of audit (time-point 2) were reviewed to identify utilisation of the recommended medications at the 2 time-points.

Results: 38 patients met the inclusion criteria. Of these, 36 (95%) were discharged on all 4 recommended drugs postcardiac event. At time-point 2, 28 (74%) patients were on all the recommended drugs and of the 26% of patients not on all drugs, the majority were not prescribed statins. Contraindications and side-effects were taken into account.

Conclusion: Adherence to current recommendations is excellent immediately post-cardiac event, however there is some loss of medication compliance between time-point 1 and 2. Further efforts should be made to educate primary and secondary care providers regarding the importance of optimising use of cardio-protective medications in this highrisk population.

Autumn 2015

British Undergraduate Cardiovascular Journal

69

Supplement A REVIEW TO DETERMINE THE EFFECTIVENESS OF NOVEL ORAL ANTICOAGULANTS COMPARED TO WARFARIN AT DECREASING ALL-CAUSE MORTALITY IN PATIENTS WITH ATRIAL FIBRILLATION Quinn L, Khaing P, Lee J, McWilliam S, Shaheen H Background: Atrial Fibrillation (AF) is a common cardiac arrhythmia associated with increased risk of stroke.

Anticoagulants are indicated to decrease the risk of stroke in patients with AF. Warfarin has previously formed the mainstay of treatment however the evidence base to support use of the Novel Oral Anticoagulants (NOAC) as an alternative to warfarin therapy is increasing.

Aims: To determine the difference in all-cause mortality between patients with AF receiving NOAC therapy compared to warfarin therapy.

To compare all-cause mortality in patients with AF receiving NOAC or warfarin therapy, who have also undergone cardiac valve surgery.

Methods: Bibliographical databases (MEDLINE, EMBASE, PubMed and Cochrane library) were screened for guidelines, evidence summaries and systematic reviews. 34 full text articles were assessed for eligibility of which 14 were included in this review.

Results: Treatment with NOAC, to include Apixaban, Rivaroxaban, Dabigatran etexilate and Edoxaban, resulted in a Relative Risk reduction ranging from 9 to 12%, depending on the meta-analysis, all with reasonably narrow confidence intervals. All Systematic reviews, except two, found this RR reduction to be statistically significant (p<0.05).

Treatment with NOAC led to an increased risk of bleeding in patients with AF who had undergone cardiac valve surgery compared to warfarin therapy.

Conclusion: NOAC as a class decrease risk of all-cause mortality compared to warfarin. Applicability of the studiesâ&#x20AC;&#x2122; findings to the general target population carries some limitations but NOAC should nevertheless be considered as an alternative to warfarin. NOAC however are unsuitable for patients with AF who have undergone cardiac valve surgery.

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British Undergraduate Cardiovascular Journal

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