Abstract P1028: Elucidating Differential Mechanisms That Underlie Phenotypic Variability In Two Independent Dcm Models

Abstract

Mutations in components of the cardiac thin filament cause disease via complex, multi-faceted myocellular mechanisms, ultimately presenting as heterogeneous, symptomatic cardiomyopathies. The heterogeneity of both the myocellular mechanism(s) involved and the clinical outcome(s) represents a challenge in ongoing efforts to link genotype to phenotype. Two DCM-associated thin filament mutations (D230N-Tm and R173W-cTnT) with similar clinical phenotypes, were selected explore the molecular basis of disease trajectory. In patient populations, D230N-Tm exhibits an earlier time of onset compared to R173W-cTnT, with children (<1yr) presenting with an often-fatal DCM. We hypothesize that the difference in time of onset can be explained by distinct myocellular mechanisms. We utilized transgenic mice expressing D230N-Tm and R173W-cTnT and defined the progression of pathogenic remodeling across 3 independent timepoints via 2D-echo. At 2 months the %FS of D230N-Tm was significantly reduced (21.79 ± 1.19) compared to NTg littermates (33.45±1.45). R173W-cTnT, however, exhibited no reduction in %FS until 4 months (22.53±0.78), thus phenocopying the patient population. Using these timepoints to guide our myocellular mechanics, contractility measurements were then utilized to assess the myocellular mechanics associated with the mutations. At 2 months D230N-Tm exhibited a decrease in the rate of contraction (4.53±0.24μm/sec) and rate of relaxation (2.88±0.23) compared to NTg. R173W-cTnT did not diverge from NTg until 4 months, exhibiting a later onset of impaired contractility. By 4 months, both mutations displayed the opposite, an increase in rate of contraction and relaxation (rate of contraction, D230N-Tm 4.49±0.18 and R173W-cTnT 5.83±0.27; and rate of relaxation, D230N-Tm 3.14±0.19 and R173W-cTnT 3.70±0.24). Our results suggest that the accelerated time course for the development of D230N-Tm – linked DCM is caused by differential myocellular mechanism(s) that induce the early reduction in contractility and relaxation observed. Ongoing studies aim to further identify possible myocellular mechanism(s) by which these mutations exhibit different myocellular mechanics.