Objectives We and others demonstrated in rats with increased cardiac afterload that the development of contractile dysfunction is associated with impaired complex I activity of the mitochondrial electron transport chain (ETC). Here, we use a rat model with xenotopic expression of Ndi1, an alternative respiratory enzyme bypassing complex I, to elucidate a mechanistic link between the development of pressure-induced contractile failure and complex I dysfunction.

Methods Weaned male Sprague-Dawley (SD) rats expressing Ndi1 and wild-type controls were subjected to increased cardiac pressure load induced by transverse aortic constriction (TAC). Survival time was documented and cardiac morphology and function were assessed by echocardiography.

Results Expression of Ndi1 had no effect on body weight, heart rate, or cardiac morphology and function. Two weeks after TAC, wild-type rats showed impaired cardiac contractile function compared with SHAM controls. There was decreased stroke volume (96.4 vs. 173.9 µl) and heart rate (332 vs. 401 bpm), resulting in significantly decreased cardiac output (33.4 vs. 69.0 ml/min). At the same time, Ndi1-expressing rats subjected to TAC maintained heart rates (389 vs. 384 bpm) and stroke volumes (136 vs. 158 µl), resulting in maintained cardiac output (51.6 vs.62.4 ml/min). Both groups showed the expected hypertrophic left ventricular walls after TAC. However, only wild-type rats showed additionally reduced left ventricular inner dimensions in diastole compared to healthy controls (5.04 vs 6.44 mm). Preliminary survival analyses indicate a slightly higher survival in Ndi1-expressing rats (87.5 vs 70.0 % after 2 weeks of pressure overload), although statistical significance has not yet been reached.

Conclusion Bypassing complex I of the respiratory chain by xenotopic expression of Ndi1 maintains contractile function and may extend survival under pressure overload. If verified in a larger cohort, these results suggest a causal role for complex I dysfunction in pressure-overload-induced heart failure.