Key Points
- To determine whether sustained compensatory increases in sympathetic drive, provoked by phospholamban overexpression, directly cause cardiomyopathy and premature mortality in the absence of preexisting heart failure.
- Generated transgenic mice engineered to overexpress phospholamban at four times baseline physiological levels.
- Assessed in vivo cardiac function, isolated cardiomyocyte contractility, and calcium kinetics at 3 months under baseline conditions and following pharmacological challenges with propranolol or isoproterenol.
- Monitored longitudinal cohorts during aging to evaluate adenylyl cyclase sensitivity, heart failure onset, and survival.
- Three-month-old transgenic mice exhibited depressed baseline cardiomyocyte mechanics and calcium kinetics that were fully reversed by isoproterenol, while propranolol markedly worsened in vivo function.
- Transgenic animals developed elevated plasma norepinephrine concentrations and increased phospholamban phosphorylation, confirming a sustained state of compensatory adrenergic stimulation.
- Aging transgenic mice developed adenylyl cyclase desensitization, exacerbating phospholamban-mediated cardiac inhibition and precipitating overt heart failure and premature mortality.
Structured PICO
PPopulationTransgenic mice overexpressing phospholamban at 4-fold normal levels
IInterventionTransgenic overexpression of phospholamban leading to compensatory increased adrenergic drive
OOutcomeDevelopment of overt heart failure and premature mortality on aging
Compensatory increases in catecholamine stimulation can be a primary causative factor in the development of cardiomyopathy and early mortality, even in the absence of preexisting heart failure.