Cardiac contractility modulation: a novel approach for the treatment of heart failure

Abstract

Heart failure is a major health problem worldwide and, despite effective therapies, is expected to grow by almost 50 % over the next 15 years. Five-year mortality remains high at 50 % over 5 years. Because of the economic burden and large impact on quality of life, substantial effort has focused on treatments with multiple medical (beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB), aldosterone antagonists, and combination of ARB/neprilysin blockers, ivabradine) and device therapies (ICD, CRT) which have been implemented to reduce disease burden and mortality. However, in the past decade only two new medical therapies and no devices have been approved by the US FDA for the treatment of heart failure. This review highlights the preclinical and clinical literature, and the implantation procedure, related to a relatively new therapeutic device for heart failure; cardiac contractility modulation (CCM). CCM delivers a biphasic high-voltage bipolar signal to the RV septum during the absolute refractory period, eliciting an acute increase in global contractility, and chronically producing a sustained improvement in quality of life, exercise tolerance, and heart failure symptoms. The technology is used commercially in Europe with nearly 3000 patients implanted worldwide. Indications include patients with reduced EF and normal or slightly prolonged QRS duration, thus filling an important therapeutic gap among the 2/3 of patients with heart failure who do not meet criteria for CRT. The mechanism by which CCM provides benefit can be seen at the cellular level where improved calcium handling (phosphorylation of phospholamban, upregulation of SERCA-2A), reversal of the fetal myocyte gene program associated with heart failure, and reverse remodeling are observed. Recent retrospective studies indicate a long-term mortality benefit. A pivotal randomized controlled study is currently being completed in the USA. CCM appears to be an effective, safe technology for the treatment of heart failure with reduced ejection fraction.

Keywords: Calcium handling; Cardiac contractility modulation; Device; Electrical therapy; HFrEF; SERCA2A.

Conflict of interest statement

DG and FA receive consulting fees from Impulse Dynamics.

Figures

Fig. 1

Incidence of heart failure in the USA. An age-dependent increase in new cases of heart failure is observed in older Americans. The incidence is greater across ages in men compared to women. (Adapted from Mozafarian et al. [1].)

Fig. 2

Annual Incidence of heart failure by race in the USA. Heart failure occurs most frequently in African Americans and Hispanics with the lowest incidence in Chinese Americans. (adapted from Mozafarian et al. [1].)

Fig. 3

Timeline depicting date of approval of device (top) and pharmacological (bottom) treatments for HFrEF. There has been a long hiatus in approved device-related therapies. (Blue arrows: FDA-approved treatments)

Fig. 4

Stratification of patients according to device-related therapeutic options. Of patients with HFrEF with NYHA class II or III, 36 % have an EF

Fig. 5

CCM signal triggers from an atrial sensed impulse to augment the next ventricular depolarization which is detected locally from the onset of the QRS (A). After a delay of 30 ms (B) a biphasic impulse is delivered (7.5 V amplitude, 22 ms duration; C), within the absolute refractory period of the ventricle. (reproduced with permission from Kleemann [31])

Fig. 6

Fundamental mechanism of action by which CCM improves contractility in HFrEF. Key actions of CCM are shown in red and include upregulation of SERCA2A, phosphorylation of phospholamban, activation of L-type calcium channels, restitution of the sodium/calcium exchanger, upregulation of metallomatrix proteins, and reduction in basement membrane fibrosis. (Reproduced with permission from Nature Reviews in Cardiology [41])

Fig. 7

Chronic effect of CCM on cardiac structure and function in a canine model of heart failure. Heart failure was induced by coronary embolism, and dogs were maintained until EF stabilized below 35 % for 2 weeks. CCM (or sham therapy) was started, and animals studied at 3 months. CCM significantly reduced LVEDP and LVEDV, and raised LV dP/dt, stroke volume, and LVEF compared to controls where LV dP/dt and LVEF actually decreased. (Adapted from Morita et al. [43].)

Fig. 8

CCM initiates biochemical remodeling and improves the fetal gene program initiated in a canine model of heart failure. After 3 months of CHF, reduced expression (mRNA) of alpha-myosin heavy chains, SERCA2A, and the ryanodine receptor, while upregulating brain natriuretic peptide. CCM normalized these changes. (Adapted from Imau et al. [45].)

Fig. 9

Changes in MLWHFQ (upper left), peak VO2 (upper right) and 6-min walk test (bottom) in patients randomized to CCM ON then CCM OFF (blue) or CCM OFF then CCM ON (red) from the FIX-HF-4 double-blinded randomized controlled trial. At 12 weeks, a significant improvement was observed in both groups for each parameter. At 24 weeks, only those with CCM ON were able to maintain the improvement. These data suggest a prominent placebo effect at 12 weeks and a sustained clinical beneficial effect at 24 weeks of CCM. (Reproduced with permission from the European Heart Journal [39])

Fig. 10

Efficacy results from FIX-HF-5 study of CCM versus optimal medical therapy (OMT) over 1 year. The primary endpoint of ventilatory aerobic threshold was not met although significant improvements in secondary endpoints of peak oxygen consumption, MLWHF questionnaire, and NHYA classification were observed in the CCM group versus OMT. (adapted with permission from Kadish et al. American Heart Journal [38])

Fig. 11

Subgroup analysis of FIX-HF-5 focusing on 150 subjects with LVEF > 25 %. Improvements in VAT, pVO2, NYHA, LVEF, and 6-min walk test were observed. For comparison, orange bars represent amount of improvement seen in the primary study. (adapted with permission from Kadish et al. American Heart Journal [38])

Fig. 12

Meta-analysis of major endpoints from key clinical trials of CCM versus optimal medical therapy. Data were analyzed using individual data points. A significant overall benefit was observed favoring CCM for pVO2 and MLWHF questionnaire, with a nearly significant benefit for 6-min walk test. (reproduced with permission from Giallauria et al. [52])

Fig. 13

Comparison of the effects of CCM and CRT on peak VO2. Studies to the left of the red line utilized CCM (narrow QRS), while those to the right employed CRT (wide QRS). A similar magnitude of effect was observed in studies from each device. (adapted with permission from European Heart Journal [65])

Fig. 14

Mortality rates for CCM versus OMT or comparator groups after long-term follow up. Based on the nature of each study, data are presented at 1, 2, 3, and 5 years following device implantation. Results from 5 groups of subjects from 4 clinical trials are displayed. At the longest follow-up time point for each study, mortality rates were the same or lower in the CCM group compared to the medically treated comparator. In one study mortality with CCM was higher in year 2. The benefit was consistent across a broad spectrum of severity of disease (Schau et al. [53] enrolled 54 patients with more severe heart failure—NYHA III–IV, EF = 23 %); Kloppe et al. [56] followed 68 patients with NYHA II–III, mean EF = 26 %); Kuyschyk et al. [54] studied 81 patients NYHA II–IV, EF = 23 %, 14 % of patients had prolonged QRS duration), while Liu et al. [55] tracked 41 subjects with NYHA III and EF = 27 %; ICD use was low in both groups. Comparator groups for each study are as follows: Schau—Seattle Heart Failure Model; Yu, and Yu (EF > 25 %)—subjects on medical therapy alone from the same database matched for age, gender, etiology of heart failure, and duration of heart failure; Kucyck—MAGGIC risk score; Kloppe—Seattle Heart Failure Model