Description:
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Mutations in cardiac troponin T (cTnT) account for approximately 5-10% of all Hypertrophic Cardiomyopathy (HCM). Residue Arg92 of cTnT represents a HCM-mutational hotspot, including Arg92Leu (R92L) and Arg92Trp (R92W). These mutations, although differing by only a single amino acid, present with varying degrees of cardiac remodeling and disease severity in the human population. Studying the differential effects of the R92 mutations on Ca
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homeostasis revealed an age-dependent disruption in down-stream calcium handling in R92W mice, including differential diastolic calcium levels and SERCA2a uptake activity. To determine the effects of treating this differential calcium handling disruption, R92L and R92W mice were treated with diltiazem hydrochloride, an L-type Ca
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channel blocker. While R92L mice showed a progressive worsening in diastolic function and remodeling throughout treatment, R92W mice showed improvement in diastolic function but no change in cardiac remodeling, suggesting an improvement but not amelioration of disease with diltiazem treatment. Of note, previous studies also suggested an increase in phospholamban (PLB) phosphorylation at Thr17 (CaMK-II-mediated) over time in R92W mice only. Thus, we hypothesized a mutation-specific role of CaMK-II in cTnT-linked HCM progression. We tested this via genetic partial inhibition of CaMK-II (AC3-I peptide) in both R92W and R92L transgenic mice. Both R92W and AC3-IxRW hearts exhibited a normalization of SERCA2a activity to non-transgenic levels over time. This improved Ca
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re-uptake was coupled with a decrease in atrial mass, improved ventricular relaxation, and normalized diastolic function only in AC3-IxRW animals, consistent with blunting of disease progression
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. In contrast, AC3-IxRL mice showed depressed SERCA2a activity, increased atrial mass and ventricular thickening, and diastolic dysfunction as compared to R92L alone mice, indicating a CaMK-II independent progression to HCM. These results suggest that closely related primary mutations can result in specific ventricular remodeling and targeting these discrete molecular secondary effects represent a novel targeted treatment approach in HCM.
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