Cardiac Contractility Modulation Research Articles

2024 update in heart failure.

In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4mg once weekly administered for 1year decreased body weight and significantly improved quality of life and the 6min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

Interpretation of electrocardiograms and results of daily ECG Holter monitoring in patients with an implanted cardiac contractility modulator

Cardiac contractility modulation (CCM) is a method of non-drug treatment of chronic heart failure (CHF) in patients with no indications for resynchronization therapy. Now, a detailed study of this method and its capabilities is ongoing, and the indications for its use are expanding. As with any other implantable device, it is important to be able to monitor the operation of the CCM, identify its dysfunction and promptly refer patients to specialized institutions. Assessment of the function of CCM- therapy can be carrying out by recording a standard 12‑channel electrocardiogram (ECG), as well as 24‑hour Holter ECG monitoring (HM-ECG). The mechanism of action of CCM-therapy is fundamentally different from that of other implantable devices. Knowledge of the features of the manifestation of CCM-therapy during instrumental studies is necessary for their correct interpretation.

Short-term efficacy and safety of cardiac contractility modulation in patients with heart failure

Objective: To investigate the short-term efficacy and safety of cardiac contractility modulation (CCM) in patients with heart failure. Methods: This was a cross-sectional study of patients with heart failure who underwent CCM placement at the First Affiliated Hospital of Xinjiang Medical University from February to June 2022. With a follow-up of 3 months, CCM sensation, impedance, percent output, and work time were monitored, and patients were compared with pre-and 3-month postoperative left ventricular ejection fraction (LVEF) values, and 6-minute walk test distance and New York Heart Association (NYHA) cardiac function classification, and the occurrence of complications was recorded. Results: CCM was successfully implanted in all 9 patients. Seven(7/9) of them were male, aged (56±14) years, 3 patients had ischaemic cardiomyopathy and 6 patients had dilated cardiomyopathy. At 3-month postoperative follow-up, threshold was stable, sense was significantly lower at follow-up than before (right ventricle: (16.3±7.0) mV vs. (8.2±1.1) mV, P<0.05; local sense: (15.7±4.9) mV vs. (6.7±2.5) mV, P<0.05), and impedance was significantly lower at follow-up than before (right ventricle (846±179) Ω vs. (470±65) Ω, P<0.05, local sense: (832±246) Ω vs. (464±63) Ω, P<0.05). The CCM output percentage was (86.9±10.7) %, the output amplitude was (6.7±0.4) V, and the daily operating time was (8.6±1.0) h. LVEF was elevated compared to preoperative ((29.4±5.2) % vs. (38.3±4.3) %, P<0.05), the 6-minute walk test was significantly longer than before ((96.8±66.7)m vs. (289.3±121.7)m, P<0.05). No significant increase in the number of NYHA Class Ⅲ-Ⅳ patients was seen (7/9 vs. 2/9, P>0.05). The patient was not re-hospitalised for worsening heart failure symptoms, had no malignant arrhythmic events and experienced significant relief of symptoms such as chest tightness and shortness of breath. No postoperative complications related to pocket hematoma, pocket infection and rupture, electrode detachment, valve function impairment, pericardial effusion, or cardiac perforation were found. Conclusions: CCM has better short-term safety and efficacy in patients with heart failure.

Initial experience with cardiac contractility modulation devices in Latin America for the treatment of heart failure

To describe the initial experience of cardiac contractility modulation (CCM) implantation in Latin America. We present the first two cases in Latin America of patients with heart failure with reduced left ventricular ejection fraction (LVEF) not candidates for cardiac resynchronization therapy in whom a CCM device was implanted. Results. In both patients we described improvement of the 6-minute walk test, functional class according to the NYHA and LVEF. The modulation of cardiac contractility is currently a treatment option for patients with heart failure in functional class III-IV, with LVEF 25-45%, and a QRS < 130 ms who are not candidates for cardiac resynchronization therapy.

Non-Pharmacological Treatment of Heart Failure-From Physical Activity to Electrical Therapies: A Literature Review.

Heart failure (HF) represents a significant global health challenge that is still responsible for increasing morbidity and mortality despite advancements in pharmacological treatments. This review investigates the effectiveness of non-pharmacological interventions in the management of HF, examining lifestyle measures, physical activity, and the role of some electrical therapies such as catheter ablation, cardiac resynchronization therapy (CRT), and cardiac contractility modulation (CCM). Structured exercise training is a cornerstone in this field, demonstrating terrific improvements in functional status, quality of life, and mortality risk reduction, particularly in patients with HF with reduced ejection fraction (HFrEF). Catheter ablation for atrial fibrillation, premature ventricular beats, and ventricular tachycardia aids in improving left ventricular function by reducing arrhythmic burden. CRT remains a key intervention for selected HF patients, helping achieve left ventricular reverse remodeling and improving symptoms. Additionally, the emerging therapy of CCM provides a novel opportunity for patients who do not meet CRT criteria or are non-responders. Integrating non-pharmacological interventions such as digital health alongside specific medications is key for optimizing outcomes in HF management. It is imperative to tailor approaches to individual patients in this diverse patient population to maximize benefits. Further research is warranted to improve treatment strategies and enhance patient outcomes in HF management.

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

[This retracts the article DOI: 10.1155/2020/1625362.].

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.

Cardiac contractility modulation in patients with heart failure - A review of the literature.

Experimental in vivo and in vitro studies showed that electric currents applied during the absolute refractory period can modulate cardiac contractility. In preclinical studies, cardiac contractility modulation (CCM) was found to improve calcium handling, reverse the foetal myocyte gene programming associated with heart failure (HF), and facilitate reverse remodeling. Randomized control trials and observational studies have provided evidence about the safety and efficacy of CCM in patients with HF. Clinically, CCM therapy is indicated to improve the 6-min hall walk, quality of life, and functional status of HF patients who remain symptomatic despite guideline-directed medical treatment without an indication for cardiac resynchronization therapy (CRT) and have a left ventricular ejection fraction (LVEF) ranging from 25 to 45%. Although there are promising results about the role of CCM in HF patients with preserved LVEF (HFpEF), further studies are needed to elucidate the role of CCM therapy in this population. Late gadolinium enhancement (LGE) assessment before CCM implantation has been proposed for guiding the lead placement. Furthermore, the optimal duration of CCM application needs further investigation. This review aims to present the existing evidence regarding the role of CCM therapy in HF patients and identify gaps and challenges that require further studies.

Molecular effects of cardiac contractility modulation in patients with heart failure of ischemic aetiology uncovered by transcriptome analysis.

Cardiac contractility modulation (CCM) is based on electrical stimulation of the heart without alteration of action potential and mechanical activation, the data on its fundamental molecular mechanisms are limited. Here we demonstrate clinical and physiological effect of 12 months CCM in 29 patients along with transcriptomic molecular data. Based on the CCM effect the patients were divided into two groups: responders (n = 13) and non-responders (n = 16). RNA-seq data were collected for 6 patients before and after CCM including 3 responders and 3 non-responders. The overall effect of CCM on gene expression was mainly provided by samples from the responder group and included the upregulation of the genes involved in the maintenance of proteostasis and mitochondrial structure and function. Using pathway enrichment analysis, we found that baseline myocardial tissue samples from responder group were characterized by upregulation of mitochondrial matrix-related genes, Z disc-protein encoding genes and muscle contraction-related genes. In summary, twelve months of ССM led to changes in signaling pathways associated with cellular respiration, apoptosis, and autophagy. The pattern of myocardial remodeling after CCM is associated with initial expression level of myocardial contractile proteins, adaptation reserves associated with mitochondria and low expression level of inflammatory molecules.

Analysis of electrotherapy in patients with implantable cardioverter-defibrillator for primary prevention of sudden cardiac death according to remote monitoring data

Aim: To determine the factors associated with development of justified and inappropriate implantable cardioverter-defibrillator (ICD) activations in patients at high risk of sudden cardiac death based on the remote monitoring systemMaterial and Methods. We analyzed remote monitoring data from 2014 to 2022 in 132 patients with ICD for primary prevention of sudden cardiac death (SCD). Patients were divided into 2 groups 1 – patients with persistent paroxysmal tachyarrhythmias; 2 – patients without persistent paroxysms of ventricular tachycardia (VT) / ventricular fibrillation (VF). In case of inappropriate shocks, the causes and possible predictors of their development were analyzed.Results. Of 132 patients, 62 (46.9%) patients appeared to have persistent VT/VF. It was found that the probability of detecting persistent paroxysms of VT/VF decreased with a history of revascularization (p = 0.030) and increased in the absence of amiodarone therapy (p = 0.012), with increasing age (p = 0.035), with decreasing left ventricular ejection fraction (LVEF) less than 35% (p = 0.016). 71 arrhythmic episodes (17.9%) in 27 (20.4%) patients were considered as false detection of tachyarrhythmias. Analyzing the causes of inappropriate electrotherapy, different types of supraventricular tachyarrhythmias in the zone of VT detection (85.9%), including atrial fibrillation (25.4%), in smaller percentage of cases there was discovered T-wave detection 4.2%, noise on the electrode – 2.8%, 7.1% – double counter due to the operation of the cardiac contractility modulation device. When analyzing factors associated with the development of false detection, reliable results were obtained with regard to the presence of a history of atrial fibrillation (p = 0.036), implanted single-chamber ICD (p = 0.028).Conclusion. The development of persistent ventricular tachyarrhythmias was noted in 47% of patients with ICD as a part of primary prevention of sudden cardiac death, and 20.4% had the development of inappropriate detection and electrotherapy. Predictors of their occurrence have been identified, which can be used as development of strategies for shock minimization.

Heartfelt Breakthroughs: Elevating Quality of Life with Cutting-Edge Advances in Heart Failure Treatment.

Heart failure is a cardiovascular condition, leading to fatigue, breathlessness, and fluid retention. It affects around 56 million people globally and is a leading cause of hospitalization and mortality. Its prevalence is rising due to aging populations and lifestyle factors. Managing heart failure demands a multidisciplinary approach, encompassing medications, lifestyle modifications, and often medical devices or surgeries. The treatment burden is substantial, impacting patients' daily lives and straining healthcare systems. Improving early detection, novel therapies, and patient education are crucial for alleviating the burden and enhancing the quality of life. There are notable advancements in the field of heart failure treatment and prevention. We will discuss significant pharmacological and device advances related to heart failure, including angiotensin receptor-neprilysin inhibitor, sodium-glucose co-transporter inhibition, glucagon-like peptide-1 agonist, cardiac resynchronization therapy, cardiac contractility modulation, mechanical circulatory support devices, and transcatheter valve interventions. We will also review novel therapies on the horizon, emerging technologies like CRISPR-based treatments for genetic anomalies, and the involvement of artificial intelligence in heart failure detection and management.

Preliminary Results In Genetic Cardiomyopathy With Significant Systolic Heart Failure Treated With Cardiac Contractility Modulation: A Single-Center Experience

Preliminary Results In Genetic Cardiomyopathy With Significant Systolic Heart Failure Treated With Cardiac Contractility Modulation: A Single-Center Experience

Advances in device-based treatment of heart failure with preserved ejection fraction: evidence from clinical trials.

Heart failure with preserved ejection fraction (HFpEF) is a group of clinical syndromes that exhibit a remarkably heterogeneous phenotype, characterized by symptoms and signs of heart failure, left ventricular diastolic dysfunction, elevated levels of natriuretic peptides, and an ejection fraction greater than or equal to 50%. With the aging of the population and the escalating prevalence of hypertension, obesity, and diabetes, the incidence of HFpEF is progressively rising. Drug therapy options for HFpEF are currently limited, and the associated high risk of cardiovascular mortality and heart failure rehospitalization significantly impact patients' quality of life and longevity while imposing a substantial economic burden on society. Recent research indicates that certain device-based therapies may serve as valuable adjuncts to drug therapy in patients with specific phenotypes of HFpEF, effectively improving symptoms and quality of life while reducing the risk of readmission for heart failure. These include inter-atrial shunt and greater splanchnic nerve ablation to reduce left ventricular filling pressure, implantable heart failure monitor to guide diuresis, left atrial pacing to correct interatrial dyssynchrony, cardiac contractility modulation to enhance cardiac calcium handling, as well as renal denervation, baroreflex activation therapy, and vagus nerve stimulation to restore the autonomic imbalance. In this review, we provide a comprehensive overview of the mechanisms and clinical evidence pertaining to these devices, with the aim of enhancing therapeutic strategies for HFpEF.

Enhancing myocardial function with cardiac contractility modulation: potential and challenges.

Cardiac contractility modulation (CCM) offers a novel therapeutic avenue for heart failure patients, particularly those unresponsive to cardiac resynchronization therapy within specific QRS duration ranges. This review elucidates CCM's mechanistic underpinnings, its impact on myocardial function, and utility across patient demographics. However, CCM is limited by insufficient data on mortality and hospitalization rate reductions, as well as the need for specialized device implantation skills. While prevailing research has concentrated on left ventricular effects, a knowledge gap persists for other patient subsets. Future inquiries should address combinatory treatment strategies, extended usage and the impact of atrial fibrillation on device implantation. Such expanded studies could refine therapeutic outcomes and widen the scope of beneficiaries.

Cost-utility of cardiac contractility modulation in patients with heart failure with reduced ejection fraction in Italy.

Cardiac contractility modulation (CCM) is a device therapy for heart failure, based on the delivery of high-voltage biphasic impulses to the right ventricular septum during the myocardial absolute refractory period. This study evaluated the cost-effectiveness of CCM therapy plus optimal medical therapy (OMT) vs. OMT alone in patients with heart failure with reduced ejection fraction. A Markov model with a lifespan time horizon was developed to assess the cost-utility using the FIX trials as main data sources. A deterministic sensitivity analysis and a probabilistic sensitivity analysis were run to analyse the decision uncertainty in the model through cost-effectiveness acceptability curve (CEAC) and cost-effectiveness acceptability frontier (CEAF). Value of information analysis was also conducted computing the expected value of perfect information (EVPI) and the expected value of partial perfect information. The base case results showed that the CCM plus OMT option was highly cost-effective compared with OMT alone with an incremental cost-utility ratio of €7034/quality-adjusted life year (QALY). The CEAC and CEAF illustrated that for all willingness to pay levels above €5600/QALY, tested up to €50000/QALY, CCM plus OMT alternative had the highest probability of being cost-effective. The EVPI per patient was estimated to be €124412 on a willingness to pay threshold of €30000/QALY. For patients with heart failure with reduced ejection fraction, CCM therapy could be cost-effective when taking a lifetime horizon. Further long-term, post-approval clinical studies are needed to verify these results in a real-world context, particularly concerning the effect of CCM therapy on mortality.

Abstract 18085: Effect of Therapies on Quality of Life in Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis

Introduction: Minnesota Living with Heart Failure (MLWHF) questionnaire is a validated tool to assess quality of life in patients with heart failure with reduced ejection fraction (HFrEF) Hypothesis: We performed this systematic review and meta-analysis to evaluate the effect of therapies on improvement in MLWHF; analyzed across randomized controlled trials (RCTs) of drug based therapy, device based therapy, autonomic modulation, and exercise. Methods: We conducted a systematic search of MEDLINE and EMBASE for RCTs measuring MLWHF at baseline and follow-up in patients with HFrEF. Primary outcome was improvement in MLWHF. Meta-analysis was stratified in groups based on medical therapy, device based therapy (cardiac resynchronization therapy and cardiac contractility modulation), autonomic modulation (vagus nerve stimulation and baroreflex activation therapy), and exercise. Mean difference (MD) with 95% Confidence Interval (CI) were reported across multiple studies included in meta-analysis. Results: A total of 23 studies met the inclusion criteria. Analysis showed statistically significant improvement in MLWHF at follow-up for drug based therapy (MD: -2.77; 95% CI: -5.10, -0.44) (Panel A), device based therapy (MD: -6.86; 95% CI: -9.60, -4.12) (Panel B), autonomic modulation (MD: -15.21; 95% CI: - 19.25, -11.17) (Panel C), and exercise group (MD: -10.05; 95% CI: -16.66, -3.43) (Panel D). Sub-group analyses based on various treatment modalities showed statistically significant improvement in MLWHF at follow-up for cardiac resynchronization therapy (MD: -8.11; 95% CI: -11.88, -4.33), cardiac contractility modulation (MD: -5.47; 95% CI: -9.46, -1.49), and baroreflex activation therapy (MD: -19.79; 95% CI: -24.90, -14.67). Conclusions: Drug based therapy, device based therapy, autonomic modulation, and exercise are associated with improvement in quality of life in patients with HFrEF.

Bridging the gap in the symptomatic heart failure patient journey: insights from the Italian scenario

ABSTRACT Background The prognosis for heart failure (HF) patients remains poor, with a high mortality rate, and a marked reduction in quality of life (QOL) and functional status. This study aims to explore the ongoing needs of HF management and the epidemiology of patients followed by Italian HF clinics, with a specific focus on cardiac contractility modulation (CCM). Research design and methods Data from patients admitted to 14 HF outpatients clinics over 4 weeks were collected and compared to the results of a survey open to physicians involved in HF management operating in Italian centers. Results One hundred and five physicians took part in the survey. Despite 94% of patients receive a regular follow-up every 3–6 months, available therapies are considered insufficient in 30% of cases. Physicians reported a lack of treatment options for 23% of symptomatic patients with reduced ejection fraction (EF) and for 66% of those without reduced EF. Approximately 3% of HF population (two patients per month per HF clinic) meets the criteria for immediate CCM treatment, which is considered a useful option by 15% of survey respondents. Conclusions Despite this relatively small percentage, considering total HF population, CCM could potentially benefit numerous HF patients, particularly the elderly, by reducing hospitalizations, improving functional capacity and QOL.

Established and Emerging Device Therapy in Heart Failure: Cardiac Contractility Modulation.

Established and Emerging Device Therapy in Heart Failure: Cardiac Contractility Modulation.

Electrical therapies in heart failure: Evolving technologies and indications

Device therapy for heart failure has rapidly evolved over 2 decades. The knowledge of indications, assessment lead and device technology has expanded to include CRT, leadless pacing and conduction system pacing such as His bundle and left bundle branch area pacing. But there is still a lack of evidence for these new technologies as well as for common indications such as atrial fibrillation and upgrading from a previous device. The role of personalized medicine will become increasingly important when selecting candidates for CRT, primary preventive ICD ablation procedures and emerging new devices such as cardiac contractility modulation (CCM). Rapidity of therapy is associated with outcome which will be a challenge. If properly implemented devices and drugs will have a large positive affect of HF outcomes.

Beyond Conventional Cardiac Resynchronisation Therapy: A Review of Electrophysiological Options in the Management of Chronic Heart Failure.

The incidence of heart failure (HF) continues to grow and burden our health care system. Electrophysiological aberrations are common amongst patients with heart failure and can contribute to worsening symptoms and prognosis. Targeting these abnormalities with cardiac and extra-cardiac device therapies and catheter ablation procedures augments cardiac function. Newer technologies aimed to improvement procedural outcomes, address known procedural limitations and target newer anatomical sites have been trialled recently. We review the role and evidence base for conventional cardiac resynchronisation therapy (CRT) and its optimisation, catheter ablation therapies for atrial arrhythmias, cardiac contractility and autonomic modulation therapies.