Biomechanics and Hypoplastic Left Heart Syndrome: Starting with Flow=Grow

Speaker Details:

Vishal Nigam
Associate Professor, Physician
Pediatric Cardiology, Seattle Children's Research Institute/UW

Lecture Details:

January 11, 2018
1:30-1:20 p.m.
Foege N130A, Wallace H. Coulter Seminar Room

Abstract:

As physician-scientist who cares for children born with cardiac defects, my research program is focused on understanding the pathogenesis of Hypoplastic Left Heart Syndrome (HLHS) and improving the care of these patients. HLHS is a condition in which children are born with left ventricle that is too small to support the systemic circulation. Current management consists of three palliative surgeries that do not result in recapitulation of a normal circulation. HLHS patients face very high morbidity and mortality, 5 year transplant-free survival is less than 70%, and are expensive to care for with initial hospitalization costs over $250,000. One of the hypothesis of the pathogenesis of HLHS is the “Flow=Grow” theory. Fetal echocardiographic data and animal experiments demonstrate that decreased blood flow into and/or out of the fetal left ventricle can perturb left ventricular growth. We are using finite element modeling and molecular biology to better understand this process. We have developed a strain based growth finite element model of fetal left ventricular growth. My laboratory has exposed embryonic mouse cardiomyocytes to cyclic stretch in order to elucidate key biomechanical responsive pathways. As a result of these experiments, we have identified a stretch responsive microRNA that can promote ventricular growth in vivo. The long term goal of this project is use molecular biology combined with multi-scale modeling to identify small molecules that can promote ventricular growth in HLHS patients.

Another challenge in caring for the HLHS is the peri-operative inflammatory response. In order to perform intracardiac surgery, patients need to undergo cardiopulmonary bypass (CPB). CPB patients experience systemic inflammation during the first 24 hours after surgery. In neonatal CPB patients, this massive inflammation reaction can cause multi-organ system dysfunction and morbidity/mortality. It is believed that exposure of blood to shear stress, plastic tubing the in the CPB circuit, and hypothermia instigates the inflammatory response. Efforts to limit this inflammation response with modified ultra-filtration and corticosteroids has had limited effectiveness. We have performed mRNA-sequencing and miRNA-sequencing from neonates undergoing CPB in order to identify key molecular pathways that can be targeted to ameliorate the post-CPB response. I hope that discussion of these topics will help spur the conversation about some of the clinical issues in Pediatric Cardiology that are amenable to bioengineering solutions.

Speaker Bio:

Vishal is physician-scientist who is also a practicing Pediatric Cardiologist. His interest in cardiac develop was sparked as Howard Hughes Medical Student Fellow in Dr. Robert J. Schwartz at Baylor College of Medicine. He pursued this interest by doing a post-doc with Deepak Srivastavsa at UT Southwestern and the Gladstone Institute at UCSF. In 2009, Vishal started his lab at UC San Diego where he developed collaborations with engineers such as Drs. Andrew McCulloch, Jeff Omens, Juan Lasheras, and Juan Carlos del Alamo. This past October, Vishal joined Seattle Children’s/UW and is continuing his R01 funded efforts to combine molecular biology and engineering to improve the understanding and treatment of complex congenital heart defects, such as Hypoplastic Left Heart Syndrome.