Preventative Cardiology in the Office: Part II
Preventative Cardiology in the Office: Part II
Author: James J. Maciejko, MS, PhD, FACC, Director, Lipid Clinic, Botsford General Hospital, Farmington Hills, MI; and Associate Professor of Medicine, Wayne State University School of Medicine, Detroit, MI.
Peer Reviewers: Sydney Goldstein, MD, Division Head Emeritus, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI; and Jon M. Sweet, MD, Assistant Professor of Medicine, Wright State University School of Medicine, OH.
Editor’s Note—Although mortality rates for coronary heart disease (CHD) have been declining in recent years, CHD still remains the no. 1 cause of death and disability in the United States. The cost of our interventional procedures and drugs to manage symptomatic CHD (e.g., balloon angioplasty, stents, low-molecular-weight heparins, glycoprotein II-b-IIIa inhibitors, and bypass surgery) should lead us to pause and reconsider the benefits of prevention and risk stratification. This issue represents part two in a two-part series that explores the identification of these risk factors and our better understanding of them and provides the primary care physcian effective strategies for intervention. Part two highlights Category II, III, and IV risk factors and provides a summary of the recommendations in order of importance.
Category II Risk Factors
Category II risk factors are those for which interventions are likely to reduce the incidence of coronary artery disease (CAD) events. As with category I risk factors (See Preventative Cardiology in the Office: Part I), they are useful for atherosclerotic cardiovascular disease (ASCVD) risk assessment and should be considered and evaluated. They should also be treated as part of an optimal risk reduction program.
Diabetes Mellitus. People with diabetes mellitus (both type I and type 2) are at increased risk for ASCVD. In the United States, about 90% of all diabetic deaths are due to ASCVD, with 75% occurring as a result of CAD alone.1,2 Recently, Haffner and colleagues reported the results of a Finnish study examining the risk of myocardial infarction (MI), over a seven-year period, in nondiabetic and Type 2 diabetic individuals.3 Nondiabetic people without a prior history of MI had a 3.5% incidence of MI. Nondiabetic individuals with a prior history of MI had an 18.8% incidence of a subsequent event. Type 2 diabetic subjects without a prior history of CHD had a 20.2% incidence of MI, and diabetics with a prior history of CHD had a 45% incidence of a subsequent event. This study clearly demonstrates that Type 2 diabetics without clinical evidence of CHD are at risk of having an MI approximately equal to the risk of a recurrent event in a nondiabetic with CHD. The study also suggests that relative to risk stratification, diabetic patients belong in the same category as patients with existing CHD and should be treated as aggressively in terms of risk reduction.
There are also good data showing that diabetic patients who suffered a MI may benefit more from lipid-lowering therapy than nondiabetic individuals. The results of a post-hoc analysis based on a 5.4 year follow-up of 202 diabetic patients with CHD from the Scandinavian Simvastatin Survival Study (4S) shows a 55% reduction in CHD events in the treatment group.4 This reduction in risk was greater than observed in the nondiabetic population (risk reduction [RR], 32%; P < 0.0001).
Whether improved control of hyperglycemia in diabetics reduces risk of ASCVD is somewhat controversial. However, the results of the Diabetes Control and Complications Trial (DCCT)1 and, in particular, the United Kingdom Prospective Diabetes Study (UKPDS)5 have provided some evidence demonstrating the importance of glycemic control for reducing ASCVD risk. DCCT participants were Type 1 diabetics and UKPDS were Type 2 diabetics.
Over a nine-year period, the DCCT looked at 1441 individuals with Type 1 diabetes who were between 13 and 39 years of age. At the beginning of the study, the participants had no significant complications other than background retinopathy. The patients were randomized into two groups. One group received standard care (1 or 2 injections of insulin daily) and achieved a HbAlc on average of 9%. The other group received intensive care (several small dose injections of insulin throughout the day) and achieved a HbAlc on average of 7%. The more tightly controlled group recorded a 76% reduction in the onset of diabetic retinopathy, a 69% reduction in neuropathy, and a 44% reduction in nephropathy compared to the standard care treatment group.1
UKPDS was a randomized controlled trial that compared the effects of intensive blood glucose control (achieved with either sulphonylurea derivatives or insulin) with conventional treatment on the risk of microvascular and macrovascular complications of diabetes. UKPDS started in 1977 and continued for 20 years. The participants were 3867 newly diagnosed Type 2 patients (median, 54 years) who, after three months of dietary treatment, had a fasting plasma glucose of 6.1-15 mmol/L. Only 0.3% of participants received lipid-lowering treatment and 11.6% were receiving antihypertensive treatment.
End points of this study were any diabetes-related end point (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction) and all-cause mortality. During the trial, the HbAlc was reduced by 11% (from 7.9 to 7.0) in the intensive treatment group compared to conventional treatment and there was a 12% decrease in the risk for any diabetic end point (P = 0.029). RR was 0.84 (95% confidence limits 0.781-1.00; P = 0.052). This included combined fatal and nonfatal MI and sudden death. There was no effect on allcause mortality, and the incidence of stroke was not affected (RR =1.11 [0.81-1.51; P = 0.52]). Likewise, there was no effect on the incidence of limb amputations or death from peripheral vascular disease (RR 0.65 [0.36-1.18; P = 0.14]). Similar to the DCCT, there was an increased incidence of hypoglycemia in the intensive treatment group. Major hypoglycemic episodes occurred on treatment with sulfonylureas in 1.4% of participants, with insulin in 1.8% and on diet alone in 0.7% of participants. Minor hypoglycemic episodes were much more common, occurring in 15-21% of patients treated with sulphonylurea derivatives, in 28% of patients treated with insulin, and in 10% of individuals treated with diet alone. There was more weight gain in the intensive treatment group.
Diabetes mellitus is a major ASCVD risk factor and is associated with changes in other cardiovascular risk factors, including lipids, blood pressure, fibrinogen, platelet activity, and insulin. The clinician should be aware of these risk factors and treat them by diet, improved glycemic control, and drug therapy. Evidence suggests that correction of lipoprotein abnormalities, raised blood pressure (BP), and smoking is beneficial.1,5
Sedentary Lifestyle. The concept that inactivity leads to an increased risk of ASCVD has become generally accepted by healthcare professionals and the public. This has led to physical inactivity becoming a major target for preventative medicine in the United States. It is estimated that 12% of all mortality in the United States may be related to lack of regular physical activity.6 However, no single study provides significant evidence of a causal relation between physical inactivity and ASCVD risk.
During the past half century, approximately 50 studies have suggested an association between physical inactivity and the prevalence or incidence of initial clinical manifestations of CHD, especially MI and sudden cardiac death.7 The diversity in the protocols used in these various studies preclude the collating of the data into a single summary statement. Several findings occurred frequently enough to allow for the formulation of preliminary conclusions. These include: 1) more active people appear to be at lower risk of cardiovascular disease; and 2) moderate amounts of exercise may be beneficial.
Exercise probably exerts its beneficial effect through a variety of mechanisms.8 Physical training improves the myocardial supply/demand relationship, lowers plasma triglycerides, raises HDL-cholesterol, reduces BP, and decreases platelet aggregation. Although no single trial of physical activity in patients with CAD has had sufficient power to convincingly demonstrate a risk reduction, intermediate end points (e.g., HDL-cholesterol and BP) are regularly improved and several meta-analyses of randomized trials support a reduction (20-30%) in coronary disease death with regular aerobic exercise.9,10
Hypoalphalipoproteinemia. There is a strong inverse epidemiologic association between plasma HDL-cholesterol concentrations and ASCVD risk. This relationship is sustained over a wide range of HDL-cholesterol plasma concentrations, and it is estimated that for every 1 mg/dL decrease in HDL-cholesterol, the relative risk for CAD events increases by 2-3%.11 The relationship appears to be equally strong in men, women, and among asymptotic individuals as well as patients with established CHD.
HDL is secreted by the intestine, the liver, and cholesteryl ester-enriched macrophages. The initial form, referred to as nascent HDL, is a precursor to the mature lipoprotein. The particle matures as it acquires unesterified cholesterol from cell membranes during cell renewal or death. The cholesterol obtained is esterified by plasma: lecithin cholesterol acyltranasferase (LCAT), and, as the lipid content rises, nascent HDL become the small HDL3 particles and, eventually, HDL2 particles. The increased cholesterol-carrying capacity of HDL2 particles is thought to be crucial to the process of reverse cholesterol transport, by which HDL particles carry cholesterol from peripheral tissues to the liver for excretion.
HDL-cholesterol concentrations are influenced by family history and by certain lifestyle factors that are also risk factors (cigarette smoking, obesity, physical inactivity). Frequently, low HDL-cholesterol concentrations are accompanied by high levels of triglycerides due to the metabolic relationship involving cholesterol ester transfer between HDL particles and triglyceride-rich lipoproteins.
Many lipid-altering agents and lifestyle factors affect several lipoproteins concurrently, and, therefore, it has been difficult to demonstrate that an independent increase in HDL-cholesterol reduces CHD risk. The HDL Intervention Trial (HIT)12 evaluated the effect of independently raising HDL-cholesterol on recurrence of coronary events in a group of men with CAD, having isolated low levels of HDL-cholesterol, and normal LDL-cholesterol and triglyceride levels. A total of 2500 men were randomized to gemfibrozil (1200 mg/d) or placebo and were followed for seven years. An 8% increase in HDL-cholesterol in the men receiving gemfibrozil was associated with a 22% reduction in the incidence of CHD death and nonfatal MI and a 26% reduction in stroke. HIT demonstrated that raising a low HDL-cholesterol level independent of lowering LDL-cholesterol is important for reducing ASCVD risk. The observation of the Helsinki Heart Study13 demonstrating that a reduction in CAD with gemfibrozil exceeded that expected from the LDL-cholesterol lowering alone, has also been interpreted by some to indicate a therapeutic benefit from raising HDL-cholesterol concentrations.
Nonpharmacologic methods for raising plasma HDL-cholesterol concentrations include exercise, weight reduction, and smoking cessation. Diets rich in mono-unsaturated fats (e.g., olive and canola oils) also raise HDL-cholesterol levels. The most effective pharmacologic agents are nicotinic acid, fibric acid derivatives, and estrogens.
Obesity. Obesity (weighing 40% more than the desirable weight range) is one of the most prevalent health problems in this country. About 30% of the U.S. population is obese.14,15 Epidemiologic studies have observed an increase in mortality from both CHD and stroke with increasing obesity.16,17 Obesity is associated with other ASCVD risk factors including low HDL-cholesterol concentration, diabetes mellitus, hypertension, and increased triglyceride concentration. It is probable that much of the increased ASCVD risk associated with obesity is mediated by these other metabolic abnormalities.
Visceral or central obesity, which can be quantified by the waist-to-hip ratio, is a common form of obesity associated with a particular metabolic syndrome of insulin resistance, low HDL-cholesterol, elevated triglycerides, LDL subclass pattern B, and hypertension. This cluster of related abnormalities is referred to as Syndrome X. The constellation of lipid abnormalities in Syndrome X is designated as the Atherogenic Lipoprotein Phenotype (ALP). ALP has been shown to increase CAD risk.18 A desirable waist-to-hip ratio for men is less than 0.9 and less than 0.8 for women. No study has specifically examined the effect of weight loss or the type of weight loss on CAD events. Obesity is included as a class II risk factor because of the probability that weight reduction will beneficially alter other important risk factors (e.g., lipoprotein abnormalities) that are associated with obesity.
Support, advice, encouragement, and interest from the primary care physician is important for a patient’s success in reducing weight. Changing behavior is difficult and does not occur quickly. Comprehensive behavioral approaches to weight loss can provide significant effect.
Postmenopausal State. CHD is the leading cause of death in adult U.S. women. Annually, there are more than 250,000 deaths from CHD. Lack of estrogen has been implicated as a risk factor for CAD, since the association between surgical or natural menopausal status and CAD was demonstrated.19,20
Most of the population-based studies on hormone replacement therapy (HRT) have demonstrated a 30-50% reduction in cardiovascular and all-cause mortality in current users of estrogen. It has been shown repeatedly both in population-based21,22 and angiographic23 studies that HRT in women with known CAD or with coronary risk factors tend to benefit much more than healthy postmenopausal women without HRT.
After 8.5 years, the Lipid Research Clinic Follow-Up Study found that there was almost a five-fold reduction in death among estrogen users with known CAD at baseline, compared with a two-fold reduction in death among estrogen users without baseline CAD.24 The Nurses’ Health Study (NHS) found that users of HRT who had one or more cardiovascular risk factors had a 50% reduction in all-cause mortality compared with an 11% reduction in HRT users without risk factors.22 In addition, angiographic studies have shown less CAD at baseline in users of HRT25 and lower mortality rates after 10 years of follow-up, with particularly significant findings in women with the more severe CAD at baseline.23 Women who have undergone percutaneous or surgical coronary revascularization also appear to benefit from HRT. Improved long-term survival has been shown for HRT users who have undergone coronary artery bypass grafting26 or percutaneous transluminal coronary angioplasty (PTCA).27 These studies strongly suggested that HRT may be an important issue for the secondary prevention of CAD or in patients with known coronary risk factors.
Despite these observational study data, prospectively randomized trials to address the effectiveness and safety of HRT for the primary and secondary prevention of CAD in postmenopausal women have just been initiated within the past several years. Results from the primary prevention study (Women’s Health Initiative) will become available during the next several years. The results of the secondary prevention study (Heart and Estrogen/progestin Replacement Study [HERS]) were recently published by Hulley and associates.28
The HERS randomized 2763 postmenopausal women with CHD (younger than 80 years), and intact uteri to either 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in one tablet daily or to placebo. The women were followed for an average of 4.1 years, and the primary outcome was the occurrence of nonfatal MI or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, stroke or transient ischemic attack, and peripheral arterial disease. Overall, there were no significant differences between groups in the primary or secondary outcomes. The lack of an overall effect occurred despite a net 11% lower LDL-cholesterol level and a 10% higher HDL-cholesterol level in the hormone group compared with the placebo group (P < 0.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year one and fewer in years four and five. More women in the hormone group than in the placebo group experienced venous thromboembolic events (including MI) and gallbladder disease.28
Based on this finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, it was not recommended to initiate HRT for secondary prevention of CHD. Hulley et al suggested that given the favorable pattern of CHD events after several years of treatment, HRT could be appropriate for women currently receiving this treatment to continue.28 While HRT is not recommended for the secondary prevention of ASCVD, no general recommendations can be given relative to primary prevention until the results of the Women’s Health Initiative Study are completed. Over the next decade, research must be aggressive in defining the optimal timing and duration of HRT, the lowest effective estrogen dose (for cardiovascular risk reduction), and further identification of patients who will benefit most from this therapy. It will be imperative for all physicians, particularly cardiologists, to remain current with the outcomes of pertinent trials and to be cognizant of the rapidly changing pharmacotherapy in this field.
Category III Risk Factors
Category III risk factors are those that are associated with an increased risk of ASCVD, which, if modified, might lower the incidence of cardiovascular events. Primary care physicians should place less emphasis on these risk factors than Category I or II risk factors. Several of the Category III risk factors accompany Category I and II risk factors.
Psychosocial and Behavioral Factors. Many behavioral and psychosocial factors are associated with increased ASCVD risk (see Table). There is increased prevalence of CHD in men, African-Americans, Hispanics, Native Americans, people with less education or income, and single people (particularly those who are divorced or separated).
| Table. Pyschosocial and Behavioral Factors Associated with Increased Risk of Atherosclerotic Cardiovascular Disease |
| Behavioral factors |
Adherence behavior |
| Psychosocial interactive factors |
Excess demand, strain, stress |
| Sociodemographic factors |
Age__________________________________________________ |
The mechanism through which psychological and social issues may influence ASCVD can be divided into two general categories: 1) direct mechanisms exerting their influence through neural endocrine effects; and 2) indirect mechanisms influencing the patient’s adherence to preventative therapeutic strategies. Interventions to improve psychosocial traits can improve adherence to medical regimens and enhance an individual psychological state. Health education programs that are targeted to the specific needs of each patient can improve adherence to risk factor modification strategies (e.g., smoking cessation, improvement in dietary habits). These programs generally consist of three phases; 1) instruction on CHD risk and importance of modification through specific intervention(s); 2) follow-up and support on an individual basis; and 3) small group discussions with peer support. This intervention approach has been successful for improving adherence to treatments for hypertension, smoking, hyperlipidemia, and CAD risk factor reduction.
Hypertriglyceridemia. Despite decades of interest and numerous clinical and epidemiological investigations, the status of the elevated serum triglyceride concentration as a risk factor for CHD remains controversial.29-31 Many prospective studies have identified hypertriglyceridemia (HTG) as a risk factor in univariate analysis, although after adjustment in multivariate analysis for HDL-cholesterol or Apo B, the association is diminished.32-35 High triglycerides are often associated with a low HDL-cholesterol concentration, suggesting that this may be responsible for the increase in CAD risk from HTG. Additionally, HTG is also associated with small, dense LDL particles and high Apo B concentrations. Small dense LDL particles and high Apo B are independent risk factors for CAD.36 HTG is also a common finding in the insulin resistance syndrome (Metabolic Syndrome X).
Reduction of serum triglycerides is correlated with a decrease in CHD risk. In the Stockholm Ischemic Heart Disease Secondary Prevention Study,37 the group treated with clofibrate and nicotinic acid had a significant reduction in the rate of mortality from CHD, which was significantly correlated with the reduction in total triglyceride levels and not with the reduction in cholesterol levels. HTG was the most common lipid abnormality in this study, occurring in 50% of the patients, whereas hypercholesterolemia was present in only 13%. In the Helsinki Heart Study,13 the reduction in CHD resulting from gemfibrozil therapy was largely localized to the subgroup with a triglyceride level of more than 204 mg/dL and a ratio of LDL-cholesterol to HDL-cholesterol of more than five.
Since HTG is commonly associated with low HDL-cholesterol, LDL pattern B (small, dense LDL) and hyperinsulinemia, management of elevated triglycerides should also focus on correcting these accompanying metabolic derangements. Lowering triglycerides will generally raise HDL-cholesterol and convert LDL pattern B to LDL pattern A (normal sized LDL).38,39 Measuring a fasting insulin level, particularly in HTG subjects with obesity and normal fasting glucose levels, can be considered. An elevated fasting insulin level in normoglycemia suggests intervention that will increase insulin sensitivity along with reducing triglycerides. Weight reduction, exercise, and diets lower in carbohydrates (i.e., < 45% of calories) and higher in protein (i.e., 20-25% of calories) can be considered. Certainly, with more marked elevations of triglycerides (> 500 mg/dL), pharmacologic therapy may be necessary and would include fibric acid derivatives, and in nondiabetic, nonhyperinsulinemic individuals, nicotinic acid may be considered.
The 1993 National Cholesterol Education Program (NCEP) guidelines40 define a favorable triglyceride as less than 200 mg/dL with 200-400 mg/dL as borderline-high triglycerides, 400-1000 mg/dL as high triglycerides, and greater than 1000 mg/dL as very high triglycerides. High triglyceride concentrations (i.e., ³ 1000 mg/dL) are associated with an increased risk of pancreatitis. Recently, Miller and associates suggested that the NCEP definition of "elevated" triglyceride levels be lowered to reflect the growing concern about the health effects of elevated lipid levels in general.41 Their research uncovered three independent predictors of CAD events: diabetes mellitus; low HDL-cholesterol levels (< 35 mg/dL); and triglyceride levels greater than 100 mg/dL. Based on their retrospective cohort study of 740 heart disease patients, the researchers emphatically state that "triglyceride levels previously considered normal are predictive of new CAD events. The cutpoints established by the National Cholesterol Education Program for elevated triglycerides (> 200 mg/dL) may need to be refined."
Lipoprotein(a). Lipoprotein(a) (Lp[a]) is a lipoprotein particle consisting of an LDL particle attached to an additional protein molecule called Apo (a).42 Numerous studies in which quantitative immunochemical methods have been used to measure Lp(a) have established that Lp(a) plasma concentrations (range, < 0.1 mg/dL to > 250 mg/dL) are strongly influenced by genetic factors.43,44 Lp(a) concentrations also vary considerably among ethnic groups. The frequency distribution in whites is skewed toward lower concentrations, while the median Lp(a) concentration in blacks is three times as high as in whites.45 Lp(a) concentrations increase by about 8% in women after menopause and estrogen replacement therapy reduces the concentration.42
Observational studies have generally observed that elevated Lp(a) concentrations are associated with CHD,46-51 CAD progression,52,53 restenosis after PTCA,54,55 cerebrovascular disease,56-58 and intermittent claudication.59-61 In a study of MI survivors with Lp(a) concentrations greater than 30 mg/dL, the relative risk was 1.75-fold higher than in subjects with Lp(a) concentrations less than 30 mg/dL.62 Recently, one study did not observe an association between Lp(a) concentrations and risk of MI in men.63
The evidence that Lp(a) is a risk factor for ASCVD is based largely on observational studies. These findings, combined with laboratory investigations demonstrating a variety of proatherogenic effects for this lipoprotein, have led to widespread interest in its concentration and as an important risk factor. Only one study has examined the usefulness of lowering Lp(a) on angiographic CAD progression. Thompson and colleagues reported that decreasing Lp(a) levels by 35% with LDL-apheresis over a two-year period did not affect CAD.64 No benefit from reducing Lp(a) was observed on angiographic progression or regression of CAD. Among conventional lipid-lowering drugs, only nicotinic acid consistently reduces Lp(a) concentrations (20-25% reduction).65
It is clear that additional studies of Lp(a) are required before its role in CHD risk can be resolved. At the present time, screening for Lp(a) is cautiously recommended and only for patients with, or with a family history of, premature ASCVD. Management of patients with elevated Lp(a) concentrations (i.e., ³ 30 mg/dL) should be directed at more aggressively lowering LDL-cholesterol and/or triglyceride concentrations.
Homocysteine. Homocystinuria refers to a group of rare inborn errors of metabolism resulting in high concentrations of plasma homocysteine (> 100 mcg/mol/L) and urinary homocysteine. A characteristic in patients with homocystinuria is premature vascular disease. Plasma homocysteine concentrations can be increased by deficiencies of vitamins B6 and B12, or folic acid.66,67
More than 75 clinical and epidemiologic studies have shown a relation between total homocysteine levels and CAD, peripheral vascular disease, stroke, or venous thrombosis.69-73 The Physician’s Health Study reported that an elevated homocysteine concentration was associated with a 3.4-fold increase in five-year MI risk.74 A recent study examined the relationship between CHD and homocysteine in a prospective cohort of 769 individuals enrolled in the Atherosclerosis Risk in Communities (ARIC) study.75 The participants were originally evaluated during a three-year span (1987-1989) and were followed for an average of 3.3 years. After controlling for a variety of CHD risk factors, only vitamin B6 was independently associated with risk of CHD. The implication of these results is that homocysteine may not be as important as prior research suggests, and more studies are needed to clarify how homocysteine, B vitamins, and ASCVD are linked.
Although elevated plasma homocysteine levels (i.e., ³ 15 mcg/mol/L) have been associated with ASCVD risk, there are no prospective interventional data. However, Rimm and associates68 reported that intake of folic acid and vitamin B6 above the current recommended dietary allowance (400 mg/d and 3 mg/d, respectively) may be important in the primary prevention of CHD in women. Based on the observational data from the Nurses Health Study,68 it would appear that a prudent, healthy diet should contain at least 400 mcg/d of folic acid and 3 mg/d of vitamin B6.
Oxidative Stress. Extensive laboratory data indicate that oxidation of LDL particles accelerates the atherogenic process. Oxidized LDL may facilitate atherosclerotic disease by recruiting T-lymphocytes, circulating monocytes, and stimulating autoantibodies into the subendothelial space of medium- and large-sized arteries.76
There have been a number of recent reports that provide strong evidence that high dietary intakes of antioxidant vitamins can significantly reduce the production of atherogenic oxidized LDL particles and significantly lower CHD incidence. A study by Regnstrom and colleagues77 indicated that there is an inverse relationship between the concentration of plasma LDL vitamin E and the severity of CHD. In 64 male survivors of MI, the lipid-adjusted serum and LDL vitamin E concentrations were significantly lower than in an age-matched control population. Based on the analysis of coronary angiograms to determine stenotic lesions, Regnstrom et al concluded that a low LDL vitamin E content may play a role in the development of stenoses of the coronary arteries and clinical CHD.
Niki and associates78 investigated the interactive effects of three antioxidants (ascorbid acid, alpha-tocopherol, and beta-carotene) and reported that vitamins C and E are the most important hydrophilic and hydrophobic antioxidants that synergistically act against oxidative stress induced by free radicals and active oxygen species. Whereas vitamin E is more effective than vitamin C in scavenging free radicals in lipoproteins, vitamin C reduces the resulting vitamin E radical, thereby breaking the free radical chain reaction. Vitamins E and C are localized in different domains of body tissues and appear to interact at the interface between the lipoprotein and water to protect the lipoprotein from oxidative damage.
The Cambridge Heart Antioxidant Study (CHAOS)79 was a prospective study designed to test the hypothesis that treatment with vitamin E would reduce the risk of MI in patients with angiographic evidence of CAD. In this double-blind, placebo-controlled study, 2002 patients were randomized to receive vitamin E (800 IU/d or 400 IU/d) or placebo. After a follow-up of 510 days (median range, 3-981 days), vitamin E treatment resulted in a reduced rate (47%) of nonfatal and fatal MI. Vitamin E did not affect serum cholesterol concentrations.
These reports add to the building of a substantial scientific basis for the antioxidant hypothesis of CHD. The results from epidemiological and basic research combine to provide strong support for this hypothesis. While no firm recommendations can be given at this time, it appears prudent to supplement the diets of individuals at high risk of CHD with vitamin E (e.g., 200-400 units/d).
Alcohol Consumption. Individuals reporting moderate amounts of alcohol intake have a 50% reduction in CAD risk compared to individuals who do not consume alcohol.80-82 Excessive consumption of alcohol is associated with increased CHD, possibly resulting from misclassification of alcoholic cardiomyopathy as CHD disease or from alcohol’s ability to produce hypertension and increase cardiac arrhythmias.83 Excessive alcohol consumption intake also produces other medical problems that can outweigh its beneficial effects on CHD risk.84 It has been suggested that the reduction in CHD risk associated with alcohol is due to the effect of alcohol alone. For example, alcohol consumption increases levels of HDL-cholesterol and Apo A-I.85,86 More important, alcohol affects several clotting mechanisms including decreasing platelet aggregation,87 lowering fibrinogen levels, and increasing fibrinolytic activities. Through reducing the coagulability of blood, alcohol may be more consequential in mitigating the risk of cardiovascular events (e.g., MI) than the risk of atherogenesis.
Among populations with high cholesterol and saturated fat diets, wine consumption is more strongly related to reduced risk of CHD than total alcohol consumption, and wine intake might explain some of the decrease rate of CHD among the French despite their high saturated fat intake.88 Bioflavonoids have been found in high concentration in red grapes and may provide an antioxidant effect and, therefore, influence CAD risk.89
Identification of patients with a current or potential alcohol problem is an important component of good preventative medicine. A small amount of alcohol (e.g., 1 glass of wine/d or 1 glass of beer/d) may have some protective effects against heart attack. Unfortunately, alcohol can be abused, and it is not possible to reliably predict who is at risk and when a person might suffer acute adverse effects (including accidents) from alcohol consumption. The challenge is to weigh potential benefits against risks for any individual. A blanket recommendation to increase alcohol intake to reduce the risk of heart attack is unwarranted.
Category IV Risk Factors
Although gender, age, and family history are not modifiable, these factors exert their influence on CAD risk, at least in part, through other risk factors previously discussed. CAD risk increases nearly linearly with age and is greater in men compared to women until approximately age 75 when the prevalence is nearly equal in most westernized populations. Below 55 years of age, the incidence of CHD among men is about three times higher than in women. After age 55, the rate of increase in men declines and that in women continues to increase so that the incidence rates in men and women become similar in older people.90
CAD clusters in families, and, therefore, a family history of premature CHD is a definite risk factor. With increasing numbers of elderly patients, the high prevalence of CHD, and increasing levels of therapeutic intervention in older patients, it is important to define premature in relation to the development of CHD. Although age is a continuous variable, cut points are useful and for the purpose of the NCEP, family history of premature CHD is defined as an MI or sudden death before 55 years of age in a father or other first-degree male relative or before 65 years of age in a mother or other first-degree female relative.40
Summary
CHD is extremely prevalent and is preventable. Coronary risk factors are involved in the genesis of atherosclerosis and the occurrence of cardiovascular events. The primary care physician must recognize these risk factors and institute treatment to eliminate or control these factors. The treatment goals for the prevention of CHD and other ASCVD should include (in order of intensity):
| • Smoking cessation;
• Reduction of LDL-cholesterol; |
< 100 mg/dL (secondary prevention) |
| • Control of BP (< 140/90 mmHg);
• Aspirin 80-325 mg/d; • Control of diabetes mellitus (hemoglobin A1c < 7%); • Physical exercise (30 minutes, 3-5 times/week); • Increase HDL-cholesterol (> 35 mg/dL); • Weight reduction (body mass index < 25 kg/m2); • Consider HRT for postmenopausal women without clinical evidence of CHD; • Reduce triglycerides (< 200 mg/dL); • Limitation of alcohol intake; • Consider supplementing diet with vitamin E (200-400 units/d) and folic acid (400 mcg/d). |
For post-MI patients, in addition to the aforementioned recommendations, consider:
• Beta-blocker therapy;
• ACE-inhibitor therapy, particularly for patients with left ventricular ejection fractions < 40%.
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