Abstract P3053: Mitochondrial Calcium Accumulation Drives The Progression Of Non-ischemic Heart Failure: Integrated Lessons From Genetic Mouse Models

Acute mitochondrial calcium ( m Ca 2+ ) uptake stimulates bioenergetics to meet increased ATP demand, but when excessive predisposes to necrotic cell death. A major unresolved controversy is whether chronic alterations in cardiomyocyte m Ca 2+ homeostasis contribute to maladaptive remodeling and contractile dysfunction in non-ischemic heart disease. We hypothesized that cardiomyocyte m Ca 2+ accumulation drives cardiac maladaptation in response to stressors that chronically increase workload and cytosolic Ca 2+ cycling. We subjected mice with adult, cardiomyocyte-specific manipulation of m Ca 2+ uptake through the mitochondrial calcium uniporter ( Mcu deletion, Mcu -cKO; MCU overexpression, MCU-Tg) or m Ca 2+ efflux through the mitochondrial sodium-calcium exchanger, NCLX (NCLX overexpression, NCLX-OE), to chronic pressure or neurohormonal overload. Fractional shortening failed to increase in Mcu -cKO mice over the first days of isoproterenol (Iso) infusion. Mortality was increased in Mcu -cKO mice over this period, and this effect was recapitulated in NCLX-OE mice infused with angiotensin II + phenylephrine (PE), although contractility did not decline in either case. Hypertrophic responses to chronic stress were attenuated in NCLX-OE but not Mcu -cKO hearts, and adenoviral NCLX expression limited mitochondrial metabolism, protein synthesis, and cell growth in neonatal rat cardiomyocytes treated with PE. These data indicate that m Ca 2+ accumulation is required for cardiac hypertrophy, but MCU is not. MCU-Tg hearts decompensated towards failure with 1-2 weeks of Iso. Although these hearts exhibited increased cardiomyocyte necrosis, deletion of the mPTP regulator cyclophilin D failed to rescue contractility, suggesting that m Ca 2+ overload causes cardiac failure, even independent of permeability transition. Fitting with this view, NCLX-OE attenuated the decline in contractile function that occurred with 12-week pressure overload. We conclude that despite initial adaptive effects, sustained m Ca 2+ elevation drives the progression of non-ischemic heart disease triggered by a chronic increase in cardiac workload. Our findings raise concern over proposed therapeutic strategies aiming to augment m Ca 2+ accumulation in heart failure.