Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physiology

First Advisor

Donal S. O'Leary

Abstract

Muscle Metaboreflex Activation occurs as a result of metabolic accumulation within active skeletal muscle that stimulates type III and IV afferents. This reflex in healthy subjects causes increased ventricular contraction, tachycardia, enhanced central blood volume mobilization, and 2 mediated vasodilation as a means to increase mean arterial pressure and thereby improve perfusion pressure of active skeletal muscle. However, to date no study has evaluated the interaction between the observed changes in ventricular and vascular dynamics or how the reflex impacts contraction relaxation dynamics before and after induction of heart failure Furthermore, no study has evaluated the impact of chronic selective ablation of skeletal muscle afferents responsible for reflex activation. In this study we addressed three questions: 1) Does muscle metaboreflex activation increase effective arterial elastance and maintain ventricular vascular coupling before and after induction of heart failure, 2) Are ventricular contraction and relaxation dynamics influenced by muscle metaboreflex activation and what is the effect of heart failure, 3) What is the contribution of TRPV1 expressing skeletal muscle afferents to muscle metaboreflex activation. We used a chronically instrumented canine model in a longitudinally designed study in which each animal serves as its own control against either induction of heart failure or treatment with intrathecal resiniferatoxin a potent dominant negative TRPV1 agonist that causes afferent ablation to assess these questions. We observed that: 1) Muscle metaboreflex activation does increase effective arterial elastance and this increase sustains ventricular vascular coupling promoting optimal energy transfer from the left ventricle to the systemic circulation and thereby increasing stroke work. In heart failure baseline levels of elastance are increased and the ventricular vascular relationship is uncoupled. Metaboreflex activation only worsens this relationship by further increasing effective arterial elastance with little to no improvements in ventricular maximal elastance. 2) The ventricular contraction and relaxation ratio is sensitive to muscle metaboreflex activation and is primarily affected by large reflex induced increases in relaxation rate. In heart failure metaboreflex activation does not alter the ratio from exercise conditions and this is due to a significant attenuation in the ability to increase relaxation rate. 3) TRPV1 sensitive skeletal muscle afferents account for 50-70% of metaboreflex induced changes in cardiovascular performance. Maximal hemodynamic responses to muscle metaboreflex activation are significantly attenuated. Based on these effects intrathecal administration of resiniferatoxin poses as a potential therapy to attenuate over sympatho-activaton during muscle metaboreflex activation in heart failure.

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