Women and Heart Disease

Background

Heart disease is the leading killer of women.
More women die from cardiovascular disease than all forms of cancer.
Men have more heart attacks than women, but women have a higher death rate.
Warning signs of heart attack in women are discomfort in the center of the chest that lasts for more than a few minutes, or goes away and comes back, uncomfortable pressure, squeezing, fullness, or pain. Discomfort in one or both arms, back, neck, jaw or stomach. Shortness of breath comes along with chest discomfort. Symptoms may also include breaking out in a cold sweat, nausea, or lightheadedness.
Large Federally funded studies aimed at determining risk factors for heart disease did not include women.
Reports from the Government Accounting Office in the early 1990's noted that women were not included in studies demonstrating the safety and efficacy of therapies for cardiovascular disease.
Since women tend to develop heart disease later than men, many women are still excluded from clinical trials on the prevention and treatment of heart disease.
Women are more susceptible to drug-induced cardiac arrhythmias, a major reason for removing medicines from the market place.

OWH has focused on cardiovascular disease as a major women's health issue for several years and has funded several research projects on this topic. These studies provide valuable insight into the sex differences of cardiovascular disease and the FDA products used to treat it.

FDA/OWH Funded Research In Cardiovascular Disease: Completed Projects Comparison of the beta-adrenergic antagonist actions of propranolol in men and women -- David Flockhart, MD, PhD, (94)
Gender-related differences in pharmacokinetics occur with many drugs, but these differences do not always predict pharmacodynamic changes. This study assessed the influence of gender and the menstrual cycle on the actions of propranolol. The results suggest that gender-related changes in propranolol pharmacokinetics do not result in different chronotropic effects.

Comparison of the potassium channel blocking actions of quinidine in men and women -- Raymond L. Woosley, MD, PhD, (94)
Torsades de pointes (TdP) is a potentially fatal cardiac arrhythmia that can occur after the administration of some drugs. This study compared the response of normal males and female subjects to the antiarrhythmic drug, quinidine, which is known to induce TdP and found that although there were no differences in pharmacokinetics or protein binding of quinidine, women had a greater response to quinidine than did men.

Administration of thrombolytic therapy to women with acute myocardial infarction. Is it too late? -- Emily B. Shacter, PhD, (96)
Women who enter the hospital with an acute myocardial infarction die at almost twice the rate of men. This study examined the data from clinical studies to determine whether the increased mortality rate in women was due to ineffective administration of thrombolytic drugs and found that a disproportionate number of men die before hospitalization, biasing clinical studies in hospitalized patients.

A comparison of gender specific utilization of implantable cardioverter defibrillator therapy and post-implantation survivability -- Steven Lascher, DVM, MPH, (97)
Implantable cardioverter defibrillators (ICDs), because of their ability to detect and treat potentially lethal ventricular arrhythmias, have become one of the most important life saving cardiac devices. This study examined gender specific utilization of ICDs and post implantation survival among the Medicare population. The results indicate that women are implanted with ICDs less frequently than men despite similar cardiac disease incidence, and older women (70-85 years) who are treated with ICD live significantly longer than men of similar age.

Gender differences in early and long-term results of coronary angioplasty with the Palmaz/Schatz stent (PSS) -- Danica Marinac-Dabic, MD, (95, 96, 97)
This project utilized a combination of retrospectively and prospectively collected data from clinical sites that participated in the New Approaches to Coronary Intervention (NACI) Registry to investigate gender differences after coronary angioplasty with the PSS; and found that although men and women are dissimilar in their baseline clinical and lesion characteristics, women treated with PSS do as well as men treated with PSS.

Ovarian steroids and cardiovascular disease: The role of gender in the effectiveness of interventional medical devices -- James Karanian, PhD, (98)
This study investigated the role of the aging and estrogens in modulating coronary function in women. Using a swine model, the investigators determined that coronary vascular function is greater in males than females and balloon injury can reduce coronary blood flow in males compared to females.

Variations in the drug-induced QT interval prolongation during the menstrual cycle -- Ana Szarfman, MD, PhD, Raymond L. Woosley, MD, PhD, (co-funded by NIH ORWH, 98)
Women have slower cardiac repolarization that is expressed as longer QTc intervals on the ECG. An evaluation of the effect of the menstrual cycle on drug-induced QT prolongation found that the drug-induced QTc prolongation was greater in women during the menstrual and ovulatory phases of the menstrual cycle than in men and women in the luteal phase.

FDA/OWH Funded Research In Cardiovascular Disease: Ongoing Projects

Women's participation in clinical drug trials for unstable angina and myocardial infarction -- Ann Farrell, MD, (00)
Women have been underrepresented in clinical trials for cardiovascular heart disease. This project is reviewing the participation of women in cardiovascular clinical trials in terms of numbers and clinical characteristics using clinical cardiovascular drug trials included in NDA submissions over the last 10 years.

Incidence and attributable risk of serious adverse events and death associated with the use of hemostasis devices by gender -- Dale Tavris (02)
The incidence of hematoma and hemorrhage associated with the use of hemostasis devices is more than twice as great in women than in men, and that the death rate associated with this problem was about five times greater in women than men. To obtain more precise gender information and to assess the various risks of hemostasis devices by device type, while controlling for potential confounding variables, this project examined over 160,000 procedures performed at 214 participating institutions. The most frequent complication of hemostasis devices observed in the study was hemorrhage (1.1%). The study confirmed the excess risk in females that was suggested above by showing that females had over twice the risk of males for hemorrhage, pulse loss, pseudo-aneurysm, and death. The study also suggested that the collagen plug devices may exert a protective effect for all adverse events combined.

FDA/OWH Research in Cardiovascular Disease: Projects Funded in FY03

Are woman at higher risk from proarrhythmic drugs? -- Jogarao Goburru, Ph.D.
This project will 1) determine the most appropriate method for correcting for heart rate when determining drug-induced changes in the QT interval in women and men; 2) determine if there are sex-related differences in the pharmacokinetics and pharmacodynamic of drugs that induce torsades; and 3) determine the optimal study design for characterizing drug effects on the QT interval in women and men.

Electrophysiological characterization of several torsadogenic drugs in isolated rabbit hearts. -- John Koerner, Ph.D.
Given the medical and economic consequences of QT interval prolongation and its associated life-threatening ventricular arrhythmia, pre-clinical models to predict QT interval prolongation and proarrhythmia are needed. The isolated rabbit heart has been shown to be sensitive to several torsadogenic drugs, and thus could fit into the preclinical strategy of early detection of a torsadogenic hazard. The present investigation will expand investigation a using the rabbit heart by characterizing torsadogenic drugs from different pharmacological classes in this model.

Cardiovascular effects of ultrasound contrast agents in intact and ovariectomized female animals. -- Mel Stratmeyer, Ph.D.
This project will examine whether contrast agent-induced damage to blood vessels can accelerate the progression of atherosclerosis in hormonally deficient females, compared to hormonally intact females. Knowledge of the potential adverse effects of contrast ultrasonography in hormone-deficient females will allow FDA to better assess the risks associated with the procedure and will enhance regulatory decision-making capabilities with regard to the use and approval of ultrasound contrast agents and regulation of ultrasound exposures.

Discovery and evaluation of interspecies biomarkers to monitor the early onset and the progression of cardiovascular toxicity associated with tiazolidinedione compounds used in the treatment of Type-2 diabetes -- Eugene Herman, Ph.D.
Thiazolidinediones are used to treat type-2 diabetes. Unexpectedly, hepatic and cardiovascular toxicities have been observed in patients treated with these compounds. At present, there is no reliable means to detect early onset of the cardiovascular toxicity, which has been reported in patients. This project will use an animal model to identify and evaluate potentially useful diagnostic biomarkers that could aid in minimizing the cardiac toxicity and in the identification of new compounds, which are devoid of this toxicity.

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