High Intrinsic Exercise Capacity Is Associated with Reduced Survival in a Rat Model of Pressure Overload

Objectives: Low exercise capacity is considered a risk factor for cardiovascular disease and for increased mortality. Both, exercise capacity and cardiac function are related to mitochondrial function and physical fitness has been found protective also in heart failure. We assessed the effect of high or low exercise capacity on survival, cardiac and mitochondrial function with cardiac pressure overload.

Methods: In rats bred for high (HCR) or low (LCR) intrinsic exercise capacity pressure overload was induced by transverse aortic constriction (TAC). Survival time after TAC and cardiac function was monitored. Cardiac substrate metabolism was measured in the isolated working heart after two and ten weeks of TAC. Respiratory capacity of isolated cardiac mitochondria and activity of complexes of the respiratory chain and antioxidative enzymes were measured.

Result: HCR and LCR differed in their exercise capacity. LCR displayed higher body weight, elevated blood glucose and reduced insulin sensitivity compared with HCR. In addition, LCR showed lower mitochondrial respiratory rates than HCR. Pressure overload led to cardiac hypertrophy after two weeks and to reduced diastolic function (E/A: HCR 10.5 ± 2.1 versus 2.0 ± 0.2 and LCR 7.4 ± 2.0 versus 1.9 ± 0.2) after 10 weeks in both lines. However, systolic function was reduced in HCR only (EF: HCR 76.4 ± 1.7 vs. 62.2 ± 2.7% and LCR 81.5 ± 1.6 versus 74.7 ± 3.3%) at this time. After 20 weeks of pressure overload, contractile function was impaired in both HCR and LCR. Unexpectedly, with pressure overload, mean survival time was 7 weeks shorter in HCR than in LCR. In the isolated working heart, 2 weeks of pressure overload led to a reduction of cardiac power ex vivo which was more pronounced in HCR than in LCR (HCR 6.0 ± 1.1 vs. 2.7 ± 0.2, and LCR 8.4 ± 1.0 vs. 3.9 ± 0.7 mW). Thus, calculated ATP production from substrate oxidation per unit of power was increased in HCR compared with LCR. Pressure overload led to increased mitochondrial respiration with pyruvate/malate as substrate. However, overall mitochondrial respiration remained unchanged. Pressure overload increased the antioxidative capacity.

Conclusion: Contrary to expectations, low intrinsic exercise capacity was associated with better survival during development of pressure overload–induced heart failure. This seemed independent of cardiac mitochondrial function.

Publication History

Article published online:
19 February 2021