PROJECTS
Elucidating new mechanisms and treatments for cardiac hypertrophy and heart failure
The Kass lab focuses on elucidating novel mechanisms and therapies for various forms of myocardial disease. We utilize animal models with pressure-overload stress, ischemic or infarction stress, neurohormone stimulation, or cytotoxic stress often combined with genetically engineered mice to dissect signaling pathways. These studies are often coupled with tests of therapeutic approaches, genetic, small molecule, and device-based to identify effective new approaches that might warrant clinical testing and translation. Both hypertrophic heart disease and depressed dilated cardiomyopathy are studied.  The methods used are highly integrative, spanning sub-cellular molecular analysis and assays to cell culture and primary cell physiologic studies, through to intact animal models spanning mouse to human. Human studies make use of endocardial biopsies and explanted human heart tissue to test signaling pathways and muscle function. Cell physiology makes use of real-time myocyte shortening/calcium data obtained in unloaded myocytes or adding force in cells that are attached to a loading system. Sarcomere function is examined in chemically permeabilized myocytes, focusing on force-calcium dependence. The lab first developed pressure-volume analysis in intact large animals, then humans, and then mice, and use the method routinely.
Half of all individuals with heart failure have what appears to be fairly normal contractile function, typically assessed from the ejection fraction. This syndrome is now known as heart failure with preserved ejection fraction, or HFpEF. HFpEF patients have marked morbidity and mortality, and there is now only one approved treatment that is a repurposed diabetes medication. In the past two decades, HFpEF evolved from a syndrome where cardiac hypertrophy with hypertension were the prominent comorbidities, to a syndrome where severe obesity and cardio metabolic syndrome are most common. In my lab, we are trying to dissect how obesity has impacted HFpEF, what the impact is on molecular signaling, metabolic substrate use, and underlying function of the sarcomeres. The scope is broad, from very novel mechanisms underlying abnormal protein translation and metabolism, to why obesity has depressed sarcomere systolic performance in human HFpEF myocytes. We use multiple molecular methods, cellular and in vivo mouse models often with gene-modulation, and importantly human myocardial tissue, to determine what are the underlying defects in HFpEF, and what we might target for impactful treatment.
Sarcomere Dysfunction
Investigating the underlying mechanisms of sarcomere dysfunction in systemic sclerosis pulmonary arterial hypertension and transthyretin amyloid cardiomyopathy.
Hypusination in Heart Failure
Cholesterol Esters in Heart Failure
The Role of ACLY in Heart Failure
Serine and One Carbon Metabolism in Heart Failure
Exogenous Acyl-carnitine Metabolism in HF
The heart primarily uses long-chain fatty acids (FA) to fuel ATP synthesis. FA taken-up by transporters (e.g. CD36 and FATP3) is first attached to carnitine by CPT1 to form acyl-carnitines (ACs) that can then be imported into mitochondria. FA metabolism is reduced in heart failure (HF) with ACs found lower in myocardium but increased in plasma. Whether cardiomyocytes can take up AC and oxidize them for use in the TCA remains unknown.
I aim to determine whether exogenous ACs can be oxidized by cardiomyocytes. Currently, I use immortalized cardiac cell lines, neonatal rat (NRVMs) and adult mouse cardiomyocytes cultured with 14C ACs and measure their oxidation via 14CO2 release.