Can Sacubitril-valsartan Improve Locomotor Muscle Microvascular Function In Heart Failure With Reduced Ejection Fraction?

INTRODUCTION: Patients with heart failure with reduced ejection fraction (HFrEF) exhibit locomotor muscle microvascular dysfunction. Sacubitril-valsartan is a recently approved, first-in-class, angiotensin receptor neprilysin inhibitor that reduces the risk of death from cardiovascular causes and hospitalization for heart failure in patients with HFrEF. Recent studies have demonstrated the potential of sacubitril-valsartan to improve brachial artery endothelium-dependent vasodilation in patients with HFrEF, but its effect on locomotor muscle microvascular function remains unknown. PURPOSE: We sought to test the hypothesis that short-term treatment with sacubitril-valsartan would improve locomotor muscle microvascular function in patients with HFrEF. METHODS: Patients with NYHA Class II-III HFrEF (n = 6; age: 70 ± 9 years; BMI: 28 ± 3 kg/m2; ejection fraction: 27 ± 9%) were studied prior to initiation (baseline) and at months 1, 2, and 3 of treatment with sacubitril-valsartan. Locomotor muscle microvascular function was assessed as leg blood flow (LBF) and leg vascular conductance (LVC) responses to passive leg movement (PLM) and were expressed as peak change (Δpeak) and total hyperemic response (area under the curve above rest; AUC). RESULTS: Sacubitril-valsartan did not improve LBFΔpeak (baseline: 421 ± 92 mL/min; 1-month: 463 ± 222 mL/min; 2-month: 469 ± 164 mL/min; 3-month: 445 ± 151 mL/min, p = 0.887) or LVCΔpeak (baseline: 493 ± 150 mL/min/100 mmHg; 1-month: 632 ± 393 mL/min/100 mmHg; 2-month: 654 ± 252 mL/min/100 mmHg; 3-month: 609 ± 219 mL/min/100 mmHg, p = 0.382). Likewise, sacubitril-valsartan did not improve LBFAUC (baseline: Δ172 ± 68 mL; 1-month: Δ170 ± 97 mL; 2-month: Δ182 ± 72 mL; 3-month: Δ212 ± 115 mL, p = 0.582) or LVCAUC (baseline: Δ198 ± 99 mL/100 mmHg; 1-month: Δ218 ± 156 mL/100 mmHg; 2-month: Δ233 ± 107 mL/100 mmHg; 3-month: Δ270 ± 167 mL/100 mmHg, p = 0.568). CONCLUSIONS: Sacubitril-valsartan does not appear to improve locomotor muscle microvascular function in patients with HFrEF. These initial findings suggest that the beneficial effect of this drug on upper limb conduit artery function reported previously may not extend to the microcirculation of an ambulatory muscle group, highlighting a heterogeneous efficacy across different regions of the peripheral vasculature. NIH, VA, and AHA