Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction

Abstract

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle. Multiple treadmill-constant speed runs to exhaustion were used to quantify CS and D' (distance coverable above CS) in healthy control (Con) and HF rats. Central function was determined via left ventricular (LV) Doppler echocardiography [fractional shortening (FS)] and a micromanometer-tipped catheter [LV end-diastolic pressure (LVEDP)]. Peripheral O₂ delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po₂, Po_{2 is}) in the soleus and white gastrocnemius during electrically induced twitch contractions (1 Hz, 8V). CS was lower in HF compared with Con (37 ± 1 vs. 44 ± 1 m/min, P < 0.001), but D' was not different (77 ± 8 vs. 69 ± 13 m, P = 0.6). HF reduced FS (23 ± 2 vs. 47 ± 2%, P < 0.001) and increased LVEDP (15 ± 1 vs. 7 ± 1 mmHg, P < 0.001). CS was related to FS (r = 0.72, P = 0.045) and LVEDP (r = -0.75, P = 0.02) only in HF. HF reduced soleus Po_{2 is} at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po_{2 is} (P > 0.05). We show in HF rats that decrements in central cardiac function relate directly with impaired exercise tolerance (i.e., CS) and that this compromised exercise tolerance is likely due to reduced perfusive and diffusive O₂ delivery to oxidative muscles.NEW & NOTEWORTHY We show that critical speed (CS), which defines the upper boundary of sustainable activity, can be resolved in heart failure (HF) animals and is diminished compared with controls. Central cardiac function is strongly related with CS in the HF animals, but not controls. Skeletal muscle O₂ delivery-to-utilization dysfunction is evident in the more oxidative, but not glycolytic, muscles of HF rats and is explained, in part, by reduced nitric oxide bioavailability.

Keywords: exercise tolerance; heart failure; muscle P; power-time relationship; reduced ejection fraction.

Fig. 1.

Echocardiographic assessment of left ventricular (LV) function. A representative rat preinfarction (A) and 7 days postinfarction (B) is presented. Two-dimensional image of LV (top) used to guide M-mode imaging (bottom) at the level of the papillary muscle. Arrows demarcate LV internal dimensions at end diastole (LVIDd) and end systole (LVIDs). M-mode imaging represents continuous measurement across 1 s for both images. EF, ejection fraction for this representative rat pre- and postinfarction; FS, fractional shortening.

Fig. 2.

Group speed-duration relationships. The group mean data for control (●) and heart failure (○) rats are presented. Solid and dashed lines represent the speed-duration modeling used to determine critical speed (CS, vertical lines from x-axis) and the distance able to be covered above CS (D′) for control and heart failure animals, respectively. This fit was used for illustrative purposes only; the individually determined CS and D′ as well as the subsequent group means are presented in Table 1. Data are means ± SE.

Fig. 3.

Group mean echocardiographic fractional shortening assessed across time. Both control (●; n = 7) and heart failure [○; n = 7 for all, except 21–23 days postinfarction (Post-21); n = 5] rats are represented. Inset images are transverse sections of healthy and infarcted left ventricles. Data are means ± SE. *P < 0.05 vs. control within time; ‡P < 0.05 vs. preinfarction (Pre) within group. Post-CS, post speed-duration testing (49–56 days); Post-7, 7–9 days postinfarction.

Fig. 4.

Central contribution to critical speed (CS). A: CS as a function of fractional shortening. B: CS as a function of left ventricular end-diastolic pressure. C: CS as a function of stroke volume. Individual heart failure (○) and control (●) rats are represented. Solid lines represent the group correlations (coefficients and P values are presented by their respective groups). Dotted lines represent theoretical relationships across the continuum of data. LVEDP, left ventricular end-diastolic pressure.

Fig. 5.

Group mean interstitial Po₂ (Po_2 is) at rest and during contractions. Electrically induced twitch contractions were initiated at time 0 (vertical dashed line). Po_2 is for both control (● and ◆; n = 6) and heart failure (○ and ◇; n = 7) rats in the soleus (○ and ●) and white gastrocnemius (◇ and ◆). Data are means ± SE. Shaded area highlights the difference between control and heart failure rats in the soleus Po_2 is profile.

Fig. 6.

Group mean soleus interstitial Po₂ (Po_2 is) at rest and during contractions before and following N^ω-nitro-l-arginine methyl ester (l-NAME) superfusion. Electrically induced twitch contractions were initiated at time 0 (vertical dashed lines). Soleus Po_2 is for both control (left) and heart failure (right) rats. Data are means ± SE. Shaded areas highlight the difference between vehicle and l-NAME conditions in the soleus Po_2 is profiles.