Asian journal of clinical cardiology october december 2014 by IJCP

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In This Issue — Transient Ischemic Attack: Part I. Diagnosis and Evaluation — Floating Bodies in the Left Atrium by 2D-echo: A Differential Diagnosis — Status of HDL in Current Scenario — Complete Heart Block in Rheumatoid Arthritis — Superficial Brachial Artery: Its Embryological and Clinical Significance

Volume 17, Number 2, October-December 2014 Pages 81-120

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Asian

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CLINICAL CARDIOLOGY

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Volume 17, Number 2, October-December 2014

Dr Deepak Chopra Chief Editorial Advisor

Padma Shri, Dr BC Roy National and National Science Communication Awardee Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

from the desk of the group editor-in-chief 86 Alternative Therapies Lower BP

KK Aggarwal

Dr Sameer Srivastava Editor, AJCC Assistant Editors: Dr Nagendra Chouhan, Dr Dharmendar Jain

AJCC Specialty Panel Advisory Board

International Dr Fayoz Shanl Dr Alain Cribier Dr Kohtian Hai Dr Tanhuay Cheem Dr Ayman Megde Dr Alan Young Dr Gaddy Grimes Dr Jung bo Geg Dr Rosli Mohd. Ali Dr S Saito National Dr Mansoor Hassan Dr RK Saran Dr SS Singhal Dr Mohd. Ahmed

Dr PK Jain Dr PK Gupta Dr Naresh Trehan Dr Sameer Shrivastava Dr Deepak Khurana Dr Ganesh K Mani Dr K S Rathor Dr Rajesh Kaushish Dr Sandeep Singh Dr Yugal Mishra Faculty Dr GK Aneja Dr Ramesh Thakur Dr Balram Bhargava Dr HK Bali Dr HM Mardikar

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IJCP Editorial Board

Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

review article 87 Transient Ischemic Attack: Part I. Diagnosis and Evaluation

B. Brent Simmons, Barbara Cirignano, Annette B. Gadegbeku

Clinical Review 92 Floating Bodies in the Left Atrium by 2D-echo: A Differential Diagnosis

S Pratheep Kumar, N Chidambaram, R Umarani, E Balasubramanium, Gauri Shankar

clinical study Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

96 Status of HDL in Current Scenario

Geetha Subramaniyan, Dharmendra Jain, Balaji Lohiya Neeraj Kumar

Printed at Entire Printers Nampally, Hyderabad ÂŠ Copyright 2014 IJCP Publications Ltd. All rights reserved. The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

case report 104 Complete Heart Block in Rheumatoid Arthritis

Kavina Marian Fernandes, Vivek GC

111 Superficial Brachial Artery: Its Embryological and Clinical Significance

Meenakshi Khullar

Note: Asian Journal of Clinical Cardiology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

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Alternative Therapies Lower BP A group of experts has reviewed all the existing studies and concluded that indeed there are alternative treatments for lowering blood pressure (BP) - with aerobic exercise leading the pack as far as strong evidence goes. Other alternative treatments - namely isometric handgrip and dynamic resistance exercises and guided breathing - also got high grades when it came to reducing high BP in some patients, according to a scientific statement from the American Heart Association published online in the journal Hypertension. “The evidence is not as strong for transcendental meditation and acupuncture, but they may help as well,” said co-senior author Sanjay Rajagopalan, MD, Professor of Cardiovascular Medicine at Ohio State University School of Medicine in Columbus. For the report, an expert panel headed by the University of Michigan’s Robert D. Brook, MD, reviewed 1,000 studies published from 2006 to 2011. They divided the studies into three major classes of alternative treatments: Behavioral therapies, noninvasive procedures and devices, and exercise. The panel did not review dietary and herbal treatments. Based on the level of evidence, they gave each an “A,” “B,” or “C” recommendation - with “A” being the highest - for implementation into clinical practice. The panel found: ÂÂ Exercise-based regimens did the best overall, with dynamic aerobic exercises getting an “A” class of recommendation, with a level of evidence of I, the highest possible. ÂÂ Dynamic resistance exercises got a “B” and isometric handgrip exercises got a “C” grade, with levels of evidence of IIA and IIB, respectively. ÂÂ Still, 4 weeks of isometric hand grip exercises resulted in some of the most impressive improvements in several studies - a 10% drop in systolic and diastolic BP. However, isometric exercise should be avoided among people with severely uncontrolled hypertension (180/110 mmHg or higher). ÂÂ As for noninvasive procedures or devices, device-guided breathing got a “B” with a level of evidence of II. Deviceguided slow breathing proved most effective in lowering BP when performed for 15-minute sessions 3-4 times a week. ÂÂ Acupuncture also got a “B,” but its level of evidence was III, meaning no benefit. ÂÂ Among behavioral techniques, transcendental meditation and biofeedback both received “B” grades, with IIBs for levels of evidence. Yoga got a C, with level of evidence of III, or no benefit, as did other meditation techniques. ÂÂ The alternative approaches that work reduce systolic BP by only 2-10 mmHg; whereas standard doses of a BP-lowering drug reduce systolic BP by about 10-15 mmHg. ÂÂ Alternative approaches are best for patients with BP levels over 120/80 mmHg who can’t tolerate or don’t respond well to standard medications.

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

review article

Transient Ischemic Attack: Part I. Diagnosis and Evaluation B. BRENT SIMMONS, BARBARA CIRIGNANO, ANNETTE B. GADEGBEKU

Abstract Transient ischemic attack is defined as transient neurologic symptoms without evidence of acute infarction. It is a common and important risk factor for future stroke, but is greatly underreported. Common symptoms are sudden and transient, and include unilateral paresis, speech disturbance, and monocular blindness. Correct and early diagnosis of transient ischemic attack versus mimicking conditions is important because early interventions can significantly reduce risk of future stroke. Nonspecific symptoms and gradual onset are more likely with mimics than with true transient ischemic attacks. Transient ischemic attacks are more likely with sudden onset, focal neurologic deficit, or speech disturbance. Urgent evaluation is necessary in patients with symptoms of transient ischemic attack and includes neuroimaging, cervicocephalic vasculature imaging, cardiac evaluation, blood pressure assessment, and routine laboratory testing. The ABCD2 (age, blood pressure, clinical presentation, diabetes mellitus, duration of symptoms) score should be determined during the initial evaluation and can help assess the immediate risk of repeat ischemia and stroke. Patients with higher ABCD2 scores should be treated as inpatients, whereas those with lower scores are at lower risk of future stroke and can be treated as outpatients.

Keywords: Transient ischemic attack, early diagnosis, urgent evaluation, stroke

ver the past 10 years, transient ischemic attack (TIA) has been redefined multiple times to reflect the transient nature of not only the symptoms, but also cerebral ischemia. The classic definition for TIA of a sudden, focal neurologic deficit for less than 24 hours was established in the 1960s and was the accepted definition for 40 years.1,2 In 2002, the TIA Working Group redefined TIA as brief neurologic dysfunction with symptoms typically lasting less than one hour, without evidence of acute infarction.1 This definition was well received; however, it has been shown that no time cutoff can reliably predict if cerebral ischemia is reversible.3 This led to the 2009 revision by the American Heart Association/American Stroke Association (AHA/ASA), which now defines TIA as a transient episode of neurologic dysfunction caused by focal cerebral, spinal cord, or retinal ischemia, without acute infarction.2 A lack of evidence of infarction on magnetic resonance imaging (MRI) in patients who have symptoms consistent with cerebral ischemia

B. BRENT SIMMONS, MD, FAAFP, is an assistant professor in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine in Philadelphia, Pa. BARBARA CIRIGNANO, MD, is a resident in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine. ANNETTE B. GADEGBEKU, MD, is an assistant professor in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine. Source: Adapted from Am Fam Physician. 2012;86(6):521-526.

distinguishes TIA from minor stroke. This article, part I of a two-part series, focuses on the diagnosis of TIA. Part II discusses treatment after TIA.4

Epidemiology Using imaging results instead of a time cutoff to diagnose TIA will impact interpretation of future and past epidemiologic data on incidence and prevalence of TIA. One study evaluated MRI in patients with TIA based on the classic definition and found that 33 percent had evidence of cerebral infarction.5 Under the new definition, those with evidence of infarction should be redefined as having a stroke, leading to a lower overall incidence of TIA.5 However, TIA is likely underreported. In a telephone survey, 2.3 percent of individuals reported that they were told by their physician that they had a TIA, but an additional 3.2 percent of patients reported having symptoms consistent with TIA but never sought medical attention.6 The overall incidence of TIA is estimated to be 200,000 to 500,000 cases per year.2 TIA is a major risk factor for future ischemic stroke, with the greatest risk occurring in the period immediately after TIA.7-9 The odds ratio for ischemic stroke following TIA is 30.4 during the first 30 days, 18.9 at one to three months, 3.16 at four to six months, and 1.87 after five years.7

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Review article TIA Mimics

Table 1. Clinical Symptoms of TIA Mimics

One of the greatest challenges family physicians face when evaluating possible TIA is distinguishing true TIA and ischemic events from TIA mimics. Physician accuracy in determining this distinction in the outpatient primary care setting historically has been poor, and a study showed that even stroke-trained neurologists have a fair amount of disagreement when diagnosing TIA.10,11

Clinical symptom

Correct and early diagnosis of TIA versus mimics is critical because early interventions (e.g., antiplatelet agents, statin therapy, blood pressureâ&#x20AC;&#x201C;lowering therapy, anticoagulation when appropriate) can lead to an 80 percent reduction in risk of recurrent ischemic events.12 The most common TIA mimics are seizures, migraines, metabolic disturbances, and syncope.10,13,14 Mimics are more likely with gradual onset of symptoms and with nonspecific symptoms (Table 113), such as memory loss or headache.13-15 TIA is more likely with sudden onset, unilateral paresis, speech disturbance, or transient monocular blindness.13,14,16 Table 2 shows which symptoms are more likely with mimics versus true TIA.13,14 A complete history and physical examination are necessary to correctly diagnose TIA in the outpatient setting.

Presentation History At initial presentation, a comprehensive history should include identification of symptoms consistent with a focal neurologic deficit, and the timing of symptom onset and resolution. This is crucial because symptoms often resolve by the time of presentation. Attention should also be given to the presence or absence of nonspecific symptoms common in TIA mimics. Witnesses of the event can also be helpful in describing symptoms not perceived by the patient. The history should elicit risk factors associated with ischemic disease, such as cigarette smoking, obesity, diabetes mellitus, dyslipidemia, and hypertension, as well as personal or family history of hypercoagulability disorders, stroke, or TIA. Symptoms of TIA occur suddenly and include a neurologic deficit or loss of function.17 It is imperative to ask about recurrent symptoms of TIA because recent, recurrent TIA (crescendo TIA) requires urgent evaluation. Mimics are more common in patients with a history of cognitive disorders, seizures, postural hypotension, and vertigo.10,14 Symptoms that generally are not suggestive of TIA include generalized weakness, dizziness, confusion, loss of consciousness, tinnitus, dysphagia, scotoma, headache, eye pain, and chest pain.17,18 It is important to note that the presence of common mimic symptoms does not exclude TIA from the

Odds ratio of a TIA mimic

Memory loss

9.17

Headache

3.71

Blurred vision

2.48

Unilateral paresis

0.35

Transient monocular blindness

0.15

Diplopia

0.14

Note: The higher the odds ratio is above 1.0, the more likely the symptom is due to a TIA mimic; the lower the odds ratio is below 1.0, the more likely the symptom is due to a TIA or stroke. TIA = Transient ischemic attack. Information from reference 13.

Table 2. Clinical Symptoms of TIA vs. TIA Mimics Clinical symptom

Percentage of TIA mimics*

Percentage of TIAs*

Unilateral paresis

29.1

18 to 26

2 to 12

14.6 to 23

2 to 36

Memory loss/cognitive impairment Headache Blurred vision

21.8

5.2

Dysarthria

12.7

20.6

Hemianopia

3.6

Transient monocular blindness

Diplopia

4.8

TIA = Transient ischemic attack. *When clinical symptoms are present at presentation. Information from references 13 and 14.

diagnosis; however, mimics should be considered in the absence of concurrent focal deficits. Table 3 presents the differential diagnosis of TIA.

Physical Examination A clinical presentation that demonstrates motor weakness and speech deficits is highly suggestive of TIA, and also may be associated with a higher risk of having an early stroke after TIA.19 The physical examination should include measurement of vital signs, a cardiovascular examination, and a comprehensive neurologic examination. Blood pressure is commonly elevated with cerebral ischemia and should be assessed, along with an evaluation for carotid bruits or cardiac arrhythmias. Careful attention should be given to focal neurologic deficits and their represented neurovascular distribution.

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Review article Table 3. Differential Diagnosis of Transient Ischemic Attack Diagnosis

Key findings

Brain tumor

Severe unilateral headache with nausea and vomiting

Central nervous system infection (e.g., meningitis, encephalitis)

Fever, headache, confusion, neck stiffness, nausea, vomiting, photophobia, change in mental status

Falls/trauma

Headache, confusion, bruising

Hypoglycemia

Confusion, weakness, diaphoresis

Migraines

Severe headaches with or without photophobia, younger age

Multiple sclerosis

Diplopia, limb weakness, paresthesia, urinary retention, optic neuritis

Seizure disorder

Confusion with or without loss of consciousness, urinary incontinence, tongue biting, tonicclonic movements

Subarachnoid hemorrhage

Severe headache with sudden onset and photophobia

Vertigo (central or peripheral)

Generalized dizziness and diaphoresis with or without hearing loss

Cranial nerve, somatic motor strength, somatic sensory, speech and language, and cerebellar system testing should be performed. The most common findings for TIA in the cranial nerve examination are diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction.17,18 Cerebellar system testing includes ocular movement and finger-to-nose and heel-to-shin movement, which may reveal nystagmus, pastpointing, dystaxia, or ataxia. Motor testing suggestive of TIA may reveal spasticity, clonus, rigidity, or unilateral weakness in the upper or lower extremities, face, and tongue. Unilateral weakness and speech disturbance are the most common presenting symptoms in patients with TIA, and these symptoms are more likely to be associated with acute cerebral infarction on MRI.20,21 In an analysis of persons with TIA, 31 to 54 percent presented with focal weakness, 25 to 42 percent presented with speech changes, 16 to 32 percent had symptoms lasting one hour or less, and 37 to 72 percent had symptoms lasting more than one hour.3

Evaluation The diagnostic evaluation of suspected TIA should be initiated as soon as possible to stratify risk of recurrent events. According to AHA/ASA guidelines, the goals of the diagnostic evaluation are to evaluate the vasculature for the mechanism and origin of the patientâ&#x20AC;&#x2122;s symptoms and to exclude nonischemic etiologies.2 Symptomatic patients should be considered as having an active stroke and evaluated urgently in an emergency department.

Imaging The AHA/ASA recommends neuroimaging within 24 hours of symptom onset. Diffusion-weighted MRI is

the preferred modality because it is more sensitive than computed tomography (CT).2 However, CT is more commonly used than MRI because of its availability and ability to quickly identify intracerebral hemorrhage.22 If a patient receives an emergent CT, a follow-up MRI should be performed when available because of its superiority in identifying cerebral infarction.2 The presence of infarction on MRI can have important prognostic implications. A study of classically defined TIA showed that patients with infarction on MRI had an in-hospital stroke rate of 19.4 percent, compared with 1.3 percent in those without evidence of infarction.23 Using the new definition, many patients with classically defined TIA would be redefined as having a minor stroke if there is evidence of acute infarction on MRI. A recent study used the new definition of TIA to evaluate patients whose symptoms resolved within 24 hours. For those with evidence of infarction on MRI (now defined as minor stroke), 7.1 percent had a stroke within the next seven days, compared with just 0.4 percent of patients without evidence of infarction.24 In patients with TIA, the cervicocephalic vasculature should be assessed for treatable atherosclerotic lesions using carotid ultrasonography/transcranial Doppler ultrasonography, magnetic resonance angiography, or CT angiography.2 A reasonable approach is to perform carotid imaging within one week of symptom onset in patients who are candidates for carotid endarterectomy.25 A meta-analysis showed that magnetic resonance angiography had 92.2 percent sensitivity and 75.7 percent specificity for the diagnosis of carotid stenosis, compared with 87.5 percent sensitivity and 75.7 percent specificity with carotid ultrasonography.26 Another study demonstrated 81 percent sensitivity and 96 percent specificity with CT angiography, compared with 92 percent sensitivity and 98 percent specificity with magnetic resonance angiography.27

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Review article Cardiac Assessment Electrocardiography should be performed during the initial evaluation. Transthoracic or transesophageal echocardiography can be used to look for a cardioembolic source and to determine the presence of patent foramen ovale, valvular disease, cardiac thrombus, and atherosclerosis.2 Prolonged cardiac monitoring with telemetry in the inpatient setting or Holter monitor in the outpatient setting is reasonable, primarily to evaluate for paroxysmal atrial fibrillation.

Laboratory Testing In the initial evaluation of TIA symptoms, blood glucose and serum electrolyte levels should be measured to help rule out hypoglycemia or an electrolyte imbalance as the cause of change in mental status. Complete blood count and coagulation studies can help determine the likelihood of hemorrhage and thrombotic disorders.2,28 For younger patients and when there is clinical suspicion of central nervous system infection, drug intoxication, or clotting disorders, additional workup to assess the potential contribution of these disorders should include rapid plasma reagin testing, cerebrospinal fluid examination, urine drug screening, and full hypercoagulability workup.2,28 A fasting lipid panel should be performed to determine cardiovascular risk and for baseline cholesterol levels, to determine the appropriate starting dose of statin therapy needed to achieve target low-density lipoprotein levels.2

Risk Stratification and Hospitalization Criteria The ABCD2 (age, blood pressure, clinical presentation, diabetes mellitus, duration of symptoms) score (Table 419) is a modified version of the original ABCD score, which was developed to determine stroke risk following TIA.19,29 The ABCD2 score has been shown to be highly predictive of the severity of stroke; higher scores correlate with higher disability and length of hospitalization.30 Additionally, a population-based study of TIA demonstrated that the ABCD2 score is highly predictive of a stroke occurring within 24 hours.29 In this study, 76 percent of patients with a recurrence had an ABCD2 score of 5 or greater.31 In a recent study, an emergency department used the ABCD2 score in a novel triage protocol. Patients with an ABCD2 score of 0 to 3 were discharged from the emergency department with an appointment for outpatient MRI and magnetic resonance angiography and an appointment with an outpatient neurology-based TIA clinic within two business days. Those with a score of 4 or 5 received cervical and intracranial vessel imaging in the emergency department. If a symptomatic lesion was identified, they

Table 4. ABCD2 Scoring System for Evaluating Stroke Risk after TIA Clinical characteristics

Points

Age ≥ 60 years

Blood pressure: systolic ≥ 140 mm Hg or diastolic ≥ 90 mm Hg

Clinical presentation Unilateral weakness

Speech impairment without weakness

Diabetes mellitus

Duration of TIA ≥ 60 minutes

10 to 59 minutes

Note: Risk of stroke at two days: 1 to 3 points = low risk (1 percent); 4 or 5 points = moderate risk (4.1 percent); 6 or 7 points = high risk (8.1 percent). TIA = Transient ischemic attack. Information from reference 19.

were admitted. If no lesion was identified, they were discharged with the follow-up appointments. All patients with an ABCD2 score greater than 5 were admitted. This approach led to lower rates of admission and lower-than expected rates of recurrent stroke, which are consistent with expedited specialized outpatient management.32 This is a practical approach that can be instituted at most facilities. However, if urgent imaging is not available through the emergency department or if urgent outpatient neurology follow-up is not available, it is reasonable to admit for observation any patient with an ABCD2 score of 3 or greater who presents within 72 hours of symptom resolution, who has evidence of focal ischemia, or who cannot complete outpatient workup within 48 hours.2,29-31 Anyone with active signs or symptoms or any intracranial lesion on imaging should be considered as having a stroke and managed accordingly.

REFERENCES 1. Albers GW, Caplan LR, Easton JD, et al.; TIA Working Group. Transient ischemic attack—proposal for a new definition. N Engl J Med. 2002;347(21):1713-1716. 2. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack. Stroke. 2009;40(6):2276-2293. 3. Shah SH, Saver JL, Kidwell CS, et al. A multicenter pooled, patient level data analysis of diffusion-weighted MRI in TIA patients [abstract]. Stroke. 2007;38(2):463. 4. Simmons BB, Cirignano B, Gadegbeku AB. Transient ischemic attack: part II. Risk factor modification and treatment. Am Fam Physician. 2012;86(6):527-532.

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Review article 5. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue-based definition of transient ischemic attack. Stroke. 2003;34(4):919-924. 6. Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology. 2003;60(9):1429-1434. 7. Thacker EL, Wiggins KL, Rice KM, et al. Short-term and long-term risk of incident ischemic stroke after transient ischemic attack. Stroke. 2010;41(2):239-243. 8. Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology. 2004;62(11):2015-2020. 9. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke. 2005;36(4):720-723. 10. Ferro JM, Falc찾o I, Rodrigues G, et al. Diagnosis of transient ischemic attack by the nonneurologist. A validation study. Stroke. 1996;27(12):2225-2229. 11. Castle J, Mlynash M, Lee K, et al. Agreement regarding diagnosis of transient ischemic attack fairly low among stroke-trained neurologists. Stroke. 2010;41(7):1367-1370. 12. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison [published correction appears in Lancet. 2008;371(9610):386]. Lancet. 2007;370(9596):1432-1442. 13. Amort M, Fluri F, Sch채fer J, et al. Transient ischemic attack versus transient ischemic attack mimics: frequency, clinical characteristics and outcome. Cerebrovasc Dis. 2011;32(1): 57-64. 14. Hand PJ, Kwan J, Lindley RI, Dennis MS, Wardlaw JM. Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke. 2006;37(3):769-775. 15. Prabhakaran S, Silver AJ, Warrior L, McClenathan B, Lee VH. Misdiagnosis of transient ischemic attacks in the emergency room. Cerebrovasc Dis. 2008;26(6):630-635. 16. Sheehan OC, Merwick A, Kelly LA, et al. Diagnostic usefulness of the ABCD2 score to distinguish transient ischemic attack and minor ischemic stroke from noncerebrovascular events: the North Dublin TIA Study. Stroke. 2009;40(11):3449-3454. 17. Shah KH, Edlow JA. Transient ischemic attack: review for the emergency physician. Ann Emerg Med. 2004;43(5): 592-604. 18. Albucher JF, Martel P, Mas JL. Clinical practice guidelines: diagnosis and immediate management of transient ischemic attacks in adults. Cerebrovasc Dis. 2005;20(4):220-225.

21. Crisostomo RA, Garcia MM, Tong DC. Detection of diffusionweighted MRI abnormalities in patients with transient ischemic attack: correlation with clinical characteristics. Stroke. 2003;34(4):932-937. 22. Edlow JA, Kim S, Pelletier AJ, Camargo CA Jr. National study on emergency department visits for transient ischemic attack, 1992-2001. Acad Emerg Med. 2006;13(6):666-672. 23. Ay H, Koroshetz WJ, Benner T, et al. Transient ischemic attack with infarction: a unique syndrome? Ann Neurol. 2005;57(5):679-686. 24. Giles MF, Albers GW, Amarenco P, et al. Early stroke risk and ABCD2 score performance in tissue- vs timedefined TIA: a multicenter study. Neurology. 2011;77(13): 1222-1228. 25. Swain S, Turner C, Tyrrell P, Rudd A; Guideline Development Group. Diagnosis and initial management of acute stroke and transient ischaemic attack: summary of NICE guidance. BMJ. 2008;337:a786. 26. Nederkoorn PJ, Mali WP, Eikelboom BC, et al. Preoperative diagnosis of carotid artery stenosis: accuracy of noninvasive testing. Stroke. 2002;33(8):2003-2008. 27. Magarelli N, Scarabino T, Simeone AL, et al. Carotid stenosis: a comparison between MR and spiral CT angiography. Neuroradiology. 1998;40(6):367-373. 28. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists [published corrections appear in Stroke. 2007;38(9):e96, and Stroke. 2007;38(6):e38]. Stroke. 2007;38(5):1655-1711. 29. Rothwell PM, Giles MF, Flossmann E, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005;366(9479): 29-36. 30. Chandratheva A, Geraghty OC, Luengo-Fernandez R, Rothwell PM; Oxford Vascular Study. ABCD2 score predicts severity rather than risk of early recurrent events after transient ischemic attack. Stroke. 2010;41(5): 851-856.

19. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283-292.

31. Chandratheva A, Mehta Z, Geraghty OC, Marquardt L, Rothwell PM; Oxford Vascular Study. Population-based study of risk and predictors of stroke in the first few hours after a TIA. Neurology. 2009;72(22):1941-1947.

20. Cucchiara BL, Messe SR, Taylor RA, et al. Is the ABCD score useful for risk stratification of patients with acute transient ischemic attack? Stroke. 2006;37(7):1710-1714.

32. Olivot JM, Wolford C, Castle J, et al. Two aces: transient ischemic attack work-up as outpatient assessment of clinical evaluation and safety. Stroke. 2011;42(7):1839-1843.

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical Review

Floating Bodies in the Left Atrium by 2D-echo: A Differential Diagnosis S Pratheep Kumar*, N Chidambaram†, R Umarani†, E Balasubramanium‡, Gauri Shankar#

Abstract Two-dimensional echocardiography (2D-echo) is sensitive in detecting floating bodies in the left atrium. Identification of a freefloating left atrial thrombus, as a source of embolus, is a common indication for 2D-echo. Screening for other cardiac conditions such as valvular heart diseases often, if not common, reveal floating bodies in the left atrium. The differential diagnosis of a floating body in the left atrium will be discussed.

Keywords: Left atrial thrombus, left atrial myxoma, floating bodies

wo-dimensional echocardiography (2D-echo) is used to diagnose a number of abnormalities pertaining to the left atrium. It is more sensitive than the M-mode echo in detecting floating bodies of the left atrium. These floating bodies are found incidentally or while screening for a source of emboli in the left atrium. A left atrial thrombus is a common indication for screening with an echocardiogram. Left atrial myxoma usually presents as a pedunculated mass with a pedicle. However, prolapsing type of left atrial myxomas present as free-floating bodies in the left atrium. A left atrial mass may lead to embolism of the major arteries.1 2D-echo helps in determining the nature, size, spatial orientation of these masses before surgical removal.2 Mentioned below are a few differential diagnoses of a free-floating body in the left atrium. ÂÂ Left atrial thrombus ÂÂ Prolapsing type of left atrial myxoma ÂÂ Papillary fibroelastomas ÂÂ Lambl’s excrescences ÂÂ Fragments of vegetations zz Bacterial vegetations zz Fungal vegetations

*Postgraduate †Professor ‡Additional Professor #Lecturer Dept. of Medicine Rajah Muthiah Medical College and Hospital, Annamalai Nagar, Tamil Nadu Address for correspondence Dr S Pratheep Kumar T5, Aero Building, Chakra Avenue, Phase II Opposite Main Road, Annamalai Nagar - 608 002, Tamil Nadu E-mail: spkthedr@yahoo.co.in

zz ÂÂ

Aseptic vegetations

Displaced pacemaker leads

LEFT ATRIAL THROMBUS The left atrium and its appendage is a common site of formation of thrombi in patients with mitral stenosis and atrial fibrillation who are not on anticoagulation. This is due to stasis of blood or a poorly contracting left atrium. The left atrial thrombus may break into a number of smaller pieces, leading to embolic events such as a stroke. However, total or partial obstruction of the mitral valve may present as a low output state. 2D-echo is sensitive in detecting thrombi of the left atrium. The thrombus is initially attached by a pedicle, enlarges gradually and spins off in the left atrium and it acquires the characteristic rounded appearance. Further deposition of thrombotic material in layers over the thrombi contributes to the shape. These have been described as the ‘Ball valve thrombus’. 2D-echo also allows the detection of a possibility of a thrombus formation by the presence of a spontaneous echo contrast. Those described as the `Ball valve thrombus’ must fulfill certain rigid criteria as defined by Welch3 namely, there must be: ÂÂ

Entire absence of attachment with consequent free motility

ÂÂ

Imprisonment in consequence of an excess in the diameter of the first narrowing in the circulatory passage ahead of it

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Such consistency and shape that the thrombus will not of necessity lodge as an embolus in the passage.

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical review Case example A 45-year-old female, a case of rheumatic mitral stenosis, presented with quadriparesis and altered sensorium. ECG of the patient showed features of atrial fibrillation with controlled ventricular rate. 2D-echo findings of the patient are shown in (Figs. 1-3). The trapping of the thrombus in the mitral valve predisposes the patient to sudden cardiac death. The patient was referred immediately for cardiac intervention. It is important to stress that oral anticoagulation may lead to fragmentation of the thrombus, leading to showers of emboli, which may be fatal.

Figure 3. Multiple serial images showing a ball valve thrombus in the left atrium getting trapped against the mitral orifice.

Thrombus

PROLAPSING TYPE OF LEFT ATRIAL MYXOMA Figure 1. Four chamber view showing stenosis of the mitral valve. LAD = 5.8 cm (left atrial diameter); MVA = 0.96 cm2 (mitral valve area).

Primary cardiac tumors of the heart are less common compared to metastatic disease of the heart. A three out of four, of these primary tumors are benign and a left atrial myxoma is the commonest (Fig. 4). Two different anatomic types of myxoma have been determined by means of echocardiography: ÂÂ

Round, which is solid and round with a non-mobile surface

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Polypoid, which is soft and irregular in shape with a mobile surface.4 Ha and co-workers showed that prolapsing and polypoid tumors were associated with embolism.

The incidence of systemic embolism is higher in tumors with an irregular and friable surface than in those with a smooth surface.5

LA Thrombus

PAPILLARY FIBROELASTOMAS

Figure 2. Four chamber view of the patient showing an associated mitral regurgitation.

Papillary fibroelastomas account for 8-10% of the primary cardiac tumors. They are small, solitary and motile bodies, which are of <1 cm in size and often confused with vegetations (Fig. 5). They may become as large as

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical review

Left atrial myxoma

4 cm. They usually arise from the mid-portion of the valve frequently involving the aortic valve followed by the mitral valve. Patients with papillary fibroelastomas are usually asymptomatic and these are identified, while screening for cardiac surgery or other indications. Although symptoms related to fibroelastomas are uncommon, there is a potential for serious morbidity, particularly among patients with large, mobile, left-sided lesions.6 Cardiac papillary fibroelastomas are present on valves, away from valvular lines of closure, and also on the endocardial surfaces of the atria and ventricles.7

LAMBLâ&#x20AC;&#x2122;S EXCRESCENCES Lamblâ&#x20AC;&#x2122;s excrescences are filiform fronds that occur at sites of valve closure. They are fine thread like strands and originate as small thrombi on endocardial surfaces and have the potential to embolize to distant organs.8 In contrast to papillary fibroelastomas, they involve the mitral valve more frequently followed by the aortic valve.

Figure 4. A left atrial myxoma.

FRAGMENTS of Vegetations Bacterial Vegetations

Papillary fibroelastoma

Figure 5. 2D-echo of a patient who presented with breathlessness showing a single small motile mass. The mass was later confirmed to be a papillary fibroelastoma by biopsy.

2D-echo is very specific in detecting vegetations of infective endocarditis (Fig. 6). The specificity is as high as 98%.9 However, the sensitivity ranges between 40-50%. Detection of these vegetations is a part of three major criteria of the Dukeâ&#x20AC;&#x2122;s criteria for infective endocarditis. The appearance and site of the vegetations depend on the etiology. Vegetations affect both the native and prosthetic valve. Detection of vegetations of the prosthetic valve is difficult. This is because of the echogenic nature of the prosthetic valves. Bacterial vegetations as a complication of rheumatic fever are small, less friable, sterile and are known as verrucae. Vegetations, primarily due to infective endocarditis are large, bulky, more friable and are destructive in nature. They are most commonly seen in the upper parts of the valve cusps.

Fungal Vegetations

VEG

Fungal vegetations are less common than bacterial vegetations and are easily identified by 2D-echo. They are larger than bacterial vegetations. They are friable and have an easy tendency to break into smaller pieces and present as septic emboli.

Aseptic Vegetations

Figure 6. 2D-echo showing bacterial vegetations.

Aseptic vegetations may be due to nonbacterial thrombotic endocarditis or systemic illnesses such as systemic lupus erythematosus (SLE) and antiphospholipid antibody

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical review SUMMARY A free-floating left atrial mass may be a major source of emboli or may be an incidental finding. The size, site of occurrence, the nature of the surface (e.g., smooth rounded or irregular) and its relation to lines of closure of valves, by 2D-echo, helps in determining the nature, characteristics and identification of the underlying condition. 3D-echo, transesophageal echo and the more recent 4D-echo provide more detail and throw light on the hemodynamic threat these bodies pose. Early surgical removal and histopathological examination of these masses may be indicated in a majority of these cases. Anticoagulation may harmful in the case of a large left ball valve thrombus.

Pacemaker

Figure 7. Two chamber view showing a displaced pacemaker in the right ventricle. Pacemaker displacements are however more common in the atria.

syndrome. Nonbacterial thrombotic endocarditis is also known as marantic endocarditis, which literally means ‘wasting away’. The vegetations are small masses of fibrin and platelets, which are easily friable and are seen along lines of closure of valves. They commonly affect the mitral and the aortic valves. Common predisposing factors are hypercoagulable states such as malignancy, sepsis and burns. Libmann sack`s endocarditis is seen in patients with SLE. These vegetations are small, warty and have destructive potential. They are commonly associated with the mitral and tricuspid valve along the atrial and ventricular surfaces and do not have a predilection for the lines of closure.

REFERENCES 1. Ando T, Abe H, Ro D. A case of embolism due to a floating thrombus migrating from the left atrial appendage to the ostium of the celiac artery. Ann Vasc Dis 2012;5(2):229-32. 2. Tahara A, Tahara N, Honda A, et al. Mobile left atrial round mass free floating in mitral regurgitation flow mimicking a whale spray. BMJ Case Rep 2014;2014. pii: bcr2013202725. 3. Welch W. Thrombosis. In: Allbutt’s System of Medicine. Macmillan: London 1899, Vol. 6, p. 720. 4. Ha JW, Kang WC, Chung N, et al. Echocardiographic and morphologic characteristics of left atrial myxoma and their relation to systemic embolism. Am J Cardiol 1999;83(11):1579-82, A8. 5. Goswami KC, Shrivastava S, Bahl VK, et al. Cardiac myxomas: clinical and echocardiographic profile. Int J Cardiol 1998;63(3):251-9. 6. Sun JP, Asher CR, Yang XS, et al. Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective and prospective study in 162 patients. Circulation 2001;103(22):2687-93. 7. Lambl VD. Papillare excrescenzen an der semilunar-klappe der aorta. Wien Med Wochenschr 1856;6:244-7.

PACEMAKER LEADS Pacemaker leads can produce an echocardiographic beam width artefact, but can be reduced by imaging from a different acoustic window. Infection of the pacemaker leads makes it difficult to confirm whether vegetations are present or not, and to differentiate them from the vegetations of infective endocarditis. Displaced pacemaker leads may also present as a floating body in specific chambers (Fig. 7). Early displacements are more frequent than late displacements and they usually affect atrial leads.10

8. Aziz F, Baciewicz FA Jr. Lambl’s excrescences: review and recommendations. Tex Heart Inst J 2007;34(3):366-8. 9. Erbel R, Rohmann S, Drexler M, Mohr-Kahaly S, Gerharz CD, Iversen S, et al. Improved diagnostic value of echocardiography in patients with infective endocarditis by transoesophageal approach. A prospective study. Eur Heart J 1988;9(1):43-53. 10. Bardy GH, Hofer B, Johnson G, Kudenchuk PJ, Poole JE, Dolack GL, et al. Implantable transvenous cardioverterdefibrillators. Circulation 1993;87(4):1152-68.

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Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical study

Status of HDL in Current Scenario GEETHA SUBRAMANIYAN*, DHARMENDRA JAIN†, BALAJI LOHIYA‡, NEERAJ KUMAR‡

Abstract Cardiovascular disease is a leading cause of death worldwide. Coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. Low-density lipoprotein-cholesterol (LDL-C) lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. Epidemiologic and observational studies have shown that high-density lipoprotein-cholesterol (HDL-C) is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk. HDL particles have key atheroprotective functions—including the capacity to efflux cellular cholesterol—in addition to having antioxidative, anti-inflammatory, antiapoptotic, antithrombotic and vasodilatory actions. Therapeutic approaches to raise HDL-C levels can target one or more of several mechanisms, including the production of apolipoprotein A-I (apoA-I) or modification of intravascular remodeling of HDL particles. However, the landscape of HDL-raising therapies is now littered with failed therapies, including niacin and the negative results with the cholesteryl ester transfer protein (CETP) inhibitors. This is attributed to potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL-raising in future studies.

Keywords: Cardiovascular disease, low-density lipoprotein-cholesterol, statins, high-density lipoprotein-cholesterol, niacin, CETP inhibitors

ardiovascular disease is a leading cause of death worldwide. Among cardiovascular disorders, coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. Low-density lipoprotein-cholesterol (LDL-C) lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. However, even with statin use, residual CHD risk from dyslipidemia remains. Epidemiologic and observational studies have shown that high-density lipoprotein-cholesterol (HDL-C) is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk.

*Emeritus Professor Dr MGR Medical University, Chennai †Assistant Professor Dept. of Cardiology ‡DM Fellow Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh Address for correspondence Dr Dharmendra Jain Assistant Professor, Dept. of Cardiology Institute of Medical Sciences, Banaras Hindu University Varanasi, Uttar Pradesh - 221 005 E-mail: djaincardio@gmail.com

Chasing HDL: Insights Approaches that target HDL remodeling can either increase the number of circulating HDL particles, or increase the duration for which apolipoprotein A-I (apoA-I) circulates by increasing its lipidation with the formation of cholesteryl ester-rich HDL or both. Mechanistic strategies to achieve these goals include the following: Inhibition of cholesteryl ester transfer protein (CETP); enhanced lipidation of apoA-I; enhanced efflux of cholesterol and phospholipids from peripheral cells to either mature spherical HDL or lipid poor apoA-I, mediated by ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) or scavenger receptor BI (SR-BI, also known as SCARB1) and inhibition of the uptake of HDL holoparticles or HDL-cholesteryl ester by the liver.1 Therapeutic approaches to raise HDL-C levels can target one or more of several mechanisms, including the production of apoA-I—the principal protein component of HDL—or modification of intravascular remodeling of HDL particles. ApoA-I-based therapies potentially increase the number of circulating HDL particles and primarily involve stimulation of apoA-I production by the liver, intestine or both. Fibrates, statins and glitazones are the best known examples of agents able to raise de novo apoA-I synthesis in hepatocytes.2 Other approaches center on infusion of recombinant apoA-I, reconstituted

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical Study HDL, partially-delipidated HDL or apoA-I mimetic peptides. In terms of physicochemical properties and biological activity, circulating HDL particles are highly heterogeneous, reflecting their dynamic and complex intravascular metabolism. Each class of HDL-raising agent tends to produce a specific profile of HDL particles.1 Although different HDL-raising agents increase absolute HDL-C levels by differing degrees, elevated amounts of large, cholesterylester-rich HDL are commonly observed upon treatment with CETP inhibitors and niacin and to a lesser degree with statins. Interestingly, similar qualitative changes in HDL profile occur as a result of regular physical exercise or moderate alcohol consumption. By contrast, reconstituted HDL and apoA-I mimetics do not provide sustained elevations of HDL-C, but transiently increase circulating levels of HDL that are small, lipidpoor and protein-rich. HDL particles have key atheroprotective functions— including the capacity to efflux cellular cholesterol—in addition to having antioxidative, anti-inflammatory, antiapoptotic, antithrombotic and vasodilatory actions. Small, protein-rich HDL are notable because of their potent antiatherogenic properties.1,3 Consistent with these findings, both reconstituted HDL and apoA-I mimetics could enhance antiatherogenic functions of HDL.4 Despite considerable research, the therapeutic value of such agents remains unclear.5,6 Large randomized studies have previously shown that lowering LDL-C by 40 mg/dL (1 mmol/L) for 4-5 years with statin therapy cuts the risks of heart attacks and strokes by about a quarter, and recent studies suggest that more intensive LDL-lowering can produce extra benefits. But, despite the use of statins, the risk of heart attacks, strokes and other vascular complications among people who have vascular disease remains high. Subnormal levels of HDL-C constitute a major cardiovascular risk factor. Low levels of HDL-C constitute a strong, independent and inverse predictor of the risk of premature development of atherosclerosis and cardiovascular disease (CVD).7 Clinical studies have shown that increasing HDL-C is an effective therapeutic strategy to slow progression of atherosclerotic disease and induce regression of coronary atherosclerosis. The antiatherogenic effects of HDL are primarily mediated by cholesterol efflux from foam cells in atherosclerotic lesions via reverse cholesterol transport. Impairment of HDL functionality has been observed within certain populations, such as patients with metabolic syndrome or type 2 diabetes. Low plasma concentrations of HDL-C are frequently a characteristic of type 2 diabetes as well

as mixed or combined dyslipidemia, renal and hepatic insufficiency states and autoimmune diseases. In addition to low HDL-C, these disease states feature a moderate or marked degree of HTG. The intravascular metabolism of triglyceride (TG)-rich lipoproteins (principally very LDL [VLDL]) is intimately linked to that of HDL. Drug-induced raising of HDL-C may lead to beneficial reduction in the cholesterol content of both VLDL and LDL; the magnitude of reduction in VLDL-cholesterol (VLDL-C) and LDL-C under these circumstances tends to differ markedly as a function of the specific mechanism of action of the pharmacological agent concerned, as well as the dose employed and the baseline lipid phenotype. Furthermore, the percentage increase in HDL-C following treatment tends to be greater in subjects with the lowest baseline levels.8 The available options for elevating low HDL-C levels are relatively few. While HDL-C levels may be increased by up to ≈10% by implementing therapeutic lifestyle changes, including weight reduction, exercise, smoking cessation and moderate alcohol consumption, many patients will also require pharmacological intervention if target levels should be set. However, there is until now no clear direct evidence that raising HDL-C really results in CVD prevention. The landscape of HDL-raising therapies is now littered with failed therapies, including niacin and the negative results with the CETP inhibitors. These trials show just how difficult it is to provide additional benefit when patients are well-treated with statins. Observational studies have shown that raising HDL-C with exercise, eating a lower saturated-fat diet, losing weight, stopping smoking and drinking small amounts of alcohol raises HDL-C and lowers cardiovascular risk. Now one always thought that was causative, that HDL going up caused the lower cardiovascular events, but it’s more appropriate to see how the HDL went up that lowered cardiovascular events. Different available drug types that raise HDL-C, like niacin and the CETP inhibitors, have all crashed and burned when we study them.

After AIM-HIGH and HPS-2 THRIVE study: where does niacin stand? AIM-HIGH–First Flop of Niacin: A Critical Review The AIM-HIGH (Atherothombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) study9 has generated much debate, even leading some to question the role of niacin in the management of cardiometabolic disease.10 The study had planned to investigate whether adding

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Clinical Study niacin (extended-release [ER] formulation) to simvastatin therapy reduced cardiovascular events in high-risk patients with controlled LDL-C levels (74 [59-87] mg/dL) and low HDL-C (35 [31-39] mg/dL; <1.03 mmol/L in men and <1.29 mmol/L in women) and elevated TGs (162 [128-218] mg/dL). The previous European Atherosclerosis Society (EAS) Consensus Panel statement has highlighted the high-risk associated with this dyslipidemic profile despite achievement of LDL-C goal.11 Patients with a history of CVD were randomly allocated to either high-dose ER niacin (titrated to 1.5-2 g/day, n = 1,718) or placebo treatment (n = 1,696), against a background of simvastatin therapy. This event-driven trial was designed to have an 85% power to detect a 25% reduction in cardiovascular events. It was planned that a sample size of 3,400 participants followed for 2.5-7 years would generate the required 800 primary events. However, the study was terminated 18 months earlier than planned due to futility, with no statistically significant differences between the groups for any of the key outcomes.

Further Analysis Revealed Several Reasons for the AIM-HIGH Trial’s Failings ÂÂ

ÂÂ

First, the planned event rates for this trial were overly ambitious for the study population. While treatment with niacin increased HDL-C levels by 25-42 mg/dL, there was also a substantial increase in HDL-C in the placebo group (by 12-38 mg/dL). Based on population studies, the difference between the two groups - 4 mg/dL – would have predicted at most a 10% difference in cardiovascular events, less than half the predicted 25% reduction on which the power calculations were based. Second, the vast majority (ca. 90%) of patients had already been treated with statin therapy for more than 1 year before the study. In addition, ca. 20% of patients had previously received niacin (treatment was discontinued for 30 days before entry to the study).

Thus, AIM-HIGH was not powered to test the potential benefits of adding niacin to statin-treated patients.

HPS-2 THRIVE – A Second Major Setback of Niacin: A Critical Review The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) study, a secondary-prevention trial testing the addition of ER niacin to statin therapy, has missed its primary endpoint and shown no clinical benefit for ER niacin. After nearly 4 years of follow-up, the combination of niacin with the antiflushing agent laropiprant did not significantly reduce the risk of the combination of coronary deaths, nonfatal myocardial infarction (MI), strokes or coronary revascularizations compared with statin therapy, according to Merck, the sponsor of the HPS-2 THRIVE trial. In a press release on 20 December 2012 announcing the results, Merck said the combination significantly increased the risk of nonfatal but serious side effects.12 One day after the Merck announcement, the European Medicines Agency announced that it would be starting a review of the safety and efficacy of Tredaptive, given the results of the HPS-2 THRIVE study.13 It will make a recommendation to the Committee on Medicinal Products for Human Use (CHMP), and an opinion on any required regulatory action is expected in January 2013.

Trial Design of HPS-2 THRIVE Might have Influenced Results The HPS-2-THRIVE was an all-comers secondaryprevention study and did not preselect patients with very low LDL-C levels. The epidemiologic relationship with HDL-C and cardiac events is inverse, but it’s inverse curvilinear, meaning that when HDL gets <40 mg/dL for men and 50 mg/dL and women, there is a signal of increased risk. But, the risk really gets steep when you get an HDL <35 or 30 mg/dL.

ÂÂ

Third, the placebo was supplemented with a lowdose of immediate-release niacin (50 mg/0.5 or 1.0 g niacin tablet) to maintain study blinding. This may have impacted the study findings given uncertainties regarding the dose-benefit curve for niacin.

With an all-comers design where baseline HDL-C levels were 50 mg/dL, for the sake of argument, a 20% increase in HDL with niacin would increase levels to 60 mg/dL, but this is the flat part of the event curve. Although powered for clinical events, the improvement in HDL would likely be insufficient to result in a significant reduction in cardiovascular events.

ÂÂ

Fourth, there was considerable use of additional lipid-modifying therapy in the placebo group. Seventy-five percent of patients in this group were receiving simvastatin doses of 40 mg/day or higher, and 21% were also receiving add-in ezetimibe.

Could there have been some sort of interaction between the laropiprant component of the niacin/laropiprant combination? Laropiprant works by blocking DP1 receptors on vascular cells to prevent flushing, but the DP1 receptors are elsewhere in body, including platelets, Cont’d on page 107...

Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

Taking point

Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

â&#x20AC;&#x153;No one should die of heart disease just because he/she cannot afford itâ&#x20AC;? About Heart Care Foundation of India

Help Us to Save Lives The Foundation seeks support, d o n a t i o n s a n d contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now... Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

Sameer Malik Heart care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund “Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people. Objectives

Who is eligible?

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office. Important Notes The patient must be a citizen of India with valid Voter ID Card/Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals. The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment. The financial assistance granted will be given directly to the treating hospital/medical center. The HCFI Fund has the right to print/publish/webcast/ web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefited). The HCFI fund does not provide assistance for any emergent heart interventions. Check List of Documents to be Submitted with application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM) BPL Card (If Card holder) Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India. To promote and train hands-only CPR. Activities of the Fund financial assistance

Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc. After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done. Drug subsidy

The HCFI Fund has tied up with Helpline pharmacy in Delhi to facilitate patients with medicines at highly discounted rates (up to 50%) post surgery.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy

HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

Case Report

Complete Heart Block in Rheumatoid Arthritis KAVINA MARIAN FERNANDES*, VIVEK GC*

Abstract Rheumatoid arthritis (RA) can affect all parts of the heart. The pericardium, endocardium, valves, myocardium and the conduction system can get involved separately or in combination. However, complete heart block is very uncommon. We describe a case of a 65-year-old lady with RA presenting with complete heart block because of its rarity and unusual feature like negative rheumatoid factor.

Keywords: Rheumatoid arthritis, complete heart block, conduction disturbances, sudden cardiac death

hythm and conduction disturbances and sudden cardiac death (SCD) are important manifestations of cardiac involvement in autoimmune rheumatic diseases (ARDs). Complete heart block (CHB) is a rare complication of rheumatoid arthritis (RA) with an approximate incidence of 1 in 1,000 patients with RA.1 CHB in RA occurs generally in patients with established erosive RA.2 It can develop suddenly, being discovered after syncope or found unexpectedly on routine physical and electrocardiographic examination.2 In patients with high activity of RA, the decrease of heart rate variability reflects severity of inflammation. Decreased heart rate variability in degree I-II RA activity, is predictor for ventricular arrhythmias, SCD and acute myocardial infarction (MI). Antibodies to cardiac conducting tissue were found significantly more often in these patients than in those without conduction abnormalities.

She had been on ayurvedic treatment. There was no history of oral ulcers, photosensitive rash, hair loss or abortions. She did not suffer from hypertension, diabetes mellitus or ischemic heart disease. There was no family history of autoimmune disorders. On examination, she was afebrile, pulse rate was 40/min, regular, blood pressure of 100/70 mmHg and respiratory rate of 14/min, jugular venous pressure (JVP) was raised and showed cannon a waves and SaO2 was 98% at room air. She had pallor and bilateral pitting pedal edema. There was no icterus, clubbing, lymphadenopathy or goiter. She had Boutonnieres deformity, swan neck deformity of index finger, ring finger of both hands, z-deformity of thumb, ulnar deviation of wrist and hallux valgus (Fig. 1). Trophic ulcers were present in the sole of the right and left foot. No nodules were palpable. Systemic examination was otherwise normal.

CASE PRESENTATION A 65-year-old female presented to our department with low-grade fever and fatigue on exertion (Class III New York Heart Association [NYHA]) of 2-week duration. She also had deforming polyarthritis since 20 years. She had stiffness in joints on getting up in the morning, which would last till late morning. The patient did not complain of giddiness, syncopal attacks, chest pain and palpitation.

*Dept. of General Medicine Vijayanagara Institute of Medical Sciences Bellary, Karnataka Address for correspondence Dr Vivek GC No. 210, 7th A Main, Vijayanagar 2nd Stage Bangalore - 560 104 E-mail: gc.vivek@gmail.com

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Figure 1. Picture showing the Boutonnieres deformity, swan neck deformity of index finger, ring finger of both hands, z-deformity of thumb, ulnar deviation of wrist and hallux valgus.

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case report Investigations revealed hemoglobin - 8 g/dL, total leukocyte count (TLC) - 14,300 cells/mm3; differential leukocyte count (DLC) was polymorphs 69%, lymphocytes - 13%, eosinophils - 12%, monocytes 6%. Erythrocyte sedimentation rate (ESR) was 65 mm/ hour, platelet count - 3.17 lac/mm3; liver function tests (SGOT - 33 IU/L, SGPT - 30 IU/L), renal function tests (urea - 25 mg/dL, creatinine - 1.2 mg/dL, sodium - 140 mEq/L, potassium - 4.2 mEq/L, chloride 102 mEq/L), blood glucose (RBS - 94 mg/dL), uric acid and thyroid function tests were normal. Urine routine showed traces of albumin. ECG showed CHB (Fig. 2). 2-D echocardiography showed LA - 3.37 cm, AO - 2.27 cm, dilated RA and RV, mild mitral regurgitation (probably functional as there was no thickening of leaflets or chordae), left ventricular ejection fraction (LVEF) - 40%, no regional wall motion abnormality. Right ventricle systolic pressure (RVSP) by tricuspid regurgitation jet 45 mmHg, and no evidence of clot, vegetation or pericardial effusion.

Figure 2. ECG showing complete heart block.

X-ray of both wrists anteroposterior (AP) view showed juxta articular osteopenia, Boutonnieres deformity at 4th distal interphalangeal (DIP) joint and narrowing of radiocarpal, intercarpal joint spaces. Left wrist X-ray also showed hitch hikers thumb, swan neck deformity of 2nd finger, Boutonnieres deformity in 4th finger (Fig. 3). X-ray of bilateral feet (AP/oblique view) showed diffuse osteopenia of the bones, narrowing of joint spaces involving tarsometatarsal joint and intertarsal joint, medial deviation of 2nd to 5th toes, lateral deviation of great toe (Fig. 4). Chest X-ray was normal.

Figure 3. X-ray of both hand and wrist (AP view) showing Boutonnieres deformity at 4th DIP joint, left wrist X-ray also showed hitch hikers thumb, swan neck deformity of 2nd finger.

Troponin I - 0.011 ng/mL (negative), rheumatoid factor/ RA test - 18 IU/mL (negative) CRP - 150.8 mg/L (raised), anti-CCP antibodies - 0.60 U/mL (negative), ANA >125 U (strongly positive); SS-A 3+, RO-52 3+, centromere B 3+. Arterial Doppler study of both lower limbs was normal, venous Doppler did not show any signs of deep venous thrombosis (DVT). The patient was administered injection atropine 0.6 mg intravenous (IV) initially and repeated 3 times. However, there was no change in the rhythm or heart rate. The patient has undergone a pacemaker implantation and continues to be well. The patient was started on methotrexate (10 mg/week) and hydroxychloroquine (400 mg/day) along with anti-inflammatory drugs.

Figure 4. X-ray of right foot (AP/oblique) showing narrowing of joint spaces involving tarsometatarsal joint and intertarsal joint, medial deviation of 2nd to 5th toes, lateral deviation of great toe.

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case report DISCUSSION RA is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extra-articular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis and hematologic abnormalities.4 The clinical diagnosis of RA is largely based on signs and symptoms of a chronic inflammatory arthritis, with laboratory and radiographic results providing important supplemental information. In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnosis.4 The most frequent site of cardiac involvement in RA is the pericardium. Cardiomyopathy, another clinically important manifestation of RA, may result from necrotizing or granulomatous myocarditis, coronary artery disease or diastolic dysfunction. Mitral regurgitation is the most common valvular abnormality in RA, occurring at a higher frequency than the general population.2 Right bundle branch block (RBBB), hemiblocks or AV blocks of any degree could occur. CHB is a rare complication of RA.1 Connective tissue diseases are responsible for <2% of cases of CHB. The transition from sinus rhythm to CHB usually appears to be sudden and permanent. However, there may be progression from first-degree heart block or blocks of the bundles or their fascicles to second-degree heart block and finally CHB. The conduction disturbances are usually mild, asymptomatic and incidentally diagnosed by electrocardiography. There is a female preponderance. In addition to standard 12-lead ECG, 24-hour Holter monitoring is most widely applied for evaluation of patients with arrhythmias and conduction abnormalities. The mean duration of RA prior to the development of the block is 10-12 years. In the case series published by Ahern et al,5 the average age for development of CHB was about 60 years, which matches our case. CHB can be due to following mechanisms: 1) Direct involvement of conducting system with granuloma; 2) extension of the inflammatory process from base of aorta to mitral valve to conduction pathways; 3) amyloidosis; 4) hemorrhage into rheumatoid nodule; 5) coronary arteritis causing

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ischemia of the conduction tissue; 6) focal myocarditis due to RA and 7) premature coronary artery disease due to accelerated atherosclerosis in patients with RA.6 Conduction blocks once established in the disease do not respond to anti-inflammatory treatment.6 If patient is symptomatic pacemaker implantation helps improve.7

CONCLUSION CHB is a rare complication of RA. It usually occurs in patients with established erosive nodular rheumatoid disease and in rheumatoid factor positive cases but can also occur in those who are seronegative although rarely. CHB usually suggests active disease though it can occur in patients with well-controlled disease.8 The transition from sinus rhythm to CHB usually appears to be sudden and permanent. Spontaneous recovery is possible, but extremely rare. If patient is symptomatic, pacemaker implantation helps improve symptoms and prognosis. The indications for a permanent pacemaker are the same as any patient of CHB without RA. Once a pacemaker has been installed, the prognosis is good in the absence of other cardiac complications such as congestive cardiac failure.

REFERENCES 1. Seferović PM, Ristić AD, Maksimović R, Simeunović DS, Ristić GG, Radovanović G, et al. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. Rheumatology (Oxford) 2006;45 Suppl 4:iv39-42. 2. Harris M. Rheumatoid heart disease with complete heart block. J Clin Pathol 1970;23(7):623-6. 3. Parnes EIa, Krasnosel’skiĭ MIa, Tsurko VV, Striuk RI. Long-term prognosis in patients with rheumatoid arthritis depending on baseline variability of cardiac rhythm. Ter Arkh 2005;77(9):77-80. 4. Shah Ankoor E. William St. Clair. Rheumatoid arthritis. In: Harrison’s Principles of Internal Medicine. 18th edition, Vol. 2, Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds.), McGraw-Hill Company: 2012:p.2738-52. 5. Ahern M, Lever JV, Cosh J. Complete heart block in rheumatoid arthritis. Ann Rheum Dis 1983;42(4):389-97. 6. Mandell BF, Villa-Forte A. Rheumatic diseases and the cardiovascular system. In: Heart Disease: A Text Book of Cardiovascular Medicine. 9th edition, Braunwald E, Zipes DP, Libby P (Eds.), WB Saunders Company p.1876-904. 7. Spragg D, Tomaselli GF. The bradyarrythmias. In: Harrison’s Principles of Internal Medicine. 18th edition, Vol. 2, Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds.), McGraw-Hill Company 2012:p.1867-70. 8. David-Chaussé J, Blanchot P, Warin J, Dehais J, Bullier R, Texier JM. Atrioventricular blocks and rheumatoid arthritis. Rev Rhum Mal Osteoartic 1976;43(3):177-83.

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neurons and respiratory tissue. It remains unknown if the lack of benefit was the result of ineffectiveness when niacin was added to simvastatin or whether the benefit was canceled out as a result of an off-target effect caused by laropiprant. This is the second major setback for physicians hoping that niacin, a drug that raises HDL-C levels, might be used clinically to reduce the risk of cardiovascular events. In May 2011, the National Heart, Lung and Blood Institute (NHLBI)-sponsored AIM-HIGH study, was halted early after showing no benefit of niacin when given in addition to statin therapy.

A Meta-analysis of 11 Niacin Trials: Still Hope for Niacin Coincidentally, a systematic review and meta-analysis by Drs Paul Lavigne and Richard Karas (Tufts Medical Center, Boston, MA) evaluated 11 studies including 9,959 subjects, primarily secondary-prevention studies, treated with niacin.14 The studies included ARBITER-2 and ARBITER-6, as well as the AIM-HIGH study. In the meta-analysis, which is published online December 19, 2012 in the Journal of the American College of Cardiology, treatment with niacin was associated with a significant 34% reduction in the composite endpoint of any CVD event and a significant 25% reduction in CHD events.

After ILLUMINATE and Dal-OUTCOME: Where does CETP Inhibitors Stand? CETP inhibitors are presently the most potent HDLraising agents available, resulting in dose-dependent HDL-C elevation of up to 100%.15 This HDL-raising effect constitutes the basis for the concept of pharmacological CETP inhibition for reduction of the residual cardiovascular risk after statin therapy. Consistent with the traditional view that cholesterol efflux capacity represents a central atheroprotective activity of HDL, enhanced reverse cholesterol transport from peripheral tissues to the liver before HDL level elevation has long been envisaged as the major antiatherogenic corollary of CETP inhibition. Of note, it is important to remember that high CETP activity, typical of metabolic diseases such as type 2 diabetes mellitus and the metabolic syndrome, enriches the TG content of HDL particles. TG-rich HDL are then subject to hydrolysis by hepatic lipase, with subsequent structural destabilization involving shedding of apoA-I and elimination from the circulation by the kidney. As a result, apoA-I turnover is accelerated.16 As small TG enriched HDL are deficient in atheroprotective activities,1

CETP inhibitors could theoretically correct not only the core lipid composition of HDL (cholesteryl ester TG ratio) but also HDL functional defects seen in patients with metabolic disease.

ILLUMINATE – First Flop Trial of CETP Inhibitors Torcetrapib: A Critical Review Torcetrapib was the first CETP inhibitor to enter a largescale, prospective, placebo-controlled interventional trial, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE), which was prematurely terminated in December 2006, because of excess cardiovascular and noncardiovascular mortality in the active treatment group. Therapy with torcetrapib was associated with considerable increases in aldosterone level and blood pressure and changes in serum electrolytes indicative of mineralocorticoid excess.17 These findings indicate that torcetrapib has off-target toxic effects unrelated to HDL- raising that involve the activation of mineralocorticoid receptors by aldosterone and result in the induction of hypertension. In contrast with torcetrapib, other CETP inhibitors such as JTT-705 and MK-825 (anacetrapib) do not increase blood pressure in humans,18 an observation which discounts a class effect.

Dal-OUTCOMES – Second Set back Trial of CETP Inhibitors – Dalcetrapib: A Critical Review The dal-OUTCOMES trial evaluated the efficacy and safety profile of dalcetrapib when added to existing standard of care in patients with stable CHD following an acute coronary syndrome (ACS).19 Roche announced that following the results of the second interim analysis of the dal-OUTCOMES Phase III trial, the independent Data and Safety Monitoring Board (DSMB) has recommended stopping the trial due to a lack of clinically meaningful efficacy.20 No safety signals relating to the dal-OUTCOMES trial were reported from the DSMB. The dal-HEART is a global development program involving six clinical trials: dal-OUTCOMES, dal-OUTCOMES 2, dal-PLAQUE 2, dal-ACUTE, dal-PLAQUE (completed) and dal-VESSEL (completed). Roche has decided to terminate the dal-OUTCOMES trial and all the studies in the dal-HEART program. Researchers hoped dalcetrapib was a CETP inhibitor that could succeed where torcetrapib failed. Torcetrapib was abandoned when studies showed it appeared to increase the risk of cardiovascular events despite substantially increasing HDL-C levels.

There is Still Hope That the More Potent CETP Inhibitors can Improve Outcomes The failure of dalcetrapib shouldn’t be that much of a surprise. The likelihood of dalcetrapib succeeding was

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Clinical Study always very low. It’s a weak CETP inhibitor. The degree of HDL increase with the drug is very modest and it doesn’t lower LDL, and the concern all along had been that it just wouldn’t be effective enough to reduce morbidity and mortality. Earlier studies showed that dalcetrapib increases HDL by about 30%, while evacetrapib and anacetrapib (Merck, Whitehouse Station, NJ) increase HDL by more than 100% and reduce LDL by 35-40%, so there is still hope that the more potent CETP inhibitors can improve outcomes in ACS patients. It’s important to see this through to completion. The researchers should not lose their nerve. There’s going to be a lot of debate that the CETP hypothesis is wrong, but one don’t know that yet. One will need to be careful not to jump to conclusions and carry out these experiments.

Anacetrapib – A Potent CETP Inhibitor – The REVEAL HPS-3 TIMI-55 Trial: A Ray of Hope Anacetrapib has been found to produce substantial reductions in blood levels of ‘bad’ LDL-C in addition to those achieved with statin drugs, and it more than doubles ‘good’ HDL-C levels. The REVEAL HPS-3 TIMI-55 trial (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) is a large, randomized placebo-controlled trial assessing the clinical effects of anacetrapib (a potent CETP inhibitor) among patients with pre-existing vascular disease. When used either as monotherapy or in combination with a statin, the CETP inhibitor anacetrapib increases HDL-C and apoA-I concentrations by about 140% and 45%, respectively and reduces LDL-C and apoB concentrations by about 30-40%. Anacetrapib has been well-tolerated in early phase studies and, importantly, has no effects on blood pressure or aldosterone levels. In the REVEAL trial, all patients receive effective LDL-lowering treatment with atorvastatin. The primary aim of REVEAL is to assess the effect of anacetrapib on the composite outcome of Major Coronary Event, defined as coronary death, myocardial infarction or coronary revascularization. The REVEAL trial is investigating whether a drug anacetrapib can drive down the risks of coronary deaths, heart attacks, strokes and other vascular complications. The study will involve 30,000 people who have some form of heart or other vascular disease. Till August 2012, over 20,000 people have been recruited into REVEAL, including over 5,000 in Europe, 6,000 in North America and 8,000 in China. It is anticipated that the recruitment of 30,000 patients will be completed during 2013, follow-up is anticipated to

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continue until 2016 and that the study results will become available in 2017.

Evacetrapib – A Potent CETP Inhibitor – ACCELERATE Study: Another Ray of Hope The phase III Study of Evacetrapib started in October 2012, ACCELERATE study (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes) will involve 11,000 people with high-risk vascular disease (HRVD). The purpose of the ACCELERATE study is to evaluate the efficacy and safety of evacetrapib in participants with HRVD. The primary objective of this study is to test the hypothesis that evacetrapib 130 mg daily, in comparison to placebo, reduces the incidence of the composite endpoint of cardiovascular death, MI, stroke, coronary revascularization or hospitalization for unstable angina in HRVD patients. The estimated primary completion date (Final data collection date for primary outcome measure) is September 2015.

Chasing HDL: Current Status and Future Perspectives Current Guidelines The European Society of Cardiology (ESC) 2011 Recommendations if drug treatment of low HDL-C is considered are Class IIa for Niacin and Class IIb for Statins and Fibrates. Presently, only niacin is approved by the Food and Drug Administration (FDA) for HDL-C elevation and can raise HDL-C levels by 20-30%. However, its use can be limited by a high incidence of flushing and, less commonly, by elevation of blood glucose and potential hepatic toxicity. Assessment of HDL functionality may be more relevant, given emerging experimental evidence of the pleiotropic potentially atheroprotective functions of HDL. Apart from its role in cholesterol efflux and lipid homeostasis, the HDL particle has been shown to exhibit a wide range of activities which include antithrombogenic, antiinflammatory, anti-oxidative, antiplatelet and vasodilatory functions.21 A recent study (reviewed in EAS Newsletter January 2011) showed that cholesterol efflux capacity had a strong inverse association with carotid intima-media thickness and the risk of angiographic coronary artery disease, irrespective of plasma lipid levels.22 There are also emerging data for a number of innovative HDL-raising therapies targeted to the acute management of high-risk patients. The findings from these studies will help in resolving whether HDL is indeed a target for therapy. The available data do not, however, exclude

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Clinical Study potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDLraising in future studies. The unexpected failure of torcetrapib highlights unresolved questions in the HDL field. Thus, the mechanistic relevance of a simple measurement of HDL-C remains controversial.4 Given the functional heterogeneity of HDL particles, whether HDL-C quantification reflects the quantity (number) or the quality (function) of HDL particles still remains to be determined. Indeed, the clinical value of measuring plasma apoA-I levels, which reflect numbers of HDL particles rather than their cholesterol load, is hotly debated.23-25 Whether our primary target should be raising HDL-C levels, normalizing HDL functionality or whether it should encompass both aspects is unknown. This uncertainty is further corroborated by the paucity of data on the influence of HDL-raising agents on HDL functionality. There is proposal that measurement of HDL-C should be combined with the evaluation of HDL function when assessing the benefit of HDL-targeted therapies. In vitro assays that focus on ‘surrogate markers of HDL functionality in vivo’ need to be developed and applied in studies of the therapeutic efficacy of CETP inhibitors. Such assays may involve measurements of the capacity of HDL to induce cellular cholesterol efflux through the ABCA1, ABCG1 and SR-BI pathways, together with determinations of lecithin: Cholesterol acyltransferase (LCAT) activity and of anti-inflammatory activities, such as the capacity to inhibit LDL oxidation and to decrease cellular expression of adhesion molecules. Such an integrated approach should be adopted for evaluation of new and promising HDL-raising agents as a prerequisite to large clinical trials assessing morbidity and mortality.

CONCLUSION Normalization of both defective biological HDL function and low HDL levels should, therefore, be the focus of pharmacological HDL-raising strategies.1,26 Influence of major HDL-raising pharmacological agents on HDL functionality should be assessed in humans, especially in the setting of hypertriglyceridemia seen in those with insulin resistance.27 Such agents include extendedrelease niacin (alone or in combination with an inhibitor of the prostaglandin D receptor),28 niacin-receptor agonists,29 fibrates, statins and other HDL-raising agents. It is encouraging that such data are now appearing in

press.30,31 With such an approach, pharmacologicallyinduced HDL-C elevation can be anticipated to finally translate into diminished cardiovascular risk and clinical benefit.

References 1. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58(3):342-74. 2. Dullens SP, Plat J, Mensink RP. Increasing apoA-I production as a target for CHD risk reduction. Nutr Metab Cardiovasc Dis 2007;17(8):616-28. 3. Kontush A, Chapman MJ. Antiatherogenic small, dense HDL - guardian angel of the arterial wall? Nat Clin Pract Cardiovasc Med 2006;3(3):144-53. 4. Ansell BJ, Fonarow GC, Fogelman AM. The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 2007;18(4):427-34. 5. Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Datta G, Garber D, et al. Potential clinical utility of highdensity lipoprotein-mimetic peptides. Curr Opin Lipidol 2006;17(4):440-4. 6. Shah PK. High-density lipoprotein mimetics: focus on synthetic high-density lipoprotein. Am J Cardiol 2007;100(11 A):S62-7. 7. Cooney MT, Dudina A, De Bacquer D, Wilhelmsen L, Sans S, Menotti A, et al; SCORE investigators. HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk. Atherosclerosis 2009;206(2): 611-6. 8. Poulter N. The impact of micronized fenofibrate on lipid subfractions and on reaching HDL-target levels in 7,098 patients with dyslipidaemia. Br J Cardiol 1999;6:682-5. 9. The AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365(24):2255-67. 10. Giugliano RP. Niacin at 56 years of age - time for an early retirement? N Engl J Med 2011;365(24):2318-20. 11. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, et al; European Atherosclerosis Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32(11):1345-61. 12. Merck. Merck announces HPS2-THRIVE study of Tredaptive (extended-release niacin/laropiprant) did not achieve primary endpoint (press release). December 20, 2012. 13. European Medicines Agency. European Medicines Agency starts review of Tredaptive, Pelzont and Trevaclyn (press release). December 21, 2012. 14. Lavigne PM, Karas RH. The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 2013;61(4):440-6.

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Clinical Study 15. Barter PJ, Kastelein JJ. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol 2006;47(3): 492-9.

B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. Ann Intern Med 2007;146(9):640-8.

16. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005;96(12):1221-32.

24. Walldius G, Jungner I. Apolipoprotein A-I versus HDL cholesterol in the prediction of risk for myocardial infarction and stroke. Curr Opin Cardiol 2007;22(4): 359-67.

17. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357(21):2109-22.

25. Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298(7):776-85.

18. Chapman MJ. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. Pharmacol Ther 2006;111(3):893-908. 19. Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, et al; dal-OUTCOMES Committees and Investigators. Rationale and design of the dalOUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158(6):896-901.e3. 20. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367(22):2089-99. 21. Rye KA, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res 2009;50 Suppl:S195-200. 22. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, highdensity lipoprotein function, and atherosclerosis. N Engl J Med 2011;364(2):127-35. 23. van der Steeg WA, Boekholdt SM, Stein EA, El-Harchaoui K, Stroes ES, Sandhu MS, et al. Role of the apolipoprotein

26. Watson KE, Ansell BJ, Watson AD, Fonarow GC. HDL function as a target of lipid-modifying therapy. Rev Cardiovasc Med 2007;8(1):1-8. 27. Kontush A, Chapman MJ. Why is HDL functionally deficient in type 2 diabetes? Curr Diab Rep 2008;8(1):51-9. 28. Lai E, De Lepeleire I, Crumley TM, Liu F, Wenning LA, Michiels N, et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther 2007;81(6):849-57. 29. Kamanna VS, Kashyap ML. Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents? Am J Cardiol 2007;100(11 A):S53-61. 30. Sviridov D, Hoang A, Ooi E, Watts G, Barrett PH, Nestel P. Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin. Atherosclerosis 2008;197(2):732-9. 31. Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, et al. Effects of high-dose atorvastatin on anti-inflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol 2007;34(7):1459-64.

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Case Report

Superficial Brachial Artery: Its Embryological and Clinical Significance Meenakshi Khullar

Abstract The principal arteries of the upper limb show a wide range of variations that are of considerable interest to orthopedic surgeons, plastic surgeons, radiologists and anatomists. We present here a case of bilateral superficial brachial artery found during the routine dissection of the upper limbs of a 50-year-old female cadaver. In both the limbs, the third part of the axillary artery divided into superficial brachial and deep brachial arteries; denominated according to their relation to the median nerve. The superficial brachial artery continued in the arm without giving any branches and ended in the cubital fossa dividing into radial and ulnar arteries. The deep brachial artery gave rise to anterior circumflex humeral, posterior circumflex humeral and profunda brachii arteries. Earlier superficial brachial artery has been reported with a prevalence rate varying from 0.2% to 25% but bilateral variation is extremely rare. The great variability of this arterial pattern may be attributed to the failure of regression of some paths of the embryonic arterial trunks.1 The embryological and clinical significance of this variant are also discussed in detail.

Keywords: Axillary artery, superficial brachial artery, deep brachial artery

xillary artery (AA) is a continuation of the subclavian artery from the outer border of the first rib. It ends at the inferior border of the teres major and continues in the arm as brachial artery. According to textbooks, an AA penetrates the dorsoventral divisions of the brachial plexus by passing between the lateral and medial roots of the median nerve. Rarely, an aberrant AA is unable to penetrate the brachial plexus. In this case, the AA is positioned superficial to the brachial plexus and then, this is known the superficial brachial artery (SBA).

The SBA has been reported by many authors because of its relatively high frequency in comparison with other vascular variations.2,3 It is necessary, however, to pay attention to the branches originating from the aberrant AAs, in addition to the various courses of the AA, in order to understand their morphogenesis.

on both the sides, the third part of the AA after giving the subscapular artery bifurcated into a SBA and a deep brachial artery. The SBA descended superficial to the lateral root of the median nerve; did not give any branch in the arm and continued as the brachial artery proper. Finally, on reaching the cubital fossa it terminated by dividing into radial and ulnar arteries. The deep brachial artery passed deep to the medial root of the median nerve and gave anterior and posterior circumflex humeral branches of AA and profunda brachii branch of brachial artery. Then it terminated by giving twigs to the muscles of arm (Fig. 1).

Case report During the routine undergraduate dissections on the upper limbs of a 50-year-old female cadaver, it was observed that

Assistant Professor Dept. of Anatomy Guru Gobind Singh Medical College Faridkot, Punjab Address for correspondence Dr Meenakshi Khullar 43, Vikas Vihar (Phase 1), Ferozepur City - 152 002, Punjab E-mail: meenakshikhullar8@gmail.com

Figure 1. Photograph showing the third part of the axillary artery (AA) dividing into the superficial brachial artery (SBA) and the deep brachial artery [BA(p)]; MN(lr) - (lateral root of median nerve) , MN(mr) - (medial root of the median nerve), MN (median nerve).

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case report Table 1. Showing the Incidence of the SBA in Various Studies Name of Author

Year

Quain12

1844

0.2

Gruber13

1848

0.4

Muller14

1903

Adachi7

1928

3.1

Miller15

1939

al6

% of cases with SBA

1953

0.12

Skopakoff4

1959

19.7

al5

McCormack et

1985

Chaudhary16

2001

4.2

Rodriguez-Niedenführ et al17

2001

4.9

Patnaik et al18

2002

Kachlik et al19

2010

Fuss et

Rao and

Ontogeny The embryological background of these variations in the vasculature of the upper limb may be explained as abnormal deviations in the normal vascular patterns. Arey and Jurjus mentioned six explanations for the variations observed:8,9 ÂÂ The choice of unusual paths in the primitive vascular plexus ÂÂ The persistence of vessels which are normally obliterated ÂÂ The disappearance of vessels which are normally retained ÂÂ An incomplete development ÂÂ The fusion and absorption of parts which are normally distinct ÂÂ A combination of factors leading to an atypical pattern normally encountered. Ontogenic basis of the present case can be easily made out if we look at Singer’s five stages of development of the brachial artery (Fig. 2):10 ÂÂ

Stage I: Originally, the subclavian artery extends to the wrist, where it terminates by dividing into terminal branches for the fingers. The distal portion of the artery becomes the interosseous artery of the adult.

ÂÂ

Stage II: The median artery arises from the interosseous artery and becomes larger while interosseous artery subsequently undergoes retrogression. During this process, the median artery fuses with the lower portion of interosseous artery and ultimately forms the main channel for the digital branches becoming the principle artery of the forearm.

ÂÂ

Stage III: In embryos of 18 mm, the ulnar artery arises from brachial artery and unites distally with the median artery to form superficial palmar arch. Digital branches arise from this arch.

ÂÂ

Stage IV: In embryo of 21 mm length, the SBA develops in the axillary region and traverses the medial surface of the arm and runs diagonally from the ulnar to the radial side of the forearm to the posterior surface of the wrist. There it divides over the carpus into branches for the dorsum of the thumb and index finger.

ÂÂ

Stage V: Finally three changes occur. When the embryo reaches the length of 23 mm the median artery undergoes retrogression becoming a small slender structure, now known as 'arteria nervi mediani'. The SBA gives off a distal branch, which anastomoses with the superficial palmar arch already present. At the elbow an anastomotic branch between brachial artery and SBA becomes enlarged sufficiently to form with the

SBA

(I)

(II)

SPA (III)

AIA

UA MA

MA MA

AIA

SPA (IV)

AIA MA

UA UA

SPA (V)

Figure 2. Stages of development of arteries of upper arm. SC = Subclavian artery; MA = Median artery; AIA = Anterior interosseous artery; SBA = Superficial brachial artery; UA = Ulnar artery; SPA = Superficial palmar arch; RA = Radial artery.

Discussion Variations in the arterial pattern of the upper limb are common and have been reported by several investigators.1 The presence of a SBA and the usual pattern of its branching in the upper arm or forearm have also been reported.4-6 The definition of the SBA was set for the first time by Adachi in 1928 and runs as follows: “The SBA is the one that runs superficial to the median nerve.”7 It may replace the main trunk or may be accompanied by an equally important, less important or more important trunk running deep to median nerve. Table 1 shows the prevalence of SBA as observed by different authors from time-to-time.

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Asian Journal of Clinical Cardiology, Volume 17, Number 2, October-December 2014

case report radiodiagnostics, particularly in cases involving traumatic injuries, as improved knowledge would allow more accurate diagnostic interpretation and surgical treatment. A

SBA

References

C UA

1. Rodríguez-Baeza A, Nebot J, Ferreira B, Reina F, Pérez J, Sañudo JR, et al. An anatomical study and ontogenetic explanation of 23 cases with variations in the main pattern of the human brachioantebrachial arteries. J Anat 1995;187(Pt 2):473-9. 2. Aharinejad S, Nourani F, Hollensteiner H. Rare case of high origin of the ulnar artery from the brachial artery. Clin Anat 1997;10(4):253-8.

AIA

SBA

3. Jurjus A, Sfeir R, Bezirdjian R. Unusual variation of the arterial pattern of the human upper limb. Anat Rec 1986;215(1):82-3. SPA "A"

4. Skopakoff C. Variability of branches and distribution of the superficial brachial artery. Anat Anz 1959;106 (17-20):356-68.

SPA "B"

Figure 3. Showing the normal development of the brachial artery in “A” and that in the present case in “B”. SBA = Superficial brachial artery; RA = Radial artery; UA = Ulnar artery; MA = Median artery; AIA = Anterior interosseous artery; SPA = Superficial palmar arch.

distal portion of the latter, the radial artery, as a major artery of the forearm; the proximal portion of the SBA atrophies correspondingly.10 In the present case, it seems that in Stage III of Singer, ulnar artery came from brachial artery as usual.10 SBA continued as radial artery and anastomosis between SBA and brachial artery developed normally (See Fig. 3). However, brachial artery between origin of SBA and ulnar artery (‘A' in Fig. 3) retrogressed and lost its communication with common interosseous artery. The SBA failed to retrogress and continued to supply radial artery. The anastomosis between SBA and brachial artery (‘B’ in Fig. 3), which usually forms proximal part of radial artery now formed proximal part of ulnar artery, thus giving appearance that ulnar artery and radial artery are terminal branches of SBA and common interosseous artery (‘C’ in Fig. 3) came as a branch of ulnar artery.

Clinical Significance Gonzalez-Compta highlighted the diagnostic, interventional and surgical significance of such a vascular variation.11 Diagnostically, it may disturb the evaluation of angiographic images. Interventionally, accidental puncture of superficially placed arteries may occur while attempting venipuncture. Surgically, it is vulnerable in both orthopedic and plastic surgery operations. Hence, the anatomic knowledge of the vascular patterns of upper limb is of crucial importance not only for neurosurgeons, but for all those involved in

5. Fuss FK, Matula CW, Tschabitscher M. The superficial brachial artery. Anat Anz 1985;160(4):285-94. 6. McCormack LJ, Cauldwell EW, Anson BJ. Brachial and antebrachial arterial patterns; a study of 750 extremities. Surg Gynecol Obstet 1953;96(1):43-54. 7. Adachi B. 1:205-10.

Arterensystem

des

japaner.

Kyoto

1928;

8. Arey LB. Development anatomy. In: Development of Arteries. 6th edition, WB Saunders Company: Philadelphia 1957:p.375-7. 9. Jurjus AR, Correa-De-Aruaujo R, Bohn RC. Bilateral double axillary artery: embryological basis and clinical implications. Clin Anat 1999;12(2):135-40. 10. Singer E. Embryological pattern persisting in the arteries of the arm. Anat Rec 1933;55(4):403-9. 11. Gonzalez-Compta X. Origin of the radial artery from the axillary artery and associated hand vascular anomalies. J Hand Surg Am 1991;16(2):293-6. 12. Quain R. Anatomy of the arteries of the human body. Taylor & Walton: London 1844:p.326-37. 13. Gruber W. Zur Anatomie der Arteria radialis. Arch Anat Physiol Wissen Med 1864:p.434-55. 14. Muller E. Beitrage zur Morphologie des Gefässytstems. I. Die Armarterien des Menschen. Anat Hefte 1903;22: 377-575. 15. Miller RA. Observations upon the arrangement of the axillary artery and brachial plexus. Am J Anat 1939;64(1):143-63. 16. Rao PV, Chaudhary SC. Superficial brachial artery terminating as radial and superficial ulnar arteries: a case report. Centr Afr J Med 2001;47(3):78-80 17. Rodríguez-Niedenführ M, Vázquez T, Nearn L, Ferreira B, Parkin I, Sañudo JR. Variations of the arterial pattern in the upper limb revisited: a morphological and statistical study, with a review of the literature. J Anat 2001;199(Pt 5):547-66. 18. Patnaik VVG, Kalsey G, Singla RK. Branching pattern of brachial artery: a morphological study. J Anat Soc Ind 2002;51(2):176-86. 19. Kachlik D, Konarik M, Baca V. Vascular patterns of upper limb: an anatomical study with accent on superficial brachial artery. Bosn J Basic Med Sci 2011;11(1):4-10.

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Ferinject® improves 6MWT distance at week 243 LSM change in 6MWT distance from baseline (m)

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