George Lab

Sharon A. George, PhD

Dr. Sharon George leads the HEART Lab – Heart Engineering: Arrhythmia Research and Therapy Lab, in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh. Research in the HEART Lab can be broadly divided into the following foci:
 

1. Cardio-Oncology: Cardiovascular diseases have long been the leading cause of death, not only in the US but also worldwide. Decades of research in this field have led to a decline in the rate of cardiovascular deaths but recently an uptick in this statistic was observed. One factor that could contribute to this increase is related to cancer and its treatment. It has long been known that most cancer chemotherapy drugs and radiation therapy have significant cardiotoxic effects that can lead to heart failure or myocarditis and death. Recent studies have also demonstrated that cancer by itself can increase the risk of cardiac diseases such as atrial fibrillation and vice versa. Thus, it is very important to understand the interaction of these two major human diseases. This led to the rise of the new field of cardio-oncology.

The HEART Lab focuses on the role of cardiac metabolism in the development of chemotherapy-induced cardiotoxicity. Impaired metabolism is a hallmark of cardiotoxicity associated with several classes of chemotherapeutic agents. Yet, there are currently no effective cardioprotective strategies to protect the heart. The research in our lab focuses on two methods of cardioprotection by preserving metabolism, 1) exercise, and 2) molecular targets of metabolism.

Aerobic exercise is known to improve cardiac metabolism and thus could be cardioprotective. In the exercise study, we use a mouse model of treadmill running during chemotherapy as well as an in vitro exercise model for our human cardiac slices. The benefits of exercise on cardiac electrical, mechanical and metabolic functions are assessed by echocardiography, electrocardiography, optical mapping and seahorse analysis. Our results indicate that 1) exercise by itself modulates cardiac function and 2) during chemotherapy exercise has a cardioprotective role. Our recent study, indicates that exercise by itself causes significant electrical remodeling and increased risk of developing arrhythmias (aberrant electrical rhythms). The benefits of exercise during chemotherapy and the mechanisms underlying these cardioprotective effects are under investigation.

Alternatively, our group is studying molecular targets in the heart that can be activated to prevent chemotherapy-induced metabolic impairment. This new direction of research includes both mouse and human heart models. Transgenic knockout and overexpression mouse models and pharmacological agonists and antagonists are being tested in study. More details coming soon.
 

2. Sex-specific mechanisms of cardiac diseases and therapy: A preponderance of recent evidence suggests that cardiac physiology and the progression of cardiac pathophysiology is sex-specific. Premenopausal women are at a lower risk of developing life threatening cardiovascular diseases compared to age-matched men. This phenomenon is typically attributed to the protective effects of estrogen, which is higher in premenopausal women.

Our cardio-oncology studies identified that there is a significant sex dimorphism in the way that adult female hearts respond to cancer chemotherapy compared to male hearts. The HEART Lab aims to understand the contribution of the sex hormones, estrogen, progesterone and testosterone, in modulating cardiac physiology and pathophysiology. We use mice and human cardiac slice models treated with varying combinations of the above sex hormones. Mice with physiologic hormone profiles as well as gonadectomized mice with reverse hormone profiles are used in this study, along with similarly treated human cardiac slices. The cardiotoxicity of chemotherapeutic drugs are tested in each of these conditions. While males are typically associated with increased morbidity after chemotherapy, we expect to see opposite effect in the reverse hormone profile mice. The functional effects and mechanistic pathways involved in this hormonal regulation of chemotherapy-induced cardiotoxicity are under investigation. The results of this study could have significant impacts in determining chemotherapy and diagnosing cardiotoxicity in a sex-specific manner. More importantly, it could highlight the need to understand the cardiac response to hormonal therapies.
 

3. Human Cardiac Organotypic slices: The HEART Lab works with human donor hearts that are not used in transplantation. These human hearts can be used as whole heart preparations, coronary perfused wedge preparations and organotypic cardiac slice preparations, to study human cardiac physiology and pathophysiology. Of particular interest to the HEART Lab is the organotypic cardiac slices which are generated from the atria or ventricles in the heart at a thickness of up to 400 microns. These slices contain cardiomyocytes in their native environment along with other cardiac cell types and are an excellent tool for preclinical drug testing and translation of findings from animal research to the clinic. These slice preparations can be cultured over several days or weeks which allow the study of both acute and chronic effects of drugs on cardiac physiology. Dr. George has used this platform to test the effects of cancer chemotherapeutic agents such as doxorubicin, sunitinib, and other drugs such as dantrolene and relaxin.
4. Multi-parametric optical mapping of cardiac physiology and pathophysiology: Optical mapping is an imaging technique used to measure cardiac function from living tissue which can range from cells to whole hearts. To study the complex, multi-faceted phenomenon that is cardiac physiology and pathophysiology, the HEART Lab uses multi-parametric imaging systems to simultaneously measure parameters of cardiac metabolism (NADH and FAD), excitation (transmembrane potential) and contraction (intracellular calcium transients) from the same field of view. This allows the study of the modulation of these individual parameters and the interrelationship between them called metabolism-excitation-contraction coupling (MEC coupling).