Effects Of Cardiac Contractility Modulation Research Articles

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.

Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway.

Metabolic remodeling contributes to the pathological process of heart failure (HF). We explored the effects of cardiac contractility modulation (CCM) on myocardial metabolic remodeling in the rabbit model with HF. The HF in rabbit model was established by pressure uploading and then CCM was applied. We evaluated the cardiac structure and function by echocardiography, serum BNP level, and hematoxylin and eosin and Masson’s trichrome staining. We detected the accumulation of glycogen and lipid droplets in myocardial tissues by periodic acid-Schiff and Oil Red O staining. Then, we measured the contents of glucose, free fatty acid (FFA), lactic acid, pyruvate, and adenosine triphosphate (ATP) levels in myocardial tissues by corresponding kits and the expression levels of key factors related to myocardial substrate uptake and utilization by western blotting were analyzed. CCM significantly restored the cardiac structure and function in the rabbit model with HF. CCM therapy further decreased the accumulation of glycogen and lipid droplets. Furthermore, CCM reduced the contents of FFA, glucose, and lactic acid, and increased pyruvate and ATP levels in HF tissues. The protein expression levels related to myocardial substrate uptake and utilization were markedly improved with CCM treatment by further activating adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-α signaling pathways.

Clinical effects of cardiac contractility modulation in patients with chronic heart failure and various forms of atrial fibrillation

<h3>ЦЕЛЬ ИССЛЕДОВАНИЯ</h3> Оценка клинической эффективности модуляции сердечной сократимости (МСС) у пациентов с хронической сердечной недостаточностью (ХСН) и различными формами фибрилляции предсердий (ФП). <h3>МАТЕРИАЛ И МЕТОДЫ</h3> В исследование включены 160 пациентов с ХСН со сниженной фракцией выброса левого желудочка (ФВЛЖ) и ФП, которые были разделены на две группы: 1-я — группа МСС — 80 пациентам на фоне оптимальной медикаментозной терапии (ОМТ) была проведена имплантация прибора Optimizer Smart, 2-я — группа сравнения — 80 пациентов получали только ОМТ. В каждой группе анализ проводился в зависимости от формы ФП. Всем исходно и через 12 мес наблюдения выполняли 12-канальную электрокардиографию (ЭКГ), трансторакальную эхокардиографию (ЭхоКГ), суточное мониторирование ЭКГ, определяли уровень NT-proBNP, проводили тест 6-минутной ходьбы (ТШХ) и оценивали качество жизни по данным Миннесотского опросника (МО). <h3>РЕЗУЛЬТАТЫ</h3> Полученные данные свидетельствуют о достоверной клинической эффективности МСС-терапии снижением ФК ХСН (<i>p</i>=0,001) через 12 мес, увеличением дистанции ТШХ (<i>p</i>=0,001), снижением количества баллов по данным МО (<i>p</i>=0,001), указывая на улучшения качества жизни. В группе МСС терапии у пациентов с пароксизмальной формой ФП отмечено достоверное снижение концентрации NT-proBNP через 12 мес (<i>p</i>=0,003). Наблюдалось уменьшение конечно-диастолического (<i>p</i>=0,009) и конечно-систолического объемов (<i>p</i>=0,001), а также достоверное уменьшение объема левого предсердия (<i>p</i>=0,004) у пациентов с постоянной ФП в группе МСС. Фиксировалось улучшение сократительной способности миокарда: прирост ФВЛЖ как у больных с пароксизмальной, так и с постоянной формой ФП, в группе МСС-терапии по сравнению с группой пациентов, получавших только ОМТ (<i>p</i>=0,001). Ширина комплекса QRS статистически значимо не увеличилась на фоне МСС-терапии при пароксизмальной и постоянной форме ФП. В группе сравнения у пациентов с постоянной ФП было статистически значимое увеличение продолжительности комплекса QRS (<i>p</i>=0,045). Общее количество желудочковых экстрасистол за сут в группе МСС-терапии не возрастало вне зависимости от формы ФП, выявлено достоверное снижение пароксизмов ФП (<i>p</i>=0,038). В группе пациентов с МСС и постоянной формой ФП отмечалось статистически значимое уменьшение пробежек желудочковой тахикардии (<i>p</i>=0,011). У пациентов с постоянной формой ФП в контрольной группе через 12 мес достоверно увеличилась частота желудочковых сокращений (<i>p</i>=0,005). <h3>ЗАКЛЮЧЕНИЕ</h3> Полученные данные нашего исследования демонстрируют, что МСС-терапия улучшает функциональное состояние, качество жизни пациентов, способствует обратному ремоделированию ЛЖ и не провоцирует увеличение различных нарушений ритма сердца.

Myocardial remodeling in patients with chronic heart failure and implanted cardiac contractility modulators

To study the effect of cardiac contractility modulation on reverse remodeling and myocardial function in patients with chronic heart failure (HF) according to echocardiography (EchoCG). In a group of 40 patients with a combination of chronic HF and atrial fibrillation (AF), the dynamics of standard EchoCG parameters and the effectiveness of myocardial work of the left ventricle (LV) against the background of 12-month therapy of cardiac contractility modulation (CCM) were analyzed. The results obtained indicate a statistically significant positive effect of CCM on LV remodeling parameters and the effectiveness of myocardial work according to EchoCG. Transthoracic echocardiography is the main imaging method and provides great opportunities for evaluating the effectiveness of HF treatment, including non-drug methods such as CCM. Evaluation of LV myocardial function in patients with HF and implanted CCM devices is a promising scientific and practical research method.

Acute effects of cardiac contractility modulation on human induced pluripotent stem cell-derived cardiomyocytes.

Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to develop a robust model to evaluate CCM in vitro. HiPSC‐CMs (iCell Cardiomyocytes2, Fujifilm Cellular Dynamic, Inc.) were studied in monolayer format plated on flexible substrate. Contractility, calcium handling, and electrophysiology were evaluated by fluorescence‐ and video‐based analysis (CellOPTIQ, Clyde Biosciences). CCM pulses were applied using an A‐M Systems 4100 pulse generator. Robust hiPSC‐CMs response was observed at 14 V/cm (64 mA) for pacing and 28 V/cm (128 mA, phase amplitude) for CCM. Under these conditions, hiPSC‐CMs displayed enhanced contractile properties including increased contraction amplitude and faster contraction kinetics. Likewise, calcium transient amplitude increased, and calcium kinetics were faster. Furthermore, electrophysiological properties were altered resulting in shortened action potential duration (APD). The observed effects subsided when the CCM stimulation was stopped. CCM‐induced increase in hiPSC‐CMs contractility was significantly more pronounced when extracellular calcium concentration was lowered from 2 mM to 0.5 mM. This study provides a comprehensive characterization of CCM effects on hiPSC‐CMs. These data represent the first study of CCM in hiPSC‐CMs and provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and effectiveness of future cardiac electrophysiology medical devices.

Left ventricular myocardial cellular perfusion against the background of cardiac contractility modulation in patients with heart failure and atrial fibrillation

Aim. To assess the effect of cardiac contractility modulation (CCM) in patients with heart failure (HF) and atrial fibrillation (AF) on left ventricular (LV) myocardial cellular perfusion using perfusion single photon emission computed tomography (SPECT).Material and methods. 99mTc-MIBI SPECT gated myocardial perfusion imaging was performed in 60 patients with HF and AF before implantation of CCM device and after 6-months follow-up. All patients received long-term optimal medication therapy for HF. Results. The results obtained indicate a significant positive effect of CCM use in patients with HF and AF on LV ejection fraction (increase from 22 [18;30] to 25,5 [19;38] (p=0,002)), LV volume (decrease in LV end-systolic volume from 187 [114;238] to 154 [100;201] (p=0,001), end-diastolic volume from 229 [174;290] to 209 [159;259] (p=0,007)), as well as myocardial perfusion values. There is a favorable myocardial perfusion dynamics, which was more pronounced in nonischemic HF: increase in SRS from 6 [5;9] to 8,0 [6;11] after 6 months (p=0,01)). The extent of impaired perfusion significantly decreases from 12 [9;17] to 9 [6;16] (p=0,04). An indicator reflecting the total impairment of LV myocardial perfusion significantly decreases: total perfusion deficit decreased from 10 [8;14] to 7 [6;14] after 6 months (p=0,02), compared with ischemia-related HF.Conclusion. Perfusion SPECT makes it possible to assess the myocardial cellular perfusion during CCM therapy in patients with HF of various origin and AF. CCM therapy improves myocardial contractility and perfusion in patients with HF and AF.

Long‐term clinical experience with cardiac contractility modulation therapy delivered by the Optimizer Smart system

AimsWe assessed long‐term effects of cardiac contractility modulation delivered by the Optimizer Smart system on quality of life, left ventricular ejection fraction (LVEF), mortality and heart failure and cardiovascular hospitalizations.Methods and resultsCCM‐REG is a prospective registry study including 503 patients from 51 European centres. Effects were evaluated in three terciles of LVEF (≤25%, 26–34% and ≥35%) and in patients with atrial fibrillation (AF) and normal sinus rhythm (NSR). Hospitalization rates were compared using a chi‐square test. Changes in functional parameters of New York Heart Association (NYHA) class, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and LVEF were assessed with Wilcoxon signed‐rank test, and event‐free survival by Kaplan–Meier analysis. For the entire cohort and each subgroup, NYHA class and MLWHFQ improved at 6, 12, 18 and 24 months (P < 0.0001). At 24 months, NYHA class, MLWHFQ and LVEF showed an average improvement of 0.6 ± 0.7, 10 ± 21 and 5.6 ± 8.4%, respectively (all P < 0.001). LVEF improved in the entire cohort and in the LVEF ≤25% subgroup with AF and NSR. In the overall cohort, heart failure hospitalizations decreased from 0.74 [95% confidence interval (CI) 0.66–0.82] prior to enrolment to 0.25 (95% CI 0.21–0.28) events per patient‐year during 2‐year follow‐up (P < 0.0001). Cardiovascular hospitalizations decreased from 1.04 (95% CI 0.95–1.13) events per patient‐year prior to enrolment to 0.39 (95% CI 0.35–0.44) events per patient‐year during 2‐year follow‐up (P < 0.0001). Similar reductions of hospitalization rates were observed in the LVEF, AF and NSR subgroups. Estimated survival was significantly better than predicted by MAGGIC at 1 and 3 years in the entire cohort and in the LVEF 26–34% and ≥35% subgroups.ConclusionsCardiac contractility modulation therapy improved functional status, quality of life, LVEF and, compared to patients' prior history, reduced heart failure hospitalization rates. Survival at 1 and 3 years was significantly better than predicted by the MAGGIC risk score.

Implantation of a cardiac contractility modulator in chronic heart failure and atrial fibrillation: results of a 6-month follow-up of one hundred patients

Aim: to study the effect of cardiac contractility modulation (CCM) in patients with chronic heart failure (CHF) and atrial fibrillation (AF). Materials and methods. In a group of 100 patients with CHF and AF, the following studies were performed before implantation of the CCM and after 6 months of follow-up: 12-channel ECG, transthoracic Echocardiography, 6-minute walk test, determination of the level of pro-natriuretic N-terminal peptide (NT-proBNP), and a questionnaire based on the Minnesota quality of life questionnaire for patients with CHF (MHFLQ). All patients received long-term optimal medication therapy for CHF before surgery. Results. The results show a positive effect of the use of MCC in patients with CHF and AF on reverse LV remodeling, functional class of CHF, and levels of NT-pro-BNP regardless of the form of AF. Conclusion. The use of MCC may be a promising treatment method in addition to optimal medication therapy in patients with CHF and AF.

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.

Stymulacja modulująca kurczliwość mięśnia sercowego — opis przypadku i przegląd piśmiennictwa

Cardiac contractility modulation (CCM) is a new implantable device that transmits electrical impulse to the heart during the absolute refractory period, which leads to an increase in myocardial contractility. This pacemaker works on several molecular levels and is dedicated to patients with heart failure (HF). The therapeutic effect is mainly due to the improvement in the circulation of calcium ions inside the cardiomyocytes. The final CCM effect leads to improved exercise capacity, increased quality of life, decreased symptoms and the number of hospitalizations as the results of HF. Device is an important alternative for patients with ineffective pharmacological therapy, who are not eligible for CRT implantation due to the narrow QRS complex, have a decreased ejection fraction, and in the New York Heart Association scale they were classified on the II–III degree. Previous studies have not demonstrated the impact of CCM on life expectancy. The effect of cardiac contractility modulation device on the improvement of everyday functioning and the reduction of hospitalization has been proven, which is important in the long-term perspective for both individual patients and the entire health care system. The case report shows an example of a patient for whom CCM was an addition to treatment.

A comprehensive individual patient data meta-analysis of the effects of cardiac contractility modulation on functional capacity and heart failure-related quality of life.

AimsCardiac contractility modulation, also referred to as CCM™, has emerged as a promising device treatment for heart failure (HF) in patients not indicated for cardiac resynchronization therapy. We performed a comprehensive individual patient data meta‐analysis of all non‐confounded prospective randomized controlled trials of CCM vs. control that have measured functional capacity and/or quality of life questionnaires in patients with HF.Methods and resultsThe Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in January 2020 to identify eligible randomized controlled trials. We also asked the sole manufacturer of the device for their list of known trials. Primary outcomes of interest were peak oxygen consumption (peak VO2), 6 min walk test distance, and quality of life measured by Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and all data were received as individual patient and individual time point data‐points. Mean differences and 95% confidence intervals (CIs) were calculated for continuous data using a fixed‐effects model. Five trials were identified, four randomized studies enrolling 801 participants for all endpoints of interest, and for peak VO2 alone (n = 60), there was an additional single arm non‐randomized trial (FIX‐HF‐5C2) with a prospective comparison of its 24 week peak VO2 data compared with the control group of the FIX‐HF‐5C control patients. Pooled analysis showed that, compared with control, CCM significantly improved peak VO2 (mean difference +0.93, 95% CI 0.56 to 1.30 mL/kg/min, P < 0.00001), 6 min walk test distance (mean difference +17.97, 95% CI 5.48 to 30.46 m, P = 0.005), and quality of life measured by MLWHFQ (mean difference −7.85, 95% CI −10.76 to −4.94, P < 0.00001). As a sensitivity analysis, we excluded the FIX‐HF‐5C2 trial (only relevant for peak VO2), and the result was similar, mean difference +0.65, 95% CI 0.21 to 1.08 mL/kg/min, P = 0.004.ConclusionsThis comprehensive meta‐analysis of individual patient data from all known randomized trials has shown that CCM provides statistically significant and clinically meaningful benefits in measures of functional capacity and HF‐related quality of life.

P3523Cardiac contractility modulation provides improved ventilatory efficiency and reduces oscillatory breathing pattern

Abstract Introduction Cardiac Contractility Modulation (CCM) is a treatment for patients with heart failure with reduced ejection fraction (HFrEF) providing improved myocardial molecular and biochemical characteristics and thus improved exercise tolerance and quality of life by application of electrical signals during the absolute refractory period. Cardiopulmonary exercise testing is an integrative method to assess exercise tolerance in heart failure patients providing insights in circulatory, respiratory and metabolic reactions during exercise. The VE/VCO2-Slope (minute ventilation/carbon dioxide production) and an oscillatory breathing pattern have widely been demonstrated to have strong prognostic value for patients with chronic heart failure. Methods Between February 2017 and January 2019 15 patients (mean age 64.4±7.9 years, NYHA 2.93±0.58) with standard indication for CCM-therapy have been enrolled in a single center in Germany. Prior to implantation of the Optimizer Smart System, symptom-limited cardiopulmonary exercise testing was performed using a bicycle ramp protocol (25W+10W/min). The Follow-up was conducted 6 weeks post implantation. The control group consisted of 45 patients (mean age 64.8±7.9 years, NYHA 2.2±0.72) with stable systolic heart failure and reduced ejection fraction. Statistical Analysis was performed by paired and unpaired t tests. Results 6 weeks after CCM-implantation the VE/VCO2-Slope showed a significant decrease (39.6±11.1 vs. 36.6±8.9, p&lt;0.05) showing changes in ventilatory efficiency whereas the control-group showed stable measurements with even an increasing tendency (33.6±7.4 vs. 34.2±7.4, p=0.43). The absolute change of the VE/VCO2-Slope between the CCM-group and control-group highlights the improvement after the intervention (−2.99±5.07 vs. 0.63±4.79, p&lt;0.05). The number of patients presenting an oscillatory breathing pattern markedly decreased with CCM-therapy (11 of 15 vs. 6 of 15, p&lt;0.05), whereas even one additional patient of the control group showed an oscillatory breathing pattern at follow up (15 of 45 vs. 16 of 45). In contrast, subjects showed no significant changes in watt-measurements (72.67 W ± 19.2 W vs. 76.57 W ± 18.5 W) or maximal oxygen uptake (1034 ml/min ± 247 ml/min vs. 1104 ml/min ± 256 ml/min) compared to baseline. Similarly, the control-group showed stable measurements for external load (79.9 W ± 16.4 W vs. 77.1 W ± 17.5 W) and peak oxygen uptake (1097 ml/min ± 225 ml/min vs. 1116 ml/min ± 330 ml/min). Conclusion Cardiac Contractility Modulation provides improved ventilatory efficiency measures by VE/VCO2-slope and reduces oscillatory breathing pattern during exercise at follow up. As the low ventilatory efficiency observed in patients with heart failure constitutes an important predictor of cardiovascular mortality these results provide an interesting insight of therapeutic effects of Cardiac Contractility Modulation apart from VO2-measurements.

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.

Effects of cardiac contractility modulation by non-excitatory electrical stimulation on exercise capacity and quality of life: An individual patient's data meta-analysis of randomized controlled trials

BackgroundAlthough cardiac contractility modulation (CCM) has emerged as a promising device treatment for heart failure (HF), the effect of CCM on functional capacity and quality of life has not been the subject of an individual patient data meta-analysis to determine its effect on measures of functional capacity and life quality. This meta-analysis is aimed at systematically reviewing the latest available randomized evidence on the effectiveness of CCM on functional capacity and quality of life indexes in patients with HF. MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in May 2013 to identify eligible randomized controlled trials comparing CCM with sham treatment or usual care. Primary outcomes of interest were peak oxygen consumption, 6-minute walk test distance and quality of life measured by Minnesota Living With Heart Failure Questionnaire. There was no sufficient information to address safety. Mean difference and 95% confidence intervals (C.I.s) were calculated for continuous data using a fixed-effects model. ResultsThree studies enrolling 641 participants were identified and included. Pooled analysis showed that, compared to control, CCM significantly improved peak oxygen consumption (mean difference +0.71, 95% C.I. 0.20 to 1.21mL/kg/min, p=0.006), 6-minute walk test distance (mean difference +13.92, 95% C.I. −0.08 to 27.91m, p=0.05) and quality of life measured by Minnesota Living With Heart Failure Questionnaire (mean difference −7.17, 95% C.I. −10.38 to −3.96, p<0.0001). ConclusionsMeta-analysis of individual patient data from randomized trials suggests that CCM has significant if somewhat modest benefits in improving measures of functional capacity and quality of life.

Clinical effects of cardiac contractility modulation (CCM) as a treatment for chronic heart failure

Cardiac contractility modulation (CCM) signals are non-excitatory signals applied during the absolute refractory period that have been shown to enhance the strength of left ventricular contraction without increasing myocardial oxygen consumption in studies carried out in animals and humans with heart failure and reduced ejection fraction. Studies from myocardial tissue of animals and humans with heart failure suggest that the mechanisms of these effects is that CCM drives expression of many genes that are abnormally expressed in heart failure towards normal, including proteins involved with calcium cycling and the myocardial contractile machinery. Clinical studies have primarily focused on patients with normal QRS durations in view of the fact that cardiac resynchronization (CRT) is a viable option for patients with prolonged QRS duration. These studies show that CCM improves exercise tolerance as indexed by peak oxygen consumption (VO(2)) and quality of life indexed by the Minnesota Living with Heart Failure Questionnaire. The device is currently available for clinical use in countries recognizing the CE mark and is undergoing additional testing in the USA under a protocol approved by the Federal Drug Administration.

The acute inotropic effects of cardiac contractility modulation (CCM) are associated with action potential duration shortening and mediated by β1-adrenoceptor signalling

Despite promising results in clinical trials conducted to date, little is known about how cardiac contractile modulation (CCM) mediated inotropic enhancement occurs and how CCM affects the electrophysiological characteristics of the heart. The aims of the present study were to 1) investigate how the stimulation parameters of the CCM signal and the location of stimulus delivery influence the contractile response, 2) characterise the effect of CCM on ventricular electrophysiology, and 3) investigate the potential physiological mechanisms underlying these acute inotropic and electrophysiological effects. Experiments were conducted in isolated rabbit hearts with simultaneous measurement of ventricular contractility and monophasic action potential duration (MAPD). Biphasic square wave pulses were applied to the left ventricle, timed to coincide with the absolute refractory period. CCM mediated responses were assessed over a range of signal amplitudes (2–30mA), durations (2–15ms) and delays from the activation of the locally recorded monophasic action potential (0–30ms). Responses were assessed during perfusion with the β1-adrenoceptor antagonist metoprolol (1.8μM) and HMR 1556 (500nM), an inhibitor of the slow delayed rectifying potassium current. Norepinephrine content was collected and assessed by ELISA from samples of coronary effluent collected during CCM. CCM induced a significant increase in left ventricular pressure (LVP) in a manner dependent upon the amplitude and duration of the CCM signal but independent of the delay of the stimulus within the action potential plateau and was associated with an increase in norepinephrine in coronary effluent (Mean: 46±9pg/ml). CCM promoted a shortening of MAPD-90% close to the site of stimulation (−19±3%) but had no effect on those recorded at distant sites (0±1%). The increase in LVP (4.7±1.8 vs. 0.7±0.9%, P<0.01) and shortening of local MAPD-90% (−15±3 vs. 1±1%, P<0.01) was abolished with metoprolol. Perfusion with HMR 1556 caused a significant inhibition of local MAPD shortening (−27±2 vs. −21±3ms, P<0.05). CCM is associated with a shortening of ventricular MAPD in a manner dependent upon β-adrenoceptor stimulation resulting from catecholamine release, a finding which may be of clinical significance in regard to the development of malignant ventricular arrhythmias. This article is part of a Special Issue entitled Possible Editorial.

Cardiac Contractility Modulation Electrical Signals Improve Myocardial Gene Expression in Patients With Heart Failure

The objective of this study was to test whether cardiac contractility modulation (CCM) electric signals induce reverse molecular remodeling in myocardium of patients with heart failure. Heart failure is associated with up-regulation of myocardial fetal and stretch response genes and down-regulation of Ca(2+) cycling genes. Treatment with CCM signals has been associated with improved symptoms and exercise tolerance in heart failure patients. We tested the impact of CCM signals on myocardial gene expression in 11 patients. Endomyocardial biopsies were obtained at baseline and 3 and 6 months thereafter. The CCM signals were delivered in random order of ON for 3 months and OFF for 3 months. Messenger ribonucleic acid expression was analyzed in the core lab by investigators blinded to treatment sequence. Expression of A- and B-type natriuretic peptides and alpha-myosin heavy chain (MHC), the sarcoplasmic reticulum genes SERCA-2a, phospholamban and ryanodine receptors, and the stretch response genes p38 mitogen activated protein kinase and p21 Ras were measured using reverse transcription-polymerase chain reaction and bands quantified in densitometric units. The 3-month therapy OFF phase was associated with increased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase, and p21 Ras and decreased expression of alpha-MHC, SERCA-2a, phospholamban, and ryanodine receptors. In contrast, the 3-month ON therapy phase resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase and p21 Ras and increased expression of alpha-MHC, SERCA-2a, phospholamban, and ryanodine receptors. The CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca(2+) cycling and stretch response genes. These changes may contribute to the clinical effects of CCM.