Protecting Against Heart Disease
Alcohol, Cholesterol, and t-PA
Researchers have long known that moderate drinking-one or two drinks a day-reduces the risk of heart attacks. Compared with teetotalers, moderate drinkers have a 30% to 40% reduction in cardiovascular mortality. Alcohol is known to have beneficial effects on levels of high-density lipoprotein (HDL) cholesterol. It may also have beneficial effects on levels of tissue-type plasminogen activator (t-PA), a major component of the fibrinolytic system. Thus alcohol may affect the pathogenesis of myocardial infarction in two ways: by reducing atherosclerosis via HDL cholesterol metabolism, and by reducing the risk of coronary thrombosis via fibrinolysis.
A group of researchers at Boston’s Brigham and Women’s Hospital studied 631 apparently healthy male physicians who participated in the Physician’s Health Study of heart disease risk reduction. A direct association was found between alcohol consumption and plasma levels of t-PA antigen, an indicator t-PA levels. Mean plasma levels of t-PA antigen for daily, weekly, monthly, and rare or never drinkers were 10.9, 9.7, 9.1, and 8.1 ng/mL, respectively. Thus, physicians at one end of the scale (who classified themselves as daily drinkers) had about 35% more t-PA antigen than physicians at the other end of the scale (who reported drinking rarely or never). The association was independent of lipid levels (total cholesterol and HDL cholesterol) and independent of nonlipid risk factors (age, body mass index, exercise frequency, systolic and diastolic blood pressure, and parental history of CHD).
Do these results indicate that people should be advised to drink? The leading investigator, Boston’s Paul Ridker, was quoted by the press as saying that physicians shouldn’t advise anyone to drink in order to cut heart disease risk; indeed, smoking prevention is “number one through number seven” on Ridker’s cardiac risk-reduction list. Ridker et al. are continuing their research on alcohol and t-PA, hoping to reproduce the activity of alcohol on t-PA without the side effects of alcohol. According to Ridker, there appear to be certain common drugs with the same beneficial effects.
In a editorial comment in the Journal of the American Medical Association, Pearson and Terry said that the relationship between alcohol and total mortality has a “J” shape, with high levels of consumption associated with increased mortality. An estimated 100,000 excess deaths annually are alcohol related-primarily accidents, homicides, cirrhosis, and hemorrhagic stroke-with these excess deaths occurring in 15- to 45-year-olds. On the other hand, perhaps 80,000 deaths-primarily due to coronary artery disease-can be attributed to abstinence, with these deaths occurring in people aged 45 years and older. “Although we agree that public health recommendations cannot indiscriminantly advocate alcohol consumption,” said Pearson and Terry, “we wonder if physicians, on a case-by-case basis, could be the solution to this conundrum … Since alcohol will continue to be available, the physician has the key role in ensuring that its well-documented detrimental effects are minimized, allowing the remainder of the adult population to receive its cardiac-protective benefits.”
Estrogen, Progesterone, and the Lipid Profile
Estrogen replacement therapy in postmenopausal women is known to improve the lipid profile-increasing high-density lipoprotein cholesterol, reducing LDL cholesterol-thus reducing the risk of heart disease. But what is the effect of progesterone on lipid levels and the risk of heart disease or cancer? According to medical investigators at the University of Maryland and University of California, San Diego, estrogen plus progesterone has a beneficial effect on the heart, and natural progesterone may offer a better benefit/risk ratio than synthetic progesterone.
The investigators reported the results from the $22 million Postmenopausal Estrogen/Progesterone (PEPI) trial begun by the National Institutes of Health in 1987. The 3-year placebo-controlled PEPI trial involved 875 healthy postmenopausal women (aged 45 to 64 years) who were given either estrogen alone, estrogen with synthetic progesterone (two different formulations) or estrogen combined with a plant-derived micronized progesterone. This is the first large-scale human trial of the natural progesterone, which has the same structure as human progesterone.
Compared with the placebo group, all subjects in the active treatment groups showed a significant elevation in high-density lipoprotein cholesterol. However, effects on HDL cholesterol were better in the natural progesterone group than in the synthetic progesterone groups. Estrogen alone increased high-density lipoprotein by 6 mg/dL, and estrogen/synthetic progesterone increased high-density lipoprotein by 2 mg/dL, with estrogen/natural progesterone falling in between. Women with the greatest rise in high-density lipoprotein reduced their risk of heart disease by 25%, said the investigators. Both active and placebo groups showed a reduction in low- density lipoprotein cholesterol, but the placebo group showed a much smaller rise.
What about adverse effects? Approximately one third of the women taking estrogen alone showed possible precancerous changes in the endometrium, necessitating drug withdrawal, while none of the women taking a combination estrogen/progesterone showed any such changes. There were no increases in the incidence of cancer, although the investigators noted that the trial did not run long enough to permit any conclusions about the risk of breast cancer. None of the subjects showed any alteration in blood pressure, and weight changes were the same in the hormone-treated groups as in the placebo group.
Micronized progesterone is used abroad, but it is not available in the United States (although apparently many women in the trial who wanted to continue taking the progesterone have been able to get it through such sources as mail-order houses selling so-called natural medicines). Despite the evidence that hormone replacement therapy (HRT) reduces the risk of heart disease, only 15% to 30% of postmenopausal women take these hormones. There will be 60 million American women 45 or older by the year 2000, and hormone replacement therapy could have a tremendous impact on their health and longevity.
Hypertensive Crisis After Discontinuing an ACE Inhibitor
Angiotensin-converting enzyme (ACE) inhibitors are widely used for reducing blood pressure in patients with hypertension. These agents act by blocking the conversion of angiotensin I to angiotensin II, thus interfering with the renin-angiotensin-aldosterone system involved in the control of blood pressure, cardiac and renal blood flow, and salt and water balance. ACE inhibitors reduce blood volume and pressure, improve blood flow to vital organs, limit cardiac damage following myocardial infarction (MI), suppress arrhythmias, improve symptoms of congestive heart failure, reduce certain factors for cardiovascular disease (elevated insulin, renin, and lipid levels) and protect against atherosclerosis. They do have side effects, however, which range from the annoying (ACE inhibitor cough) to the disastrous (fetal damage when taken during pregnancy). Recently McAlister and Lewanczuk reported on another possible disastrous side effect: hypertensive crisis after drug withdrawal.
McAlister and Lewanczuk described a 52-year-old man who manifested severe hypertension after abrupt withdrawal of ACE inhibitor therapy. His blood pressure had been well controlled on 30 mg of lisinopril per day (Zestril / Stuart, Prinivil / Merck); however, he had forgotten to take the drug for the 3 days before admission. On presentation he had an acute inferior myocardial infarction, a blood pressure of 240/140 mm Hg, and a pulse rate of 75 beats per minute. He had grade II hypertensive retinopathy and a fourth heart sound, although his apex was normal and there was no evidence of neurological compromise, peripheral vascular disease, or renal bruits. Serum potassium was 4.8 mmol/L, creatinine was 115 mol/L, and serum renin was subsequently reported at 72.7 ng/L (normal 3.5 to 14.5 ng/L).
The patient was treated with intravenous metoprolol (10 mg), nitroglycerin (70 g/min) and morphine (9 mg), but his blood pressure did not improve. Intravenous (IV) enalaprilat (0.625 mg) was tried, with good effect (blood pressure decreased to 180/94 mm Hg). After blood pressure control, the patient was treated with aspirin, streptokinase, and IV heparin. He eventually required coronary angioplasty. Blood pressure was controlled with lisinopril 10 mg daily and metoprolol 100 mg twice daily.
According to McALister and Lewanczuk, suppression of the negative feedback loop with an ACE inhibitor results in an increase in serum renin. When the ACE inhibitor is abruptly discontinued, the result could be unopposed renin action, leading to accumulation of angiotensin II and therefore systemic vasoconstriction and hypertension. “Since use of ACE inhibitors is widespread, many patients could be at risk of such rebound hypertension,” said the investigators. “We therefore argue for caution in ACE-inhibitor withdrawal.” Tapering the drug during withdrawal may be necessary, as it is with other antihypertensive medications, including beta- blockers and central alpha-agonists.
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