Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond

Abstract

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.

Keywords: Cardiac contractility modulation; Heart failure; Pathophysiology; Preserved ejection fraction; Treatment.

Figure 1

Impact of cardiac contractility modulation (CCM) on phosphorylation of troponin I (A), myosin‐binding protein C (MyBPC) (B), titin (C), and protein kinase G (PKG) and A (PKA) activity (D–F) in patients with heart failure with reduced ejection fraction (HFrEF). (A–D) Mean ± standard error of the mean of the ratio of phosphorylated to total MyBPC, of phosphorylated to total troponin I (TnI), of phosphorylated to total titin, and of PKA‐induced phosphorylation of titin to total titin, respectively, in endomyocardial biopsies from the right ventricle (RV) or left ventricle (LV) before (black bars), 30 min after (white bars), and 3 months after initiating CCM (grey bars) of two HFrEF patients, as indicated. (E, F) Mean ± standard error of the mean of PKG activity (pmol/min/mg protein) and PKA activity (ng/µL), respectively, in the RV and LV at the same time points after initiating CCM in two HFrEF patients.

Figure 2

Imaging mass spectrometry of endomyocardial biopsies. Ion density distributions of m/z‐values 986 Da and 921 Da (α‐crystallin B chain) are significantly increased after 3 months (3m) in comparison to prior (p) cardiac contractility modulation intervention. (A) Left ventricle (LV) and (B) right ventricle (RV) endomyocardial biopsies (P < 0.001). (C) Receiver operating characteristic (ROC) values show the discrimination capability of m/z 956 Da/921 Da between shortly after/prior, 3 months/shortly after and 3 months/prior cardiac contractility modulation intervention in the LV (upper table) and RV (lower table) [area under the curve (AUC) > 0.6] of two heart failure with reduced ejection fraction patients. (D) String database analysis56 demonstrating the interaction between α‐crystallin B chain (CryAB) and titin. (a) stands for shortly after cardiac contractility modulation intervention.

Figure 3

Impact of cardiac contractility modulation (CCM) on muscle sympathetic nerve activity (MSNA). (A) Bar graphs depict MSNA (au/min) at baseline and 3 months after (follow‐up), off stimulation (left panel), or on stimulation (right panel). MSNA did not acutely change during short on/off stimulations, either at baseline (white circles left panel vs. white circles right panel) nor 3 months later (black circles left panel vs. black circles right panel). After 3 months of treatment, MSNA basal levels (black circles) were significantly reduced compared to baseline (white circles), suggesting that CCM induces a remodelling process, which includes at least indirectly also the sympathetic nerve activity. (B) Representative sympathetic nerve recording of a heart failure with reduced ejection fraction patient with CCM stimulation one day after implantation (left) and after 3 months of intermittent therapy. Note the remarkable reduction in sympathetic burst incidence with chronic CCM stimulation (at baseline; 100%; after 3‐month CCM stimulation: ∼50%). ECG, electrocardiogram; FBP, phospholamban.