Cause And Effect Of Cardiovascular Disease Biology Essay


Cardiovascular Diseases are the number one cause of death globally: more people die annually from cardiovascular diseases than from any other cause (1). Serum levels of lipids and lipoprotein lipids have proven to be among the most potent and best substantiated risk factors for atherosclerosis . Dys-lipoproteinemias constitute a major risk factor for atherosclerosis and coronary artery disease, and their proper recognition and management can reduce cardiovascular and total mortality rates. The fundamentals of lipidology have importance for the daily practice of cardiovascular medicine.

Different components of lipids and lipoprotein lipids have been subjected to testing for control of coronary heart disease. Initially Cholesterol and Triglycerides and then Low density lipoproteins (LDL) , High density Lipoproteins (HDL) and even plasma apolipoproteins involved in the metabolism of fatty acids have been incorporated .

The latest National Cholesterol Education Program Adult Treatment Panel III, in which low-density lipoprotein (LDL) cholesterol lowering targets were made more aggressive, there is currently an intense focus on aggressive interventions to lower LDL cholesterol(2).

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In the past decade, high-density lipoproteins (HDL) have also emerged as a new potential therapeutic target for the treatment of cardiovascular disease. The key role of HDL as a carrier of excess cellular cholesterol in the reverse cholesterol transport pathway is believed to provide protection against atherosclerosis.

Epidemiologic studies have shown an inverse correlation between HDL cholesterol levels and the risk of cardiovascular disease(3) .Increasing the HDL cholesterol level by 1 mg may reduce the risk of cardiovascular disease by 3 percent (4, 5). The development of drugs to increase HDL cholesterol levels for either the short term or the long term represents an exciting new approach to the treatment of high-risk patients with cardiovascular disease. Men presenting with premature CAD have a low HDL (< 35 mg/dL) (67%) almost as frequently as they smoke (67%) and more frequently than they have hypertension(6).

The new ATP III guidelines do not specify a particular treatment goal but there are several strategies available to raise HDL. The guidelines mention the use of nicotinic acid or fibrates in patients with CAD and isolated low HDL. Statins are also available. As shown in all major statin trials, statins produce a modest rise in HDL (5% to 10%)(6).

The most commonly employed lifestyle changes to elevate HDL include exercise, weight reduction, smoking cessation, and moderated alcohol consumption. Estrogen therapy does raise HDL, but proof of any benefit from hormone replacement therapy in preventing cardiac events is still lacking. Another well-known, but little-utilized agent is niacin (7).

Anecdotal experience with clinical practices of cardiology clinics in Pakistan have shown remarkable under-management of HDL cholesterol levels in patients presenting to clinics. Cardiologists mainly target LDL cholesterol and total cholesterol in their clinical practice and HDL cholesterol remains neglected although it has greater clinical implications. However no local clinical data is available regarding the clinical practices of cardiologists especially with respect to HDL cholesterol levels.

Pakistanis belong to an ethnic group, which has the highest rates of coronary heart disease (CHD). According to the official estimates, cardiovascular disease (CVD) results in more than 100,000 deaths every year in Pakistan, however, the actual figure may be much higher than that (8) . Moreover a number of studies carried out overseas on South Asians also revealed high levels of triglycerides and low levels of High Density Lipoprotein (HDL) - cholesterol in this ethnic group (9). "Low baseline HDL-cholesterol" in Pakistani population may have been one of the factors contributing to high rates of CAD. In fact, the prevalence of "low-HDL-cholesterol" (<35 mg/dl) in our population is 45.8% which is among the highest reported in the literature (8).But the levels of Low HDL Cholesterol levels in the above mentioned study are below the current standard levels of <40 as designated by ATP-III guidelines

So HDL cholesterol needs more attention during the management of coronary heart disease for better primary and secondary prevention of heart disease in Pakistan.

Cardiology and primary care practices require comprehensive routine lipid management program to ensure most patients receive optimal therapy with statins and other lipid lowering agents.

Review of literature:

Lipids are a broad group of naturally occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others.

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Lipids may be broadly defined as hydrophobic or amphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits : ketoacyl and isoprene groups.(10) Using this approach, lipids may be divided into eight categories:

Fatty acyls




Saccharo-lipids and polyketides (condensation of ketoacyl subunits)

Sterol lipids: (such as cholesterol , bile acids and their conjugates)

Prenol lipids (derived from condensation of isoprene subunits).

Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides.

Lipids also encompass molecules such as fatty acids and their derivatives (including tri-glycerides, di-glycerides, and monoglycerides and phospholipids), as well as other sterol-containing metabolites such as cholesterol.(11) Although humans and other mammals use various biosynthetic pathways to both break down and synthesize lipids, some essential lipids cannot be made this way and must be obtained from the diet.

Figure 1: Structure of some common lipids.

Biochemistry of Lipids :

The Lipid transport system has developed to carry the hydrophobic fat molecules from site of origin to sites of utilization through plasma, the aqueous environment. The apolipoproteins ( the proteins that mediate the process ) are conserved throughout evolution. Most apolipoproteins are derived from ancestral gene and contain both hydrophilic and hydrophobic domains. This enables these proteins to bridge the interface between the aqueous environment of plasma and phospholipid content of the lipoprotein. The major types of lipids that circulate include :

Cholesteryl esters




Cholesterol contributes an essential component of mammalian cell membranes and furnishes substrate for steroid hormones and bile acids. Many cell functions depend critically on membrane cholesterol, and cells tightly regulate cholesterol content. Most of the cholesterol in plasma circulates in the form of cholesteryl esters, in the core of lipoprotein particles. The enzyme lecithin cholesterol acyl-transferase (LCAT) forms cholesteryl-esters in the blood compartment by transferring a fatty acyl chain from phosphatidyl-choline to cholesterol.

Triglycerides (TG):

Triglycerides consist of a three-carbon glycerol backbone covalently linked to three fatty acids. The fatty acid composition varies in terms of chain length and presence of double bonds (degree of saturation). Triglyceride molecules are non-polar and hydrophobic; they are transported in the core of the lipoprotein. Hydrolysis of triglycerides by lipases generates free fatty acids used for energy.


Phospholipids, constituents of all cellular membranes, consist of a glycerol molecule linked to two fatty acids. The fatty acids differ in length and in the presence of a mono-unsaturated or poly-unsaturated double bonds. The third carbon of the glycerol moiety carries a phosphate group to which one of four molecules are linked:

Choline (phosphatidyl-choline or lecithin)

Ethanolamine (phosphatidyl-ethanolamine)

Serine (phosphatidyl-serine)

Inositol (phosphatidy-linositol)

A related phospholipid, sphingomyelin, has special functions in the plasma membrane in the formation of membrane microdomains. Phospholipids are polar molecules, more soluble than triglycerides or cholesterol or its esters. Phospholipids participate in signal transduction pathways: Hydrolysis by membrane-associated phospholipases generates second messengers such as diacyl glycerols, lysophospholipids, phosphatidic acids, and free fatty acids such as Arachidonate that can regulate many cell functions.

FIG : 2 Self-organization of phospholipids: a spherical liposome, a micelle and a lipid bilayer.


Lipoproteins are complex macromolecular structures, composed of an envelope of phospholipids and free cholesterol, a core of cholesteryl esters, and triglycerides. The classification of lipoproteins reflects their density in plasma (1.006 gm/ml) as gauged by flotation in the ultracentrifuge. The triglyceride-rich lipoproteins consisting of chylomicrons and very-low-density lipoprotein (VLDL) have a density less than 1.006 gm/ml. The rest of the ultracentrifuged plasma consists of low-density lipoprotein (LDL), HDL, and lipoprotein (a) (Lp[a]).


Apolipoproteins have four major roles:

(1) Assembly and secretion of the lipoprotein (apo B100 and B48);

(2) Structural integrity of the lipoprotein (apo B, apo E, apo AI, apo AII);

(3) Co-activators or inhibitors of enzymes (apo AI, CI, CII, CIII);

(4) Binding or docking to specific receptors and proteins for cellular uptake of the entire particle or selective uptake of a lipid component (apo AI, B100, E) .

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The role of several apolipoproteins (AIV, AV, D, and J) remain incompletely understood.

Receptors and processing enzymes :

Many proteins regulate the synthesis, secretion, and metabolic fate of lipoproteins . The discovery of the LDL receptor was able to achieve a landmark in understanding cholesterol metabolism and receptor-mediated endocytosis. The LDL receptor regulates the entry of cholesterol into cells, control mechanisms alter its expression on the cell surface, depending on need

The LDL receptor-related peptide, which mediates the uptake of chylomicron remnants and VLDL, preferentially recognizes apolipoprotein E (apo E). The LDL receptor-related peptide interacts with hepatic lipase. A specific VLDL receptor also exists. The interaction between hepatocytes and the various lipoproteins containing apo E is complex and involves cell surface proteoglycans that provide a scaffolding for lipolytic enzymes (lipoprotein lipase and hepatic lipase) involved in remnant lipoprotein recognition. Macrophages express receptors that bind modified (especially oxidized) lipoproteins. These scavenger lipoprotein receptors mediate the uptake of oxidized LDL into macrophages. In contrast to the exquisitely regulated LDL receptor, high cellular cholesterol content does not suppress scavenger receptors, enabling the intimal macrophages to accumulate abundant cholesterol, become foam cells, and form fatty streaks. Endothelial cells can also take up modified lipoproteins through a specific receptor such as Lox-1.

At least two physiologically relevant receptors bind HDL particles: the scavenger receptor class B (SR-B1; also named CLA-1 in humans) and the adenosine triphosphate-binding cassette transporter A1 (ABCA1). SR-B1 is a receptor for HDL (also for LDL and VLDL, but with less affinity). SR-B1 mediates the selective uptake of HDL cholesteryl esters in steroidogenic tissues, hepatocytes, and endothelium. The ABCA1 mediates cellular phospholipid (and possibly cholesterol) efflux and is necessary and essential for HDL biogenesis.

Lipoprotein Metabolism and Transport:

Lipoprotein transport system has two major roles:

1. Transport of TGs from the intestine and the liver to fat tissue or muscle, sites of utilization.

2. Transport of Cholesterol to peripheral tissues, for either membrane synthesis, steroid hormone production, or to the liver for bile acid synthesis.


Upon ingestion of TGs pancreatic lipases hydrolyze them to FFAs and monoglycerides or diglycerides. Emulsification by bile salts leads to formation of intestinal micelles. Micelles resemble lipoproteins (they consist of phospholipids, free cholesterol, bile acids, diglycerides and monoglycerides, FFAs, and glycerol).

The mechanism of micelle uptake by the intestinal brush border cells still unclear. The advent of inhibitors of cholesterol uptake has re-emphasized interest in the mechanisms of intestinal fat absorption. After uptake into intestinal cells, fatty acids undergo re-esterification to form TGs and its packing into chylomicrons inside the intestinal cell and enter the portal circulation. Chylomicrons contain apo B48, the amino-terminal component of apo B100. In the intestine the apo B gene is modified during transcription into mRNA ). Only intestinal cells express ApoB.

Chylomicrons rapidly enter the plasma compartment after meals. In capillaries of adipose tissue or muscle cells in the peripheral circulation, chylomicrons face an enzyme lipoprotein lipase (LPL), attached to heparan sulfate and present on the luminal surface of endothelial cells . LPL activityis mediated by an activator apo CII and by an inhibitor apo CIII . Lipoprotein lipase cleaves all fatty acyl residues attached to glycerol, making three molecules of FFA for each molecule of glycerol. Muscle cells rapidly take up fatty acids. Adipose cells can store triglycerides made from fatty acids for energy utilization- a process that requires insulin.

Fatty acids also can bind to fatty acid-binding proteins and reach liver, where they are re-packaged in VLDL. Peripheral resistance to insulin can thus increase the delivery of FFAs to the liver with resultant increase in VLDL secretion and increased apo B particles in plasma. The remnant particles, derived from chylomicrons following Lipoprotein Lipase action, contain apo E and enter liver for degradation and re-utilization of their main constituents.


Hepatic secretion of VLDL particles serve as readily available triglycerides to meet energy demand. VLDLs are triglyceride-rich lipoproteins (smaller than chylomicrons), they have apo B100 as their main apolipoprotein. As opposed to apo B48, apo B100 contains a domain recognized by the LDL receptor . VLDL particles follow the same catabolic pathway through LPL as chylomicrons . During hydrolysis of TG-rich lipoproteins by LPL, an exchange of proteins and lipids takes place: VLDL particles (and chylomicrons) acquire apo Cs and apo E, in part from HDL particles.

VLDLs also exchange triglycerides for cholesteryl esters from HDL . Such bidirectional transfer among lipoproteins serves for :

Acquisition of specific apo-lipoproteins by lipoproteins that will dictate their metabolism.

Transfer of phospholipids onto nascent HDL particles , the phospholipid envelope becomes redundant and is shed off to apo AI , to form new HDL particles.

Tansfer of cholesterol from HDL to VLDL remnants so that it can be metabolized in the liver. (This exchange constitutes major part of the reverse cholesterol transport pathway)

VLDL particles have relatively more cholesterol, after hydrolysis of triglycerides. They shed apo-lipoproteins (especially the apo-lipoprotein C ) and acquire apo E. The VLDL remnant lipoprotein, called intermediate-density lipoprotein (IDL), is taken up by the liver or further cleaved by hepatic lipase to form an LDL particle. Most hepatic receptors have ability to recognize apo E, an interaction that mediates uptake of several classes of lipoproteins including VLDL and IDL protein.


LDL particles contain mainly the cholesteryl esters packaged with the protein moiety apo B100. Normally, TG constitute only 4 to 8 percent of the LDL mass . In the presence of high plasma levels of TGs, LDL particles become enriched in TGs and depleted in cholesteryl esters. LDL particle size varies in size according to the content of TGs or Cholesteryl esters.

The LDL particles serve as the main carriers of cholesterol. Cells internalize LDL via the LDL receptor (LDL-R) . LDL particles contain one molecule of apo B.The LDL-R localizes in a region of the plasma membrane rich in the protein clathrin.Once bound to the receptor, clathrin polymerizes and forms an endosome that contains LDL bound to its receptor, a portion of the plasma membrane, and clathrin. These internalized particles then fuse with lysosomes whose catabolic enzymes will in turn release free cholesterol and degrade apo B. The LDL-R will then detaches from its ligand and recycles to the plasma membrane.

Cells tightly regulate cholesterol content by:

Cholesterol synthesis in the smooth endoplasmic reticulum (via the rate-limiting step hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase)

(2) Receptor-mediated endocytosis of LDL (two mechanisms under the control of the steroid-responsive element binding protein [SREBP])

(3) Cholesterol efflux from plasma membrane to cholesterol acceptor particles.

(4) intracellular cholesterol esterification via the enzyme acyl-CoA: cholesteryl acyltransferase (ACAT)

In presence of sufficient cell cholesterol , the cell can decrease its input of cholesterol by decreasing the de novo synthesis. The cell can also decrease the amount of cholesterol that enters the cell via the LDL-R, increase the amount stored as cholesteryl esters, and promote the removal of cholesterol by increasing its movement to the plasma membrane for efflux.


Epidemiological studies have depicted an inverse relationship between plasma levels of HDL cholesterol and coronary artery disease. HDL promotes reverse cholesterol transport , prevent oxidation of lipoproteins and exert anti-inflammatory actions in vitro.

Apolipoprotein (apo) A-I and apo A-II are the two major protein components of HDL. In the general population, an inverse relation between CHD and plasma levels of apo A-I has been demonstrated. However, an association between CHD risk and apo A-II levels has not been clearly shown, and the role of apo A-II in atherogenesis is not well defined.

Apo-lipoprotein AI is the main protein of HDL and is synthesized in the intestine and liver. Approximately 80 percent of HDL cholesterol originates from the liver and 20%t from the intestines .

Apo A1 acquires phospholipids from cell membranes and from phospholipids shed during hydrolysis of TG-rich lipoproteins. It promotes its phosphorylation via cyclic adenosine monophosphate, which increases the efflux of phospholipids and cholesterol form a nascent HDL particle . HDL particle, containing apo AI and phospholipids , resembles a flattened disk in which the phospholipids form a bilayer surrounded by two molecules of apo AI arranged in a circular fashion at the periphery of the disk . These HDL particles will start further cellular cholesterol efflux. On reaching a cell membrane, the HDL particles will capture membrane-associated cholesterol and promote the efflux of free cholesterol onto other HDL particles.

Thr formation of HDL particles appears to involve two steps:


Not requiring ABCA1.

Cellular cholesterol from peripheral cells such as macrophages does not contribute significantly to overall HDL-C mass but they may have an important effect on export of cholesterol from atherom.

The plasma enzyme LCAT, an enzyme activated by apo AI, esterifies the free cholesterol . LCAT transfers a fatty acid chain from R2 position of a phospholipid to the 3′-OH residue of cholesterol, resulting in the formation of a cholesteryl ester . In a process ' selective uptake of cholesterol', HDL also provides cholesterol to steroid hormone-producing tissues and the liver through the SR-B1 receptor .

Cholesteryl esters move to the core of the lipoprotein, as they are hydrophobic and the HDL particle now assumes a spherical configuration - HDL3. With further esterification, the HDL particle increases in size to become the bigger HDL22. Cholesterol within HDL particles can exchange with TG-rich lipoproteins via cholesteryl ester transfer protein (CETP), which mediates an exchange of cholesterol from HDL to triglyceride-rich lipoprotein and triglyceride movement from triglyceride-rich lipoprotein onto HDL . Inhibition of CETP increases HDL-C in the blood and represents a therapeutic target for cardiovascular disease prevention.

Phospholipid transfer protein (PLTP) mediates the transfer of phospholipids between triglyceride-rich lipoprotein and HDL particles. The TG-enriched HDL is denoted as HDL2b. Hepatic lipase can hydrolyze triglycerides and endothelial lipase can hydrolyze phospholipids within these particles, converting them back to HDL 3 particles .

One of the mechanism of reverse cholesterol transport includes the uptake of cellular cholesterol from extra-hepatic tissues such as lipid-laden macrophages and its esterification by LCAT, transport by large HDL particles, and exchange for one TG molecule by CETP. Originally on HDL particle, the cholesterol molecule can be taken up by hepatic receptors on a TG-rich lipoprotein or LDL particle. Therefore the HDL particles acts as a shuttles amongst tissue cholesterol, triglyceride-rich lipoprotein, and the liver.

Reverse cholesterol transport by HDL contributes a small but important portion of the plasma HDL levels. The catabolism of HDL particles has initiated a debate among lipoprotein researchers. The protein component of HDL particles exchanges with lipoproteins of other classes. The kidneys appear to be elimination route of apolipoprotein AI and other HDL apolipoproteins. The lipid component of HDL particles also follows a different metabolic route .


Low HDL-C levels may directly promote atherogenesis, particularly when there is some elevation in LDL-C; often occur in the presence of increased concentrations of atherogenic lipoproteins (e.g., triglyceride-rich VLDL remnants, small LDL particles); and are often part of the metabolic syndrome, a constellation of lipid, nonlipid (e.g., hypertension impaired fasting glucose), and emerging (e.g., pro-thrombotic/ pro-inflammatory states) risk factors. Under certain conditions, such as the presence of infection, the roles of HDL-C as marker and causative agent may be intertwined (12).

An accompanying study found that human acute-phase HDL had elevated Serum Amyloid A content and 58% lower apo A-I content, and promoted LDL oxidation in human aortic endothelial cell and smooth muscle cell coculture (12). Thus, infection or inflammation appears to cause proatherogenic changes in both concentration and function of HDL.

Hypertriglyceridemia is strongly associated with low HDL-C levels , and the FCR of apo A-I is elevated in patients with this combined lipid abnormality. Even when triglycerides are normal, however, persons with low HDL-C tend to have small HDL-C particles and elevated FCR (13), perhaps resulting from lipase overactivity independent of a primary increase in triglycerides .

Not only are low HDL-C concentrations often found in patients with CHD , but genetic syndromes of high HDL-C have been linked to longevity and a rare occurrence of premature cardiac events .

Niacin (nicotinic acid), probably the most effective HDLC- raising agent, decreases the FCR of apo A-I (14) . In contrast, fibrates, statins, and oral estrogen raise HDL-C levels by increasing the TR(15-17) . Ethanol also raises HDL levels by increasing the TR of apo AI (18); however, the risks associated with promoting alcohol consumption are generally considered to make this an inadvisable HDL-raising strategy. Some believe that grapeseed oil has an HDL-raising effect, but there is a lack of scientific evidence to support this.

Niacin decreases the FCR of apo A-I, reportedly by selectively reducing hepatic uptake of HDL apo A-I without impairing hepatic uptake of HDL cholesteryl esters. The resulting increase in levels of apo A-I containing HDL particles augments RCT by promoting apo A-I-mediated cellular cholesterol efflux(19).

HDL Working group consensus:

On January 12 to 13, 2001, a distinguished international group of 25 investigators with expertise in epidemiology, endocrinology, molecular biology, public health, lipid metabolism, cardiovascular medicine, and preventive cardiology (Appendix) met in Scottsdale, Arizona, to discuss the latest research on low levels of high-density lipoprotein cholesterol (HDL-C) as a risk factor for coronary heart disease (CHD) (20) .

The Working Group reached agreement on several points (Table 2) , most importantly:

Raising HDL-C levels is useful in atheroprevention, in addition to reducing low-density lipoprotein cholesterol (LDL-C) levels.

Further basic and clinical research is essential in order to improve our ability to raise high-density lipoprotein (HDL) levels.

The NCEP Adult Treatment Panel Guidelines :

The Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) was published in May 2001(21) . The full report of ATP III was published in December 2002(2).

All ATP reports have identified low-density lipoprotein cholesterol (LDL-C) as the primary target of cholesterol lowering therapy. Many prospective studies have shown that high serum concentrations of LDL-C are a major risk factor for coronary heart disease (CHD). A large number of RCTs, moreover, have documented that lowering of LDL-C levels will reduce the risk for major coronary events.

In ATP II,(22) evidence for the benefit of LDL-lowering therapy was based on analysis and meta-analysis of RCTs that were carried out with therapies other than HMG CoA reductase inhibitors (statins). ATP II specified low HDL cholesterol (<35 mg/dL) as one of several major risk factors used to modify the therapeutic goal for LDL cholesterol. The definition of a low HDL was set to be the same for both men and women because of the view that a given level of HDL would impart the same risk for men and women.

ATP III (21) (23) reviewed new data from 5 large RCTs with statins. Results of several smaller RCTs with statins and other drugs also were examined. On the basis of accumulated evidence from epidemiological studies and RCTs, ATP III proposed a treatment algorithm for LDL-lowering therapy.In addition multiple lines of evidence strongly intimate that HDL plays a direct role in the atherogenic process. If so, it is a potential target for therapy. The ATP III provides evidence-based recommendations on the management of high blood cholesterol and related disorders. For development of its recommendations, ATP III places primary emphasis on large, randomized, controlled clinical trials (RCTs). In the past decade, a series of large RCTs have yielded a vast body of data for these recommendations. Other lines of evidence, including prospective epidemiological studies. Since the publication of ATP III, 5 major clinical trials with statin therapy and clinical end points had published. These include the Heart Protection Study (HPS),(24) the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),(25) Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial (ALLHAT-LLT),(26) Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA),(27) and the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial.(28) These trials addressed issues that had not been adequately addressed in previous statin trials. The results appear to have important implications for the management of patients with lipid disorders, particularly for high-risk patients. They further required some rethinking of the treatment thresholds of ATP III recommendations.

The 2004 Update - Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines (29) examined the results of all of these studies and assessed their implications in relation to the ATP III report. The ATP Guidelines came out with following evidence statements with regards to HDL cholesterol levels:

A low HDL-cholesterol level is strongly and inversely associated with risk for CHD.

Population studies show a continuous rise in risk for CHD as HDL-cholesterol levels decline . Higher risk for CHD at lower HDL levels is multifactorial in causation. Although the inverse relationship between HDL cholesterol and CHD shows no inflection points, any reduction in HDL cholesterol from population means is accompanied by increased risk for CHD .

Clinical trials provide suggestive evidence that raising HDL-cholesterol levels will reduce risk for CHD . However, it remains uncertain whether raising HDL-cholesterol levels per se, independent of other changes in lipid and/or nonlipid risk factors, will reduce risk for CHD.

Atherogenic dyslipidemia commonly occurs in persons with premature CHD . Moreover, atherogenic dyslipidemia strongly associates with abdominal obesity, obesity, and physical inactivity . Weight reduction and increased physical activity will mitigate atherogenic dyslipidemia .

Drugs that modify atherogenic dyslipidemia yield a moderate reduction in CHD risk .

Following recommendations were proposed by the ATP Guidelines regarding levels of HDL cholesterol :

A categorical low HDL cholesterol should be defined as a level of <40 mg/dL, in both men and women.

A specific HDL-cholesterol goal level to reach with HDL-raising therapy is not identified. However, nondrug and drug therapies that raise HDL-cholesterol levels and are part of management of other lipid and nonlipid risk factors should be encouraged.

For management of atherogenic dyslipidemia, emphasis in management should be given to life-habit modification-weight control and increased physical activity.

Consideration should be given to treatment of atherogenic dyslipidemia with specific drug therapy, i.e., fibrates or nicotinic acid, in higher risk persons.

To what levels should HDL be raised? The new ATP III guidelines do not specify a particular treatment goal because the panel considered the evidence to be insufficient. But there are several strategies available to raise HDL. The guidelines mention the use of nicotinic acid or fibrates in patients with CAD and isolated low HDL.

Statins are also available. As shown in all major statin trials, statins produce a modest rise in HDL (5% to 10%). The mechanism of this increase is not well known, although one theory is that they increase the production of Apo A-1, the major protein in HDL. For example, in the AFCAPS/TexCAPS trial, a high LDL and a low HDL conferred approximately the same risk of CAD events. Lovastatin neutralized that risk -- suggesting a beneficial effect from a modest rise in HDL(30).

Moreover, in the VA-HIT trial, where total LDL did not change substantially and triglycerides decreased 31%, a 6% increase in HDL was associated with a 22% reduction in coronary events. In a subsequent analysis, the investigators presented evidence to suggest that at least 25% of the benefits seen in the trial could be attributed to the rise in HDL; in contrast, the change in triglycerides did not account for any of the clinical benefits seen (31).

Local Data:

Increasing prevalence of cardiovascular disease (CVD) risk factors are reported in many countries with emerging economies. These countries are faced with the double burden of infectious diseases, infant mortality, and under-nutrition and emerging epidemic of CVD, linked in part with obesity. The prevalence of CVD among inhabitants and migrants from the South Asian subcontinent is inordinately high and severe (32).

Prevalence of insulin resistance, low plasma HDL-cholesterol, hypertriglyceridaemia and diabetes has been reported among South Asians and may be more important than conventional risk factors (smoking, high LDL-cholesterol, hypertenon) in the etiology of coronary heart disease (CHD) in these populations. For unknown reasons, prevalence of complications associated with increased abdominal fat is higher for a given level of obesity in South Asians than in Europeans(33).

Pakistanis belong to an ethnic group, which has the highest rates of coronary heart disease (CHD).(34) According to the official estimates, cardiovascular disease (CVD) results in more than 100,000 deaths every year(35, 36), however, the actual figure may be much higher than that. There have been only few reports on the detailed analysis of lipids in normal healthy Pakistani subjects and during mid 1980s. In a study in 2004, carried out at the Family Medicine Department of the Aga Khan University, the mean values of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides in ambulatory Pakistanis were found to be 209±179 mg/dl, 40±8 mg/dl, 125±54 mg/dl and 166±50 mg/dl, respectively (37). The level od HDL cholesterol was around 40 mg/dl as quoted by this data which is actually corresponding to the levels of HDL cholesterol as designated by the ATP III guidelines. There have been other studies who signified a lower baseline level of HDL cholesterol (8) in Pakistani adult population. Moreover in this study they isolated people with Isolated low HDL cholesterol and low HDL cholesterol. The frequencies of "low HDL-cholesterol" and "isolated low HDL-cholesterol" were found to be 45.8% and 29.4%, respectively, which are a very high percentage when compared to other population data. Mean HDL-cholesterol concentration was significantly higher among the younger age group (<50 years) compared to the older (>50 years) group (p=0.001). Similarly, mean HDL-cholesterol levels were also found to be significantly higher among females as compared to males (p=0.001). That was probably indicates a positive influence of female sex hormones on HDL-cholesterol levels (8).

In fact, the prevalence of "low-HDL-cholesterol" (<35 mg/dl) in our population is 45.8% which is among the highest reported in the literature. For example, reported prevalence of 31% in men and 13% in women in Tehran's

urban population., a prevalence of 9.5% in Indian females and 6.5% in Indian males (8). The prevalence of "isolated low HDL-cholesterol"(HDL< 40 mg/dl and triglycerides < 150 mg/dl) in our normal healthy subjects was found to be 29.4% in this study , again, this frequency is very high compared to the values reported in the literature.This might be the contributing factor for higher prevalence of Coronary artery disease in our area of the world. Our dietary habits and sedentary life style, in addition to the genetic make up, may have been contributing to these lipid abnormalities.

Coronary artery disease patients and HDL Cholesterol:

Coronary artey disease patients represents the High risk population for control of Modifiable risk factors for coronary artery disease. Control of LDL , HDL, and other lipids is the main stay of secondary prevention of the Coronary artery disease. Despite continued physician and public education, treatment goals for individuals with CHD are not being met . We don't have local guidelines for LDL , HDL Cholesterol management with respect to high risk population . However even with NCEP ATP III guidelines as the standard there are problems of compliance and poor cholesterol management in these patients. This is a global issue , multiple surveys assessing physician compliance with the NCEP ATP guidelines have found only 11% to 25% of patients with CHD at the recommended LDL-C goal (38, 39) and the compliance with control of HDL cholesterol levels are further lower.

A two-part survey of nine European countries known as EUROASPIRE found that although cholesterol medications use had increased from 21% to 49% among patients with hyperlipidemia, most patients with CHD were not at goal cholesterol levels(40, 41). We lack any local data with this respect and specially in accordance with the achievement of HDL cholesterol levls.

Primary care physicians are the first contact of the patients with any ailment, and a great deal of attention has been focused on the poor adherence of primary care physicians to adequate therapy with statins and the NCEP-ATP guidelines. Cardiologists intuitively appear to be more aggressive in managing dyslipidemia especially among patients with CAD or its equivalent. They are expected to control the levels of LDL and HDL cholesterol more adequately The finding of poor compliance with the NCEP III guidelines in a pure cardiology based practice fully affiliated with a very active internal medicine residency program is therefore unexpected.

Very limited data is available with respect to control of adequate levels of HDL cholesterol according to NCEP ATP guidelines in a pure cardiology based practice. A study was undertaken to assess the compliance of cardiologists to the NCEP III guidelines in an ambulatory care setting(42).

A retrospective chart review of 386 patients managed in a large urban cardiology practice was undertaken. This study demonstrates only 43% of patients (all with documented coronary heart disease) in this practice were on statins and of those on statins only 62% were at target goal of the LDL cholesterol, HDL cholesterol and triglycerides despite two or more years of follow up. This demonstrates a global poor performance by urban cardiologist.

Yet again we have no local data on this very important public health problem, which has global nature of impact. Despite search on Pakmedinet , Google and Pubmed no local reference was available.

The reason to conduct this study was to see practices of cardiologist at a pure cardiology based practice with respect to the optimal HDL cholesterol levels in patients presenting with established coronary artery disease.