Nigam Lab

As a physician-scientist who cares for children born with cardiac defects, my research program’s R01 funded efforts combine molecular biology and engineering to improve the understanding and treatment of complex congenital heart defects.

Our team aims to improve the care of young cardiac patients by focusing on three areas:

  1. Discovering and applying innovative solutions for hypoplastic left heart syndrome (HLHS) – a rare, complex form of congenital heart diseases
  2. Improving the outcomes for children undergoing cardiac surgery with cardiopulmonary bypass and mechanical circulatory support
  3. Inventing new tools and processes that make surgery management safer and easier

Our lab is actively engaged in bench-to-bedside research to determine the best ways to care for children with congenital or acquired heart disease. Positioned on the edge of research and patient care, we work to uncover solutions to clinically relevant cardiovascular problems.

Hypoplastic Left Heart Syndrome

We have several areas of focus, one of which is to improve the understanding of and develop effective solutions for hypoplastic left heart syndrome (HLHS). HLHS is a rare, complex condition in which children are born with a 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 patients are expensive to care for with initial hospitalization costs over $250,000.

One of the hypotheses of the pathogenesis of HLHS is 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. As a result of our lab’s experiments, we have identified a stretch responsive microRNA that can promote ventricular growth in vivo. The long-term goal of this project is to use molecular biology combined with multi-scale modeling to identify small molecules that can promote ventricular growth in HLHS patients.

Cardiopulmonary Bypass Inflammatory Response

Our lab is also focusing on creating new methods to lessen or prevent the inflammatory response that occurs after pediatric patients undergo cardiopulmonary bypass (CPB). The vast majority of pediatric open-heart surgeries require the patient to be supported by CPB in order to give the surgeon a bloodless field to operate in, while also minimizing ischemic damage to the body. However, CPB patients experience significant post-CPB inflammation, which is especially severe in neonatal patients. While post-CPB organ dysfunction is seen in multiple organs, we are focusing on the heart and brain because of the severity of dysfunction and long-term impact of damage to these organs. Given the organ dysfunction, morbidity, mortality and costs associated with CPB, there is a pressing need to understand the pathogenic molecular and cellular changes that occur during and after CPB. We are taking steps to address those gaps in scientific knowledge that prevent us from identifying potential drugs that could effectively limit or eliminate the CPB-associated organ disfunction.

To address these issues, we are investigating how cardio-pulmonary activates biomechanical responsive pathways in circulating blood cells. CPB has been performed in the same way for the past 50 years, with little or no change in the way it is approached or managed. It is believed that exposure of blood to shear stress, plastic tubing 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. Our work is helping spur the conversation about some of the clinical issues in pediatric cardiology that are amenable to bioengineering solutions. Ultimately, we want to prevent an inflammatory response from occurring during CPB.

Investigator Biography

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Physical Address

Center for Developmental Biology and Regenerative Medicine
1900 Ninth Ave.
Seattle, WA 98101