SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction

Area of Science:

• Cardiology
• Pharmacology
• Physiology

Background:

• Impaired ventricular relaxation affects left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF).
• Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) is crucial for myocardial relaxation and is impaired in HFpEF.

Purpose of the Study:

• To investigate the effects of istaroxime, a SERCA2a agonist, on lusitropic and hemodynamic function during exercise in HFpEF patients and controls.
• To assess istaroxime's impact on cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function.

Main Methods:

• A single-blind, crossover study involving 15 HFpEF patients and 11 controls performing upright cycle exercise with right-sided heart catheterization.
• Participants received either istaroxime (0.5 μg/kg/min) or placebo, with an exploratory analysis of a higher istaroxime dose (1.0 μg/kg/min).
• Measurements included cardiac output, PCWP, diastolic function, and end-systolic elastance (Ees) at rest and during exercise.

Main Results:

• HFpEF patients exhibited higher resting PCWP and reduced exercise tissue Doppler velocities compared to controls.
• Low-dose istaroxime (0.5 μg/kg/min) showed no significant effects on resting or exercise hemodynamics in either group.
• Control subjects demonstrated a greater increase in Ees during exercise. A higher istaroxime dose (1.0 μg/kg/min) showed a trend towards lower exercise PCWP in HFpEF patients.

Conclusions:

• Low-dose istaroxime did not improve cardiac filling pressures or relaxation parameters in HFpEF patients during exercise.
• Higher doses of istaroxime may potentially reduce exercise-induced PCWP elevation in HFpEF patients.
• Further research is warranted to explore the efficacy of higher istaroxime doses in HFpEF management.