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.

Although the care of patients presenting with a myocardial infarction (MI) has improved considerably over recent years, mortality in this group is still relatively high. To preserve myocardial function, it is crucial that blood flow is restored as quickly as possible to ischemic areas after an infarction, but this return of flow itself induces detrimental processes that eventually can lead to increased myocardial damage and cell death, a process indicated by the term ischemia-reperfusion injury (IRI). Myocardial IRI is, among others, associated with extensive alterations in energy metabolism, ion homeostasis, bioelectrical signaling pathways and autonomic balance. Current cardioprotective strategies against IRI consist of ischemic, pharmaceutical, stem-cell or mechanical conditioning strategies. Despite substantial pre-clinical progress with these approaches, clinical translation remains challenging. Therefore, alternative approaches are still necessary to reduce the clinical complications associated with IRI. Cardioprotective strategies applying neuromodulation or a form of electrical stimulation may provide for such an angle. It is the goal of this review to provide insight into the molecular and electrical consequences of IRI in the myocardium. Moreover, conditioning strategies that use neuromodulation or a form of electrical stimulation that are of interest for cardioprotection against IRI will be highlighted and explored.

1.1 Aims: 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). 1.2 Methods and results: 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. 1.3 Conclusion: 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. 1.4 Translational perspective 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 to optimize the contractile response to CCM stimulation. The present study revealed that CCM enhanced 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.