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Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heart failure with preserved ejection fraction (HFpEF) is characterized by peripheral vascular dysregulation at both rest and during exercise. Prior studies have demonstrated that blood flow to skeletal muscle is closely regulated by sympathetic (α-adrenergic) vasoconstriction and the interaction of vasoactive substances released locally during exercise that counteract α-adrenergic vasoconstriction. This phenomenon, known as “functional sympatholysis” helps facilitate exercise hyperemia and has been shown to decline via aging and disease-related changes in α1-adrenergic function but this has not been studied in HFpEF. Thus, the overall objective of this study was to characterize peripheral α1-adrenergic vasoconstriction in HFpEF. We hypothesized that both resting α1-mediated vasoconstriction and the magnitude of functional sympatholysis would be diminished in HFpEF compared to healthy, age-matched control (CON) subjects.Six patients with HFpEF (3 male, 70±3 yrs) and six CON (3 male, 67±1 yrs) completed this study. Leg blood flow (LBF, ultrasound Doppler) was evaluated at rest and during dynamic single leg knee-extension exercise (0, 5 and 10 Watts) before and after local, intra-arterial administration of Phenylephrine (PE, α1-adrenergic agonist). PE-mediated changes in LBF (%Δ) at rest and during exercise were compared between groups. The magnitude of functional sympatholysis was calculated as the difference between PE-induced %Δ LBF from rest to exercise.At rest, the PE-induced %Δ LBF was smaller in HFpEF (HFpEF: -17±2% vs. CON: -31±8%, P=0.01). While PE-induced %Δ LBF were similar between groups during exercise, when these responses were compared to %Δ LBF at rest, the calculated magnitude of sympatholysis was significantly reduced in HFpEF (0W: -4±3%, 5W: -5±4%, 10W: -8±3%) compared to CON (0W: -17±7%, 5W: -20±8%, 10W: -25±6%). These data demonstrate a marked diminution in both α1-adrenergic responsiveness at rest and the ability to attenuate α1-adrenergic mediated vasoconstriction during exercise (functional sympatholysis) in patients with HFpEF. Diminished α1-adrenergic signaling and impaired functional sympatholysis may represent an important aspect of HFpEF pathophysiology that likely contribute to vascular dysregulation in this patient group. Funded in part by grants from the National Institutes of Health (T32HL139451) and the Veterans Health Administration (I01RX001311, IK2RX003670, IK2CX002114). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: HFpEF is characterized by peripheral vascular dysfunction, which likely underlies clinical presentations such as dyspnea on exertion and severe exercise intolerance in this population. HMG-CoA reductase inhibitors, also known as “statins,” can exert beneficial pleiotropic effects on the vasculature that may be related to improvements in nitric oxide (NO) signalling. However, it has yet to be investigated whether statin therapy can improve vascular function in patients with HFpEF. We hypothesized that 30-day statin therapy would improve upper limb conduit vessel and microvascular function, as determined by brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH), respectively, and improve locomotor muscle microvascular responsiveness, as determined by passive limb movement (PLM). Methods: Using a double-blind, parallel design, patients with HFpEF were studied before and after randomization to 30 days of statin therapy (atorvastatin, 10 mg; QD, n = 4) or placebo ( n = 3). FMD, RH, and PLM testing was performed via ultrasonography according to published guidelines. Results: Compared to baseline values, FMD tended to improve following statin therapy (2.8 ± 2.4% to 4.7 ± 1.5%, day 0 to day 30, P=0.06), with no change following placebo (P=0.87). FMD adjusted for shear also tended to improve following statin therapy (0.09 ± 0.08AU to 0.15 ± 0.03AU, day 0 to day 30, P=0.07), with no change following placebo (P=0.79). RH was unchanged following both statin (P=0.24) and placebo (P=0.31) interventions. PLM AUC appeared to improve following statin therapy (98 ± 62ml to 184 ± 111ml, day 0 to day 30, P=0.22), with no change following placebo (P=0.64). The peak blood flow response to PLM was unchanged in both statin (P=0.31) and placebo (P=0.28) groups. Conclusions: While no statistically significant differences were observed, qualitative analyses suggest that statin therapy may improve upper limb conduit vessel function and locomotor muscle microvascular responsiveness in patients with HFpEF, supporting the potential efficacy of this drug class to improve vascular function. These improvements in vascular reactivity provide preliminary evidence for improved NO bioavailability that may translate to improvements in functional capacity and exercise tolerance in this patient group. Funded in part by grants from the U.S. Department of Veteran’s Affairs (1I01CX002152, D.W.W., 1IK2RX003670, K.B.) and the National Institutes of Health (5T32HL139451, K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.