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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.
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.
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.