Biomechanics and Mechanobiology of Pulmonary Hypertension due to Left Heart Disease

Pulmonary hypertension (PH) due to left heart failure (PH-LHF) is the most common cause of PH and is associated with a high morbidity and mortality. LHF impacts nearly 5.9 million adults and contributes to 1 out of every 9 deaths in the United States. Due to a lack of well-characterized animal models and the limitations of human subjects research, investigations into disease pathophysiology and progression have been limited and much of current understanding of the mechanisms of this disease remains speculative. We hypothesize the biomechanical and mechanobiological mechanisms are key to disease progression, especially at the pulmonary capillaries.  In particular, we hypothesize the increased cyclic stretch and decreased wall shear stress drive the transition from isolated post-capillary pulmonary hypertension (aka pulmonary venous hypertension) to combined pre-/post-capillary pulmonary hypertension. To investigate these mechanical mechanisms, we apply multiscale computational and experimental approaches including in vitro studies, ex vivo studies, and in vivo studies in both large and small animal models of disease.  We use a similar suite of methods to investigate the determinants of right ventricular failure, which is the common final pathway in most forms of PH.  Our results suggest novel therapeutic strategies for this common and deadly form of disease.