Acute Biomechanical Effects of Cardiac Contractility Modulation in Living Myocardial Slices from End-Stage Heart Failure Patients

TL;DR

This study shows that cardiac contractility modulation can improve heart muscle strength in patients with severe heart failure, depending on the stimulation settings used.

Contribution

The study demonstrates the acute biomechanical effects of CCM on myocardial slices from end-stage heart failure patients.

Findings

CCM increased maximum contractile force and area under the contractile curve in heart failure myocardial slices.

The positive inotropic response to CCM increased with higher stimulation delay, duration, and amplitude.

CCM attenuated the negative force-frequency relationship in heart failure myocardial slices.

Abstract

Proof-of-concept to determine the direct biomechanical effects of cardiac contractility modulation (CCM) on living myocardial slices (LMS) from patients with end-stage heart failure (HF). Left ventricular LMS from patients with end-stage HF were produced and cultured in a biomimetic system with mechanical loading and electrical stimulation. CCM stimulation (80 mA, 40 ms delay, 21 ms duration) enhanced maximum contractile force (CCM: 1229 µN (587–2658) vs. baseline: 1066 µN (529–2128), p = 0.05) and area under the contractile curve (CCM: 297 (151–562) vs. baseline: 243 (129–464), p = 0.05) but did not significantly impact contractile duration, time to peak, or time to relaxation. Increasing CCM stimulation delay, duration, and amplitude resulted in a higher fraction of LMS with a positive inotropic response. Furthermore, CCM attenuated the negative force-frequency relationship in HF-LMS. CCM stimulation enhanced contractile force in HF-LMS. The fraction of LMS exerting a positive inotropic response to CCM increased with increasing delay, duration, and amplitude settings, suggesting that personalizing stimulation parameters could optimize the beneficial effects of CCM. CCM is a novel device-based therapy that may improve contractile function, ejection fraction, functional outcomes, and quality of life in patients with heart failure. However, continuous efforts are needed to identify true responders to CCM therapy, understand the exact mechanisms, and optimize the contractile response to CCM stimulation. The present study revealed that CCM enhanced the contractile force of HF-LMS in a stimulation setting-dependent manner, reaching a larger fraction of the myocardium while increasing delay, duration, and amplitude. This understanding may contribute to the individualization of CCM stimulation settings.

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