Jourdan E. Triebwasser, MD, MA
Department of Obstetrics & Gynecology
Division of Maternal-Fetal Medicine
Study of Primary Care after Preeclampsia: The See PCP Study
Project Abstract: Hypertensive disorders of pregnancy (HDP), including preeclampsia (PEC), are common and increase lifelong risk for hypertension, diabetes, ischemic heart disease, stroke, and heart failure. Black women are at increased risk for HDP and long-term cardiovascular disease (CVD). The American College of Obstetricians and Gynecologists and the American Heart Association emphasize the postpartum period as an important opportunity to continue to engage these women at high-risk for future CVD. In a retrospective study by our team, we found that among women with HDP, only 32% attended a primary care or cardiology visit within 12 months of delivery. Additionally, among women with HDP attending a postpartum obstetric visit, counseling on 1) follow-up with primary care and 2) cardiovascular risk occurred at 25% and 8% of visits, respectively. Despite a large body of evidence connecting HDP to future adverse cardiovascular outcomes, there is a significant gap in research regarding best practices for transitions of care and prevention of CVD after complicated pregnancies. Our aim is to explore barriers to transitions of care after HDP, both for patients and providers. To this end, we will perform semi-structured interviews regarding CVD risk and transitions of care with women with HDP and obstetric care providers. Interviews will be transcribed and analyzed for patterns and themes. We will also evaluate associations between social determinants of health and preventative care visits through phone surveys of women with HDP. Our findings will inform the design of an intervention trial to improve transitions of care from obstetrics to preventative care providers with the goal of securing extramural funding.
Nadine Al-Naamani, MD, MS
Instructor, Department of Medicine
Division of Pulmonary, Allergy and Critical Care
Sex Hormones and Obesity in Pulmonary Arterial Hypertension
Project Abstract: Pulmonary arterial hypertension (PAH) is a female predominant disease that affects the pulmonary vasculature leading to increased pulmonary artery pressure and pulmonary vascular resistance, right ventricular dysfunction and eventually death. Sex and sex hormones contribute to the pathophysiology of PAH and are also associated with PAH disease severity. Obesity is a risk factor for PAH and obesity also contributes to sex hormone dysregulation in women with increased estrogen production. The association between obesity and sex hormones in women with PAH has not been previously explored. Using a well-phenotyped cohort of PAH women enrolled in the Penn Pulmonary Hypertension Database, we will measure subcutaneous and visceral adipose tissue on chest CT scans and measure plasma sex hormone levels. The overall hypothesis of this proposal is that obesity, specifically increased subcutaneous adipose tissue is associated with pulmonary hemodynamics and estrogen levels in post-menopausal women with PAH.
Kimberly Forde-McLean, MD PhD MHS
Assistant Professor, Department of Medicine
Division of Gastroenterology
The Impact of Sex, Menopausal Status and Parity on Prevalence of Left Ventricular Diastolic Dysfunction (LVDD) in Patents Evaluated for Liver Transplantation: A Sub-analysis of Data from the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) Study
Project Abstract: Left ventricular diastolic dysfunction (LVDD) is a leading cause of morbidity and mortality in the United States and is associated with the development of heart failure with preserved ejection fraction (HFpEF).
HFpEF is more prevalent with advancing age and female sex. While men are more likely to develop heart failure on the basis of ischemic heart disease, women are more likely to develop heart failure on the basis of diastolic dysfunction. Compensatory changes associated with chronic liver disease establish a milieu that may contribute to the development of and progression of LVDD. Given the sex predominance of LVDD and the basic science data that suggests that estrogens protect the heart from the effects of hypertension and ventricular remodeling, this proposal will examine sex differences in the prevalence of LVDD in a cohort of chronic liver disease patients being referred for liver transplantation and enrolled in the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) study. In addition, we will study the effect of postmenopausal status and parity on the prevalence of LVDD in this cohort.
Ana Recober, MD
Assistant Professor, Departments of Neurology and Pediatrics
Shana E. McCormack, MD
Assistant Professor, Department of Pediatrics
Division of Endocrinology and Diabetes
Mechanisms of Increased Cardiovascular Disease Risk in Women with Migraine
Project Abstract: Women with migraine have increased cardiovascular disease (CVD) risk. The mechanisms underlying this association remain unknown, thus there are no rational CVD prevention strategies specific to women with migraine. Chronic inflammation is one plausible mechanism for the association between migraine and CVD because it is implicated in the pathophysiology of both conditions. Our hypothesis is that some women have a heightened inflammatory response to the Western diet that sensitizes them to stimuli leading to migraine attacks. These attacks produce abnormal sympathetic activation and cardiovascular reactivity, known risk factors for CVD. Obesity adds chronic low-grade inflammation and further exacerbates these risks.
We will perform deep phenotyping in 4 groups of women (with and without migraine; with and without obesity). Aim 1 will test the effects of a high-fat/high-carbohydrate (HFHC) “Western” meal on candidate modulators of CVD risk. We expect that the exaggerated post-prandial inflammatory response to a HFHC meal in women with migraine will be associated with increased variability in sympathetic activation and abnormal vascular reactivity. Aim 2 will measure the impact of obesity on candidate modulators of CVD risk. We hypothesize that obesity exacerbates risk parameters more in women with migraine.
This project will catalyze a collaborative R01 application between two investigators with complementary expertise (Neurology, Endocrinology) focused on deep phenotyping of women with migraine and testing of targeted interventions. We will also bank serum and microbiome samples for ancillary studies, to include genomics, metabolomics and/or proteomics for identification of novel biomarkers of CVD in this high-risk and understudied population.
Lisa D. Levine, MD, MSCE
Assistant Professor, Maternal Fetal Medicine
Department of Obstetrics and Gynecology
Angiogenic Factors to Predict Cardiac Dysfunction During and After Preeclampsia
Project Abstract: Preeclampsia affects 3-7% of pregnancies worldwide and is a leading cause of morbidity worldwide. Emerging data indicate that cardiac dysfunction occurs in many women with preeclampsia and can persist well beyond the postpartum period. Additionally, preeclampsia is considered a risk factor for long-term cardiovascular disease, as strong as diabetes or a lifetime of smoking. The mechanisms behind these observations remain poorly understood, and diagnostic and prognostic tests are lacking. We do, however, know that both women with preterm preeclampsia (<37 weeks) and African American women are two of the groups at highest risk for long-term cardiac risks. Our preliminary data suggest that cardiac dysfunction in preeclampsia is caused by an angiogenic imbalance in the heart, triggered by the late gestational secretion from the placenta of sFlt1, an endogenous soluble inhibitor of VEGF. We propose to rigorously test the hypothesis that sFlt1 is associated with cardiac dysfunction in a particularly high risk group of women – African American women with severe preterm preeclampsia.
Scott M. Damrauer, MD
Assistant Professor, Department of Surgery
Division of Vascular Surgery and Endovascular Therapy
Use of an Innovative Aptamer-based, Highly Multiplexed, Proteomic Approach to Identify Novel Biomarkers for Peripheral Arterial Disease in Women
Project Abstract: Peripheral arterial disease (PAD) a leading cause of chronic, non-communicable disease worldwide and in many countries disproportionately affects women. Women present consistently with more advanced disease and have worse outcomes than men. The identification of circulating biomarkers can facilitate early diagnosis and treatment, offer insight into disease pathophysiology, and suggest new therapeutic targets for drug development. Despite this, detailed, unbiased studies aimed at biomarker discovery are lacking in women. The following grant proposal seeks to utilize a cutting edge, aptamer-based, highly multiplexed, proteomic approach to identify novel biomarkers for PAD in women. A case-control design will be used to simultaneously compare the relative levels of 1,129 circulating plasma proteins in a small number of women with early onset, severe disease with those of carefully matched controls. Potential biomarkers, identified as differentially expressed proteins, will be verified by standard enzyme linked immunosorbent assays (ELISA) in a larger case-control validation cohort of women with less severe disease and appropriately matched controls. The identification of novel, validated biomarkers will assist in early diagnosis of PAD, shed insight into the underlying pathophysiology of atherosclerosis in women, and offer new potential therapeutic targets for PAD prevention.
Rebecca Ruebner, MD, MSCE
Instructor, Department of Pediatrics
Division of Nephrology
Risk Factors for Left Ventricular Hypertrophy and Cardiovascular Disease in Young Women with Chronic Kidney Disease
Project Abstract: Chronic kidney disease (CKD) is associated with significantly increased risk of cardiovascular disease and mortality, particularly for children and young adults who develop kidney disease early in life. Several studies have suggested that young women with CKD are at particularly increased risk of early cardiovascular disease and cardiac-related death; however, the mechanisms underlying this increased risk of death are unclear. Recent reports from an ongoing national cohort study of children and adolescents with CKD, the Chronic Kidney Disease in Children (CKiD) Study, have shown that young women with kidney disease have a greater than 4-fold increased risk of left ventricular hypertrophy (LVH) compared to young men. LVH is known to be a significant predictor of future cardiovascular events, including increased incidence of heart failure, ventricular arrhythmias, myocardial infarction and sudden cardiac death. It is not known why women with CKD are more prone to develop LVH at similar levels of hypertension than their male counterparts. We propose an ancillary study leveraging prospectively collected data from the CKiD multicenter longitudinal cohort study to further explore gender-specific risk factors for LVH in children and young adults with CKD. We will explore gender differences in prevalence of cardiovascular disease risk factors and assess whether the effect of these risk factors on development of LVH is modified by gender. Elucidation of the mechanisms leading to this excess risk of LVH in young women with CKD will identify potential future targets for intervention to prevent cardiovascular events and early mortality in this high-risk population.
Rachana Shah, MD
Assistant Professor, Department of Pediatrics
Division of Endocrinology and Diabetes
Cardiometabolic Risk Profiling in Adolescent PCOS
Project Abstract: Polycystic ovarian syndrome (PCOS), which affects 6-10% of reproductive age women in the United States, represents a major independent risk factor for cardiometabolic disease. Even after controlling for obesity, women with PCOS have increased rates of type 2 diabetes, dyslipidemia, metabolic syndrome, and cardiovascular morbidity and mortality. Identification and treatment of early metabolic derangement, particularly in adolescents, could guide preventive and therapeutic measures. Recently, early and sensitive cardiometabolic phenotypes (including expanded lipoprotein and inflammatory profiling) have been examined in obesity and adult PCOS; studies in adolescents PCOS, however, are lacking. As the underlying cause of PCOS is still not understood, discovery-focused studies to identify pathogenic targets are also relevant and necessary—and may be more revealing in the early stages of disease as captured in adolescence. We propose a pilot study in adolescent PCOS to document complete metabolic phenotype and explore novel pathophysiologic factors. Our goal is to look beyond traditional metabolic risk factors for more comprehensive phenotyping of apolipoproteins, lipoprotein particle size and subclass, HDL-mediated cholesterol efflux capacity, systemic inflammatory markers, plasma metabolomics, and oral microbiome composition. We hypothesize that, compared to controls, adolescents with PCOS will have more atherogenic lipoprotein profiles, increased inflammatory milieu, and alterations of metabolomic phenotype and oral microbiome composition. Results of these studies will provide a rationale for clinical trials of standard and novel therapeutics as well as pre-clinical functional studies of candidate causal factors, with the ultimate goal of preventing PCOS-related metabolic dysfunction and cardiovascular disease.
Yuchi Han MD, MMSc
Assistant Professor, Department of Medicine
Division of Cardiology
Novel Cardiac Magnetic Resonance Imaging in Patients with Pulmonary Hypertension
Project Abstract: Pulmonary hypertension is highly prevalent in heart failure patients and its severity strongly predicts mortality. A subset of patients with pulmonary venous hypertension (PVH) as a result of heart failure and valvular heart disease develop a reactive component of arterial hypertension that mimics pulmonary arterial hypertension (PAH). Drug therapies that target endothelin-1 and nitric oxide signaling appear to improve hemodynamic parameters in this subset of patients. Identifying this reactive subgroup of patients is vital, since pulmonary hypertension is common in patients with heart failure and PAH specific therapies can worsen heart failure in patients who do not have the reactive form of PAH. Currently, accurate diagnosis and differentiation of these patients rely heavily on invasive hemodynamic assessment by right heart catheterization due to poor accuracy and reliability of Doppler echocardiographic indices. We propose to identify novel non-invasive parameters using time-resolved 3D Phase contrast cardiovascular magnetic resonance imaging to study patients with heart failure with preserved ejection fraction with and without reactive PAH, and compare with patients who have PAH. There is a striking preponderance of women with PAH and reactive pulmonary hypertension associated with heart failure with preserved ejection fraction. The novel imaging parameters may have a significant impact in how pulmonary hypertension is diagnosed and monitored and thus significantly impact women’s cardiovascular health.
Rachel R. Kelz, MD, MSCE, FACS
Assistant Professor, Department of Surgery
Division of Endocrine and Oncologic Surgery
Disparities in Lower Extremity Bypass Outcomes for Women within the State of Pennsylvania: Who is at-risk and what can we tell them to minimize their risk?
Project Abstract: Peripheral vascular disease (PVD) is estimated to affect over ten million people in the United States. As the American population ages, more people are being diagnosed and treated for PVD. Women comprise the majority of the aging population. Women with PVD are more likely to be asymptomatic and present with more advanced disease. Lower extremity bypass (LEB) is frequently performed for treatment of PVD. While LEB can restore quality of life and productivity when successful, graft failure is often associated with amputation resulting in significant disability. Studies have shown that men have improved outcomes following LEB surgery when compared to women. Differences in preoperative severity of disease, hospital expertise and referral patterns may affect outcomes ranging from graft failure/amputation and death to cost. Institutional differences in LEB volume, presence of vascular surgical training programs, and the hospital setting may affect outcomes between genders. Other disparities related to socioeconomic status, race and age might also potentiate or mitigate the gender disparities. The aims of this study are to 1) evaluate outcomes for women undergoing LEB surgery for PVD when compared to male patients and2) identify hospital characteristics associated with optimal patient outcomes for women undergoing LEB for PVD. We propose the use of data from the Pennsylvania Healthcare Cost Containment Council to answer these questions. We expect the findings from this analysis to result in publications, collaborations, and grant proposals to address gender-relevant interventions that have promise to improve the delivery of surgical care for women.
Julio A. Chirinos, MD
Assistant Professor, Department of Medicine
Division of Cardiology
Prospective risk factors for increased arterial wave reflections with aging in women and men
Project Abstract: Wave reflections arising in peripheral arteries and returning to the proximal aorta during mid-to-late systole are important determinants of left ventricular afterload (i.e., work load). Wave reflections have been associated with left ventricular remodeling and are a known stimulus for abnormal diastolic function in vitro and in vivo. Furthermore, increased wave reflections have recently been shown to be a strong risk factor for developing future heart failure. However, the factors that favor an abnormal progression of wave reflections as men and women age are unclear, because all studies that have assessed the correlates of wave reflections to date have done so in a cross-sectional fashion. Given that the levels of arterial function at any given point in time are related to arterial structure which is affected by many factors over the lifetime, we believe that the relationship between prevalent risk factors and a single arterial measurement is subject to important confounding by the lifetime exposure history of individuals. Therefore, the aim of this proposal is to assess the factors associated with changes in wave reflections over time among unselected men and women from the general population. We propose to assess this in a population that naturally demonstrates pronounced wave reflections (PREVENCION Study population). We will assess various candidate factors as predictors of worsening wave reflections as well as gender differences in the rates of wave reflection changes over time among men and women and its determinants. This investigation is highly relevant to women’s health because women demonstrate greater levels of wave reflections than men. Given recent data that strongly links wave reflections with incident heart failure risk, it is possible that wave reflections are implicated in gender differences in the susceptibility to develop ventricular remodeling and heart failure with preserved ejection fraction in older women. Findings from this study may direct future research efforts towards slowing the progression of wave reflections with aging in men and women.
Alexis Ogdie-Beatty, MD
Instructor, Department of Medicine
Division of Rheumatology
Managing Hyperlipidemia in Rheumatoid Arthritis: Is Female Sex a Risk Factor for Non-receipt of Screening and Therapy?
Project Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that is 2-3 times more common among women than men and may result in permanent joint damage and disability. Over the past 5-10 years, attention has been drawn to the increased mortality among patients with RA, much of which is the result of premature cardiovascular disease. While there is now substantial evidence to support the increased risk of cardiovascular disease among RA patients, very few studies have examined the management of traditional cardiovascular risk factors in RA. The objectives of this study are to test whether a) RA patients are screened for hyperlipidemia, b) current ATPIII guidelines are being followed and c) proposed modifications to risk calculations change the proportion of RA patients that should be receiving lipid lowering therapy. Furthermore, I will assess whether female sex and age less than 50 years are risk factors for non-receipt of therapy. These objectives will be addressed in a retrospective cohort study utilizing data on over 5,000 RA patients from the Penn Data Store. This pilot grant will form the basis for future studies in CHD risk management among patients with RA, a disease which predominantly affects women, and result in preliminary data for large population-based studies examining CHD risk management among RA patients.
Kerri Akaya Smith, MD
Instructor, Department of Medicine, Pulmonary, Allergy, and Critical Care Division
The Effect of Oral Contraceptives on Right Ventricular Structure and Function
Project Abstract: Rationale: Pulmonary arterial hypertension is a progressive disease of the pulmonary arteries that leads to right ventricular hypertrophy and eventual failure. It occurs predominantly in women but the influence of sex hormones on the pulmonary vasculature and right ventricular function are poorly understood. Indeed, the increased incidence of this disease amongst women is difficult to explain as existing data demonstrate that estrogen has a vasodilatory effect on the pulmonary circulation and suggest a beneficial effect on ventricular remodeling. Oral contraceptives are widely used and have complex effects on the hormonal milieu of the women taking them. Although there are several case reports in the literature suggesting that oral contraceptives may predispose to the development pulmonary hypertension, there have been no studies examining the relationship of contraceptive use, if any, to the development of pulmonary vascular disease and subsequent right ventricular dysfunction. Objective: To determine whether a history of oral contraceptive use is associated with right ventricular structure and function in a cohort of adults free of clinical cardiovascular disease. Methods: History and duration of exposure to oral contraceptives was assessed by self report questionnaire. RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume (RVEDV), and end-systolic volume (RVESV) were measured by MRI in 1957 men and 1738 post-menopausal women. The relationship between oral contraceptive use and RV parameters will be assessed with multivariable linear regression.
Sheela N. Magge, MD, MSCE & Andrea Kelly, MD, MSCE
Assistant Professors of Pediatrics, Division of Endocrinology/Diabetes
Vitamin D Supplementation and Outcomes in Obese, African American Adolescent Females
Project Abstract: Vitamin D deficiency/insufficiency is common throughout the lifespan, and across all race and ethnic groups. With many children vitamin D deficient, the American Academy of Pediatrics (AAP) recently increased the suggested supplementation dose to 400 IU daily in all children including adolescents. These recommendations target rickets prevention, but address neither the vitamin D supplementation necessary to optimize bone health nor nontraditional vitamin D roles: a number of studies have identified an association between vitamin D deficiency and cardiometabolic risk factors. Complicating matters, African-Americans are at increased risk of vitamin D deficiency, obesity, and insulin resistance while obesity is associated lower circulating vitamin D levels (25OHD). Vitamin D deficiency is also more common in female adolescents. Thus, the dearth of evidence for treatment and prevention of vitamin D deficiency in obese, African American females is particularly problematic. To examine the effect of vitamin D supplementation upon 25OHD in obese, African American females with vitamin D deficiency/insufficiency, subjects will be randomized to receive cholecalciferol 400 IU or 5000 IU daily for 3 months. Serum 25OHD, parathyroid hormone, glucose, insulin, and CVD risk markers will be obtained at baseline and post-treatment. This pilot study will provide data on serum 25OHD responses to vitamin D at doses more likely to meaningfully impact 25OHD than the current AAP supplementation guideline. Responses to supplementation can then inform future studies aimed at addressing outcomes of vitamin D replacement on insulin sensitivity and CVD risk in obese females.
Grace J. Wang, MD
Assistant Professor of Surgery, Division of Vascular and Endovascular Surgery
Gender Differences in the Intima-media Thickness of the Femoral Artery
Project Abstract: Purpose: Gender differences have been shown in the presentation and outcome of peripheral arterial disease. The mechanisms behind this are unclear. We are undertaking this investigation to detect the presence of gender differences in intima-media thickness (IMT) of the femoral artery. Methods: Femoral artery duplex will be performed on 100 consecutive male and 100 female patients at the Hospital of the University of Pennsylvania. B-mode ultrasonography will be used to measure the IMT of the femoral artery. Demographic data including gender, age, body mass index, presence or absence of medical co-morbidities such as diabetes, hypertension, renal failure, hyperlipidemia, will be recorded for both groups. Continuous variables will be compared using student’s t-test while chi-square analysis will be used to compare categorical variables. . Multivariable logistic regression analysis will be performed to detect significant factors associated with gender. Results: The investigator anticipates finding a gender-related difference in IMT. This may or may not be more pronounced within the pre-menopausal female group, secondary to hormone-related differences. Conclusions: Gender-related differences in femoral IMT has not been studied or described. This will contribute to a greater understanding of the process of atherosclerosis. It will also allow us to pursue the study of gender-related differences in vascular remodeling of peripheral vessels following intervention.
Rajat Deo, MD
Assistant Professor, Medicine, Division of Cardiovascular Medicine
A Comparison of Risk Factors for Cardiovascular Death and Sudden Cardiac Death Using a Competing Risk Analysis in Women
Project Abstract: Sudden cardiac death is an important clinical and public health problem that is highly specific for arrhythmic events including spontaneous ventricular tachycardia or ventricular fibrillation. Cardiovascular death events, however, are often preceded by premonitory, cardiopulmonary symptoms and can be the consequence of long-standing coronary heart disease or congestive heart failure. We proposed to compare risk factors for sudden cardiac death to those of non-sudden cardiovascular death among women enrolled in the Hormone and Estrogen Replacement Study. The HERS trial was a randomized, placebo-controlled trial that evaluated the effect of hormone replacement therapy on women with coronary heart disease. Our project proposed to utilize a series of steps to evaluate the competing risk of sudden cardiac death and non-sudden cardiovascular death events in this population. We will first use a Dox proportional hazards model to evaluate the independent association of baseline demographics and time-dependent covariates with sudden cardiac death and non-sudden cardiac death, censoring follow-up at other kinds of death. We will then compare the strength of associations of baseline and time-dependent risk factors with each of these outcomes. Finally, we will estimate the competing risk cumulative incidence of sudden cardiac death and non-sudden cardiac death. This method estimates cumulative incidence of first events without attempting to remove other causes of death. Finally, we will compare the effects of baseline and time-dependent covariates on cumulative incidence of sudden cardiac death, non-sudden cardiac death, and death from other causes, all considered as competing risks.
Yi Jin, PhD, MS
Research Assistant Professor, Pharmacology
Cardiovascular Effects of Progestins and Their Metabolites
Project Abstract: Progestins are commonly used in hormone therapy for women, e.g., contraceptives and hormone replacement therapy. Progestins exert diverse effects on cardiovascular systems, and the mechanism of which is not well understood. The natural progestin progesterone is believed to have beneficial cardiovascular effects, whereas the synthetic progestins are either neutral or harmful. Women using contraceptives and hormone replacement therapy are subject to potentially long term harmful cardiovascular effects, thus, the understanding of the molecular mechanism of progestin effects is of paramount importance. Exogenous progestins undergo extensive metabolism to form a variety of metabolites that may have diverse activities towards hormone receptors. The activities of the metabolites on cardiovascular system are largely unexplored. We hypothesize that progestin metabolites have regulatory cardiovascular functions that have been attributed to the parent progestin. Herein, pilot studies are proposed to (1) determine the vascular metabolism of progesterone and in vitro metabolism of two representative synthetic progestins; (2) characterize the activities of progesterone and its metabolites to trans-activate different hormone receptors; and (3) examine the direct effects of progesterone and its metabolites on vascular function. The results of these studies will lay the foundation and test feasibility for the investigation of the identities and availabilities of progestin metabolites in vascular system and their receptor binding properties and cardiovascular effects. The finding of this research will impact directly on the use and design of hormone therapy and help define new strategies to improve cardiovascular health of women.
Lilie Lin, MD
Assistant Professor, Radiation Oncology
Reducing Cardiac Morbidity for Women with Left Sided Breast Cancer: The Potential of Proton Radiotherapy
Project Abstract: Breast cancer is the second leading cause of cancer related mortality and is the most common non-skin cancer in women. Surgery is the mainstay of treatment, however, postoperative breast or chest wall radiotherapy and chemotherapy are routinely given in both early and locally advanced breast cancer. Cardiac morbidity is a well known late effect of therapy – both chemotherapy and radiation therapy. Radiation techniques to minimize cardiac damage have been studied. However, many of these studies were done in women with early stage breast cancer who do not require nodal irradiation. If patients require radiation of regional lymphatics, radiation fields are expanded potentially resulting in increased dose to surrounding normal tissues. Improvements in normal tissue sparing may be accomplished with proton therapy which has physical advantages over photon beam therapy. The aims of this study are: 1) To quantify the dose to the left ventricle, whole heart, and coronary vessels with standard three dimensional conformal radiotherapy using cardiac MRI. 2) To determine the impact of intrafraction motion on dose to the whole heart, left ventricle, and coronary vessels from either photon or proton beam therapy and to identify the optimal point in the respiratory cycle where dose to the myocardium and left ventricle is minimized. 3) To perform a comparative analysis of dose deposition to the left ventricle, whole heart, and main coronary arteries as identified on cardiac gated MRI using intensity modulated radiotherapy, 3D conformal radiotherapy, and scanning proton beam therapy for women receiving left breast or chest wall radiotherapy.
Hillary R. Bogner, MD, MSCE
Assistant Professor, Family Medicine and Community Health
Integrating Hypertension and Depression Management Among Older Women
Project Abstract: Older women experience a disproportionate burden of hypertension and depression. Despite the importance and prevalence of hypertension, control tends to be poor among older adult women. Poor adherence to medications for the treatment of hypertension and depression remains a significant impediment to improving care. Depression contributes to poor adherence to treatment recommendations. An integrated intervention addressing depression and hypertension in primary care would improve outcomes for both conditions and would be feasible in real world practices with competing demands for limited resources. The aims of this study are to: (1) To determine if an integrated intervention strategy focused on improving adherence among women aged 50 years and older with clinically significant depression and hypertension results in improved (a) adherence to antihypertensive medications (b) adherence to antidepressants (c) blood pressure control and (d) depression remission and response over a 3 month interval. We will carry out a randomized controlled trial of the Integrated Care Intervention versus Usual Care. Key components of the Integrated Care Intervention are: (a) provision of an individualized program to improve adherence that recognizes women’s social and cultural context; and (b) integration of hypertension and depression management. Factors affecting adherence will be addressed using a 4-step problem solving process. Our work should foster the development of integrated interventions for cardiovascular disease and depression.
Bonnie Ky, MD
Division of Cardiovascular Medicine
The Role of Circulating Neuregulin in Trastuzumab-Induced Cardiomyopathy
Project Abstract: Significant advances have been made in the treatment options for breast cancer, but cardiac toxicity associated with chemotherapy remains a critically important issue. More than 20% of breast carcinomas overexpress the HER2/neu (ErbB2) gene and are thus particularly responsive to trastuzumab (Herceptin), a monoclonal antibody that binds to the extracellular domain of ErbB2. However, a portion of these patients go on to develop significant cardiac dysfunction. The pathogenesis of trastuzumab-induced cardiomyopahty is still unclear. Basic science evidence would suggest that trastuzumab-related cardiac damage may be related to the inhibition of the NRG/ErbB pathway in cardiomypcytes. Animal studies have demonstrated a critical role for the neuregulin (NRG)/ErbB signaling pathway for fetal heart development and adult cardiac function. NRG-1 activates the ErbB signaling pathway, and promotes the growth and survival of cardiomyocytes. NRG-1/ErbB deficient animals develop a dilated cardiomyopathy phenotype, increased susceptibility to cardiac injury, and decreased survival. However, whether these findings translate to humans are unknown. The overall objective of this proposal is to define the biologic and clinical relevance of circulating neuregulin as it relates to the risk of developing trastuzumab-induced cardiomyopathy. We have preliminary evidence that neuregulin-1β (NRG-1β) levels are significantly decreased in subjects with chemotherapy-induced heart failure. We will extend these findings by defining the association between levels of NRG-1β and risk of cardiac dysfunction in a cohort of patients who receive trastuzumab therapy. Our study will provide important insight into the role of NRG-1β in chemotherapy-induced cardiomyopathy and its potential clinical utility as a prognostic tool.
Sindhu K. Srinivas, MD, MSCE
Assistant Professor, Obstetrics and Gynecology
Evaluating Short Term Cardiovascular Risk after Preeclampsia in African American Women
Project Abstract: Cardiovascular disease (CVD) is the leading cause of death in women, both in the United States and worldwide. Recent studies suggest that hypertensive disease of pregnancy (gestational hypertension or preeclampsia) is associated with future cardiovascular morbidity and death. Given their retrospective nature, these studies are unable to identify when these women begin to incur increased risk for CVD. Preeclampsia is a pregnancy-specific syndrome broadly defined as the presence of hypertension and proteinuria. It is a major contributor to maternal and perinatal morbidity worldwide. Despite continued research to understand the underlying mechanisms responsible for the development of preeclampsia, the only known treatment is delivery. It has been difficult to identify women at-risk for CVD early and the observed association between preeclampsia and CVD provides a tremendous opportunity to determine when and if lifestyle modification and/or medical intervention may prevent significant cardiovascular morbidity and mortality. If preeclampsia is an early manifestation of cardiovascular disease, identifying the time period at which these women have an increased risk and targeting this group at an earlier age might have a significant impact on long-term cardiovascular morbidity and mortality. Unique to this study will be a cardiovascular risk evaluation (components of the metabolic syndrome in non-pregnant African American women, 1-4 years from delivery, with a history of hypertensive disease in pregnancy and those without this history. African American women are the subjects of this proposal since these women are disproportionately affected by both preeclampsia and CVD. We hypothesize that African American women with a history of preeclampsia will have a higher prevalence of objective cardiovascular risk factors shortly after delivery. This will enable future targeted early prevention/intervention trials in women at risk for future CVD to ensue.
Najjia N. Mahmoud, MD
Assistant Professor, Surgery
Division of Colorectal Surgery
The Influence of Gender on Colorectal Surgical Outcomes and Operative Decision-making
Project Abstract: The purpose of this study is to examine gender-related issues specific to the surgical treatment of colon and rectal cancer. There is evidence to suggest that, although the disease strikes men and women in equal numbers, sugical planning, intraoperative decision-making, and functional outcomes may differ greatly between genders. Differences in anatomy, preoperative function, and referral patterns may affect outcomes ranging from local recurrence rates and anal sphincter preservation to survival. Differences in type of institution (university versus community hospital, for example), surgery specialty training, hospital surgical volume, hospital setting, and region may affect outcomes between genders, but very little is known about this to date. There is data demonstrating that rates of screening colonoscopy, although increasing in recent years for both men and women, lag behind in female patients nationally, and that far fewer African American and Hispanic women are referred for screening. We propose to investigate the question of whether these disparities also extend to differences in technically complex procedures such as colectomy and proctectomy, and to the complicated preoperative and postoperative medical decision-making that accompanies treatment. The SEER-Medicare database brings together Medicare administrative claims data with detailed clinical tumor registry data. We propose the use of SEER-Medicare date to answer these questions.
Zachary F. Meisel, MD, MPH
Assistant Professor, Emergency Medicine
Impact of Gender on Prehospital Management of Chest Pain
Project Abstract: Gender disparities in cardiac care have been demonstrated in emergency department (ED), in-hospital, and outpatient care. However, the impact of gender on the out-of-hospital evaluation and management of patients with chest pain who are in route to the hospital has not been studied. The identification of the nature and extent of prehospital gaps in quality of cardiovascular care for women has specific relevance because of the time-sensitive nature of cardiac syndromes and the influence that prehospital evaluation and treatment has on hospital-based care. We propose to conduct a retrospective cohort study that will seek to identify gender disparities in the out-of-hospital care of chest pain patients brought to two urban hospitals by a city-run emergency medical services (EMS) system. We will compare the prehospital use of therapeutic and diagnostic interventions, which have been proven to improve outcomes in cardiovascular syndromes, for male and female patients with chest pain.
Suman Lata Sood, MD
Instructor, Medicine, Division of Hematology/Oncology
A Phase II, Randomized, Double-Blind, Placebo-Controlled Feasibility Study of the Effects of Statin Use on the Coagulation System in Women with Metastatic Breast Cancer
Project Abstract: Venous thromboembolic disease (VTE) is a serious and potentially fatal disorder that especially affects the oncology population. Statins are widely used medications that have been shown to be safe in a number of settings. Interesting preclinical data exists which suggests that statins may decrease the risk of thrombogenesis by decreasing platelet activation, promoting fibrinolytic pathways, and down regulating the coagulation cascade. Several observational studies have demonstrated an association of statins with reduced risk of VTE, and that this association may be stronger in women than in men. It would be of great benefit to develop an non-anticoagulant strategy of VTE prophylaxis for metastatic breast cancer patients, who are at increased risk of developing venous thromboembolism and not tolerating anticoagulation, especially during active treatment with chemotherapy or hormonal therapy. As a first step in examining the potential clinical intervention, a phase II randomized, double blind, placebo controlled study is proposed to assess the feasibility of studying the effect of statin use on the coagulation system in patients with metastatic breast cancer. Sixty women with metastatic breast cancer undergoing chemotherapy and sixty women with metastatic breast cancer under treatment with hormonal therapy will be enrolled in the trial. Subjects in the chemotherapy and hormonal therapy groups will be randomized to either the placebo or the statin arm. Baseline coagulation markers will be drawn and then re-evaluated at the end of 12 weeks. Feasibility criteria will be assessed as the primary study endpoint.
Alexis A. Topjian, MD
Assistant Professor, Anesthesia, Critical Care
Association of Gender and Age with Survival Outcomes after In-Hospital Cardiac Arrest
Project Abstract: Survival outcomes after cardiac arrest are related to patient, facility and process of care factors. Pre-clinical studies suggest that estrogen is neuroprotective when administered before or immediately following cardiac arrest. Following human out-of-hospital cardiac arrest, female gender < 50 years of age is associated with better survival than age matched males. In-hospital cardiac arrest patients, process of care and outcomes are very different from the out-of-hospital setting. The relationship of gender and age to important process of care and survival outcomes following in-hospital cardiac arrest is unknown. Our objective is to determine the association of gender and age with in-hospital cardiac arrest event survival, with appropriate control for confounding patient and hospital characteristics. We will conduct a multivariable analysis using logistic regression of the world's largest cohort of in-hospital cardiac arrests, > 100,000 cardiac arrests reported by more than 350 hospitals to the American Heart Association's National Registry of CPR. We hypothesize that female gender is associated with better cardiac arrest survival outcomes than male gender, even when controlling for important patient, hospital and process of care factors. To further assess if presumed relative presence of estrogen (menarche/menopause) modifies the effect of gender on survival outcomes, we hypothesize that women of child-bearing age (13-50 years) will have better survival outcomes than girls <13 years (presumed pre-menarche) and women >50 years (presumed post-menopause) and age matched males. We expect the findings from this analysis to provide a springboard for future research, publications, collaborations, and grant proposals to address gender-relevant interventions that have promise to improve outcomes following cardiac arrest.
Angela M. Mills, MD
Assistant Professor, Emergency Medicine
A Randomized trial of an ED Tobacco Cessation Intervention with Parenting Women
Project Abstract: Tobacco is the leading cause of preventable death in the US, and exposure to passive smoke is a leading cause of morbidity and mortality in children. While 21% of Americans smoke, ED patients have a much higher rate of 40%. Approximately 40% of children who present to EDs live in households with caregivers who smoke. As many patients use the ED as their primary source of healthcare, the ED may be their only source for tobacco cessation information. While 50-60% of ED patients are asked about smoking, only 6-9% are counseled in cessation. Interventions in the ED may occur during "teachable moments," and a higher percentage of patients will quit if the reason for visit is related to their smoking.
We hypothesize mothers of young children may be more motivated to quit smoking if given a brief motivational interview (BMI) in an ED setting tailored to the effects of tobacco smoke on their own and their children's health.
The principal investigator will collaborate with the transdisciplinary Tobacco Use Research Center to develop and test a BMI tailored to parenting female smokers with young children. Patients will be randomized to BMI with Quitline card (smoking cessation hotline) and one-week follow-up phone call. The control group will be advised to quit and given the Quitline card. Both groups will be compared at one month with regard to stage of readiness to change, steps taken to reduce tobacco consumption, and successful quit rates, measured by self-report and a biological marker of nicotine use.
Susan A. Colilla, PhD, MPH
Instructor of Epidemiology in Biostatistics and Epidemiology
Estrogen Metabolism Gene Polymorphisms as Independent Risk Factors for Cardiovascular Disease in Women
Project Abstract: Heart disease is uncommon in premenopausal women, but the risk increases dramatically after menopause, and it is likely due to the loss of the protective effects of estrogen. Surprisingly, exogenous hormone replacement therapy in postmenopausal women has not shown the expected beneficial cardioprotective results. Estrogens have favorable effects on lipids, endothelial function and remodeling but recent studies have suggested that some of the cardiovascular effects of estrogen may be attributed to intracellular estradiol metabolites. We hypothesize that polymorphisms in estrogen metabolism genes will have an independent effect on cardiovascular risk factors and cardiovascular outcomes and in part may explain the variable effects of estrogen replacement therapy.
Data from randomly selected control subjects participating in a recently completed population-based case-control study for breast and endometrial cancer in women will be tested for an association between estrogen metabolism gene polymorphisms and cardiovascular disease risk factors. We will also examine if estrogen metabolism gene polymorphisms can independently predict a cardiovascular disease outcome in these women. The goal will be to generate and streamline etiologic hypotheses about the relationship of estrogen metabolism gene polymorphisms, environmental factors and cardiovascular disease. This pilot project will focus the specific aims and provide preliminary data for an NIH grant proposal examining the relationship between estrogen levels, estrogen metabolism genes, environmental factors and heart disease in a current cohort study (SWAN) of perimenopausal women.
Darren Taichman, MD, PhD
Assistant Professor of Medicine in Pulmonary, Allergy and Critical Care Division
Serotonin Activity and Cognitive Deficits in Patients with Pulmonary Arterial Hypertension
Project Abstract: Pulmonary arterial hypertension (PAH) predominantly affects young women, causing progressive functional impairment, cardiopulmonary failure and premature death. While recent advances in therapy have increased survival, these women continue to suffer with significant limitations in exercise capacity. Further, disease effects beyond the cardiovascular system impose additional burdens on quality of life. The effects of PAH beyond the cardiovascular system, however, have not been well studied particularly the effects on brain function. We have recently developed a simple research tool for the identification of cognitive dysfunction in patients with PAH, and have shown that over half of patients tested have clinically significant cognitive impairments. Emerging data suggests that abnormalities in serotonin signaling might be important in the development of PAH as well as cognitive dysfunction. We therefore propose to evaluate the association of cognitive deficits dysfunction. We therefore propose to evaluate the association of cognitive deficits with abnormal serotonin signaling by determining:
The prevalence of cognitive deficits in patients with PAH.
Plasma serotonin transporter activity among PAH patients with and without cognitive deficits.
The relationship between serotonin transporter activity and the presence of cognitive deficits in patients with PAH.
Marna S. Barrett, PhD
Assistant Professor of Psychology in Psychiatry
Engagement and Attrition in Community Mental Health Settings
Project Aim: Relying on established partnerships with two community mental health centers, the proposed study is designed to assess and document those factors most predictive of dropout for female consumers of public mental health services. Factors influencing engagement and attrition will be examined at several points during the initiation of services as well as examining the relation between attrition and mental distress. The purpose of this initial investigation is for understanding attrition patterns and their correlates; designing interventions to improve service utilization; and, providing the most effective treatment in the most efficient manner.
Harold I. Litt, MD, PhD
Assistant Professor of Radiology
Gender Differences in Imaging Evaluation of Patients Suspected of Having Pulmonary Embolism
Project Aim: This project will expand on a preliminary study that determined marked gender differences in the utilization of Computed Tomography examinations performed for suspected pulmonary embolism of patients seen in the Emergency Department at HUP. This next phase of the project will investigate the usage of V/Q scans. Through an analysis of ED records, this study will attempt to determine which clinical factors, such as chief complaint, previous medical history, EKG findings, or other, may be contributing to this gender difference in utilization of diagnostic imaging studies. The goal is to foster more appropriate resource utilization as well as improved care for women suspected of having pulmonary embolism.
Marina Catallozzi, MD
Relationship Choices of Adolescent Women: Characterizing the Phenomenon of Older Partners
Project Aim: This preliminary study will explore the prevalence of young women having sex with older men and will begin to identify reasons for, and factors associated with, this behavior. Increasing understanding of this phenomenon to assist with the development of policy initiatives regarding training curricula for health care providers as well as with appropriate interventions for adolescents who are at highest risk for negative outcomes associated with this behavior.
Peter Foster Cronholm, MD
Instructor, Family Practice and Community Medicine
The Association between Low-Literacy and Exposure to Domestic Violence in Prenatal Patients
Project Aim: A cross sectional study to assess the association between literacy level and exposure to domestic violence in prenatal patients; and, a specific hypothesis that low literacy levels will be associated with higher levels of exposure to domestic violence in prenatal patients. Low literacy and DV are associated with low self-efficacy. Interventions targeting variables that mediate self-efficacy may reduce adverse outcomes associated with DV.
Evaline A. Alessandrini, MD, MSCE
Assistant Professor, Pediatrics and Epidemiology
“Caring for Kids: Illnesses and Injuries”- A Community Intervention
Project Aim: Project motivated by the frequency with which impoverished mothers rely on emergency departments as the usual source of health care for their children.
To examine the effects of a community-based education and skills intervention on maternal knowledge of common childhood illness and skills and confidence in caring for their children
To examine the effects of a community-based education and skills intervention on the use of health (particularly emergency) services by children of mothers involved in this project.
Elizabeth Datner, MD
Assistant Professor, Emergency Medicine
Evaluating Emergency Department Services Provided to Women Reporting Domestic Violence
Project Aim: To implement a clearly defined, routine intervention strategy in the Emergency Department at the Hospital of the University of Pennsylvania in cases of women patients who report being in abusive relationships; and, to use the transtheoretical Model of Behavioral Change to evaluate the effectiveness of physician-based intervention.
Carmen Guerra, MD
Assistant Professor, Medicine
Division of General Internal Medicine
The Association between Literacy and the Knowledge, Attitudes, and Behavior about Screening Mammography in Urban Hispanic Women
Project Aim: To determine whether functional health literacy:
correlates with knowledge about screening mammography
correlates with more negative attitudes about screening mammography
is an independent predictor of poor compliance with screening mammography as determined by self-report
Catherine S. Bradley, MD
Instructor, Obstetrics & Gynecology
Fellow, Urogynecology and Reconstructive Pelvic Surgery
Female Urinary Incontinence: Developing and Pilot Testing a Diagnostic Questionnaire
Project Aim: To develop and pilot test a diagnostic symptom questionnaire, which can accurately classify women into the most common types of female urinary incontinence.
Jennifer Tjia, MD
Fellow, Division of General Internal Medicine
The Use of Tamoxifen for Breast Cancer Prevention: Assessing the Preferences of Minority and Older Women
Project Aim: To obtain data about the extent and determinants of interest in Tamoxifen use for breast cancer prevention by older, lower income, and minority women.
Judd E. Hollander, MD
Associate Professor, Emergency Medicine
The Effect of Written Informed Consent on Domestic Violence Screening
Project Aim: To determine whether the use of informed consent biases the results of standardized domestic violence screening assessments in the ED; to compare written versus verbal consent with the prediction that written consent is less efficacious in detecting domestic violence.
Raquel M. Schears, MD, MPH
Assistant Professor, Emergency Medicine
Gender Bias in Resuscitation Practices
Project Aim: To determine whether gender bias exists in resuscitation practices used for victims of non-traumatic cardiac arrest.
Sally Yael Segel, MD
Fellow in Maternal Fetal Medicine, Obstetrics and Gynecology
Duration of Antibiotic Therapy after Pre-term Premature Rupture of Fetal Membranes
Project Aim: To determine if the duration of Ampicillin therapy affects the ability of a woman with PPROM to achieve a seven day latency period from rupture of fetal membranes to delivery.
Joseph Bernstein, MD
Assistant Professor, Orthopedic Surgery
Patient Preference for Outcome: The Role of Gender in the treatment Threshold for Meniscal Tears
Project Aim: To assess gender differences in patient attitudes toward potential treatment outcomes for suspected meniscal tears of the knee.
Allan Gottschalk, MD, PhD
Assistant Professor, Anesthesia
The Impact of Preemptive Analgesia on Pain and Recovery from Major Surgery in Women: Pilot Studies
Project Aim: To obtain pilot data to support a future NIH study focused on gender differences in acute pain therapy by examining the gender variations in impact of preemptive analgesic methods in post-operative pain.
James M. Nicholson, MD
Clinical Instructor and OB Coordinator
Family Practice and Community Medicine
AMOR-IPAT: The Active Management of Risk in Pregnancy at Term: A Prospective Multidisciplinary Pilot Study of Nulliparous Pregnancy
Project Aim: To assess the feasibility of a randomized control trial of the Active Management of Risk in Pregnancy at Term (AMOR-IPAT) protocol, which aims to reduce cesarean section, rates in high-risk pregnancies.
Susan Gennaro DSN, RN, FAAN
Associate Professor, School of Nursing
Project Aim: To compare health outcomes in mothers of term and preterm infants. Controlling for parity, race, age, comparisons were made of two groups of mothers for the first four postpartum months.
Emma J. Brown, PhD, RN, CS
Research Assistant Professor and Coordinator
Center for Urban Health Research School of Nursing
Barriers to Preventive Health and Primary Care Services for Women Who Use Crack Cocaine
Project Aim: To identify retrospectively the barriers to preventive and primary health care faced by women who use crack cocaine; to describe and classify these structural, financial, and personal barriers; to identify sources of primary care readily available to these women, sources that will then provide ongoing health services to the study sample; to monitor prospectively the women’s patterns of using these preventive and primary-care services after barriers have been reduced or eliminated.
Elizabeth Datner, MD
Assistant Professor, Emergency Medicine
Utilization of the Emergency Medical/911 System as an Identifier of Domestic Violence
Project Aim: To yield important data on the potential for the EMS/911 system to be used to reach out to women at risk of domestic violence- identifying what reasons the domestic violence victims gave for calling 911, as compared to reasons given by non-victims, thereby developing preliminary indicators for future intervention.
Anne Blackwood, MD
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Dr. Blackwood's areas of research interest are molecular epidemiology and cancer genetics, specifically in the development of risk prediction methodologies and preventive interventions in the hereditary breast cancer population.
Modifiers of Breast Canter Risk among BRCA1 Mutation Carriers: Polygene Interactions
Project Aim: To investigate hypotheses related to the modification of breast cancer penetrance among BRCA1 mutation carriers. The risk modifiers being investigated include reproductive factors and the genotypes of several carcinogen-metabolizing genes. This study also investigates possible interactions between these carcinogen-metabolizing genotypes and reproductive factors in modifying breast cancer penetrance among BRCA1 mutation carriers.
Annie Steinberg, MD
Assistant Professor, Departments of Psychiatry and Pediatrics
Director, Deafness and Family Communication Center, CSH of CHOP
Lip reading in the Stirrups
Project Aim: Through a series of focus groups, to address deaf women experiences, perceptions, attitudes, and beliefs about their health and health care experiences.
Joan Von Feldt, MD
Assistant Professor, Medicine
Project Aim: To evaluate the use of an abbreviated cognitive screen which can be used in a practitioner's office to identify and evaluate cognitive dysfunction in a cohort of women with Systemic Lupus Erythematosus (SLE), an illness that more commonly affects women of minority status. The screen has the potential to become a useful tool to follow a patient's clinical response to therapeutic interventions.