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Volume 14, Number 12, April 2012

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IJCP Group of PublicationsDr Sanjiv Chopra

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Dr KK AggarwalCMD, Publisher, Group Editor-in-Chief

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Anand Gopal BhatnagarEditorial Anchor

Journal ofCLINICALCARDIOLOGYA

sian

FrOM tHE DESK OF GrOuP EDItOr-IN-CHIEF

413 Five things Physicians and Patients should Question

KK Aggarwal

rEVIEw ArtIClE

415 Newer Hypolipidemics on the Block

Princy Louis Palatty, Manasa M, Apoorva Naik, Archana Kaveri B, Bhavishya Kirthi Anna Walder, Manohar Prabu, Manjeshwar Shrinath Baliga

423 CAD: A true Pandemic and a Comprehensive Surveillance System is the Need of the Hour

G Kannan, NN Rajendran, JSN Murthy, GB Tharani

ClINICAl StuDy

429 Prevalence and Prognosis of right Ventricular Infarction in Acute Inferior wall Infarction

R Vinoth kumar, SM Rajendran, SMK Swaminatha Gurukul, NN Anand, Padma

432 Efficacy and Tolerability of Trandolapril in Mild-to-moderate Hypertension: A Double-blind Comparison with Enalapril

Jyothi R, Pundarikaksha HP, Srinivasa Prabhu NC, Girish K, Vasundhara K

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413AsianJournalofClinicalCardiology, Vol. 14, No. 12, April 2012

Five Things Physicians and Patients should Question

AmericAn college of cArdiology

Don’t perform stress cardiac imaging or advanced noninvasive imaging in the initial evaluation of patients without cardiac symptoms unless high-risk markers are present. Asymptomatic, low-risk patients account for upto 45% of unnecessary ‘screening.’ Testing should be performed only when the following findings are present: Diabetes in patients >40-year-old; peripheral arterial disease or >2% yearly risk for coronary heart disease events.Don’t perform annual stress cardiac imaging or advanced noninvasive imaging as part of routine follow-up in asymptomatic patients. Performing stress cardiac imaging or advanced noninvasive imaging in patients without symptoms on a serial or scheduled pattern (e.g., every 1-2 years or at a heart procedure anniversary) rarely results in any meaningful change in patient management. This practice may, in fact, lead to unnecessary invasive procedures and excess radiation exposure without any proven impact on patients’ outcomes. An exception to this rule would be for patients more than five years after a bypass operation.Don’t perform stress cardiac imaging or advanced noninvasive imaging as a preoperative assessment in patients scheduled to undergo low-risk noncardiac surgery. Noninvasive testing is not useful for patients undergoing low-risk non-cardiac surgery (e.g. cataract removal). These types of tests do not change the patient’s clinical management or outcomes and will result in increased costs.Don’t perform echocardiography as routine follow-up for mild, asymptomatic native valve disease in adult patients with no change in signs or symptoms. Patients with native valve disease usually have years without symptoms before the onset of deterioration. An echocardiogram is not recommended yearly unless there is a change in clinical status.Don’t perform stenting of nonculprit lesions during percutaneous coronary intervention (PCI) for uncomplicated hemodynamically stable ST-segment elevation myocardial infarction (STEMI). Stent placement in a noninfarct artery during primary PCI for STEMI in a hemodynamically stable patient may lead to increased mortality and complications. While potentially beneficial in patients with hemodynamic compromise, intervention beyond the culprit lesion during primary PCI has not demonstrated benefit in clinical trials to date.

AmericAn Society of nucleAr cArdiology

Don’t perform stress cardiac imaging or coronary angiography in patients without cardiac symptoms unless high-risk markers are present. Asymptomatic, low-risk patients account for upto 45% of inappropriate stress

Dr KK AggarwalPadma Shri and Dr BC Roy National AwardeeSr. Physician and Cardiologist, Moolchand Medcity, New DelhiPresident, Heart Care Foundation of IndiaGroup Editor-in-Chief, IJCP Group and eMedinewSChairman Ethical Committee, Delhi Medical CouncilDirector, IMA AKN Sinha Institute (08-09)Hony. Finance Secretary, IMA (07-08)Chairman, IMA AMS (06-07)President, Delhi Medical Association (05-06)[email protected]://twitter.com/DrKKAggarwalKrishan Kumar Aggarwal (Facebook)

fromthedeskofgroupeditor-in-Chief

414 AsianJournalofClinicalCardiology, Vol. 14, No. 12, April 2012

testing. Testing should be performed only when the following findings are present: Diabetes in patients older than 40-year-old, peripheral arterial disease and >2% yearly coronary heart disease event rate.Don’t perform cardiac imaging for patients who are at low-risk: Chest pain patients at low-risk of cardiac death and myocardial infarction (based on history, physical exam, electrocardiograms and cardiac biomarkers) do not merit stress radionuclide myocardial perfusion imaging or stress echocardiography as an initial testing strategy if they have a normal electrocardiogram (without baseline ST-abnormalities, left ventricular hypertrophy, pre-excitation, bundle branch block, intraventricular conduction delay, paced rhythm or on digoxin therapy) and are able to exercise. Don’t perform radionuclide imaging as part of routine follow-up in asymptomatic patients: Performing stress radionuclide imaging in patients without symptoms on a serial or scheduled pattern (e.g., every 1-2 years or at a heart procedure anniversary) rarely results in any meaningful change in patient management. This practice may lead to unnecessary invasive procedures and excess radiation exposure without any proven impact on patients’ outcomes. An exception to this rule would be for patients more than five years after a bypass operation. Don’t perform cardiac imaging as a preoperative assessment in patients scheduled to undergo low- or intermediate-risk noncardiac surgery: Noninvasive testing is not useful for patients undergoing low-risk noncardiac surgery or with no cardiac symptoms or clinical risk factors undergoing intermediate-risk noncardiac surgery. These types of testing do not change the patient’s clinical management or outcomes and will result in increased costs. Therefore, it is not appropriate to perform cardiac imaging procedures for noncardiac surgery risk assessment in patients with no cardiac symptoms, clinical risk factors or who have moderate-to-good functional capacity.Use methods to reduce radiation exposure in cardiac imaging, whenever possible, including not performing such tests when limited benefits are likely. The key step to reduce or eliminate radiation exposure is appropriate selection of any test or procedure for a specific person, in keeping with medical society recommendations, such as appropriate use criteria. Healthcare providers should incorporate new methodologies in cardiac imaging to reduce patient exposure to radiation while maintaining high-quality test results.

fromthedeskofgroupeditor-in-Chief


Cardiovascular diseases (CVDs) are the commonest cause of death the worldover. Hyperlipidemia is the harbinger of myocardial

infarction and stroke. The incidence of hyperlipidemia is 42.9% in USA and similar in other countries also. Reducing the incidence of hyperlipidemia would reduce the deaths due to CVD. This review addresses the probable available agents that reduce cholesterol and triglyceride levels.

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyper-lipidemia denotes increased levels of triglycerides.

Hyperlipidemia has become one of the most common problems in day-to-day life. The sedentary lifestyle today in particular has enhanced its risk, especially in upper middle class and upper class societies. Intake of fat and the carbohydrate rich diet style of India has also added to its increasing intensity. Some of them

Newer Hypolipidemics on the BlockprinCyLouispALAtty*,mAnAsAm**,ApoorvAnAik†,ArChAnAkAveriB†,BhAvishyAkirthiAnnAWALder‡,mAnohArprABu‡,mAnJeshWArshrinAthBALigA§

*ProfessorDept. of Pharmacology**2nd Year MBBS†4th Year MBBS‡3rd Year MBBS§Dept. of Research and DevelopmentFr. Muller Medical College, Mangalore, KarnatakaAddressforcorrespondenceDr Princy Louis PalattyProfessor, Dept. of Pharmacology302, Binary Homes, Kottara Ashoknagar, Mangalore - 575 006, KarnatakaE-mail: [email protected], [email protected]

AbStrAct

Hypolipidemics are much widely used in the present day scenario as a sure prophylactic to tackle cardiovascular disease and stroke, which are leading cause of death across the world. Moreover, hyperlipidemia is not just a metabolic disorder, but it also runs in family, making hypolipidemics more important and necessary. Hence, newer and more efficient drugs are being released. The statins and fibrates, especially rosuvastatin and fenofibrate, have a lot less complications then their early counterparts. Ezetimibe or orlistat reduce absorption of cholesterol; beclobrinic acid has a unique action. Chinese red-yeast rice has a pathetic hypolipidemic action. In this article, we have reviewed the status of new drugs like micronized fenofibrate, 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate, lentysine and gugulipid.

keywords:Hypolipidemia, hypercholesterolemia, triacylglycerols, phospholipids, apoproteins, ezetimibe

include refined low polyunsaturated fatty acids (PUFA) oils, increased use of egg and meet, ‘refined’ low fiber containing carbohydrates. Hyperlipoproteinemias or hyperlipidemias are included under metabolic disorders. Hence, more importance has to be given to these disorders to prevent further complications.

lipid And lipoproteinS

Four major lipid classes are present in lipoproteins: Triacylglycerols (16%), phospholipids (30%), cholesterol (14%) and cholesteryl esters (36%) and a much smaller fraction of unesterified long-chain fatty acids (4%). This latter fraction, the free- fatty acids (FFA), is metabolically the most active of the plasma lipids.

Because fat is less dense than water, the density of a lipoprotein decreases as the proportion of lipid to protein increases (Table 1). Four major groups of lipoproteins have been identified that are important physiologically and in clinical diagnosis. These are: i) Chylomicrons, derived from intestinal absorption of triacylglycerol and other lipids; ii) very low-density lipoproteins (VLDL or pre-β-lipoproteins), derived from the liver for the export of triacylglycerol; iii) low-density lipoproteins (LDL or β-lipoproteins), representing a final stage in the catabolism of VLDL and iv) high-density lipoproteins (HDL or β-lipoproteins), involved in cholesterol transport and also in VLDL and chylomicron metabolism. Triacylglycerol is the predominant lipid in chylomicrons and VLDL, whereas cholesterol and phospholipid are the predominant lipids in LDL and HDL, respectively (Table 1). Lipoproteins may be

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RNA editing enzyme. Apo C-I, C-II and C-III are smaller polypeptides (molecular mass 7,000-9,000 Da) freely transferable between several different lipoproteins. Apo E is found in VLDL, HDL, chylomicrons and chylomicron remnants; it accounts for 5-10% of total VLDL apolipoproteins in normal subjects.

Apolipoproteins carry out several roles: They form part of the structure of the lipoprotein, e.g., apo B. They are enzyme cofactors, e.g., C-II for lipoprotein lipase, A-I for lecithin: Cholesterol acyltransferase, or enzyme inhibitors, e.g., apo A-II and apo C-III for lipoprotein lipase, apo C-I for cholesteryl ester transfer protein.They act as ligands for interaction with lipoprotein receptors in tissues, e.g., apo B-100 and apo E for the LDL receptor, apo E for the LDL-receptor-related protein (LRP), which has been identified as the remnant receptor, and apo A-I for the HDL receptor.

The functions of apo A-IV and apo D, however, are not yet clearly defined, although apo D is believed to be an important factor in human neurodegenerative disorders.

familial Hyperproteinemia

Lipoproteins are metabolized in liver. Like all other nutrients, defect of lipid metabolism also results in disorders. These are mainly classified as: (i) Hypo- or hyperlipoproteinemia; (ii) primary or secondary disorder and (iii) inherited or acquired. Primary

table 1. Composition of Lipoproteins in Human Plasmalipoprotein Source Density (g/ml) Protein

(%)lipid (%)

Main lipid component

Apoproteins

Chylomicrons Intestine <0.95 1-2 98-99 Triacylglycerol A-I, A-II, A-IV, B-48, C-I, C-II, C-III, E

VLDL Liver (intestine) 0.95-1.006 7-10 90-93 Triacylglycerol B-100, C-I,C-II, C-IIIIDL VLDL 1.006-1.019 11 89 Triacylglycerol,

cholesterolB-100, E

LDL VLDL 1.019-1.063 21 79 Cholesterol B-100HDL Liver, intestine,

VLDL, chylomicronsPhospholipids,

cholesterol A-I, A-II, A-IV, C-I, C-II,

C-III, D, EHDL1 1.019-1.063 32 68HDL2 1.063-1.210 33 67HDL3 1.125-1.210 57 43Pre-β-HDL >1.210 A-IAlb/FFA Adipose tissue >1.281 99 1 FFA

separated according to their electrophoretic properties into α-, β- and pre-β-lipoproteins.

The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules. These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane. The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein, constituting nearly 70% of some HDL and as little as 1% of chylomicrons. Some apolipoproteins are integral and cannot be removed, whereas others are free to transfer to other lipoproteins.

types of Apolipoproteins

Lipids are transported in the plasma as lipoproteins. Apolipoproteins constitute one of the building blocks of lipoproteins, in turn fat. Some of them are A I-IV, B-48, B-100, C-I, II, III… D and E-10.

One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein. The major apolipoproteins of HDL (β-lipoprotein) are designated A (Table 1). The main apolipoprotein of LDL (β-lipoprotein) is apolipoprotein B (apo B) (B-100), which is found also in VLDL. Chylomicrons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver. Apo B-100 is one of the longest single polypeptide chains known, having 4,536 amino acids and a molecular mass of 5,50,000 Da. Apo B-48 (48% of B-100) is formed from the same mRNA as apo B-100 after the introduction of a stop signal by an

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disorders are usually inherited, while acquired involve abnormal lipoprotein patterns secondary to diseases like diabetes mellitus, hypothyroidism, kidney diseases and atherosclerosis. Secondary patterns are very similar to primary inherited conditions. Virtually all primary conditions are defects at some stage in lipoprotein formation, transport or destruction. All abnormalities are not harmful.

familial lipoprotein lipase deficiency (type i)

It is a condition of hypertriacylglycerolemia due to lipoprotein lipase (LPL) deficiency, abnormal LPL or apo C-II deficiency causing inactive LPL (Table 2). There is slow clearance of chylomicrons and VLDL, low levels of LDL and HDL; no increased risk of coronary disease.

familial Hypercholesterolemia (type iia)

This involves defective LDL receptors or mutation in ligand region of apo B-100, causing elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease (Table 2).

familial type iii Hyperlipoproteinemia

It is broad-beta disease, or remnant removal disease also called ‘Familial dysbetalipoproteinemia’. It is due to deficiency in remnant clearance by the liver due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor (Table 2).

familial Hypertriacylglycerolemia (type iV)

This is a condition of overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia, resulting in rise of cholesterol level with VLDL (Table 2). LDL and HDL tend to be subnormal. This type of pattern is commonly associated with coronary heart disease (CHD), type 2 diabetes mellitus, obesity, alcoholism and administration of progestational hormones.

otHer HyperlipoproteinemiAS

Other hyperlipoproteinemias involve ‘hepatic lipase‘ deficiency leading to accumulation of large triacylglycerol-rich HDL and VLDL remnants. Patients have xanthomas and CHD. Cholesterol acyltransferase (LCAT) deficiency’ i.e. absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disk incapable of taking up and esterifying cholesterol hence, plasma concentrations of cholesteryl esters and lysolecithin

are low. An abnormal LDL fraction, lipoprotein X, is present, also found in patients with cholestasis. VLDL is abnormal (β-VLDL). ‘Familial lipoprotein excess’, which may result in premature CHD due to atherosclerosis, plus thrombosis due to inhibition of fibrinolysis. ’Familial hyperalphalipoproteinemia’ is a defect of increased concentration of HDL. It is a rare condition apparently beneficial to health and longevity.

complicAtionS of HyperlipoproteinemiA

Hyperlipoproteinemia results in further complications, of which atherosclerosis is a serious one. It is recognized that triacylglycerols are independent risk factors. Atherosclerosis is characterized by deposition of cholesterol and cholesterol ester into artery wall. Diseases with prolonged elevation of LDL, VLDL, chylomicron remnants or LDL in blob are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL concentrations and CHD, marking the LDL: HDL cholesterol is a good predictive parameter.

genetic bASiS of fAmiliAl dySlipidemiA And HypertenSion

The genetic and environmental determinants of hypertension, lipid abnormalities and coronary artery disease (CAD) were studied for 15 years in Utah in population-based multigenerational pedigrees (2,500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships) siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type 2 diabetes (271 subjects among 16 pedigrees), LPL deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several ‘intermediate phenotypes’ associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for LDL cholesterol, lipoprotein (a) (Lp[a]), low HDL cholesterol and high apo B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or

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table 2. Frederickson’s Classification Hyperlipoproteinemiastype lipoprotein fraction

elevatedCholesterol

leveltG

levelMetabolic

effect Features Management

I Chylomicrons Normal ++ Lipoprotein lipase deficiency

Eruptive xanthomas; hepatomegaly; pain

abdomen

Restriction of fat

II A LDL ++ Normal LDL receptor defect; apo B+

Atherosclerosis, CAD, tuberous xanthoma

Low cholesterol and saturated fat. Give PUFA and drugs

(statins)II B LDL and VLDL ++ + Apo B + Apo

C II+Corneal arcus ,,

III Broad beta; VLDL and chylomicrons

++ + Abnormal apo E; apo C-II +

Palmar xanthoma. High incidences of vascular

disease

Reduction of weight, restriction of fat and

cholesterol. Give PUFA and drugs

IV VLDL + ++ Over production of VLDL; apo

C-II +

Associated with diabetes mellitus, ischemic heart

disease, obesity

Reduction of body weight. Restrict

carbohydrate and cholesterol

V VLDL chylomicrons Normal ++ Secondary to other causes

Ischemic heart diseases High PUFA intake, hypolipidemic drugs

hypertension have included LDL-receptor defects, LPL deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen and ‘glucocorticoid remediable aldosteronism (GRA) hypertension.

HyperlipidemiA, pregnAncy And pAncreAtitiS

Hypertriglyceridemia is a recognized complication of pregnancy. In patients with familial hyper-triglyceridemia, the biochemical changes are greatly enhanced during pregnancy and may be associated with acute pancreatitis, a potentially fatal triad. Three patients were studied, in one of whom previously undiagnosed hyperlipidemia resulted in a fatal attack of fulminant acute pancreatitis. In the other two patients, this complication was avoided by close monitoring and restriction of dietary facts. A history of episodic abdominal cramps, often beginning in early childhood or the presence of lipemic fasting plasma should alert the clinician to the presence of severe familial hypertriglyceridemia. Early diagnosis allows for the institution of relatively simple management strategies, which diminish the risk of pancreatitis.

pharmacotherapy

Hence, treatment for hyperlipoproteinemias or hypoli-pidemias is very important. Hyperlipidemia needs to be

controlled by means of diet mainly. Drugs serving this purpose are very useful and are the succour in familial disorders, which can’t be controlled by diet. Moreover, bringing down cholesterol levels is necessary to reduce risk of mortality and morbidity. Drugs are restored after at least a trial of or 3-month period of low fat diet with exercise. Along with all the use of drugs, dietary restriction is to be followed throughout (refer Table 3).

Many drugs have been introduced over the years for the treatment of hyperlipidemia. These drug are mainly involved in reducing body cholesterols by either decreasing the synthesis (statins), increasing metabolism (fibrates), or by obstructing the absorption and increasing excretion (resins). The summary of these hyperlipidemic agents are in Table 4.

ezetimibe

CHD is the leading cause of death in United States. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recommends new lower cholesterol levels, particularly for patients at moderate and high-risk for coronary disease. LDL cholesterol is primarily the target of hypolipidemic drugs. The NCEP ATP III recommends an LDL cholesterol goal of <100 mg/dl in high-risk patients and an LDL cholesterol goal of <70 mg/dl as a therapeutic option, especially in patients with very high-risk of CHD. Statins are

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potent LDL cholesterol-lowering drugs, but they are not as effective as fibrates and niacin in improving levels of triglycerides or HDL cholesterol. Ezetimibe represents a new class of hypolipidemic drugs that inhibit cholesterol absorption in the small intestine. The combination of ezetimibe with statins has been more effective than monotherapy alone in many randomized trials. LDL cholesterol reduction with statin occurs mainly with the initial dose, with relatively smaller reductions seen at higher doses. Ezetimibe was also shown to be useful in various population subgroups such as African-Americans, men and women, elderly and aged, and also those with kidney disease.

fibric Acid deriVAtiVeS

micronized fenofibrate

Fenofibrate reduces serum triglycerides, total choles-terol and LDL cholesterol and raises HDL cholesterol to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb and III hyperlipidemias as well. To this extent, it may be considered a broader-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function). Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Cost-effectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia. The need for dosage titration of the micronized preparation from 67 mg/day upward to a final dose

of 200 mg/day is also not supported by peer-reviewed literature (except in the case of renal impairment). Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.

prostaglandin Synthesis inhibitors

Beclobrinic acid is a new hypolipidemic agent, which inhibits in vitro human platelet activation by blocking prostaglandin synthesis.

Effects and the mechanism of the antiplatelet actions of beclobrinic acid (BBA) free acid form of a new hypolipidemic agent beclobrate 2-[4-(4-Chlorobenzyl)phenoxy]-2-methylbutyric acid ethyl ester; Ethyl(±)-2-[[α(-(4-chlorophenyl)-4-tolyl]oxy]-2-methylbutyrate, were examined using human platelets. Platelet-rich plasma (PRP) which has been prelabeled with (14C)-serotonin was incubated with BBA for one minute before the addition of various agonists. BBA (0.1-1.5 mM) inhibited platelet aggregation and serotonin secretion induced by ADP, epinephrine, arachidonic acid and collagen in a concentration-dependent manner. BBA also inhibited arachidonic acid-induced production of malondialdehyde (MDA), a by-product of prostaglandins, in a concentration-dependent manner. However, upto 1.0 mM BBA did not inhibit platelet aggregation induced by U46619, a stable analog of prostaglandin H2. In other experiments, BBA also blocked thrombin-induced release of (3H)-arachidonic acid from platelet phospholipids. These findings suggest that: (a) BBA inhibits platelet aggregation and serotonin secretion by inhibiting prostaglandin synthesis at two steps: First, by interfering with the release of arachidonic acid from platelet phospholipids and second by inhibiting its conversion into prostaglandins and (b) BBA does not inhibit the action of prostaglandins on human platelets.

1-methyl-4-piperidyl bis(p-chlorophenoxy) Acetate (SaH 42-348): A new Hypolipidemic Agent

Animal studies have shown a promising noble (SaH-2-438) which is chemically 1-methyl-4-piperidyl bis (p-chlorophenoxy) acetate. This agent is 8-9 times more active on a weight for weight basis than chlorphenoxy isobutyric acid ethyl ester (CPIB) and in common with CPIB lowers the level of all major classes of serum lipid. No increase in liver lipid content was seen in animals treated with SaH 42-348, although hepatomegaly was seen after treatment

table 3. ClassificationHMG-CoA reductase inhibitor

LevostatinSimvastatinPravastatin AtorvastatinRosuvastatinFluvastatin

Fibric acid derivativesGemfibrozilClofibrateColesevelamFenofibrateBezafibrateCiprofibrate

Bile acid binding resinsCholestyramineColestipolColesevelam

OthersEzetimibe: Sterol absorption inhibitorBeclobrinic acid: PG synthesis inhibitorsLentysine, gugulipid: Plant productsChinese red-yeast rice: Genetically modified

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table 4. Summary of Hypolipidemic AgentsSubclass Mechanism of

action Effects Clinical applications Pharmacokinetics, toxicities,

interactions Statins Atorvastatin, simvastatin, rosuvastatin

Inhibit HMG-CoA reductase

Reduce cholesterol synthesis and up-regulate LDL receptors on hepatocytes modest reduction in triglyceride

Atherosclerotic vascular disease (primary and secondary prevention) acute coronary syndromes

Oral duration 12-24 hours Toxicity: Myopathy, hepatic dysfunction Interactions: CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors

Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious Fibrates Fenofibrate, gemfibrozil

Peroxisome PPAR-α agonists

Decrease secretion of VLDL increase lipoprotein lipase activity increase HDL

Hypertriglyceridemia, low HDL

Oral duration 3-24 hours Toxicity: Myopathy, hepatic dysfunction

Bile acid sequestrants Colestipol Binds bile acids

in gut prevents reabsorption increases cholesterol catabolism up-regulates LDL receptors

Decreases LDL Elevated LDL, digitalis toxicity, pruritus

Oral taken with meals not absorbed Toxicity: Constipation, bloating interferes with absorption of some drugs and vitamins

Cholestyramine, colesevelam: Similar to colestipol Sterol absorption inhibitor Ezetimibe Blocks sterol

transporter NPC1L1 in intestine brush border

Inhibits reabsorption of cholesterol excreted in bile decreases LDL and phytosterols

Elevated LDL, phytosterolemia

Oral duration 24 hours Toxicity: Low incidence of hepatic dysfunction, myositis

Niacin Decreases catabolism of apo AI reduces VLDL secretion from liver

Increases HDL decreases Lp(a), LDL and triglycerides

Low HDL elevated VLDL, LDL, Lp(a)

Oral large doses Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity may reduce glucose tolerance

with SaH 42-348 or with CPIB. Evidence available suggests that the mechanism of action of SaH 42-348 in lowering serum cholesterol in the rat differs from that of CPIB. Thus, it was not possible to demonstrate that SaH 42-348 inhibited cholesterol biosynthesis in vivo, while the inhibitory effect of CPIB was readily demonstrated. In addition, n-propylthiouracil (PTU) inhibited the hypocholesterolemic activity of CPIB in both normolipemic and hyperlipemic rats, whereas the activity of SaH 42-348 was unaffected by PTU.

plant Sterols and Stenols

Consumption of diet which is low in saturated and trans-fats yet high in fibers, lower the ‘bad cholesterol’

(LDL) that keep the heart and blood vessels healthy. ‘Phytosterols’ in fruits, vegetables, vegetable oils, nuts and seeds amounts to ‘plant sterols’ and ‘plant stenols’ that reduce absorption of cholesterol.

Sources: Wheat, peanut, vegetable oil (corn, sesame, conola, and olive oil), almonds, brussels sprouts, etc.

Plant sterols and stenols resemble cholesterol in terms of chemical structure. They prevent intestinal cholesterol absorption, hence lowering LDL. Studies have shown that, sterols and stenols lower LDL cholesterol by average 6% and perhaps 14% in four weeks.

Daily requirement: 2 g/day as by NCEP.

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Adverse effect

Plant sterols and stenols have been studied for >50 years. They are both safe and effective in lowering cholesterol. However, large doses may cause nausea, indigestion, diarrhea and also interferes with absorption of fat soluble vitamin. Pregnant and breastfeeding women should be cautious in term consumption. Moreover, they cannot substitute for cholesterol lowering medication and are advocated in combination, not monotherapy.

These can be either obtained naturally from plants and their products (e.g., Lentysine, gugulipid) or from genetically modified once (e.g., red yeast rice). Few of plant hypolipidemic agents are discussed below.

lentysine

It is a new hypolipidemic agent from a mushroom. Lentysine is one of the naturally obtained hypolipidemic agent. It was recently discovered that few of the edible mushrooms contained a chemical named lentysine, which was found to act as a hypolipidemic agent. Hence, in patients with high fat diet, consumption of these mushrooms was found to be noted useful. Its action on serum and liver lipids in rats has been investigated. Lentysine markedly reduced serum cholesterol, phospholipids and triglycerides, both in intact rats and in animals fed a high fat diet. However, this substance showed no effect on liver lipid levels, and enlargement of liver was not observed in rats treated with lentysine.

gugulipid

It is another naturally occurring cholesterol-lowering agent. Gugulipid has been studied and was proved very much useful. The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for >2,000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum gugul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the

active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.

cholesterol-lowering effects of a proprietary chinese red-yeast-rice dietary Supplement

Red yeast rice is one of the genetically modified rice, which contains hypolipidemic agent from yeast. The cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement was examined in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-week controlled trial at a university research center. Eighty-three healthy subjects with hyperlipidemia, who were not being treated with lipid-lowering drugs participated. Subjects were treated with red-yeast-rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol and HDL, and LDL cholesterol measured at Weeks 8, 9, 11 and 12. Cholesterol concentrations decreased significantly between baseline and 8-week in the red-yeast-rice-treated group compared with the placebo-treated group. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. Hence, red-yeast-rice proved to provide a new, novel, food-based approach to lower cholesterol in the general population.

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US Census Bureau population estimates. Available at:www.census.gov/popest/national/asrh/files/NC-EST2008-ALLDATA-R-File 14.csv.Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System: prevalence and trends data. Available at: www.apps.nccd.cdc.gov/brfess/index.asp.Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735-52. Kromhout D, Menotti A, Kesteloot H, Sans S. Prevention of coronary heart disease by diet and lifestyle: evidence

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mechanism of Action

Sterols and Stenols (Similar chemically to cholesterol)

Cholesterol absorbed in intestine

LDL levels in blood

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from prospective cross-cultural, cohort, and intervention studies. Circulation 2002;105(7):893-8. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135-43.Goldberg IJ, Merkel M. Lipoprotein lipase: physiology, biochemistry, and molecular biology. Front Biosci 2001;6:D388-405.Christie WW. Lipid Analysis. 3rd edition, The Oily Press: Bridgwater; 2003.Gurr MI, Harwood JL, Frayn K. Lipid Biochemistry. Blackwell Publishing 2002.Dowhan W, Bogdanov M. Functional roles of lipids in membranes. In: Biochemistry of Lipids, Lipoproteins, and Membranes. 4th edition, Vance DE, Vance JE (Eds.), Elsevier, Amsterdam 2002:p.1-36.Shelness GS, Sellers JA. Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol 2001;12(2): 151-7. Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005;19(4):471-82. Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Ther 1992;6(2):103-10. Williams RR, Hunt SC, Hopkins PN, Wu LL, Hasstedt SJ, Berry TD, et al. Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. Am J Hypertens 1993;6(11 Pt 2):319S-327S.

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De Chalain TM, Michell WL, Berger GM. Hyperlipidemia, pregnancy and pancreatitis. Surg Gynecol Obstet 1988;167(6):469-73.Katragadda S, Rai F, Arora R. Dual inhibition, newer paradigms for cholesterol lowering. Am J Ther 2010;17(4):e88-99.Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother 1999;33(10): 1083-103.Anwer K, Gabis J, Romstedt K, Gojer C, Huzoor-Akbar. Beclobrinic acid - a new hypolipidemic agent - inhibits in vitro human platelet activation by blocking prostaglandin synthesis. Life Sci 1985;37(1):63-70.Alan R, Lawrence A, Robert S, Joseph H. Laboratory studies of methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348):Sandoz pharmaceuticals, Research Department, Hanover, N.J., USA 17th January 1969.Rokujo T, Kikuch H, Tensho A, Tsukitani Y, Takenawa T, Yoshida K. Iyakushigen Institute for Medical Research, Tokyo, Fujisawa Pharmaceutical Co. Ltd. 29 December 1969. Urizar NL, Moore DD. Gugulipid: a natural cholesterol-lowering agent. Annu Rev Nutr 2003;23:303-13.Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999;69(2):231-6.

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CAD: A True Pandemic and a Comprehensive Surveillance System is the Need of the HourgkAnnAn*,nnrAJendrAn**,Jsnmurthy†,gBthArAni‡

AbStrAct

Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle harden and narrow. According to the Global Burden of Disease Study, the developing countries contributed 3.5 million of the 6.2 million global deaths from CAD in 1990. The prevalence of CAD in India has more than doubled in the past two decades. India topped the world with 1,531,534 cardiovascular disease-related deaths in 2002, and based on WHO report, 2009, CAD currently occupies the first place in cause of death. A comprehensive surveillance system of risk factors and CAD will be an invaluable public health research tool for monitoring population health status, guiding resource allocation and policy, identifying and prioritizing interventions for subpopulations at particular risk that would help to bring down the true pandemic which is on the climb.

keywords:Coronary artery disease, pandemic, surveillance system, health status

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*Assistant ProfessorDept. of Pharmacy Practice, Faculty of PharmacySri Ramachandra University, Porur, Chennai**ProfessorSwami Vivekananda College of Pharmacy, Erode, Chennai†Professor and HeadDept. of Cardiology, Sri Ramachandra University, Porur, Chennai‡Professor and HeadSaveetha Medical College, Thandalam, ChennaiAddressforcorrespondenceDr G KannanAssistant Professor, Dept. of Pharmacy Practice, Faculty of PharmacySri Ramachandra University, Porur, Chennai - 600 116E-mail: [email protected]

Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle harden and narrow (Bhati K, 2011; Heart

Diseases, 2011). The result is the loss of oxygen and nutrients to myocardial tissue because of diminished coronary blood flow (Springhouse, 2005). This reduction in blood flow can lead to acute coronary syndrome (angina or myocardial infarction). CAD is on the climb and has become a true pandemic that respects no borders.

preVAlence of cAd

global Scenario

The term ‘prevalence’ of CAD usually refers to the estimated population of people who are managing CAD at any given time (American Heart Association, 2004). The proportion of deaths due to CAD is projected to rise from 59% in 2002 to 69% in 2030 (Mathers and

Loncar, 2006). The WHO (2006) estimates that at least 20 million people survive CAD-related heart attacks and strokes every year around the world; many require continuing costly clinical care. By 2030, almost 23.6 million people will die from CADs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death (WHO-Cardiovascular Disease: Prevention and Control, 2006). A recent evaluation of WHO in the cause of death in 2009, CAD and stroke were placed as first (7,185,353 deaths) and second (5,704,843 deaths) in rank among total deaths (6,830,586,985) of all kind of diseases. Moreover, the rate of death is rising more in the under-developed countries than the developed countries, because of their lifestyle and socioeconomic factors (WHO, 2009).

According to the Global Burden of Disease Study, the developing countries contributed 3.5 million of the 6.2 million global deaths from CAD in 1990. The projections estimate that these countries will account for 7.8 million of the 11.1 million deaths due to CAD in 2020 (Murray et al, 1996). Disability-adjusted life years (DALYs) lost can be thought of as ‘healthy years of life lost’. They indicate the total burden of a disease, as opposed to simply the resulting deaths. Murray et al (1996) calculate that in India and China, a spectacular rise in the number of DALYs is expected in the coming years - from a figure of <25 million DALYs in each country in 1990, to 30 million and 35 million in India and China, respectively, in 2020. CAD is decreasing

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in many developed countries, but is increasing in developing and transitional countries, partly as a result of increasing longevity, urbanization and lifestyle changes. CAD is responsible for 10% of DALYs lost in low and middle-income countries and 18% in high-income countries (Global Burden of Coronary Heart Disease, 2002).

CAD is the most common cause of death (and premature death) in the UK. One in 5 men and one in 7 women die from CAD. There are 94,000 deaths from CAD in the UK each year (Greenlund et al, 2006). With regard to incidence, data from the Atherosclerosis Risk In Communities (ARIC) and Cardiovascular Health Study indicate that annually, 7,85,000 Americans have a new coronary attack and 4,70,000 have a recurrent attack; in addition, approximately 1,95,000 silent myocardial infarctions occur each year. This assumes that 21% of the 9,35,000 first and recurrent myocardial infarctions are silent (Thom et al, 2001; Boland et al, 2002). Tables 1 and 2 depict the CAD prevalence in urban and rural population of developed countries and developing countries.

indian Scenario

The prevalence of CAD in India has more than doubled in the past two decades. This has occurred both in the rural and urban populations, although it is higher

in urban than in rural population, with a greater prevalence in affluent groups (Chadha et al, 1990; Enas et al, 1992; Singh et al, 1997). Enas et al (1996) and Enas et al (1999). It is estimated that 9.2 million productive years of life were lost in India in 2000, with an expected increase to 17.9 million years in 2030. Table 3 depicts the CAD prevalence with respect to age group, sample size of the study population in different parts of India.Salient features of the CAD epidemic in India:

Incidence of CAD in young Indians is about 12-16%, which is higher than any other ethnic group (Mammi et al, 1991).Age-standardized estimates for DALYs lost due to CAD per 1,000 population in India are three times higher than in developed countries (Negus et al, 1994).About 5-10% of heart attacks occur in Indian men and women younger than 40 years (Mackay and Mensah, 2004).India topped the world with 1,531,534 cardiovascular disease-related deaths in 2002, and occupied first place in cause of death in current moment based on WHO report, 2009 (Yusuf et al, 2004; WHO, 2009). Median age of first heart attack in Indians is 53 years (WHO, 2009).1,55,88,000 DALYs (WHO, 2009).

table 1. CAD in Urban and Rural Population of Developed CountriesAuthor year Age group Place Sample size CAD prevalence (%)urban populationCalvet et al. 2010 45-75 France 300 50.0Arzamendi et al. 2010 20-65 Developed countries 1,260 49.0Iwasaki et al. 2011 30-70 Japan 135 9.20Icaza et al. 2009 35-74 USA General population 6.95Kivimaki et al. 2011a 30-70 UK 5,533 0.70Jain et al. 2011 35-75 London (UK) 2,369 22.0Kivimaki et al. 2011b 30-70 London (UK) 7,095 0.027Ong et al. 2011 30-70 UK 698 5.00Stansby et al. 2011 68 UK 473 30.0Ebrahim et al. 2011 20-70 UK 1,63,471 4.35Secrest et al. 2011 24-32 USA 317 2.50rural populationOizumi et al. 2008 30-70 Japan 2,938 3.19Idris et al. 2008 30-70 UK 1,087 50.0Konishi et al. 1990 40-59 Japan 8,835 88.0

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table 2. CAD in Urban and Rural Population of Developing Countries (Excluding India)Author year Age group Place Sample size CAD prevalence (%)urban populationGrau et al. 2010 30-70 France + Spain 420 + 562 0.98

Chin et al. 2009 30-70 Malaysia 2,030 10.35

Hatmi et al. 2007 20-45 Iran 3,000 25.75

Hariharan et al. 2010 30-70 Trinidad + Tobago 1,082 1.20

Sadeghi et al. 2006 35-70 Iran 6,498 29.90

Kalra et al. 2011 35-86 Nepal 142 38.00

Icaza et al. 2009 35-74 Chile General population 1.80

Icaza et al. 2009 35-74 China General population 0.85

Icaza et al. 2009 35-74 Spain General population 3.70

Ozdemir et al. 2010 30-70 Turkey 24 33.33

Vaidya et al. 2009 35 - < Eastern Nepal - 5.70

rural populationOnat et al. 2010 45-74 Turkey 1,655 11.50

Pitsavos et al. 2008 30-70 Greek 2,172 1.36

Pavlović et al. 2004 37-56 Croatia 3,544 3.70

table 3. Prevalence of CAD in Population of IndiaAuthor year Age group Place Sample size CAD prevalence (%)South IndiaGeetha et al. 2011 30-70 Chennai (Tamil Nadu) 2,350 2.93Mohan et al. 2010a 30-70 Chennai (Tamil Nadu) - 5.40Mohan et al. 2010b 30-70 Chennai (Tamil Nadu) - 11.0Kumaran et al. 2002 30-70 Mysore 435 21.75Mohan et al. 2001 20-70 Chennai (Tamil Nadu) 1,262 11.0Stein et al. 1996 Mysore 517 10.0Begom et al. 1995 25-65 South India (Urban) 506 13.9North IndiaSingh et al. 2011 <15 Chandigarh 196 0.000045Kumar et al. 2006 >35 North India (Urban + Rural) 7,169 3.96Ahmad et al. 2005 25-70 Delhi (Urban) 14,000 0.2-0.9Ahmad et al. 2005 25-70 Delhi (Rural) 14,000 0.1-0.4Singh et al. 1997 25-64 Moradabad 3,575 1.5-3.0Chadha et al. 1997 25-64 Delhi (Urban + Rural) 13,723 96.7 (Urban) + 27.1 (Rural)Begom et al. 1995 25-65 North India (Urban) 506 61.6west IndiaLanjewar et al. 2005 25-70 Mumbai 3,871 4.20Rastogi et al. 2004 30-70 Western India 350 1.88Pinto et al. 2004 35-64 Goa 371 13.2East IndiaHazarika et al. 2002 30-70 Assam 1,015 61.0Bhattacharyya 2003 30-70 Kolkata 28 + 62 39 + 60

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need of tHe Hour

Prospective studies on the relative role and importance of traditional and newer risk factors are urgently needed in Indians within the subcontinent as much of the knowledge of risk factors for CAD has been acquired from studies conducted in the Western population. It is widely believed that the association of these risk factors with CAD in different subpopulations needs to be ascertained, and there is speculation that differences might range from the frequency of presence of classical risk factors to their total absence or irrelevance in these populations. A cost-effective preventive strategy will need to focus on reducing risk factors both in the individual and in the population at large.

Effective screening, evaluation and management strategies for CAD are well-established in high-income countries, but these strategies have not been fully implemented in India which was noted by Mohan et al (2001). A key factor that hampers the development of such preventive strategies in developing countries such as India is the meager amount (8%) of published literature on CAD research available from these countries (Mackay and Mensah, 2004). Of particular concern to India is not only the high burden of CAD, but also the effects of these diseases on the productive workforce aged 35-65 years. Heart diseases are rising in Asian Indians 5-10 years earlier than in other populations around the world. The mean age for first presentation of acute myocardial infarction in Indians is 53 years. CAD that manifests at a younger age can have devastating consequences for an individual, the family and society. Prevention of these deaths in young people is a nation’s moral responsibility (Sharma and Ganguly, 2005). A strategy involving prevention of CADs long before their onset will be more cost-effective than providing interventions at a stage when the disease is well-established.

Therefore, it is imperative to undertake large population-based, prospective studies in developing countries such as India to identify CAD risk factors, both conventional and novel. Careful scrutiny of available scientific evidence for modifiable CAD risk factors (elevated serum total and LDL-C, low HDL-C, smoking, diabetes, hypertension, low level of physical activity and central obesity) in association with genetically predisposing factors like Lp(a) in Indian population may be helpful in formulating a more immediate CAD prevention strategy.

Given the explosion of diabetes and CAD in India and in view of the differences in race, culture, way of life,

diet, stress and strain and the myriad other factors, increased emphasis on lifestyle modification, including diet, exercise, weight reduction and whenever relevant, stress reduction, is urgently needed. A comprehensive surveillance system of risk factors and CAD will be an invaluable public health research tool for monitoring population health status, guiding resource allocation and policy, identifying and prioritizing interventions for subpopulations at particular risk, identifying disparities in outcomes and planning and evaluating health programs. Carefully planned prevention programs with intervention strategies by catching the vulnerable individuals at an early age could also be taken up in different parts of the country to prevent the twin epidemic of diabetes and CAD; as both have common causative factors, and prevention strategies could also be combined judiciously to prevent both disorders, as this would make it more cost-effective.

Resources should be directed towards applying the existing knowledge base to tackle the CAD epidemic in policy, capacity building and research arenas. Control of the CAD epidemic in the Indian subcontinent is tenable in the foreseeable future, provided that policy makers, health professionals and the lay public in the Indian subcontinent acknowledge its potential impact and promptly act to address to make a major step towards CAD free society.

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Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11):e442. Mohan V, Deepa R, Rani SS, Premalatha G; Chennai Urban Population Study (CUPS No. 5). Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 2001;38(3):682-7.Mohan V, Vassy JL, Pradeepa R, Deepa M, Subashini S. The Indian type 2 diabetes risk score also helps identify those at risk of macrovascular disease and neuropathy (CURES-77). J Assoc Physicians India 2010a; 58:430-3. Mohan V, Venkatraman JV, Pradeepa R. Epidemiology of cardiovascular disease in type 2 diabetes: the Indian scenario. J Diabetes Sci Technol 2010;4(1): 158-70. Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Disease, Injuries and Risk Factors in 1990 and Projected to 2020. Harvard University Press: Boston, Ma; 1996.Oizumi T, Daimon M, Jimbu Y, Wada K, Kameda W, Susa S, et al. Impaired glucose tolerance is a risk factor for stroke in a Japanese sample - the Funagata study. Metabolism 2008;57(3):333-8.Onat A, Uğur M, Ciçek G, Ayhan E, Doğan Y, Kaya H, et al. The Turkish Adult Risk Factor survey 2009: similar cardiovascular mortality in rural and urban areas. Turk Kardiyol Dern Ars 2010;38(3):159-63.Ong P, Athanasiadis A, Borgulya G, Voehringer M, Sechtem U. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J Am Coll Cardiol 2011;57(2):147-52.Ozdemir H, Ciftçi E, Tapisiz A, Ince E, Tutar E, Atalay S, et al. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey. J Trop Pediatr 2010;56(4):260-2. Pavlović M, Corović N, Gomzi M, Simić D, Jazbec A, Tiljak MK. Smoking habits, signs of chronic diseases and survival in inland and coastal regions of Croatia: a follow-up study. Coll Antropol 2004;28(2):689-700.Pinto RJ, Bhagwat AR, Loya YS, Sharma S. Coronary artery disease in premenopausal Indian women: risk factors and angiographic profile. Indian Heart J 1992;44(2):99-101.Pitsavos C, Kavouras SA, Panagiotakos DB, Arapi S, Anastasiou CA, Zombolos S, et al; GREECS Study Investigators. Physical activity status and acute coronary syndromes survival The GREECS (Greek Study of Acute Coronary Syndromes) study. J Am Coll Cardiol 2008; 27;51(21):2034-9.Rastogi T, Vaz M, Spiegelman D, Reddy KS, Bharathi AV, Stampfer MJ, et al. Physical activity and risk of coronary heart disease in India. Int J Epidemiol 2004;33(4):759-67.

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Sharma M, Ganguly NK. Premature coronary artery disease in Indians and its associated risk factors. Vasc Health Risk Manag 2005;1(3):217-25.

Singh RB, Rastogi SS, Rao PV, Das S, Madhu SV, Das AK, et al. Diet and lifestyle guidelines and desirable levels of risk factors for the prevention of diabetes and its vascular complications in Indians: a scientific statement of The International College of Nutrition. Indian Consensus Group for the Prevention of Diabetes. J Cardiovasc Risk 1997;4(3):201-8.

Singh S, Aulakh R, Bhalla AK, Suri D, Manojkumar-R, Narula N, et al. Is Kawasaki disease incidence rising in Chandigarh, North India? Arch Dis Child 2011;96(2): 137-40.

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Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ. Fetal growth and coronary heart disease in South India. Lancet 1996;348:1269-73.

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Acute myocardial infarction (MI) remains among the most common problems encountered in Internal Medicine or Adult Cardiology. It is

established that nearly 20 million persons suffer from coronary artery disease (CAD) in India and about 2.5 million die every year. Once considered rare and clinically unimportant, infarction of right ventricle (RV) is now recognized as a common clinical event occurring in one-third of patients with inferior wall MI (IWMI). Some anterior wall infarctions are also associated with RV infarction in 5% autopsies. Isolated RV infarction was also reported. The introduction of right precordial electrocardiography by Erhardt et al made identification and diagnosis of RVMI practical and easy. Clinical studies have identified RV involvement as a major prognostic indicator in patient with inferior wall infarction and its proper recognition and treatment have assured increasing importance.

mAteriAl And metHodS

This study was conducted in Sree Balaji Medical College, Chrompet, Chennai, during the period of November 2007 to May 2009. A total number of 50

Prevalence and Prognosis of Right Ventricular Infarction in Acute Inferior Wall InfarctionrvinothkumAr*,smrAJendrAn**,smksWAminAthAgurukuL†,nnAnAnd‡,pAdmA‡

patients admitted to intensive care unit (ICU) were studied. There were 40 male and 10 female patients ranging in age from 34 to 80 years. Patients with acute IWMI, which is evidenced by ST elevation >1 mm in II, III, aVF and substantial increase in cardiac enzymes (creatine phosphokinase-MB [CPK-MB]), were included and patients with previous history of MI and an anterior wall infarction were excluded from the study. History taking, physical examination, laboratory investigations were performed in all subjects. CPK-MB level in serum was estimated 12-24 hours after the onset of symptoms, or at admission if the patient presented later than this period. CPK-MB was estimated photometrically. The normal values for our laboratory were upto 24 IU/l. All patients admitted in the ICU were put on continuous cardiac monitoring for at least 48 hours and later if required. Patients were seen at frequent intervals and meticulous progress notes were maintained.

reSultS

Fifty acute inferior wall infarction patients were studied. Twenty patients had evidence of RV infarction (40%). Average overall age in patients with RVMI was 53 and without RVMI was 55. The youngest in RVMI group was 38 years and that in the isolated IWMI group was 34 years. The commonest presentation among the patients in our study was original type of chest pain (90%). In this study, 30 patients were

*Assistant Professor**Professor†Professor and Head‡Associate Professor Dept. of General MedicineSree Balaji Medical College, Chennai

AbStrAct

In patients with acute inferior wall infarction, right ventricular (RV) involvement is one of the strongest predictors of in-hospital deaths. In this study, we sought to evaluate the prognostic impact of RV infarction in patients with acute inferior wall infarction. The in-hospital clinical outcome of 50 patients admitted to the coronary care unit with acute inferior wall infarction was analyzed and the presence of RV infarction was diagnosed by ECG and echocardiography. The total incidence of RV infarction in acute inferior wall infarction was 40%. The incidence of hypotension is more in patients with RV infarction (80%) as compared to patients with isolated inferior wall infarction (30%). Patients with associated RV infarction had significantly higher incidence of major complications (85% vs 13%) and in-hospital mortality (25% vs 10%) compared to patients with isolated inferior wall infarction. This increased risk is related to the presence of RV myocardial involvement itself rather than the extent of left ventricular (LV) myocardial damage.

keywords:Prognostic, RV infarction, in-hospital mortality

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smokers. Out of 30 patients, 15 patients had RVMI and 15 patients had isolated IWMI.

In this study, 19 patients had diabetes and 16 patients had hypertension. Of these 19 diabetics, seven patients had RVMI and 12 patients had inferior wall infarction without RVMI. Of the 16 hypertensives, six patients had RV infarction and 10 patients had inferior wall infarction without RV involvement.

Hypotension was present in 25 patients (50%); 16 patients with RVMI had hypotension (80%). Six patients had bradycardia and jugular venous pressure (JVP) was raised in 25 patients. Five patients with RVMI had bradycardia (25%) and 16 patients with RVMI had increase JVP. In patients with RV infarction, RVS3 was noted in two patients and RVS4 in two patients. Complete heart block was present in six patients. Of those, five patients had RV infarction and one patient had IWMI without RV involvement. Incidence of complete heart block in patients with RV infarction in our study was 25%.

Figure 2.

Isolated IWMI

RV infarction

50

40

30

20

10

0

1st degree heart block

Type 1 2nd degree heart block

Type 2 2nd degree heart block

Complete heart block

VPC Ventricular tachycardia

Figure 1.

RV infarction Isolated IWMI

cardiac enzymes

CPK-MB levels were raised in all patients with inferior wall infarction. In patients with RV infarction, it ranged from 68 to 116 IU/l with an average of 93.2 IU/l. In patients without RV infarction, it ranged from 62 to 128 IU/l with an average of 87.2.

echocardiogram

Of the 20 patients who had RV infarction, everyone showed hypokinesis of diaphragmatic wall of RV. Five patients showed RV dilatation and one showed tricuspid regurgitation. Among the 50 patients, 18 were thrombolyzed; of these, 12 did not have RV infarction and six had RV infarction. Fluid therapy was done in 13 patients with RV infarction. Amount of fluid varied from 1 to 2 liters of normal saline.

There were eight deaths among the 50 study subjects. Of these eight deaths, five had RVMI and three had isolated IWMI.

diScuSSion

Incidence of RVMI in acute IWMI varied from 5 to 43% in an autopsy series with a mean around 19%. Based on radionucleotide ventriculography of technetium pyrophosphate scintiography, Wacken et al found out the incidence of RV infarction in inferior wall infarction to be 37.5% and Braat et al found it to be 43%. In our study, the incidence of RV infarction in inferior wall was 40%, comparable with other results. There was no significant difference in the mean age in both groups of patients.

40%60%

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Increased incidence of RV infarction in patients having chronic respiratory disease has been studied by Virmani et al and Klade. In our study, out of 40 male patients, 30 gave history of smoking for >10 years. Out of those 30, 15 patients had RV infarction. This indicates that smoking significantly increases the risk of development of acute MI. A study conducted by Gottelieb et al showed a better prognosis for smokers, but no such findings were obtained in our study.

Cohn et al described a high incidence of systemic venous congestion and hypotension in their patients with RV infarction. Candell Fierre et al found similar hemodynamic disturbances in patients with RV infarction.

In our study, the incidence of hypotension and raised JVP in patients with RV infarction was 80%, whereas it was only 30% in patients without RV infarction. These results correlate with the study conducted by Cohn et al. In Zehender study, bradycardia was found in 9% of patients with RV infarction and 3% of patients without RV infarction. Incidence of heart block with varying degrees was 25% in our study.

In our study, out of 50 patients, 18 patients received thrombolytic therapy and 30 patients did not receive thrombolytic therapy. In the nonthrombolytic group, five patients died, whereas in thrombolytic group three patients died. The most common cause for contraindication for thrombolytic therapy was late presentation.

In Zehender’s study, the mortality rate associated with RV infarction was 31%, whereas in isolated IWMI it was 6%. In our study, the mortality rate associated with RV infarction was 25% and mortality associated with isolated IWMI was 10%. These results correlate with the study conducted by Zehender et al.

concluSion

Fifty patients admitted with acute inferior wall infarction were studied for the evidence of RV infarction by electrocardiogram. The incidence of RV infarction is 40%. Presence of systemic hypotension and raised JVP were observed in significant number of RV infarct

patients. This study also points out the utility of V4R in diagnosing RV infarction in patients with inferior wall infarction. All patients with RV infarction showed ST elevation in V4R. Thrombolysis was given only in 38% of patients. There was no significant difference in overall mortality between the thrombolyzed group and nonthrombolyzed group. Mortality associated with RV infarction is 25%, whereas mortality in isolated IWMI is only 10%. This shows that presence of RV infarction has a bad prognosis in patients with IWMI.

This study based on ECG findings alone, for diagnosis of RV infarction has its own limitations. Evaluation of the presence and extent of RV infarction by other noninvasive investigation remains of utmost importance. Yet, this was an attempt for early recognition of RV infarction in patient with inferior wall infarction and to study the unique hemodynamic and conduction disturbance to aid in the proper management.

SuggeSted reAding

Erhardt LR, Sjõgen A, Wahlberg I. Single right-sided precordial lead in the diagnosis of right ventricular involvement in inferior wall infarction. Am Heart J 1976;91(5):571-6.Pasterrak RC, Braunwald E, Sobel BE. Acute myocardial infarction. In: Braunwald’s Heart disease. A Textbook of Cardiovascular Medicine. Vol II, 7th edition, WB Saunders 2005:p.1103-67.Braunwald E, Sobel BE. Acute myocardial infarction. In: Braunwald’s Heart diseases: A Textbook of Cardiovascular Medicine. Vol II, 7th edition, WB Saunders.Braat SH, Brugada P, de Zwaan C, Coenegracht JM, Wellens HJ. Value of electrocardiogram in diagnosing right ventricular involvement in patients with an acute inferior wall myocardial infarction. Br Heart J 1983;49(4):368-72Cohn JN, Guiha NH, Border MI, Limas CJ. Right ventricular infarction. Clinical and hemodynamic features. Am J Cardiol 1974;33(2):209-14.Zehender KK, Kapser W, Kauder E, Schõnthaler M, Geibel A, Olschewski M, et al. Right ventricular infarction as an independent predictor of prognosis after acute inferior myocardial infarction. N Engl J Med 1993;328(14):981-8.

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Hypertension is one of the most prevalent vascular diseases in the world and posses a major public health problem. Angiotensin-

converting enzyme inhibitors (ACEIs) are accepted as first-line therapy in the treatment of hypertension and heart failure.1 The principle antihypertensive effect is through renin-angiotensin-aldosterone (RAA) mechanism.2 They offer distinct advantages such as preventing or reversing cardiovascular remodeling,3 diabetic complications,4 improving endothelial function5 and also enhancing fibrinolysis.6 The American Heart Association and American College of Cardiology (AHA/ACC) recommend ACEIs as standard therapy in patients who are at high-risk for cardiovascular morbidity and mortality.7 In recent years, there has been a rapid growth in the number of

Efficacy and Tolerability of Trandolapril in Mild-to-moderate Hypertension: A Double-blind Comparison with EnalaprilJyothir*,pundArikAkshAhp**,srinivAsAprABhunC†,girishk‡,vAsundhArAk*

ACEIs entering the market. Most have claimed some sort of advantages based on differences in pharmacokinetics, metabolism or tissue ACE binding.

Trandolapril is a new nonsulfhydryl lipophilic ACEI. The main pharmocodynamic effects of trandolapril are achieved by reduction in plasma angiotensin-II levels, which leads to a reduction in total peripheral vascular resistance, blood pressure (BP) and decreased sodium and water retention by the kidney.8 It has an effective long duration of action in the dose of 2-4 mg daily and is well-tolerated with minor adverse events.9 Few studies were done in Indian population to compare its efficacy and tolerability with other ACEIs. The present study was undertaken to compare the efficacy and tolerability of trandolapril with enalapril in mild-to- moderate essential hypertension.

mAteriAl And metHodS

The present study was a randomized, double-blind, parallel, comparative clinical trial carried out in Kempegowda Institute of Medical Sciences Hospital and Research Centre, Bangalore, over a period of one year. The study protocol was approved by the Institution Ethical Committee, and conducted in accordance with the Declaration of Helsinki. After obtaining written informed consent, 120 patients

*Assistant Professor**Professor and Head †Professor ‡Associate ProfessorDept. of PharmacologyKempegowda Institute of Medical Sciences, BangaloreAddressforcorrespondenceDr Jyothi RAssistant Professor, Dept. of PharmacologyNo-3, KIMS Staff Quarters, KIMS Campus BSK-II Stage, Bangalore - 70, KarnatakaE-mail: [email protected]

AbStrAct

Objective: To compare the efficacy and tolerability between trandolapril and enalapril in mild-to-moderate hypertension. Material and Methods: This was a prospective, double-blind, parallel, comparative clinical trial involving 120 patients with mild-to-moderate hypertension. Patients were randomized to receive trandolapril 2-4 mg once-daily and enalapril 5-10 mg once-daily. The participants were followed for eight weeks. Results: Both the drugs achieved effective control of blood pressure (BP) at the end of eight weeks. The mean reduction in systolic BP (SBP) was 22.17 mmHg with trandolapril and 21.47 mmHg with enalapril group; the mean reduction of diastolic BP (DBP) was 9.57 mmHg with trandolapril and 11.13 mmHg with enalapril. Adverse events developed in 11 (18.3%) and 12 (20%) patients in trandolapril and enalapril group, respectively. Conclusion: The efficacy and tolerability of trandolapril was comparable to enalapril in mild-to-moderate hypertension with minor adverse events.

keywords:Hypertension, ACEIs, trandolapril, enalapril

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of either sex in the age group of 20-60 years with mild-to-moderate hypertension (sitting diastolic BP [DBP] between 90-110 mmHg) were recruited for the study. Patients who were previously receiving antihypertensive medication were given two weeks’ washout prior to entry into the study. Patients with the following conditions were excluded from the study; pregnant and lactating women, patients with history of drug allergy or intolerance to ACEIs, patients unwilling to comply with the protocol requirement, patients with severe hypertension, patients already on antihypertensive drugs or other medications known to affect the outcome of the study, patients who had participated in other clinical trials in the past one month, patients with history or evidence of renal, hepatic or neurological disease, patients with uncontrolled diabetes and patients with suspected bilateral renal artery stenosis or single kidney. A detailed medical history, clinical examination, anthropometric measurements and baseline laboratory investigations were carried out.

Patients fulfilling the study criteria were randomly assigned to two groups of 60 each to receive either trandolapril 2 mg or enalapril 5 mg. The BP was recorded at baseline, at 2, 4 and 8 weeks. BP was recorded 3 times at each visit after five minutes of rest in a sitting posture. Compliance was monitored by pill count method. Patients were monitored for adverse events throughout the study period.

Laboratory investigations like Hb%, WBC count, blood urea, serum creatinine, lipid profile, serum electrolytes (sodium and potassium), FBS, urine analysis and ECG were done at baseline and at the end of eight weeks. Romhilt-Esters point score system10 was used to detect left ventricular hypertrophy (LVH) by using ECG.

Data was expressed in percentages and mean ± SD. Student ‘t’ test was used to find the significance of systolic BP (SBP) and DBP between the two groups. ANOVA was used to find the significance of SBP and DBP during the study period within each group.

reSultS

Out of 120 patients, 64 were men and 56 women. The mean age in trandolapril and enalapril group was 51.21 ± 6.0 and 50.57 ± 6.16 years, respectively. Sixty-eight (56.66%) patients were from urban and 52 (43.33%) from rural area.

The mean SBP at baseline in the trandolapril group was 151.57 ± 7.63 mmHg compared with 151.07 ± 7.14 mmHg in the enalapril group. The mean DBP at baseline

in the trandolapril group was 98.40 ± 4.49 mmHg compared with 100.53 ± 5.66 mmHg in the enalapril group (Table 1). There were no significant differences between the two groups with respect to demographic and baseline characteristics.

The most frequent comorbid conditions present in both groups included type 2 diabetes mellitus in 16.66% (n = 20), obesity (body mass index [BMI] ≥25 kg/m2) in 28.33% (n = 34), diabesity in 9.16% (n = 11) and LVH based on ECG changes in 9.16% (n = 11) of patients (Table 2). At the end of two and four weeks, 38% and 75% of the study subjects in trandolapril group and 27% and 58% in the enalapril group achieved reduction in DBP to <90 mmHg and reduction in DBP at four weeks was shown to be significant (p < 0.05). The dose of trandolapril was increased from 2-4 mg in 25% (n = 15) and enalapril from 5-10 mg in 41.7% (n = 25) of patients at the end four weeks in patients who did not show DBP reduction to <90 mmHg with the initial dose.

The mean SBP/DBP in the trandolapril group was 151.57 ± 7.63/98.40 ± 4.49 at baseline, 144.30 ± 7.12/ 94.27 ± 4.58 after two weeks, 137.13 ± 6.16/91.45 ± 3.02 after four weeks and 129.40 ± 1.12/88.83 ± 1.34 after eight weeks. Mean fall in SBP and DBP was shown to be 22.17 and 9.57 mmHg (Table 3). The mean SBP/DBP in the enalapril group was 151.07 ± 7.14/100.53 ± 5.66 at baseline, 143.73 ± 7.34/95.80 ± 4.75 after two weeks, 136.23 ± 6.19/ 91.87 ± 2.85 after four weeks and 129.60 ± 0.81/89.23 ± 1.17 after eight weeks.

table 1. Demographic and Basic CharacteristicsCharacteristics trandolapril EnalaprilAge (years) 51.20 ± 6.01 51.57 ± 6.16Sex: Male/Female (N) 33/27 31/29Location: Urban/Rural (N) 28/32 40/20Basal SBP (Mean ± SD) mmHg 151.57 ± 7.63 151.07 ± 7.14Basal DBP (Mean ± SD) mmHg 98.40 ± 4.49 100.53 ± 5.66

N = 60 in each group. Values are mean ± standard deviation (SD)

table 2. Comorbid Conditions in Study GroupsComorbid conditions trandolapril EnalaprilType 2 diabetes mellitus 11 (18.3) 9 (15)Obesity 18 (30) 16 (26.7)Diabesity 5 (8.3) 6 (10)LVH 5 (8.3) 6 (10)

Numbers in parenthesis indicates percentage.

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Mean fall in SBP and DBP was shown to be 22.17 and 9.57 mmHg (Table 3). Mean fall in SBP and DBP was shown to be 21.47 and 11.23 mmHg. There was no significant difference in mean fall in SBP and DBP in both groups.

ECG was recorded in all patients at baseline and at the end of eight weeks. Eleven patients from both groups had pre-existing changes suggestive of LVH. Out of 11, one patient in trandolapril group showed partial reversal of LVH. All laboratory parameters both at baseline and at the end of eight weeks were within normal limits.

Adverse events were encountered in 18.33% (n = 11) and 20% (n = 12) of patients in trandolapril and enalapril group, respectively. Cough (6.6%), headache (3.3%) and myalgia (3.3%) were experienced in the trandolapril group. Giddiness (6.6%), cough (5%), headache (3.3%) and fatigue (3.3%) were seen in the enalapril group (Table 4). The most common adverse event from both groups was cough in 5.8% (n = 7). All the adverse events were mild, transient and did not require any treatment, discontinuation of medication or withdrawal from the study.

diScuSSion

In the present study, reduction in DBP to <90 mmHg was achieved in 75% of patients who received

trandolapril 2 mg and in 58% of those who received enalapril 5 mg for four weeks. All patients achieved target DBP reduction by the end of eight weeks after doubling of dose in both groups. Similar findings were observed in studies carried out by Shankar et al,11 they had shown that 98.4% patients with trandolapril and 93% with enalapril achieved target DBP reduction at the end of eight weeks. In the present study, mean reduction in SBP and DBP was 22.17 and 9.57 mmHg in trandolapril group.

In two noncomparative trials, where trandolapril was administered for a period of two weeks to 12 months in mild-to-moderate hypertension, mean reduction in SBP ranged from 7 to 31 mmHg and in DBP from 8 to 20 mmHg.12,13 Many controlled clinical trials have found that trandolapril produces clinically significant BP reduction and achieves target BP level in patients with hypertension.14,15 The observations reflect that trandolapril is equally efficacious and comparable to enalapril and that trandolapril offers a satisfactory approach for reduction of BP in mild-to-moderate hypertension. In this study, one patient from trandolapril group with LVH showed partial reversal.

Schmieder16 observed in a meta-analysis that ACEIs brought about early and significant decrease in LVH mass and wall thickness in 13% of patients with a mean duration of 25 weeks. In this regard, there is a need to conduct further studies to confirm the observation.

In the present study, cough was the common adverse event in both the groups, which accounted for 6.66% and 5% of patients, respectively. Many studies have proposed that bradykinin and substance P were responsible for the production of cough.17,18 In many studies, it was observed that the incidence of cough ranged from 2.3-39.1% and drug withdrawal was minimal.19,21 In the present study, we observed that cough was mild, transient and did not require discontinuation of medication or withdrawal from the study.

table 4. Adverse Events in the Study GroupAdverse events trandolapril EnalaprilCough 4 (6.66) 3 (5)Giddiness 1 (1.66) 4 (6.66)Headache 2 (3.33) 2 (3.33)Fatigue 1 (1.66) 2 (3.33)Myalgia 2 (3.33) 1 (1.66)Abdominal discomfort 1 (1.66) 0 (0)total 11 (18.33) 12 (20)

Numbers in parenthesis indicates percentage.

table 3. Changes in SBP and DBP in Trandolapril and Enalapril Groups during the StudyVisits trandolapril Enalapril

SBP DBP SBP DBPBasal 151.57 ± 7.63 98.40 ± 4.49 151.07 ± 7.14 100.53 ± 5.662 weeks 144.30 ± 7.12 94.27 ± 4.58 143.73 ± 7.34 95.80 ± 4.754 weeks 137.13 ± 6.16 91.45 ± 3.02 136.23 ± 6.19 91.87 ± 2.858 weeks 129.40 ± 1.12 88.83 ± 1.34 129.60 ± 0.81 89.23 ± 1.17

Values are mean ± standard deviation (SD). No statistical significance between two groups.

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concluSion

The present study suggests that the efficacy and tolerability of trandolapril were comparable to enalapril in mild-to-moderate hypertension. Both drugs effectively controlled SBP and DBP at the end of eight weeks and were well-tolerated with few minor adverse events.

Acknowledgment

Authors are thankful to M/s Hetero Drugs, Hyderabad for providing the clinical supplies.

referenceS

Hoffman BB. Therapy of Hypertension. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th edition, Brunton LL, Lazo JS, Parker KL (Eds.) McGraw-Hill Co: New York 2006:p. 845-50.World Health Organization. Hypertension Control. World Health Organization. Geneva. 1996. WHO Technical Reports Series. 862.Reddy R, Chahoud G, Mehta JL. Modulation of cardiovascular remodeling with statins: fact or fiction? Curr Vasc Pharmacol 2005;3(1):69-79.Ramos-Nino ME, Blumen SR. Benefits of ACE inhibitors in diabetes. Clin Med Therapeut 2009;1:1041-51.Parmley WW. Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am J Med 1998;105(1A):27S-31S.Dézsi L. Fibrinolytic actions of ACE inhibitors: a significant plus beyond antihypertensive therapeutic effects. Cardiovasc Res 2000;47(4):642-4. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al; American College of Cardiology/American Heart Association. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38(7):2101-13.Diaz A, Ducharme A. Update on the use of trandolapril in the management of cardiovascular disorders. Vasc Health Risk Manag 2008;4(6):1147-58.Wiseman LR, McTavish D. Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs 1994;48(1):71-90.Hsieh BP, Pham MX, Froelicher VF. Prognostic value of electrocardiographic criteria for left ventricular hypertrophy. Am Heart J 2005;150(1):161-7.

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Shankar PK, Vidyasagar S, Adiga S, Naidu MU, Usha Rani P, Rao D, et al. Efficacy and tolerability of trandolapril in mild to moderate hypertension - a double blind comparative clinical trial with enalapril in Indian population. Indian J Physiol Pharmacol 2006;50(4):421-6.Backhouse CI, Orofiamma B, Pauly NC. Long-term therapy with trandolapril, a new nonsulfhydryl ACE inhibitor, in hypertension: a multicenter international trial. Investigator Study Group. J Cardiovasc Pharmacol 1994;23 Suppl 4:S86-90. Poirier L, Bourgeois J, Lacourcière Y. Once-daily trandolapril compared with the twice-daily formulation in the treatment of mild to moderate essential hypertension: assessment by conventional and ambulatory blood pressures. J Clin Pharmacol 1993;33(9):832-6.Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al; INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290(21):2805-16.Tytus RH, Burgess ED, Assouline L, Vanjaka A. A 26-week, prospective, open-label, uncontrolled, multicenter study to evaluate the effect of an escalating-dose regimen of trandolapril on change in blood pressure in treatment-naive and concurrently treated adult hypertensive subjects (TRAIL). Clin Ther 2007;29(2):305-15.Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996;275(19):1507-13.Dendorfer A, Wolfrum S, Dominiak P. Pharmacology and cardiovascular implications of the kinin-kallikrein system. Jpn J Pharmacol 1999;79(4):403-26.Ho CY, Gu Q, Hong JL, Lee LY. Prostaglandin E(2) enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat. Am J Respir Crit Care Med 2000;162(2 Pt 1):528-33.Adalet K, Buyukozturk K. Trandolapril in overweight patients with mild-to-moderate essential hypertension: the Turkish multicentre trandolapril study. Curr Ther Res 1996;57(12):980-9.Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, et al; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351(20): 2058-68.Gosse P, Vaur L, Dutrey-Dupagne C, Genes N, Destrée D, Elkik F. Evaluation of trandolapril alone or in combination with a calcium channel blocker in hypertensive patients over 60 years of age. Ann Cardiol Angeiol (Paris) 1995;44(9):517-24.

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photoquiz

Cyanosis in an Older Woman

An 82-year-old woman presented to the emergency department with right-sided leg pain and paresthesias that had lasted for five

days. The patient had been bedridden for several years because of dementia.

Examination revealed diffusely scattered cyanosis on the foot (see accompanying figure), ankle, and calf, but sparing the knee. Peripheral pulses, including popliteal, posterior tibial, and dorsal pedis, were absent on the affected side.

QueStion

Based on the patient’s history and physical examination, which one of the following is the most likely diagnosis?

A. Blue toe syndrome.

B. Buerger disease.

Source: Adapted from Am Fam Physician. 2010;81(12):1491-1492.

seethefoLLoWingpAgefordisCussion.

C. Diabetic gangrene.

D. Diffuse acute limb ischemia.

E. Postthrombotic syndrome.


photoquiz

diScuSSion

The answer is D: diffuse acute limb ischemia.

Diffuse acute limb ischemia is caused by a sudden decrease in limb perfusion that threatens limb viability within two weeks of the acute event. The condition is called critical limb ischemia when symptoms last for more than two weeks.1

Skin examination typically shows a cool, pale extremity with delayed capillary refill. The level of occlusion is generally one joint above the line of demarcation between the normal and ischemic areas. The classic symptoms of large artery occlusion are described as the five Ps: pain, paleness, pallor, paresthesia, and paralysis. Irreversible damage occurs within six hours of ischemia. When arterial occlusion occurs in the setting of well-developed collateral circulation, the symptoms may be less remarkable (e.g., intolerance to ambulation, modest pain, paresthesia). Limb ischemia is more common in lower extremities than in upper extremities. Diagnosis can be made using arterial Doppler evaluation and angiography. Angiography is confirmatory and demonstrates the location and severity of the obstruction.2

Acute limb ischemia is usually caused by embolic events, and therefore warrants investigation for an embolic source. Most embolic events are of cardiac or large artery origin. Cardiac disorders that can cause embolism include atrial fibrillation, myocardial infarction, and ventricular aneurysm. Atherosclerosis, or aneurysm of the aorta and other large arteries, is another embolic source of embolism. Although less common, a venous thrombus may enter systemic circulation through a patent foramen ovale or other septal defect.2 Arterial thrombosis may occur in atheromatous, aneurysmal, or traumatized vessels.

Treatment of embolism includes prompt initiation of heparin to prevent propagation of the clot,1 followed by intra-arterial thrombolytic therapy with urokinase or surgical intervention (embolectomy or a bypass procedure). Nonviable tissue requires debridement, and amputation if necessary.3 Delayed amputation increases the risk of infection, myoglobinuria, acute renal failure, and hyperkalemia. After successful limb salvage, continuous anticoagulation with heparin followed by oral warfarin is recommended to prevent recurrence.2

Blue toe syndrome is an acute embolic event at the digital artery that leads to sudden, painful cyanosis in the toe despite strong pedal pulse and a warm foot.4 This condition is analogous to transient ischemic attack

in the central nervous system and leads to an impending ischemic event.

Buerger disease is inflammation of distal arteries and veins causing ischemic pain and ulceration. Pathology shows inflammation of vessels; however, atherosclerosis is typically absent. Risk factors include Asian descent and cigarette smoking.2

Diabetic gangrene manifests as a nonhealing ulcer, typically on the toe. It is caused by the combination of arterial atherosclerosis and peripheral nerve damage. Diabetic gangrene typically develops after long-standing diabetes mellitus with multiple foot infections.

Postthrombotic syndrome is a common complication of deep venous thrombosis. Typical features include pain, swelling, and heaviness; a stasis ulcer may develop.5

referenceS

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(suppl S): S5-67.Creager MA, Dzau VJ. Vascular disease of the extremities. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17 ed. New York, NY: McGraw-Hill; 2008.Clagett GP, Sobel M, Jackson MR, Lip GY, Tangelder M, Verhaeghe R. Antithrombotic therapy in peripheral artery occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):609S-626S.Karmody AM, Powers SR, Monaco VJ, Leather RP. “Blue toe” syndrome. An indication for limb salvage surgery. Arch Surg. 1976;111(11):1263-1268.Kahn SR. The post-thrombotic syndrome: progress and pitfalls. Br J Haematol. 2006;134(4):357-365.

1.

2.

3.

4.

5.

Summary tableCondition CharacteristicsBlue toe syndrome Acrocyanosis with strong pedal pulse

and warm footBuerger disease Small and medium vessel vasculitis

causing ischemic pain and ulceration; more common in smokers and persons of Asian descent

Diabetic gangrene Nonhealing ulcer, typically in persons with long-standing history of diabetes mellitus and multiple foot infections

Diffuse acute limb ischemia

Progressive pain, paleness, pallor, paresthesia, and paralysis

Postthrombotic syndrome

Pain, swelling, and heaviness; stasis ulcer may develop


prACtiCeguideLines

ACCF/AHA Release Guideline for Early Cardiovascular Risk Assessment

Atherosclerotic cardiovascular disease is the leading cause of death among adults in the United States. Because coronary heart

disease (CHD) has a long asymptomatic latent period, there is an opportunity for early preventive measures. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have created a guideline to assist physicians with the early cardiovascular risk assessment of asymptomatic adults. The goal of this assessment is to guide targeted preventive efforts based on the patient’s individual risk. Initial evaluation includes broadly categorizing patients by risk. Further intervention is based on these risk assessments.

recommendAtionS

global risk Scoring

Global risk scores (e.g., Framingham Risk Score) that include multiple traditional cardiovascular risk factors effectively combine individual risk factor measurements into a single quantitative estimate of risk. These scores should be used in all cardiac risk assessment evaluations to guide the initiation of targeted preventive measures.

family History and genomic testing

Family history of atherothrombotic cardiovascular disease should be obtained, although genotype testing is not recommended.

laboratory testing

Lipoprotein and Apolipoprotein. Lipid measurements, including lipoprotein levels, apolipoprotein levels, and particle size/density, beyond the standard lipid profile are not recommended.

Natriuretic Peptide. Measurement of natriuretic peptide levels is not recommended.

C-Reactive Protein. Measurement of C-reactive protein levels can be useful in selecting candidates for statin

Source: Adapted from Am Fam Physician. 2011;84(2):234-235.

therapy in the following patients: men 50 years and older and women 60 years and older with a low-density lipoprotein cholesterol level less than 130 mg per dL (3.37 mmol per L) who are not on lipid-lowering medications, hormone therapy, or immunosuppressant therapy and do not have clinical CHD, diabetes mellitus, chronic kidney disease, severe inflammatory conditions, or contraindications to statins. Measurement of C-reactive protein levels may be reasonable in younger patients with intermediate cardiovascular risk, but is not recommended for high-risk patients.

A1C. Measurement of A1C levels may be reasonable in patients without diabetes to assess cardiovascular risk.

Microalbuminuria. Urinalysis to detect microalbuminuria is reasonable in patients with hypertension or diabetes, and may be reasonable in intermediate-risk patients without these conditions.

Lipoprotein-Associated Phospholipase A2. Measurement of lipoprotein-associated phospholipase A2 levels may be reasonable in intermediate-risk patients.

imaging and other testing

Resting Electrocardiography (ECG). Resting ECG is reasonable in patients with hypertension or diabetes, and may be considered in patients without these conditions.

Transthoracic Echocardiography. Echocardiography to detect left ventricular hypertrophy may be considered in patients with hypertension, but is not recommended in those without hypertension.

Carotid Intima-Media Thickness. Measurement of carotid intima-media thickness is reasonable in intermediate-risk patients; however, high-quality results are dependent on properly performing the test.

Brachial/Peripheral Flow–Mediated Dilation. Peripheral arterial flow–mediated dilation is not recommended.

Arterial Stiffness. Measurement of arterial stiffness is not recommended outside of research settings.


prACtiCeguideLines

Ankle-Brachial Index. Measurement of ankle-brachial index is reasonable for intermediate-risk patients.

Exercise and stress ECG. Exercise ECG may be considered in intermediate-risk patients (including sedentary adults who are considering a vigorous exercise program), particularly if non-ECG markers, such as exercise capacity, are noted.

Stress Echocardiography. Stress echocardiography is not recommended in low- or intermediate-risk patients. It is used mainly in the advanced cardiac evaluation of symptomatic patients to estimate prognosis in those with known coronary artery disease and to assess those with known or suspected valvular heart disease.

Myocardial Perfusion Imaging. Stress myocardial perfusion imaging may be considered in patients with diabetes or a strong family history of CHD, or if a previous risk assessment suggested high risk of CHD. It is not

indicated for patients with low or intermediate risk, and is used mainly in the advanced cardiac evaluation of symptomatic patients and to estimate prognosis in patients with known coronary artery disease.

Calcium Scoring Methods. Measurement of cardiac calcium levels is reasonable in patients with intermediate risk (10 to 20 percent 10-year risk), may be reasonable in those with low to intermediate risk (6 to 10 percent 10-year risk), and is not recommended in patients with low risk (less than 6 percent 10-year risk). Measurement of cardiac calcium levels is reasonable in patients 40 years and older with diabetes.

Coronary Computed Tomography Angiography. Coro-nary computed tomography angiography is not recommended.

Magnetic Resonance Imaging. Magnetic resonance imaging for detection of vascular plaque is not recommended.


News and Views

non-Hdl-c leVelS linked to riSk for cArdioVASculAr eVentS

Levels of non-high-density lipoprotein cholesterol (non-HDL-C) among users of statins is linked to the risk for a major cardiovascular event, such as a heart attack or stroke, more strongly than are levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). The finding, from a meta-analysis of data from eight trials comprising a total of 62,154 patients, is published in the March 28 issue of JAMA. (Source: Medscape)

freQuent cHocolAte conSumption linked to lower bmi

A recent study showed that frequent chocolate consumption was associated with lower body mass index (BMI), even when adjusting for calorie intake, saturated fat intake and mood. Beatrice A. Golomb, MD, PhD, associate professor of medicine at the University of California, San Diego and colleagues described their findings in a research letter published in the March 26 issue of the Archives of Internal Medicine. (Source: Medscape)

cleArer meAning of frAilty needed in cVd

It is time to adopt a consistent definition of frailty and simple metrics to evaluate older adults with cardiovascular disease (CVD), according to a review. Evidence, although sparse, suggests that simple, well-established performance measures can be highly predictive of clinical outcomes in these patients, reported Rebecca Gary, PhD, RN, from the Nell Hodgson Woodruff School of Nursing at Emory University in Atlanta. (Source: Medpage Today)

coronAry StentS proVide Solid long-term reSultS in younger AdultS

Young adults who received coronary artery stents through age 40 had excellent short- and long-term results, and the Italian researchers who reported this finding say the devices should be the treatment of choice in this age group. (Source: Medscape)

infection mAy trigger VenouS clotS

A new study found that factors increasing the risk of hospitalization for venous thromboembolism included: Infection (especially respiratory tract infection), erythropoiesis-stimulating drugs and blood transfusion. These factors, particularly infection, are not included in traditional risk assessment for hospitalized patients. (Mary Rogers, PhD, of the University of Michigan in Ann Arbor, and colleagues in Circulation: Journal of the American Heart Association.)

StAtinS often ignored After Surgery

A new study has shown that failure to restart statins after head and neck surgery is associated with an elevated risk for death and other cardiovascular adverse outcomes. Among patients who died or had a myocardial infarction, unstable angina, stroke or congestive heart failure at 30 days, 75% had been chronic statin users and had not had the treatment restarted within four days after the surgery, reported Vineet Chopra, MD, of the University of Michigan in Ann Arbor. (Annual meeting of the Society of Hospital Medicine.)

AAA repAir weAker for women

Women have a lower chance of surviving elective open abdominal aortic repair, and this retrospective evaluated whether the same holds true for elective endovascular aneurysm (EVAR) repair. For women, elective EVAR resulted in significantly greater mortality rates than men and a greater incidence of intraoperative and postoperative complications. (Manish Mehta, MD, MPH, of the Institute for Vascular Health and Disease at Albany Medical College in Albany, N.Y., and colleagues reported in April issue of the Journal of Vascular Surgery.)

be cAutiouS wHen giVing pAinkillerS to pAtientS witH HigH cHoleSterol

One should not give long-term nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen to patients with high cholesterol. In a swine model study published in the journal Surgery, Dr Frank Sellke, chief of cardiothoracic surgery and research at Rhode Island

AroundthegLoBe


AroundthegLoBe

Hospital found that a high-cholesterol diet reduced blood flow to the heart muscle in animal models with chronic heart disease when given daily naproxen.

They also found reduced levels of prostacyclin, a compound that dilates blood vessels and prevents blood clots. These findings suggest that there may be a stronger risk of negative effects on the heart in patients who have high cholesterol levels and are taking NSAIDs as a form of pain or inflammation relief.

(Source: (http://csinews.emedinews in/2012/04/10/be cau-tious-when-giving-painkillers-to-patients-with-high-cholesterol/)

moSt fAt people don’t tHink tHey Are fAt: Study

NEW DELHI: How many fat people think they are fat? “Hardly,” said half a dozen doctors TOI spoke to. Most of them said, “Majority of our obese patients don’t think they are fat enough to be in trouble.” Experts now say misperception of weight is becoming a major barrier to weight loss - a serious problem in India which has seen a nearly 20% increase in overweight population rates between 1998 and 2005. Take for example a recent University of Illinois study by researchers who surveyed over 3,500 college applicants. More than a third couldn’t report their weight accurately and overweight and obese men were more likely to underestimate their weight than women. In physical exams, the height, weight and BMI of 3,622 18- to 20-year-old applicants to the Mexican University were recorded. Around 33.6% were overweight or obese, but only 16.9% described themselves as being in those categories. Women seemed to be a better judge of their weight than men with the gap between the former’s perception and reality on their weight being smaller-

27.8% of women were actually overweight or obese, but only 21.2% believed that they were. The study findings have serious implications for India where currently, one in 5 men and over one in 6 women are overweight. In some urban areas, the rates are as high as 40%. (Source: TOI, Apr. 9, 2012)

mitrAl regurgitAtion: eArly HAzArd, lAter gAinS following tAVi

Moderate-to-severe mitral regurgitation (MR) is relatively common in patients undergoing transcatheter aortic valve implantation and is associated with a doubling in risk of 30-day death, a new series suggests. Beyond this initial period, however, survival among MR patients is just as good as among patients with no MR, and MR itself is likely to improve over time, authors of a new analysis say. (Source: Medscape)

cArdiAc biomArkerS in nonVAlVulAr Af

Two common cardiac biomarkers - troponin I and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) can improve risk prediction among patients with nonvalvular atrial fibrillation (AF), a RE-LY substudy showed. Elevations of both biomarkers were associated with greater risks of stroke or systemic embolism, vascular mortality and a composite of thromboembolic events, according to Ziad Hijazi, MD, of Uppsala University in Sweden, and colleagues. High troponin I levels also were associated with increased risks of myocardial infarction (MI) and major bleeding, the researchers reported online in Circulation: Journal of the American Heart Association. [Medpage]


Lighter Side of Medicine

one dAy i decided to Quit…

I quit my job, my relationship, my spirituality. I wanted to quit my life. I went to the woods to have one last talk with God.

“God”, I said. “Can you give me one good reason not to quit?”

His answer surprised me. “Look around”, He said. “Do you see the fern and the bamboo?”

“Yes”, I replied.

“When I planted the fern and the bamboo seeds, I took very good care of them. I gave them light. I gave them water. The fern quickly grew from the earth. Its brilliant green covered the floor. Yet nothing came from the bamboo seed. But I did not quit on the bamboo. In the second year the Fern grew more vibrant and plentiful. And again, nothing came from the bamboo seed. But I did not quit on the bamboo”. He said.

“In the third year, there was still nothing from the bamboo seed. But I would not quit. In the fourth year, again, there was nothing from the bamboo seed. “I would not quit.” He said.

“Then in the fifth year a tiny sprout emerged from the earth. Compared to the fern it was seemingly small and insignificant. But just 6 months later the bamboo rose to over 100 feet tall. It had spent the five years growing roots. Those roots made it strong and gave it what it needed to survive. I would not give any of my creations a challenge it could not handle.” He said to me.

“Did you know, my child, that all this time you have been struggling, you have actually been growing roots.”

“I would not quit on the bamboo. I will never quit on you”.

Don’t compare yourself to others.” He said. “The bamboo had a different purpose than the fern. Yet, they both make the forest beautiful.”

Your time will come, “God said to me.” You will rise high!

“How high should I rise?” I asked.

How high will the bamboo rise?” He asked in return.

“As high as it can?” I questioned.

Anin

spir

Atio

nAL

stor

y “Yes.” He said, “Give me glory by rising as high as you can”.

I left the forest and bring back this story. I hope these words can help you see that God will never give up on you. He will never give up on you. Never regret a day in your life.

—Dr GM Singh

Dr. Good and Dr. Bad

Dr KK Aggarwal

SItuAtION: A patient had an episode of TIA.

lESSON: The recommended dose of aspirin for stroke prevention is 300 mg/day as against coronary artery disease prevention where the dose is 150 mg/day.

Start aspirin 150 mg/day

Start aspirin 300 mg/day

©IJ

CP

Aca

de

my

LAug

hA

Whi

Le feline pHySicS

law of cat inertia

A cat at rest will tend to remain at rest, unless acted upon by some outside force-such as the opening of cat food, or a nearby scurrying mouse.

—Dr GM Singh

LighterreAding

An optimist is the human personification of spring.

—Susan J. Bissonette

The attempt to silence a man is the greatest honour you can bestow on him. It means that you recognize his superiority to yourself.

—Joseph Sobran

quot

es


Information for AuthorsManuscripts 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.

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Journal ofCLINICALCARDIOLOGYA

sian


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.

referencesThese 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:

ArticlesPaintal 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.

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

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

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For Editorial Correspondence Dr KK AggarwalGroup Editor-in-Chief

Asian Journal of Clinical CardiologyE - 219, Greater Kailash, Part - 1,

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Website: www.ijcpgroup.com

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