Prevention of coronary heart disease Part I. Primary prevention

Volume 45 Number 12 December 1999

Prevention

of Coronary Di-

Heart

Part I. Primary Prevention

Philip R. Liebson, MD Professor of Medicine and Preventive Medicine Section of Cardiology Rush Medical College Chicago, Illinois

Ezra A. Amsterdam,

MD

Professor of Medicine Division of Cardiology University of California. Davis Davis. California

Prevention

of Coronary Disease

Part I. Primary The Scope of Coronary Review of Epidemiologic Clinical Trials Epidemiology Pathoanatomic Studies Clinical Trials

Heart

Prevention

Heart Disease Prevention: Introduction and Pathoanatomic

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Studies and 502 502 510 513

Specific Issues in Primary Prevention of Coronary Heart Disease Office Evaluation and Intervention in Primary Prevention Specific Components of Risk Factor Assessment

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Summary

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References

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Prevention

of Coronary Disease

Heart

Part I. Primary Prevention The Scope of Coronary Introduction

Heart Disease Prevention:

The scope and magnitude of coronary heart disease (CHD) are great, and therefore care must be taken in focusing on issues that bear on the understanding and treatment of this condition. Because significant morbidity or mortality can develop at the first clinical presentation of CHD and because CHD remains the largest cause of disease mortality in the United States, it is understandable that attempts to prevent overt disease are important. This is the first part of a two-part review of primary and secondary prevention issues in CHD. This part will cover the major risk factors for CHD and focus on the scope of primary prevention. The second part will cover special issues in CHD risk including age, women’s issues, race, genetics, nutrition and emerging risk factors, modifications of risk factor intervention in secondary CHD prevention, and when and how to assess the presence of subclinical CHD, including the use of electron beam cardiac tomography (the “heart scan”). Specific topics in the second part will also include such emerging risk factors as homocysteine and antioxidants and the roles of aspirin, angiotensin-converting enzyme (ACE) inhibitors, and P-blockers in primary and secondary prevention. Primary prevention of CHD is defined as the modification or the prevention of risk factors that lead to a first coronary event (angina, myocardial infarction [MI], or sudden cardiac death). Secondary prevention includes measures to minimize the possibility of a recurrent coronary event. Although the mortality from clinical CHD has been decreasing steadily, CHD remains a major cause of morbidity and mortality and causes loss of productivity in many individuals who are still in middle age. Despite the widespread publicity about risk factors for CHD and lifestyle modification needed to reduce risk, the impact of the control of tangible risk factors has not reached levels that could affect further

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declines in prevalence.This will be especially important in the near future becausethe number of individuals older than 60 years will continue to increasesubstantially. For the physician, the important elements in the successful modification of risk are as follows: (1) knowledge of the disease process, (2) knowledge of epidemiologic evidence of substantive risk factors, (3) awareness of established evidence that certain interventions will be successful in the prevention of clinical coronary events, (4) confidence that the modification of risk factors is important and can be successfully accomplished, and (5) ability to transmit to the patient the importance of risk-factor modification to support a successful change in lifestyle. Clinical CHD attacks suddenly and, frequently, dramatically. The established clinical presentations. in order of increasing severity, are angina pectoris, MI, and cardiac arrest. Although by definition angina is associated with reversible ischemia, MI produces irreversible damage and cardiac arrest is almost invariably fatal. Unfortunately, MI and sudden cardiac death account for a substantial percentage of the first clinical presentations of coronary artery disease in men and women. Epidemiologic, animal, and clinical pathologic studies have established the association of diet and sedentary lifestyle with CHD. Based on this evidence, the importance of ingested saturated fats, cholesterol, and total calories in facilitating the development of the atheromatous plaque has been well established. The ancillary importance of smoking, hyper-

tension, diabetesmellitus, and lack of exercise in facilitating plaque development and instability has also been well established. These studies will be reviewed. There is substantial evidence that decreased lipid levels, smoking cessation, control of blood pressure, weight reduction, and exercise decrease the risk for coronary events. However, there is also a widespread belief

that only intervention for high-risk patients and older patients is costeffective and productive. We will discuss the reasons for the application of risk-factor modification at all ages and cost considerations. Similarly, although there has been ample evidence that lowering of low-density lipoprotein (LDL) cholesterol levels, cessation of smoking, management of hypertension, control of diabetes, weight reduction, and exercise are appropriate interventions to reduce risk, recent clinical trials and epidemiologic studies have indicated that the use of antiplatelet agents and certain vitamins (C, E, and folic acid) that may act as antioxidants (C and E) or decrease homocysteine levels (folic acid) may have a role in the further reduction of risk. The benefit of aspirin for high-risk

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patients has been fairly well established. The specific issues that relate to the use of antiplatelet agents, antioxidants, and homocysteine levels will be discussed in the second part of this review. Less conclusive evidence has been found for the other interventions, possibly because of the lack of long-term clinical trials. The modification of certain lipid factors such as lipoprotein(a), or Lp(a), and dense LDL has been attempted, but the effects on risk have not been fully elucidated. In summary, the first part of this review addresses the issue of the patient without CHD who may be at risk for a coronary event. The purpose is to provide a comprehensive background of the issues and a guideline for the physician for appropriate evaluation and intervention.

Review of Epidemiologic and Clinical Trials

and Pathoanatomic

Studies

Epidemiology Several lines of epidemiologic investigation have led to the determination of the importance of specific risk factors as predictors of coronary events. By 1910, heart disease had become the most common cause of death in the United States.’ At about the same time, life insurance investigations indicated an excess of 30% mortality over 3 to 5 years in applicants with systolic blood pressure (SBP) higher than 153 mm Hg who were accepted for life insurance. 2,3 In 1912, Herrick published his clinical observations that linked coronary atherosis and thrombosis with MI. Although much clinical observational literature about CHD was published over the next few decades, there was virtually no epidemiologic interest in the assessment of this condition, probably because of the complexity of the disease state, the general impression that CHD was an inevitable result of aging, and the primitive investigational tools that were available for the investigation of chronic disease states of noninfective causation. Yet, interesting changes were being observed in the vital statistics of conditions relevant to atherosclerosis. For example, although hypertension was subsequently demonstrated to be a risk factor for both stroke and CHD, there was a disparity in secular changes of mortality rates for these closely related conditions. Secular trends in death rates indicated a decrease in hypertensive disease mortality that began in 1940,2 although stroke mortality rates had been decreasing since 1900. On the other hand, CHD mortality increased until the mid-1960s before the initial drop in

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mortality. The decreasein stroke and hypertensivedisease mortality could not be explainedby a pervasivetreatmentof hypertensionbecause antihypertensivemedication that is common now was unavailablethen and the need to even treat what is now accepted as a hypertensive level was questioned, unless malignant hypertension was present. Similarly, there was no overriding interest in the prevention of CHD because the epidemiologic methodology and the risk factors were poorly defined.5,6 Early progress in epidemiology was stimulated by initial metabolic nutritional studies by Ancel Keys and others.7-9 Other early contributions included a publication that related geographic differences in CHD rates to dietary differences, especially fat.* At about the same time, Anitschkow,9 who was working with diets in rabbits, produced atherosclerotic lesions with cholesterol feedings and concluded that rabbit atherosclerosis was analogous to human atherosclerosis. Concurrent clinical investigations by Joslin and others in diabetics led to the conclusion that early arteriosclerosis was a result of excess fat in the diet and blood.‘,“’ In later work, Keys and others determined that saturated fat ingestion led to an increase in cholesterol levels in the blood and that unsaturated fat ingestion led to a decrease in blood cholesterol levels.‘.” Stimulated by these findings, Keys” conducted field studies that resulted in the Seven Countries Study, a large, prospective, epidemiologic study reported in 1970. The Seven Countries Study showed that saturated fat intake was associated with CHD risk in a variety of countries and that this risk was mediated through plasma cholesterol.” This early finding from the Seven Countries Study has been further substantiated by a more recent report in which a correlation coefficient of 0.78 was found between CHD mortality and an index for intake of saturated fats and dietary cholesterol. I3 For example, more recent data from a 26-country study indicate that the slope of the Keys score for determining serum cholesterol based on the intake of fats correlated closely (r = 0.80) with the slope of CHD mortality 10 years later.6 The results of this early work on fats and cholesterol led to further epidemiologic studies and eventually to clinical trials that have further refined the evidence for risk of lipids and the risk benefits of modification. The risk for coronary events must be clearly differentiated when one is dealing with primary prevention versus secondary prevention. Primary prevention deals with an individual without evident history of CHD. Secondary prevention is indicated after a clinical event (angina, Ml, or cardiac arrest) or when there is evidence of significant coronary artery disease. The risks for outcome events are different, as would be expected.

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For example, in a Finnish study of 2541 white men (age, 40 to 69 years) with or without CHD who were followed up for over 10 years, those without preexisting disease had lo-year mortality rates from 1.7% to 4.9% with increasing cholesterol levels at baseline, whereas the IO-year mortality rates for those with preexisting CHD varied from 3.8% to 19.6% with increasing cholesterol levels.14 The recent decline in mortality from CHD in the United States has been investigated in regard to expected mortality with a computer-simulated model with Framingham risk predictors; the 1990 statistics were evaluated based on the statistics that were predicted if the risk-factor levels, case-fatality rates, and event rates in those with and without CHD remained the same as in 1980.15 The results indicated a CHD mortality rate 34% below that predicted from the 1980 data. The calculations suggested that reduction of primary and secondary risk factors accounted for about 50% of the decline; the ratio of decline was twice as high in individuals with preexisting CHD than in those without preexisting disease. (Approximately 34% of the total decline was a result of secondary prevention and 16% was a result of primary prevention.) In regard to other major causes of mortality, the decrease in cardiovascular mortality over the past few decades has also been associated with a lessening in the incremental increase for lung cancer and, less distinctly, for other cancers (based on a study of mortality trends in 27 countries between 1950 and 1987).16 This concordance of trends suggests some common causes that may be susceptible to preventive measures. Some of the factors that may be held in common between CHD and lung cancer include smoking and nutritional factors and, possibly, psychosocial and other environmental factors. The association of fat intake with colorectal cancer is another example of the commonality of risk with CHD. In this regard, there appears to be a parallelism in the development of angiogenesis in atherosclerosis and cancer. l7 It has been established that angiogenesis is necessary for tumor growth and, similarly, that atherosclerotic plaque growth appears to require neovascularization of the vasa vasorum and the intima of the arterial wa11.17-lg On the basis of these studies, Isner17 has postulated that restriction of plaque growth could be accomplished by limitation of angiogenesis. Possible approaches to limit angiogenesis include barriers to transendothelial migration of angiogenic cytokine-carrying cells, of metalloproteinase inhibitors, and of other matrix proteins such as thrombospondin or heparan sulfate, all of which appear to downregulate angiogenesis. A study by Moulton et all9 demonstrated that angiogenesis inhibitors can reduce not only intimal revascularization but also plaque growth. 504

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The long-term epidemiologic studies of multiple potential risk, such as the Framingham, Tecumseh, and Bogalusa studies, have provided invaluable information on the establishment of risk factors for cardiovascular disease in general and CHD specifically. At approximately the time that the Framingham Heart Study was initiated (1948) cardiovascular disease accounted for more than 50% of the deaths in the United States.20 Among the voluminous contributions of the Framingham Study is the evidence for a stepwise incremental risk for cardiovascular disease based on glucose intolerance, SBP, cigarette smoking, and left ventricular hypertrophy (LVH) seen on an electrocardiogram (ECG) or echocardiogram. For example, the Framingham Study established the g-year probability of a cardiovascular event, predominantly a coronary event, as increasing from l/l000 at the lowest level of certain risk factors (no smoking, glucose intolerance, or LVH with SBP of 105 mm Hg, and total cholesterol of 185 mg/dL) to over 60/l 000 with the presence of these factors and an SBP of more than 18.5 mm Hg and a blood cholesterol of 335 mg/dL.“’ The Framingham Study also provided evidence for the potential CHD risk of hypertriglyceridemia in women, for the importance of SBP rather than diastolic blood pressure (DBP) alone as the predominant blood pressure risk factor, that fluctuations of blood pressure were more important than basal blood pressure in risk, and that an impaired glucose tolerance was an independent risk factor for CHD. Evidence for decreased risk as a result of smoking cessation and the importance of socioeconomic factors in coronary risk are some other contributions of the Framingham Study. An evaluation of 7733 participants in the Framingham Study determined that the lifetime risk for the development of CHD after age 40 years was 1 in 2 for men and 1 in 3 for women.” Epidemiologic studies of the risk for CHD in women have been given increasing prominence and focus over the last decade. One example is the Nurses’ Health Study, a prospective evaluation of 48,470 postmenopausal women conducted by the Harvard School of Public Health.‘2 One of the key findings was that current estrogen use in postmenopausal women has reduced the risk for primary coronary events by more than 50%. Although there has been a paucity of intervention studies, a substantial number of similar epidemiologic evaluations have demonstrated similar postmenopausal risk reductions for CHD with estrogen replacement. In one prospective clinical trial of estrogen and progestin versus placebo, the Heart and Estrogen/Progestin Replacement Study, a lack of significant effect by estrogen over a 4-year period in postmenopausal subjects with established CHD was found.‘j The relevance of this finding to primary prevention has not been demonstrated. DM,

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The primary focus of the Multiple Risk Factor Intervention Trial (MRFIT) wastheeffectof interventionfor menconsideredto be athigh risk for CHD on the basisof high cholesterollevels,hypertension,andcigarette smoking.24In addition,follow-up included a large numberof male screenees(361,662)who wereassessed periodicallyfor outcomeevents,without intervention.Over a 6-yearperiod,the CHD and total mortality increased progressivelywith increasingtotal cholesteroland blood pressurelevels. When the risks of eachof the two risk factorswere adjustedfor the other risk factor, the CHD mortality risk, which increasedgradually from the lowestpercentileof DBP (69 mm Hg), beganto increasemoreprecipitously at the 85thpercentile(DBP of 94 mm Hg). Similarly, for total cholesterol, the 6-yearCHD mortality rate alsoincreasedmore precipitouslyabovethe 85th percentile(253 mg/dL). It is interestingthat, when the two spansof valuesarecompared,a DBP in the 85thpercentilewould now be definedas stage1 (formerly “mild”) hypertension,whereasa total cholesterolof 253 mg/dL would certainly be consideredin the high rangeaccordingto the NationalCholesterolEducationProgram(NCEP) guidelines.In theMRFIT data,comparablerisk for CHD-relateddeathfor theestablishedcholesterol cutoff of 200 mg/dL would be a DBP of 80 mg Hg, which is well below a hypertensivelevel. There is also recentevidencefor the impact of risk factors in a generally low-risk population.In the Adventist Health Study, 27,658male and female Seventh-DayAdventists were evaluatedover 6 years,and a qualitative similarity of risk for fatal or nonfatalMI wasfound.25Even in this low-risk population, diabetes,hypertension,cigarette smoking, relative weight, and physical inactivity imparted distinct risk for events. The Bogalusastudy has provided much epidemiologic information on risk-factor prevalencein the young, and especially in the comparisonof differencesbetweenwhite andblack people,by the tracking of theserisk factors through adolescenceandyoung adulthood.26,27 Someof the most valuable comparisons are based on autopsy data of adolescentsand young adults who died as a result of accidents or other noncoronary causes.For example, althoughwhite adults have more extensiveatheromatousinvolvement of the aortathan do black adults,after ante mortem risk factors are controlled for, aortic fatty streaksare more prevalentin black adolescentsthan in white adolescents.On the otherhand,the correlation of fatty streakswith LDL cholesterol levels was higher in black people than in white people in a 26-country study (0.73 vs 0.49). The racial difference in aortic fatty streaksearly in adulthoodand in subsequentfibrous plaqueslater in life suggeststhe possibility that factorsthat

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affect the development of fatty streaks may differ from those that affect progression to fibrous plaques. As with fat and cholesterol, epidemiologic investigation of hypertension increased in the 1960s and 1970s. This work was influenced by the development of efficacious antihypertensive agents in the 1950s and 1960s including rauwolfia, hydralazine, and the thiazide diuretics. There was substantial evidence that the treatment of malignant hypertension decreased its high mortality. However, clinical trials such as the Veterans Administration Study28 and the Hypertension Detection and Follow-up” had to demonstrate that treatment of previously “acceptable” levels of high blood pressure decreased cardiovascular morbidity and mortality, although effects on CHD mortality had not yet been unequivocally demonstrated. In 1972, early work on hypertension led to the first National High Blood Pressure Education Program, promulgated by the National Institutes of Health. Subsequent revisions of these guidelines for hypertension control have been developed; the last revision was published in 1997.“O More recently, the NCEP series has also been developed, with revisions by the National Institutes of Health; the last revision was published in 1993. 31 Both the NCEP and the National High Blood Pressure Education Program have been influential in providing physicians with guidelines on the diagnosis and the management of hypertension and lipid disorders, to control cardiovascular disease in general and CHD in particular. Surveys such as the National Health Surveys of 1960-1962 and the periodic Nutritional Examinational Surveys in the 1970s which demonstrated secular decreases in blood pressure for both black people and white people, have been of particular merit in the determination of gender and racial differences in risk factors. The surveys also indicated that between 1960 and 1980 there had been a decrease in purchases of cigarette tobacco (-27%) milk and cream (-24%) butter (-33%), eggs (-12%) and animal fats and oils (-39%) and an increase in the purchase of vegetable fat and oils (+58%) and fish (+ 23%).32 Although these dietary trends appear to be consistent with the observed decline in CHD mortality that began in the mid-1960s there are no substantiated data to confirm that changes in salt and alcohol intake or in body weight have contributed to the decrease in hypertension, although it certainly appears to be more than coincidental.2 The decline in cardiovascular disease mortality from the mid-1960s is predominantly that of CHD (80%). Between 198 1 and 199 1, the age-adjusted CHD mortality rate decreased

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by 3.8%.’This decreasewas found in men and women and black and white individuals. Epidemiologic investigation of cigarette smoking and CHD beganin the 1940s(although tobaccohad been given a bad name earlier in the centuryby moralists without any scientific substantiation).Before 1940, severalreportshad suggestedthe influence of cigarettesmoking on lung cancer,but in 1940,in a report from the Mayo Clinic on the use of the then relatively new case-controlmethodology to retrospectively study the recordsof men with a diagnosisof anginapectoris or MI, a positive relationship betweensmoking and CHD incidence was found.33In the early 1950s a surveyof 187,766men conductedby theAmerican Cancer Society, which was popularly known at the time as the Hammond and Horn Study, provided further evidence for a link between cigarette smoking and CHD. 34These men were followed up for 3 years, and a substantialpercentageof deathsover the 3 yearswas the result of CHD. Theseresultsallowed for a calculation of risk that indicatedthat smokers had twice the risk as nonsmokersfor CHD-related death. The widely publicized SurgeonGeneral’sreport of 1964 and further epidemiologic studieshave had an impact on ratesof cigarettesmoking, which decreasedfrom 52% in 1964to 35% in 1983amongmen and from 34% to 30% amongwomen in the sameperiod.2However,smoking is still a substantialproblem, especiallyamong adolescentsand young adults. The influence of physical activity on coronary risk was brought to generalrecognition by anotherlandmark seriesof observationalstudies. In a study of transportand postal workers in London, the workers were surveyedabout their physical activity during work, and data on body physique were incorporated.35 Subsequentmortality data led to the hypothesisthat men who have jobs that involve physical activity have less CHD than thosewho do sedentarywork and that the CHD they have is less severeand develops later. Similar findings were obtained in a study of US railway workers.36Theseinvestigationslaid the groundwork for more extensivestudiesthat took place overlonger periods,which will be discussedlater in this article. The risk for CHD is especially high for individuals with diabetes. Autopsy studiesreveala higher prevalenceof 2-vesseland3-vesselcoronary artery disease in individuals with diabetes than in individuals without diabetes.37The influence of such factors in diabetesas higher insulin levels in non-insulin-dependent diabetes, glycosylation of lipoproteins,increasedlipid levels, and the influence of insulin on blood pressuremay all contributeto the high prevalenceof CHD in individuals

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with diabetes. The Framingham Study findings indicate that not only did glucose intolerance increase the risk for CHD but the risk was greater for women with diabetes than it was for men with diabetes.38339 It is well-known that women have a more favorable risk status for CHD at a given age than men. The age-adjusted difference in risk for CHD demonstrates a favorable effect in women at a given age, even up to 100 years. The reasons that have been suggested are relatively lower LDL cholesterol levels until menopause and persistently higher levels of highdensity lipoprotein (HDL) cholesterol in women. The question of the effect of standard risk factors on the age-related prevalence of CHD, presumably based on the factors’ contribution to the accumulated coronary plaque burden, has been evaluated recently. A prospective follow-up study in a Finnish population of 14,786 middleaged men and women found that differences in serum total cholesterol level, blood pressure, body mass index, and diabetes prevalence explained only one third of the age-related increase in CHD risk in men and 50% to 60% of the age-related increase in women.“a It appeared that differences in the major risk factors explained a predominant part of the sex difference for CHD. Of the major risk factors, smoking rate and LDL cholesterol levels appeared to most substantially influence the increased risk of CHD in men. The relative influence of heredity and environment in the development of CHD and the prevalence of risk factors can be assessed by interfamilial comparisons. by interpopulation comparisons, and, more specifically, by comparative studies of twins. For example, in an evaluation of 21,005 Swedish twins who were born between 1886 and 1925, with an average of 26 years’ follow-up, Marenberg et al”’ used the age of death of one twin as a result of CHD to predict the risk of death of the other twin as a result of CHD. The hazard for death as a result of CHD if a man’s monozygotic twin died of CHD before the age of 55 years was 8 times that of a man whose twin did not die of CHD before the age of 55 years. For male dizygotic twins, the hazard was approximately half that value. For female monozygotic twins, the hazard ratio was 15, and the hazard for female dizygotic twins was similar to that for male dizygotic twins. The magnitude of the difference decreased with age as the age of the first twin who died of CHD increased. These relative hazards were found to be little influenced by the other standard risk factors. These results underscore the importance of coronary risk for an individual with a first-degree family member in whom CHD developed before the family member was 55 years old.

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By the mid 1980s it was generally accepted that high serum cholesterol (specifically high LDL cholesterol and low HDL cholesterol), cigarette smoking, hypertension, and diabetes were major risk factors for the development of CHD, with significant independent contributions of age, male sex, overweight, and sedentary lifestyle. More recently, other factors have been shown to contribute to the risk for CHD, including triglyceride levels, Lp(a), thrombotic factors, homocysteine, iron, immunologic components, and infectious agents. The relative importance of these factors will be considered in this and a forthcoming issue of Disease-a-Month, fathoanatomical

Studies

In addition to the large body of classical information that has been generated on the development of the atherosclerotic plaque since Virchow’s publication,42 interesting new studies have revised some of our concepts about the pathophysiology of atherosclerosis. For many years, one of the fairly established paradigms was that atherosclerosis was degenerative; then the paradigm was that the primary event in atherosclerosis was endothelial denudation related to insults by various risk factors.43 Most recently, it has been shown that endothelial denudation is not essential as the initiating step in the atheromatous process but that endothelial dysfunction precedes denudation.43 Endothelial dysfunction has been found with diabetes, with elevated LDL cholesterol, with hypertension, with cigarette smoking, with elevated homocysteine levels, with some genetic alterations, and, interestingly, with some microorganisms, including herpesvirus and Chlamydia. There is increasing interest in the potential significance of an inflammatory process in the initiation of atherosclerosis. Although the concept of inflammation as a preceding event in atherosclerosis is old, recently applied immunologic techniques have opened up new vistas for the potential impact of antecedent inflammatory factors, specifically, the identification of specific types of macrophages regulated by T-cell cytokines such as interferon-y, and interleukins 2, 4 and 1O.44 It has been demonstrated that monocyte entry into the intima is mediated in part by vascular adhesion molecule-l (VCAM-l), a cell surface protein that is expressed both by endothelium and by smooth muscle.45 Epidemiologic investigations have demonstrated that elevated concentrations of intercellular adhesion molecule- 1 are associated with increased risk of future coronary events.46 Moreover, the mean plasma levels appear to increase with increasing prevalence of the usual cardio-

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vascular risk factors, and there is an independent association of each risk factor with adhesion-molecule level. Other studies have linked selectins, a family of adhesion glycoproteins, with intimal hyperplasia as a response to experimental balloon injury of the intima.47,48 The potential for blockers of adhesion molecules to modify intimal hyperplasia has been demonstrated.48 There is some evidence that the angiotensin II gene polymorphism may relate to CHD risk. Tummala et a145 demonstrated an interesting association of angiotensin II with vascular-cell adhesion. They infused angiotensin II into rats for 6 days and demonstrated the activation of VCAM- 1 protein and messenger ribonucleic acid expression. Similarly, cultured aortic smooth muscle cells that were exposed to angiotensin I1 significantly increased VCAM- I messenger ribonucleic acid expression. What is the relation, if any, of classic risk factors and adhesion molecules? Oxidized LDL molecules are known to produce multiple effects that facilitate the atheromatous process. Among these effects are induction of VCAM-1 and intercellular adhesion molecule-l and the increase of levels of platelet-dependent growth factor and other growth factors in endothelial and smooth muscle cells.4” These effects, however, do not necessarily prove a direct causal relationship between oxidized LDL and the recruitment of inflammatory cells into atherosclerotic lesions. AlexandersO reviewed evidence that suggested that both atherosclerosis and hypertension may independently enhance the oxidative stress on the arterial wall. The effect of hypertension on induction of such oxidative stress may result from medial thickening, from decreasing oxygen diffusion, or from dysfunctional endothelium. On the other hand, there is some possibility that blood pressure may be elevated by inactivation of endothehum-derived nitrous oxide and thus interfere with vasodilatation.“’ The relationship of an infectious etiology to the development of atherosclerosis was suggested recently from observations in which vascular lesions similar to human atherosclerosis were induced in chickens that were experimentally infected with avian herpesvirus.“* Subsequently, observations in humans have suggested that a number of organisms, including cytomegalovirus, Chlamydia pneumoniae, Helicobacter pylori, and herpes simplex virus, may be primary etiologic agents or cofactors in the development of atherosclerosis.“* For example, Muhlstein et a153 studied specimens of coronary vessels from 90 symptomatic patients who underwent coronary atherectomy and compared the specimens with 24 normal coronary specimens. They isolated Chlamydia species from almost 80% of the coronary atherectomy specimens,

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whereas Chlumydia species was isolated from only 1 of the normal specimens. There is also some evidence from animal models studied by the same investigators that Cpneumoniae infection accelerates intimal thickening in association with a cholesterol-enhanced diet.54 Possible pathophysiologic mechanisms of infectious agents in atherogenesis and restenosis are direct infection of endothelial cells leading to a procoagulant balance, effects on the growth of vascular smooth muscle cells, alteration of cytokines and other mediators, induction of leukocyte adhesion molecules, and disruption of an advanced atheromatous plaque.54 Several recent epidemiologic studies lead to questions about the possible role of infectious agents and atherogenesis. Ridker et a155 did not find that IgG antibodies against herpes simplex or cytomegalovirus were markers for increased atheromatous risk. This same investigative group also found no evidence of an association between C pneumoniae IgG seropositivity and risks of future MI.56 Epstein5’ in commenting on these and other studies concerning the possible role of infection and atherogenesis, cautioned that many of the previous studies were crosssectional and evaluated patients after atherosclerosis developed, that retrospective analysis was associated with study bias, and that prospective studies have, of necessity, to deal with CHD events rather than the presence of coronary artery disease per se in evaluation of the association with infection. Additional studies with animal models and multiple prospective seroepidemiologic studies with heterogeneous populations have to be accomplished before any conclusions can be made about infectious agents as contributors to atherogenesis. Endothelial dysfunction may be present not only in atherosclerotic arteries but also in arteries that are resistant to atherosclerosis, such as forearm blood vessels and the microcirculation. The measurement of forearm blood-flow dynamics may have some role in the prediction of risk. The impact on the relative presence of the common risk factors for CHD and the composition of the plaque, distribution, and plaque vulnerability has yet to be determined. 58 Nonetheless, there is substantial evidence for experimental interventions that lead to plaque stabilization. These include lowering of plasma LDL cholesterol, elevation of HDL cholesterol, use of antioxidants, exercise conditioning, avoidance of psychosocial stress, ACE inhibition, antihypertensive treatment, and use of estrogen.58 Clinical studies of coronary arteries by angiography and outcome by coronary events have provided substantial evidence for the stabilization of atheromatous plaques by significant lowering of plasma LDL cholesterol levels.

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Muller et a159have recently evaluated triggers to acute coronary events, especially MI. These triggers presumably produce coronary events by adversely affecting the coronary blood flow-myocardial oxygen consumption ratio, such as with increased catecholamines that result from exercise or stress or with thrombogenesis that develops with stress or cigarette smoking. Although there are no specific guidelines for primary prevention based on the decrease of the trigger mechanism in subjects without clinical CHD, the impact of a positive test for subclinical but significant coronary artery disease may lead to use of drugs such as P-blockers, which lower heart rate, and ACE inhibitors, which may influence fibrinolysis to decrease thrombosis. The use of small doses of antiplatelet agents as primary prevention has resulted in beneficial effects on primary risk in several large epidemiologic studies, such as the Physician’s Health Study.60

ClinicalTrials Just as epidemiologic studies and pathoanatomic correlations have established the role of classic risk factors in the development of CHD, clinical trials over the past 3 decades have established that, at least for elevated lipid levels and hypertension, there is substantial evidence that intervention to lower LDL cholesterol levels and decrease blood pressure have impacted beneficially on cardiovascular events and, more specifically, on coronary events. However, it was only recently that there was firm evidence for a decrease in coronary events with antihypertensive intervention. Although these interventions and guidelines for interventions in primary prevention will be elaborated more fully, there remains considerable controversy about primary prevention as to what levels of abnormal lipid or blood pressure should be used for the initiation of pharmacologic intervention, what the target lipid or blood pressure level should be, and what drugs to initiate. There is less concrete information about pharmacologic intervention for diabetes to specifically decrease CHD risk, aside from the efforts to maintain adequate glucose levels and decrease lipid levels to accepted values. As for lifestyle modification, prospective clinical trials of smoking cessation. weight reduction, and activity modification are quite difficult to accomplish, especially for primary prevention. However, some valuable studies have been successful in nonpharmacologic intervention for lipid modification, especially when the study subjects were well-motivated. The beneficial effect of intensive lifestyle changes on coronary artery disease found by Omish et a161provides significant objective evidence that risk-factor modification can sometimes reverse the basic pathologic process.

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Specific Issues in Primary

Prevention

of CHD

Office Evaluation and Intervention in Primary Prevention The practice of primary prevention of CHD in an office setting varies with the training and inclination of the physician. In our practices, which involve large groups of cardiologists, there is a wide spectrum of approaches to primary prevention. If we consider primary prevention as the appropriate responsibility of the primary care physician rather than the cardiologist, then the internist, the family medicine practitioner, the obstetrician, and the geriatrician are in the forefront of such prevention in adults. It is unlikely that any physician in this group of primary practitioners will, at first contact with a patient, fail to obtain a history of CHD to separate primary from secondary prevention and determine the history of hypertension, diabetes mellitus, and smoking. It is less likely that a history of activity status, previous cholesterol test results, diet or family history of early CHD will be obtained. The physical examination is most likely to include the blood pressure and cardiac examination and possibly an evaluation of the retinal arterioles and carotid pulses. The examination is less likely to include auscultation for carotid, abdominal, and femoral bruits or peripheral pulses, and there is a less than even chance that a careful evaluation for tendinous or tuberous xanthomas will be obtained. The laboratory examination of this hypothetical patient will certainly be focused on the problem the patient is initially seen with. However, for a first-time evaluation for a routine check-up, a lipid level is likely to be obtained; a complete lipid profile is less likely to be accomplished; electrolytes, blood suger, and blood urea nitrogen and creatinine will probably be evaluated; and usually, in a subject in middle-age, an ECG will be performed. We have described a comprehensive preventive cardiology examination, which, in our opinion, is appropriate for any person who walks into the office of a primary physician for the first time (with the exception of the ECG for younger individuals). Every person in the United States who is older than 20 years has some risk for development of an atheromatous plaque, with a plaque burden that starts to develop in adolescence. There is no way to determine the extent of subclinical coronary artery disease except by certain clinical tests, which will be discussed in the second part of this review. It is diffcult to justify the lack of an enthusiastic approach to preventive cardiology. First, CHD is the chief killer in this country. Second, CHD is frequently first seen with an irreversible first clinical event. Third, every

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patient is a candidate for preventive practices. Fourth, clearcut guidelines are available for the determination of risk and the initiation of interventions. Fifth, prevention does not require expensive high-tech interventions. In the United States, a person dies of cardiovascular disease every 34 seconds.22 Should we wait until a plaque burden has reached the point of significant disease before we attempt intervention? Before we discuss various guidelines for comprehensive risk reduction, let us look at the list of primary prevention targets. The targets are (I ) smoking cessation, (2) decrease in LDL cholesterol levels, (3) modification of HDL cholesterol and triglycerides, (4) adequate blood pressure, (5) weight management, and (6) some form of activity at least 3 times a week. There is no argument that these targets can be reached with varying ease. There is also no argument that lifestyle modification is an important part of primary risk intervention, which is generally difficult for the physician because it is usually not a part of medical school or residency training. Kottke et a162,63have published several cogent reports about the difficulty of practicing preventive cardiology in the office setting (Table 1). It is key to the practice of prevention for physicians to overcome certain barriers to their implementation of preventive services.“’ For the physician, these barriers include a lack of understanding of the benefit of prevention, deficient skills to assist in lifestyle modification, a lack of knowledge of guidelines for intervention, inadequate financial return for the time spent, the perception that the patient does not need or want the intervention, the sense that the intervention will not really affect risk substantially, discomfort with primary prevention being a part of his or her role, and, overall, a general lack of commitment. In a busy office practice, which becomes busier every day. the physician has to make time for preventive services.6” Several approaches to motivate physicians in the practice of preventive cardiology have been studied. 63.64 Other members of the office staff obtaining ancillary information about diet and activity, automatic reminders on charts about the obtainment of lipid levels, and follow-up calls to patients about specific quit-smoking dates have all been successful. Some offices have incorporated nutritionists or behaviorists as part of a general preventive cardiology services package. However. this is impractical in many physicians’ offices. The automatic reminder on the chart about specific preventive cardiology measures for all patients would be the most effective preliminary step to ensure that the physician has at least updated the risk factors for an individual patient. In

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TABLE1. Physician

issues in preventive

services

Know ledge of benetit Physician skills, confidence, and commitment Guidelines for intervention Financial return Perceived effectiveness of intervention Determining patient’s perception of intervention need Perceived as legitimate part of professional role Adapted

from reference

62, with permission.

most offices, the assistance of the nurse and the office staff would be the most practical means of setting up reminders to the physicians based on cues in the charts. Because the management of cholesterol levels is a standard that can be used to judge physicians’ practices, several studies have evaluated the practice of preventive cardiology with the use of this standard. In one study, a stratified random sample of 2332 office-based physicians that involved more than 50,000 office visits to adult patients from 1991 to 1992 was used.(j5 The results indicated that less than 10% of the patients received annual cholesterol screening. The likelihood of screening increased with white race, private insurance, and the advancing age of the patient. Nonobese patients and patients with diabetes were also more likely to be screened, and younger patients and patients with cardiovascular disease and private insurance were more likely to receive counselling. Clearly, the demographic profile, the insurance status, and the clinical status of the patient appears to play a strong role in decisions on preventive cardiology practices. The point to be made here is that preventive cardiology screening should be independent of these factors. An area of concern for many physicians and health care administrators is the cost-effectivess of preventive cardiology practices. The assessment of cost-effectivess is complex and involves estimated lives saved and morbidity decreased on one side of the ledger, with cost of intervention, including drug and laboratory test costs and physician and ancillary staff time, on the other side. Several analyses have been accomplished for modification of lipid abnormalities. A general consideration is that the lowering of cholesterol by 10% over several decades can decrease CHD incidence by 30%. 66 Most of the studies of the modification of lipid abnormalities have involved secondary prevention. For example, using information from the Simvastatin Secondary Prevention Trial, Yusuf and Anand@’ calculated that use of a statin agent to lower LDL cholesterol prevented a major cardiovascular event at a 5-year cost of $11,000 to

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$12,000 and prevented a death at approximately twice that cost. using a computer simulated model that estimated riskGoldman et a1,67 factor-specific annual incidence of CHD and risk of recurrent coronary events, estimated that the use of a statin in individuals with a serum cholesterol level greater than 250 mg/dL is associated with a cost of $25,000 per year of life saved. 67 For primary prevention in men 35 to 84 years old with cholesterol levels between 250 and 299 mg/dL, costs were between $27,000 and $690,000 per year of life saved, depending on age, smoking, weight, and DBP.“7 After the publication of the NCEP guidelines, a nationally representative sample of cardiologists was surveyed to determine their recommendations for pharmacologic treatment of hypercholesterolemia.68 The cardiologists were given 12 representative case studies. The 346 responding cardiologists recommended pharmacologic treatment based on published cost-effectiveness analysis. Interestingly, there appeared to be more aggressive intervention for primary prevention than for secondary prevention based on the NCEP guidelines. It was estimated that the 12 hypothetical case studies cost from less than $10,000 to $1 ,OOO,OOOper year of life saved. Thus, although cost-effectiveness appears to be important when physicians make decisions, the range of cost-effectiveness varies considerably. In connection with costs in an office setting that average $10,000 or more per year of life saved, a more recent assessment of population-wide educational approaches to reduce cholesterol levels (in which results reported in the Stanford Three Community Study, the Stanford Five-City Project, and the North Karelia Study were used) indicated a cost of only $3200 per year of life saved, 69 which compares favorably with an individual patient approach. Community interventions included media campaigns, direct preventive cardiology education through community activities, and face-to-face instruction. The costs of selected antihypertensive and lipid-lowering agents are listed in Table 2. Throughout Europe and the United States, guidelines on primary and secondary prevention of CHD appear periodically (Table 3).30,“‘.70.7i The guidelines vary considerably depending on the expert panel involved. The constituency of the panel may include primary practitioners, cardiologists, epidemiologists, basic science investigators. and allied health care professionals. For example, the latest Joint European Societies (Cardiology, Atherosclerosis, and Hypertension) guidelines (1997) advocate use of a coronary risk chart, separate for men and women, to evaluate age, total cholesterol level, smoking habit (yes or

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TABLE United

2. Average States*

wholesale

values

of selected

antihypertensive

agents

in the

Daily

Cost

Dose

Agent Antihypertensive Agents Diuretic Chlorthalidone Beta-blocker Metwolol (Toprol XL) ACE inhibitor Enalapril Lisinopril Calcium channel blocker Amlodipine Lipid-Lowering Agents Statins Atowstatin

Pravastatin Simvastatin Bile acid sequestrant Cholestryamine (Questran; 378 g can Nicotinic acid Niacin Niaspan (LA) Fibric acid derivatives Gemfibrozil Fenofibrate 1 1999.

Cost information

25 mg

$0.72

smg

$0.56

10 mg 1omg

$2.20 $0.93

1omg

$2.17

10 mg

40% 10 mg 20 mg 10 mg 20 mg

$1.87 $2.90 $1.26 $1.39 $2.19 $2.61 $2.19 $2.81

2 packets 2 scoops

$3.69 $2.14

2g 2g

<$O.lO $1.84

1.2 g

$1.88 $0.74

20% 2omg

Flwastatin

*Ott

and lipid lowering

60 packets,

provided

9 g each)

67 mg by Rush-Presbyterian

St. Luke’s

Medical

Center

Pharmacy.

no), and SBP to calculate risk.71 Intervention is based on a lo-year risk for a coronary event; a risk of more than 20% or evidence for target organ damage are indications for aggressive intervention. In the United States, separate guidelines have been formulated for lipid lowering (NCEP Guidelines, 1993)31 and hypertension (Joint National Committee, or JNC VI, 1997). 3o A consensus panel of the American College of Cardiology has presented a guide for comprehensive risk reduction for secondary prevention. 72 In addition, the American College of Physicians (ACP) has also developed a guideline for CHD prevention with the use of cholesterol screening. 73y74 These guidelines combine “evidence-based” and “consensus-based” approaches.75T76 It has been argued that the NCEP lipid guidelines drew on “biological and clinical

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3. A comparison

of several

Guidelines

Who

to Screen

WEP ACP

Older than 20 years with total cholesterol at least every 5 Years Total cholesterol for men aged 3565 years and for women aged 4565 years only. Otherwise, only if evidence for CHD or other atheromatous disease. All patients with atherosclerotic disease and those with other CHD risk factors

TABLE

Europe

High

Risk

primary

Characteristics

prevention

(Aside

guidelines

from

Lipid

Levels)

At least 2 of the following: hypertension, smoking, diabetes, man older than 45 years, woman older than 55 years or postmenopausal, family history of premature CHD (before the ages of 55 years for men and 65 years for women), evidence of stroke, TIA, or cerebrovascular disease Same as NCEP Absolute CHD risk > 20% over 10 years or will exceed 20% if projected to age 60. Risk analysis: age, smoking, blood pressure, total cholesterol (separate analysis based on sex)

NCEP

ACP Europe

NCEP, Natlonal

Cholesterol Education Program; ACP. American College of Physicians; Europe, Second Joint Task Force of European and Other Societies: CHD, coronary heart disease: TM. transient ischemic attack. Adapted from references 31. 71, and 73.

plausibilities of potential benefit,“75 wheras the ACP guidelines relied more heavily on results of epidemiologic data and randomized. clinical trials of cholesterol results that reported clinical outcomes. The ACP guidelines are based partially on the assumption that there is no established evidence that treatment of young adults will have a net benefit, but that the incidence of CHD begins to rise at the age of 40 years in men and at the age of 50 years in women. Therefore, the ACP guidelines suggest initial cholesterol screening at the age of 35 years for men and at the age of 45 years for women. Cholesterol testing is not mandated for low-risk groups. There is also no recommended screening for men and women aged 75 years or older, but discretion is recommended in the screening of those individuals who are 65 to 75 years old.7” The NCEP program, on the other hand, recommends cholesterol screening for everyone aged 20 years or older. at least once every 5 years. The objective is early intervention to decrease the plaque burden over many years. With NCEP guidelines, young adults with borderline highrisk or high-risk LDL cholesterol levels (130-J 59 mg/dL and > 159 mg/dL, respectively) would be evaluated. It should be noted that. based on national screening surveys, 12% of men aged 20 to 34 years and 8% of premenopausal women have high-risk LDL cholesterol levels.76 For the elderly, there is increasing evidence for reduced risk from reduction of lipid levels. although the relative impact of lipid components on risk

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in the elderly is somewhatdifferent from the impact on risk in younger individuals. Grundy5has conceptualizedCHD risk factors by classifying them as causal,conditional, and predisposingrisk factors.In addition, he recommendsthe conceptof plaqueburdenasa separaterisk categoryin primary presention.Causalrisk factors include cigarettesmoking, hypertension, elevatedtotal cholesterolor LDL cholesterol,low HDL cholesterol,and elevated blood glucose. These are the risk factors that most strongly impact CHD risk. Conditional risk factors are associatedindependently with CHD risk, but direct causallinks have not yet beendeterminedfor theserisk factors.Serumtriglycerides,Lp(a), small LDL particles,homocysteine and coagulation factors such as fibrinogen, and plasminogen activatorinhibitor-l are conditional risk factors.Predisposingrisk factors influence CHD risk by intensification of causalrisk factors and include obesity,insulin resistance,physical inactivity, family history of premature CHD, male sex,and socioeconomicand behavioralfactors. Various risk profiles havebeenusedas quantitativerisk predictors.The Framingham risk profile hasgone througha numberof revisions.77-79 In the most recently reported application, age, total cholesterol, HDL cholesterol, SBP and DBP, smoking, presenceof diabetes,and ECGLVH were used, with a separateformula for men and women.79These risk predictor formulae were basedon the latest NCEP guidelines and appeared to effectively predict outcome events when applied to a prospective12-yearfollow-up of more than 5000 men andwomen in the Framingham Study.79 In regard to the generaloffice practice of preventivecardiology, it is clear that a motivated physician is essentialfor an effective practice.The motivation of the patient is also essential,especially in primary prevention, becauselifestyle change may be more difficult for a seemingly healthy individual. The use of charts to indicate progressand realistic short-term goals is important. Whether risk charts such as the Framingham risk chart will be of assistancedependson the patient’s conceptof risk. A changingrisk percentage,basedon effective intervention, may be a tangible messageto the patient about progressbecause diseasesymptomatology cannotbe usedin primary prevention.The risk charts also help the patientto understandthe relative importanceof each risk factor.80One caveatabout the Framingham risk chart, however,is that the CHD risks of severe hypertension, marked smoking, and extremelyelevatedcholesterollevels areunderstatedby therisk scoresor are not really proportionalto their true risk.80This should be taken into

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TABLE

4. Treatment

decisions

Primary

Prevention

Target

based

Fewer than 2 risk factors 2 risk factors or more Risk

an LDL cholesterol

<160mg/dL < 130 rng/dL

Factors

Male sex (especially over age 40) Family history Diabetes mellitus HDL cholesterol < 35 mg/dL Triglycerides > 200 mg/dL Hypertension Overweight/obesity Smoking HDL, High-density

lipoprotein.

account if risk charts are to be used. Another consideration is the lack of a gradient of risk between desirable levels of LDL cholesterol (between 100 and 129 mg/dL) and borderline high levels of LDL cholesterol (between 130 and 159 mg/dL). The Framingham risk score reflects a predominantly white population and may not accurately be applied to other racial groups, especially lower risk populations such as the Hispanic or Asian populations.81 Finally, some instruments, including the Framingham risk score, do not demonstrate an increased risk in women with increasing age between 55 and 75 years, which contradicts epidemiologic evidenceSs2 Specific

Components

of Risk Factor Assessment

Lipids The total cholesterol level, which does not require fasting for the test, has been shown to correlate with CHD risk over a large range of values. The reason for this is that total cholesterol strongly reflects LDL cholesterol levels, which constitute approximately 65% of total cholesterol. The plasma LDL cholesterol is currently the primary target for lipid modification in primary prevention. However, some women with high HDL cholesterol levels (in the 90-100 mg/dL range) will have relatively high total cholesterol, which suggests some risk unless a lipid profile is determined. The current recommendations of the NCEP are not stratified for age (Table 4). Thus for primary prevention for all ages, an LDL cholesterol value of more than 160 mg/dL is considered high, a value of 130 to 150 mg/dL is considered borderline high, and a value of less than 130 mg/dL is considered desirable. It should be noted that the only difference

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between primary prevention and secondary prevention is a target desirable LDL cholesterol level of less than 100 mg/dL in the latter. At present, the armamentarium for lowering LDL cholesterol mainly includes dietary intervention and the use of drugs. The dietary intervention involves limitation of fat calories, saturated fats, and cholesterol and limited increase in polyunsaturated fats and, perhaps, in monounsaturated fats. Drug intervention primarily includes hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, with resins and niacin as supplementary agents. Compared with LDL cholesterol, HDL cholesterol is a strong inverse risk factor, especially with levels above 60 mg/dL. Although the NCEP guideline for an acceptable HDL cholesterol level is more than 35 mg/dL, many believe that a level of 45 mg/dL is the lowest acceptable level for men and 50 mg/dL is the lowest acceptable level for women, as indicated in the latest Framingham risk score. 78 Unlike the case for LDL cholesterol, there is as yet no evidence based on clinical trials that isolated unacceptable (low) HDL cholesterol levels require drug treatment. However, lifestyle modification is the keystone of HDL cholesterol intervention. Effective lifestyle changes that beneficially influence HDL cholesterol levels include smoking cessation, weight reduction for overweight patients, and increased activity for sedentary patients. For low HDL cholesterol levels associated with high triglycerides, niacin and fibrates are the drugs of choice, with niacin being somewhat more potent in raising HDL cholesterol levels. In general, HDL cholesterol levels tend to rise as triglyceride levels decrease, although triglyceride levels tend to decrease before the beneficial change in HDL cholesterol levels. At present, HDL cholesterol levels are quite important for risk assessment, especially in relation to LDL cholesterol levels. Although high triglyceride levels are associated with increased risk for CHD, it is difficult to isolate the risk effects of triglycerides from those of HDL cholesterol, partly because of the inverse relationship between plasma levels of the two. Of the lipid components, high triglycerides are the one factor most likely to cause an acute event (acute pancreatitis), usually with levels above 1000 mg/dL. Current guidelines state that a triglyceride level of less than 200 mg/dL is acceptable, although there is evidence that the viscosity of blood, which may also influence coronary risk, increases with triglyceride levels above 100 to 150 mg/dL. It is likely that in future guidelines 150 mg/dL will be the desired cutoff. As with interventions for high LDL cholesterol, in the management of high triglycerides, lifestyle change is used first and drug intervention is used

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second. For lifestyle modification, the similarities to intervention for LDL cholesterol include modification of lipid calories, decrease in saturated fats and cholesterol intake, and limited increase in polyunsaturated fats and, possibly, in monounsaturated fatty acids. Beyond this, dietary intervention for high triglycerides includes limitation of alcohol intake, use of complex carbohydrates rather than refined sugars, and limitation of total caloric intake for overweight patients. Increased exercise and cessation of smoking may also be effective. For drug intervention in hypertriglyceridemia, fibrates are the most effective, followed by nicotinic acid. It is an important precept in hypertriglyceridemia that conditions such as hypothyroidism, liver disease, diabetes, excess alcohol intake, excess estrogen intake, and nephrotic syndrome, among other conditions, should be ruled out and that, in many cases, treatment of such conditions would supercede specific triglyceride-lowering therapy. We have dealt in general with epidemiologic studies relevant to evaluation of CHD risk. More specifically, for risk from high cholesterol, the Framingham Heart Study, MRFIT screenees, and the Honolulu Heart Study, among others, provided invaluable information on the rising risk for a coronary event with increasing lipid levels. The Framingham Study demonstrated increased CHD risk with total cholesterol levels that increase from 100 mg/dL, with the event rate ratio of 3: 1 with total cholesterol levels of 300 mg/dL versus 100 mg/dL.83 For the MRFIT screenees evaluation, researchers looked at CHD-related death rates rather than incidence of CHD events.8” Here again, there was an increased event rate beginning at the lowest total cholesterol level (140 mg/L). In this case, the 6-year age-adjusted CHD-related death rate per 1000 men increased from just less than 4 with levels of 140 mg/dL to just more than 16 at 300 mg/dL, a 4-fold increase. Epidemiologic studies that show the relationship between diet and CHD include the Seven Countries Study, which was previously discussed, the Japan-Honolulu-San Francisoco Study, the Zutphen Study, the Honolulu Heart Program, the Ireland-Boston Study, and the Western Electric Study, among others. In the Japan-Honolulu-San Francisco study, diets and CHD rates of Japanese people living in these three environments were evaluated and a strong correlation between saturated fat intake and CHD was demonstrated.*” A strong correlation between dietary cholesterol and risk for CHD was demonstrated in the other studies. In the Western Electric Study, a 19-year follow-up study, researchers demonstrated a 37% reduction in total mortality with an average decrease of 200 mg of cholesterol per 100 kcal.s6

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523

There is substantial evidence from clinical trials for lipid-lowering intervention in primary prevention.We will confine our discussion to studiesof primary prevention,which are relevantto this review. One of the first of thesetrials was the Lipid ResearchClinics Primary PreventionTrial (publishedin 1984).87This study included 3800 hypercholesterolemic middle-aged men who were initially placed on lipidlowering diets, partially to determine compliance. After this, the men were randomizedto a bile acid sequestrantor placebo.The study showed a 9% reduction in total cholesterol comparedwith placebo and a 19% reduction in coronaryevents,which is approximatelya 1:2 ratio for lipid changeversusthe eventrate decreaseseenin other clinical trials and in epidemiologic comparison studies such as Framingham. More recent meta-analysesof clinical trials suggesta more profound 1:3 ratio for cholesteroldecreaseversusoutcomebenefit.88 The Helsinki Heart Study (published in 1987) addedto these results with the finding that the study group, who were given a fibric acid derivative, gemtibrozil, had 34% fewer coronary events than the placebo group.89In comparison with the 19% decreasein the Lipid Research Clinics Primary PreventionTrial, this increasedbenefit was assumedto be derivednot only from the 8% decreasein LDL cholesterollevels but from a 10% increasein HDL cholesterollevels. In anotherprimary prevention intervention trial, the Oslo Study Diet and Antismoking Trial (published in 1986), researcherslooked at not only CHD eventrate but also CHD-related deathsand total mortality.90 Dietary managementand smoking cessation were used without drug intervention.Diet alone decreasedtotal cholesterollevels by 13% in the treatmentgroup versus 3% in the control group. A five-year follow-up after the initiation of intervention demonstrated45% fewer events (nonfatal MI, fatal MI, and suddendeath) in the treatment group and 33% fewer total deaths.Moreover,continuedfollow-up over 3 to 4 years after the end of the trial demonstrateda wider divergenceof up to a 40% decreasein total mortality. Therehavebeensomeconcernsaboutpossibleadverseeffectsof lipidlowering drugs. A meta-analysis of 35 clinical trials of cholesterol lowering of 2 years’ duration or more (including both primary and secondaryprevention),which was publishedin 1995,was performedto evaluatethe separateeffects of cholesterollowering and other effects of the variousinterventions.91Sometrials were associatedwith increasesin non-CHD mortality and total mortality (tibrate trials). Estrogen and dextrothyroxin increasedCHD mortality in men. However,therewere no

524

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specific effects independent of cholesterol lowering due to diet, niacin, statins, or bile acid resins. Although the adverse effects were seen mainly in the Coronary Drug Project, a secondary prevention trial, 92 long-term follow-up of the nicotinic acid group 9 years after the trial ended demonstrated a 15year decrease in total mortality. 93 Of the 3 agents with adverse effects in the trial, D-thyroxine is no longer used, estrogens are not used for men, and clofibrate is rarely used for lipid lowering. In addition to concern about the possible adverse drug effects, there is also concern about the possible hazards of excessive decreases in cholesterol levels. These concerns have led some highly knowledgeable authorities in cardiovascular epidemiology to recommend that a cholesterol lowering strategy for primary prevention be “put on hold.“94 The salient arguments given for this include an observed association between low blood cholesterol and noncardiovascular deaths in men and women, no association between high blood cholesterol and cardiovascular disease in women, and an increase in non-CHD-related death rates in primary prevention trials. These arguments were addressed and refuted by Stamler et a1.95 Briefly, increased mortality seen in some trials at lower cholesterol levels appears to be a result of other possible contending factors such as smoking and alcohol intake. Also, confounding of this finding by the presence of covert chronic disease, which may decrease total cholesterol levels, should also be considered. The general health of the population studied also will, of course, affect results. For example, in the Honolulu Heart Study, a 23-year follow-up of 8006 men of Japanese ancestry, separate evaluation of the study population by confounding medical conditions (heavy drinking or smoking, chronic non-cardiac disease) or absence of these conditions demonstrated increased all-cause mortality in the low cholesterol group only in the confounding stratum.96 This finding would tend to indicate that low cholesterol without confounding conditions does not produce adverse effects. The trend for increased mortality with lower total cholesterol values usually begins below a level of 160 mg/dL, at about the 10th percentile for middle-aged men and women. 97 Therefore, in primary intervention, in which the target for total cholesterol is just below 200 mg/dL (LDL cholesterol below 130 mg/dL), this issue is rarely faced. In fact, a total cholesterol of 160 mg/dL has not been reached in any cholesterollowering trials so far.98 The more recent lipid-lowering primary prevention trials have relied primarily on statins, and some discussion of their results is warranted.

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There are fewer of these trials than there are of secondary prevention trials because of the higher expected event rate in the latter and probably because of the increased expected compliance of the study population after a coronary event. Also, many of the trials have relied on the identification of coronary artery disease by coronary angiography, which usually mandated only after a coronary event or after symptoms suggestive of myocardial ischemia are seen. Two recent primary prevention trials of note include the West of Scotland Coronary Prevention Study (results published in 1995 and 1998)99,100 and the Air Force Texas Coronary Prevention Atherosclerosis Study (AFCAPVTexCAPS; results published in 1997 and 1998).101,102 In the West of Scotland Trial, 6595 middle-aged men without a history of MI who had high LDL cholesterol (> 252 mg/dL) were evaluated to determine the extent to which reduction of LDL cholesterol influenced CHD risk.99,100 The average follow-up was almost 5 years. To qualify for randomization to statin or placebo, the participants had to have a substantial decrease in LDL cholesterol by diet alone (from > 252 mg/dL before dietary intervention to > 155 mg/dL after a 4-week diet). The treatment regimen was 40 mg/d of pravastatin or placebo. In the treatment group, total cholesterol was decreased by 20% and LDL cholesterol was decreased by 26%; there was no significant effect in the placebo group. Pravastatin reduced coronary events by 3 1% (5.5% of treatment group vs 7.9% of placebo group). Although this is only a 2.4% reduction in total risk, it could impact 12,000 deaths a year in the United States. Morevover, the risk of death from all cardiovascular causes was decreased by 32% (1.6% in the treatment group vs 2.3% in the placebo group, P = .033). No excess of noncardiovascular death was observed in the treatment group. The maximum benefit of about a 45% risk reduction was observed with a 24% reduction of LDL cholesterol. This interesting finding is being followed up in a number of current prospective studies to determine the optimum level of LDL cholesterol to reach for risk reduction. Further reduction did not further decrease coronary risk. The AFCAPS/TexCAPS is a primary prevention trial with participants who had normal to mildly elevated cholesterol levels.101,102 A total of 5608 men (age range, 45-73 years) and 997 women (age range, 55-73 years) who had serum cholesterol levels between 180 and 264 mg/dL (LDL cholesterol 130-190 mg/dL) and low to low-acceptable HDL cholesterol (< 46 mg/dL for men and < 48 mg/dL for women) with triglycerides less than 400 mg/dL were followed up for an average of 5.2 years after randomization to as much as 40 mg/d of lovastatin or placebo.

526

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The study was terminated after the second interim analysis because of the beneficial effect seen. Key findings from this study include the following: (1) LDL cholesterol decreased by 25%, triglyceride levels decreased by 18%, and HDL cholesterol levels increased by 6%. (2) Coronary events (MI, unstable angina, or sudden death) were 37% lower in the treatment group (6.8% in the treatment group vs 10.9% in the placebo group). (3) There was no difference in overall mortality between the 2 groups. (4) There was no indication of excess adverse effects in the treatment group versus the placebo group. (4) There were no differences in effects between women and men. (5) An outcome benefit began within the first year of treatment. The results indicate that, for primary presention, within a few years, there is a significant decrease in coronary events with intervention in subjects with modestly elevated LDL cholesterol levels. Although the many secondary prevention trials of lipid-lowering therapy cannot be extrapolated to primary prevention, studies of changes in coronary artery atheromatous lesions determined by quantitative angiography can apply even to covert disease, as is frequently the case with primary prevention. Numerous studies of serial changes in coronary lesion anatomy have been accomplished in subjects with CHD or with symptoms or stress tests that suggest ischemic heart disease. These studies include the National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study (1984), the Cholesterol Lowering Atherosclerosis Studies (CLASI and II; 1987 and 1990), the Familial Atherosclerosis Treatment Study (1990) the St. Thomas Atherosclerosis Regression Study (1992) the Monitored Atherosclerosis Regression Study ( 1993), the Multicentre Anti-Atheroma Study (1994), the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries ( 1993 and 199.5) the Regression Growth Evaluation Statin Study (1995 and 1996), the Canadian Coronary Atherosclerosis Intervention Trial (I 994) the Multicenter Coronary Intervention Study (I 997) and the Lipoprotein and Coronary Atherosclerosis Study ( 1997). These studies included an initial evaluation of the distribution of coronary lesions and some quantitative measure of severity, an intervention with a lipid-lowering agent, and a follow-up angiogram. Study intervals were 2 to 5 years. Although outcome events other than changes in angiographic lesions were also evaluated, what concerns us here is simply the variation in angiographic lesions based on intervention. The outcomes of angiographic results were usually decribed semiquantitatively (progression, no change, or regression), as average change in the mean percent

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diameter stenosis(lumen diameter of lesion/lumen diameter of normal artery) or as changein minimum luminal diameter (lumen diameter at lesion). In most studies,a computer-assistedevaluationwas neededfor suchmeticulous study.A confoundingfactor in serial studies,asidefrom normal interindividual differencein arterysizeanddistortion producedby the imaging equipment,is the tendencyof the lumen to dilate in response to a developingatheromatousplaqueearly in lesion development.103 Although in earlier trials bile acid sequestrantsand nicotinic acid were used as the major lipid-reducing agents, later trials were focused on statins. A key issue in these trials was the demonstrationof adequate complianceto dietary intervention beforerandomizationto drug therapy or placebo.Thus, well-motivated or compliant study groupswere important for the successfulcompletion of theseinterventions.The CLAS was the first study to demonstratethe regressionof somelesions (16%) associated with a general decreasein LDL cholesterol of 43%.lo4 Some studiesshowedcertain lipoprotein classesto be significant predictorsof progression;for example,in the CLAS, apoplipoproteinC-III contentof HDL was indicative of triglyceride-rich lipoprotein metabolism.lo5 In the Familial AtherosclerosisTreatmentStudy, Lp(a) and the Lp(a)/HDL cholesterol ratio were preductive of baseline percent stenosis,but the effect was substantiallydecreasedby the lowering of LDL cholesterol.106 Meta-analysis of 5 coronary studies demonstratedthat drug and diet intervention decreasedprogressionof CHD by approximately one half and increasedregressionof CHD threefold.lo7The CanadianCoronary AtherosclerosisInterventionTrial, in contrastto other coronary studies, demonstratedthe main benefit in lesions with less than SO%,occlusion rather than in significant lesions.lo8 This has some bearing on possible adverserisk becausethere is increasingevidencethat lesions of 30% to 50%, which are more prevalent than more obstructive lesions, are frequently likely to becomethe culprit vesselsin a future coronaryevent. Considerablestudy has been focusedon the relationship of LDL and other lipoproteins to the endothelium, thrombogenesis,and vascular dysfunction and on the effects of intervention to lower LDL cholesterol levels or possiblechangesin the constitution of the LDL molecule.109It is known that native LDL haslittle effect on cells within the arterial wall. On the other hand, oxidized or acetylated LDL binds avidly with macrophagesand other sites, and producestoxic effects that affect the endothelium,platelet adhesion,platelet-dependentthrombin generation, monocyte recruitment, free radical production, and other proliferative processesthat facilitate atherogenesis. 1lo Small, dense LDL particles

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appear particularly susceptible to oxidation and appear to induce endothelial vasomotor dysfunction.’ ’ l-1 l5 Although endothelial function has been evaluated in conjunction with LDL cholesterol levels in the higher range in most studies, a recent publication by Steinberg et al 116 sheds light on the range of LDL cholesterol levels in which endothelial dysfunction may be present. These investigators found that endothelium-dependent vasodilatation was impaired in subjects in which the total cholesterol or LDL cholesterol level exceeded the 25th percentile (total cholesterol 195 mg/dL). The results of this study suggest that a noninvasive approache to the evaluation of endothelial dysfunction relevant to cholesterol levels may be one way to determine the aggressiveness of lipid-lowering intervention.113 High resolution ultrasonography may be used as just such an approach, by the measurement of the diameter of an artery during endotheliumdependent stimulation. 117J18 This is accomplished with the use of an ultrasound device with a high frequency transducer that is placed over the arm above the brachial artery or over the thigh above the femoral artery. The vessel diameter can be easily identified, and the lumen diameter can be measured. Because hypercholesterolemia produces a diffuse effect on the arterial system, such an evaluation could lead to more specific use of aggressive lipid-lowering therapy in certain cases and represents one more tool in the indirect evaluation of subclinical coronary artery disease. More direct evaluation of the coronary vasculature in young men with familial hypercholesterolemia (including the measurement of myocardial blood flow in the basal state and during dipyridamole-induced hyperemia and the use of positron emission tomography and oxygen- 15labeled water for evaluation) has demonstrated a decrease in coronary flow reserve. ’ I9 In other studies, the association between LDL and platelet metabolism has been studied. In vitro studies have shown that the contact of LDL with washed platelets results in a relative acidification of the platelets, although this effect is maximum at relatively low LDL concentrations (25-50 mg/dL) . 12’ Acidification appears to increase platelet responsiveness to activating agents and thus increase thrombogenesis and adverse effects on the endothelium. The evidence that relatively low concentrations of LDL are needed to produce a maximum effect suggests that there may be interindividual variations in short-term and long-term effects of LDL on platelet pH, which may play a role in susceptibility to atherogenesis. 12’ In summary, there is substantial evidence that LDL cholesterol levels bear on risk for coronary events and atheromatous coronary lesions (and

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other vascular lesions) and increase the propensity for oxidation and other biochemical changes in the molecule. This increase leads to vascular dysfunction by bringing about changes in the vascular endothelium and intima, which increase factors that support oxidation. Recent studies suggest that even LDL cholesterol levels near 130 mg/dL may be above the threshold for such vascular dysruption. Moreover, decreased LDL cholesterol levels have led to beneficial effects on coronary events and changes in coronary vascular lesions and endothelial function. The interrelations of LDL, HDL, and very low density lipoprotein (VLDL) particles are important in the determination of the relative importance of LDL and VLDL in the increasing risk of atherosclerosis and in the determination of the improtance of HDL in the decreasing risk of atherosclerosis. VLDL is produced in the liver and primarily contains triglyceride. As VLDL passes through the circulation, it is converted by biochemical interactions with HDL particles to an intermediate density lipoprotein. Some of these VLDL remnant particles are taken up by the liver, and some of the intermediate density lipoprotein particles, through an increase in cholesterol, a decrease in triglycerides, and a removal of apolipoproteins other than apolipoprotein B (apoB), are converted into LDL. The major apolipoprotein class of VLDL and LDL, apoB, is associated with increased risk for CHD. The major apolipoprotein of HDL, apoA1, is associated with decreased risk for CHD. The role of HDL in decreasing the risk for atherosclerosis has been under considerable investigation. As we have mentioned, there are no guidelines for drug use at present for isolated HDL cholesterol levels below acceptable risk values when LDL cholesterol and triglyceride levels are acceptable. The interventions recommended in that case are exercise, smoking cessation, and weight reduction when applicable. The beneficial effect of HDL in general may reside in its role in reverse cholesterol transport. 122 It is postulated that apoA1 binds at cell-surface binding sites, which leads to translocation of cholesterol from the cell to the plasma membrane. 123 HDL is produced as nascent particles in the liver and small intestine and is composed of a variety of apolipoproteins and phospholipids. Cholesterol is transferred to these nascent particles from triglyceride-rich lipoproteins, and by means of lecithin-cholesterol acyl transferase, the cholesterol is esterified and moves into the core of the HDL particle. HDL is cleared of its cholesteryl esters by two mechanisms. (1) A cholesteryl ester transfer protein transfers some of the cholestryl ester to intermediate density lipoprotein and VLDL in exchange for triglyceride and, ultimately, the cholesterol is returned to liver receptors by means of the LDL receptor. (2) The cholesteryl ester may be taken up 530

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by the liver directly from the HDL molecule.‘** Approximately 75% of cholesteryl ester is ultimately taken up by the liver. In addition to strong epidemiologic evidence for the protective effect of HDL on the risk for atherosclerosis and metabolic studies that demonstrate the role of HDL in reverse cholesterol transport, animal model studies have demonstrated the efficacy of adminstration of HDL or apoAI-liposome complexes to inhibit the progression of atherosclerosis.” A recent study of 4 patients with familial hypercholesterolemia showed that a single intravenous injection of reconstituted proapoAI-phospholipid complexes increased fecal bile salt excretion by 39% and increased neutral sterol excretion by 30%, which suggests that this intervention may have increased cholesterol transport from extrahepatic tissues to the liver.‘*” The key to the efficacy of HDL appears to be its interaction with cholesterol in foam cells of the arterial wall. If this is the case, it may be that the small. lipid-rich plaques, which are most likely to rupture and lead to MI, would be most accessible to cholestreol uptake by HDL. Other recent studies suggest an association between apoA1 and prostacycline. It was recently discovered that apoA1 has prostacycline-stabilizing properties. 125 Moreover, the apoA1 level is markedly lower in patients with unstable angina and acute MI. ‘X This may constitute another link in the chain of evidence to support the protective role of HDL. In connection with this, prostacycline has been shown to preserve myocardial integrity in acute myocardial ischemia.“’ A common finding is that many individuals with CHD have acceptable total cholesterol and LDL cholesterol values but low HDL cholesterol.‘28-130 Miller et a112* found that recurrent events developed in more than 60% of patients with CHD who had guideline acceptable mean total cholesterol levels of 175 mg/dL and LDL cholesterol levels of 115 mg/dL. These findings have led to some questions about how to fit intervention into the guidelines when the only lipid unacceptability is a low HDL cholesterol. Although general calorie reduction helps raise HDL cholesterol values in overweight individuals, a low fat-calorie diet with a decrease in saturated fats will tend to lower HDL cholesterol even further in an individual who is not overweight. On the other hand, although an increase in monounsaturated or polyunsaturated fats will not lower HDL cholesterol, it will tend not to raise HDL cholesterol while is lowers LDL cholesterol still further.‘~(’ Many clinical trials in which HDL cholesterol was raised showed an improvement in the rate of CHD events independent of effects on the lowering of LDL cholesterol or total cholesterol.‘30 The newest NCEP guidelines account for HDL cholesterol levels by the recognition of increased risk with HDL cholesterol below 35 mg/dL DM.

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531

and of decreasedrisk with HDL cholesterol levels of 60 mg/dL and above.31To addressthe issue of HDL cholesterol in these guidelines, Groveret a1131 took a random sampleof 3678men andwomen who were recruited into the Lipid ResearchClinics Prevalenceand Follow-up Studiesand followed up with them for an averageof 12 years,applying the NCEP, Framingham CoronaryRisk Model, andCanadianConsensus Conferencescreeningguidelinesand using receiver-operatingcharacteristic curves for coronary eventsin relation to lipid values.131The results indicated that the ratio of total cholesterol to HDL cholesterol was as accuratea predictor for adverseevents as individual lipid values were. From thesecalculations, Grover et al concludedthat becausethe HDL cholesterolvalue of less than 3.5mg/dL is usedas an indication for clinical attentionin the CanadianConsensusConferenceand NCEP guidelines, the relative importance of HDL cholesterolmay be undervalued, especially with HDL cholesterol valuesbetween 35 and 45 mg/dL. On the basis of their calculations, a total cholesterol/HDL cholesterolratio of less than 4.5 or an LDL cholesterol/HDL cholesterolratio of lessthan 3.2 would be consideredan acceptablecutoff for risk. In recent animal studies,HDL-modifying genesthat may be overexpressed or inactivated in mice have been evaluated.132These genes encodefor apolipoproteinssuch as AI and for proteins that act on the HDL particle to affect cholesteroltransferor storage.It has beenfound, for example,that overexpressionof lecithin cholesterolacyl transferase increasestotal cholesterolby 20% to 60%, mainly in HDL, and prevents diet-inducedatherosclerosis.133 In summary, HDL cholesterolis a strong inverserisk factor for CHD. There is no guideline for drug intervention for isolated low levels of HDL cholesterol(eg, < 35 mg/dl) with acceptableLDL cholesteroland triglyceride levels. Recommendedlifestyle modification in certaincases may increase HDL cholesterol level through exercise,general caloric reduction for overweight patients, and smoking cessation. The total cholesterol/HDL cholesterol ratio or LDL cholesterol/HDL cholesterol ratio may provide as good, if not better, an estimation of risk as the isolated HDL cholesterolvalue. We come now to the questionof isolated triglyceride levels and CHD risk. This has been a controversial subject for the past 2 or 3 decades. Triglyceride per se is not involved in the atheroscleroticprocess but triglyceride levels in the plasma may signal an excessof VLDL, VLDL remnants,or chylomicrons,which containcholesteroland arepotentially atherogenic.Certainpreceptscanbe summarizedhere.(1) Both estrogen and alcohol raisetriglyceride levels, but the effect of alcohol may not be 532

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chronic. (2) As with the LDL particle, chylomicron remnants and VLDL or its remnants can enter the subendothelial space of the blood vessel wa11.134 (3) Except for the effect of estrogen or alcohol, there is an inverse relationship in the changing levels of HDL cholesterol and triglycerides. In multivariate analysis, triglyceride is rarely associated with risk when adjusted for HDL cholesterol level. In the inverse relationship of HDL cholesterol and triglyceride, a low HDL cholesterol level with a high triglyceride level may reflect atherogenic disorders of triglyceride-rich lipoproteins. The triglyceride volume in VLDL may be exchanged with HDL cholesterol, which increases the cholesterol burden of these proatherogenic VLDL particles and increases cholesterol delivery to the arterial wall. Situations in which triglycerides may be high and HDL cholesterol may be low in association with a proatherogenie VLDL or remnant particle include abdominal (central) obesity, diabetes mellitus, and insulin resistance. This combination has sometimes been called “syndrome X.” Because triglyceride and chylomicron remnant levels vary throughout the day, one might speculate that the fluctuations of these levels rather than the fasting triglyceride level, which is now used for evaluation, may be of greater importance in the assessment of potential CHD risk. Indeed, it has been demonstrated that postprandial triglyceride and chylomicron remnants appear to be risk predictors that are independent of other risk factors, including HDL cholesterol. 13s As with HDL cholesterol levels, the NCEP guidelines may fall short with the prediction of risk based on just triglyceride levels. One recommendation for further risk-factor guidelines is to use the LDL cholesterol/HDL cholesterol ratio (or the total cholesterol/HDL cholesterol ratio) in conjunction with the triglyceride level. For example, if the triglyceride level is more than 400 mg/dL and the LDL cholesterol/HDL cholesterol ratio is more than 4, drug intervention may be considered. In this case, nicotinic acid might produce a favorable response by increasing HDL cholesterol and by lowering triglyceride and LDL cholesterol. Alternatively, one of the statins would have similar effects, predominantly on the lowering of LDL cholesterol. The topic of drug therapy will be considered more fully later in this section. There has been increasing attention on the roles of apoprotein levels and subfractions of lipoprotein particles in risk prediction. The relative concentration of the lipoprotein and cholesterol moiety may be important. For example, it has been found that in hypobetalipoproteinemia, in which LDL levels are quite low, the level of LDL cholesterol correlates with levels of fibrinogen, plasminogen activator inhibitor-l antigen, and DM,

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533

tissue plasminogen activator antigen, with increasing levels of the hemostatic risk factors as LDL cholesterol levels are increased.136 On the other hand, the density of the LDL particle itself appears to influence risk. Austin et a1137have characterized 2 phenotypes, A and B. Phenotype B, which is associated with a high risk for CHD, has a predominantly high-density LDL particle that has a particular affinity for the arterial wall, in contast with the low-density LDL particle in phenotype A, a low-risk phenotype. A low HDL cholesterol level, a’ high triglyceride level, insulin resistance, and, frequently, abdominal obesity are also associated with phenotype B. The LDL cholesterol level cannot be used to differentiate phenotypes. It is possible that LDL subtype evaluation may play a role in additional risk-factor assessment when standardization techinques have been accomplished, provided that there is evidence for a significant risk benefit from this additional analysis. In several studies, the values of apoA1 and apoB have been considered as candidates for significant improvement in risk factor analysis.138,‘39 Most of the studies have been observational and retrospective. In one prospective study, after controlling for lipid values and other standard risk-factor covariates, researchers demonstrated independent associations of plasma apoB and apoA1 levels with risk for first coronary events for a 5year period. 139 The measurement of plasma apoB concentrations has been standardized, but the superiority of apoB over the total cholesterol/HDL cholesterol ratio in the prediction of coronary events appears to be modest.139 In a review of retrospective and prospective studies that relate the association of plasma lipoprotein levels with CHD, it was concluded that although levels of apoB and Lp(a) (of which we will comment) were often more strongly associated with coronary artery disease than the standard lipid measures, there were too few prospective studies to make definitive recommendations. 140 Three other lipoproteins are relevant to this discussion. ApoE subtypes have been associated with independent CHD risk.141 Apo E, which is present in chylomicrons, VLDL, and VLDL remnants, is not present in LDL but nevertheless binds to the LDL receptor. There are 3 isofoims of apoE (E2, E3, and IX), which produce 6 phenotypes. Different alleles are associated with variation in plasma triglycerides and LDL levels. For example, LDL levels are increased with the E4 allele. On the other hand, the E2 allele is associated with lower cholesterol levels, possibly because of upregulation of the LDL receptor in the liver, which is in turn associated with a lower rate of transfer of cholesterol-rich remnant particles to the liver. 141 HDL subclasses have been shown to provide variations in CHD risk. Although for years researchers had been investigating 2 subfractions, 534

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HDL2 and HDL3, with the purpose of determining whether there were differences in risk associated with each, recent work with further subtyping is based on the size of the HDL particle. Five subtypes of HDL have been identified with gradient gel electrophoresis. In order from largest to smallest, they are HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c. These studies suggest that the HDL2b subclass, the largest particle, appears to provide the strongest inverse risk. HDL subclass analysis has demonstrated associations with estrogens, alcohol, and body mass. ‘42 For example body mass index appears to correlate with increased HDL3b and lower levels of HDL2b. In postmenopausal women, estrogen replacement is associated with increased HDL3a and HDL2a. Alcohol is associated primarily with increased HDL2b.14’ Further studies in which HDL2 and HDL3 are evaluated suggest that HDL2 is the stronger (inverse) predictor of ischemic heart disease.‘4”T’44 In another study, the 2 smallest HDL subclasses (HDL3b and HDL3c) showed a positive association with CHD.lJS Because of these studies and the work on dense LDL, there is increasing interest in particle size analysis of both LDL and HDL to further evaluate risk.‘46,‘47 Nuclear magnetic resonance (NMR) spectroscopy is being used to profile these particles.‘48 By this technique, the 5 HDL subclasses mentioned previously, the 3 LDL subclasses, and as many as 6 VLDL subclasses can be isolated and analyzed according to size. The value of this analysis is the evidence that, for given lipid and lipoprotein levels, predominance of large VLDL particles and small HDL particles produce an increased risk for CHD, by a factor as high as 15.14” Overall, however, the improvement in CHD prediction is only modest.‘“” It should also be noted that, despite these results, other studies have demonstrated an increased risk in smaller triglyceride-rich VLDL particles.‘50,‘s’ NMR spectroscopy is less time-consuming and labor-intensive than other approaches, which may increase its use. At present, the value of NMR spectroscopy may be confined to the evaluation of patients with recurrent CHD events despite acceptable routine lipid levels, and it is not a practical screening tool for primary prevention. Lp(a) consists of an LDL particle and an attached apolipoprotein(a). Lp(a) competes with plasminogen for binding with plasminogen receptor sites because of a high sequence homology of ape(a) with plasminogen. In case-control studies, Lp(a) levels have been found to be higher in patients with CHD than in control subjects.15? In a recently reported prospective study of carotid disease progression. ape(a) phenotypes of low molecular weight with high antifibrinolytic activity DM,

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were found to be a leading risk factor of advanced stages of atherosclerosis.153 On the other hand, plasma concentration of Lp(a) was useful in the prediction of early atherosclerosis in subjects with high LDL cholesterol levels. Other studies have shown no correlation between Lp(a) levels and risk for CHD.152 The complexity of evaluating the results of Lp(a) studies, aside from study design methodology, collection and storage of samples, and statistical analysis, is the known ethnic variability in distribution of Lp(a) levels and ape(a) isoforms.154 Although in US studies Lp(a) levels are higher in black people than in white people, black people have a lower frequency of smaller ape(a) isoforms.155 It is known that Lp(a) accumulates at the site of atherosclerotic lesions.156 The use of Lp(a) testing for risk factor evaluation, especially primary risk, remains problematical. Standardization of procedure has not yet been affected although the NHLBI has recently awarded a contract for such standardization.154 Presently, the cut-off for “high” plasma Lp(a) concentrations is anywhere from 20 to 40 mg/dL, although investigators in this field usually use a cutoff of 20 mg/dL, especially with the presence of high LDL cholesterol levels.154 The significance of these values in black patients is open to question. Although nicotinic acid decreases Lp(a) levels, studies that indicate the significance of the lowering of Lp(a) levels with the modification of risk have not been accomplished. Through the efforts of the NHLBI, the Centers for Disease Control, and the National Bureau of Standards, lipid determinations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides have been standardized in the United States. For example, the standards require a precision of measurement with a coefficient of variation less than 5%. This means the accurate detection, for example, of a change of total cholesterol greater than 12 mg/dL on the,side of 250 mg/dL or 10 mg/dL on either side of 200 mg/dL. Similar standards are used for the other lipid components that are assayed (HDL cholesterol and triglycerides). LDL cholesterol is not directly measured, but is derived from the other values using the Friedewald formula: TC = HDLC + LDLC + Triglyceride/S. The use of triglyceride/5 is based on the expected ratio of 1:5 for cholesterol-triglyceride concentration in VLDL when triglyceride levels are less than 400 mg/dL. If triglyceride levels are high, the formula is inaccurate and LDL cholesterol concentration must be obtained directly by ultracentrifugation. Although nonfasting samples allow reasonable approximations of 24 hours average total cholesterol and HDL choles-

536

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terol, 14-hour fasting samples are needed to determining usual triglyceride levels and allow for calculation of LDL cholesterol. Recently, capillary blood samples studied with desk top analyzers have been used more frequently to evaluate lipid profiles, as a substitute for venous samples. There appears to be a 5% higher total cholesterol value in capillary samples. 157 Values for fasting HDL cholesterol and triglycerides may also vary considerably; they are usually around 10% higher for triglycerides and 10% lower for HDL cholesterol. The overall bias in one study was found to be 4% above the value obtained with venous blood samples. The screening of capillary blood appears to be a reasonably rapid approach for initial screening, which will allow the use of more standard techniques if abnormalities are found. For example, by screening for either total cholesterol or LDL cholesterol, researchers correctly identified more than 90% of those with LDL cholesterol above 130 mg/dL by venous blood drawing techniques. 157 The approaches to lipid intervention in primary prevention are outlined in Tables 4 through 7. The first step is to ensure that the patient is aware of the significance of lipid levels and the need for serial study. Diet is extremely important. A diet survey by a nutritionist is helpful (Table 8). We advise our patients to provide a list of all food ingested on 2 weekdays and 1 weekend day, including snacks, salad dressings, amounts of butter, and percent of fat in milk. The standard approach to the lowering of both LDL cholesterol and triglycerides in primary prevention is initially a fat intake of less than 30% of calories, with one third saturated fats, one third polyunsaturated fats, and one third monounsaturated fats, and a daily cholesterol intake of less than 300 mg (rule of 3s). For particularly high LDL cholesterol and triglycerides, a decrease of fat calories to below 20% and a decrease of cholesterol to below 200 mg/d is recommended. For high triglycerides, additional recommended measures are reduction of total calories for overweight patients, increased activity, substitution of complex carbohydrates for refined sugars, and avoidance of alcohol. Drug intervention in primary prevention should be used only for high levels of LDL cholesterol or triglycerides (Table 9). We refer readers to an excellent, recent, concise review of the drug treatment of lipid disorders by Knopp.158 The statins are the drugs of choice to lower LDL cholesterol. Their mechanism of action is competitive inhibition of hydoxymethylglutarylcoenzyme A, a precursor of cholesterol, which decreases LDL concentrations by upregulating LDL receptor activity. There are 6 statins available in the United States (atorvastatin, cerivastatin. fluvastatin, lovastatin,

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TABLE

5. Significant

lipid risk factors

and differences

*Based

versus secondary

prevention

goals*

LDL cholesterol z 190 mg/dL HDL cholesterol c 35 mg/dL Triglycerides > 200 mg/dL HDL cholesterol > 60 mg/d

Risk factors

Negative risk factor Primary vs Secondary LDL cholesterol Primary Secondary Both

for primary

Prevention

Goals for Lipidst < 130 mg/dL < 100 mg/dL HDL cholesterol > 35 mg/dL Triglycerides < 200 mg/dL

on NCEP guidelines.31

TSecondary prevention includes individuals with CHD, significant transient ischemic attack, and peripheral vascular disease. LDL, Low-density lipoprotein: HDL. high-density lipoprotein.

coronary

artery

disease,

stroke

or

pravastatin, simvastatin). Maximum plasma LDL cholesterol reduction is anywhere from 25% ( with fluvastatin) to 60% (with atorvastatin). In addition, plasma triglycerides are reduced by 10% to 30% and plasma HDL cholesterol is increased by 5% to 12%. The statin is administered as a single dose, optimally in the evening. Lovastatin may be administered with meals in the morning or in the evening. Statins may have the ancillary effects of decreasing fibrinogen levels and viscosity and activating nitric oxide synthetase. The side effects of statins are minimal and include muscle aches, gastrointestinal complaints, and, rarely, hepatitis. Myopathy may occur rarely and is indicated by a serum creatine kinase of more than 1000 U/L. Periodic evaluation of creatine kinase and hepatic enzymes is recommended. Creatin kinase or liver enzyme values more than 3 times the upper limits of normal are reasons for stopping the medications, even if the patient is asymptomatic. The risk for myositis increases in patients with organ transplants who are on immunosuppressants, especially cyclosporine, and in patients concomitantly receiving nicotinic acid or fibric acid derivatives (gemfibrozil, fenofibrate, and clofibrate). Concurrent use of erythromycin also increases the risk for myositis. Itraconazole increases statin levels. Bile acid resins are relatively “user-unfriendly” because of their grittiness. The 2 resins used are colestipol and cholestyramine, which are given once or twice a day in a suspension of fruit juice. The resins are safe because they are not absorbed. Their mechanism of action is the removal of enterohepatic circulating cholesterol from the intestine through binding and elimination. LDL receptors are increased and LDL cholesterol levels are decreased by 10% to 20%, with a modest increase in HDL cholesterol. 538

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TABLE

6. Primary

prevention

Lifestyle

Modification

Smoking

cessation

in high risk patients

Encourage patient family support

Lipid management AHA Step I diet

Weight control Hypertension control Physical activity pogram Therapy

LDL cholesterol HMG CoA reductase Bile acid sequestrant Triglyceride Fibric acid derivatives Nicotinic acid HDL cholesterol

AHA, Amencan

Target:

< 130 mg/dL

Target:

< 150200

inhibitor

Fibrate or nicotinic acid if triglyceride is elevated HMG CoA if LDL cholesterol is elevated Blood pressure

lipoprotein:

and enlist

(c 30% fat calories, 10% saturated fat, 10% monounsaturated fat, 10% polyunsaturated fat, < 300 mg of cholesterol) Like Step I except < 7% saturated fat, i 200 of mg cholesterol To BMI of 21 to 25 if above 25 < 2.5 g sodium (< 6 g NaCI), limit alcohol 30 minutes 3 times a week

AHA Step II diet

Pharmacologic

to stop smoking

Target: > 4045 possible

i 140/90 < X30/85 < 125/75

mg/dL

mg/dL

with lifestyle

change

if

with diabetes with renal disease

Heart Association; BMI, body mass index: NaCI, sodium HMG, shydroxy-3methylgluteryl; &A, coenzyme A.

chloride;

LDL, low-density

If triglyceride levels are initially high, they may increase because of increased VLDL production by the liver in response to the agent. The resins are excellent drugs to use in combination with statins to lower LDL cholesterol. The main side effects of resins are abdominal bloating and constipation. The use of psyllium fiber or prune juice may minimize these symptoms. Because the resins also bind ingested drugs such as warfarin and digoxin, care must be taken not to administer the bile acid resins within 2 to 3 hours after these other drugs are ingested. Nicotinic acid is the most potent agent used to increase HDL cholesterol levels; it can increase HDL cholesterol levels by as much as 30%. Nicotinic acid may also effectively lower triglycerides. Other effects include the change of small, dense LDL to less atherogenic larger particles and a decrease in Lp(a). The mechanism of action of nicotinic acid is inhibition of free fatty acid mobilization from the periphery, which decreases hepatic VLDL synthesis and also possibly decreases converDM.

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TABLE

7. Nutritional

Lipld Abnormalities Total fat saturated fat Monounsaturated Polyunsaturated Cholesterol Camdrate Protein Addltlonal,

guidelines

(LDL

cholesterol,

Trlglycerldes) < 30% of calories 8%10% of calories 10%15% of calories 10% of calories <3OOmg 55%60% complex carbohydrates 15%2oOm

fat fat

for High

Decrease total calories Curtail alcohol

Triglycerides to reach

BMI of 21-25

Hvwrtension Sodium chloride Same as for triglycerides LDL, Low-density

<6g/d

lipoprotein.

sion of VLDL to LDL. The main side effect is flushing of the skin, which usually decreases after repeated adminstration. This side effect can usually be prevented by administration of 1 adult aspirin 30 to 60 minutes before each niacin dose. Nicotinic acid is started at a low dose that is given twice a day and gradually increased to as much as 3 g/d. Adverse effects include hepatotoxicity, glucose intolerance, and exacerbation of gout. Liver function and blood sugar should be determined periodically. Acanthosis nigricans and diarrhea are also adverse effects that may warrant drug cessation. Long-acting nicotinic acid produces less flushing reactions but may increase hepatotoxicity, and the effect on lipid levels may be lower. Fibrates are the drugs of choice for the lowering of triglycerides and have a strong effect on the raising of HDL cholesterol. These drugs upregulate apoA1 gene expression and the LDL cholesterol gene. Oxidation of fatty acids is increased and triglyceride-rich lipoprotein secretion from the liver is decreased. In addition to the beneficial effects fibrates have on HDL cholesterol and triglyceride levels, they may have variable effects on LDL cholesterol. With high LDL cholesterol levels, fibrates may lower serum LDL cholesterol and increase the buoyance of LDL particles, both of which are favorable effects. If LDL cholesterol levels are low, however, they may be increased by fibrates. Side effects include rash, gastrointestinal symptoms, and liver function abnormalities (less than with nicotinic acid). Fibrates increase warfarin activity in the blood by displacement from albumin-binding sites. They are contraindi540

DM, December

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TABLE

8. Registered

dietitian

services

Evaluate present diet Recommend specific changes in diet Monitor nutrition in follow-up Inform patient of new low-fat products Keep physician informed (patient chart

record,

consult

note to physician)

cated in patients with gall stones. Gemfibrozil has been the most common drug used; it is given in a standard dose of 600 mg twice a day. Fenofibrate, which has recently become available, can be given in graded doses of 67 mg as many as 3 times a day and may cause fewer gastrointestinal side effects. Other therapies include oat bran, soluble fiber, and psyllium, which may modestly lower LDL cholesterol. Postmenopausal oral estrogen therapy decreases LDL cholesterol, raises HDL cholesterol and triglyceride levels, and has been shown to decrease CHD events in postmenopausal women. Hypertension Hypertension is a recognized risk factor not only for CHD but also for stroke, LVH, congestive heart failure, kidney disease, and aortic dissection.159y160 There is excellent evidence from clinical trials that treatment of the lower and middle ranges of hypertension, and of malignant hypertension, decreases mortality and morbidity from cardiovascular disease.16’ For example, a recent prospective study of US physicians showed that hypertension was associated with a two-fold increased risk for total cardiovascular disease, MI, and cardiovascular death.162 In the MRFIT, a 10 l/2-year follow-up of 12,866 men who were randomized to receive special intervention or usual care, of whom 62% had hypertension, mortality rates were lower for the special intervention group than for the usual care group during the follow-up period, although the differences were not statistically significant. 163 However, during the post-trial years, the beneficial difference widened for CHD-related death rates and reached statistical significance for all-cause mortality. It should be emphasized that this was a study in which both comparison groups were receiving antihypertensive intervention. Some of the beneficial results in the later period were attributed to lower thiazide diuretic dosing because diuretics had been shown to be associated with a slightly increased risk of mortality in the earlier part of the study; the increased risk of mortality was possibly a result of dysrrhymias associated with lower potassium levels. Meta-analyses of clinical trials of hypertension therapy have suggested an overall decrease of 35% to 40% of stroke incidence and 14% to 18% DM,

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TABLE

9. Efficacy

of lipid lowering

agents

LDL cholesterol Statins Bile acid sequestrant Nicotinic acid Fibrates LDL, Low-density

lipoprotein:

HDL cholesterol

d-20%60% &15%30% hO%25% slightly 1 or t HDL, high-density

1‘6%15% I-1%5% ?15%30% 1‘10%15%

Triglycerides h%25% 0 or t J20%50% J20%50%

lipoprotein

of CHD.164-166 The current guidelines use SBP of 140 mm Hg or more and DBP of 90 mm Hg or less as the definition of hypertension, although target goals well below these values are recommended for patients with diabetes and chronic renal disease.30 Meta-analyses aside, randomized clinical trials of hypertension therapy evaluated separately have demonstrated efficacy for the reduction of mortality and morbidity, mostly from stroke and not CHD. These studies were generally confined to participants younger than 70 years old. More recent studies on hypertension in the elderly, including the Systolic Hypertension in the Elderly Program (SHEP; 1991), the Medical Research Council in the Elderly (1992), the Swedish Trial of Old Patients with Hypertension (1993), and the Systolic Hypertension in Europe study (1997), have demonstrated the efficacy of drug intervention in the elderly, whether for isolated systolic hypertension or diastolic hypertension. 167,168Moreover, these studies were accomplished with the use of a diuretic alone in 46% of SHEP participants and a calcium channel blocker alone in 59% of the Systolic Hypertension in Europe participants. Of interest was the evidence in SHEP that the patients in the study with type II diabetes benefited more from diuretic therapy than did the patients without diabetes, despite the commonly held precept that thiazide diuretics are potentially harmful for people with diabetes.‘67 These studies also demonstrated that the protective effect of the treatment of the elderly extends to reduction of CHD risk. One of the major issues in the treatment of hypertension is the possibility of a harmful effect of lowering the blood pressure levels too aggressively. Certainly, there is some justification in patients with underlying coronary artery disease, in which diastolic perfusion of the left ventricular myocardium is limited, especially with the additional adverse effect of LVH, present in a substantial minority of hypertensive patients. The current JNC VI guidelines recommend a blood pressure of 130/85 mm Hg or less for patients with diabetes and an even lower blood pressure (5 125/75 mm Hg) for patients with renal parenchymal disease and more than 1 g of proteinuria in 24 hours (Tables 10 and 11).30 Some 542

DM, December

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TABLE

10.

Classification

of blood

pressures

Systolic

Class Optimal Normal High normal Hypertensive Stage I Stage 2 Stage 3 Based

for adults

on the Joint Natlonal

Committee

(mm

Hg)

Diastolic

< 120 c 130 130139

-c 80 < 85 8589

14ck159 16@179 2 180

90.99 10@109 2 110

guldellnes.30

observational studies and clinical trials showed increased adverse cardiovascular events when the blood pressure is lowered below 135/85 mm Hg.169-171 These findings have been mostly confined to patients with established CHD. Other epidemiologic studies and clinical trials analyses show no such J curve. I72 A recent publication from the Hypertension Optimal Treatment Trial indicates no such J curve when various blood pressure targets below 140/90 mm Hg were obtained as end points of antihypertensive therapy. I73 These targeted DBPs were less than 90 mm Hg, less than 85 mm Hg, and less than 80 mm Hg. Less than 2% of the patients entered in the study had a prior MI. At the end of the study, the 3 groups reached mean targeted blood pressures of 144/85 mm Hg, 141/83 mm Hg, and I40/8 1 mm Hg, respectively. There was no evidence of a J curve. There was a slight but nonsignificant increase in cardiovascular deaths and total mortality at the lowest targeted blood pressures, which was not associated with increase in MI or with stroke. In other studies that involved participants without previous CHD, such as the Treatment of Mild Hypertension Study, blood pressures well below 140/90 mm Hg have been reached without an increase in mortality or cardiovascular morbidity, although the Treatment of Mild Hypertension Study did not have cardiovascular events as a primary outcome.174 We can conclude that, at the present time, it is safe to attempt to lower blood pressure to less than 140/90 mm Hg for primary prevention, with a lower target for patients with diabetes, renal parenchymal disease, and significant proteinuria, according to the latest JNC VI guidelines. Another issue is the screening blood pressure to be used. Epidemiologic studies and clinical trial blood pressure determinations at entry are based on several blood pressures taken during a few visits. These are considered casual blood pressures and are not necessarily reflective of 24-hour blood pressures. There has been increased interest in the use of the monitoring of 24-hour ambulatory blood pressure as a DM,

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TABLE earlv

11. Therapeutic approaches initiation of drua theraav

in hypertension

including

Conditlon

Blood

Diabetes Renal insufficiency Heart failure TOD Multiple risk factors CHD No risk factors, no TOD All others from 130/85 mm Hg: initiate

and treatment

and

Pressure

> 130/85

mm Hg

> 140/90

mm Hg

> 160/1OO lifestyle

mm Hg

modification

TOD LVH CHD Heart failure Strohe/TIA Nephropathy Peripheral arterial Retinopathy

risk stratification

Rlsk

disease

JOD, Target organ damage: G-/D. coronary heart disease; sient ischemic attack; CVD, cardiovascular disease. Modified from Joint National Committee guidelines30

factors

Dyslipidemia Smoking Diabetes Age, older than 60 years Men Postmenopausal women Family history of CVD (men younger than 55 years, women younger than 65 years) LVH, left ventricular

hypertrophy;

J/A, tran-

more accurate assessment of risk. 175 This requires careful standardization of the equipment for monitoring and analysis, which has not yet been effectively accomplished on a large scale. Nevertheless, careful studies with locally standardized equipment have demonstrated a closer correlation of 24-hour blood pressure with LVH and cardiovascular morbidity. This correlation related especially to the lack of blood pressure decreases at night in women, but not in men,176,177 and was independent of covariates, including blood pressure itself. The monitoring of ambulatory blood pressure has a role in situations in which “white-coat hypertension” is suspected (ie, the clinic blood pressure is at hypertensive levels, whereas the blood pressure taken at home or at work is norma1).178 Most studies of this phenomenon have demonstrated a relatively benign outcome of white-coat hypertension.179,180 However, in patients with white-coat hypertension, there may be a slightly increased tendency for LVH to develop, compared with patients who are normotensive, but this tendency is lower than that in patients with hypertension. ’ 8’ A major risk consideration in hypertension is the prevalence of LVH, which is high even with mild hypertension.182-186 LVH has been demon544

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TABLE

I.2

Smoking

cessation

guidelines

Ascertain patient’s interest in smoking cessation Quit-smoking mess@e at each visit Set quit-smoking date Call patient on quit-smoking date Counseling by physician and other health care professional Reliance on ancillary procedures: Nicotine patch: 21 mg to 14 mg to 7 mg to stop (over 1012 Nicotine gum: 2 mg or 4 mg

weeks)

strated to be a strong risk factor for cardiovascular events in patients without clinical heart disease. As a target organ effect, the risk of LVH is, of course, different from other risk factors (lipid levels, smoking, diabetes, etc), which do not necessarily reflect target organ damage. The latest JNC VI guidelines acknowledge the increased risk of LVH in individuals with hypertension but reserve evaluation for LVH for individuals with untreated stage I hypertension with no other risk factors and no other target organ damage because earlier drug intervention may be considered if LVH is present. 3o Although Electrocardiography is used for the diagnosis of LVH, it is much less sensitive than echo in the diagnosis of hypertension (5%-10% yield vs 15%-40% yield). However, because of cost considerations, quality control of echo measurements, and logistics of screening, Electrocardiography is still the primary clinical tool for evaluation of LVH. Despite the JNC VI guidelines, there is something to be said for echo evaluation for every patient with hypertension with the presence of other significant risk factors because of the incentive to begin drug therapy sooner, especially in stage I hypertension. Because of the comparative costs of echocardiography versus electrocardiography, it has been recommended that an echo study that is limited to the calculation of left ventricular mass be developed.tg7 Although this suggestion has some justification, the measurement variability in most clinical echo laboratories accounts for a large standard deviation and decreases the efficacy of echo for serial studies that evaluate regression of hypertrophy. The evidence for increased risk of LVH in patients with hypertension for cardiovascular events independent of blood pressure levels suggests that regression of LVH is a desirable target goal. Although many studies of antihypertensive agents have demonstrated regression of LVH with a wide variety of agents (even with the use of nuritional-hygienic therapy alone in stage I hypertension),188-191 t her e is as yet a paucity of data from prospective studies that demonstrates a significant effect of regression on cardiovascular morbidity and mortality and on the risk for CHD, as DM,

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TABLE

13.

Diabetes

mellitus guidelines

Blood pressure Proteinuria or microalbuminuria No proteinuria Fasting BS 2 hr post-prandial BS Hemoglobin A, Lipid, exercise, smoking Carbohydrates Alcohol

To < 130/%5 mm Hg ACE inhibitor Lowdose diuretic < 115 mg/dL < 140 mg/dL < 7% or < 1% above lab normal As indicated in other sections Complex, unrefined, high in fiber 2 equivalent drinks I2 time a week

BS, Blood sugar.

primary prevention. In one prospective study of monotherapy in mild to moderate hypertension (stage I and II), there was a significant reduction in left ventricular mass by some of the agents only in the highest tertile of initial blood pressure, and in the lower blood pressure range, left ventricular mass tended to increase despite the effective lowering of blood pressure. 192 Clinical trials are now underway in which it will be determined whether a decrease in left ventricular mass in hypertension determined by echo will have a significant effect on cardiac events.lg9 Meanwhile, to determine whether aggressive antihypertensive drugs should be initiated rather than nutritional-hygienic modification only, it is recommended that echo assessment for LVH be performed as an initial study in hypertension management for patients in whom stage I hypertension is present and other risk factors are minimal. There may be some question about whether aerobic exercise modifies changes in left ventricular mass because exercise will tend to cause “physiologic hypertrophy.” This issue is not settled but is worthy of a clinical trial. However, the consequences of increased left ventricular mass with exercise do not appear to increase cardiovascular risk. The current JNC VI guidelines recognize “high normal blood pressure” (130-139/85-89 mm Hg) as a classifiable entity.30 Even in this range, the risk for cardiovascular events is greater than that for lower blood pressure (1 lo/70 is optimal). For such high normal blood pressure values, some researchers recommend a more aggressive approach (antihypertensive drugs) after a trial of lifestyle modification if target organ damage is present (ie, kidney damage, LVH, eyeground changes, or evidence for cerebrovascular or cardiac disease).193 There is recent evidence that the treatment of hypertension is inadequate. In the 1988 to 1991 National Health and Nutrition Examination Survey, about one fourth of those patients with a diagnosis of hyperten546

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TABLE

14.

Exercise

and metabolic-cardiovascular

Reduction of blood pressure and heart rate improvement in myccardial oxygen consumption k-creased parasympathetic tone Favorable changes in fibrinolytic system Reduction of obesity Decreased insulin resistance Decreased triglycerides Increased HDL cholesterol Enhanced glucose tolerance

response

demand

sion had a blood pressure of less than 140/90 mm Hg.194 In a recent study of 800 men with hypertension at Department of Veterans Affairs Sites, about 40% had blood pressures of more than 160/90 mm Hg despite an average of 6 hypertension-related visits a year, which indicates the inadequacy of intervention.‘95 As for comparative gender effects, in a recent study in which comparisions were made among effective antihypertensive treatments used in a subgroup meta-analysis of antihypertensive treatment trials, in terms of relative risk for cardiovascular events, treatment benefit did not differ between men and women.‘9h In regard to specific antihypertensive therapy, there is recent evidence that short-acting calcium channel blockers, especially in higher doses, have been associated with increased risk for MI.197 In some metaanalyses, ACE inhibitors appeared to be more effective than other classes of agents in decreasing left ventricular mass.189,190 The clinical outcome benefit remains to be examined. It is important that lifestyle modification be accomplished by all patients. Approximately one third of patients have salt sensitivity of blood pressure. The standard lifestyle modification components are decreased salt intake, increased activity, and weight reduction for overweight individuals. These interventions meld well with lifestyle modification for lipid abnormalities. The associated clustering of hypertension with lipid abnormalities, insulin resistance, glucose intolerance, obesity, low levels of HDL cholesterol, and high triglyceride levels suggests some commonality of pathogenesis. There is substantial evidence that increased insulin levels, which result from insulin resistance, influence arterial resistance and angiotensin activity, both of which may increase blood pressure. In terms of therapeutic approaches, these findings also suggest a commonality of interventions that may have multiple effects on different risk factors for CHD.

Cigarette Smoking Of the “big three” CHD risk factors, cigarette smoking is the most diffiDM.

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cult to treat but the most potentially rewarding, not only for cardiovascular risk but also for other life-threatening illnesses, such as a variety of cancers and chronic obstructive lung disease. Autopsy studies have shown the correlation of smoking with the development of atherosclerosis.1g8,1gg There is a significant decrease in risk for MI shortly after smoking cessation for both men and women, probably because of the effect of smoking on thrombogenesis. 200,201 It has been estimated that smoking has contributed to as many as 30% of all CHD-related deaths in the United States202 Smoking is the most alterable risk factor for premature morbidity and mortality in the United States. Health care costs have been shown to be as much as 40% higher for smokers than for nonsmokers.203 The effects of smoking on factors related to the atheromatous process are many and varied. Smoking is associated with an increase in thromboxane A, generation, predominantly from platelets and prostacycline F,, 204 which suggests accelerated interaction of platelets with the arterial’vessel wall. Long-term smoking has been shown to impair endothelium-dependent coronary vasodilatation independent of the presence of atherosclerotic lesions.205 Even passive smoking has biochemical effects, including deterioration of oxygen delivery and use in the myocardium, coronary vasoconstriction, platelet activation, and endothelial damage. Other effects include accelerated lipid peroxidation, LDL modification that leads to increased oxidation, and accumulation of LDL in macrophages.206$207 The relative risks for passive smoking in the workplace appear to be equal to that for passive smoking in the home. 208 Moreover, there is little evidence that there is a dose response for short-term passive exposure versus long-term passive exposure; the risk differences rest primarily on the intensity of exposure. 209 A recently published meta-analysis of 18 epidemiologic studies indicates a relative risk increase for CHD of 25% for individuals who are exposed to passive smoking compared with those who are not exposed to passive smoking. 210 A significant dose-responsive curve based on intensity of exposure was found. Although somewhat less than 30% of the adult population are smokers, almost half of those who were ever smokers in the United States have quit and more than 30% of current smokers attempt to quit each year. Of interest is a survey published in 1990 that indicated that almost 50% of smokers who tried to quit on their own in the previous 10 years were successful, but less than 35% who used smoking-cessation programs succeeded.21 1 Smoking-cessation programs were just evolving at the time of this survey, and it is possible that with more standardized programs and third party payments, the success rate will increase. 548

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In epidemiologic studies, it has been found that cigarette smoking modifies the association between the change in body mass index during young adulthood and the 25year risk for coronary mortality and virtually negates the effect of body weight on risk,8-14 when smokers and nonsmokers are compared. 212 There is ample evidence that cigarette smoking blunts the tendency to gain weight. This has to be considered in the evaluation of overweight patients who are smokers and suggests that the first intervention in primary prevention should be smoking cessation. Smoking cessation guidelines are listed in Table 12. The target intervention goal of zero cigarettes is easy to identify. The methods are difficult. Physicians have had little training in lifestyle modification. However, there have been recent analyses of smoking-cessation programs that identify the problems and possible solutions. Kottke et al*‘” evaluated 39 controlled trials of smoking cessation. Successful interventions included face-to-face advice by both physician and nonphysician counselors, number of reinforcing sessions, and duration of reinforcing sessions. Even so, the results were not spectacular, although there was a significant 8.4% difference in smoking cessation between intervention and control groups. The interventions averaged 5 contacts with the therapist within 1 month. The use of nicotine gum alone was less successful. There was no study of the use of the nicotine patch. At present, a successful cessation program should result in a 25% to 40% cessation rate that lasts 1 year or more for smokers who participate. (Getting smokers to participate is the main hurdle). Studies of the costeffectiveness of smoking-cessation programs may have some bearing on future third party payers’ support for smoking-cessation programs. One analysis of short-term benefits for MI and stroke in the United States indicates that in the first year, smoking cessation would result in almost 1000 fewer hospitalizations for MI and a little more than 500 fewer hospitalizations for stroke, with the assumption that there is a 1% reduction in incidence rates caused by smoking cessation2t4 Over 7 years, this same 1% reduction in risk would mean a reduction of more than 60,000 hospitalizations for MI. The total savings for all hospitalizations in this 7-year period would be more than $3 billion in health costs. In terms of a single smoking cessation, this would reduce anticipated medical costs by $47 in the first year and by $853 over 7 years. The estimated decline of relative risk for MI with smoking cessation reaches close to 1 by 50 months from the time of smoking cessation, from an initial value of 3 to 4. Another recent study on the use and cost-effectiveness of smoking cessation services under several insurance plans found that smoking cessation rates ranged from 28% of users with full coverage of a behavDM,

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ioral program and nicotine replacement to 38% of users with partial coverage (full coverage for behavioral modification, 50% coverage for nicotine replacement). 215 Because only 2.4% of smokers with reduced coverage used the program and 10% of smokers with full coverage used the program, the estimated percentage of all smokers who would quit smoking per year ranged from less than 1% for partial coverage to 3% for full coverage. It has been estimated that a fully covered smoking-cessation program costs $883 per year per life saved, which is far more cost effective than lipid-lowering or blood pressure-lowering interventions.215 The approach to the treatment of a cigarette smoker is first to ask whether he or she wants to quit. The determination of a quit-smoking date is the first important step of entry into a smoking-cessation program. For those who wish to continue smoking, a quit-smoking message from the physician at each office visit should be standard practice. Many patients are successful using a nicotine patch (21 mg, 14 mg, 7 mg in decreasing steps over lo-12 weeks). Contact with both a physician and another health care counselor, most optimally a behaviorist, is essential. Various behavioral practices may be effective for individual patients, including cigarette fading (going to a lower nicotine brand) and attempts to have the patient place cigarette packages in inaccessable places and smoke the first cigarette later in the day. Discussions with the smoker’s family or significant other are helpful in the attempt at smoking cessation. In an epidemiologic evaluation from the Honolulu Heart Study, it was found that high fish intake decreases the risk for cardiovascular mortality for smokers.216 This decrease was most pronounced for those who smoked more than 30 cigarettes (1 l/2 packs) per day. Nonetheless, the risk of CHD mortality remained increased compared with that of nonsmokers. Individuals who cease smoking tend to have a modest gain in weight. There has been some concern about the possible increase in risk as a result of this slight gain. Any increase in risk is more than balanced by the decreased risk from smoking cessation. A recent epidemiologic analysis indicated a IO-year weight gain with smoking cessation that averaged 10 to 12 lb for women and about 10 lb for men.217 Smoking cessation is one reason behavioral modification should be in the curriculum of every medical school. It is essential that the practicing physician who takes an interest in preventive cardiology learn some behavioral techniques in smoking cessation. Diabetes Mellitus and Insulin Hyperglycemia appears to be an independent risk factor for CHD.218 The effects of glycemic control in individuals with diabetes and modifi-

550

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cation of CHD risk have not been assessed, although microvascular complications of diabetes are improved by strict glycemic control.219 Diabetes mellitus is associated with increased lipid abnormalities and hypertension. Much of the risk of CHD for patients with diabetes is caused by lipid abnormalities, although factors that relate to insulin levels and blood glucose also appear to have some independent role.220 The risks of CHD complications after MI are also higher for patients with diabetes than for patients without diabetes, which indicates the special importance of CHD prevention for patients with diabetes. Diabetes poses a special problem for women. Women with diabetes appear to have a greater difference in lipid abnormalities and CHD events than women without diabetes and men with or without diabetes.22’ Of equal importance. a 6-year follow-up study of patients with diabetes who smoked and patients with diabetes who did not smoke demonstrated a significant increment of risk of cardiovascular mortality as a result of smoking only in women with diabetes.22” Most of this increased mortality was a result of CHD mortality. Even individuals in whom diabetes develops appear to have an increase in risk factors compared with controls in whom diabetes does not develop. In an 8-year follow-up of the San Antonio Heart Study, at baseline, subjects in whom diabetes developed during that 8-year period had higher levels of total cholesterol, LDL cholesterol, and triglyceride, had lower HDL cholesterol levels, and had higher fasting glucose and insulin levels.2’3 When subjects with impaired glucose tolerance without actual diabetes at baseline were eliminated, the greater atherogenic lipid pattern was still evident compared with participents in whom diabetes did not develop. Diabetes appears to affect cardiac structure and function even early in its course. In a study of the cardiovascular status of young patients with insulin-dependent diabetes mellitus (average age, 17.6 years), left ventricular mass, contractility, and blood pressure were increased compared with age-matched controls. 224 In this and other studies, a correlation was found between increased left ventricular mass and microalbuminuria, which suggests a parallelism of alterations in cardiac and renal function. From an epidemiologic viewpoint, the increased cardiac systolic performance may not be salubrious because geometric remodeling patterns with LVH that are associated with increased systolic performance have been shown to increase the risk for cardiovascular events.‘2s In an echocardiographic study, researchers used acoustic densitometry, which allows some assessment of fibrotic changes in the heart, and demonstrated abnormally increased echodensity in asymptomatic nonhy-

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pertensive patients with diabetes and with normal regional and global left ventricular systolic performance and normal maximal exercise test results.226 This suggests a possible increase in collagen deposition, which could eventually affect diastolic performance, microvascular flow, and even oxygen extraction by the myocardium. Insulin appears to increase CHD risk independent of the presence of diabetes. A recently published meta-analysis of prospective populationbased cohorts and nested case-control studies demonstrated a weak positive association of insulin levels and subsequent risk for cardiovascular disease (RR = 1.18, 95% CI = 1.08-1.29).227 One concern about the results of this study was the great number of confounding variables that required statistical adjustment, which made comparisons difficult in the meta-analysis. Insulin affects lipid concentrations and may influence blood pressure and other factors, so statistical adjustment for these factors may eliminate some of the risk that should be attributed to insulin. In a study of 2103 men without ischemic heart disease who were followed up for 5 years, a modest risk of high fasting-insulin concentrations for ischemic heart disease (RR = 1.6) compared with control subjects was found, after adjustment was made for blood pressure, use of medications, family history of ischemic heart disease, and lipid levels.228 High insulin levels in individuals without diabetes are associated with a cluster of metabolic abnormalities, including hypertension, impaired fibrinolysis, impaired-glucose uptake, and dyslipidemia. This finding is especially prevalent for overweight patients with abdominal obesity.229 In contrast to the higher cardiovascular risk associated with diabetes for women, there is a greater prevalence of cardiovascular disease in men with hyperinsulinemia than in women with hyperinsulinemia.230,231 The difference may be partially explained by the increased central obesity in men with high insulin levels, unlike the diabetic state in women, in which an android state and high cardiovascular risk are more prevalent. It is possible that increased abdominal fat, which is more active than fat deposits in the gynoid areas, may lead to insulin resistance and thus raise insulin levels. The question is, which comes first? The primary preventive cardiology approach for patients with diabetes is careful control of glucose with the use of serial blood sugar and hemoglobin A,, determinations and correction of lipid abnormalities (Table 13). It is extremely important, especially for women, that cigarettesmoking cessation be implemented. In patients with hypertension, blood pressure levels should be brought to 13OBO mm Hg, which is below the 140/90 mm Hg guidelines for individuals without diabetes. If significant 552

DM, December

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renal parenchymal disease is present, as evidenced by macroalbuminuria (and some would suggest even with microalbuminuria), target blood pressure levels should be brought down still further to 125/75 mm Hg. The diabetic diet should account for lipid abnormalities, and nutritional guidelines similar to those for hypertriglyceridemia should be used. Alcohol should be avoided, if possible, but should certainly be limited to 1 to 2 drinks a day, with closer evaluation of lipid profiles and blood sugar levels if alcohol is consumed regularly. Exercise and weight reduction may decrease insulin resistance in overweight patients with diabetes. The especially strong risk for CHD in patients with diabetes should provide motivation for the physician and for the patient to adhere to risk modification guidelines. Physical Activity There is incontrovertible evidence that a sedentary lifestyle is an independent risk for CHD. In a meta-analysis of epidemiologic studies of physical activity in the prevention of CHD, Berlin and Colditz2s2 found a relative risk of CHD-related death of I .9 for patients with sedentary occupations compared with those with active occupations.“s2 Several possible mechanisms for the beneficial effects of physical activity on cardiovascular risks have been suggested.233.‘34 These include an antiatherogenic effect of increased HDL cholesterol and of decreased LDL cholesterol and triglycerides; favorable effects on platelet adhesiveness, fibinolysis, and blood viscosity; more efficient cardiac use of oxygen with conditioning; increased vagal tone, which may reduce lifethreatening ventricular dysrhythmias; and reduction of blood pressure.“” Several individual studies are of special interest. In a survey from Eastern Finland, physical activity at work and leisure time was studied with a 7-year follow-up. 23s Low physical activity at work was associated with increased risk for MI in men and women, when age, serum total cholesterol, DBP, height, weight, and smoking were controlled for. When the relative risk for MI was compared with the more physically active workers of the same sex, the risk was higher in women with lower activity than in men with lower activity (2.4 vs 1.5). In comparison with physical activity at work, low physical activity during leisure time was significantly associated with increased mortality, but not with increased incidence of stroke or MI. A characteristic of low physical activity at work was sitting, such as in the following positions: desk worker, watchmaker, assembly line worker with light materials, cashier. general office worker, and foreman. In a more recent investigation of leisure-time physical activity in Finland, a physical activity questionnaire was used to evaluate 1453 men DM,

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(age range, 42-60 years) who did not have cardiovascular disease or cancer and included a 5-year follow-up.236 Maximum oxygen uptake was also measured at baseline. Higher levels of both leisure-time physical activity and cardiorespiratory fitness had a strong inverse association with risk for MI. Leisure-time physical activity was graded as follows (in order of increasing activity): fishing, 2.4 metabolic equivalent (MET); nonconditioning physical activity, 2.7 MET; hunting, 3.6 MET; walking, 4.2 MET; gardening, 4.3 MET; gymnastics, 5.0 MET; rowing, 5.4 MET; bicycling, 5.8 MET; jogging, 10.1 MET. Paffenberger et a1237 examined physical activity and other life-style characteristics of more than 16,000 Harvard alumni (only men at the time) over a 16-year period (from 1962-1978). Exercise that related to decreased mortality included walking, stair climbing, and sports. There was a dose effect in that death rates declined as weekly activity increased from less than 500 kcal/wk to 3500 kcal/wk. Examples of calculations might be of interest for comparison purposes. According to the study calculations, walking a city block (perhaps 200-300 ft) rated 8 kcal, climbing 10 stairs rated 4 kcal, light sports rated 5 kcal/min, and vigorous sports rated 10 kcal/min. A more recent follow-up with a questionnaire by this group showed that moderately vigorous sports activity at the intensity of 4.5 MET was associated with a 23% reduction in risk of death.238 The analysis was based on surveys from the early or mid-1960s in comparison with a follow-up survey from 1977. Decreases in risk were found for increased physical activity, smoking cessation, maintenance of normal blood pressure, and avoidance of obesity. In order of decreasing magnitude of additional years of life and adjusted for other risk factors, these lifestyle and body mass indicators were as follows: (1) moderate sports activity and smoking cessation: 2.49 years of life, (2) physical activity index increased to > 2000 kcal/wk and smoking cessation: 2.07, (3) smoking cessation: 1.46, (4) remained normotensive versus hypertensive: 0.9 1, (5) moderately vigorous sports activity alone: 0.72, (6) BMI remained below 26 versus increased: 0.65, (7) physical activity index increased to > 2000 kcal/wk: 0.37. Clearly, smoking cessation contributes significantly to decreased risk in association with physical activity. In a 23-year follow-up study of physical activity and CHD morbidity and mortality in 8006 middle-aged Japanese-American men, which included evaluations according to tertile of physical activity, Rodrigues et al also demonstrated a graded inverse relative risk for CHD according to tertile using univariate analysis. 239 After adjustment for standard risk factor covariates, however, the relative risk for CHD in the highest tertile of phys554

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ical activity group still remained significantly lower than that for the lowest tertile of activity group (RR = 0.85) although the difference was not statistically significant with the use of 95% CIs. The results suggest that because of the beneficial effect of physical activity on covariate risk factors, adjustment for these risk factors that are beneficially influenced may understate the actual risk reduction from physical activity. How vigorously must one exercise to significantly decrease risk? The MRFIT showed little benefit from exercising beyond a moderate level.“40 On the other hand, there is evidence that activity less than moderate exercise has no impact on lower rates of cardiovascular mortality.241 Because of differering participants and differing conclusions about optimal intensity to decreased CHD risk and the type of exercise needed, the results of the studies discussed indicate that further clarification is needed. Treadmill exercise testing has been used as an isolated means to evaluate physical fitness and consquent risk for cardiovascular mortality. In a study of 4276 men followed up in the Lipid Research Clinics, the duration of exercise and heart rate during submaximal exercise were used to evaluate physical fitness. 242 Follow-up was accomplished for a period of 8.5 years. As with results from physical fitness surveys, individuals with a lower level of physical fitness had a higher risk for death from CHD and cardiovascular disease, after adjustment for age and cardiovascular risk-factor covariates. Based on dichotomization of values for change in heart rate and for time during exercise, the relative risks for CHD-related death and for cardiovascular disease in the lower fitness group were 3.2 and 2.8. respectively. This study suggests that the objective evaluation of physical fitness through stress testing may provide additional risk factor identification. Given the evidence for decreased risk with physical activity, how can risk be modified by a supervised program in primary prevention? For older men, low level activity (walking) has been associated with a reduced risk of death from all causes.23-’ In the context of primary prevention in the office setting, it is helpful if physical activity is evaluated by a standardized questionnaire and a responsive healthcare professional is available to discuss exercise prescriptions with the patient. It is now recommended that physical activity be performed for 30 to 60 minutes 4 to 6 times a week.744 Exercise should include aerobic activities, which minimize blood pressure elevations in comparison with resistive exercises. Aerobic exercises include bicycling, jogging, rapid walking, swimming, and other recreational sports that require movement. There is some training effect from resistive exercises, however, and these exercises can supplement aerobic exercise. In some cases. especially for the elderly or infirm, when aerobic DM,

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exercises may result in falls or are diflicult to accomplish, resistive exercises can be the optimal form of physical activity. Resistive exercises should be done 2 to 3 times a week, based on 8 to 10 exercise sets with 10 to 15 repetitions per set. 244 Physical activity should be measured in total kcal per week. In those who are physically lit, efforts should be made to increase energy expenditure to 3500 kcal/wk, based on the Paffenberger studies and other guidelines.245 Lifestyle modification by the increase of physical activity can be rewarding to the patient, not only in the decreased risk provided but also by an engendered feeling of well-being. The risk for adverse coronary events during exercise is low, especially for individuals without clinical CHD. Although for patients who exercise, the risk for MI is 2 to 6 times higher within 1 hour after exercising compared with those who were sedentary during that hour, the risk is inversely related to the average leisure-time activity of the subjects.245,246 Exercise stress testing is recommended for men older than 35 years and women older than 40 years who wish to begin moderate or severe exercise. Stress testing also provides some information on physical fitness status that may guide exercise prescriptions. A resting ECG is mandatory before a stress test and should be evaluated by the physician before the patient is scheduled for the stress test. Musculoskeletal and respiratory conditions that may limit physical activity must be adequately evaluated. The benefits of exercise on cardiovascular risk and metabolism are listed in Table 14.

Summary The first concern in primary prevention is the physician’s belief that primary prevention is important for all adults and that intervention can significantly affect risk. Given the coronary plaque burden over many years and the importance of the development of healthy lifestyles early in adulthood to decrease coronary plaque burden, there are excellent reasons to begin prevention even with young adults. At the very least, a patient seen for any reason should provide a smoking history, have knowledge of the presence of early CHD in first-degree relatives and measurements of blood pressure, height, and weight, provide evidence for a cholesterol level within 5 years (after age 20 according to NCEP guidelines or in middle age according to ACP guidelines), and be given an assessment of glucose tolerance or diabetes. Information about alcohol intake and physical activity status are also of some importance. Other than height, weight, and blood pressure, during the physical examination, the physician should initially assess the strength of pulses in the lower extremities, evidence for carotid or femoral bruits, and eyegrounds 556

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for retinal arterial changes, and the skin and subcutaneous tissue should be examined for xanthomas and the eyes should be examined for cornea1 arcus and xanthelesma. These elements should be part of any initial examination by a primary care physician and are not extraordinary. In addition to lipid and blood sugar analyses, other evaluations may include blood urea nitrogen and creatinine and electrolytes in patients with hypertension or diabetes or in patients who are on antihypertensive agents. It may be prudent to obtain an ECG for patients who are older than 40 years. The elements mentioned above are the elements of the history, physical examination, and laboratory examination in subjects without a past hisory of CHD and with no clinical evidence for CHD. Primary prevention management begins with a discussion of risk factors with the patient. The key interventions aim at the lowering of blood pressure to at least less than 140/90 mm Hg, the complete cessation of smoking, the lowering of lipid levels to less than 130 mg/dL. the lowering of triglycerides to less than 200 mg/dL (or. some would argue. < 150 mg/dL), and the attempt to keep HDL cholesterol above 35 mg/dL (more than 40 to 45 mg/dL is a better goal) with the use of lifestyle modification For patients with diabetes, strict control of glucose levels is essential to minimize disease of the microvasculature and possibly to minimize progressive renal disease. There are several lifestyle modifications for lipids. For patients with elevated LDL cholesterol, modifications include a less than 30% fat calorie diet and less than 300 mg of cholesterol intake daily, with fat calories approximately equally distributed among saturated fats, polyunsaturated fats, and monounsaturated fats (l/3, l/3, l/3; rule of 3s). The assistance of a dietitian is extremely helpful in this regard. For patients with a low HDL cholesterol, weight reduction (for overweight patients) by calorie control and increased physical activity and smoking cessation will have some modest effect. For patients with elevated triglycerides, a diet similar to that for lowering of LDL cholesterol with the addition of stricter calorie limitation, avoidance of refined sugars, increase in complex carbohydrates, and avoidance of alcohol will be helpful. A decrease in the percent of fat calories to 20% to 25% will be of assistance to those patients with particularly high triglycerides. The treatment of underlying conditions such as diabetes mellitus. hypothyroidism, liver disease, and some renal conditions may also significantly modify high triglycerides. For patients with hypertension, limitation of sodium to 2 gm/d (6 gm sodium chloride), limitation of alcohol to 1 to 2 drinks a day, increased physical activity, and weight reduction are the key lifestyle moditications. DM,

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Smoking cessation requires frequent single or group intervention sessions by both the physician and a second health care professional, whether a nurse or behaviorist, with an attempt to set a quit-smoking date and follow-up visit. Nicotine patches, gum, and clonidine have been useful adjuncts. Exercise testing should be reserved for patients who are older than 3.5 to 40 years who want to begin fairly rigorous exercise programs. Activity programs should include at least 3 sessions a week for 30 minutes with warm-up and slow-down periods. A total of 3500 kcal/wk of exercise activity is recommended. The overweight patient should have a scale and weigh himself or herself every morning after getting out of bed. The purpose of this is not to see weight loss but to guard against weight gain. Diet surveys should include 2 weekdays and 1 weekend day. The key to prevention is physician and patient motivation. Motivation of the patient should include an understanding of the purpose of primary prevention and of the importance of short-term goals (specific short-term goals involve weight target, lipid levels, blood pressure, and smoking cessation date). Proactive health care can save many lives and decrease CHD’ morbidity in the productive years, which should extend well beyond the age of 65 years if appropriate prevention is continued. The authors acknowledge the excellent secretarial assistance of Carmen Trujillo-Garcia.

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