My doctoral and initial postdoctoral experiences were in the field of autonomic innervation to sweat glands and skin in pathological states. These studies, under the tutelage of Timothy Cowen, PhD, at Royal Free Hospital during my graduate studies, and Peter Smith, PhD, at University of Kansas during my postdoctoral studies, resulted in 16 published papers. This research initially focused on the effect of growth factors on neuronal remodeling in skin and progressed to novel expression and function of neurotrophic factors. My studies clearly showed that autonomic neurons rely on adjacent neurons for trophic support—a concept that was novel at the time.
I was interested in the clinical challenge of sudden cardiac death and arrhythmogenesis, and I turned my focus to aberrant cardiac neuronal remodeling in the heart. These studies were started in the Smith Laboratory, where I focused on post-infarction remodeling, and continued in my second postdoctoral/research associateship program position in the laboratory of Beth Habecker, PhD, at Oregon Health and Science University. I demonstrated that inflammatory cells were potent inducers of aberrant nerve growth following a myocardial infarct. This research also showed that inflammatory cells in the peri-infarct zone dedifferentiated to more primitive phenotypes that promoted nerve growth.
My independent studies, initially at Oregon Health and Science University, have resulted in a National Institutes of Health R01 award and appointment to assistant professor at Cedars-Sinai. My R01 studies focus on thromboembolic complications, which are the most common reason for mortality or rehospitalization in heart failure patients. Thrombi that develop in the atrial or ventricular chambers (endocardial thrombi) can break off and cause thromboembolic events in other parts of the body or interfere with cardiac output. My research focuses on endocardial endothelial dysfunction as a key contributor to a prothrombotic state in heart failure. I have characterized endocardial dysfunction and thrombosis in a transgenic mouse model of heart failure. In these studies, I evaluated the mechanism for endocardial dysfunction and demonstrated attenuation in the anticoagulant activated protein C pathway and corresponding increases in thrombin generation and von Willebrand factor (vWF) extrusion as key determinants of endocardial endothelial dysfunction, and endocardial thrombosis promotion, in the progression of heart failure.
Having identified the endocardial lining of the heart as a likely contributor to formation of cardiac thrombi, I turned to human endocardial endothelial cells from heart failure patients to understand this dysfunction better. My basic premise was that if we can promote endothelial health, then we should be able to reduce the risk of thromboembolic complications. Since cardiac sympathetic neuronal drive is increased early in heart failure, I targeted nerve-endothelial crosstalk as a key driver of endothelial dysfunction. Through treatment of cultured human endocardial endothelial cells, I was able to demonstrate that beta-adrenergic receptor blockade was useful for attenuating the pro-thrombotic phenotype of these cells from heart failure patients. Critically, key neuropeptides improved endothelial function.
Anticoagulation for reducing thromboembolic events carries risks of gastrointestinal bleeding. My studies should provide an alternative therapeutic tool that addresses the core endothelial dysfunction. These studies will have translational implications not only for heart failure patients, but also for other conditions in which thromboembolic complications are an issue, particularly in atrial fibrillation patients.