Cardiac Contractility Modulation Signals Research Articles

Abstract 11951: Acute Cardiac Contractility Modulation Assessment in Conventional 2D Monolayers and 3D Engineered Cardiac Tissues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Introduction: Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical simulations are delivered to the myocardium during the absolute refractory period. We previously evaluated the effects of the standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, on flexible substrate. Hypothesis: In the present study, we sought to extend these results to 3D microphysiological systems to develop a human-based model to evaluate various clinical CCM pulse parameters in vitro. Methods: HiPSC-CMs were studied in conventional 2D monolayer format, on stiff substrate (i.e., glass), and as 3D human engineered cardiac tissues (ECTs). Cardiac contractile properties were evaluated by video-based analysis and custom force analysis. CCM pulses were assessed at varying clinical ‘doses’ using a commercial pulse generator. Robust response was observed at physiological Ca concentrations [1.8 mM] for 3D ECTs. Results: Under standard acute CCM stimulation 3D ECTs displayed enhanced contractile properties including increased peak contraction amplitude (i.e., force), and faster contraction and relaxation kinetics. Moreover, 3D ECTs displayed enhanced contractility in a CCM pulse parameter dependent manner. The observed effects subsided when the acute CCM stimulation was stopped and gradually returned to baseline. Under comparable conditions, conventional 2D monolayer hiPSC-CMs, on stiff substrate, displayed neutral response. Conclusions: These data represent the first study of acute CCM stimulation in a 3D hiPSC-CM model and provides a preclinical model to assess various CCM signals in human cardiac tissues prior to in vivo animal studies.

Abstract P1123: Establishment Of An In Vitro Method To Evaluate Chronic Cardiac Contractility Modulation Signals In 3d Human Engineered Cardiac Tissues

Background: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical simulations to the heart during the absolute refractory period to enhance cardiac function. We previously evaluated the acute effects of CCM in isolated rabbit-CM and 2D hiPSC-CM monolayers, on flexible substrate, and found enhanced calcium and contractility. In the present study, we sought to extend these results to chronic studies in 3D human engineered cardiac tissues (ECTs) to develop a robust model to evaluate the long-term effects of CCM stimulation in vitro on intact human cardiac tissues. Methods: HiPSC-CMs and cardiac fibroblasts in a fibrin-based gel were combined to form ECTs (Figure 1). Morphology and contractility were evaluated. We found ECTs displayed baseline peak contraction amplitude of 194.8±80.8 a.u., (n=5) and peak force and stress of 26.5±6.8 uN, (n=5) and 87.9±22.0.8 Pa, (n=5) respectively. ECT displayed robust baseline electrophysiological (AP) properties and calcium handling properties. Chronic CCM pulses (i.e., 30 minutes) were applied using a commercial pulse generator. Under these conditions ECTs displayed enhanced contractile kinetics 29.0±0.04 %, (P<0.01, n=4), relaxation kinetics 23.0±0.05 %, (P<0.05, n=4), and shorter duration 32.0±0.03 %, (P<0.01, n=4) relative to time matched control. Conclusion: This study provides a comprehensive characterization of chronic CCM effects on 3D ECTs. Future studies will investigate prolonged time points. These data provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and efficacy of future cardiac electrophysiology medical devices. Disclaimer: The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.

Abstract 334: Acute Effects of Nonexcitatory Electrical Stimulation During Systole in Human-induced Pluripotent Stem Cell Derived Cardiomyocytes

Cardiac contractility modulation (CCM) is a cardiac therapy whereby non-excitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. CCM is indicated for patients with heart failure (Class III/IV) and reduced ejection fraction. We previously evaluated the effects of CCM and found isolated adult rabbit cardiomyocytes (rabbit-CMs) display a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human stem-cell cardiomyocytes (hiPSC-CMs). hiPSC-CMs were studied in both monolayer and isolated cells and results compared to that of rabbit-CMs. Contractility, calcium handling and electrophysiology was evaluated by image and fluorescence analysis. CCM was applied with a custom device covering a range of pulse parameters including standard clinical parameters (Figure 1). Pacing threshold was determined and stimulation performed at twice the diastolic capture threshold. Robust contractile response was observed at 16 V/cm, 70 mA for pacing and 28 V/cm, 120 mA for CCM. Under these conditions hiPSC-CMs and rabbit-CMs displayed increased contraction amplitude of 30 % (1.79 a.u., CCM vs 1.38 a.u., Control) and 22 % (3.67 a.u., CCM vs 3.00 a.u., Control) respectively and faster kinetics that subsided when the CCM signal was eliminated. This study provides a comprehensive characterization of the effects of CCM on hiPSC-CMs and rabbit-CMs in parallel under identical experimental conditions. These data provide the first study of CCM in hiPSC-CMs and demonstrates the potential utility of hiPSC-CMs to evaluate safety and effectiveness of cardiac medical devices.

Cardiac contractility modulation for treatment of chronic heart failure

The worldwide prevalence of heart failure is 1-2% with aportion of >10% in patients older than 70years. In addition to treatment of causal determined factors and lifestyle modification, basic treatment consists of guideline-directed medical therapy with angiotensin-converting enzyme inhibitors (ACE), β‑blockers (BB), mineralocorticoid receptor antagonists (MRA), diuretics, digitalis (class IIb recommendation), angiotensin receptor blockers (ARB), Iƒ-channel blockers plus recently recommended in the guidelines angiotensin receptor neprilysin inhibitor (ARNI) to substitute the ACE inhibitor (classIb). Cardiac contractility modulation (CCM) is adevice-based electrical therapy for the treatment of refractory heart failure symptoms. CCM signals are relatively high intensity, nonexcitatory signals applied during the absolute refractory period that have been shown to enhance the strength of left ventricular (LV) contraction and improve exercise tolerance and quality of life. The mechanisms of action appear to involve effects on myocardial gene expression and normalization of myocardial key-proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with symptomatic heart failure and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. Actually, for the first time, CCM has been referenced in the current Heart Failure Guidelines. Prognostic data with regard to mortality are currently being evaluated in case series; some of which have since been published. Approval by the US Food and Drug Administration (FDA) is expected within the next months.

Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF

Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF

Cardiac contractility modulation. A new form of therapy for patients with heart failure and narrow QRS complex?

Cardiac contractility modulation (CCM) is a stimulation therapy by an implantable impulse generator, which enhances ventricular contractile performance by delivering CCM impulses to the right ventricle during the absolute refractory period. The CCM signals mediate increased inotropy by prolonging the duration of the action potential, which leads to an enhanced influx of calcium into cardiomyocytes and a greater release of calcium by the sarcoplasmic reticulum. The increase of cardiac contractility is not associated with increased oxygen consumption. Several small studies have shown that CCM therapy can safely improve symptoms of heart failure and peak oxygen consumption in patients with moderate to severe heart failure who are not eligible for resynchronization therapy. Therefore, CCM is a novel potential therapy for patients with heart failure, an ejection fraction ≤ 35 % and a normal QRS duration < 130ms. However, apart from selecting appropriate patients for CCM therapy there are still unanswered questions, such as the impact of CCM therapy on established clinical endpoints. At present no data are available which have shown that CCM therapy leads to reduction of hospitalization for heart failure or mortality.

Cardiac contractility modulation: first experience in heart failure patients with reduced ejection fraction and permanent atrial fibrillation

Cardiac contractility modulation (CCM) is an electrical therapy for heart failure (HF) with reduced ejection fraction. Sinus rhythm is deemed necessary for effective treatment because the current CCM signal delivery algorithm requires sequential sensing of a p wave, followed by depolarizations at each ventricular lead. In case of atrial fibrillation (AF) CCM is inhibited. This study demonstrates the feasibility of CCM therapy in patients with permanent AF by circumventing the requirement for sensing of a natural p wave. Five CCM patients with AF received a pacemaker or implantable cardioverter/defibrillator (ICD) upgrade to cardiac resynchronization therapy (CRT) with low atrial sensitivity, which resulted in compulsory atrial stimulation followed by biventricular pacing. The CCM system recognized the atrial stimuli as p waves, which led to CCM signal delivery. Three patients developed permanent AF after a mean follow-up of 40 months of CCM therapy. Two patients had permanent AF at the time of CCM device implantation. All pacemaker or ICD devices were successfully upgraded to CRT. Cardiac resynchronization therapy stimulation rates of ≥96% and CCM stimulation rates between 60% and 95% were achieved. Clinical condition of the patients improved (mean NYHA class -0.7, left ventricular ejection fraction +2%, Minnesota living with HF questionnaire -15.6 points). CCM signal delivery is feasible in HF patients with permanent AF by sequential atrial-ventricular pacing, so that the atrial pacing spike is interpreted as a p wave by the CCM signal delivery algorithm. This experimental approach can be considered in individual cases. A new CCM algorithm, which does not require an atrial electrode, is desirable.

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.

A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: Rationale, design, and baseline patient characteristics

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. Prior research in experimental and human heart failure has shown that CCM signals normalize phosphorylation of key proteins and expression of genes coding for proteins involved in regulation of calcium cycling and contraction. The results of prior clinical studies of CCM have supported its safety and efficacy. A large-scale clinical study, the FIX-HF-5 study, is currently underway to test the safety and efficacy of this treatment. In this article, we provide an overview of the system used to deliver CCM signals, the implant procedure, and the details and rationale of the FIX-HF-5 study design. Baseline characteristics for patients randomized in this trial are also presented.

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.

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure

We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients. One hundred and sixty-four subjects with ejection fraction (EF) < 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3 +/- 6.7% vs. 29.8 +/- 7.8%), VO2,peak (14.1 +/- 3.0 vs. 13.6 +/- 2.7 mL/kg/min), and MLWHFQ (38.9 +/- 27.4 vs. 36.5 +/- 27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40 +/- 3.0 vs. 0.37 +/- 3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (-0.86 +/- 3.06 mL/kg/min) and increased in patients switched to active treatment (0.16 +/- 2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06 +/- 15.33 vs. -9.70 +/- 16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70 +/- 16.57), and decreased further in patients switched to active treatment (-0.70 +/- 15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P = 0.03 for each parameter). In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period.

First use of cardiac contractility modulation (CCM) in a patient failing CRT therapy: Clinical and technical aspects of combined therapies

Cardiac contractility modulating (CCM) signals delivered by the OPTIMIZER System are being investigated as a treatment for medically refractory heart failure. Previous chronic studies of CCM have excluded patients with prolonged QRS and a cardiac resynchronization therapy (CRT) device. However, symptoms persist in more than 25% of these CRT patients. CCM may offer a therapeutic option for these non-responders. Here we report the first use of CCM signals in a patient who did not respond to treatment with a CRT-D device. We show that the implantation is technically feasible, that the OPTIMIZER and CRT-D devices can coexist without interference and that acute haemodynamic and clinical improvements can be observed. The results suggest that systematic investigation of CCM treatment in CRT non-responders is warranted.

Cardiac Contractility Modulation (CCM) Is Equally Effective in Patients with Normal or Prolonged QRS Duration: Results of a Responder's Analysis

Purpose: We previously showed that CCM signals delivered by the OPTIMIZER™ System improve exercise tolerance in heart failure. Patients with a clear indication for cardiac resynchronization therapy (CRT) were excluded. However, there was a group of patients with mildly prolonged QRS duration. We determined if the effectiveness of CCM is different in patients whose QRS duration is normal (< 120ms) or prolonged (≥ 120ms). Methods:161 patients with EF < 35% and NYHA Class II or III symptoms were implanted with an OPTIMIZER System and randomized (blinded) to receive (n = 77, Grp1) or not receive (n = 84, Grp2) CCM treatment for 3 months, followed by a 3 month crossover period with the opposite treatment.

Therapy With Cardiac Contractility Modulation Electrical Signals Improves Left Ventricular Function and Remodeling in Dogs With Chronic Heart Failure

This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF). Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption. In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group). In CCM-only treated dogs, LV ejection fraction (EF) increased (27 +/- 1% vs. 33 +/- 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 +/- 1% vs. 23 +/- 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone. In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.

Full Length Article

<h3>Background</h3> Cardiac contractility modulation signals are associated with acutely improved hemodynamics, but chronic clinical impact is not defined. <h3>Objectives</h3> The purpose of this randomized, double-blind, pilot study was to determine the feasibility of safely and effectively delivering cardiac contractility modulation signals in patients with heart failure. <h3>Methods</h3> Forty-nine subjects with ejection fraction <35%, normal QRS duration (105 ± 15 ms), and New York Heart Association (NYHA) class III or IV heart failure despite medical therapy received a cardiac contractility modulation pulse generator. Patients were randomized to have their devices programmed to deliver cardiac contractility modulation signals (n = 25, treatment group) or to remain off (n = 24, control group) for 6 months. Evaluations included NYHA class, 6-minute walk, cardiopulmonary stress test, Minnesota Living with Heart Failure Questionnaire, and Holter monitoring. <h3>Results</h3> Although most baseline features were balanced between groups, ejection fraction (31.4% ± 7.4% vs 24.9% ± 6.5%, <i>P</i> = .003), end-diastolic dimension (52.1 ± 21.4 mm vs 62.5 ± 6.2 mm, <i>P</i> = .01), peak VO₂ (16.0 ± 2.9 mL O₂/kg/min vs 14.3 ± 2.8 mL O₂/kg/min, <i>P</i> = .02), and anaerobic threshold (12.3 ± 2.5 mL O₂/kg/min vs 10.6 ± 2.4 mL O₂/kg/min, <i>P</i> = .01) were worse in the treatment group than in the control group. Nevertheless, one death occurred in the control group, and more patients in the treatment group were free of hospitalization for any cause at 6 months (84% vs 62%). No change in ectopy was observed. Compared with baseline, 6-minute walk (13.4 m), peak VO₂ (0.2 mL O₂/kg/min), and anaerobic threshold (0.8 mL O₂/kg/min) increased more in the treatment group than in control. None of these differences were statistically significant (small sample size). NYHA and Minnesota Living with Heart Failure Questionnaire changed similarly in the two groups. <h3>Conclusion</h3> Despite a sicker population in the treatment group, no specific safety concerns emerged with chronic cardiac contractility modulation signal administration. Further study is required to definitively define the safety and efficacy of cardiac contractility modulation signals.

Nonexcitatory, cardiac contractility modulation electrical impulses: Feasibility study for advanced heart failure in patients with normal QRS duration

Cardiac contractility modulation signals are associated with acutely improved hemodynamics, but chronic clinical impact is not defined. The purpose of this randomized, double-blind, pilot study was to determine the feasibility of safely and effectively delivering cardiac contractility modulation signals in patients with heart failure. Forty-nine subjects with ejection fraction <35%, normal QRS duration (105 +/- 15 ms), and New York Heart Association (NYHA) class III or IV heart failure despite medical therapy received a cardiac contractility modulation pulse generator. Patients were randomized to have their devices programmed to deliver cardiac contractility modulation signals (n = 25, treatment group) or to remain off (n = 24, control group) for 6 months. Evaluations included NYHA class, 6-minute walk, cardiopulmonary stress test, Minnesota Living with Heart Failure Questionnaire, and Holter monitoring. Although most baseline features were balanced between groups, ejection fraction (31.4% +/- 7.4% vs 24.9% +/- 6.5%, P = .003), end-diastolic dimension (52.1 +/- 21.4 mm vs 62.5 +/- 6.2 mm, P = .01), peak VO(2) (16.0 +/- 2.9 mL O(2)/kg/min vs 14.3 +/- 2.8 mL O(2)/kg/min, P = .02), and anaerobic threshold (12.3 +/- 2.5 mL O(2)/kg/min vs 10.6 +/- 2.4 mL O(2)/kg/min, P = .01) were worse in the treatment group than in the control group. Nevertheless, one death occurred in the control group, and more patients in the treatment group were free of hospitalization for any cause at 6 months (84% vs 62%). No change in ectopy was observed. Compared with baseline, 6-minute walk (13.4 m), peak VO(2) (0.2 mL O(2)/kg/min), and anaerobic threshold (0.8 mL O(2)/kg/min) increased more in the treatment group than in control. None of these differences were statistically significant (small sample size). NYHA and Minnesota Living with Heart Failure Questionnaire changed similarly in the two groups. Despite a sicker population in the treatment group, no specific safety concerns emerged with chronic cardiac contractility modulation signal administration. Further study is required to definitively define the safety and efficacy of cardiac contractility modulation signals.

P4-90: Effects of CCM (cardiac contractility modulation) signal delivery on left ventricular contractility

Non-excitatory cardiac stimulation during the refractory period is a novel modality for treating chronic heart failure. Stimuli with an amplitude of up to 7.5 V and a duration of up to 24 ms are delivered during the absolute refractory period. Experimental studies show that CCM stimulation (CCMS) leads to elevated intracellular Ca++ levels and is associated with increased contractility (C) as determined by the velocity of ventricular pressure rise (dp/dt). The FIX-CHF-3 study has proven the safety and acute effectiveness of this therapy. Long-term hemodynamic effects of CCMS are investigated in the European FIX-CHF-4 study.

Effects of CCM (Cardiac Contractility Modulation) signal delivery on left ventricular contractility

Effects of CCM (Cardiac Contractility Modulation) signal delivery on left ventricular contractility

Long-term effects of non-excitatory cardiac contractility modulation electric signals on the progression of heart failure in dogs.

We previously showed that acute delivery of non-excitatory cardiac contractility modulation (CCM) electric signal during the absolute refractory period improved LV function in dogs with chronic heart failure (HF). In the present study we examined the long-term effects of CCM signal delivery on the progression of LV dysfunction and remodeling in dogs with chronic HF. Chronic HF was produced in 12 dogs by multiple sequential intracoronary microembolizations. The CCM signal was delivered using a lead implanted in the distal anterior coronary vein. A right ventricular and a right atrial lead were implanted and used for timing of CCM signal delivery. In six dogs, CCM signals were delivered continuously for 6 h daily with an average amplitude of 3.3 V for 3 months. Six HF dogs did not have leads implanted and served as controls. In control dogs, LV end-diastolic volume (EDV) and LV end-systolic volume (ESV) increased (64+/-5 ml vs. 75+/-6 ml, P=0.003; 46+/-4 ml vs. 57+/-4 ml, P=0.003; respectively), and ejection fraction (EF) decreased (28+/-1% vs. 23+/-1%, P=0.001) over the course of 3 months of follow-up. In contrast, CCM-treated dogs showed a smaller increase in EDV (66+/-4 vs. 73+/-5 ml, P=0.01), no change in ESV, and an increase in EF from 31+/-1 to 34+/-2% (P=0.04) after 3 months of therapy. In dogs with HF, long-term CCM therapy prevents progressive LV dysfunction and attenuates global LV remodeling. These findings provide compelling rationale for exploring the use of CCM for the treatment of patients with chronic HF.

Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure

Background: Nonexcitatory electrical, signals termed cardiac contractility modulation (CCM) have been shown to improve contractile force of isolated papillary muscles. In this study, we examined the effects of CCM signal delivery on left ventricular function in dogs with chronic heart failure (HF). Methods and Results: Chronic HF (ejection fraction ≤35%) was produced in 7 dogs by intracoronary microembolizations. The CCM signal was delivered during the absolute refractory period using a lead implanted in the anterior coronary vein. A right ventricular and an atrial lead were implanted and used for timing of the CCM signal delivery. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5, and 6 hours after initiating CCM signal delivery. Ejection fraction increased from 31 ± 1% at baseline to 41 ± 1% at 1 hour (P <.05), 42 ± 1% at 3 hours (P <.05), and 44 ± 2% at 6 hours (P <.05). Similarly, stroke volume increased from 26 ± 2 mL to 31 ± 3 mL at 1 hour (P <.05), 33 ± 3 mL at 3 hours (P <.05), and 34 ± 3 mL at 6 hours (P <.05). There were no significant changes compared to baseline in ejection fraction or stroke volume in 5 HF control dogs studied for up to 4 hours. Conclusion: In dogs with HF, CCM signal delivery for 6 hours elicited marked improvement in LV function. This novel approach may represent a useful adjunctive therapy for the treatment of patients with HF.