Abstract
Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder and is determined by mutation of sarcomeric genes including cardiac troponin T (cTnT). Delayed relaxation and diastolic dysfunction are the main determinants of symptoms in patients. Here we use a mouse model of HCM carrying the clinically-relevant Δ160E cTnT mutation to assess isometric twitch tension from ventricular trabeculae. As compared to wild type siblings, Δ160E mice display prolonged kinetics of both force development and relaxation, blunted force frequency response with reduced active tension at high stimulation frequency, and increased occurrence of spontaneous contractions. The role of T-tubular defects in determining contraction abnormalities has been investigated using a multi-photon random access microscopy to dissect the spatio-temporal relationship between T-tubular electrical activity and Ca2+ release in isolated cardiomyocytes. We found a significant number of tubular elements failing in propagating AP with correspondent delay of local Ca2+ release. At variance with wild type we also observe increased beat-to-beat variability of Ca2+ rise as well as higher spark frequency. In Δ160E mice, electro-mechanical defects are associated with structural and ultra-structural alteration assessed by confocal and electron microscopy. Although T-tubular density and regularity are both significantly reduced in mutant the entity of such structural changes is modest and can hardly account for the observed functional alterations. Transmission electron microscopy reveals additional ultra-structural alterations spanning the Z-line, potentially contributing to non-homogeneous Ca2+ release and contractile dysfunction.
Published Version
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