Pressure overload induced heart failure may be due to impaired respiratory capacity and a defect in complex I

Objectives: Mitochondrial dysfunction has been implicated in the mechanism of heart failure. We recently described a reduction in respiratory capacity in failing rat hearts. However, the exact mechanism is not yet understood. We tested individual complex activities in addition to respiratory capacity of isolated mitochondria from failing hearts.

Methods: Rats underwent transverse aortic constriction (TAC) to induce heart failure. Cardiac function was assessed by echocardiography and mitochondria were isolated by differenzial centrifugation. We measured mitochondrial respiration rates and complex activities.

Results: 20 weeks after TAC, hearts were hypertrophied (LVPWD: 2.71 ± 0.19 vs. 1.98 ± 0.24 mm), dilated (LVEDD: 9.44 ± 0.46 vs. 7.98 ± 0.27 mm) and showed evidence of contractile dysfunction (fractional shortening: 25.4 ± 1 vs. 39.8 ± 1.6%). Maximal mitochondrial respiratory capacity (state 3) was significantly reduced for complex I substrates (glutamate natomsO/min/mg: 293 ± 64 vs. 503 ± 91; pyruvate+malate: 299 ± 102 vs. 615 ± 107; palmitoylcarnitine+malate: 241 ± 27 vs. 521 ± 83) but not for the complex II substrate succinate (609 ± 84 vs. 667 ± 88). Assessment of the activities of the four individual respiratory chain complexes revealed significant impairment in complex I (798 ± 39 vs. 934 ± 44, p < 0.05) and normal activities for complex II-IV (II: 41 ± 2 vs. 43 ± 3; III: 9772 ± 691 vs. 8270 ± 412; IV: 13042 ± 831 vs. 10363 ± 1231). Proteomic analysis revealed significant remodelling of all four complexes, but complex I was most affected.

Conclusions: Our findings suggest a specific defect in complex I of the respiratory chain in rats with pressure-overload induced heart failure. The findings further suggest, that heart failure in response to pressure overload may be related to failure of the respiratory chain to generate the required amounts of ATP.