The FDA Office of Women’s Health (OWH) awards research grants for 1-2 year studies to support FDA regulatory decision-making and advance the science of women’s health. OWH has funded research projects that address health issues affecting women across their lifespan. This page highlights OWH-funded research related to cardiovascular disease.
Sex differences in Drug-Induced QT Prolongation and Torsades De Pointes Establishing an Invitro Model for High-Throughput Screening and Risk Assessment of Torsadogenic Drugs (Special Funding Initiative)- Li Pang, MD/NCTR
Numerous drugs have the potential adverse effect of lengthening the heart’s electrical cycle and cause the heart to stop beat accidently (torsade de pointes /TdP). Women are at a much higher risk than men for experiencing drug-induced irregular beats. Due to the absence of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced arrhythmia (irregular rhythm). Several clinical and animal studies suggest that sex hormones may play an important role in determining the sex differences of drug-induced irregular beats. Recent progress in induced pluripotent stem cell (iPSC) technology (a technology that can induce stem cells directly from adult cells and make them capable of giving rise to several different types of cells) has made it possible in utilizing human heart muscle cell (iPSC-hCMs) model to investigate influences of both genetic and sex hormones on heart ion channel gene expression and heart muscle cell function. In our previous study supported by the FDA Office of Women’s Health (OWH), we found that genetic-based differences in male and female iPSC-hCMs alone were sufficient to determine bigger responses of female cells to drugs that are known to cause TdP. We would like to confirm the result found in our pilot study with additional iPSC-hCMs lines derived from other healthy male and female donors. The success of the study will provide valuable information in understanding the mechanisms of sex differences in human heart muscle cell beating process and risk assessment of drug-induced arrhythmia in both men and women.
Analysis of Sex Specific Differences in Quality of Life Measures for Heart Failure- Anindita Saha, BS/CDRH
Cardiovascular disease is the number one cause of death for women in the world. In recent years, approximately 1 in every 4 deaths in the United States results from heart disease, with similar rates among men and women. Therefore, it is critical for patient care and regulatory decisions that valuable tools such as patient-reported outcomes (PROs) be properly developed and calibrated for both male and female patients. In this study, we will evaluate gender differences in responses to the Kansas City Cardiomyopathy Questionnaire (KCCQ), a PRO measure of symptoms and functioning in heart failure patients. If the observed response differences warrant, we will provide a recommendation to analyze scores for female and male patients so that all individuals receive proper care, and the FDA makes regulatory decisions based on analyses that account for female-male differences. PROs are the report of a patient’s health condition that comes directly from the patient, without interpretation by others. These instruments can be formatted as items, questionnaires, or event diaries and can deliver information on a patient’s function, activities of daily life, symptom severity, or quality of life. PRO measures provide essential information in clinical care and regulatory decisions by evaluating health status from the patient’s perspective. In this way, PROs compliment other clinical measures to provide the full picture of a patient’s health status. PROs are often used in heart failure clinical trials to provide the patient’s perspective of a treatment and to predict adverse events. The KCCQ is a widely used PRO measures for heart failure patients in clinical trials. The KCCQ was scientifically developed and evaluated based on study samples that were historically majority male. However, male and female patients have different heart failure presentations. Male and female patients with the same disease stage and severity can respond systematically differently to questions, yielding different overall scores [1, 2]. Ultimately, the goal of this research is to facilitate accurate measurement of important outcomes in clinical trials for heart failure patients to ensure the best care for all patients.
1. Berg, S.K., et al., DenHeart: Differences in physical and mental health across cardiac diagnoses at hospital discharge. J Psychosom Res, 2017. 94: p. 1-9.
2. Comin-Colet, J., et al., Health-related Quality of Life of Patients With Chronic Systolic Heart Failure in Spain: Results of the VIDA-IC Study. Rev Esp Cardiol (Engl Ed), 2016. 69(3): p. 256-71.
Evaluation of the Safety and Effectiveness of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) for Atrial Fibrillation in Underrepresented Subgroups in Premarket Clinical Trials Using Combined Clinical and Statistical Modeling Approaches. (Special Funding Initiative) - Robbert Zusterzeel, MD/CDER
Irregular heartbeat, more commonly called “atrial fibrillation (AF)”, can cause blood clots formed in the heart to spread to the brain and cause a stroke. To prevent this, doctors usually prescribe a drug called “warfarin”. However, due to its association with high bleeding risk, warfarin requires frequent dose adjustment and monitoring by a specialist and is thus cumbersome to use. In the last 7 years, a new set of drugs, known as Non-Vitamin K Antagonist Oral Anticoagulants (NOACs), were approved by FDA for use in AF as a possible alternative to warfarin. This project will evaluate sex and race specific risks of stroke, bleeding and death associated with NOAC therapy by combining data from multiple clinical trials. New computational modeling methods and statistical approaches will be implemented to estimate the risks of outcomes in demographic subgroups.
Translational regulatory science to advance drug safety in women combining in silico modeling and clinical approaches - David Strauss, MD, PhD/CDER
Fourteen drugs have been removed from the market worldwide because they cause an abnormal heart rhythm that leads to sudden death and up to 70% of the cases occur in women. The exact reason for this higher rate in women is unknown, but it may be because (1) women are exposed to higher drug levels due to smaller body size, (2) women break down the drugs and transport the drugs to the heart differently, or (3) women’s hearts are inherently more susceptible to drugs that cause abnormal heart rhythms. We performed two clinical studies where an equal number of women and men received multiple drugs with low and high arrhythmic risk and that affect different ion channels in the heart. We took blood samples to measure the amount of drug in the blood and record electrocardiograms (“EKG”) to assess the effect of the drugs on the ion channels of the heart. We also combined drugs to determine if the EKG signature of potentially harmful drugs can be converted into the EKG signature of safe drugs by the ion channel effects of a second drug. Results showed that the EKG can be used to differentiate ion channel effects caused by drugs with different arrhythmic risk. There were no differences in the relationship between drug concentration and EKG changes of men vs. women. This study suggests that the higher drug-induced arrhythmic risk in women compared to men is not due to larger concentration-dependent EKG effects. However, women are often exposed to higher drug levels than men, which likely contribute to women’s higher drug-induced arrhythmic risk.
Sex-specific analysis of percutaneous left atrial appendage closure (LAAC) device for stroke prevention in patients with atrial fibrillation - Hongying (Helen) Jiang, PhD/CDRH
Atrial fibrillation (AF) is a cardiac arrhythmia that manifests as irregular heartbeat. According to the U.S. Centers for Disease Control, AF affected approximately 2.66 million people in the United States in 2010, and the numbers are expected to increase over time. AF is the most common arrhythmia in the US, and its prevalence increases with aging. Patients with AF are at increased risk of having blood clots, stroke, and heart failure. More than 30% of strokes in individuals over the age of 75 years are due to AF, presumably due to thromboembolism from the left atrial appendage (LAA). Oral anticoagulation therapy with warfarin or more recently approved novel anticoagulants are the standard of care to reduce risks of blood clots and stroke. Emerging new technologies in stroke prevention have been undergoing development rapidly. One new technology is the percutaneous LAA closure (or occlusion) device. The LAA is a small pouch, often shaped like a windsock, which connects and empties into the left atrium, the top chamber of the left side of the heart. This structure is prone to form and collect blood clots, in particular in patients with AF. When a blood clot travels from the LAA to the systemic blood circulation and travels to the brain, it may result in stroke. The percutaneous LAA closure device is a novel technology that closes the LAA via percutaneous vascular access, and thus prevents blood clots from entering the systemic circulation and reduces stroke risk. It is recognized that there are sex-specific differences in the pathophysiology of stroke and AF. Moreover, women (particularly elderly women) often have more challenging vascular anatomies (e.g. smaller blood vessels and heart sizes) for percutaneous procedures vs. men, and more often have higher rates of surgical complications. It is unknown whether these sex differences impact the effectiveness and safety of this new LAA closure device for stroke prevention. Our goal is to answer this question by pooling and analyzing both pre-market and post-market data available at the FDA on this type of device via an in-depth statistical analysis. This study will help us better understand sex difference in stroke prevention and increase the assurance the safety and effectiveness of the LAA closure device in women.
Evaluation of thromboembolic events following C1-inhibitor therapy - Paul Buehler, PharmD, PhD/CBER
Hereditary angioedema (HAE) is a rare potentially life threatening disorder associated with a deficiency of functional C1-esterase inhibitor (C1INH), and it is more severe and frequent in female population than in men. Until recently, there was no HAE-targeted therapy available in the United States, and only fresh-frozen plasma or attenuated androgens were used to provide some relief during acute attacks. Since 2008, DHRR/CBER approved three C1INH products for replacement therapy in patients with HAE for the treatment of acute attacks and for prophylaxis. According to the available database and recent publications, C1INH therapy in HAE patients is associated with a risk of thromboembolic events. Thrombosis also has been predominantly reported in women and appears to depend on hormonal status. This project will focus on the evaluation of a risk of thromboembolic events due to C1INH administration at supraphysiological levels and elucidation of possible underlying mechanisms. Secondly, to assure safety and effectiveness of C1INH treatment in case of recently proposed concomitant administration of C1INH and pharmaceutical heparins, this project will focus on the evaluation of the C1INH potentiation by heparin and the impact of various compositions and conditions on possible thrombotic events. The proposed studies, both in vitro and in animal models, are essential for the development of reliable biomarkers to evaluate and predict thromboembolic events in women during C1INH therapies, as well as for elucidating the mechanisms for possible enhancement of currently available C1INH therapies by pharmaceutical heparins and its impact on a risk of thrombosis.
Developing biomarkers for trastuzumab-induced cardiotoxicity - Wen Jin Wu, MD, PhD/CDER
Trastuzumab (also known as Herceptin®) is a humanized monoclonal antibody directed against extracellular domain of human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of breast cancers that are HER2-positive. Trastuzumab provides considerable therapeutic benefits in HER2-positive breast cancers and improves disease free and overall survival after adjuvant chemotherapy. However, trastuzumab treatment is also associated with cardiac dysfunction. There are no clinically approved biomarkers that can be used to predict the cardiac dysfunction induced by trastuzumab. Furthermore, several large clinical trials have shown that cardiomyopathy induced by trastuzumab maybe potentially irreversible in some patients. Therefore, it is important to develop biomarkers and sensitive and specific testing methods that could be used to detect cardiotoxicity induced by trastuzumab. Using echocardiography, we recently found that trastuzumab significantly reduced left ventricular performance in mice. Importantly, this trastuzumab-induced cardiac dysfunction was associated with elevated level of cardiac myosin light chain 1 (cMLC-1) in mice sera, suggesting that cMLC1 could be a potential biomarker for trastuzumab-induced cardiotoxicity. The goal of this study is to further investigate the mechanisms of trastuzumab-induced cardiotoxicity and to collaborate with clinical investigators at Massachusetts General Hospital (MGH), Harvard University to validate the potential biomarker that we identified based on our preclinical studies. This proposed collaborative study may yield biomarkers that could be used to predict trastuzumab-induced cardiac dysfunction and to help define the risks and the benefits of trastuzumab treatment.
Sex and racial difference in prosthetic aortic valve selection and risk factors for patient outcome - an observational study of Medicare beneficiaries - Dongyi Du, MD, PhD/CDRH
Calcium and material characterization in women using dual-energy CT: Phase II - Nicholas Petrick, PhD/CDRH
Cardiovascular disease is the leading cause of death for American women and women have higher cardiovascular mortality rates compared with men. Large numbers of cardiovascular events occur in asymptomatic people who do not belong to high risk groups. Risk-based markers, such as coronary artery calcium score, have been suggested as methods for identifying candidates for primary prevention of coronary artery disease (CAD) through risk-factor modification. The calcium score, related to the amount of calcium found in coronary vessels, is used as a summary measure of coronary health, with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts, smaller arteries, and different anatomy than men. While research in standardizing CT quantification of coronary calcium has been carried out, little has been done to 1) address gender differences, 2) develop methods for systematically quantifying measurement error or 3) validate the performance of calcium scoring and plaque material characterization in dual-energy CT. In Phase I (OWH funded 2014-15), we are evaluating the accuracy and precision of calcium scoring in single- and dual-energy CT scans through static phantom studies. Our initial results show that vessel size and gender-based anatomy are significant factors that strongly influence calcium scoring. In Phase II, we propose to investigate how quantitative coronary calcium scoring and plaque material characterization are affected by gender difference and CT acquisition techniques with a special focus on measuring and optimizing performance of dual-energy CT in women. We will build on our initial static phantom studies by developing a dynamic motion controller that allows the impact of heart motion to be accounted for. We are also proposing a substantial expansion to evaluate the potential of dual-energy CT for characterizing the material composition of coronary plaques and in particular to validate how well dual-energy CT can differentiate hard from soft plaques. While the phantoms developed are specific to coronary vessel measurements, the general approaches and validation methods developed will generalize to the assessment of technical performance for other quantitative imaging biomarkers.
Cardiovascular Risk of Testosterone Treatment in Women (Special Funding) - Lai-Ming Lee, PhD/CDER
A variety of testosterone products are used off-label for the treatment of female sexual dysfunction (FSD). Due to the chronic nature of FSD, these products are anticipated to be used as long-term therapy in women. Therefore, assessment of cardiovascular risk will be an important factor in the risk/benefit determination. The Framingham General Cardiovascular Risk Score predicts the 10-year risk of all cardiovascular events including coronary heart disease, stroke, transient ischemic attacks, and heart failure. The variables used in the formula are age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein, use of hypertension medication, smoking status, and history of diabetes. We hypothesize that the Framingham General Cardiovascular Risk Score will be useful in estimating cardiovascular risk of drug products in Phase 3 trials. We will use available data to determine the utility of the Framingham General Risk Score to estimate the cardiovascular risk in women exposed to drug products with a likelihood of a cardiovascular signal. If successful, this formula would be applied to androgens and androgen-like products being evaluated for the treatment of female sexual dysfunctions in women.
Optimization of an in silico cardiac cell model for predicting sex differences in drug-induced proarrhythmia risk (Special Funding) - Wendy Wu, PhD/CDER
Capturing Sex-Specific Data in Regulatory Submissions and National Vascular Quality Initiative Registry - Danica Marinac-Dabic, MD, PhD/CDRH
Addressing the unmet medical needs for cardioprotection in women receiving chemotherapy - Ashutosh Rao, PhD/CDER (Supplementary funds)
The FDA regulates several oncology agents, including anthracyclines, monoclonal antibodies and cytokines that are known to induce oxidative damage and cardiac dysfunction. Younger women appear to be sensitive to cardiac dysfunction from chronic exposure to chemotherapy. Taken together with the fact that heart disease is the number one killer of women in the US, cardioprotection in women remains an unmet medical need. This project designed and validated a preclinical model for testing of both anticancer potential and cardiac safety, where spontaneously hypertensive rats (SHRs) were implanted with a syngeneic breast cancer cell line (SST-2). Using this model the project identified an inverse correlation between cardiac stress and circulating reproductive hormone levels using doxorubicin for proof-of-principle studies. This study is currently investigating reproductive hormone supplementation with doxorubicin for potential chemoprotection. The project is leveraging the SHR/SST-2 preclinical model to investigate a mechanistic link between hormone levels, oxidative stress, and cardiac health in females, as a means to provide critical, missing information on the mechanism behind female cardiac sensitivity. The results of this study may potentially enable the development of personalized therapies that can provide a mechanistically-sound treatment window to maximize anticancer activity while minimizing cardiotoxicity in women receiving chemotherapy.
Individual patient-data meta-analysis and post-market analysis as a method for improving data quality in demographic subgroups (Support for implementation of FDASIA Section 907 Action Plan) - Daniel Canos, PhD, MPH/CDRH
Women have been underrepresented in clinical trials for medical devices and cardiovascular devices in particular. Therefore, the results of these trials primarily reflect outcomes in men. Directly addressing the FDASIA 907 Action Plan priorities of improving the quality and public availability of demographic subgroup data this project combines clinical trial data submitted to the FDA as part of pre-market approval applications. This allows for the analysis of sex-differences in medical devices, hereby leveraging existing clinical data and improving methodology for performing sex-specific analysis as individual clinical trials are often underpowered to detect potential sex-differences. Furthermore, this project pools pre-market and post-market data to assess sex-differences in real-world use thereby strengthening the system to make better use of data once medical products are available on the market. By combining already existing pre-market clinical trial data and assessing post-market real-world performance, this study will be able to quickly evaluate device performance in demographic subgroups. Next to recommendations for future individual-patient data meta-analyses as a result of this project, this will also lead to rapid implementation into the regulatory review process and guidance documents, better clinical trial designs, and improve women’s health supporting multiple FDASIA priorities and action items.
Ensuring accessible supply of safe and effective drugs: Quantifying women-specific pro-arrhythmia risk of drug therapies (OWH Women's Health Cardiovascular Research Fellowship) - David Strauss, MD/PhD/CDER
Prolongation of the heart rate corrected QT (QTc) interval by drugs has been used as a surrogate for developing Torsade de Pointes (Torsade), a cardiac arrhythmia that can cause sudden cardiac death. Women are disproportionally affected by pro-arrhythmic effects of certain drugs compared to men. While some studies have suggested that women have greater drug-induced QTc prolongation compared to men, recent work has found that there is no sex difference in QTc prolongation for certain drugs. This indicates that QTc prolongation is likely not the best marker for actual Torsade risk and does not explain sex-differences in Torsade risk on its own. Instead of evaluating the effects of drug-induced QTc prolongation, this project will quantify real-world sex-specific risk of Torsade using multiple pre-market and post-market databases. The data will be used to develop Torsade risk models based on multiple predictors in women and men separately.
Abdominal Aortic, Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes-AAA CARE - Tina Morrison PhD/CDRH