Heart disease is the leading cause of death for women. Women often experience heart disease differently than men. For example, men have more heart attacks than women, but women have a higher heart attack death rate. Women experience higher bleeding rates during percutaneous coronary interventions (PCI) performed through femoral arterial access. Women are also more susceptible to drug-induced cardiac arrhythmias.
FDA’s Office of Women’s Health (OWH) supports research to provide valuable insight into sex differences in the diagnosis and treatment of cardiovascular disease. OWH has funded 65 studies (12 ongoing and 53 completed) that examine issues such as QT interval prolongation, cardiotoxicity from breast cancer drugs, and sex differences in various cardiac interventional therapies. The results of the completed studies have led to a better understanding of cardiovascular disease in women and contributed to the development of guidance documents for drug and device development for men and women.
Current OWH-funded Research on Cardiovascular Disease (Listed by Funding Year)
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.
Preclinical test methods for percutaneously implanted heart valves - effect of non-circular valve configuration after implantation on valve leaflet dynamics- Terry Woods, PhD/CDRH
Thousands of elderly American women suffer from narrowing of the aortic heart valve each year. Transcatheter aortic valve replacement (TAVR) has become a life-saving therapy for many of these patients in recent years. FDA has approved five TAVR devices. TAVR devices are typically manufactured to have a circular shape. However, imaging has shown that TAVR devices can take on a non-circular shape, like a triangle or the letter “D”, after implantation. These changes can affect how the valve leaflets open and close when the heart is beating and could impact how the device functions long-term. This project aims to address the research question – How does the non-circular shape affect how TAVR devices function long-term? The research findings will help guide industry in developing appropriate testing and aid reviewers in assessing the test results provided in applications for new TAVR devices. Thus the outcomes from the study will help ensure that TAVR devices function appropriately for the expected device lifetime, directly supporting the CDRH vision of delivering safe, effective, and high quality medical devices for the American public first in the world.
Sex-specific outcomes with cardiac resynchronization therapy - Daniel Canos, PhD/CDRH (Supplementary funds)
A pilot study for evaluating genetic influences on sex differences of drug-induced – proarrhythmia - Li Pang, MD/ NCTR
Drug-induced proarrhythmia (heartbeat irregular) is a major safety issue in drug development. Women are at a higher risk than men for drug-induced QT prolongation and Torsades de Pointes (TdP), a rare but lethal heart rhythm problem, which can cause the heart to stop beating. Due to the absence of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced irregular beats. Sex hormones are believed to play predominant roles in determining the sex differences of drug-induced TdP. Recently, progresses in induced pluripotent stem cell (iPSC) technology have made it possible in utilizing an in vitro iPSC-derived cardiomyocytes (iPSC-CMs) model to test influences of both genetic and sex hormones on heart ion channel gene expression and heart cell function. This pilot study will use subject-specific iPSC-CMs from both men and women to investigate genetic influences on sex-differences of drug-induced TdP. The proposed study will supplement another OWH-funded project in evaluating effects of sex hormones on drug-induced TdP. The combination of the two studies will provide valuable information in understanding the mechanisms of sex differences in heart cell beating process and risk assessment of drug-induced TdP in both men and women.
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.
Novel therapeutic approaches to prevent drug-induced torsade de pointes - Norman Stockbridge, 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.
This project will perform a clinical study where an equal number of women and men will receive multiple drugs that affect different ion channels in the heart. This project will take 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. This project will also combine drugs to determine if the potentially harmful effects of one drug can be prevented by the beneficial effects of a second drug. This work will examine the reasons for why women and men respond differently to drugs and why women are at higher risk for some types of abnormal heart rhythms caused by drugs. In addition, the project will determine if drug-induced abnormal heart rhythms may be able to be prevented by combining drugs. Together, this will ensure the safer use of drugs in women.
Publications from this project:
-Vicente J, Simlund J, Johannesen L, Sundh F, Florian J, Ugander M, Wagner GS, Woosley RL, Strauss DG. Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk. J Electrocardiol. 2015 Jul-Aug;48(4):533-8.
-Vicente J, Johannesen L, Mason JW, Pueyo E, Stockbridge N, Strauss DG. Sex differences in drug-induced changes in ventricular repolarization. J Electrocardiol. 2015 Aug 4. pii: S0022-0736(15)00226-5. doi: 10.1016/j.jelectrocard.2015.08.004.
Develop animal and cellular models to investigate the mechanisms of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine to support post-marketing surveillance of these antibody-based HER2-targeted therapies, and characterize novel serum biomarker of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine - Wen Jin Wu, MD, PhD, CDER
Breast cancer is one of the most common cancers diagnosed in the U.S. women. Trastuzumab (Herceptin®) is a humanized monoclonal antibody that binds to a cell surface protein called human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of HER2-positive breast cancer. HER2 is a member of HER family receptors, involved in the development and progression of human breast cancer. HER2-positive breast cancers tend to be more aggressive than other types of breast cancer. Clinical studies have found that trastuzumab is associated with sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. The mechanisms by which trastuzumab induces cardiac damage remain unclear. Currently there are no approved biomarkers that can be used to predict the occurrence of cardiac damage induced by trastuzumab. Recently, pertuzumab and ado-trastuzumab emtansine, both of which are also directed against HER2, have been approved for the treatment of HER2-positive breast cancer. This study focuses on identification of biomarkers for the detection of cardiac damage induced by trastuzumab, pertuzumab and ado-trastuzumab emtansine. Information obtained from this study may enhance post-marketing surveillance of cardiac adverse effects associated with use of antibody-based HER2-targeted therapies.
Calcium and material characterization in women using dual-energy computed tomography - Nicholas Petrick, PhD, CDRH
Large numbers of cardiovascular events occur in asymptomatic people who do not have a high level of risk in terms of multivariable risk scores. Novel risk markers (e.g., CT coronary calcium scoring) have been suggested as additional ways to identify patients for primary prevention of coronary artery disease (CAD). The calcium score is a summary measure of coronary health with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts and smaller arteries than men increasing the error in calcium scoring in women. Little research has been conducted to address gender differences or to develop methods for quantifying calcium score measurement error. In addition, little work has been done validating the performance of calcium scoring in dual-energy CT scans. Dual-energy CT has the ability to differentiate tissues and may reduce x-ray dose. This research project will investigate how quantitative coronary calcium scoring is affected by CT acquisition techniques with a special focus on quantifying and comparing the accuracy and precision of single- and dual-energy CT in women. The project will identify gender differences in calcium scoring and determine how CT acquisitions can be optimized to both minimize measurement error and the x-ray dose to the patient.
Blood pressure threshold for cardiovascular disease risk: an assessment of sex-based criterion - Ching-Wei Chang, NCTR
Cardiovascular disease (CVD) is the leading cause of death for both women and men in the United States. Blood pressure is one of the seven metrics used by the American Heart Association to assess cardiovascular health, and hypertension (uncontrolled elevated BP) is considered a primary risk factor for CVD. Under current blood pressure (BP) guidelines for assessing hypertension, the prevalence of hypertension is higher in men than in women and averaged BP is generally higher in men, yet women tend to have worse outcomes after a cardiovascular disease event. Due to these inconsistencies, it is reasonable to explore whether current BP guidelines for hypertension should be modified to reflect sex-difference. The proposed study will present a systematic review of published literature and analyze summarized data from existing studies to examine whether BP guidelines for cardiovascular disease risk should vary by sex. Consequently, if warranted, new BP guidelines for hypertension will be determined to appropriately reflect differences between women and men. The results of the proposed study may play a critical role in determining whether women will benefit from sex-specific hypertension guidelines. Thus, findings from this study will enable improvements in antihypertensive treatment and management practices for women.
Sex differences in drug-induced QT prolongation and torsade de pointes: establishing an in vitro model for high-throughput scre ening and risk assessment of torsadogenic drugs - Li Pang, MD, NCTR
Numerous drugs have the potential adverse effect of prolonging the QT interval, a marker for torsade de pointes (TdP), which can cause the heart to stop beating. Women are at a much higher risk than men for experiencing drug-induced TdP. As sex hormones are believed to play an important role in determining why women are more susceptible to drug-induced TdP, this study will establish a model to simulate sex differences in drug-induced QT prolongation and TdP by evaluating drug effects on human heart cells from men and women treated with sex hormones. This project will test the model for high-throughput screening and risk assessment of QT prolonging drugs. The innovative model established in this study will 1) strengthen FDA’s ability to detect and rapidly analyze cardiac safety problems that are associated with new drug approval; 2) aid pharmaceutical companies in identifying compounds that may do more harm to women before costly clinical trials are conducted; and 3) provide valuable information to physicians for potential TdP risk of many QT prolonging drugs and guide them in prescribing those drugs to different subgroups of patients, particularly women versus men.
Abdominal Aortic, Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes-AAA CARE - Tina Morrison PhD/CDRH