Abstract 2272: Blunted Exercise-induced Left Ventricular Hypertrophy in Heterozygous cMyBP-C Knock-in Mutant Mice
Familial hypertrophic cardiomyopathy (FHC) is characterized by left ventricular hypertrophy (LVH) and is often associated with mutations in the cardiac myosin-binding protein C (cMyBP-C) gene. FHC is a common cause of sudden death in young athletes. In the present study we examined the effect of voluntary wheel running on cardiac function in two targeted cMyBP-C mouse models. The first model is a heterozygous knock-in (KI), which carries a human point mutation (G>A transition on the last nucleotide of exon 6), and expresses ~80% of wild-type (WT) as well as ~2% of mutant cMyBP-C. The other is a heterozygous knock-out (KO), which carries only one functional allele and expresses ~75% of WT cMyBP-C. Both groups were compared to WT littermates (9 wks, n = 10 –12). Cardiac phenotype was evaluated by echo-doppler before and after a 12 week running period. Before running LV mass to body weight ratio (LVMd/BW) was 20% higher in KI than WT (4.6±0.2 vs 3.8±0.1 mg/g, p<0.01), and cardiac output was 33% higher in KI (24±1 vs 18±1 ml/min, p<0.01). In contrast, KO mice did not exhibit any LVH or altered cardiac output when compared to WT. Running distance tended to be lower in KI than WT (337±92 vs 596±109 km, p=0.09), did not differ in KO and WT, and was not correlated to the basal degree of hypertrophy. Physiological exercise increased LVMd/BW by ~20% in KO and WT (p<0.01), but had no further effect in KI mice. Therefore the LVMd/BW post-running did not differ between the groups. Similarly, running increased cardiac output by 20% in WT (p<0.05) and by 48% in KO mice (p<0.01) but had no further effect in KI mice. Running slightly increased LV internal diameter in KO and WT, but not in KI mice. The increase in LV end-diastolic and end-systolic volumes (by 20 –70%, p<0.05) after exercise did not vary between the groups. Interestingly, running decreased fractional shortening and increased heart rate by ~10% only in KI (p<0.05). In conclusion the different data obtained in KI and KO suggest that haploinsufficiency of cMyBP-C alone does not cause early LVH, altered running capacity, or abnormal exercise-induced LVH. On the other hand, the additional presence of mutant cMyBP-C is sufficient to cause early LVH, impaired voluntary exercise and blunted exercise-induced LVH.