Altered hemodynamics in transgenic mice harboring mutant tropomyosin linked to hypertrophic cardiomyopathy

We used transgenic (TG) mice overexpressing mutant alpha -tropomyosin [alph a -Tm( Asp175Asn)], linked to familial hypertrophic cardiomyopathy (FHC), t o test the hypothesis that this mutation impairs cardiac function by alteri ng the sensitivity of myofilaments to Ca2+. Left ventricular (LV) pressure was measured in anesthetized nontransgenic (NTG) and TG mice. In control co nditions, LV relaxation was 6,970 +/- 297 mmHg/s in NTG and 5,624 +/- 392 m mHg/s in TG mice (P < 0.05). During <beta>-adrenergic stimulation, the rate of relaxation increased to 8,411 +/- 323 mmHg/s in NTG and to 6,080 +/- 41 3 mmHg/s in TG mice (P < 0.05). We measured the pCa-force relationship (pCa = -log [Ca2+]) in skinned fiber bundles from LV papillary muscles of NTG a nd TG hearts. In control conditions, the Ca2+ concentration producing 50% m aximal force (pCa(50)) was 5.77 +/- 0.02 in NTG and 5.84 +/- 0.01 in TG myo filament bundles (P < 0.05). After protein kinase A-dependent phosphorylati on, the pCa(50) was 5.71 +/- 0.01 in NTG and 5.77 +/- 0.02 in TG myofilamen t bundles (P < 0.05). Our results indicate that mutant <alpha>-Tm(Asp175Asn ) increases myofilament Ca2+-sensitivity, which results in decreased relaxa tion rate and blunted response to beta -adrenergic stimulation.