Central Cardiac Determinants of the Speed‐duration Relationship in Heart Failure Rats
Authors: Craig Jesse C. , Colburn Trenton D. , Caldwell Jacob T. , Hirai Daniel M. , Tabuchi Ayaka , Merino Joseph H. , Ade Carl J. , Poole David C. , Musch Timothy I. 
Published: June 2021

The framework of exercise tolerance across species, in health and disease, is well defined by the speed‐duration relationship which integrates multiple physiological systems to accurately predict time‐to‐exhaustion. The parameters of this relationship, critical speed (CS) and the distance that can be covered above CS (D′), represent the aerobic and ‘anaerobic’ capacities of the animal. A cardinal symptom of heart failure (HF) is exercise intolerance. In HF a cardiac insult and peripheral dysfunction conflate to reduce exercise tolerance, however, the contribution of each to the speed‐duration relationship remains unknown. Therefore, the purpose of this investigation was to establish the speed‐duration relationship in a model of HF and elucidate the mechanism(s) that determine CS and D′. Specifically, we tested the hypotheses that: 1) CS (but not D′) would be reduced in HF; 2) measurements of heart function would correlate with CS; and 3) muscle interstitial space O2 partial pressure (PO2is determined by O2 delivery‐to‐utilization matching) would be reduced in an oxidative (soleus, SOL) but not a low‐oxidative (white gastrocnemius, WG) muscle in HF.METHODSNine adult female Sprague‐Dawley rats were randomized to control (CON; n = 4) or HF (n = 5) groups. HF was induced via surgical myocardial infarction (MI) of the left ventricle (LV) and the rats were given ≥ 21 days to recover (MI size: 32 ± 3% of LV wall). Multiple constant speed treadmill runs to exhaustion were used to determine CS and D′. Doppler echocardiography and micromanometer‐tipped catheters were used to evaluate heart function (i.e., fractional shortening and LV end‐diastolic pressure (LVEDP), respectively) following CS and D′ determination. The Oxyphor G4 was injected into the muscles and phosphorescence quenching employed to determine the temporal profile of PO2is in the SOL and WG during electrically‐induced contractions (1 Hz, 8 V, 180 s).RESULTSHF reduced fractional shortening (HF: 24 ± 2, CON: 48 ± 3%) and increased LVEDP (HF: 16 ± 2, CON: 6 ± 1 mmHg; both p < 0.001). CS was reduced in HF rats compared to CON (38 ± 1 vs 45 ± 1 m/min; p < 0.001) but D′ was not different (HF: 79 ± 13, CON: 61 ± 13 m; p = 0.35). CS was correlated positively with FS (r = 0.9, p < 0.01) and negatively with LVEDP (r = −0.76, p = 0.01). HF reduced SOL resting PO2is and attenuated the contraction‐induced decrease (both p < 0.01) but had no effect on WG PO2is (all p > 0.05).CONCLUSIONCS and D′ can be resolved in an animal model of HF where CS is reduced but D′ is not. Crucially, this HF model is free from prescription therapeutics that confound interpretation of the mechanistic relationship between HF and CS or D′ in humans. We show that in this model of moderate HF (i.e., LVEDP < 20 mmHg), where skeletal muscle oxidative function is thought to be preserved, decrements in central cardiac function relate directly to impaired exercise tolerance likely due to reduced perfusive and diffusive O2 ‐delivery to oxidative muscle fibers.Support or Funding InformationNIH HL‐2‐108328This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.