Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure

Abstract

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 μg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Fig. 1.

Hemodynamic responses: mean arterial pressure (MAP), heart rate (HR), left ventricular volumes (LVVs), cardiac output (CO), and nonischemic vascular conductance (NIVC) and during rest, mild exercise (Ex) and mild exercise with muscle metaboreflex activation (Ex + MMA), in control (A) and heart failure (B) conditions, before (black bars) and after α₁-blockade (striped bars). Bpm, beats/min. *Between bars, significant pairwise comparison (P < 0.05); †significant change from the previous setting; ♣significant pairwise comparison in left ventricle stroke volume (P < 0.05); #significant change in stroke volume from the previous setting (P < 0.05); *brackets, significant effect of settings or conditions (horizontal: rest, Ex, MMA; vertical: control, α₁-blockade).

Fig. 2.

Left ventricular hemodynamic and function responses: coronary blood flow (CBF), coronary vascular conductance (CVC), maximal rate of left ventricular pressure change (dP/dt_max), and preload recruitable stroke work (PRSW) and during Ex and Ex + MMA in control (A) and heart failure (B) before (black bars) and after α₁-blockade conditions (striped bars). Symbols are as defined in Fig. 1.

Fig. 3.

Relationship between coronary vasodilation and cardiac power at rest, during exercise and with muscle metaboreflex activation before (A) and after (B) induction of heart failure during control experiments (●) and after α₁-adrenergic blockade (□). Coronary vasodilation in response to the increases cardiac power that occurred with exercise and metaboreflex activation was greater after α₁-adrenergic blockade in control experiments. In heart failure, α₁-adrenergic blockade reversed the coronary vasoconstriction seen with metaboreflex activation into vasodilation and markedly improved the ability to raise cardiac power.

Fig. 4.

Ratio between change in CVC (ΔCVC) and change in cardiac power (ΔCP) in normal (top) and heart failure (bottom). The black bars represent control, and the striped bars represent the corresponding values after α₁-blockade. Both are compared across rest to mild exercise (rest to Ex) and mild exercise to muscle metaboreflex activation (Ex to MMA). *Above setting, significant pairwise comparison (P < 0.05); †significant decrease from the previous setting (P < 0.05).

Fig. 5.

Relationship between CBF and left ventricular contractility as indexed by dP/dt_max and PRSW before and after the induction of heart failure. Because no significant difference between control and α₁-blockade was found (P > 0.05), a single relationship is represented by a single line. Normal, circles; heart failure, triangles; black symbols, control experiments; white symbols, α₁-blockade.