Clustering of cardiovascular risk factors: Targeting high-risk individuals

Clustering of Cardiovascular Risk Factors: Targeting High-Risk Individuals Jacques Genest Jr., MD, and Jeffrey S. Cohn, PhD Cardiovascular risk factors have traditionally been divided into 2 categories: modifiable risk factors (smoking, hypertension, elevated cholesterol, reduced high density lipopratein cholesterol, and diabetes), and nonmodifiable risk factors (age, gender, and hereditary factors). However, more recent data indicate clustering of several metabolic and familial factors that are often related to each other. A pattern of lipoprotein abnormalities characterized by increased hepatic production of apolipoprotein B-containing lipoprotein particles, high blood pressure, visceral obesity, and peripheral insulin resistance are identified with increasing frequency in subjects with premature coronary artery disease (CAD). The metabolic substrates for many such disorders are being uncovered, and genetic analysis of affected kindred have, often with conflicting results, suggested associations with candidate genes. In the context of a multifactorial approach, aggressive tre~,;,ient of lipaprotein disorders in high-risk individuals, or in the secondary prevention of cardiovascular diseases, has resulted in a decreased rate of progression of CAD and a marked reduction in clinical events. Further work in the field of hemostatic factors has shown that fibrinogen, activated coagulation factor VII, spontaneous platelet aggregation, and elevated levels of plasminogen activator inhibitor-1 (PAl-l), are all associated with

CAD. There is a strong association between lipids (especially triglyceride-rich lipoproteins) and fibrinogen, PAl-l, and activation of factor VII. In addition, vascular function, especially endothelial cell physiology, has been shown to be compromised in the presence of multiple risk factors and to be improved with intensive therapy aimed at reducing risk factors, especially plasma lipoprotein levels. The implications for clinical practice are important. In the primary prevention of cardiovascular disease, proper risk stratification must be carried out with specific attention given to lifestyle changes. Cessation of smoking and changes in diet (both qualitative and quantitative), exercise, and serenity are often required. In the prevention of cardiovascular disease in subjects at high risk, or in the secondary prevention of CAD, a clear justification exists for aggressive lifestyle changes, often coupled with lipid-lowering therapy and adequate blood pressure control. Basic research is providing us with a better understanding of the molecular interadions between lipoproteins and hemostatic factors. It is becoming increasingly necessary to develop novel pharmaceutical agents with the combined ability to reduce atherogenic lipoprotein levels while also reducing susceptibility to thrombosis. (Am J Cardiol 1995; 76:8A-20A)

oronary artery disease (CAD) represents the major cause of death and morbidity in Western society. 1 In the past 30 years, large-scale epidemiologic studies performed on different cohorts worldwide have identified a number of risk factors associated with CAD. The semantic work of Keys et al2 defined the complex interrelations between nutrition, age, blood pressure, and serum cholesterol, and the probability of developing CAD. With the advent of primary prevention trials 3,4aimed at reducing cholesterol to reduce cardiovascular risk, a new era in the screening and treatment of subjects considered at risk was begun. Trials of secondary prevention, focus-

ing on survivors of acute myocardial infarction, showed a benefit in reducing morbidity in the long-term treatment of subjects with plasma cholesterol disorders. 5 Recommendations were, therefore, put forth for an aggressive approach in the secondary prevention of cardiovascular disease. 6 The once clear distinction between primary and secondary prevention of CAD has become blurred with the advent of clinical trials involving angiographic documentation of disease progression. Many such trials have been performed on subjects with quantifiable coronary arteriosclerosis but with no prior myocardial infarction. These trials, performed during the past 10 years, 7-2° have shown that CAD may be stabilized with aggressive lipidlowering therapy and that in some cases angioFrom the Cardiovascular Genetics Laboratoryand the Hyperiipidemia and Atherosclerosis Research Group; Clinical Research Institute of graphic regression of CAD may take place. Table I Montr6al; and Department of Medicine, Cardiology Services,H6pital summarizes the results of 14 regression studies H6teI-Dieu de Montr6al, Montreal, Quebec, Canada. performed to date, in which coronary angiography Address for reprints: Jacques Genest, Jr., MD, Cardiovascular was used to assess the rate of progression of Genetics Laboratory, Clinical ResearchInstituteof Montreal, 110 Pine Avenue West, Montr6al, Quebec, Canada H2W 1R7. disease in placebo and treatment groups. These

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trials, compared with primary prevention trials, were performed in high-risk individuals. In addition, the magnitude of decrease in low density lipoprotein cholesterol (LDL-C) was far greater than seen in the Lipid Research Clinics Coronary Primary Prevention TriaP or the Helsinki study,4 where mean cholesterol reduction averaged approximately 10%. In contrast, the mean cholesterol reduction in the regression trials was approximately 30%. 21 An important concept in the pathogenesis of acute coronary symptoms has been the role of unstable arteriosclerotic plaque rupture with subsequent thrombosis, leading to severe stenosis or complete obstruction and clinical events. 22,23 The Familial Atherosclerosis Treatment Study (FATS) 13 showed that the main impact of aggressive therapy was on the stabilization and the lack of progression of lesions once considered to be clinically insignificant, i.e., lesions with < 50% cross-sectional stenosis and lesions with 50-70% stenosis. 24 Waters et a125 analyzed the clinical outcome of patients in the nicardipine regression study26 and divided patients into those who had angiographic evidence of progression and those who did not. Clinical events were more frequent in the progressors than in patients who did not have evidence of CAD progression. Similarly, most of the clinical events seen in the FATS trial occurred in subjects with lesions <70% stenosis. 24 Intensive treatment aimed at reducing LDL-C prevented these lesions from leading to clinical outcomes. Similar findings were reported in the Cholesterol Lowering Atherosclerosis Study (CLAS). 27 The degree of angiographic regression observed in these trials is, on average, remarkably little. However, a marked reduction in clinical events (positive stress tests, angina, myocardial infarct), need for revascularization procedures (coronary artery by-pass grafting or percutaneous transluminal coronary angioplasty), and cardiac mortality was observed, and in a meta-analysis of 14 regression trials, total mortality was significantly reduced. 21 It now appears that the main benefit of intensive lipid-lowering therapy may be the improvement in endothelial cell function, including a normal vasodilator response to acetylcholine.28 Even short-term, aggressive lipid-lowering treatment may lead to marked improvement of perfusion abnormalities in patients with CAD. 29 The recently published Scandinavian Simvastatin Survival Study has unequivocally shown the benefit of

TABLE I Angiographic Regression Trials Using Low Density Lipoprotein-Lowering Medication Study

Subjects(n)

NHLBI II7 CLAS Is CLAS II9 POSCH ~° Ufestyle N US-SCOR 12. FATS 13 LARS 14 " STARS is HARP 16 Heidelberg1 r MARS is CCAIT 19 SCRIP 2°

116 162 103 838 48 72 120 37 90 79 38 270 331 300

Changes in Cholesterol (%) -32 -43 -43 -37 -37 -38 -46

Chol LDL LDL LDL LDL LDL LDL

-36 -41 - 16 -39 -29 -22

LDL LDL Chol LDL LDL LDL

"Familial hypercholesterolemic subjects. Chol = cholesterol; HDL = high density lipoprotein; LDL = low density lipoprotein. Trial abbreviations: CLAS = Cholesterol Lowering Atherosclerosis Study; CCAIT = Canadian Coronary Atherosclerosis Intervention Trial; FATS = Familial Atherosclerosis Treatment Study; HARP = Harvard Atherosclerosis Reversibility Project; I.ARS = LOL-Apheresis Regression Study; MARS = Monitored Atherosderosis Regression Study; NHLB/= National Heart, Lung, and Blood Institute; POSCH = Program on the Surgical Control of the Hypedipidemios; SCRIP = Stanford Coronary Artery Risk Intervention Pro ect; STARS = St Thomas' Atherosclerosis RegressionStudy; US-SCOR = United StatesSpecia ized Centers of Research.

lipid-lowering therapy in reducing mortality in patients with CAD. 3° The weight of evidence favors the intensive treatment of subjects with documented CAD 21 and appears to be most effective in preventing the progression of lesions with < 70% cross-sectional stenosis. By inference, it appears that early CAD can be prevented or, if present, stabilized. Therefore, it is important to identify patients who would benefit best from intensive lipid-lowering therapy and to develop a strategy both to identify these high-risk individuals and to treat them. The Adult Treatment Panel II of the National Cholesterol Education Program 6 has put forth clear and succinct guidelines for the identification and treatment of lipoprotein disorders. The guidelines suggest a targeted high-risk approach i n subjects with established CAD, or at high risk of developing CAD, while advising a more conservative approach in subjects at low risk. Table II shows the Adult Treatment Panel II risk factors for developing CAD. When assessing plasma lipoprotein levels in the determination of cardiovascular risk, one must keep in mind that several factors may affect plasma lipid and lipoprotein levels and contribute to the misclassification of lipoprotein disorders (Table III).

TARGETING HIGH-RISK INDIVIDUALS The concept of identifying high-risk individuals is based on probabilities. For the present discussion, high-risk individuals are divided into those

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TABLE II National Cholesterol Education Program Adult Treatment Panel I1: Risk Factors

Risk Factors Nonmodifiable Men age > 45 years Women age > 55 years Family history of myocardial infarction or sudden death before age 55 years in a male or 65 years in a female parent or sibling Modifiable Hyperlension LDL >4.2 mmol/liter HDL <0.9 retool/liter Cigarette smoking Diabetes Subtrad 1 risk factor if HDL > 1.60 retool/liter

TABLE III Factors that Affect Lipoprotein Levels

Diet (high saturated fat diet, alcohol) Age Gender Obesily Medications (thiazides, I3 blockers, steroids, probucol, hormones) Diabetes Thyroid status Uver disease Renal disease Cigarette smoking Medical status of patient when sampled

with established CAD, those with genetic or familial lipoprotein disorders, and those with multiple risk factors for CAD. Secondary prevention (established CAD): As documented in previous trials, 5 secondary prevention should include patients with a prior myocardial infarction, those who have undergone revascularization procedures (coronary artery by-pass grafting or percutaneous transluminal coronary angioplasty), and those with angiographically documented CAD. Similarly, patients with clinical evidence of angina (including a positive electrocardiogram stress test or stress myocardial scanning) are candidates for aggressive lipid-lowering therapy with a pharmacologic treatment initiation level of 3.4 mmol/liter, with an aim of reducing the LDL-C to 2.6 mmol/liter in accordance with the recommendations from Adult Treatment Panel 11.6 A second aim is to increase high density lipoprotein cholesterol (HDL-C) levels to >0.9 mmol/liter and reduce triglycerides to <2.3 mmol/liter. Some have advocated a more aggressive approach aimed at normalizing the lipoprotein profile and suggest that ideal targets should be < 2.84 mmol/liter for LDL, < 1.13 mmol/liter for triglycerides, and > 1.42 mmol/liter for H D L (Stanford Coronary Artery Risk Intervention Project--SCRIP2°). The current consensus is that subjects with established CAD should be intensively treated 6 and that treatment IOA

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results in a marked decrease in morbidity, need for hospitalization, revascularization procedures, and mortality. 2!

Genetic or familial lipoprotein disorders: A distinction is made between genetic and familial lipoprotein disorders, such as hypercholesterolemia or familial defective apolipoprotein B100 (apolipoprotein BArg3500...,Gin;genetic), in which the molecular defect has been identified, from the familial clustering of lipoprotein abnormalities as seen in familial combined hyperlipoproteinemia/ hyperapolipoprotein B syndrome,31-33or syndrome X (familial), in which the precise molecular defect is unknown and in which the interaction between genetic predisposition and environmental variables is more complex than in monogenic disorders.

Genetic lipoprotein disorders: Familial hypercholesterolemia is due to defects in the LDL receptor gene and was identified approximately 60 years ago. 34 The clinical diagnosis is based on the triad of severe hypercholesterolemia, cutaneous manifestations (xanthomas, xanthelasmas, and premature corneal arcus), and premature CAD. 35The pioneering studies of Brown and Goldstein 36,37on patients with familial hypercholesterolemia have shown defective clearance of LDL particles in affected subjects. This led to the discovery of the LDL receptor and the concept of receptor-mediated endocytosis37 for which Goldstein and Brown received the Nobel Prize in 1985. Since then, > 150 mutations that cause familial hypercholesterolemia have been documented.38 Interestingly, some mutations, especially those in which no LDL receptor protein is produced, are associated with worse clinical outcome than mutations that partly affect the function of the LDL receptor. 39 In patients with premature CAD, familial hypercholesterolemia accounts for approximately 3-5% of cases, 4°,41 even in populations rich in genetic disorders. 41 Based on a single study,4° the prevalence of FH in the general population is thought to be approximately 1:500. This prevalence, with pockets having a higher prevalence, 42 approaches 1:250 in regions where a founder effect is identified. In general, plasma cholesterol levels in heterozygous patients are double those of the normal population, reaching 8-12 mmol/liter, with the major portion being LDL-C. The other lipoproteins are generally within normal limits. The age at onset of CAD in patients with familial hypercholesterolemia is approximately 55 years in women and 45 years in men. 43 Patients with familial hypercholesterolemia often require long-term lipid-lowering therapy, often JULY 13, 1995

with combination drug therapy. 35 Diet is of limited usefulness in treating patients with familial hypercholesterolemia. 44 Familial defective apolipoprotein B-I O0 is phenotypically indistinguishable from familial hypercholesterolemia. 45 Characterized in subjects with an abnormal plasma residence time for LDL particles, 46 the defect has been identified as a single amino acid substitution in the apolipoprotein B (apolipoprotein BArg3500--,Gln),resulting in defective receptor binding. 47 The diagnosis is based on the use of allele-specific oligonucleotide hybridization after amplification of the region within the apolipoprotein B gene that contains the mutation. 45 Patients with defective apolipoprotein B-100 (apolipoprotein B3500)respond, in general, to 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. The frequency of the disorder is unknown in most populations but may approach 1:500, a prevalence similar to that of familial hypercholesterolemia.47

Dysbetalipoproteinemia (type 111 hyperlipoproteinemia) 48 is a rare lipoprotein disorder characterized

by elevations in triglycerides and total cholesterol. It is identified by elevations in intermediate density lipoproteins. The molecular defect has been identified as several mutations within the apolipoprotein E gene, leading to the accumulation of apolipoprotein E-containing lipoprotein particles in plasma. The most common mutation is an amino acid substitution (apolipoprotein E2 Arg158--~Cys), reflecting a relatively common polymorphism of the apolipoprotein E gene. 49 When present as the homozygous trait apolipoprotein E2/2, subjects are at risk of developing type III hyperlipoproteinemia. The prevalence of the apolipoprotein E2/2 is approximately 5% in the general population; of these, < 1 in 100 will develop the clinical manifestations of type III hyperlipoproteinemia.5° The current concept is that a second genetic disorder, along with the apolipoprotein E2/2 phenotype, is necessary for expression of the disorder. This "second hit" is currently unknown. Type III hyperlipoproteinemia accounts for <0.5% of cases of premature CAD. 41 Usually it is well controlled by diet alone or with fibric acid derivatives or niacin. 48 Familial lipoprotein disorders: Goldstein et al 4° analyzed the results from 176 families of probands who survived an acute myocardial infarction and characterized the lipoprotein abnormalities. Based on these family studies, the authors defined a new disorder, familial combined hyperlipidemia, characterized by the presence of hypercholesterolemia or hypertriglyceridemia, or both, in members of the

TABLE IV Familial Lipoprotein Disorders Associated with

Coronary Artery Disease Syndrome* Familialhypercholeslerolemia

Prevalence(%) 2-5%

Familial defective apolipoprotein Bas00 Polygenic familial hypercholeslerolemia FCH / hyperopolipoprotein

? ? 20

FTgHA't"

11

FHA Dysbetolipoproteinemia Familial Lp(o) excess Syndrome X'l" Familial dyslipidemic hypertension

4 < ]

15

"FCH = familial combined hypertipoproteinemia; FHA = familial hypoolphalipoprotelnernio; FTgHA = familial hypertriglyceridemio with hypoalpholipoprotelnemia; Lp(a) = lipoprotein porlicle(o). "i'Strong environmental influence (diet, exercise, physical activity).

same families.4° This disorder was much more frequent than familial hypercholesterolemia and was seen in 10% of survivors of myocardial infarction. Two other groups have reported similar findings.51,52 A similar prevalence of familial combined hyperlipoproteinemia31 was identified in our analysis of premature CAD probands. An excellent review of familial lipoprotein disorders has been published recently. 33 The routine measurement of HDL-C, apolipoprotein A-I and B, lipoprotein particle(a), and apolipoprotein E isoforms have allowed a better definition of familial disorders. When using cutpoints based on percentiles for a given population, 53 the prevalence of lipoprotein disorders can be established, as shown in Table IV. In patients with premature CAD, the most common lipoprotein disorders are combined disorders, with increases in LDL-particle number, reflected by increased total plasma apolipoprotein B, and a decrease in HDL particles. Elevations in apolipoprotein B--containing lipoprotein particles can be manifested by increases in very low density lipoprotein, intermediate density lipoprotein, or LDL particles, alone or in combination. The prevalence of disorders such as familial hypercholesterolemia (based on strict diagnostic criteria) 35 is approximately 3-5% in most studies of premature C A D . 31,41 The presence of familial hypertriglyceridemia with decreases in HDL-C was 11% in our study and that of "pure" familial hypoalphalipoproteinemia was 4%. When apolipoprotein B measurement was included, an additional 5% of families had familial hyperapolipoprotein B. 31 We have reported that the prevalence of lipoprotein disorders in premature CAD is approximately 55% 31 (Table IV), if familial lipoprotein(a) excess is included.54 When families are examined, using similar cut-points to define lipoprotein abnormalities, more than half the probands had a familial A SYMPOSIUM: MANAGEMENT OF HYPERLIPIDEMIA | I A

ides, LDL-C, and HDL-C. A high-risk group of subjects, characterized by an elevated LDL-C: HDL-C ratio ( > 5) and triglycerides > 2.3 mmol/ Patients with Controls Coronary Artery Disease liter, had a 10-fold increase in cardiovascular risk (n = 901) (n = 321) over a 6-year period (from 24 to 241 cardiovascular HDL-C 4.4 19.3 events per 1,000 subjects over 6 years), compared HDL-C + TG 4.2 9.7 with individuals with an LDL-C:HDL-C ratio of HDL-C + LDI_-C 0.2 3.7 H D b C + TG + LDL-C 0.2 3.7 < 5 and triglycerides < 2.3 mmol/liter. This highTG 9.0 9.7 risk group comprised only 4.3% of the PROCAM TG + LDL-C 3.2 LDL-C 9.0 12.1 study participants. Further, the prevalence of diaAll 27.0 61 .I betes within this high-risk group was 16% and The cut-points used were: high density lipoprotein cholesterol (HDL-C) <10th hypertension was 43%. 60Taken together, the PROpercentile; triglycerides fiG) >90th percentile; and low density lipoprotein cholesterol (LDL-C) > 90th percentile, motched for age. TG = triglycerides. CAM data strongly suggest that a subgroup of patients can be identified in which clustering of risk lipoprotein disorder (Table IV). 31 When apolipo- factors imparts a strong risk for the development of protein A-I and B measurements were performed CAD. Although the role of triglycerides in the in the families of patients with premature CAD, epidemiology of CAD often has been cast in doubt most of these disorders were associated with an by multivariate analysis (reviewed by Austin61), the increase in total apolipoprotein B levels and these data suggest that triglycerides, in combination with familial combined syndromes share the common other risk factors or lipoprotein abnormalities, may characteristic of elevated apolipoprotein B. 55 Al- be important in the development of CAD. though the metabolic abnormalities are now better SYNDROME X: In a semantic Banting lecture, characterized in these familial syndromes, no asso- Reaven 62 described a syndrome of peripheral insuciation with candidate genes has so far provided a lin resistance with hyperglycemia, dyslipoproteinmolecular basis for these disorders. 56-58 emia characterized predominantly by hypertriglycAnother familial syndrome of dyslipoprotein- eridemia and low HDL-C, high blood pressure, emia (elevated triglycerides and reduced HDL-C) and visceral obesity. Reaven's "syndrome X" has and high blood pressure has been called "familial no relation to the cardiologist's syndrome X (chardyslipidemic hypertension" and was characterized acterized by anginal episodes in the absence of by Williams et al.59 This syndrome was first identifixed coronary lesions), and the term preferably fied in subjects with essential hypertension in should not be used to describe this constellation of whom lipid abnormalities were found frequently. When the authors used the Lipid Research Clinic's metabolic abnormalities. The relation between cut-points for age- and gender-matched subjects, hyperinsulinemia and hypertension has been recog30% of patients had elevated triglyceride levels, nized 63 and the coexistence of these disorders has 19% had elevated LDL-C, and 39% had decreased been referred to as "the deadly quartet. ''64 The HDL-C (Table V). The prevalence of this disorder prevalence of this metabolic syndrome in patients was approximately 12% in subjects with essential with CAD is not known with certainty and depends hypertension. Of interest, many of these subjects largely on the diagnostic criteria used to define had a body weight > 130% of ideal values. In abnormality. The diagnostic criteria are still not addition, 7 of 63 probands with familial dyslipid- fully defined, but the combination of fasting hyperemic hypertension documented by Williams et aP 9 glycemia, an impaired oral glucose tolerance test, had diabetes or elevated fasting glucose. There- hypertriglyceridemia with a low HDL-C, hyperinsufore, it is likely that many kindred examined by linemia, high blood pressure, and visceral obesity Williams et al had familial combined hyperlipopro- are components of this disorder. Multiple risk iadors: Based on case-control teinemia with or without the manifestations of peripheral insulin resistance and abdominal obe- studies and using the risk factors as described in the Adult Treatment Panel I and II, we have found sity (see below). Metabolic syndromes: HYPERTRIGLYCERIDE- that subjects with CAD have, on average, more individual risk factors than healthy control populaMIA AND ALTERED L D L - C ' H D L - C RATIO" In a simple and elegant analysis of the 4,559 participants of the tions. 41,65 Compared with the Framingham Heart Prospective Cardiovascular M~nster study (PRO- Study, men with premature CAD had a high CAM), Assman and Schulte 6° stratified cardiovas- prevalence of cardiovascular risk factors; only 3% cular risk according to plasma levels of triglycer- of subjects with CAD had <2 risk factors, cornTABLEV Prevalenceof Lipoprotein Abnormalities in Men with Premature Coronary Artery Disease

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pared with 35% in the Framingham Heart Study control group. 65 Similar findings were reported by McNicoll et a141in a different population. Cigarette smoking remains a powerful and independent cardiovascular risk factor. On multivariate analysis of men with premature CAD, it is the strongest discriminator of all risk factors (Table VI). 66 Similarly, a family history of CAD or sudden death is seen frequently in subjects with premature CAD 41 and is considered an independent cardiovascular risk factor for the development of CAD. 6,67 Based on the data presented herein, subjects at risk of developing CAD often have clustering of multiple risk factors. Monogenic disorders, such as familial hypercholesterolemia, that have a profound effect on lipoprotein metabolism are unusual in patients with premature CAD and account for approximately 5% of cases of CAD. It may be argued that most of the information n e e d e d for proper cardiovascular risk stratification can be obtained from a medical history and physical examination. Laboratory tests, especially cholesterol, triglycerides, and HDL-C levels, then allow a more complete coronary risk profile and assist the physician in the decision to implement dietary or pharmacologic therapy. 68

SCREENING STRATEGIES Arteriosclerosis and CAD are good examples of chronic diseases in which genetic predisposition and environmental factors contribute to the manifestation of these major causes of death in the Western world. One of the goals of medical care in our society is to identify and treat the conditions leading to heart disease and, in the process, retard progression of the disease and increase the quantity as well as, we hope, the quality of life. To do so, we must develop tools to identify and treat individuals who present a high risk of developing CAD, without either placing undue burden on individuals and society or using so much of our resources as to hamper other programs, such as infant mortality, acquired immunodeficiency syndrome prevention, education, and care of the elderly, t o name only a few. Based on the data presented, the best screening method (and perhaps the cheapest) is a visit to the primary care physician. In the context of general medical care, cardiovascular risk stratification can be made with remarkably little more than a thorough medical history and careful clinical examination. Most of the information required for cardiovascular risk stratification can be obtained in the physician's office, with the exception of plasma lipoprotein cholesterol

TABLE Vl Stepwise Discrirninant Analysis of Cardiovascular Risk Factors in Coronary Artery Disease 66

Variable Smoking Hypertension Low HDL-C Diabetes ElevatedLDL-C Upoprotein particle(a)

Model r2 ~" 0.371 0.114 0.094 0.050 0.008 0.003

p Value 0.001 0.001 0.001 0.001 0.002 0.061

Forabbreviations,seeTableV.

anti triglyceride levels. Family history, socioeconomic level, the presence of risk factors (Table II) and blood pressure can readily be obtained in the doctor's office. We will argue that for the purpose of cardiovascular risk stratification, a total cholesterol is not clinically useful and that a fasting lipoprotein profile is required. 65,66From the information gathered, a global risk assessment can then be made or calculated from the data generated from the Framingham Heart Study. 6s Healthcare strategies are evolving continuously and respond to the need of individuals and populations to maintain wellness within a society. Human life is finite and the quality of life becomes an important preoccupation in the allocation of healthcare resources. Chronic diseases present a major burden to medical care, and too often the ills of society---deficiencies and excesses alike---contribute to create the environment where such diseases can flourish.

ATHEROSCLEROSIS AND THROMBOSIS IN CORONARY ARTERY DISEASE An often ignored corollary to multiple cardiovascular risk factors is the effects on other pathophysiologic mechanisms, especially prothrombotic phenomena. In the past few years, we have learned that a close relation exists between hemostatic parameters and metabolic syndromes associated with CAD. This relation, in turn, can lead to enhanced thrombogenesis and acceleration of acute coronary syndromes.23 In light of current knowledge, the initiation of the atherosclerotic plaque is dependent on traditional cardiovascular risk factors, such as the male gender, increasing age, cigarette smoking, hypertension, elevated levels of LDL, decreased levels of HDL, and diabetes. Once a fatty streak is formed, it can evolve into a fibrous plaque, a step that involves the interplay of endothelial cells, monocyte-macrophages, smooth muscle cells, and platelets, as well as a .large variety of chemical messengers (interleukins and growth factors). With continued growth, the plaque undergoes morphoA SYMPOSIUM: MANAGEMENT OF HYPERLIPIDEMIA

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logic changes and its physical characteristics and location within the arterial tree will in part determine its fragility to continued oscillatory and shear stress. 22,23 The effects of stress on the atherosclerotic plaque can lead to its fracture and subsequent thrombosis, with clinical consequences varying from asymptomatic plaque growth to unstable ischemic syndromes, to acute infarction and death. As will be discussed later, several lines of research have shown strong links between lipoproteins and coagulation factors. The effects of triglyceride-rich lipoproteins on fibrinogen, on the activation of coagulation factor VII and plasminogen activator inhibitor-l, and potentially on spontaneous platelet aggregation have now been documented. The characterization of lipoprotein(a) has suggested a role for decreased fibrinolysis by apolipoprotein(a) and accelerated atherosclerosis. Atherosclerosis and hemostatic factors: Hemostatic factors represent a broad group of proteins, phospholipids, prostaglandins, and cell types that act in a complex fashion to produce a blood clot at sites of tissue injury (to prevent blood loss and enhance repair). Although a classification of hemostatic factors is necessarily imperfect and incomplete, they can be classified as coagulation factors, endothelial cells, and fibrinolytic and platelet factors. In large prospective epidemiologic studies, several of these hemostatic factors have been reported to be associated with CAD. FIBRINOGEN; Fibrinogen levels have been shown to be associated with cardiovascular disease, and this association is independent of other cardiovascular risk factors. There is, nevertheless, a strong association between fibrinogen levels, serum cholesterol, and triglyceride levels. Fibrinogen levels are associated with the presence of angina, 69 the severity of C A D , 70'71 and the possibility of recurrent cardiovascular events. 72 These observations have been confirmed in several recent studies, especially the Northwick Park study, 73 the Framingham study, TMthe PROCAM study, 75 and others. 76-79 Plasma fibrinogen levels are correlated with age, body mass index, the presence of diabetes, and serum cholesterol. 79 The recent publication of a genetic polymorphism at the fibrinogen locus suggests that genetic variability of the fibrinogen gene (or one closely linked to it) is associated with atherosclerotic disease. 8° FACTOR VII" Several studies have shown an association between levels of coagulation factor VII and CAD. Although levels of factor VIIa (antigen) did not correlate with CAD in the PRO-

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CAM study, 75 activated factor VII (coagulant activity, VIIc) levels were positively associated with CAD in several other studies. 81 In the prospective Northwick Park study, factor VII coagulant (VIIc) activity was associated with CAD; further, plasma levels of cholesterol and triglycerides were directly related to factor VIIc levels. 72 The effect of diet on plasma factor VII and VIIc levels has been reviewed in detail. 82 Although acute elevations in triglycerides may increase the formation of factor VIIc, this effect does not appear to be related to dietary fat composition.83The mechanism of activation of factor VII by triglycerides (or triglyceriderich lipoproteins) remains to be elucidated. PLATELETS: The role of platelets has been explored recently in the pathogenesis of atherosclerosis. Not only do platelets aggregate at sites of tissue injury, especially at sites of endothelial cell denudation, but they secrete a potent mitogenic protein, platelet-derived growth factor. In addition, platelets contain receptors for the von Willebrand factor, fibrinogen (the IIb/IIIa receptor) and lipoprotein(a) (most likely the IIb receptor on platelets). Spontaneous platelet aggregation has been shown, in a relatively small study of 149 patients followed for 5 years after their myocardial infarction, to have predictive value in survival and recurrent cardiac events. 84In the Caerphilly study,85 platelet aggregation, induced by collagen, thrombin and adenosine diphosphate, was increased in subjects with CAD. Platelet count has also been shown to be a predictor of CAD mortality in a Norwegian study. 86These findings lend pathophysiologic support to the use of aspirin in the secondary and primary prevention of CAD. Although aspirin is not thought to inhibit the progression of atherosclerosis, it prevents platelet aggregationna phenomenon important in acute coronary syndromes. PLASMINOGEN ACTIVATOR INHIBITOR (PAl-l):

Since its discovery, platelet activator inhibitor-1 has been associated with CAD. In a study by Hamsten et al, 87 young survivors of myocardial infarction had higher levels of platelet activator inhibitor-1 than controls, strongly suggesting that impaired fibrinolysis may be important in the progression of atherosclerosis and in acute coronary syndromes. Hypertriglyceridemia is associated with elevations in plasma levels of factor VII coagulant activity and platelet activator inhibitor187; interestingly, the association of platelet activator inhibitor-1 release is associated with triglyceriderich rather than normotriglyceridemic very low

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 JULY 13, 1995

density lipoprotein. In addition, elevated plasma levels of platelet activator inhibitor-1 are seen in syndrome X. 88 Because LDL may also stimulate the release of platelet activator inhibitor-1 from the hepatoma HepG2 cell lines, it is tempting to postulate that the number of apolipoprotein B--containing lipoprotein particles (especially triglycerideenriched) may be important in the release of platelet activator inhibitor-1 from cells. The postprandial state is characterized by a redistribution of apolipoprotein from a higher to a lower density, with an increase in very low density lipoprotein triglycerides.89 Thus, it is conceivable that the postprandial state represents a procoagulant state characterized by enhanced levels of coagulation and decreased fibrinolysis. Unfortunately, to date, no prospective data exist on the link between platelet activator inhibitor-1 and CAD.

POSTPRANDIAL LIPOPROTEINS AND ATHEROSCLEROSIS The role of postprandial lipoproteins in the pathogenesis of CAD was first suggested by studies performed in the 1950s, in which patients with CAD were found to have increased postprandial lipemia compared with control subjects. 90-93 Casecontrol studies have substantiated the relation between elevated levels of plasma lipids in the fed state and the presence of coronary atherosclerosis. 94-96 In a recent study by Patsch et al, 97 plasma lipid levels were measured in the fed and fasted state in 61 men with severe CAD (documented by angiography) and in 40 control subjects. The control subjects had a coronary score of zero, whereas the patients with CAD had a score >50. The concentration of plasma triglyceride 6 and 8 hours after meal-feeding was a powerful discriminator of patients with CAD. Postprandial triglyceride measurements were found by logistic regression analysis to be 68% accurate in predicting the presence or absence of disease. Multivariate analysis demonstrated that HDL2-C, apolipoprotein B, age, and postprandial triglyceride level were statistically independent predictors of CAD, and correctly classified 82% of the subjects studied. It is significant that fasting triglyceride concentration, unlike triglyceride concentration in the fed state, was not found to be an independent risk factor for disease, which agrees with the majority of epidemiologic studies to date. 6: This study, therefore, provides strong evidence that the magnitude of postprandial triglyceridemia is of primary importance in the etiology of coronary disease.

It is generally believed that the potential atherogenicity of the postprandial state is due to the presence in plasma of remnant lipoproteins that are formed during the lipolysis of triglyceride-rich lipoproteins. Cholesterol-enriched lipoprotein remnants are a characteristic feature of the hypercholesterolemia induced by feeding large amounts of dietary cholesterol to experimental animals and these lipoproteins are primarily responsible for dietary cholesterol-induced atherosclerosis. 9a,99 Remnant lipoproteins resemble the 13-very low density lipoproteins, which accumulate in the plasma of patients with type III hyperlipoproteinemia or in patients with hepatic lipase deficiency. Catabolism of chylomicron and very low density lipoprotein remnant lipoproteins is defective in these individuals, and increased levels of circulating remnant lipoproteins are associated with the presence of premature vascular disease. 1°° In vitro experimental evidence supports the concept that triglyceride-rich lipoproteins and their remnants are potentially atherogenic. A number of investigators have shown that these lipoproteins have the ability to induce lipid accumulation in cultured macrophages. 98,99A°1-1°3Cholesterol-laden macrophages, or foam cells, derived from blood monocytes, 1°4,1°5 are the characteristic cell type of atherosclerotic lesions. Their formation in tissue culture experiments in the presence of different lipoproteins is considered to be a measure of that lipoprotein's potential atherogenicity. The recognition and uptake of remnant lipoproteins by macrophages is receptor-mediated, 1°6-1°8 and appears to require apolipoprotein E as a ligand. :°9A1° Remnant lipoproteins have also been shown to be cytotoxic to both cultured macrophages 1:1 and vascular endothelial cells. 112,:13 Postprandial lipemic sera from individuals with pronounced postprandial triglyceridemia were cytotoxic; however, this was not the case for sera isolated from these subjects in the fasted state or sera from individuals with more normal postprandial triglyceridemia. Of particular interest was the finding that HDL in either the lipolysis mixture or the culture dishes was able to inhibit this toxicity. H1 These in vivo and in vitro observations, taken together, support the concept that partially catabolized triglyceride-rich lipoproteins or remnant lipoproteins have the potential to initiate and promote atherosclerosis. It has been assumed that in the fed state the majority of circulating remnant lipoproteins are chylomicron remnants containing apolipoprotein B-48 of intestinal origin. However,

A SYMPOSIUM:MANAGEMENTOF HYPERLIPIDEMIA 15A

apolipoprotein B-100-containing triglyceride-rich lipoproteins of hepatic origin also make a significant contribution to postprandial triglyceridemia. After a fat load, 15-20% of the increase in plasma triglyceride concentration has been shown to be due to triglyceride contained within apolipoprotein B-100-triglyceride-rich lipoproteins. TM If one considers the total triglyceride in plasma during the postprandial period, and not just the increment in plasma triglyceride, apolipoprotein B-100-triglyceride-rich lipoproteins are responsible for > 50% of triglyceride transport. Therefore, apolipoprotein B-100-triglyceride-rich lipoprotein remnants are also a feature of postprandial plasma, although it remains to be determined what role these lipoproteins have in atherogenesis. Further studies are also required to determine whether changes to LDL and HDL in the fed state influence the potential atherogenicity of postprandial plasma.

POSTPRANDIAL LIPOPROTEINS AND THROMBOSIS Recent studies suggest that lipoproteins can affect thrombus formation by altering coagulation factors, fibrinolysis, platelet function, prostacyclin metabolism, and endothelial cell function. 115 An elevation in the plasma concentration 0f LDL increases platelet aggregation, decreases prostacydin production, and impairs endothelial ceil function. H5 In contrast, HDL produces favorable alterations in prostacyclin metabolism and promotes normal endothelial cell function. As the plasma concentration and lipid composition of both LDL and HDL are modified in the fed compared with the fasted state, postprandial events are implicated as important determinants of vascular reactivity. An equally significant influence has been demonstrated for plasma triglyceride, which has apparent procoagulant activity. In the Mfinster Heart Study n6 and the Northwick Park Heart Study, 72 factor VII coagulant activity and plasma fibrinogen concentration were significant predictors of ischemic heart disease and were associated with increased plasma triglyceride levels. Drugs that lower plasma triglyceride, in turn, decrease factor VII activity and also reduce plasma fibrinogen levels. 117,118 Generation of free fatty acids by lipolysis of triglyceride-rich lipoproteins in patients with lipoprotein lipase deficiency also results in activation of factor V I I . 119 It has been proposed that triglyceride-rich lipoproteins (both very low density lipoprotein and chylomicrons) increase factor VII activity, either by affecting the conversion of native single-chain factor VII to its fully activated 2-chain species, x2°or by 16A

reducing the plasma clearance rate of factor VII through direct physical association. 12x Recent evidence suggests that an increase in plasma factor VII coagulant activity as a function of plasma triglyceride concentration in the fasted state is attributable to an increase in both mass and activity of factor VII, and that this increase in activity is dependent on an increase of factor VII-phospholipid complex rather than activated factor VII double-chain form. 122 In the fed state, activity but not mass of factor VII is increased, and activation is proportional to free fatty acid production during lipolysis of triglyceride-rich lipoproteins. 81 Apparent activation of plasma factor VII by postprandial triglyceridemia, independent of dietary fat composition, has also been demonstrated by Miller et al. 83 In addition, postprandial triglyceride-rich lipoproteins are able to influence hemorrheologic parameters, because plasma viscosity and erythrocyte aggregation are increased in healthy normolipidemic individuals after they have been fed a fat-rich meal. 123 Thus, in the fed state, triglyceride-rich lipoproteins can have a potentially detrimental effect on blood flow characteristics as well as plasma coagulability.

EFFECT OF MEDICATION ON HEMOSTATIC FACTORS The recent finding that the HMG-CoA reductase inhibitor pravastatin can decrease plateletthrombus deposition in an ex vivo model is of interest. TM In this study, Lacoste et aP 24 used a fragment of pig artery exposed to human venous blood in subjects treated with pravastatin or placebo. Their results indicate that treatment with pravastatin may decrease platelet deposition. Whether this is a specific drug effect or a class effect remains to be determined. The class of drugs belonging to the fibric acid derivatives has been shown to have an effect on plasma fibrinogen levels. 125Clofibrate, bezafibrate, fenofibrate, and ciprofibrate have been shown to decrease fibrinogen levels, whereas gemfibrozil did not in 2 studies. 118,126-129Fenofibrate was shown in 2 small studies to slow the progression of coronary atherosclerosis.130, TM Gemfibrozil was recently found to reduce plasma levels of platelet activator inhibitor-1 by reducing the production of mRNA in endothelial cells. 132In a separate study, however, gemfibrozil was not associated with increased plasma levels of platelet activator inhibitor-1.133 In addition, gemfibrozil reduces factor VII-phospholipid complex, in which is found activated factor VIIc. TM The fibrates are

THE AMERICANJOURNAL OF CARDIOLOGY VOLUME76 JULY 13, 1995

very effective in reducing very low density lipoprotein production by the liver and increase lipoprotein lipase activity, thereby accelerating the catabolism of very low density lipoprotein triglycerides and increasing the rate of formation of LDL particles. Their action on hemostatic parameters is, however, drug-dependent. Thus, it seems that, as a class of drugs, fibrates may have divergent mechanisms of action on hemostatic factors.

CONCLUSION The widespread use of lipid-lowering medication or large-scale screening programs for cholesterol disorders in the population at large cannot be recommended. Rather, a targeted approach aimed at the identification and treatment of high-risk individuals appears warranted. The evaluation of cardiovascular risk should be performed by qualified health professionals, who should seek to identify, first by careful clinical history and examination, then with the selective use of laboratory tests, those individuals who would benefit best from pharmaceutical intervention. Although much time is spent on the identification of monogenic disorders, these are relatively infrequent. The association of multiple risk factors, especially the coexistence of visceral obesity, high blood pressure, elevated plasma (or serum) glucose, and lipoprotein cholesterol abnormalities, must be sought diligently. In addition, a family history and the presence of cigarette smoking represent important and independent risk factors. The concept that many risk factors are interrelated and that many metabolic abnormalities may adversely affect the atherothrombotic process has been substantiated. It has now been established that the correction of these metabolic disorders results in a decrease in global cardiovascular risk and that aggressive treatment of risk factors, especially lipoprotein disorders, leads to a decrease in the rate of progression of CAD. In turn, this is associated with a reduction in clinical events. Prevention of CAD is possible in high-risk individuals; the treatment modalities must, however, be multifactorial, aggressive, and sustained. Acknowledgments:This study was supported by a scholarship from the Medical Research Council of Canada, and the Ou6bec chapter of the Heart and Stroke Foundation of Canada. The authors thank Paule Marchand for her patient and expert editorial assistance. 1. Reeder BA, Lanzon R, Man Y, Nalr C, Petrasovits A, eds. Cardiovascular Disease in Canada. Canada: Health and Welfare, 1991.

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HR, Williams IT, Johnstone IM, Champagne MA, Kranss RM, Farquhar JW. Effects of intensive multiple risk factor reduction on coronary risk intervention in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project. ~ t i o n 1994;89:975-990. 21. Sniderman AD, Ghezzo RH. Meta analysis of the clinical outcomes of recent quantitative angiographic trials to lower plasma LDL in patients with CAD. Can J Card/o/1994;10(suppl B):10B--16B. 22. Badimon J J, Fnster V, Chesebro JH, Badimon L Coronary atherosclerosis: a multifactorial disease. C/radation 1993;87(suppl III):III-3-111-16. 23. Fnster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronarysyndromes.N Eng/J Med 1992;326:242-250,310-318. 24. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insight into prevention of plaque disruption and clinical events in coronary artery disease. Circulation 1993;87:1781-1791. 25. Waters D, Craven T, Lesperance J. Prognostic significance of progression of coronary atherosclerosis.Circulation 1993;87:1067-1075. 26. Waters D, Lesperance J, Francetich M, Causey D, Theroux P, Chiang YK, Hodon G, Lemarbre L, Reitman M, Joyal M, Gosselin G, Dyrda I, Macer J, Havel R.I. A controlled clinical trial to assess the effect of a calcium channel blocker on the progressionof coronary atheroselerosis.Cbruiaa~,z 1990;,82:19401953. 27. Cashin-HemphiU L Mack W, LaBree L, Hodis HN, Shircore A, Seizer RH, Blankenhoru DH. Coronary progression predicts future cardiac events. (Abstr.) C/rcu/at/on 1993;88:I363. 28. Ludmer PL, Selwin AP, Shook TL Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl JMed 1986;315:1046-1051. 29. Gould LK, Martuc~ JP, Goldberg DI, Hess MJ, Edens RP, Latifi R, Dudrick SJ. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronazy artery disease. Cin~ation 1994;89:1530-1538. 30. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol loweringin A.A,~A.patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:138.3-1389. 31. Genest J Jr, Martin S, McNamara JR, Ordovas JM, Jenner JL Meyers R, Sflberman SR, Wilson PWF, Salem DN, Schaefer El. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992;85: 2025-2033. 32. Schaefer EJ, Genest J Jr, Ordovas JM, Salem DN, Wilson PWF. Familial lipoprotein disorders and premature coronary artery disease. Curr Opin Lipidol 1993;4:288-298. 33. Schaefer EJ. Familial lipoprotein disorders and premature coronary artery disease. MealC//n NorthAm 1994;78:21-39. 34. Muller C. Xanthomata, hypercholesterolemia, angina pectoris. Aeta Med Scant/1938;89:75. 35. Davignon J, Roy M, Dufour R, Roederer G. Familial hypereholesterolemia. In: Steiner G, Shafrir E, eds. Primary Hyperiipidemias. New York: McGraw-Hill, 1991:201-234. 36. Brown MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis.Sc/awae 1986;232:34--47. 37. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425--430. 38. Hobbs I-IH, Brown MS, Goldstein JL Molecular genetics of the LDL receptor gene in familial hypemholesterolemia.Hum Murat 1992;1:445-466. 39. Moorjani S, Roy M, Gagne C, Davignon J, Brun D, Toussaint M, Lambert M, Campeau L Blaichman S, Lupien P. Homozygnnsfamilial hypercholesterolemia among French Canadians in Qu6bec Province.Arteriosc/avs/s1989;9:211216. 40. Goldstein JL, Schrott HG, Ha,~ard WR, Bierman EL, Mutuisky AG. Hyperiipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperiipidenfia. J Clin Invest 1973;52:1544-1568. 41. MeNicoil S, Latour Y, Rondeau C, Bouthillier D, Davignon J, Genest J Jr. Cardiovascular risk factors and lipoprotein profile in premature CAD in French Canadians: impact of the NCEP 11guidelines. Can J Cardiol 1995;11:109-116. 42. Moorjani S, Roy M, Tortes A, Betard C, Gagne C, Lambert M, Brun D, Davignon J, Lupien P. Mutations of low density lipeprotein receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygnnsfamilial hypercholesterolemia.Lancet 1993;341:1303-1306. 43. Stone NS, Levy RI, Fredrickson DS, Verter J. Coronazy artery disease in 116 kindred with familial type II hyperiipoproteinemia.Circulation 1974;49:476488. 44. Hunninghake DB, Stein EA, Dujovne CA, Harris WS, Feldman EB, Miller VT, Tobert JA, Laskarzewski PM, Quiter E, Held J, Taylor AM,

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116. Balleisen L, Assmann G, Bailey J, Epping P-H, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population. H. Baseline data on the relation to blood pressure, blood glucose, uric acid, and lipid fi-actions.Thromb Haemostas 1985;54:721-723. 117. Almer LO, KjeUstrom T. The fibrinolytic system and coagulation during banzafibrate b'eatment of h y p e r t r i g l y c e r i d e m i a . A t ~ 1986;61:81-85. ]18. Bo M, Bonino F, Neirotti M, Oottero M, Pemigotti L, Molaschi M, Fabris F. Hemorrheologic and coagulative pattern in hypercholestemlemic subjects treated with lipid lowering drugs.Ans/o/ogy 1991;42:106-113. ] 19. Mitropoulos KA, Miller G J, Watts GF, Durrington PN. Lipolysis of triglyceride-rich lipoproteins activates coagulant factor VII: a study in familial lipoprotein-lipase deficiency.Athovsc/eros/s 1992495:119-125. 120. Mitropoulos KA, Martin JC, Reeves BEA, Esnouf MP. The activation of the contact phase of coagulation by physiological surfaces in plasma: the effect of large negatively charged liposomal vesicles. B/ood 1989;73:1525-1533. 121. Carvalho de Soma J, Bruckbert E, Giral P, Sofia C, Chapman J, Truffert J, Dairou F, de Gennes JL, Caen J'P. Coagulation factor VII and plasma triglycerides: decreased catabolism as a poss~le mechanism of factor VII hyperactivity. Haemostasis 1989;19:125-130. 122. Negri M, Arigliano PL, Talamini G, Carlini S, Manzato F, Bonadonna G. Levels of plasma factor VII and factor VII activated forms as a function of plasma triglyceride levels.Atherosc/ems/s1993;99:55--61. 123. Schfitz E, Schuff-Wemer P, Gfitmer Y, Schulz S, Armstrong VW. Investigations intO the haemorheological significanceof postprandial and fasting hypertriglyceridaemia. Eur J Clin Invest 1993;23:270-276. 124. Lacoste LL, Lain JYT, Hung J. Pravachol decreases cholesterol and platelet thrombus fom3ation in coronary patients. (Abstx.) Can J Cardio11993;9: 83E, 125. Davignon J. Fibrates: a review of important issues and recent findings. Can J Card/o/1994;10(suppl B):61B--71B. ] 26. Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect

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THE AMERICANJOURNALOF CARDIOLOGY VOLUME76 JULY 13, 1995