Coronary heart disease in women: battle is won, but the war remains.

According to the most recent report of the US National Heart, Lung, and Blood Institute, mortality from coronary heart disease has declined in women from one in three to one in four. Due to massive campaigning efforts in educating the medical community and the general public, coronary heart disease has become increasingly recognized as a woman's disease. Indeed, it is the number one killer in women, exceeding cancer and infectious diseases. Numerous observational studies, clinical trials, and reports have indicated that there are gender-specific differences in the presentation, diagnosis, treatment, and outcomes of coronary heart disease. One common theme, not only in United States, but world-wide is the underutilization of known and validated medical and interventional therapies in women compared to men. Even though previously conducted large, randomized controlled trials had limited numbers of women, recent large scale cardiac trials in women have enabled the development of evidence-based guidelines for coronary heart disease diagnosis and management in women. Importantly, menopausal hormone therapy and antioxidant vitamin therapy do not protect post-menopausal women from coronary heart disease. Aggressive life-style and pharmacologic management of known coronary risk factors in women should be a top priority to improve coronary heart disease morbidity and mortality. Research data continue to emerge to fill the gaps of how gender affects atherosclerosis; in the meantime, continued patient and physician education to increase awareness of coronary heart disease may help to eliminate some of the gender-based disparities in the delivery of coronary care to women.

From adrenoceptor mechanisms to clinical therapeutics: Raymond Ahlquist, Ph.D., 1914-1983.

Identification of two distinct types of adrenotropic receptors, alpha and beta, by Raymond Ahlquist provided the scientific basis that enabled the development of drugs to selectively block adrenoceptor function. These pharmacotherapeutic advances have improved the care of patients with coronary and hypertensive cardiovascular disease.

Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease.

OBJECTIVES: This study sought to determine the independent association of renal insufficiency with cardiovascular risk among women with known coronary heart disease (CHD). BACKGROUND: Although patients with end-stage renal disease and proteinuria are at high risk for cardiovascular events, little is known about the cardiovascular risk associated with moderate renal insufficiency. METHODS: The Heart and Estrogen/progestin Replacement Study (HERS) was a clinical trial among 2,763 women with coronary disease who were randomized to conjugated estrogen plus progestins or identical placebo and followed for a mean of 4.1 years. Women were categorized as having normal renal function (creatinine < 1.2 mg/dl; n = 2,012), mild renal insufficiency (1.2 mg/dl to 1.4 mg/dl; n = 567) and moderate renal insufficiency (>1.4 mg/dl; n = 182). We examined the independent association of renal function with incident cardiovascular events including CHD death, nonfatal myocardial infarction, hospitalization for unstable angina, stroke and transient ischemic attacks. RESULTS: Compared with women with normal renal function, those with mild and moderate renal insufficiency were older, more likely to be black, have a history of hypertension and diabetes and have higher serum levels of triglycerides and lipoprotein(a). After multivariate adjustment, both mild (relative hazards [RH] = 1.24; 95% confidence interval [CI]: 1.0 to 1.5) and moderate renal insufficiency (RH = 1.57; 95% CI: 1.2 to 2.1) were independently associated with increased risk for cardiovascular events compared with women with normal renal function. CONCLUSIONS: Renal insufficiency is an independent risk factor for cardiovascular events in postmenopausal women with known coronary artery disease. Renal function may add helpful information to CHD risk stratification.

Percutaneous transluminal coronary angioplasty in women compared with men.

OBJECTIVES: This study compares in-hospital and long-term outcome after angioplasty in women and men. BACKGROUND: The recognition that coronary artery disease is the most common cause of death in women has increased interest in outcome studies of coronary artery disease in women. METHODS: Patients who had previous coronary revascularization and those who underwent angioplasty in the setting of acute myocardial infarction were excluded. Angioplasty was performed with standard methods. Clinical data were retrieved from a clinical data base and analyzed with standard statistical methods. RESULTS: There were 2,845 women and 7,940 men. The women were older (62 +/- 11 vs. 57 +/- 10 years) and had more hypertension (54.5% vs. 40.1%), diabetes (19.3% vs. 11.7%), grade III to IV angina (71.5% vs. 58.4%) and congestive failure (4.3% vs. 2.1%) than men (all p < 0.0001). More men had a previous myocardial infarction (35.4% vs. 31.0%) and were taller and weighed more (all p < 0.0001). The men had lower ejection fractions and more multivessel disease (31.0% vs. 25.2%) (both p < 0.0001). In women there was a trend toward more Q wave myocardial infarctions (1.1% vs. 0.75%, p = 0.10), and hospital mortality was higher (0.7% vs. 0.1%, p < 0.0001). Angina at follow-up was more common in women 40.2% vs. 26.7%, p < 0.0001). The multivariate correlates of in-hospital death were short stature, reduced ejection fraction and multivessel disease, with trends for older age and female gender. Five-year survival was 95% in men and 92% in women (p = 0.0002). However, female gender was not a multivariate correlate of long-term survival and was accounted for by other characteristics, primarily age. The multivariate correlates of long-term survival were older age, congestive failure, reduced ejection fraction, multivessel disease, diabetes, hypertension and a trend for severe angina. No difference between women and men was noted in long-term freedom from myocardial infarction. There were more additional procedures in men than in women. CONCLUSIONS: Despite higher in-hospital mortality, long-term mortality and clinical outcome were similar in both genders when age and body habitus were accounted for.

Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.

The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Prevalence of silent myocardial ischemia and arrhythmias in patients with coronary heart disease undergoing gastrointestinal tract endoscopic procedures.

BACKGROUND: Since the introduction of gastrointestinal tract endoscopic procedures, there has been concern about cardiovascular complications, especially in patients with coronary heart disease. Although, in general, these procedures are safe, previous studies have documented perturbations in blood pressure, heart documented perturbations in blood pressure, heart rate, and oxygen saturation, as well as the occurrence of arrhythmias and nonspecific ST-segment electrocardiographic changes during such procedures. No studies, however, have specifically addressed the prevalence of silent myocardial ischemia and arrhythmias in patients with well-established coronary heart disease. METHODS: During a 15-month period, 25 hospitalized patients with well-defined coronary heart disease underwent continuous ambulatory electrocardiographic recording during endoscopic procedures requiring intravenous sedation, as well as during a prolonged baseline period. All patients were considered clinically stable, although 92% were categorized as being at intermediate or high coronary risk by standard risk stratification criteria. Eleven patients (44%) had had previous myocardial infarction, and 68% reported a history of angina. RESULTS: Although 24% of patients had one or more episodes of electrocardiographic ischemia during the recording periods, no patient had evidence of ischemia exclusively during the endoscopic procedure. Arrhythmias were no more frequent during the endoscopic procedures than during a corresponding baseline period. Symptomatic angina or serious arrhythmias did not occur during the procedures. CONCLUSIONS: Our data suggest that endoscopic procedures in patients with stable but severe coronary heart disease, when performed with standard medications, monitoring, and techniques, rarely result in silent or symptomatic myocardial ischemia or serious arrhythmias. In addition, although asymptomatic minor arrhythmias are common during endoscopic procedures, their occurrence appears less frequent than during daily hospital life.

Response to exercise in patients taking psychotropic drugs. Arrhythmias and the QT interval (QT wave peak).

Psychotropic drugs may prolong the QT interval, potentially predisposing to ventricular arrhythmias and/or sudden death. Exercise prescribed as therapy for depression may also prolong the QT interval and augment arrhythmia risk. To determine QT-interval (QT wave peak, or QTPK) response to exercise in patients receiving psychotropic drugs, treadmill exercise testing was performed on 20 mentally competent psychiatric inpatients clinically free of heart disease. Twenty-four-hour ambulatory ECGs were performed within one day of exercise testing to detect arrhythmias during routine daily activities. Exercise test results for psychiatric patients were compared with those of normal subjects receiving no medication. Separate regression lines relating heart rate of QTPK interval, calculated for each group, showed no significant difference. No serious arrhythmias occurred during routine daily activities or exercise. Patients without heart disease taking psychotropic drugs have appropriate QTPK-interval shortening with exercise.

Uncomplicated acute myocardial infarction: long-term management.

The components of long-term management of the patient recovered from uncomplicated myocardial infarction include identification and alteration of nonatherosclerotic factors that might increase the risk of early reinfarction or sudden coronary death, alteration of modifiable coronary atherosclerotic risk factors to prevent progression or induce regression of the atherosclerotic process, and optimal restoration and maintenance of residual cardiovascular function to help improve the quality of life of the patient.

Is there a bias against performing coronary revascularization in women?

This study compares referral to coronary revascularization after diagnostic cardiac catheterization in 8,133 women and 25,785 men. Although gender played a role, angiographic severity of coronary disease was the most important determinant of the selection of patients for revascularization.

Education of the patient with cardiac disease in the twenty-first century: an overview.

The current status of education, behavioral change, and use of technology identifies a need for professionals who can develop interactive educational programs and apply existing techniques in a cost-effective manner. The general public, including patients with cardiac disease, are sophisticated consumers of information technology and demand quality production. The challenge is to train specialists to produce educational programs, to instruct health professionals in use of these programs, to deliver appropriate messages, to teach needed skills to patients with cardiac disease, and to evaluate the outcomes. Unless incentives to restore cardiac patients to an optimal functional status with few recurrences and complications are as tangible as are incentives for treating acute cardiac illnesses, the appropriate use of technology to educate patients with heart disease is unlikely to develop. However, the trend to increased ambulatory care under prospective payment systems makes it likely that technology will be applied to improve the efficiency in maintaining health and preventing acute illness. The potential benefits to the nation are substantial.

Design and methods of the Raloxifene Use for The Heart (RUTH) study.

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop.

The value of serum total cholesterol measurement in predicting coronary heart disease (CHD) is well established in middle-aged men, but has been questioned in middle-aged women and older people of both sexes. To address this, the most recent follow-up data from 25 populations in 22 US and international cohort studies were presented and analyzed at a recent National Heart, Lung, and Blood Institute (NHLBI) workshop. Crude relative and absolute excess risks of fatal CHD were determined for individual studies and pooled across studies to determine pooled risk estimates. Serum total cholesterol and low-density-lipoprotein (LDL) cholesterol levels predicted fatal CHD in middle-aged (< 65 years) and older (> or = 65 years) men and women, though the strength and consistency of these relationships in older women were diminished. High-density-lipoprotein (HDL) cholesterol levels inversely predicted CHD in middle-aged men and women and in older women, but not in older men. Data for minority groups and for overseas populations were similar to those for white people in the United States. Relative risk estimates were generally lower for older than for middle-aged subjects, but absolute excess risk was greater. Older people and middle-aged women with elevated cholesterol levels are clearly at increased risk of coronary disease; whether this risk can be modified by dietary or drug therapy, and at what level intervention is appropriate, must not be determined.

Cardiovascular disease in the elderly.

The current worldwide explosive increase in the numbers of older persons is unprecedented in history. In the 1990s and beyond, the preponderance of patients with cardiovascular illness will be elderly, with a substantial subset among the frail elderly, 85 years old and older. Cardiovascular disease remains the leading cause of death and disability in this population, and cardiovascular risk increases steadily with age. Pascal defined old age as "just a time that is farther from the beginning and nearer to the end." Elderly persons, with and without cardiovascular disease, vary widely in their physical, behavioral, cognitive, and emotional functioning; severity of illness; and expectations from medical care. The challenge to the clinical and research communities alike is to delineate the appropriate components of preventive, diagnostic, and therapeutic care for elderly cardiac patients in our society, interventions that are likely to relieve suffering, restore function so as to limit disability and dependency, and maintain a dignified and meaningful life-style for the end years of life. Major societal strides have been made in redefining both the onset of old age and its limitations. The eighteenth century poet, Robert Burns, wrote of his fears that he would be 45 years old at a time when life expectancy was 40 years; he saw himself as being weary, wrinkled, creeping, and joyless. For, ance that five-and-forty's speel'd, See crasy, weary, joyless Eild, Wi' wrinkled face, Comes hostin', hirplin', owre the field, Wi' creepin' pace. Burns died at the age of 37 years. A more attractive option is offered by Abraham Joshua Heschel, 1907-1972. According to all the standards we employ ... the aged person is condemned as inferior. ... Conditioned to operating as a machine for making and spending money, with all other relationships dependent upon its efficiency, the moment the machine is out of order and beyond repair, one begins to feel like a ghost without a sense of reality. ... Regarding himself as a person who has outlived his usefulness, he feels as if he has to apologize for being alive. May I suggest that ... old age be regarded not as the age of stagnation but as the age of opportunities for inner growth. ... The years of old age ... are indeed formative years, rich in possibilities to unlearn the follies of a lifetime, to see through inbred deceptions, to deepen understanding and compassion, to widen the horizon of honesty, to refine the sense of fairness.

Venous thrombosis in relation to fibrinogen and factor VII genes among African-Americans.

We evaluated the relation between venous thrombosis and plasma fibrinogen levels, the HaeIII and BcI polymorphisms of the beta fibrinogen gene, and the MspI polymorphisms of the factor VII gene in a case-control study of African-Americans. The study included 91 venous thrombosis cases and 185 control subjects obtained from a hospital in Atlanta, Georgia. High plasma fibrinogen was associated with increased risk of venous thrombosis, but the finding was not statistically significant. There was little association between the HaeIII polymorphisms and the BclI polymorphisms and the risk of venous thrombosis. The prevalence of the M2/M2 genotype of the factor VII gene was higher among cases than controls, but the difference was not statistically significant. The prevalence of the HaeIII H2 allele and the BclI B2 allele of the beta fibrinogen gene, both of which have been associated with slightly higher levels of plasma fibrinogen in most studies, is considerably lower among African-Americans in this study than it is among Whites in the United States and among Northern Europeans. The study is limited by its small size. However, despite this limitation, it supports the belief that increased plasma fibrinogen levels are associated with increased venous thrombosis risk. The study also indicated that the HaeIII and the BclI polymorphisms of the beta fibrinogen gene and the MspI polymorphisms of the factor VII gene are not strong determinants of venous thrombosis.

Exercise testing and training of the elderly coronary patient.

The majority of US patients with clinical evidence of coronary heart disease are elderly. Appropriately prescribed and designed exercise training can improve physical and psychologic functional status and encourage maintenance of an independent life-style. Exercise testing, in addition to helping identify elderly coronary patients at high risk of recurrent events who warrant added therapies, can guide the recommendations for their exercise regimen.

The relationship between polymorphisms in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans.

STUDY OBJECTIVES: To determine whether the polymorphic dinucleotide repeats found in intron 4 of the endothelial cell nitric oxide synthase (ecNOS) gene and the platelet GPIIIa PLA(1)/A(2) polymorphism are associated with myocardial infarction (MI) and venous thromboembolism (VTE) in African Americans. Because these two genes may interact physiologically, the third objective was to determine if there was a relationship between the polymorphisms with respect to MI and VTE. DESIGN: A hospital-based case-control study. After informed consent was obtained, blood used for DNA extraction was drawn from the subjects. SETTING: The study was conducted in the Anticoagulant Clinic and the Cardiology Clinic at Grady Memorial Hospital in Atlanta Georgia. PATIENTS: Subjects were recruited from African-American patients with a reported history of MI (n = 110) or VTE (n = 91). Control subjects (n = 185) without a history of cardiovascular or venous disease were recruited from an outpatient clinic. MEASUREMENTS AND RESULTS: The 393 ecNOS allele was more common among MI cases (36%; p = 0.01) and VTE cases (35%; p = 0.04) than among control subjects (26%). There was no association between the GPIIIa genotypes and either MI or VTE. However, among the MI subjects, there was a strong association between the ecNOS 393/393 genotype and the Pl(A2) allele. It was also found that the frequency of the 393 allele was higher in African-American persons (0.26) compared with what has been reported for Australian Caucasians (0. 14) and Japanese (0.10). CONCLUSIONS: The 393 allele but not the Pl(A2) allele was significantly associated with both MI and VTE in African Americans. Homozygosity for the 393 allele was significantly associated to the diagnosis of MI prior to the age of 45. The combination of the 393 allele and a Pl(A2) allele was also highly associated with MI. The frequency of the 393 allele was significantly higher in African Americans than what has been reported for other populations. This study furthers not only extends the association of the 393 allele to VTE but has demonstrated an interaction with the Pl(A2) allele with respect to MI.

Hypertension and other cardiovascular risk factors in women.

Coronary heart disease (CHD) is the leading cause of death in U.S. women, causing about 250,000 deaths annually. More than one-third of women aged 55 to 64 with CHD are disabled by their disease, and this increases to 55% in women 75 years and older. Risk factors are highly prevalent in U.S. women aged 20 to 74 years: > 1/3 have hypertension, > 1/4 have hypercholesterolemia, > 1/4 are overweight, and > 1/4 are sedentary. Additionally, diabetes mellitus imparts greater risk for women than for men. Risk factor prevalence is greater in women of lower socioeconomic status and lower educational level. The decrease in coronary risk factors has been less pronounced in women than in men in the past 2 to 3 decades; the decrease in coronary and cardiovascular mortality has also been less pronounced for women than for men. For example, 51% of white women and 79% of black women > 45 years of age have hypertension; 71% of women > 65 years of age have hypertension. Systolic blood pressure peaks in middle age for men but continues to increase in women until beyond age 80. Hypertension is more prevalent in women than men after age 65, and women incur more complications than men from hypertension. There is an equal current prevalence of cigarette smoking in both genders due to increased smoking cessation in men. Cigarette smoking doubles to triples the risk of myocardial infarction, even in premenopausal women. Young to middle aged women have higher HDL cholesterol and lower LDL cholesterol levels than men. Total cholesterol levels in white women increase with age at least to age 70; LDL cholesterol levels rise progressively to exceed those in men. The postmenopausal increase in total cholesterol is far less in black women. The association of physical fitness with a more favorable coronary risk profile is more pronounced for women than men. Education is important; unless women consider CHD as part of their illness experience, they are unlikely to heed preventive messages.

Mutations in the genes regulating methylene tetrahydrofolate reductase (MTHFR C-->T677) and cystathione beta-synthase (CBS G-->A919, CBS T-->c833) are not associated with myocardial infarction in African Americans.

Moderate hyperhomocysteinemia is a putative risk factor for cardiovascular disease. Molecular studies have demonstrated increased plasma homocysteine levels in the presence of DNA mutations in either the methylenetetrahydrofolate reductase (MTHFR) enzyme found in the remethylation pathway or the enzyme cystathione beta-synthase (CBS) of the transsulfuration pathway. To determine whether the mutation C-->T677 in the MTHFR gene or the T-->C833/844ins68 and G-->A919 mutations in the CBS gene are associated with myocardial infarction (MI) in African Americans, DNA was analyzed from samples obtained from a case-control study conducted at a large, inner-city hospital. One-hundred ten African American subjects with a diagnosis of MI and 185 race- and age-matched controls were recruited. Our results demonstrated that 15% of the MI cases were heterozygous for the C-->T677 (MTHFR) mutation, while 1.8% were homozygous. When compared to the controls in which 15% were heterozygous and 2.1% were homozygous, no significant association with MI was observed. In addition, 34% of the cases were heterozygous for the T-->C833 (CBS) mutation while 6% were homozygous. This is compared to 32% and 5% of the controls having the heterozygous and homozygous genotype, respectively. No significant association was observed for the T-->C833 (CBS) mutation among the cases and controls. Although this mutation has no significant association with MI, the prevalence of the heterozygous state was higher than what has been reported for whites (12%). No mutations for G-->A919 (CBS) were detected in the cases or controls. The racial differences of the CBS T-->C833 polymorphism suggest that further investigation into the other areas of the CBS gene is needed.

A racial difference in the prevalence of the Arg506-->Gln mutation.

Several recent studies have reported that the factor V Arg506-->Gln mutation is present in 3-10% of adults of European descent. To determine if the prevalence is comparable among Blacks, we have initiated a case-control study in a large urban hospital in Atlanta which serves a substantial black population. We have evaluated 131 black subjects with confirmed venous or arterial thrombosis and 61 black subjects without a history of thrombosis. Only one case and one control were positive for the Arg506-->Gln mutation. We conclude that the mutation is more common among Whites than Blacks.

The role of the t-PA I/D and PAI-1 4G/5G polymorphisms in African-American adults with a diagnosis of myocardial infarction or venous thromboembolism.

To determine whether or not the PAI-1 4G/5G and t-PA I/D polymorphisms in African-Americans were linked to cardiovascular disease, the association of these polymorphisms to disease expression was analyzed in a recently completed case-control study of myocardial infarction or venous thromboembolism among African-Americans. All African-Americans patients with a history of venous thromboembolism attending an anticoagulant clinic, and patients with a history of a MI attending a cardiology clinic at a large local urban public hospital were eligible for inclusion as cases in the study. In this study it was observed that there was a statistically significant association between the D allele of the t-PA I/D polymorphism and venous thromboembolism and a nonsignificant association between the D allele and myocardial infarction among African-Americans. t-PA antigen levels were statistically significantly higher among both myocardial infarction and venous thromboembolism cases compared with control subjects. The genotypes were unrelated to t-PA plasma levels. There was no association between either myocardial infarction or venous thromboembolism and the 4G/5G PAI-1 genotype. It was also found that genotype frequencies for both PAI-1 4G/5G and t-PA I/D polymorphisms in African-American adults were different from those reported for both U.S. Causcians and Europeans.