Access Type

Open Access Dissertation

Date of Award

January 2021

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physiology

First Advisor

Phillip D. Levy

Abstract

Acute heart failure (HF) with underlying ischemic cardiomyopathy (ICM) is one of the leading causes of cardiovascular associated death in the United States. Acute HF pathophysiology involves a complex interplay of neurohormonal activation, increased cardiac ventricular pressures (fluid overload), vasoconstriction, impaired renal function, and progressive end-organ failure. Serelaxin (SLX), a recombinant form of the human hormone relaxin 2, is a vasodilator and an ideal pharmacological agent to treat acute HF. Though SLX was associated with positive preliminary outcome data for acute HF it however failed to provide benefit during clinical trials. Greater understanding of cardiac and renal parameters may elucidate these neutral findings. We addressed two specific questions: 1) To what extent does SLX treatment of acute HF with underlying ICM improve cardiac associated hemodynamics and biomarkers 2) To what extent does SLX treatment of acute HF with underlying ICM improve renal associated hemodynamics and biomarkers. Our study utilized a novel, highly translatable canine model of acute-on-chronic heart failure, data were collected before and after the induction of ICM, following acute HF, and during and after SLX/placebo treatment over 30 days. We found 1) SLX does not significantly improve acute HF blunted cardiac hemodynamics or biomarkers, 30 days post-treatment vs placebo. 2) Acute HF blunted renal hemodynamics and biomarkers were not significantly improved following SLX treatment vs placebo. As such, SLX did not significantly improve acute HF associated cardiac and renal hemodynamics, which further parallels the finds of the human RELAX- AHF2 clinical trial results that show little to no significant improvement in SLX in improving acute HF-linked parameters and outcomes.

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