AJCC-October

Peer Review Journal

ISSN 0972-70035

Single Copy Rs. 300/-

www.ijcpgroup.com

Volume 14, Number 6, October 2011, Pages 181-216

Dr KK Aggarwal Group Editor-in-Chief

Dr Praveen Chandra Guest Editor

Head Office: E - 219, Greater Kailash, Part 1, New Delhi - 48, India. e-Mail: emedinews@gmail.com, Website: www.ijcpgroup.com

eMedinewS is now available online on www.emedinews.in or www.emedinews.org From the Desk of Editor-in-Chief Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal

President, Heart Care Foundation of India; Sr Consultant and Dean Medical Education, Moolchand Medcity; Member, Delhi Medical Council; Past President, Delhi Medical Association; Past President, IMA New Delhi Branch; Past Hony Director. IMA AKN Sinha Institute, Chairman IMA Academy of Medical Specialities & Hony Finance Secretary National IMA; Editor-in-Chief IJCP Group of Publications & Hony Visiting Professor (Clinical Research) DIPSAR

16 October 2011, Sunday Dear Colleague, Why it is important to consult a qualified doctor in emergency?

One should not ignore warning signals as “time is life” in medical science. The three cardinal warning signals are: anything which is unusual, anything which cannot be explained and any symptom appearing for the first time in life. Time is life is an old saying. In heart attack, time is muscle and in brain, time is brain. Most acute emergencies will require emergent evaluation and treatment. Delay in treatment even of minutes can take away the life. In emergency one should not waste time to think, rush to a bigger hospital with full facilities and make sure that the person is attended to in time. Many hospitals may have ill equipped emergency departments or may have inadequately trained staff. In nursing homes the ER doctor may be from other systems of medicine. Most quacks and unqualified medical practitioners will the diagnosis and a precious time will often be lost which may lead to high mortality and morbidity.

In emergency medicine, the ‘Golden Hour’ refers to the first hour following traumatic injury being sustained by a casualty, during which there is the highest likelihood that prompt medical treatment will prevent death. If bleeding can be stopped and person can be infused enough fluids within first hour, most trauma death can be avoided. ‘Platinum ten minutes’ refer to first 10 minutes after trauma and indicate the importance of starting first aid within ten minutes to reduce the chances of death. Door to ECG Time: One should get an ECG within 10 minutes of chest pain.

A prolonged door-to-ECG time is associated with an increased risk of clinical outcomes in patients with ST-elevation heart attack.

Door-to-Doctor Time in Stroke: In emergency department arrival to initial physician evaluation should be less than 10 minutes in stroke or the mortality will be high. Door-to-neurologist time: In emergency department arrival to Paralysis Stroke Team Notification time should be less than 15 minutes. Door to CT scan time is the time before which the CT should be done in suspected paralysis. In the emergency department arrival to CT Scan initiation in stroke should be less than 25 minutes.

Door-to-CT Interpretation in stroke should be <45 minutes. Door to tPA time is the treatment window in paralysis: 80% of eligible paralysis patients presenting to the emergency department should be treated with tPA clot dissolving drug within 60 minutes. Door-to-antibiotic time in community-acquired pneumonia (CAP) is the time to start antibiotics. All patients hospitalized with CAP should receive antibiotics within 4 hours of admission Door-to-antibiotic time in meningitis (brain inflammation) of more than 6 hours is linked to high mortality (8.64 times).

Door-to-needle time in acute heart attack is the time before which the clot-dissolving drug should be given. In ST elevation heart attack, the doorto-needle time should be less than 30 minutes. Door-to-balloon time in angioplasty: Primary percutaneous coronary intervention is now preferred for most patients if it can be performed by an experienced operator within 90 minutes from presentation to the emergency department.

Dr KK Aggarwal Group Editor-in-Chief Fitness Update Six weeks of weight training increases bone density Osteoporosis or decreased bone density is a significant health problem in women and some men. Bone density, which decreases with age, is affected by bone loading, nutrition, and hormone status. Weight training is widely used as a method of preserving or increasing bone density. A study from Loyola Marymount University in Los Angeles found that bone density in the hip and spine increased by 2.7-7.7 percent in men but did not change in women, following a 24-week weight-training program that included squats and deadlifts. Weight training increases bone density more in men than women.

Malaria Update What the National Drug Policy of India says What is the treatment of mixed infections?

All cases of mixed infection are to be treated as Pf as per the drug policy applicable in the area plus primaquine for 14 days.

There are various kinds of ACTs. All consist of an artemisinin derivative (artesunate, artemether, artether or dihydroartemisinin) combined with a synthetic antimalarial (amodiaquine, lumefantrine, mefloquine or sulfadoxine-pyrimethamine). The ACT used in Government health services, (artesunate + sulfadoxine-pyrimethamine (SP) is considered optimal in India, and which is therefore used. The dose is 4 mg/kg body weight of artesunate (AS) daily for 3 days, combined with 25mg/ kg of sulfadoxine + 1.25 mg of pyrimethamine (SP) on the first day.

Strength of each artesunate tablet is 50 mg and each SP tablet contains 500mg sulfadoxine and 25mg pyrimethamine. ACT should be given only to confirmed P. falciparum cases found positive by microscopy or RDT. Other ACTs (see above) which have been duly registered

and authorized for marketing in India may be used as alternatives to artesunate + SP, for example in cases with hypersensitivity to sulphonamides.

According to current WHO guidelines, ACTs can be given in the second and third trimester of pregnancy. In the first trimester, they should be avoided, given the still relatively scarce data on their safety, unless no other effective antimalarial treatment is available. The recommended treatment in the first trimester of pregnancy is quinine orally.

—AC Dhariwal, Hitendrasinh G Thakor, Directorate of NVBDCP, New Delhi

Medicine Update What is the risk of transmission of the infection with hepatitis B from the carriers?

HBsAg–positive women who are pregnant should be counseled to inform their doctors so that hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine can be administered to their newborn immediately after delivery. HBIG and concurrent hepatitis B vaccine have been shown to be 95% efficacious in the prevention of perinatal transmission of HBV. Transmission of HBV from infected health care workers to patients has also been shown to occur in rare instances. The risk of infection after blood transfusion and transplantation of nonhepatic solid organs (kidneys, lungs, heart) from persons with isolated anti– HBc is low i.e. 0% to 13%. The risk of infection after transplantation of liver from HBsAg –negative, anti–HBc positive donors has been reported to be as high as 75% and is related to the HBV immune status of the recipients.

—Dr Neelam Mohan, Director Pediatric Gastroenterology, Hepatology and Liver Transplantation, Medanta – The Medicity)

Online Submission

Volume 14, Number 6, October 2011

An IJCP Group Publication

Contents From the Desk of Group Editor-in-Chief

Dr KK Aggarwal Group Editor-in-Chief IJCP Group emedinews@gmail.com

Dr Praveen Chandra Guest Editor, AJCC praveen.chandra@ medanta.org

Cigarettes Hurt Women’s Hearts more than Men’s

185

KK Aggarwal

Assistant Editor: Dr Nagendra Chouhan

Review Article

AJCC Speciality Panel

From Reperfusion to Regeneration and Beyond... 186

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 Faculty Dr GK Aneja Dr Ramesh Thakur Dr Balram Bhargava Dr HK Bali Dr HM Mardikar Dr Sanjay Mehrotra Dr Vivek Menon

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Anand Gopal Bhatnagar Editorial Anchor

Dr Keyur Parikh Dr Ajit Mullasari Dr Kirti Punamiya Dr MS Hiramath Dr VS Narain Dr SK Dwivedi Dr Raja Baru Panwar Dr Vijay Trehan Dr Rakesh Verma Dr Suman Bhandari Dr Ravi Kasliwal Dr Atul Abhyankar Dr Tejas Patel Dr Samir Dani

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor

IJCP Editorial Board

Vinod K Shah, Kavita K Shalia

Noninvasive Risk Stratification for Identification of Patients at Risk for Sudden Cardiac Death 196 Dharmendra Jain

imaging and investigation

Tissue Doppler Imaging in a Patient of Ventricular Septal Defect with Acute Aortic Regurgitation 199 SR Mittal

case report

Common Presentation of Uncommon Condition: Acute Heart Failure due to Ruptured Sinus of Valsalva 200 Anil Wanjari, Parimal Tayde, Vikram Kokate

Dr Alka Kriplani, Asian Journal of Obs & Gynae Practice Dr VP Sood, Asian Journal of Ear, Nose and Throat Dr Praveen Chandra, Asian Journal of Clinical Cardiology Dr Swati Y Bhave, Asian Journal of Paediatric Practice Dr Vijay Viswanathan, The Asian Journal of Diabetology Dr KMK Masthan, Indian Journal of Multidisciplinary Dentistry Dr M Paul Anand, Dr SK Parashar, Cardiology Dr CR Anand Moses, Dr Sidhartha Das, Dr Ramachandran, Dr Samith A Shetty, Diabetology Dr Ajay Kumar, Gastroenterology Dr Hasmukh J Shroff, Dermatology Dr Georgi Abraham, Nephrology Dr Sidharth Kumar Das, Rheumatology

Expert Opinion

Which Patients with Impaired Ventricular Function should Receive ACE Inhibitors?

203

Anjan Lal Dutta

clinical algorithm

Suggested Approach to the Patient with Suspected Heart Failure

205

Dr V Nagarajan, Neurology Dr Thankam Verma, Dr Kamala Selvaraj, Obs and Gyne

Advisory Bodies Heart Care Foundation of India Overseas Indian Peoples Foundation

Research Review

From the Journals ...

206

Volume 14, Number 6, October 2011

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

Emedinews Section

From eMedinewS

208

Lighter reading

Lighter Reading

Š Copyright 2011 IJCP Publications Pvt. 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 Pvt. 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.

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.

212

Dr. Good and Dr. Bad Situation: A

patient with angiography.

Get admitted for 24 hours

Mediclaim

wanted

You can go after six hours

Š IJCP Academy

Printed at IG Printers Pvt. Ltd., New Delhi E-mail: igprinter@rediffmail.com

Lesson: If you can justify that due to technological

advances, hospitalization is required for less than 24 hours, Mediclaim will be applicable.

Dr KK Aggarwal

Editorial & Business Offices Delhi

Mumbai

Kolkata

Bangalore

Chennai

Hyderabad

Dr Veena Aggarwal 9811036687 E - 219, Greater Kailash, Part 1, New Delhi - 110 048 Cont.: 011-40587513 editorial@ijcp.com drveena@ijcp.com drveenaijcp@gmail.com Subscription Dinesh: 9891272006 subscribe@ijcp.com Ritu: 09831363901 ritu@ijcp.com

Mr. Nilesh Aggarwal 9818421222

Sr. BM Ritu Saigal 9831363901

Sr. BM H Chandrashekar 9845232974

Sr. BM Venugopal 9849083558

Flat 5E, Merlin Estate Geetanjali 25/8 Diamond Harbour Road Kolkata - 700 008 Cont.: 24452066 ritu@ijcp.com

Arora Business Centre, 111/1 & 111/2, Dickenson Road (Near Manipal Centre) Bangalore - 560 042 Cont.: 25586337 chandra@ijcp.com

Sr. BM Chitra Mohan 9841213823 40A, Ganapathypuram Main Road Radhanagar Chromepet Chennai - 600 044 Cont.: 22650144 chitra@ijcp.com

Building No. D-10 Flat No 43, 4th Floor Asmita Co-operative Housing Society Marvey Road Near Charkop Naka Malad (W) Mumbai - 400 095 nilesh.ijcp@gmail.com

Sr.: Senior; BM: Business Manager

H. No. 16-2-751/A/70 First Floor Karan Bagh Gaddiannaram Dil Sukh Nagar Hyderabad 500 059 Cont.: 65454254 venu@ijcp.com

From the Desk of Group Editor-in-Chief

Cigarettes Hurt Womenâ&#x20AC;&#x2122;s Hearts more than Menâ&#x20AC;&#x2122;s

Dr KK Aggarwal Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

A

ccording to the results of a large systematic review and meta-analysis, compared with nonsmokers, women smokers have a 25% greater relative risk of coronary heart blockages than men who smoke independent of other cardiovascular risk factors.

The study in Lancet by Rachel R Huxley, DPhil, from the University of Minnesota in Minneapolis, and Mark Woodward PhD, from Johns Hopkins University in Baltimore, further shows that the risk increases by 2% for every additional year of study follow-up.

Women might extract a greater quantity of carcinogens and other toxic agents from the same number of cigarettes than men. This explains why women who smoke have double the risk of lung cancer compared with their male counterparts.

Men who quit smoking also fared better than women who quit.

Although more men than women smoke, those women who do smoke have a greater risk of coronary heart disease and therefore targeting of both sexes is imperative for cessation of smoking. n

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

n

n

185

Review Article

From Reperfusion to Regeneration and Beyond...

Vinod K Shah*, Kavita K Shalia

Abstract The pathophysiology of AMI is a thrombotic occlusion of coronary artery leading to the death of heart muscles. The treatment therefore aims at restoration of the blood supply by reopening the artery that can be achieved pharmacologically as well as mechanically. Done in a timely manner, we are able to salvage at best only 2-4% of the myocardium at six months. The notion of repairing or regenerating lost myocardium via cell-based therapies is highly appealing. While every attempt must be made to optimize reperfusion and regeneration techniques, we must also look at prevention of atherosclerosis and cascade of acute events.

Key words: Coronary thrombosis, reperfusion, thrombolysis, streptokinase, tissue plasminogen activator

Reperfusion: A First Step towards Survival Coronary thrombosis, as the mechanism of acute myocardial infarction (AMI), was postulated in a Landmark study by DeWood and colleagues,1 who performed coronary angiography in the initial hours of AMI and found coronary occlusion to be present in 87% of patients studied within four hours of symptom onset. The nature of occlusion was shown to be thrombotic at emergency coronary artery bypass graft (CABG). A basis of reperfusion therapy was laid by the late 1970s in classical studies by Reimer, Jennings and colleagues.2,3 In their classical experiments in a canine model of coronary occlusion and reperfusion, myocardial cell death began within 15 minutes of occlusion and proceeded rapidly in a wave front from endocardium to epicardium. Myocardial salvage could be achieved by releasing the occlusion within a narrow time frame (<3-6 hours). The degree of salvage was inversely proportional to the duration of ischemia and occurred in a reverse wave front from epicardium to endocardium. The extent of necrosis could be modified by changing metabolic demands and varying collateral blood supply as well as the duration of occlusion. *Interventional Cardiologist Sir HN Hospital and Research Centre, Mumbai Address for correspondence Dr Vinod K Shah Interventional Cardiologist Sir HN Hospital and Research Centre Sir HN Hospital and Medical Research Society Raja Ram Mohan Road, Mumbai - 400 004 E-mail: vkshah45@hotmail.com

186

A pooled analysis of 58 studies (n = 14,214 angiographic observations) formed the basis for an overall profile of patency rates of several commonly used reperfusion regimens.4 In the absence of thrombolytic therapy, spontaneous perfusion was observed early after ST elevated myocardial infarction (STEMI) in only 15-21% of patients at 60-90 minutes after study entry. No further increases were observed within the first day, but subsequent follow-up demonstrated gradually increasing patency rates to about 60% by three weeks associated with spontaneous, aspirin or heparin facilitated intrinsic thrombolysis. All thrombolytic regimens improved early patency rates although the speed of thrombolysis varied. Streptokinase achieved the lowest patency rates at 60 and 90 minutes (48 and 51%, respectively).

Intermediate and roughly similar (patency) were (was) achieved by APSAC (anisoylated plasminogen streptokinase activator complex) and 3-hour tissue plasminogen activator (tPA) infusions (About 60% at 60 minutes and 70% at 90 minutes). Accelerated tPA infusion regimens achieved higher patency rates (74 and 84%, respectively). Combination therapy with reduced dose of tPA and abciximab had improved patency rates further upto 91 and 94%, respectively. In contrast to varying early patency with different regimens, patency rates at 3-24 hours and beyond have been found to be similar. Reocclusion rates have been generally higher after fibrin specific therapy than after nonfibrin agents (13% vs 8%) especially in the absence of optimal concurrent IV heparin in fibrin specific therapies.5 Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article The importance of concomitant heparin for maximizing the effect of tPA was demonstrated in an angiographic study by the Heparin and Aspirin Reperfusion Therapy (HART) investigators.6 The validity of these composite patency rates generated from many studies of varying design and size including ours7,8 was confirmed by a single large GUSTO angiographic study.9 This study enabled clear demonstration of the importance of early (90 minutes) Thrombolysis in Myocardial Infarction (TIMI) Grade 3 perfusion compared to TIMI II and TIMI I as an accurate predictor of mortality outcomes. Rates of complete (Grade 3) perfusion at 90 minutes were 54% with accelerated tPA, 29% with streptokinase plus subcutaneous heparin and 31% with streptokinase and IV heparin. Mortality at 30 days was lowest with TIMI III flow (4.4%); highest 8.9% among those with absent flow and intermediate in those with partial (TIMI II) flow (7.4%). The failure of ‘catch-up’ phenomenon by streptokinase to equalize survival rates indirectly underscores the relative importance of early reperfusion over late patency.

The use of fibrinolytic therapy has been studied extensively in more than 2,00,000 patients in randomized clinical trials. It is logically ideal for widespread use almost at any medical facility.

GUSTO 1 convincingly demonstrated that the potential of fibrinolytic agents to save myocardium and lives depends primarily on their ability to induce early, complete and sustained coronary artery recanalization.

Reperfusion by thrombolysis is an ‘illusion’ created by the imperfect barometer of the static 90 minutes angiographic view of coronary patency. Clinical and experimental data clearly demonstrate a sobering deterioration of benefit derived from coronary recanalization that is not early, nor rapid with incomplete reflow, with critical residual stenosis, unaccompanied by tissue level reperfusion, diminished by cyclical patency or frank reocclusion or possibly negated by reperfusion injury. Relative and absolute contraindications to thrombolytic therapy are also frequently noted e.g. severe hypertension, recent cerebrovascular accident, recent surgery or history of gastrointestinal hemorrhage. Thus appreciation of the limitations of current thrombolytic regimens has created a new window of opportunity to enhance the quality of reperfusion therapy for AMI. Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

The concept of catheter-based reperfusion for STEMI was introduced in 1979, when Rentrop and colleagues10 reported the pilot experience with balloon angioplasty to open the occluded infarct artery in seven patients. The field of catheter-based reperfusion for STEMI was subsequently developed through a series of observations and reports from multiple centers as well as randomized trials. The trials of catheter-based reperfusion compared with fibrinolysis have shown the advantage of angioplasty and stenting over pharmacologic therapy, even accounting for delays encountered in transporting the patients to PCI facilities. For many years there has been an active debate as to which reperfusion therapy is better.

Cumulatively 23 randomized trials in 7,739 patients showed an advantage for primary angioplasty in terms of short-term reduction of mortality, reinfarction and stroke.11 The vast majority of these patients underwent balloon angioplasty, but in recent years the use of stenting has largely replaced balloon angiolplasty. As summarized in pooled data of nine trials for primary stenting, the results were better for reduction of reinfarction and repeat target vessel revascularization.

However, in this combined study of 4,433 patients, there was actually an increase in mortality of 17% at 30 days which was statistically insignificant when compared with balloon angioplasty.12 Primary angioplasty may be the preferred approach in patients with extensive MI who have immediate access to a cardiac catheterization laboratory with experienced personnel. Patients, having: 1) Contraindication to thrombolytic therapy, 2) cardiogenic shock, 3) prior coronary bypass surgery or 4) stuttering onset of pain are candidates only for primary angioplasty.

Poor candidates are those in whom undue delays in access to catheterization laboratories facility would be expected or those with complex coronary artery disease including left main disease or a small MI. Distal embolization and microvascular dysfunction remain a major problem with both the technologies.

While experienced operator and high volume centers performing primary angioplasties are required for performing primary angioplasties, pharmacologic therapy can be instituted by almost any medical personnel at all times at any place all over the world.

Angioplasty saved 20 more lives/1,000 as compared to thrombolytic therapy clearly showing the superiority of the treatment.12 187

Review Article Boersma et al13 have shown in a systematic evaluation of fibrinolytic therapy that when applied within the first hour of symptom onset, 65/1,000 patients treated are saved as compared to only 29 lives saved when given three hours or more after infarct onset. Similar results were seen in the Gruppo Italano per lo Studio della Streptochinasi nell’ infarto Miocardico (GISSI)-I trial.14 Regrettably, the same studies showed that only a small fraction (3-5%) of patients presented within this golden hour. In contrast, mechanical reperfusion restores flow almost simultaneously with its successful application. Recently, investigators in the Stent versus thrombolysis for occluded coronary arteries in patients with AMI (STOP AMI) trial demonstrated that myocardial salvage index was significantly higher for angioplasty than for lysis at any interval from symptom onset and particularly so after the initial three hours.15 Besides early administration of therapy, complete reperfusion (TIMI 3) flow in the infarct artery at 90 minutes is also an important predictor of improved outcomes. When brisk flow is achieved with lytic therapy, substantial attrition of the benefit occurs because of intermittent patency (25%), reocclusion (13%) and impaired microvascular flow or no re-flow (23%). This concept of ‘illusion of reperfusion’ reflects our overestimation of the actual rate of complete reperfusion induced by lytic therapy which probably occurs in only 25% of those treated. Because, as compared to lytic treatment, primary angioplasty is capable of achieving TIMI 3 flow in at least 15-35% more patients, it is reasonable to assume that this difference in the patency rates will translate into clinical benefits.16 In a pooled analysis of 4 PAMI trials, Stone et al have shown that mortality at six months with TIMI 3 flow was 2.6% versus 6.1% with TIMI 2 flow and 22.2% with TIMI 1 flow. Further preangioplasty flow had a significant impact on the ability to achieve successful reperfusion as well as six months mortality after angioplasty wherein success rate was 98.1% for TIMI 3 flow as compared to 91.5%, if there was TIMI 0 flow before intervention.17 This observation becomes very important in considering strategies to facilitate primary angioplasty. Now that we have entered third decade in reperfusion therapy we can expect significant improvements in all aspects and finally optimal 188

outcomes and reduction in fatality and morbidity and improvement of long-term survival of AMI. Salavage of Myocardium However, after the introduction of these two modalities of reperfusion almost 20 years ago, there is very little evidence in the reduction of long-term mortality with the current established reperfusion therapies. On the other hand there is no evidence that the patients are presenting earlier with STEMI. Rapid reperfusion of the occluded arteries is of great importance in salvaging ischemic myocardium and limiting the size of infarct. This reduces early complications and significantly reduces mortality rates. Unfortunately, myocardial necrosis starts rapidly and the ‘damage is done’ largely before patients reach the hospital and before myocardial reperfusion at the tissue level is achieved. Although, it is mandatory and worthwhile to refine strategies to optimize reperfusion, it is still more essential to look beyond reperfusion and emphasize to prevent the sinister sequelae that is unleashed following the rupture of a plaque, subsequent MI and its complications.

Post MI remains a major cause of morbidity and mortality. Congestive heart failure is the commonest cause of frequent hospitalization after MI with 50% of the patients dying within five years of diagnosis.

Despite optimal pharmacotherapy and mechanical devices, the morbidity and mortality remains high.

Left ventricular (LV) function is the single important determinant factor for improved long-term survival after an AMI. Contemporary reperfusion strategies using percutaneous interventions are shown to be associated with only modest improvements in global LV function as evidenced by 2-4% increase in the ejection fraction (EF) at six months after an AMI.18 Thus a great amount of enthusiasm has been generated and research is going on to salvage the lost myocardium after an AMI. Cardiac transplant seems to be an ideal option for a vast number of these patients, but due to lack of donor hearts not even a partial demand can be met. Other measures like heart assist devices and pacemakers have shown not to prolong survival and are not cost-effective. Various strategies like thrombectomies and distal protection devices have been tried to improve the microvascular dysfunction that occurs after the reperfusion of myocardium Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article but have failed to salvage the myocardium.19 A host of pharmacotherapies have failed miserably except perhaps high-dose adenosine, the story for which is not completely closed. Other modalities like COOL MI, HOT MI, APEX MI and post-conditioning of MI,20-22 have not held any promise as shown by the studies. However, therapies with P13K inhibitors hold promise in preventing reperfusion injuries.23 The goal of reperfusion therapy is to restore the full nutritive myocardial flow and salvage myocardium, thereby reducing the mortality and morbidity. Tremendous resources, patients, physicians and industry alike have been expended while trying to achieve this goal. The results of these exercises have been mixed. Given the less than ideal results of salvaging ischemic myocardium, there is a great interest in myocardial regeneration or replacement therapy.

Regeneration Towards New Life The dogma that the heart is a terminally differentiated organ incapable of self-renewal has been challenged.

Although, the cells derived from resident cardiomyocytes or circulating cells have regenerating capacity, their ability to minimize the deleterious effects of ventricular myocardial remodeling is limited. The surviving cardiomyocytes bordering the infarct zone becomes hypertrophied as part of adaptive mechanism to compensate for the loss of myocardium. However, the normal angiogenesis after the MI is insufficient to meet the greater demands for oxygen and nutrients to prevent the apoptosis of the hypertrophied cardiomyocytes.

Therefore, increasing the perfusion to infarcted myocardium to enhance oxygen and nutrients through the formation of new vessels has the potential to improve the cardiac function. Currently, the treatment of AMI is reperfusion strategies. Primary angioplasty is the treatment of choice. However, reversal of heart failure would require not only restoration of blood supply but also replacement of myocytes. This can be achieved collectively by stem cells which will increase neoangiogenesis and also replace the lost cardiomyocytes by transdifferentiation. Since, early reports in animal models more than 10 years ago,24‑29 the stem cell field has made enormous advances in moving towards clinically applicable treatment options, and we are now at the dawn of a new era. Cell therapy seems to be a viable and probably the cheapest option available.

Recent experimental studies in animals suggested that Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

bone marrow progenitor cells might contribute to the regeneration of infarcted myocardium and enhance LV function in the peri-infarct region. In addition, it is possible that some of the cells transferred have differentiated into cardiomyocytes.30-33 These positive results gave way to clinical trials on human beings wherein transplantation of bone marrow cells (BMCs) into the target coronary artery was carried out.34-47 The results from small clinical studies suggest that therapy with adult bone marrow-derived cells reduces infarct size and improves LV functions and perfusion.

However, an extensive meta-analysis by Abdel-Latif et al48 of 18 eligible studies (n = 999 patients) involving adult bone marrow cells such as bone marrow nuclear cells, bone marrow mesenchymal cells and bone marrow-derived circulating progenitor cells measuring the same outcomes, demonstrated that, as compared to controls, bone marrow transplantation improved LVEF (pooled difference of 3.66%; 95% confidence interval [CI], 1.93-5.4%, p < 0.001); reduced infarct scar size (–5.49%; 95% CI: –9.1% to –1.8%; p = 0.003); and reduced LV end-systolic volume (– 4.8% ml; 95% CI–8.2 to –1.41ml; p = 0.006). This and other meta-analysis by Hristov et al,49 and Lipinski et al,50 of AMI studies demonstrated similar conclusion of modest improvements in physiologic and anatomic parameters in patients with AMI beyond conventional therapy. This further suggests carrying out multicenter randomized trials targeted to address the impact of intracoronary cell therapy on important outcomes and long-term event-free survival as compared to conventional therapy.

As the clinical trials continue at bedside, the research at benchside should not be abandoned. The basic research could make these trials effective and more specific. These include pre-treatment of the target tissues by use of cytokines and genetic strategies to favorably enhance active cell recruitment, their survival, retention, as well as rejuvenating the ‘sick’ cells before transplant. The recent development in this field, is to generate embryonic stem cell (ESC)like cells, called inducible pluripotent stem cells (iPS), by reprogramming adult somatic cells with genes regulating ESC pluripotency.51,52 While current strategies are not enough to salvage the myocardium, physicians will have to change their mind set by restricting their use to reperfusion modalities and use of antithrombotic, anticoagulants and devices 189

Review Article to improve the salvage of myocardium. They have to revolutionary think about newer ways which has been elusive in the last 20 years. Though every attempt must be made to optimize reperfusion and regeneration techniques, we must also look at prevention of atherosclerosis, rupture of plaque and the cascade of events following it, which are very difficult to arrest.

Our view of the mechanisms underlying the acute complications of atherosclerosis has shifted remarkably in the last decade. In the past era, we relied on flow limiting arterial stenoses and functional indexes of end-organ ischemia to guide our therapies. We held high-grade stenosis responsible for the bulk of acute ischemic complications of atherosclerosis. Considerable clinical data have compelled a reassessment of these concepts and have demonstrated that by identifying a plaque, a region or a patient before the development of infarction has obvious great advantages. This will enable us to treat at this stage which will help in inhibiting the cascade of events, its sequelae of complications which are difficult to arrest.

agonists, angiotensin-converting enzyme inhibitors, angiotensin II type I receptor antagonists, calcium channel blockers and aspirin.53 Apart from lowering LDL levels, upcoming therapies with a similar effect on coronary plaque are to accelerate reverse cholesterol transport by intravenous infusion of synthetic highdensity lipoprotein (HDL) wherein synthetic HDL particle containing complexes of phospholipids with either native or a variant form of native apolipoprotein (apo) A-1 Milano, are repeatedly infused intravenously.

Experiments with animal models have convincingly shown that induction of reverse cholesterol transport by infusion of phospholipids vesicles or either type of synthetic HDL leads to rapid mobilization of cholesterol from tissues, promotes fecal excretion of steroids and reverses endothelial dysfunction induced by hypercholesterolemia. Although at experimental stage, it is a promising way to stabilize the inflamed plaque.54-57 Other therapeutic targets that have emerged from the view point of pathophysiologic mechanism of vulnerable plaque are passivation of the endothelium, inhibition of inflammatory cytokine, inhibition of protease expression and inhibition of platelets.

Current findings establish the importance of qualitative aspects of plaques as decisive determinants of their propensity to cause acute complications, the so-called ‘vulnerable plaques’. This came from observations that in patients the ruptured-culprit plaque responsible for infarction, did not cause significant flow-limiting stenosis and was characterized by large necrotic lipid core and a thin fibrous cap which separated the core from the circulating blood. The formation of such thin-cap fibroatheromata results from a reactive inflammatory response of the growing plaque to continuous accumulation of lipids derived from lowdensity lipoprotein (LDL). Consequently adequate control of both lipid accumulation and inflammation in the plaque are crucial in the prevention of plaque rupture. Therefore, preventive measures taken are to stabilize the inflamed plaque which include reduction of LDL in the vessel wall by aggressively reducing serum LDL cholesterol levels and inhibition of LDL oxidation. At present, these requirements are pharmacologically best fulfilled by statins. It is also becoming increasingly evident that other cardiovascular drugs may also increase plaque stability such as peroxisome proliferators activated receptor α and γ

The final common pathway leading to fatal MI is the predominance of collagen breakdown over collagen synthesis in the fibrous cap. And, quite unexpectedly, the extracellular matrix and matrix degrading enzymes are both a target and a modulator in plaque destabilization.58,59 Matrix metalloproteinases (MMPs) form a large family of enzymes that collectively can degrade all components of the extracellular matrix, and there is widespread interest in developing specific MMP inhibitors for the prevention of atherosclerotic lesion progression and plaque rupture.60-64 Targeting at upfront of the cascade of coagulation and thus preventing formation of thrombus after plaque rupture is another area for pharmacologic intervention. Rupture of the plaque leads to the activation of the coagulation cascade by release of tissue factor. With this respect, clinical application of tissue factor pathway inhibitor (TFPI) for the prevention of thrombosis is considered. In cell culture systems in vitro and in various animal models recombinant TFPI is shown to prevent thrombosis and restenosis after arterial injury.65-68 Local gene transfer of an adenovirus encoding human TFPI into rabbits and pigs has been reported to prevent platelet-dependent thrombosis.69,70 and restenosis.71 Thus recombinant

And Beyond...

190

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article TFPI or TFPI gene transfer may attenuate thrombosis after arterial injury in the animal model however, a pioneering work on atherosclerotic patients is required to prove the clinical effect of TFPI.72 Another target is at the step of stabilization of thrombus. Agents inhibiting the formation of stable platelet plugs, but leaving behind intact platelet coverage, might block thrombosis possibly without eliciting major adverse bleeding effects. With this respect blocking the Gas6receptor- αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis. Inhibition of Gas6-receptor involved in the signaling pathways controlling irreversible aggregation could be a novel treatment paradigm.73 The above approaches are restricted to patients with severe clinical indication of the disease and are apt only if given to prevent the incidence which is predicted to occur 100% in a patient. In majority of the cases rupture of the plaque and its consequences are uncontrollable.

Recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Identifying genetic markers that increase the susceptibility of plaque rupture or increase susceptibility for thrombosis and subsequent MI could help in taking precautionary steps. Risk specific identification of genes can be evaluated in two ways, either by identifying high-risk individuals or for implicating therapy.74 Genetic linkage analyzes of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to coronary heart disease (CHD) or MI, however, genes that contribute to genetic susceptibility to these conditions remain to be identified definitively.75‑80 Current knowledge of the risk attributable to these variants is applicable only to a population and not to individuals. Providing patient-specific risk information based on genomic markers awaits a more comprehensive understanding of how these variants interact with each patient’s genetic background and other risk factors. Genetic tests that will add to the clinical utility of the traditional risk markers will have to go though intense prospective validation for their use as markers in identifying high-risk individuals or as potential drug targets. Thus, it would be worthwhile to continue to define strategies to optimize reperfusion; it appears that even more Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

emphasis should be placed on preventing these events. This has been the beginning of defining genes responsible for MI, such that at some point the risk could be ascertained very early in life. This could allow for appropriate lifestyle modification and if necessary treatment to prevent MI. Conclusion For aging diseases like atherosclerosis therapy starts from various levels encompassing prevention to cure.

We at present, have been able to some extent control risk factors to slow down the process of atherosclerosis and reperfuse the arteries at acute event but are not much successful in repairing the damaged myocardium.

Efforts are being directed towards regenerating myocardium through stem cells, however, preventing the rupture of the plaque or subsequent thrombosis in high-risk patients should also be aimed.

References 1. DeWood MA, Spores J, Nostke R, Mouser LT, Burroughs R, Golden MS, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303(10):897‑902.

2. Reimer KA, Lowe JE, Rasmussen MM, Jenneigs RB. The wave front phenomenon of myocardial ischemic cell death. I. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977;56(5):786-94.

3. Reimer KA, Jennings RB. The wavefront phenomenon of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40(6):633-44.

4. Granger CB, White HD, Bates ER, Ohman EM, Califf RH. A pooled analysis of arterial patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1994; 74(12):1220-8.

5. Barbagelata NA, Granger CB, Oqueli E, Suarez LD, Borruel M, Topol EJ, et al. TIMI grade 3 flow and reocclusion arter intravenous thrombolytic therapy: a pooled analysis. Am Heart J 1997;133(3):273-82.

6. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction.

Heparin-Aspirin Reperfusion Trial (HART) Investigators. N Engl J Med 1990;323(21):1433-7.

7. Shah VK, Daruwala DF, Karnik RD, Kumbla DK, Vijan VM. Coronary artery recanalisation following

191

Review Article IV urokinase therapy. J Assoc Physicians India 1987;35(1):23.

8. Gandhi MJ, Parikh JA, Kumbla DK, Shah VK, Pahalajani DB. Coronary artery recanalisation following IV urokinase therapy. The 9th Asian Pacific Congress of Cardiology. Auckland, New Zealand Feb, 1987.

9. The GUSTO Investigators. An International randomised trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329(10):673‑82.

10. Rentrop KP, Blanke H, Karsch KR, Kreuzer H. Initial experience with transluminal recanalization of the recently occluded infarct-related coronary artery in acute myocardial infarction - comparison with conventionally treated patients. Clin Cardiol 1979;2(2):92-105.

11. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20.

12. Nordmann AJ, Bucher H, Hengstler P, Harr T, Young J. Primary stenting versus primary balloon angioplasty for treating acute myocardial infarction. Cochrane Database Syst Rev 2005;(2):CD005313.

13. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of golden hour. Lancet 1996;348:771-5.

14. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo italiano per lo Studio della Streptochinasi nell’ infarto Miocardico [GISSI]. Lancet 1986;1:397-402.

15. Schömig A, Kastrati A, Dirschinger J, Mehilli J, Schricke U, Pache J, et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction.

Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 2000;343:385-91.

16. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;88(3):1361-74.

17. Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O’Keefe J, et al. Predictors of in-hospital and 6-month outcome after acute myocardial infarction in the reperfusion era: the Primary Angioplasty in Myocardial Infarction (PAMI) trial.

J Am Coll Cardiol 1995;25(2):370-7.

18. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, et al. Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Investigators. Comparison of angioplasty with stenting, with or without abciximab in acute myocardial infarction. New Engl J Med 2002; 346:957-66.

192

19. Kunadian B, Dunning J, Vijayalakshmi K, Thornley‑AR, de Belder MA. Meta-analysis of randomized trials comparing anti-embolic devices with standard PCI for improving myocardial reperfusion in patients with acute myocardial infarction. Catheter Cardiovasc Interv 2007; 69:488-96.

20. Dixon SR, Griffin JJ Rizik D, et al. A prospective randomized trial of mild systemic hypothermia during PCI treatment of ST elevation MI. 53rd Annual Scientific Session of the American College of Cardiology.

New Orleans Los Angeles, March, 2004.

21. Shandling AH, Ellestad MH, Hart GB, Crump R, Marlo D, Van Natta Bruce, et al. Hyperbaric oxygen and thrombolysis in myocardial infarction. The Hot MI Pilot Study. Am Heart J 1997;134:544-50.

22. Staat P, Rioufol G, Plot C, Cottin Y, Cung TT, L’Huillier I, et al. Postconditioning the human heart.

Circulation 2005;112(12):2143-8.

23. Doukas J, Wrasidlo W, Noronha G, Dneprovskaia‑E, Hood J, Soll R. Isoform-selective P13K inhibitors as novel therapeutics for the treatment of acute myocardial infarction. Biochem Soc Trans 2007;35(Pt 2): 204-6.

24. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001; 344:1750-7.

25. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett 2002;530:239-43.

26. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana‑F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114:763-76.

27. Laflamme MA, Myerson D, Saffitz JE, Murry CE. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res 2002;90:634-40.

28. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, et al. Chimerism of the transplanted heart. N Engl J Med 2002;346:5-15.

29. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Natl Med 2001;7:430-6.

30. Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, et al. Autologous transplantation of bone marrow cells improves damaged heart function.

Circulation 1999;100:II247-II256.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article 31. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-5.

32. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.

J Clin Invest 2001;107:1395-402.

33. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001;98:10344-9.

34. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913-8.

35. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).

Circulation 2002;106:3009-17.

36. Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J Am Coll Cardiol 2004;44:1690.

37. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.

38. Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration) trial. Circulation 2006;113:1287-94.

39. Sachachinger V, Erbs S, Elasser A, Haberbosch W, Hambrecht R, Hölschermann H, et al. REPAIR-AMI Investigators. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1199-209.

40. Fernández-Avilés F, San Román JA, García-Frade J, Fernández ME, Peñarrubia MJ, de la Fuente L, et al.

Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction.

Circ Res 2004;95:742-8.

41. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, et al. Autologous bone marrow-derived stem-cell transfer in patients with STsegment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2005;367:113-21.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

42. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.

N Engl J Med 2006;355:1199-209.

43. Shah VK, Tanavde V, Desai AJ, Jankharia B, Vasvani JB, Desai SS, et al. Bone marrow cells for myocardial repair: a new therapeutic concept. Indian Heart J 2007;59:482-90.

44. Shah VK, Tanavde V, Desai AJ, Jankharia BJ, Vasvani JB, Desai M, et al. Autologous bone marrow cells in acute myocardial infarction: clinical follow-up of 2 years. Indian Heart J 2007;59:394.

45. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107(18):2294-302.

46. Chen SI, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction.

Am J Cardiol 2004;94:92-95.

47. Erb S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, et al. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res 2005;97:756-62.

48. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult bone marrowderived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007;167:989-97.

49. Hristov M, Heussen N, Schober A, Weber C. Intracoronary infusion of autologous bone marrow cells and left ventricular function after acute myocardial infarction: a meta-analysis. J Cell Mol Med 2006;10:727‑33.

50. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, et al. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 2007;50: 1761-7.

51. Sanz-Ruiz R, Gutiérrez Ibañes E, Arranz AV, Fernández Santos ME, Fernández PL, Fernández-Avilés F. Phases I-III clinical trials using adult stem cells. Stem Cells Int 2010;2010:579142.

52. Shah VK, Shalia KK. Stem cell therapy in acute myocardial infarction: a pot of gold or pandora’s box.

Stem Cells International 2011;53:1-20.

53. Kovanen PT, Pentikäinen MO. Pharmacologic prevention of coronary plaque rupture: the major cause of acute coronary syndromes. Heart Metab 2007;36:9-14.

193

Review Article 54. Newton RS, Krause BR. HDL therapy for the acute treatment of atherosclerosis. Atheroscler Suppl 2002; 3:31-8.

55. Tardif JC, Gregoire J, L’Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. For the effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675-82.

56. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, et al. High-dose recombinant apolipoprotein A-I (milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization. Circulation 2001; 103:3047-50.

57. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300.

58. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94:2493‑503.

65. Jang Y, Guzman LA, Lincoff AM, Gottsauner-Wolf M, Forudi F, et al. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 1995;92:3041-50.

66. Brown DM, Kania NM, Chol ET, Lantieri LA, Pasia EN, Wun TC, et al. Local irrigation with tissue factor pathway inhibitors inhibits intimal hyperplasia induced by arterial interventions. Arch Surg 1996; 131:1086-90.

67. Asada Y, Hara S, Tsuneyoshi A, Hatakeyama K, Kisanuki A, Marutsuka K, et al. Fibrin-rich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta. Thromb Haemost 1998;80:506-11.

68. St. Pierre J, Yang LY, Tamirisa K, Scherrer D, De Ciechi P, Eisenberg P, et al. Tissue factor pathway inhibitor attenuates procoagulant activity and upregulated of tissue factor at the site of ballooninduced arterial injury in pigs. Arterioscler Thromb Vasc Biol 1999;19:2263-8.

59. Shah VK, Shalia KK, Abraham A, Kudalkar K, Payannavar S, Wakvalkar A, et al. Matrix degrading enzymes in acute myocardial infarction. Indian Heart J 2007;59:415.

69. Nishida T, Ueno H, Atsuchi N, Kawano R, Asada Y, Nakahara Y, et al. Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress-induced recurrent thrombosis in the injured carotid artery of the rabbit. Circ Res 1999;84:1446-52.

60. Bendeck MP, Irvin C, Reidy MA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res 1996;78:38-43.

70. Zoldhelyi P, McNatt J, Shelat HS, Yamamoto Y, Chen ZQ, Willerson JT. Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human TFPI. Circulation 2000;101:289-95.

61. Botos I, Scapozza L, Zhang D, Liotta LA, Meyer EF. Batimastat, a potent matrix metalloproteinase inhibitor, exhibits an unexpected mode of binding. Proc Natl Acad Sci USA 1996;93:2749-54.

71. Atsuchi N, Nishida T, Marutsuka K, Asada Y, Kamikubo Y, Takeshita A, et al. Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries. Circulation 2001;103:570-5.

62. Zempo N, Koyama N, Kenagy RD, Lea HJ, Clowes AW. Regulation of vascular smooth muscle cell migration and proliferation in vitro and injured rat arteries by a synthetic matrix metalloproteinase inhibitor.

Arterioscler Thromb Vasc Biol 1996;16:28-33.

63. George SJ. Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Expert Opin Investig Drugs 2000;9:993-1007.

64. Bellosta S, Canavesi M, Favari E, Cominacini L, Gaviraghi G, Fumagalli R, et al. Lacidipine [correction of Lalsoacidipine] modulates the secretion of matrix

194

metalloproteinase-9 by human macrophages. J Pharmacol Exp Ther 2001;296:736-43.

72. Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor. Basic and clinical aspects. Arterioscler Thromb Vasc Biol 2002;22:539-48.

73. Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest 2005;115:237-46.

74. Topol EJ, Smith J, Plow EF, Wang QK. Genetic Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet 2006;15 Spec. No 2: R117-23.

75. Yamada Y, Matsuo H, Segawa T, Watanabe S, Kato K, Hibino T, et al. Assessment of genetic risk for myocardial infarction. Thromb Haemost 2006;96:220-7.

76. Miller DT, Ridker PM, Libby P, Kwiatkowski DJ. Atherosclerosis: the path from genomics to therapeutics.

J Am Coll Cardiol 2007;49:1589-99.

77. Anderson JL, Carlquist JF, Horne BD, Hopkins PN. Progress in unraveling the genetics of coronary artery

disease and myocardial infarction. Curr Atheroscler Rep 2007;9:179-86.

78. Nishihama K, Yamada Y, Matsuo H, Segawa T, Watanabe S, Kato K, et al. Association of gene polymorphisms with myocardial infarction in individuals with or without conventional coronary risk factors. Int J Mol Med 2007;19:129-41.

79. Yamada Y, Ichihara S, Nishida T. Molecular Genetics of Myocardial infarction. Genomic Med 2008;2:7-22.

80. Roberts R. Genetics of premature myocardial infarction.

Curr Atheroscler Rep 2008;10:186-93.

n

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

n

n

195

Review ARticle

Noninvasive Risk Stratification for Identification of Patients at Risk for Sudden Cardiac Death Dharmendra Jain

Abstract Noninvasive risk stratification techniques may be useful to identify patients who do not have low LVEF who nevertheless are at substantial risk for SCD. Key words: Risk stratification, sudden cardiac death, LVEF

G

iven the availability of therapies to prevent sudden cardiac death (SCD) due to otherwise fatal ventricular tachyarrhythmias, it is important to differentiate noninvasive risk stratification techniques that enhance the ability to identify SCD from total mortality. The relative ability for each of the described techniques varies and the optimal way to combine and use these techniques in clinical practice remains unclear. Low left ventricular ejection fraction (LVEF), which is the most widely used test on which International Classification of Diseases (ICD) intervention is recommended, does not have a particularly high discriminatory ability to identify SCD rather than non-SCD mortality.

Although data exist supporting the concept that noninvasive risk stratification techniques may be useful to identify patients with low LVEF who are at low risk for SCD, this requires further testing. There are also data to support the concept that noninvasive risk stratification techniques may be useful to identify patients who do not have low LVEF who nevertheless are at substantial risk for SCD. Because most SCD occurs in this latter group, substantial effort is justified in evaluating, testing and ultimately implementing risk stratification strategies in this group.

Definition of Sudden Cardiac Death The ICD-10, Tenth Revision defines SCD as death from any cardiac disease that occurs out of hospital, in an emergency department or in an individual reported dead on arrival to a hospital. In addition, death should

Attending Consultant, Dept. of Interventional Cardiology Max Heart and Vascular Institute, New Delhi

196

occur within one hour after the onset of symptoms.

SCD may be due to ventricular tachycardia/fibrillation, asystole or nonarrhythmic causes. This article focuses on risk factors for ventricular tachycardia/fibrillation.

Incidence The annual incidence of sudden arrhythmic deaths has been estimated between 1,84,000 and 4,62,000 in the US.  Only 2-15% reach the hospital  Vast majority have structural heart disease, predominantly coronary artery disease (CAD) Approach to Improve Outcome Related to Sudden Cardiac Death  Secondary prevention Improve resuscitation: AHA ‘chain of survival’ n early access to medical care, early CPR, early defibrillation and early advanced care n Treat survivors  Primary prevention n Identify the ‘at risk’ patient prior to the event n Treat the ‘at risk’ patient Underlying Heart Disease Among patients with SCD, an overwhelming majority has some form of structural heart disease, most commonly CAD in the United States. This article is limited to risk stratification techniques for ischemic, dilated and hypertrophic cardiomyopathies. Although other types of structural heart disease and inherited ion channel abnormalities are also associated with a risk for SCD, the risk stratification strategies and data in these entities are diverse.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Review Article Risk Stratification Techniques and Pathophysiology of SCD The specific techniques focus on detection of:  Slowed ventricular conduction  Heterogeneities in ventricular repolarization  Imbalance in autonomic tone  Extent of myocardial damage and scar formation  Ventricular ectopy Noninvasive Techniques  Left ventricular ejection fraction  ECG-based techniques: QRS duration, QT interval/QT dispersion, signal averaged ECG, short-term heart rate variability.  Long-term ambulatory ECG (Holter)-based techniques: Ventricular ectopy/nonsustained ventricular tachycardia, long-term heart rate variability, heart rate turbulence.  Exercise test/functional status-based techniques: Exercise capacity and New York Heart Association class, heart rate recovery and recovery ventricular ectopy, T-wave alternans; Baroreceptor sensitivity.

Other Testing, Techniques and Approaches that should be Considered Evaluation of myocardial ischemia is important, as this may serve as an important trigger for life-threatening ventricular arrhythmias, either in patients with preexisting substrate or less commonly, as a primary cause. Electrophysiologic testing has demonstrated utility in identifying the substrate for sustained ventricular tachycardia. Newer techniques such as characterization of infarct size and/or morphology by contrast enhanced MRI could provide information on susceptibility to ventricular tachyarrhythmias. Newer approaches that encompass a more general evaluation of ‘vulnerability’ to sudden death, including genetic profiling, serum markers and new imaging approaches, may be developed. Finally, if risk stratification is to be applied to a population with an overall low risk of SCD to identify a subgroup with more significant risk, it is likely that multiple tests will need to be incorporated into a risk stratification strategy.

Current Status of Risk Stratification Multiple techniques are available with variable amounts of retrospective and prospective data in support of each Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

technique. Even the most promising techniques (i.e.

LVEF) have limited sensitivity to identify the patient at risk for SCD. Patient-based Approach to Risk Stratification The specific goal for the individual patient should be identified. There is no consensus on the level of risk that justifies an intervention. It is important to consider the type of underlying heart disease and other factors that may have time-dependent effects on risk, such as myocardial infarction or coronary artery bypass surgery.

Using the Risk Stratification Techniques to Prevent SCD The approach to prevention of SCD is multifactorial.

Maximize appropriate medical therapies - β-blockers, ACE inhibitors/angiotensin receptor blockers. Consider implantable cardioverter-defibrillator in high-risk patients, as defined in prior 2006 ACC/AHA/ESC guidelines.

Referral to a Specialist Because of a lack of clinical trial data establishing a comprehensive risk stratification strategy that can be Noninvasive Risk Stratification Techniques to Identify the ‘At Risk’ Patient Prior to the Event  Ejection fraction  ECG-based techniques n QRS duration n QT interval, QT dispersion n Signal averaged ECG n Short-term heart rate variability  Baroreceptor sensitivity  Long-term ambulatory ECG (Holter)-based techniques n Ventricular ectopy and nonsustained VT n Long-term HRV n Heart rate turbulence  Exercise test/functional status based techniques n Exercise capacity and NYHA class n Heart rate recovery and recovery ventricular ectopy n Microvolt T-wave alternans

197

Review Article easily applied, there is ambiguity in the evaluation of the patient for risk for SCD. A specialist well-versed in these techniques and their relative value in various clinical scenarios may provide guidance regarding their use and interpretation.





Left Ventricular Ejection Fraction

Low LVEF is a well-demonstrated risk factor for SCD. Although low LVEF has been effectively used to select high-risk patients for application of therapy to prevent sudden arrhythmic death, LVEF has limited sensitivity: The majority of SCDs occur in patients with more preserved LVEF. Electrocardiogram 







QRS duration: Most retrospective analyses show increased QRS duration is likely a risk factor for SCD. Clinical utility to guide selection of therapy has not yet been tested.

QT interval and QT dispersion: Some retrospective analyses data show that abnormalities in cardiac repolarization are risk factors for SCD. Clinical utility to guide selection of therapy has not yet been tested.

Signal-averaged ECG (SAECG): An abnormal SAECG is likely a risk factor for SCD, based predominantly on prospective analyses. Clinical utility to guide selection of therapy has been tested, but not yet demonstrated.

Short-term heart rate variability (HRV): Limited data link impaired short-term HRV to increased risk for SCD. Clinical utility to guide selection of therapy has not yet been tested.

Long-term Ambulatory ECG Recording (Holter) 

Ventricular ectopy and NSVT: The presence of ventricular arrhythmias (VPBs, NSVT) on Holter monitoring is a well-demonstrated risk factor for SCD. In some populations, the presence of NSVT has been effectively used to select highrisk patients for application of therapy to prevent sudden arrhythmic death. This may also have limited sensitivity.

Long-term HRV: Low HRV is a risk factor for mortality, but likely is not specific for SCD. Clinical utility to guide selection of therapy has been tested, but not demonstrated.

Heart rate turbulence: Emerging data show that abnormal heart rate turbulence is a likely risk factor for SCD. Clinical utility to guide selection of therapy has not yet been tested.

Exercise Test/Functional Status 









Exercise capacity and NYHA class: Increasing severity of heart failure is a likely risk.

Factor for SCD, although it may be more predictive of risk for progressive pump failure.

Clinical utility to guide selection of therapy has not yet been tested.

Heart rate recovery and recovery ventricular ectopy: Limited data show that low heart rate recovery and ventricular ectopy during recovery are risk factors for SCD. Clinical utility to guide selection of therapy has not yet been tested.

T-wave alternans: A moderate amount of prospective data suggests that abnormal T-wave alternans is a risk factor for SCD. Clinical utility to guide selection of therapy has been evaluated, but the results to date are inconsistent.

Baroreceptor Sensitivity

A moderate amount of data suggests that low BRS is a risk factor for SCD. Clinical utility to guide selection of therapy has not yet been tested.

Challenges for Risk Stratification 









Risk is continuous function and not a dichotomous determination.

No consensus on level of risk that justifies an intervention.

How do we deal with time-dependent changes in risk?

Do we need to implement a multi-component risk stratification strategy?

Need more clinical trial data focused on risk stratification. n

198

n

n

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

imaging and investigation

Tissue Doppler Imaging in a Patient of Ventricular Septal Defect with Acute Aortic Regurgitation SR Mittal

Abstract Tissue Doppler imaging of a case of ventricular septal defect with acute aortic regurgitation is presented. There was significant blunting of Aa wave with normal Ea velocity. This finding can also differentiate acute from chronic aortic regurgitation.

Key words: Aortic regurgitation, diastolic dysfunction, echocardiography, tissue Doppler imaging, ventricular septal defect

A

22-year-old male with recent onset of progressive breathlessness was referred for echocardiography.

Routine echocardiographic evaluation revealed a subaortic ventricular septal defect (9.6 mm) with left to right shunt, mild-to-moderate aortic regurgitation, premature closure of mitral valve (Fig. 1), diastolic mitral regurgitation and restrictive pattern of mitral flow (Fig. 2). Tissue Doppler images of medial and lateral mitral annulus are shown in Figure 3 and 4. In both parts of mitral annulus, early diastolic velocity (Ea) was normal with marked reduction in late diastolic velocity (Aa). This suggests that active relaxation was normal with significant impairment of compliance. This finding can also differentiate chronic aortic regurgitation from acute aortic regurgitation. In chronic regurgitation with heart failure, early relaxation velocity progressively decreases as left ventricular dysfunction deteriorates.

We could not find any reference on this topic in literature. Pericardial constriction also produces restrictive physiology with normal early relaxation velocity on tissue Doppler imaging.

Figure 1. M-mode echocardiograph showing mid-diastolic closure of mitral valve.

LV = Left ventricle; M = Mitral valve; RV = Right ventricle.

Figure 2. Pulsed Doppler evaluation showing restrictive pattern of mitral flow and diastolic mitral regurgitation.

E = Early diastolic flow.

Figure 3. Tissue Doppler imaging of medial mitral annulus.

Figure 4. Tissue Doppler imaging of lateral mitral annulus.

Aa = Late diastolic velocity;

Aa = Late diastolic velocity;

Ea = Early diastolic velocity;

Ea = Early diastolic velocity;

Sa = Systolic velocity.

Sa = Systolic velocity.

Ex-Senior Professor and Head Dept. of Cardiology St. Francis Hospital, Ajmer, Rajasthan Address for correspondence Dr SR Mittal XI /101, Brahampuri, Ajmer, Rajasthan - 305 001 E-mail: sarweshwar_mittal@rediffmail.com

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

199

case report

Common Presentation of Uncommon Condition: Acute Heart Failure due to Ruptured Sinus of Valsalva Anil Wanjari*, Parimal Tayde**, Vikram Kokate†

Abstract We describe a case of a patient with a recent onset of continuous murmur and acute right congestive heart failure, diagnosed to have ruptured aneurysm of the noncoronary sinus of Valsalva, by transthoracic two-dimensional echocardiography.

Key words: Transthoracic echocardiography, congenital, coronary sinus of valsalva aneurysm

Case Report A 28-year-old male presented with a history of acute dyspnea, congestive heart failure and tachycardia.

Clinical examination revealed a pulse of 110/min regular, collapsing in nature and blood pressure was 120/50 mmHg. The neck veins were distended and the liver was palpable 2 cm below the right costal margin.

There was pedal edema and bilateral basal crackles were present. On auscultation, a Grade IV/VI continuous, harsh murmur, was heard maximal along the left sternal border, also audible all over precordium.

Laboratory examination revealed normal hemogram, electrolytes, liver function tests and creatinine. Chest X-ray demonstrated cardiomegaly with engorged pulmonary vessels and bilateral pleural effusion.

Transthoracic two-dimensional echocardiography demonstrated an aorta-to-right atrial communication through a ruptured noncoronary sinus of Valsalva. There was enlargement of the right-sided chambers. ColorDoppler technique showed shunting from the sinus of Valsalva with the typical ‘wind sock’ appearance into the right ventricle1-6 and, passing through the tricuspid leaflets, into the right atrium (Fig. 1 and 2). The *Professor **Assistant Professor † Resident Dept. of Medicine Jawaharlal Nehru Medical College Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra Address for correspondence Dr Parimal Tayde Assistant Professor Dept. of Medicine Datta Meghe Institute of Medical Sciences Sawangi, Wardha, Maharashtra - 442 001 E-mail: parimaltayde@yahoo.co.in

200

Figure 1. Transthoracic two-dimensional echocardiography: Short axis view shows normal coronary sinus and a mobile ‘wind sock’ aneurysm protruding into right ventricle.

Figure 2. Short axis view with color-Doppler technique shows the shunting blood flow from the sinus of Valsalva through the ‘wind sock’ into the right ventricle.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Case Report possibility of infective endocarditis was excluded on the basis of patient’s history and laboratory investigations.

Before the widespread use of echocardiography for cardiac evaluation, ruptured sinus of Valsalva in the living patient was rarely described and most of these reports came from autopsy.1 Aneurysms of the sinus of Valsalva account for less than 1% of congenital cardiac anomalies.2 The basic defect is the absence of the media in the sinus wall, which appears to be due to a lack of continuity between the media of the aorta and the annulus of the aortic valve.5 Ninety percent of these aneurysms originates in the right or noncoronary sinus and rupture into the right ventricle or the right atrium. Aneurysm arising in the noncoronary sinus almost always ruptures into the right atrium. Aneurysms arising in the right coronary sinus generally communicate with the right ventricle.

Rarely, rupture may occur into the pericardium, the pleural space or the left heart chambers.3 Complications of rupture of aneurysms of sinus of Valsalva are aortic regurgitation, coronary insufficiency, arrhythmias and rupture.4

Conventional two-dimensional echocardiography is a useful means to diagnose ruptured sinus of Valsalva aneurysm.

References 1. Dev V, Goswami KC, Shrivastava S, Bahl VK, Saxena A. Echocardiographic diagnosis of aneurysm of the sinus of Valsalva. Am Heart J 1993;126(4):930-6.

2. Mok CK, Cheung KI, Wang RY. Unruptured right coronary sinus to left ventricle aneurysm diagnosed by cross sectional echocardiography. Br Heart J 1985;53(2):226-9.

3. Henze A, Huttunen H, Bjõrk VO. Ruptured sinus of valsalva aneurysms. Scand J Thorac Cardiovasc Surg 1983;17(3):249-53.

4. Rigo T, Zeppellini R, Cucchini F. Rupture of an aneurysm of the noncoronary sinus of valsalva into the right atrium: the ‘wind sock’ echocardiographic appearance. Ital Heart J 2001;2(3):237-8.

5. Edwards JE, Burchell HB. The pathological anatomy of deficiencies between the aortic root and the heart, including aortic sinus aneurysms. Thorax 1957;12(2):125-39.

6. Ahmad RA, Sturman S, Watson RD. Unruptured aneurysm of the sinus of Valsalva presenting with isolated heart block: echocardiographic diagnosis and successful surgical repair. Br Heart J 1989;61(4):375-7.

n

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

n

n

201

Back to Future

202

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Expert Opinion

Which Patients with Impaired Ventricular Function should Receive ACE Inhibitors?

Anjan Lal Dutta

A

ngiotensin-converting enzyme inhibitors (ACEIs) as a class of drugs have statutory effect of blocking the renin-angiotensin-aldosterone system (RAAS). RAAS blockade inhibits the deleterious effects of angiotensin II, responsible for worsening left ventricular (LV) dysfunction. Moreover, by preventing LV remodeling after myocardial infarction (MI), ACEIs prevent development of LV dysfunction and failure.

ACEIs should therefore be used in all cases of MI if not contraindicated to prevent LV dysfunction and also at any situation of impaired LV function-ischemic or nonischemic to prevent worsening of heart failure (Table 1). The clinical benefits include reduction in mortality, re-hospitalization, progress of heart failure, observed in men and women, diabetic and nondiabetic, ischemic and nonischemic heart failure.

Dosage of ACEI

Table 1. Indications of ACEIs in Heart Failure (European Society of Cardiology Guidelines - 2005) Setting

Class of indication

All patients with symptomatic heart failure with reduced LVEF belonging to NYHA Class II-IV

I

LV systolic dysfunction with or without symptom after MI

I

LV systolic dysfunction (LVEF <40-45%) without symptom.

No previous MI

I

Diastolic heart failure

II A

Table 2. ACE Inhibitor Dose Starting dose

Target dose

Captopril

6.25 mg t.i.d.

50-100 mg t.i.d.

Enalapril

2.5 mg b.i.d.

10-20 mg/daily

Lisinopril

2.5-5 mg/daily

30-35 mg/daily

Ramipril

2.5 mg/daily

5-10 mg/daily

1 mg/daily

4 mg daily

The dose of ACEIs should not be titrated based on symptomatic improvement alone but uptitrated to the dosage shown to be effective in the large controlled trials in heart failure and LV dysfunction (Table 2).

of heart failure, with preserved LV systolic function (Class II A indication).

Which ACEI?

Side Effects

Although the RAAS blockade is a class effect of ACEIs, but some differences exist regarding tissue specificities.

Beneficial effect in large trials are mostly with captopril, enalapril, ramipril, lisinopril and trandolapril.

Angioneurotic edema is rare; but cough is quite common. It may become an important limitation of ACEIs in 15-20% patients and is considered a class effect. Patients not tolerating ACEIs should be switched to angiotensin receptor blockers (ARBs).

LV Diastolic Heart Failure Controversy exists regarding pharmaceutical therapy in diastolic heart failure. ACEIs may improve relaxation and cardiac distensibility and regress LV hypertrophy on long-term therapy. Accordingly, ACEIs are recommended for treatment of patients with symptoms

Professor Dept. of Cardiology Vivekananda Institute of Medical Sciences, Kolkata Consultant Dept. of Cardiology Peerless Hospital and BK Roy Research Centre, Kolkata

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Trandolapril

Dosing  Start with low-dose.  Double the dose at two weeks interval (faster titration in asymptomatic LV dysfunction, mild heart failure, hypertension and inhospitalized patients).  Try to achieve the target dose or highest tolerated dose.

Worsening Renal Failure

Some rise of serum creatinine (<30%) is expected at the beginning of treatment but it plateaus within a few 203

expert opinion Contraindications Both for ACEIs and ARBs

History of angioneurotic edema Pregnancy Bilateral renal artery stenosis

Caution Significant renal dysfunction Hyperkalemia (Serum K+ >5 mg mEq/l) Symptomatic hypotension (SBP <90 mmHg) Problem solving Hypotension

Reconsider need for other BP lowering drugs, nitrate, CCBs, other vasodilators If no fluid retention, consider reducing or discontinuing diuretics Reduce dose of ACEIs

Cough Exclude other causes of cough (lung/ bronchial disease, pulmonary edema).

If very troublesome and no other detectable cause is detected, consider changing to ARB.

weeks. No action is needed. Continue to monitor. If serum creatinine continues to rise, stop ACEI or ARB. Seek nephrologistâ&#x20AC;&#x2122;s opinion.

If serum K+ level >6 mEq/l stop ACEI. Seek nephrologistâ&#x20AC;&#x2122;s opinion. Reconsider concomitant use of nephrotoxic drug, NSAIDs, potassium supplement, potassium - sparing diuretics.

ACE Inhibitor, ARB or Both?

ACEIs should be the first-line of treatment. If there is intolerance to ACEI or persistent cough with ACEI change to ARB. ACEI and ARB combination data in heart failure studies are not uniform and adequate enough to justify its routine use.

Only ARB as first-line of treatment in heart failure is not recommended unless ACEI intolerance or side effects as above are present. n

204

n

n

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

clinical algorithm

Suggested Approach to the Patient with Suspected Heart Failure Patient with suspected heart failure Dyspnea present?

Yes

No

ECG and chest radiograph

Abnormal

Normal

Echocardiogram

Consider other causes.

Normal Consider other causes.

Consider other causes.

Abnormal

Dilated cardiomyopathy

Diastolic dysfunction

Technically unsatisfactory Radionucleotide scan

Systolic dysfunction

Abnormal More detailed history, physical, and laboratory testing  Medical history: anemia, cardiotoxic medications, chest irradiation, collagen vascular disease, CAD, diabetes mellitus, hemochromatosis, hypercholesterolemia, hypertension, infectious disease, peripheral vascular disease, pheochromocytoma, rheumatic fever, sexually transmitted disease, thyroid disease, valvular heart disease  Social history: international travel, substance abuse (alcohol, drugs)  Family history: CAD, cardiac conduction abnormality, cardiomyopathy, skeletal myopathy, sudden death  Physical examination: abnormal deep tendon reflexes, bradycardia or tachycardia, bronze skin, cardiac arrhythmia, dependent edema, diminished peripheral pulses or arterial bruits, displaced cardiac apex, elevated blood pressure, heart murmur, hepatomegaly or hepatojugular reflux, joint inflammation, jugular venous distention, pallor, pericardial rub, pulmonary rales, third heart sound, thyromegaly or thyroid nodule, weight loss or gain  Laboratory tests: antinuclear antibodies and rheumatoid factor (if connective tissue disease is suspected), complete blood count, liver and kidney function tests, HIV screening (in high-risk patient), metanephrines (if pheochromocytoma is suspected), thyroid-stimulating hormone, serum electrolytes and lipid panel, serum ferritin (if hemochromatosis is suspected), urinalysis, viral titers (if patient had recent viral infection)  Coronary angiography in patient with CAD and angina  Endomyocardial biopsy in patient with dilated cardiomyopathy and rapidly progressive symptoms

Normal Consider other causes.

Cause identified?

No Establish severity.

Treat heart failure.

Treat comorbid conditions.

Yes Establish severity.

Treat cause.

Treat heart failure.

Treat comorbid conditions.

ECG = Electrocardiogram; CAD = Coronary artery disease; HIV = Human immunodeficiency virus.

Source: Adapted from Am Fam Physician. 2004;70(11):2145-2152.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

205

Research Review

From the Journals ...

The Role of Echocardiography in the Management of Atrial Fibrillation Atrial fibrillation is the most common arrhythmia in clinical practice and is associated with significant mortality and morbidity due to stroke. Echocardiography plays a critical role in defining the clinical context of the arrhythmia and guiding management.

Transesophageal echocardiography is used to exclude intracardiac thrombus to facilitate early cardioversion.

Emerging technologies such as catheter ablation and left atrial appendage occlusion have expanded the role of echocardiography such that it is essential to achieve a high standard of cardiac imaging to optimize patient outcomes.

Wheeler R, Masani ND. Eur J Echocardiogr 2011;12(10):i33-i38.

A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity Rationale: Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors and Raf-1/ B-Raf, kinases that are upstream of extracellular signalregulated kinases (ERKs) and signal cardiomyocyte survival in the setting of stress. Objectives: To explore the potential use of zebrafish as a preclinical model to predict cardiotoxicity and to determine whether sorafenib has associated cardiotoxicity, and, if so, define the mechanisms. Methods and Results: We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib).

Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirusmediated gene transfer of constitutively active MEK1, which restores ERK activity even in the presence of 206

sorafenib. Whereas growth factor-induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenibinduced cardiomyopathy in zebrafish. Conclusions: Zebrafish may be a valuable preclinical tool to predict cardiotoxicity. The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act through a hereto-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs. Cheng H, Kari G, Dicker AP, et al.

Circ Res 2011 Oct. 13. [Epub ahead of print]

Ischemia-induced up-regulation of Tolllike Receptor 2 in Circulating Monocytes in Cardiogenic Shock Aims: To investigate the role of toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarction (AMI) and in cardiogenic shock (CS). Methods and Results: In patients with uncomplicated AMI (n = 20), CS (n = 30) and in age-matched healthy controls (HC; n = 20), TLR2 expression on monocytes was assessed by flow cytometry. Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL6) expression in monocytes was analyzed by intracellular cytokine staining. TLR2 expression was increased in patients with AMI compared with HC (mean fluorescence intensity [MFI] 111.1 ± 8.2 vs 66.9 ± 1.5, p < 0.001). In patients with CS, TLR2 expression was further increased (132.8 ± 5.6 MFI, p = 0.009 vs AMI). This was accompanied by an increased expression of the proinflammatory cytokines TNF­­-α (4.3 ± 1.6% in AMI vs 20.5 ± 5.9% in CS, p = 0.004) and IL-6 (6.3 ± 1.6% in AMI vs 20.6 ± 6.2% in CS, p = 0.032). Furthermore, in all patients with myocardial infarction (AMI + CS; n = 50), a strong correlation between the monocytic TLR2 expression Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Research Review and the symptom to reperfusion time (r2 = 0.706, p < 0.001) was found, implying tissue hypoxia dependency. Symptom to reperfusion time is a main factor to influence TLR2 expression but not the presence of CS. TLR2 expression of mononuclear cells exposed in vitro to hypoxia was assessed by flow cytometry and western blot. In vitro measurements showed a hypoxiamediated monocytic TLR2 expression up-regulation.

Conclusion: We demonstrate TLR2 up-regulation and increased proinflammatory cytokine expression in circulating monocytes in AMI/CS depending on disease severity, implying an important role of TLR2 expression in ischemic injury.

Selejan S, Pöss J, Walter F, et al. Eur Heart J 2011 Oct. 13.

[Epub ahead of print]

Hemostatic Therapy in Experimental Intracerebral Hemorrhage associated with the Direct Thrombin Inhibitor Dabigatran Background and Purpose: Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.

Methods: In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly.

Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μl) or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results: DE substantially prolonged tail vein bleeding time and ecarin clotting time for four hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first three hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective.

Prevention of hematoma growth and reversal of tail Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

vein bleeding time by PCC were dose-dependent.

Conclusions: The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.

Zhou W, Schwarting S, Illanes S, et al. Stroke 2011 Oct. 13.

[Epub ahead of print]

Evaluation of Multicontrast MRI Including Fat Suppression and Inversion Recovery Spin Echo for Identification of Intraplaque Hemorrhage and Lipid Core in Human Carotid Plaque Using the Mahalanobis Distance Measure Intra-plaque hemorrhage (IPH) and lipid core, characteristics of rupture prone carotid plaques, are often visualized in vivo with MRI using T1 weighted gradient and spin echo, respectively. Increasing magnetic field strength may help to identify IPH and lipid core better. As a proof of concept, automatic segmentation of plaque components was performed with the Mahalanobis distance (MD) measure derived from image contrast from multicontrast MR images including inversion recovery spin echo and T1 weighted gradient echo with fat suppression. After MRI of nine formaldehyde-fixated autopsy specimens, the MDs and Euclidean Distances between plaque component intensities were calculated for each MR weighting. The distances from the carotid bifurcation and the size and shape of calcification spots were used as landmarks for coregistration of MRI and histology.

MD between collagen/cell-rich area and IPH was largest with inversion recovery spin echo (4.2/9.3, respectively), between collagen/cell-rich area/foam cells and lipid core with T1 weighted gradient echo with fat suppression (26.9/38.2/4.6, respectively). The accuracy of detection of IPH, cell-rich area, and collagen increased when the MD classifier was used compared with the Euclidean Distance classifier. The enhanced conspicuity of lipid core and IPH in human carotid artery plaque, using ex vivo T1 weighted gradient echo with fat suppression and inversion recovery spin echo MRI and MD classifiers, demands further in vivo evaluation in patients.

Te Boekhorst BC, van ‘t Klooster R, Bovens SM, et al. Magn Reson Med 2011 Oct. 13. [Epub ahead of print]

207

Emedinews Section

From eMedinewS

Screening ECG Still not Supported by Evidence

Same-day Discharge Safe for Some Stent Patients

No new evidence has surfaced since 2004 to justify screening asymptomatic adults for coronary artery disease (CAD) with resting or exercise ECG, according to a literature review by the US Preventive Services Task Force (USPSTF).

Overnight observation after elective percutaneous coronary intervention (PCI) may not be necessary for selected low-risk patients, a large registry study suggested.

Antihypertensives before bed may Lower BP Taking antihypertensive medication at night may do a better job of controlling blood pressure than taking them in the morning, researchers found. In a review and meta-analysis, evening administration significantly lowered 24-hour mean systolic and diastolic blood pressures compared with morning dosing, Ping Zhao, MD, of Sichuan University in China, and colleagues reported online in Cochrane Reviews. (Source: Medpage Today) Restless Legs Tied to Hypertension Middle-age women with self-reported restless legs syndrome (RLS) were as much as 41% more likely to have hypertension as women who did not have the neurologic disorder, analysis of a cohort from the Nurses’ Health Study showed. Overall, women with RLS symptoms had a 20% higher prevalence of hypertension. The odds of hypertension increased with the frequency of symptoms, topping out at 41% among women who had 15 or more episodes per month. (Source: Medpage Today) ECG ‘Noise’ Predicts Death after MI Certain ECG signals that were once considered ‘noise’ are associated with a higher risk of death following a non-ST-segment elevation myocardial infarction acute coronary syndrome (NSTEMI ACS), according to computational ECG analysis of the MERLINTIMI36 trial.

208

MRI Safe for most Patients with Cardiac Devices Fewer than 1% of patients with implanted cardiac devices encountered device-related problems during magnetic resonance imaging (MRI). MRI can be used safely in selected patients with implanted devices.

In three of 438 patients (0.3%), MRI triggered back-up programming mode in implanted devices.

Right ventricular sensing and atrial and ventricular lead impedance values declined immediately after MRI. Long-term follow-up revealed decreased right ventricular sensing and lead impedance, increased right ventricular capture and reduced battery voltage.

None of the changes required revision or replacement of an implanted device, as reported in the October issue of Annals of Internal Medicine by Dr Saman Nazarian, of Johns Hopkins. (MedPage) Statins Lower Mortality in Patients with Atrial Fibrillation Among patients with atrial fibrillation, those who are taking a statin are less likely to die during four years follow-up (28%) than those who are not taking a statin (42%) as per Dr Jason Salamon, of the Albert Einstein College of Medicine in New York City. But statin use was not associated with reductions in all-cause or heart failure hospitalization. There is an inflammatorymediated process in atrial fibrillation. Statins, which have anti-inflammatory properties, distinct from their lipid-lowering capabilities, may prevent atrial fibrillation.

Three Steps for Predicting Diabetes A simple, three questions approach is enough to accurately identify people at risk for type 2 diabetes in Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

eMedinewS Section the next five years. Individuals who are 55 or older, are obese (body mass index (BMI) >30) and have a family history of diabetes have a 20% risk of developing type 2 diabetes over five years of follow-up, as per Dr Harold Bays, MD, of the Louisville Metabolic and Atherosclerosis Research Center in Kentucky. Younger individuals with a BMI <25 and no family history of the disease, however, have an almost negligible five-year risk (0.3%).

Shift Work at Increased Risk of Heart Disease Younger shift workers have elevated levels of stressrelated cortisol that may place them at increased cardiovascular risk, according to Dutch researcher Dr Laura Manenschijn from Erasmus Medical Center in Rotterdam in the Journal of Clinical Endocrinology and Metabolism.  In younger shift workers (<40 years of age), hair cortisol levels were significantly higher at 48.53 pg/mg hair compared with 26.42 pg/mg hair in day workers.  BMI was significantly higher in young shift workers (27.2) compared to their day-worker counterparts (23.7).  Cortisol may contribute to the increased prevalence of obesity and cardiovascular risk.

Higher HDL Lowers Cardiovascular Risk in Type 2 Diabetes Higher high-density lipoprotein (HDL) levels in patients with type 2 diabetes significantly reduced the odds of hospitalization related to cardiovascular disease, data from a large cohort study showed. Every 5 mg/dl increase in baseline HDL was associated with a 6% reduction in the CVD hospitalization risk. During a mean follow-up of 55.8 months, each 5 mg/dl increase in HDL was associated with a 4% lower risk. (Source: Medpage Today) Do not give Clopidogrel Aspirin Combination for Preventing Strokes The US FDA has stopped a study examining if a combination of clopidogrel and aspirin could help prevent subcortical strokes. The National Institute of Neurological Disorders and Stroke made the decision after determining that patients taking the combination were at a higher risk of bleeding events and death. For stroke the combination does not offer any protection, but does put one at increased risk for bleeding.

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

What is the absolute risk of acute heart attack after sex?

Sexual act is a transient trigger that increases risk of heart attack for only a two-hour period. The absolute increase in risk is very small. A 50 year-old man with no cardiac disease with an annual baseline risk of heart attack of 1% would increase his annual risk of heart attack to only 1.01% from weekly sexual activity. A person with a high annual risk for a heart attack of 10% would increase the annual risk to only 10.1% from weekly sexual activity.

-Dr KK Aggarwal, Group Editor in Chief, IJCP Group of Publications and eMedinews

Fitness Update Exercise Helps Prevent Heart Failure in Cancer Patients

Cardiotoxicity, or treatment-induced heart failure, is a serious side effect of chemotherapy, a treatment given to cancer patients. The condition affects physical fitness, physical therapy and quality-of-life. While previous research shows that exercise can help heart failure patients and cancer survivors, no work has been done to test the effect of exercise in cancer survivors with treatment-induced heart failure. Researchers from Vanderbilt University and the University of Texas at San Antonio conducted a pilot study to test a small group of patients who were recovering from various forms of cancer, and who were diagnosed with cardiotoxicity. The patients underwent an exercisebased treatment program for 16 weeks, and researchers measured cardiovascular fitness. While patients were only able to perform a low amount of moderate activity at the beginning of the intervention, they were able to perform more and more exercise as time passed and physical fitness improved. Researchers measured quality-of-life and mental health (using questionnaires), and both were improved significantly as a result of the intervention. Study authors note that exercise programs for patients suffering from cancer or treatment-induced heart failure need to be designed by a professional.

Weakness in Heart Attack Therapy Identified

Scientists didn’t have a plausible research-based answer until now, according to the UCSF researchers. In a 209

eMedinewS Section paper published this month in the scientific journal Science Translational Medicine, researchers offer an explanation of why a gap exists between the success of human trials and rodent experiments. Researchers use bone marrow from young, healthy donor rodents to treat mice that had heart attacks. However in humans, bone marrow cells came from the patients themselvestypically older - after they suffered heart attacks.

“It’s very important to consider the disease, whenever you think about treatments that involve returning cells into the same person from whom they were taken,” said the paper’s senior author Matt Springer, PhD, associate professor of medicine in the UCSF Division of Cardiology and UCSF Cardiovascular Research Institute. “The very disease you’re trying to treat might actually cause a problem for those cells, and that seems to be the case here. “Heart attacks are very complicated, and are hard to treat even with pharmacology and interventional therapies,” said Xiaoyin Wang, MD, lead author, and an associate research specialist at the UCSF Cardiovascular Research Institute. “It’s difficult to get reasonable and realistic results to heal heart attacks.









-Rajat Bhatnagar, International Sports & Fitness Distribution, LLC, http://www.isfdistribution.com

Medicolegal Update What is a Grievous Hurt-Indian Penal Code?



It is very difficult to draw a line between those bodily hurts which are serious and those which are slight. To make out the offense of voluntarily causing grievous hurt, there must be some specific hurt, voluntarily inflicted and coming within the scope of following as per law. According to Indian Penal Code Section 320, the following kinds of hurt are designated as ‘grievous’. 





210

Emasculation: It means depriving a male of masculine power.

Permanent privation of sight of either eye: The gravity lies in the permanency because it deprives a person the use of the organ of sight.

Permanent privation of the hearing of either ear: It deprives a man of his sense of hearing. Injury to the tympanum or auditory nerve or by thrusting something into the ear which causes deafness.

Privation of any member or joint: The term ‘member’ means an organ or a limb being part of man capable of performing a distinct function. It includes, nose, mouth, hands, feet, phalanges, etc.

Destruction or permanent impairing of the powers of any member or joint: The use of limbs and joints of body are essential to the discharge of the normal functions of the body. Their deprivation causes lifelong crippling and makes the person defenseless and miserable.

Permanent disfiguration of the head or face: The word ‘disfigure’ means to cause some external injuries which detracts from personal appearance but does not weaken a person.

Fracture or dislocation of a bone or tooth: It is not necessary that a bone should be cut through and through; cut should be upto the medulla.

If there is a break by cutting or splintering of the bone or there is a rupture or fissure in it, it would amount to a fracture but the doctor must document the dimension of fracture and duration/ age correlation with age of injury. Dislocation means displacement. Mere looseness of teeth will not amount to dislocation. It has to prove that the tooth was originally not loose and that there was fracture or dislocation by the injury.

Any hurt which endangers life or which causes the victim to be in severe bodily pain or unable to follow his ordinary pursuits for a period of 20 days: A wound may cause intense pain, prolonged disease or long-lasting body injury but does not fall under any of the seven clauses. A body injury/ beating may not mutilate the sufferer or fracture his bones but may be so harsh and painful that it may cause even death. The eighth clause provides for such hurts. This includes three different types of hurt.

These are:  



Any hurt which endangers life Any hurt which causes the victim to be in severe bodily pain for a period of 20 days Any hurt which prevents the victim from following his ordinary pursuits for a period of 20 days.

-Dr Sudhir Gupta, Additional Prof, Forensic Medicine & Toxicology, AIIMS

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

eMedinewS Section Legal Question of the Day What action can be taken to improve the following situation?

“On 4th Oct. 2011, S Naskar, 53 year-old, male of Ramnagar village near Haldia, an industrial town, was bitten by a viper snake. He was taken to the Haldia State General Hospital. No treatment was given there and he was referred to the Tamluk district hospital about 60 km away. There he was given only 5 vials of AVS (antiviper serum) and was transferred to the NRS Medical College Hospital at Kolkata, where, on 5th October (Nabami of Durga Puja), he was admitted in the Male Medical Ward on Bed No. 8 and had to purchase 10 vials of AVS from outside.”

Ans. This is a disappointing and unacceptable situation that should not be quietly and silently accepted without protest if any change has to be brought about. I suggest the following:  Write letters to the three hospitals concerned under the RTI Act to get relevant information.  At the same time, without waiting for RTI replies, send a proper (legally drafted) complaint to the state health authorities under the West Bengal Clinical Establishments Act, 1950.  Send a complaint to the West Bengal Medical Council against doctors of the Haldia State General Hospital who sent away a viper snake bite patient without proper treatment. Even if the hospital did not have the medicine, the hospital should have procured the same urgently and administered it to the patient without loss of time.  Most likely, the Haldia State General Hospital and the NRS hospital would be covered under the CPA, 1986. A consumer complaint seeking compensation can be filed there.  Later, at an appropriate stage, a writ petition or a PIL may be filed in Calcutta High Court.  All the above should be done with legal guidance.

-Dr MC Gupta, Advocate

Lab Update Total Cholesterol

Total cholesterol has been found to correlate with total and cardiovascular mortality in the 30-50 years age Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

group. Cardiovascular mortality increases 9% for each 10 mg/dl increase in total cholesterol over the baseline value of 180 mg/dl. Approximately 80% of the adult male population has values greater than this, so the use of the median 95% of the population to establish a normal range (as is traditional in lab medicine in general) has no utility for this test. Excess mortality has been shown not to correlate with cholesterol levels in the >50 years age group, probably because of the depressive effects on cholesterol levels expressed by various chronic diseases to which older individuals are prone.

-Dr Arpan Gandhi and Dr Navin Dang

An Inspirational Story Knowing Yourself

Control, fear, doubt and anger; these are the real deadly killers of the human race. We hurt ourselves by feeling these emotions and we hurt others by directing these emotions at them.

But what if we could direct unconditional love to whomever we meet? What then? Could we help the world be a better place? Maybe, maybe not but we’d certainly help ourselves. Why do we let other people hurt us? Because we put expectations on them, expectations that we ourselves have failed to live upto with others.

If you love someone you feel it and that feeling is yours.

Look at children. We still love our children when they disappoint us why not our workmates, teachers, friends and most of all partners? It’s because we put conditions on what we give out.

Who hasn’t bought a present or done a job around the house expecting something in return - why? If you want to help someone or give something you choose to do it because you want to, not for ‘Brownie Points’.

No other reason than just because you want to - that is showing love.

You can help an old lady with her groceries and it feels good so why not with everything else. When you learn that giving love without expectation is the purest of all faith, then and only then, will you be on the road to really knowing yourself.

-Ms Ritu Sinha

211

lighter reading

Lighter Reading

Idioms

Word Scramble: Atrial Fibrillation

Blood is thicker than water: The family bond is closer than anything else.

Causes

Put a sock in it: To tell noisy person or a group to be quiet.

Atrial fibrillation causes: A SHIT Alcohol Stenosis

5.

6.

7.

8.

9. geltmaoirdracoecr 10. opeltcme olobd lecl nouct 11. igixndo urgd eellv 12. opbntmrhroi meit

Infarction/I schemia Thyrotoxicosis

Answers to word scramble will be provided in Asian Journal of Clinical Cardiology, November 2011.



An elderly lady is on the witness stand in a small town courtroom. The prosecutor asks her if she knows the defense attorney and she says, “Yes, I do.

He’s a drunkard. He’s never sober. I’ve known him all his life.” The defense attorney asks her, “Ma’am, do you know the prosecutor?’ She answers, “Yes, I do. He’s a cheat. He cheated all through school.

He cheated on the bar exam and he cheats on his wife.” The judge asks both lawyers to approach the bench. He says, “If either one of you asks that old woman if she knows me, you’re both going to jail for a year.”

Answers to Word Scramble Asian Journal of Clinical Cardiology Sep. 2011 Causes  

Murphy’s Laws for Humor Irrespective of the direction of the wind, the smoke from the cigarette will always tend to go to the nonsmoker!

Thrombosis Atheroma plaque

Symptoms     

212

iippttaalsno xcsieeer linotracene nnaaig eitntrasn iiccsmhe kcaatt

Exams and Tests

Hypertension

Laugh a While

iyhyhrpoisdmter ochlalo npylumoar sebmolim napmeuino

Signs and Symptoms

Mnemonic



1.

2.

3.

4.



Chest pain Anxiety Fainting Palpitations Shortness of breath Sweating

Emergency Treatments  

Angioplasty Open heart surgery

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Asian Journal of Clinical Cardiology strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter -

- -

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript - Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

-

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

-

All pages should be numbered consecutively beginning with the title page.

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

- The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

- A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

- The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

- A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary - The summary of not more than 200 words. It must convey the essential features of the paper.

- It should not contain abbreviations, footnotes or references.

Introduction - The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods - These should be described in sufficient detail to permit evaluation and duplication of the work by others.

- Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: - The statistical universe i.e., the population from which the sample for the study is selected.

- Method of selecting the sample (cases, subjects, etc. from the statistical universe).

- Method of allocating the subjects into different groups.

- Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

-

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

-

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

Confidence intervals for the measurements should be provided wherever appropriate.

Results These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

213

Discussion -

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g. practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles

-

Do not use clips/staples on photographs and artwork.

-

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as ‘Fig.’.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________

Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

2. Total number of pages ________________________

Books

6. Suggestions for reviewers (name and postal address)

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1._ _______________

2.____________

2._ _______________

Articles in Books

3.____________

3._ _______________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

4.____________

4._ _______________

Tables -

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends - These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

-

214

Figures - Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

- All photomicrographs should indicate the magnification of the print.

- Special features should be indicated by arrows or letters which contrast with the background.

- The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

- Color illustrations will be accepted if they make a contribution to the understanding of the article.

The legend must include enough information to permit interpretation of the figure without reference to the text.

3. Number of tables ____________________________ 4. Number of figures ___________________________ 5. Special requests _____________________________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Asian Journal of Clinical Cardiology E - 219, Greater Kailash, Part - 1, New Delhi - 110 048. Phone: 011-40587513 E-mail: editorial@ijcp.com, emedinew@gmail.com Website: www.ijcpgroup.com

Asian Journal of Clinical Cardiology, Vol. 14, No. 6, October 2011

R.N.I. No. 71217/98 Date of Posting 25-26 Same Month

REGISTRATION NO. DL (S)-01/3288/2010-2012 POSTED IN NDPSO NEW DELHI

One of the leading medical publication groups in Asia.

A Pioneer in Medical Journalism with publications in various specialities that brings to you the latest happenings, technological developments, vision into the future and much more in the medical field.

Since 21 years, IJCP Group has been providing viable and cost-effective media and communication solutions to the pharma and healthcare companies in getting their message across the target audiences.

IJCP is the preferred media partner of leading pharmaceutical and healthcare companies in India as well as some Asian countries.

A BASE OF 1 LAC READERSHIP

Dr KK Aggarwal

CMD, Publisher and Group Editor-in-Chief Dr Dr Dr Dr Dr Dr Dr

Alka Kriplani VP Sood Praveen Chandra Swati Y Bhave Vijay Viswanathan M Paul Anand CR Anand Moses

Anand Gopal Bhatnagar

Dr Veena Aggarwal

Editorial Anchor

Joint MD and Group Executive Editor

Dr Dr Dr Dr Dr Dr Dr

Dr Kamala Selvaraj Dr Georgi Abraham Dr Sidharth Kumar Das Dr V Nagarajan Dr Thankam Verma Dr KMK Masthan Dr Hasmukh J Shroff

IJCP Publications Pvt. Ltd.

Sidhartha Das Wiqar Sheikh Ajay Kumar Koushik Lahiri A Ramachandran Samith A Shetty SK Parashar

E - 219, Greater Kailash, Part 1, New Delhi - 110 048 Tel.: 011-40587513 E-mail: editorial@ijcp.com, emedinews@gmail.com, drveena@ijcp.com Subscription Office: Flat 5E, Merin Estate, Geetanjali, 25/8 Diamond Harbour Road, Kolkata - 700 008 Mobile: 9831363901, E-mail: subscribe@ijcp.com, Website: www.ijcpgroup.com