Understanding hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, and a major cause of sudden death and heart failure. We have assembled an international multi-disciplinary team to perform a multi-scale analysis of how mutations that alter function of the myosin motor induce cellular- and tissue-level phenotypes. We are using two different platforms for these studies:

   a. Human iPSC-derived cardiomyocytes that are CRISPR-edited with β-myosin mutations. Major areas of investigation include the mechanisms of hypertrophy and hypercontractility, the role of altered metabolism and mitochondrial function and computational modeling.

   b. Human myocardium obtained from patients undergoing surgical myectomies. Using an integrated multi-omics approach we have uncovered dramatic alterations in myocardial metabolism and mitochondrial function in HCM. Human data will be compared to iPSC-CM data to determine how well iPSC-CM models recapitulate human disease.

Mitochondrial structure and function: from normal physiology to human disease

The human heart utilizes an amazing 6 kg of ATP daily to power contraction. Alterations in mitochondrial function and morphology are thus common to many cardiovascular diseases. We are exploring:

   a. The role of alterations in mitochondrial structure and function in normal physiology (such as exercise) and the role of these alterations in enhancing cardiovascular health/cardioprotection.

   b. Alterations of mitochondrial function and morphology, including fusion, fission, autophagy, mitophagy and biogenesis, in HCM.

Single cell analysis of mitochondrial heterogeneity

Current methods for assessment of mitochondrial function cannot detect cellular-level heterogeneity in mitochondrial response to stress. We have developed a high-throughput imaging platform which allows us to measure single cell mitochondrial function simultaneously in hundreds or cells and have uncovered previously unknown components of the mitochondrial response to oxidative stress. We have extended this platform to be able to image heterogeneity in mitochondrial function within a single cardiomyocyte. Our ultimate goal is to determine the role of mitochondrial heterogeneity in cell life-death decision-making.

hiPSC-CM Pharmacogenomics: the role of gene variants in anthracycline cardiotoxicity

Anthracyclines are highly effective chemotherapeutic agents however, their use is limited by dose-dependent cardiotoxicity. Using GWAS, we have identified several gene variants linked to anthracycline cardiotoxicity. However, the mechanism by which these variants influence cardiotoxicity is unknown. We are using hiPSC-CMs to confirm the cardiotoxicity modulating effects of these variants, determine their mechanisms and search for new cardioprotective agents.

Differences between right and left ventricular responses to stress and susceptibility to heart failure

Many children with congenital heart disease (CHD) have a right, rather than left, ventricle as their main systemic pump (e.g., those with hypoplastic left heart syndrome). We are using both murine models and isolated cardiomyocytes to explore differences between the right and left ventricular response to stresses experienced by patients with CHD, including increased afterload, preload and oxidative injury. We have identified RV-unique alterations in microRNAs, angiogenesis regulators, oxidative injury pathways, and mitochondrial function. 

Immune modulation in pediatric heart failure

In collaboration with project leader Dr. Meghna Patel (Pediatric Cardiology) we are using CyTOF to explore alterations in immune system function in children with heart failure, before and after implantation of a left ventricular assist device. We are searching for immune system biomarkers that predict adverse outcomes after VAD implantation. We are also utilizing this platform to examine immune function after pediatric heart transplant.

Post-transplant lymphoproliferative disease

Working with a multi-disciplinary team of Stanford investigators from transplant surgery, pediatrics and pathology, we have recently completed a 1000 patient clinic trial aiming to develop biomarkers for the detection and monitoring of post-transplant lymphoproliferative disorder in pediatric solid organ transplant patients. Trial enrollment is complete and data analysis is ongoing.