Elsevier

JACC: Heart Failure

Volume 11, Issue 7, July 2023, Pages 760-771
JACC: Heart Failure

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

https://doi.org/10.1016/j.jchf.2023.02.006Get rights and content

Abstract

Background

Impaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF.

Objectives

This study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects.

Methods

Eleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 μg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 μg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography).

Results

Patients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 μg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 μg/kg/min during exercise, PCWP during the 1.0 μg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s′, suggesting a mild inotropic effect.

Conclusions

Low-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068)

Section snippets

Study recruitment

As previously described,9 patients with HFpEF were recruited from a university cardiology clinic (University of Texas Southwestern Medical Center, Dallas, Texas, USA). Patients were invited to participate if they were >60 years of age, had undergone hospitalization for HF, had evidence of congestion by either chest radiograph or elevated filling pressures (resting PCWP or LV end-diastolic pressures >16 mm Hg), and had an LV ejection fraction >50%. N-terminal pro–B-type natriuretic peptide

Demographics

Demographic data for HFpEF and senior control subjects are shown in Table 1. A total of 15 patients with HFpEF were enrolled; however, 2 were excluded. One patient with a history of paroxysmal atrial fibrillation developed atrial fibrillation shortly after the right-sided heart catheter was placed, and it reverted to sinus rhythm after the catheter was removed. A second patient was deemed not to have HFpEF on the basis of very low cardiac filling pressures during exercise. Otherwise, there were

Discussion

This study tested the effect of SERCA2a stimulation in facilitating ventricular relaxation and reducing PCWP rise during exercise in patients with HFpEF by using istaroxime, a novel SERCA2a agonist. The primary finding was that istaroxime, infused at a rate 0.5 μg/kg/min, had no meaningful effect on PCWP or markers of relaxation (e′, IVRT) at rest or exercise. An exploratory aim using a higher dose of 1.0 μg/kg/min had a small effect on end-expiratory PCWP reduction of 2 mm Hg during exercise,

Conclusions

Istaroxime, when given at a dose of 0.5 μg/kg/min, had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during submaximal exercise. A higher dose of 1.0 μg/kg/min had no effect on diastolic relaxation across conditions but did lead to a nominal decrease in PCWP of 2.2 mm Hg during exercise compared with saline placebo infusion. The effectiveness of istaroxime on PCWP reduction was inversely correlated with BMI. Future studies using a higher dose

Funding Support and Author Disclosures

This project was supported by the National Institutes of Health (grant RO1 AG17479). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Acknowledgments

The authors would like to thank CVie Therapeutics for providing istaroxime.

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