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Patients with hypertrophic cardiomyopathy (HCM), particularly young adults, can die from arrhythmia but the mechanism underlying abnormal rhythm formation remains unknown. C57Bl6 x CBA/Ca mice carrying a cardiac actin (ACTC) E99K (Glu99Lys) mutation reproduce many aspects of human HCM including increased myofilament Ca(2+) sensitivity and sudden death in a proportion (up to 40%) of young (28-40 day old) animals. We studied the hearts of transgenic (TG - ACTC E99K) mice and their non-transgenic (NTG) littermates when they were in their vulnerable period (28-40 days old) and when they were adult (8-12 weeks old). Ventricular myocytes were isolated from the hearts of TG and NTG mice at these two time points. We also examined the hearts of mice that died suddenly (SCD). SCD animals had approximately four times more collagen compared with age-matched NTG mice yet myocyte cell size was normal. Young TG mice had double the collagen content of NTG mice. Contraction and Ca(2+) transients were greater in cells from young TG mice compared with their NTG littermates but not in cells from adult mice (TG or NTG). Cells from young TG mice had greater propensity for Ca(2+) waves than NTG littermates and, despite similar SR Ca(2+) content, a proportion of these cells had larger Ca(2+) spark mass. We found that the probability of SCD in young TG mice is increased when the mutation is expressed in animals with a CBA/Ca background and almost eliminated in mice bred on a C57Bl6 background.

Original publication




Journal article


American Journal of Physiology - Heart and Circulatory Physiology

Publication Date



ajpheart.00244.2017 - ajpheart.00244.2017