Skeletal Muscle Oxygen Delivery and Utilization during Exercise in Heart Failure with Preserved Ejection Fraction: Role of Sympathetic (α‐adrenergic) Vasoconstriction

Abstract

BACKGROUNDHeart Failure with preserved ejection fraction (HFpEF) is characterized by severe exercise intolerance underpinned by low aerobic capacity (VO2peak). It is likely low VO2peak in HFpEF is not only related to deficits in cardiac function, but also peripheral vascular and skeletal muscle dysfunction that may disrupt the balance between O2 delivery and utilization. There is emerging evidence for sympathetic nervous system overactivity in patients with HFpEF that results in excessive vasoconstriction in the peripheral circulation, and may therefore contribute to dysregulation of exercising muscle blood flow. We tested the hypothesis that pharmacological blockade of sympathetic (α‐adrenergic) vasoconstriction would increase blood flow, O2 delivery and utilization of exercising skeletal muscle to a greater extent in HFpEF compared to healthy control subjects.METHODSFour healthy control (CON) (2 M, 69±3 yrs) and three HFpEF (1 M, 71±3) volunteers participated in this study. Femoral blood flow (FBF) was assessed by ultrasound Doppler. Catheters were placed in the femoral artery and vein for drug infusions and determination of arterial and venous O2 content (CaO2 and CvO2, respectively). O2 utilization of the exercising leg was calculated via the Fick equation: VO2 = FBF∙(CaO2‐CvO2), and O2 delivery was calculated as FBF∙CaO2. Measurements were made at rest and during dynamic single‐leg knee‐extension (KE) exercise (5 W) before and after intra‐arterial infusion of the α‐adrenergic antagonist phentolamine (PHEN).RESULTSBaseline FBF, O2 delivery, and VO2 were similar between groups. At rest, PHEN increased FBF and O2 delivery similarly in both groups, while the increase in VO2 tended to be smaller in patients with HFpEF compared to CON (+3±2 vs. +14±5 ml/min; respectively, P=0.09). During KE exercise, a ≍20‐30% decrement in FBF (2052±261 vs. 2529±230 ml/min; HFpEF vs. CON, P=0.23), O2 delivery (282±27 vs. 392±35 ml/min, HFpEF vs. CON, P=0.07), and VO2 (193±25 vs. 284±31 ml/min; HFpEF vs. CON, P=0.09) were observed in patients with HFpEF. PHEN increased exercising muscle FBF (+243±45 vs. +247±58 ml/min; HFpEF vs. CON) and O2 delivery (+51±9 vs. +34±19 ml/min; HFpEF vs. CON) similarly between groups, while the PHEN‐induced increase in VO2 tended to be greater in patients with HFpEF (+20±12 vs. +6±7 ml/min; HFpEF vs. CON, P=0.32).CONCLUSIONTaken together, these preliminary data suggest a reduction in FBF, O2 delivery and utilization during small muscle mass exercise in patients with HFpEF that may be, in part but not fully, explained by excessive sympathetic (α‐adrenergic) vasoconstriction in this patient group.