Induction of heart failure by minimally invasive aortic constriction in mice: Reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction

ObjectiveMitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice is considered a model for compensated hypertrophy but not for heart failure. We assessed the suitability of minimally invasive transverse aortic constriction to induce heart failure in C57BL/6 mice and assessed mitochondrial biogenesis and function.MethodsMinimally invasive transverse aortic constriction was performed through a ministernotomy without intubation (minimally invasive transverse aortic constriction, n = 68; sham operation, n = 43). Hypertrophy was assessed based on heart weight/body weight ratios and histologic analyses, and contractile function was assessed based on intracardiac Millar pressure measurements. Expression of selected metabolic genes was assessed with reverse transcription–polymerase chain reaction and Western blotting. Maximal respiratory capacity (state 3) of isolated mitochondria was measured with a Clark-type electrode.ResultsSurvival was 62%. Within 7 weeks, minimally invasive transverse aortic constriction induced significant hypertrophy (heart weight/body weight ratio: 10.08 ± 0.28 mg/g for minimally invasive transverse aortic constriction vs 4.66 ± 0.07 mg/g for sham operation; n = 68; P < .01). Fifty-seven percent of mice undergoing minimally invasive transverse aortic constriction displayed signs of heart failure (pleural effusions, dyspnea, weight loss, and dp/dtmax of 3114 ± 422 mm Hg/s, P < .05). All of them had heart weight/body weight ratios of greater than 10. Mice undergoing minimally invasive transverse aortic constriction with heart weight/body weight ratios of less than 10 had normal contractile function (dp/dtmax of 6471 ± 292 mm Hg/s vs dp/dtmax of 6933 ± 205 mmHg/s in sham mice) and no clinical signs of heart failure. The mitochondrial coactivator peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) was downregulated in failing hearts only. PGC-1α and fatty acid oxidation gene expression were also decreased in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced in all hearts subjected to pressure overload.ConclusionsContractile dysfunction and heart failure can be induced in wild-type mice by means of minimally invasive aortic constriction. Pressure overload–induced heart failure in mice is associated with mitochondrial dysfunction, as characterized by downregulation of PGC-1α and reduced oxidative capacity