Key result
Parvalbumin gene transfer corrected slow cardiac muscle relaxation caused by alpha-tropomyosin mutations in isolated rat myocytes (T50R reduced from 44.2 ms to 29.8 ms) and transgenic mice.
Why the study?
Does parvalbumin expression improve slow cardiac muscle relaxation in preclinical models of hypertrophic cardiomyopathy-linked alpha-tropomyosin mutations?
Does parvalbumin expression improve slow cardiac muscle relaxation in preclinical models of hypertrophic cardiomyopathy-linked alpha-tropomyosin mutations?
Absolute Event Rate: 29.8% vs 44.2%
Parvalbumin gene transfer can correct the slow cardiac muscle relaxation associated with hypertrophic cardiomyopathy-linked alpha-tropomyosin mutations in preclinical models.
Should not yet change HCM practice; leaves open parvalbumin gene transfer as therapy for alpha-tropomyosin mutations.
Hypertrophic cardiomyopathy mutations A63V and E180G in alpha-tropomyosin (alpha-Tm) have been shown to cause slow cardiac muscle relaxation. In this study, we used two complementary genetic strategies, gene transfer in isolated rat myocytes and transgenesis in mice, to ascertain whether parvalbumin (Parv), a myoplasmic calcium buffer, could correct the diastolic dysfunction caused by these mutations. Sarcomere shortening measurements in rat cardiac myocytes expressing the alpha-Tm A63V mutant revealed a slower time to 50% relengthening (T50R: 44.2+/-1.4 ms in A63V, 36.8+/-1.0 ms in controls; n=96 to 108; P<0.001) when compared with controls. Dual gene transfer of alpha-Tm A63V and Parv caused a marked decrease in T50R (29.8+/-1.0 ms). However, this increase in relaxation rate was accompanied with a decrease in shortening amplitude (114.6+/-4.4 nm in A63+Parv, 137.8+/-5.3 nm in controls). Using an asynchronous gene transfer strategy, Parv expression was reduced (from approximately 0.12 to approximately 0.016 mmol/L), slow relaxation redressed, and shortening amplitude maintained (T50R=33.9+/-1.6 ms, sarcomere shortening amplitude=132.2+/-7.0 nm in A63V+PVdelayed; n=56). Transgenic mice expressing the E180G alpha-Tm mutation and mice expressing Parv in the heart were crossed. In isolated adult myocytes, the alpha-Tm mutation alone (E180G+/PV-) had slower sarcomere relengthening kinetics than the controls (T90R: 199+/-7 ms in E180G+/PV-, 130+/-4 ms in E180G-/PV-; n=71 to 72), but when coexpressed with Parv, cellular relaxation was faster (T90R: 36+/-4 ms in E180G+/PV+). Collectively, these findings show that slow relaxation caused by alpha-Tm mutants can be corrected by modifying calcium handling with Parv.
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Coutu et al. (2004) studied Hypertrophic cardiomyopathy. Parvalbumin (Parv) gene transfer vs. Mutant alpha-tropomyosin without Parvalbumin was evaluated on Time to 50% relengthening (T50R) in rat cardiac myocytes expressing alpha-Tm A63V. Parvalbumin gene transfer corrected slow cardiac muscle relaxation caused by alpha-tropomyosin mutations in isolated rat myocytes (T50R reduced from 44.2 ms to 29.8 ms) and transgenic mice.
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