Cardiac Contractility Modulation Group Research Articles

Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCMassay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Clinical effects of cardiac contractility modulation in heart failure with mildly reduced systolic function.

AimsIncreasing attention is being given to patients with heart failure and ‘mid‐range’ left ventricular ejection fraction (LVEF, ≥40% and <50%) for whom there are no approved therapies that improve prognosis. We aim to assess for the first time the effects of cardiac contractility modulation (CCM) therapy in this patient population.Methods and resultsWe assessed the effects of 6‐ month CCM therapy on functional status, exercise tolerance and quality of life in a subgroup of 53 patients with a LVEF of 40–45% recruited in previous CCM studies, including 37 patients in the CCM group and 16 in the control group. New York Heart Association classification improved by ≥1 class from baseline to 24 weeks in 80.6% (95% confidence interval [62.5%, 92.5%]) of patients in the CCM group compared with 57.1% in the control group (95% confidence interval [28.9%, 82.3%], P = 0.15). Six‐minute walk distance increased significantly in the CCM group with a net between‐group treatment effect of 53.9 ± 74.2 m (P = 0.05). Peak VO2 improved in the CCM group with a net between‐group treatment effect of 2.0 ± 2.8 mL/kg/min (P = 0.02). Minnesota Living with Heart Failure Questionnaire score decreased from baseline to 24 weeks with a net between‐group treatment effect of −13.1 ± 21.0 (P = 0.10). There were no significant differences in the adverse event rate between the CCM and control groups.ConclusionsThese preliminary results suggest that CCM exerts favourable effects on exercise tolerance and quality of life in patients with LVEF in the range of 40–45% with an acceptable safety profile. Further randomized controlled studies are planned to prove these effects.

Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model.

BackgroundCardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on structural and electrical remodeling in a rabbit model of chronic heart failure (CHF).MethodsThirty rabbits were randomly divided into the sham, CHF, and CCM groups. The CHF model was induced 12 weeks after trans-aortic constriction by pressure unloading and CCM was delivered to the myocardium for 4 weeks. Corrected QT intervals, the ventricular effective refractory period, and inducibility of ventricular tachycardia were measured by an electrophysiological examination. Connective tissue growth factor, galectin-3, Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were measured by western blotting.ResultsThe CHF group had a significantly prolonged corrected QT interval and ventricular effective refractory period, and increased inducibility of ventricular tachycardia. Prominent myocardial fibrosis and increased hydroxyproline content were observed in the CHF group, but these were suppressed in the CCM group. Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were significantly lower in the CHF group, but treatment with CCM partially restored their levels.ConclusionsCCM attenuates myocardial structural and electrical remodeling during CHF. These findings provide evidence for clinical use of CCM in treating CHF.

All-Cause Mortality Outcomes of Usage of Cardiac Contractility Modulation in Patients With Dilated Cardiomyopathy Ineligible for Cardiac Re-Synchronization Therapy: An Updated Meta-Analysis of Randomized Controlled Trials.

IntroductionDilated cardiomyopathy has been associated with remarkably high mortality despite guideline-directed therapy. This study compares the all-cause mortality rate between a cardiac contractility modulation group and a standard therapy group in patients with dilated cardiomyopathy who were monitored via follow-up for 12 weeks or more.Materials and methodsWe conducted a systematic search of Medline (PubMed) and Cochrane Central Register of Controlled Trials for abstracts and fully published studies (from inception to October 2018). We searched for articles comparing cardiac contractility modulation device therapy with standard therapy for patients with dilated cardiomyopathy between September 1, 2018, and October 30, 2018.Only fully published randomized clinical trials comparing all-cause mortality outcomes of device therapy and standard therapy for patients with dilated cardiomyopathy were included in our meta-analysis. A total of 673 studies were identified. Studies that were systematic reviews or meta-analyses, study designs or protocols, trials on other regimens, wherein medical therapy was not compared, or wherein the primary outcome of mortality was not assessed, were excluded.Data were abstracted by two independent reviewers. A random-effect model using the Mantel-Haenszel method calculated the weighted risk ratio (RR). Statistical analyses were performed using Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration; Copenhagen). The primary outcome of interest was a comparison of all-cause mortality between the two groups when patients were monitored via follow-up for 12 weeks or more.ResultsFour fully published randomized clinical trials met the inclusion criteria of our analysis. A random-effect model using the Mantel-Haenszel method calculated the weighted RR. Our analysis included a total of 930 patients. The cardiac contractility modulation therapy group showed no significant reduction in all-cause mortality compared to the standard therapy group (RR, 0.63; 95% CI, 0.29-1.35; P = .23). However, the trend was toward device therapy. Tests for statistical heterogeneity did not show any significant heterogeneity (P = .82, I2 = 0%).ConclusionsCardiac contractility modulation device therapy is not associated with significant all-cause mortality reduction in patients with dilated cardiomyopathy. Our meta-analysis underscores the need for a large randomized controlled trial on the efficacy of cardiac contractility modulation in a population with dilated cardiomyopathy who are ineligible for cardiac resynchronization therapy.

Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway.

The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3β, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3β, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.

Outcomes of Cardiac Contractility Modulation: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Background Cardiac contractility modulation (CCM) is a device therapy for systolic heart failure (HF) in patients with narrow QRS. We aimed to perform an updated meta-analysis of the randomized clinical trials (RCTs) to assess the efficacy and safety of CCM therapy. Methods We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) between January 2001 and June 2018. Outcomes of interest were peak oxygen consumption (peak VO2), 6-Minute Walk Distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ), HF hospitalizations, cardiac arrhythmias, pacemaker/ICD malfunctioning, all-cause hospitalizations, and mortality. Data were expressed as standardized mean difference (SMD) or odds ratio (OR). Results Four RCTs including 801 patients (CCM n = 394) were available for analysis. The mean age was 59.63 ± 0.84 years, mean ejection fraction was 29.14 ± 1.22%, and mean QRS duration was 106.23 ± 1.65 msec. Mean follow-up duration was six months. CCM was associated with improved MLWHFQ (SMD -0.69, p = 0.0008). There were no differences in HF hospitalizations (OR 0.76, p = 0.12), 6MWD (SMD 0.67, p = 0.10), arrhythmias (OR 1.40, p = 0.14), pacemaker/ICD malfunction/sensing defect (OR 2.23, p = 0.06), all-cause hospitalizations (OR 0.73, p = 0.33), or all-cause mortality (OR 1.04, p = 0.92) between the CCM and non-CCM groups. Conclusions Short-term treatment with CCM may improve MLFHQ without significant difference in 6MWD, arrhythmic events, HF hospitalizations, all-cause hospitalizations, and all-cause mortality. There is a trend towards increased pacemaker/ICD device malfunction. Larger RCTs might be needed to determine if the CCM therapy will be beneficial with longer follow-up.

Cardiac contractility modulation improves left ventricular systolic function partially via miR-25 mediated SERCA2A expression in rabbit trans aortic constriction heart failure model.

The purpose of this study was to investigate the underlying mechanism of cardiac contractility modulation (CCM) in improving trans aortic constriction (TAC)-induced heart failure (HF) left ventricular (LV) systolic function. A total of 25 New Zealand white rabbits were randomly divided into 5 groups: sham operation group (SHM), TAC-induced HF group (HF), TAC-induced HF followed by CCM stimulation group (HF + CCM), TAC-induced HF followed by injection of anti-miR-25 group (HF + anti-miR-25), TAC-induced HF followed by CCM stimulation and AAV9-miR-25 injection group (HF + CCM + miR-25). CCM current was performed 6 hours a day for 4 weeks. The left ventricle ejection fraction (LVEF) was measured by ultrasound. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used for measuring RNA and protein levels. The sarcoplasmic reticulum calcium ATPase (SERCA2A) and LVEF were reduced, while the miR-25 expression was improved in HF group compared to SHM group. Conversely, the SERCA2A and LVEF were improved, and the miR-25 reduced in the HF + CCM and the HF + anti-miR-25 groups compared to the HF group. Moreover, the SERCA2A and LVEF were reduced, while the miR-25 was improved in the HF + CCM + miR-25 group compared to the HF + CCM group. CCM is a potentially effective procedure for improving LV systolic function, which might partially by inhibiting miR-25 expression, further improved SERCA2A expression in TAC HF models.

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. Methods: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were measured by western blot analysis. Results: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were down regulated. Conclusion: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-β1/Smad3 signaling pathway in CHF rabbits.

Biventricular Pacing Cardiac Contractility Modulation Improves Cardiac Contractile Function via Upregulating SERCA2 and miR-133 in a Rabbit Model of Congestive Heart Failure

Objective: To compare the effects of biventricular electrical pacing and conventional single-ventricular pacing for cardiac contractility modulation (CCM) on cardiac contractile function and to delineate the underlying molecular mechanisms. Methods: Forty rabbits were divided into four groups before surgery: healthy control, HF sham, HF left ventricular pacing CCM (LVP-CCM), and HF biventricular pacing CCM (BVP-CCM) groups with n=10 for each group. A rabbit model of chronic heart failure was established by ligating ascending aortic root of rabbits. Then electrical stimulations during the absolute refractory period were delivered to the anterior wall of left ventricle in the LVP-CCM group and on the anterior wall of both left and right ventricles in the BVP-CCM group lasting six hours per day for seven days. Changes in ventricular structure, cardiac function and electrocardiogram were monitored before and after CCM stimulation. Results: Compared with the sham-operated group, heart weight, heart weight index, LV end-systolic diameter (LVESD), LV end-diastolic diameter (LVEDD) in the LVP-CCM and BVP-CCM groups were significantly decreased (p<0.05), while LV ejection fraction (LVEF) and fractional shortening fraction (FS) were increased (p<0.05). Notably all these changes were consistently found to be greater in BVP-CCM than in LVP-CCM. Moreover, plasma BNP levels were highest in the HF sham-control group, followed by the LVP-CCM group, and lowest in the BVP-CCM group (p<0.05). Furthermore, sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) protein levels were upregulated by 1.7 and 2.4 fold, along with simultaneous upregulation of a cardiac-enriched microRNA miR-133 levels by 2.6 and 3.3 fold, in LVP-CCM and BVP-CCM, respectively, compared to sham. Conclusions: Biventricular pacing CCM is superior to conventional monoventricular pacing CCM, producing greater improvement cardiac contractile function. Greater upregulation of SERCA2 and miR-133 may account, at least partially, for the improvement by BVP-CCM.