Abnormal Vascular, Metabolic, and Neural Function During Exercise in Heart Failure With Preserved Ejection Fraction

Protocol 1.1: To test hypothesis 1.1 the investigators will measure rapid onset vasodilation in response to a single KE contraction as a marker of vascular responsiveness to muscle contraction, as well as the dynamic onset, and steady state vasodilatory responses to continuous KE exercise. The rapid onset vasodilatory (ROV) response to a brief (1-second) single isometric knee extension contraction will be measured as described by our collaborators50. Subjects will perform single contractions at 5, 10 or 20% of their maximal voluntary contraction (MVC). Beat-by-beat local vascular responses (i.e. femoral blood flow; FBF and vascular conductance; FVC) will be recorded continuously for 30-seconds with the initial response (first un-interrupted cardiac cycle post-contraction), peak response (maximal increase), latency (time to peak response) and area under the curve (total vasodilator response across 30-seconds) analyzed to fully characterize ROV in HFpEF. Additionally, the vascular and hemodynamic response to dynamic KE exercise (beat-by-beat onset and steady state FBF and FVC) will be measured from the onset of exercise for six minutes at submaximal work rates (10, 15 W, and 60% maximal work rate). These trials will be performed individually and with 20 minutes of rest between conditions to ensure that patients will be able to complete each of these trials. In addition to local vascular hemodynamics, systemic hemodynamics (HR, MAP, CO, SV) will be monitored throughout to confirm that any alterations in local blood flow are independent of central cardiovascular adjustments (See Fig. 2, Day 2)

Hypothesis 1.2: Skeletal muscle V̇O2 kinetics will be slowed in HFpEF.

Protocol 1.2: Breath-by-breath pulmonary V̇O2 kinetics will be measured during cycle exercise at a relatively light work rate of 20 W (~30% V̇O2 peak) to characterize V̇O2 kinetics where there is no cardiac limitation, allowing for a submaximal assessment of "peripheral" oxidative efficiency during large muscle mass exercise. During cycle exercise, V̇O2 kinetics will be measured in conjunction near infrared spectroscopy as a marker of the coupling between oxygen delivery and demand (see Fig. 2, Day 3).

Hypothesis 1.3: HFpEF patients will demonstrate elevated MSNA at rest, and exaggerated metaboreflex sensitivity during exercise.

Protocol 1.3: Microneurography will be used to measure multi-unit muscle sympathetic nerve discharge in subjects at rest, during dynamic knee extension exercise (30, 40% MVC), and during 2 minutes and 15 seconds of post-exercise ischemia (PEI) achieved via inflation of a blood pressure cuff to supra-systolic pressure. This approach allows for experimental isolation of the metaboreflex contribution to changes in MSNA and hemodynamics by preventing washout of metabolites produced by muscle contraction during exercise. Importantly, the sympathetic response is independent of the confounding activation of the mechanoreflex or central command as muscle contractions are no longer being performed. A cold pressor test will be utilized to confirm specific sensitivity to the metaboreflex and not generalized sensitivity to sympathoexcitatory stimuli. Multi-unit post-ganglionic MSNA will be recorded from the peroneal nerve using standard microneurographic techniques and quantified as burst frequency (bursts/min), burst incidence (burst/100 cardiac cycles) and total activity (burst frequency x mean burst amplitude).

Experimental Series 2 - Global Hypothesis 2: isolating peripheral adaptations to exercise training using single KE exercise training will improve peripheral vascular, metabolic, and neural function and result in greater functional capacity in HFpEF.

Approach: Hypothesis 2.1: Isolated KE exercise training will improve the vasodilatory response to exercise, speed V̇O2 kinetics, and reduce MSNA at rest HFpEF.

Protocol 2.1: 1) Vascular response: ROV will be assessed as described in protocol 1. Subjects will perform single contractions at 5, 10 or 20% of their pre- and post-testing maximal voluntary contraction (MVC). The peripheral hemodynamic response to dynamic KE exercise (beat-by-beat onset and steady state) will be measured continuously from the onset of exercise for six minutes at the same absolute (10, and 15 W) and relative (60% of post-intervention maximal work rate) exercise intensities. Local vascular (FBF, FVC) and systemic (HR, MAP, CO, SV) hemodynamics will be monitored throughout these trials to confirm that any alterations in local blood flow are independent of central cardiovascular adaptations (See Fig 2, Day 2). 2) V̇O2 Kinetics: Breath-by-breath Pulmonary V̇O2 kinetics will be measured during isolated single KE exercise and during upright cycle exercise. Dynamic KE exercise will be performed for six minutes at the same absolute submaximal work rates (10 and 15 W) as well as the same relative (60% post-intervention maximal work rate; see Fig 2, Day 2) in conjunction with beat-by-beat blood flow measures. Additionally, V̇O2 kinetics will be assessed during mild intensity cycle exercise at 20 W and utilized as a marker of intervention efficacy as discussed above (see Fig. 2, Day 3). 3) MSNA: Microneurography will be used to measure multi-unit muscle sympathetic nerve discharge in subjects at rest, during knee extension exercise, and PEI (See Fig 2, Day 3).

Hypothesis 2.2: Single KE exercise training will improve whole body exercise tolerance, peak V̇O2, and functional capacity in HFpEF.

Protocol 2.2: In addition to submaximal V̇O2 kinetics: maximal KE work rate, peak V̇O2 during cycle exercise, and performance in the 6-minute walk test will be re-evaluated after isolated quadriceps exercise training in the same manner as prior to the intervention (see specific exercise training protocol below).