绝对不应期电刺激对正常及心力衰竭右心室乳头肌收缩功能的影响

为观察绝对不应期 (ARP)电刺激对健康和慢性心力衰竭 (简称心衰 )兔离体乳头肌收缩功能的影响。将 34只家兔随机分为健康和心衰兔两组 ,复制心肌梗死 (MI)心衰模型 ,分离兔右心室乳头肌、灌流并给予 1Hz刺激使其等长收缩 ,于该基础刺激的ARP给予双相方波电流刺激 (称之CCM)。观察乳头肌的最大张力 (PT)及其微分 ( +dT/dt)的变化。结果 :CCM刺激时健康组PT及其 +dT/dt比刺激前分别增加 1 5 %和 1 9% (P <0 .0 5 ) ,心衰组增加1 8%和 2 0 % (P <0 .0 5 ) ,且两组PT皆随着CCM刺激就开始增加 ,在几次CCM刺激后达到稳定的水平 ,不同时间点之间PT无差异 ,CCM刺激一旦停止 ,张力就恢复到刺激前的水平。结论 :于ARP发放电刺激能明显增强正常及衰竭心肌的收缩功能 ,且起效快 ,稳定性强 ,研究提示该方法是一种新的有效的调节心肌收缩的途径。     

Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle

BACKGROUND: Myocardial contractility can be altered using voltage clamp techniques by modulating amplitude and duration of the action potential resulting in enhanced calcium entry in the cell of isolated muscle strips (Non-Excitatory Currents; NEC). Extracellular electrical stimuli delivered during the absolute refractory period (Cardiac Contractility Modulation; CCM) have recently been shown to produce inotropic effects in-vivo. AIM: Understanding the cellular mechanism, underlying the CCM effect, is essential for evaluating its clinical potential. We tested the hypothesis that NEC and CCM modulate contractility via similar cellular mechanisms. METHODS: Square wave electric currents were applied in the organ bath to isometrically contracting rabbit RV papillary muscle and human failing trabecular muscle during the absolute refractory period (ARP). RESULTS: These currents, which did not initiate new action potentials or contractions, modulated action potential duration (shortened or lengthened) and contractility (enhanced or depressed) in a manner that depended upon their amplitude, duration and delay from the pacing stimulus. The contractility modulation effect in the rabbit RV papillary muscle was markedly blunted after exposure to ryanodine, indicating that the sarcoplasmic reticulum plays an important role in the contractility modulation. CONCLUSION: Like voltage clamping, extracellular currents applied during the ARP can similarly modulate action potential duration in-vitro and modulate myocardial contractility by similar intracellular mechanisms. This concept provides the potential of a therapeutic strategy in patients with heart failure to enhance contractility.     

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 相似文献   

Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high‐voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid‐range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.     

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.     

Improving left ventricular contraction by stimulation during the absolute refractory period. Cardiac contractility modulation

Cardiac contractility modulating (CCM) signals are nonexcitatory signals applied during the absolute refractory period and have been shown to enhance the strength of left ventricular contraction in studies performed in animals and humans with heart failure. In patients with congestive heart failure, improvement of exercise tolerance and quality of life have been shown. Recent studies from myocardial biopsies demonstrate that CCM treatment normalizes expression of many genes that are abnormally expressed in heart failure, including proteins involved with calcium cycling. These findings suggest that CCM might be an alternative or even additional electrical treatment option for patients with heart failure and normal QRS duration delivered by a pacemaker, e.g., a rechargeable device without any antibradycardiac or antitachycardiac function.     

心脏收缩调节刺激对心肌细胞钙动力学的影响

目的通过计算机理论模拟心肌细胞电生理模型,在心肌动作电位(AP)绝对不应期内施加非兴奋性电刺激,观察胞内自由钙离子浓度变化及心脏收缩调节。方法在人心室细胞电生理模型的基础上,根据近年相关实验成果,通过改造以模拟衰竭心肌细胞的电生理特性。结果改造后模型的AP和胞内钙浓度变化,和临床发现非常相似。心脏收缩调节刺激大大增强了钠-钙交换器活性,在AP间期更多的钙离子经过此交换器进入胞内,逐拍提高了肌浆网内的钙浓度峰值,因而下一搏中有更多的钙离子释放到胞浆中,从而逐渐提高了细胞内的自由钙浓度,最后收敛于一个稳定值,AP的延长和胞内钙活动密切相关。结论适宜的AP绝对不应期刺激能提高肌浆网内钙的集聚,增强心肌收缩。     

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Modulation of myocardial function by pyruvate.

OBJECTIVES: Pyruvate is an intermediate product of glycolytic metabolism that has a positive inotropic effect in animal models and in failing human hearts. The main objective of the present work was to clarify the mechanisms underlying this inotropic effect. METHODS: Isotonic and isometric twitches were recorded before and after the addition of pyruvate (3, 10 and 15 mM) to rabbit papillary muscles (n = 10) and human atrial trabeculae (n = 6) degrading glucose 9 mM and acetate 5 mM as metabolic substrates. In another protocol, undertaken in rabbit papillary muscles (n = 8), pyruvate was added in the presence of an inhibitor of mitochondrial pyruvate uptake (alpha-cyano-4-hydroxycinnamate [HCm]; 0.5 mM), and using octanoate 5 mM as metabolic substrate. Calculated parameters: active tension (AT); maximum velocity of tension rise (dT/dtmax); maximum velocity of tension decline (dT/dtmin); peak shortening (PS); maximum velocity of shortening (dL/dtmax); maximum velocity of lengthening (dL/dtmin) and time to half relaxation (tHR). Values are presented as means +/- SEM. RESULTS: In rabbit papillary muscles, pyruvate caused an initial transient negative inotropic effect (maximum at 3 min), followed by a sustained increase in myocardial contractility that stabilized 15 min later. The maximum negative inotropic effect was observed with 3 mM of pyruvate, decreasing AT by 13 +/- 4%, dT/dtmax by 14 +/- 5%, dT/dtmin by 9 +/- 3%, PS by 13 +/- 4% and dL/dtmax by 13 +/- 5%. Maximum positive inotropic effect was observed with 10 mM, which increased AT by 45.0 +/- 9.5%, dT/dtmax by 20.5 +/- 7.4%, PS by 33.4 +/- 9.6%, dL/dtmin by 35.5 +/- 12.1, and tHR by 27.8 +/- 3.2%, without significantly altering dL/dtmax or dT/dtmin. In the presence of HCm, the positive inotropic effect was not only observed but even enhanced. In human atrial trabeculae the addition of pyruvate also induced a similar increase in contractility, but the transient negative inotropic effect was absent. CONCLUSIONS: The addition of pyruvate caused a dose dependent positive inotropic effect observed in rabbit papillary muscles as well as in human atrial trabeculae. The effect of pyruvate in rabbit papillary muscles does not depend on its mitochondrial uptake and metabolism. This may be particularly relevant during myocardial ischemia when pyruvate concentration is increased and mitochondrial function is impaired. These characteristics give pyruvate a suitable profile for the metabolic protection of the heart.     

Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption

BackgroundPrevious studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO₂) in both patients and dogs with chronic HF.Methods and ResultsSix dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO₂ was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 ± 1 versus 31 ± 2 %, P = .001) without increasing MVO₂ (257 ± 41 versus 180 ± 34 μmol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 ± 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO₂ (13.6 ± 9.7 versus 12.5 ± 7.2 mL O₂/min).ConclusionsThe study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO₂.     

Therapie der chronischen Herzinsuffizienz durch kardiale Kontraktionsmodulation (CCM)

Cardiac contractility modulation (CCM) is a device therapy for patients with systolic heart failure. CCM therapy applies non-excitatory signals during the absolute refractory period of the heart cycle. It influences myocardial contractility by modulating the regulation of calcium cycling. CCM therapy has been proven to enhance peak VO(2), quality of life and exercise tolerance in patients with congestive heart failure. It can be used as an additional therapy to an implantable cardioverter defibrillator (ICD), if present. CCM therapy should be considered in symptomatic patients with congestive heart failure, a left ventricular ejection fraction ≤35% and NYHA class?II-III. Atrial fibrillation, high grade arrhythmias and an AV block of more than 300?ms represent contraindications. Patients with a left bundle branch block of >120?ms should be considered for the implantation of a biventricular ICD prior to implantation of a CCM device.     

Electrical signals applied during the absolute refractory period: an investigational treatment for advanced heart failure in patients with normal QRS duration

Cardiac resynchronization therapy has been shown to be an effective treatment for patients with systolic ventricular dysfunction, prolonged (>120 ms) QRS duration, and New York Heart Association (NYHA) functional class III or IV symptoms despite optimal medical therapy. However, studies show that a majority of heart failure patients have QRS duration <120 ms. We have been investigating the potential utility of cardiac contractility modulating (CCM) signals as a treatment option for such patients. Cardiac contractility modulating signals are non-excitatory signals applied during the absolute refractory period using a pacemaker-like device that connects to the heart with pacemaker leads. Acute studies carried out in animals and humans with heart failure suggest that CCM signals can enhance the strength of left ventricular contraction. Results of initial long-term studies designed mainly to demonstrate feasibility and provide preliminary indication of safety in patients with medically refractory NYHA functional class III heart failure are summarized. The results of these preclinical and clinical studies formed the basis for proceeding with two prospective, randomized clinical studies currently underway to definitively test the safety and efficacy of this treatment.     

Electrical signals applied during the absolute refractory period: an investigational treatment for advanced heart failure in patients with normal QRS duration.

Cardiac resynchronization therapy has been shown to be an effective treatment for patients with systolic ventricular dysfunction, prolonged (>120 ms) QRS duration, and New York Heart Association (NYHA) functional class III or IV symptoms despite optimal medical therapy. However, studies show that a majority of heart failure patients have QRS duration <120 ms. We have been investigating the potential utility of cardiac contractility modulating (CCM) signals as a treatment option for such patients. Cardiac contractility modulating signals are non-excitatory signals applied during the absolute refractory period using a pacemaker-like device that connects to the heart with pacemaker leads. Acute studies carried out in animals and humans with heart failure suggest that CCM signals can enhance the strength of left ventricular contraction. Results of initial long-term studies designed mainly to demonstrate feasibility and provide preliminary indication of safety in patients with medically refractory NYHA functional class III heart failure are summarized. The results of these preclinical and clinical studies formed the basis for proceeding with two prospective, randomized clinical studies currently underway to definitively test the safety and efficacy of this treatment.     

Altered myocardial contractility and energetics in hypertrophied myocardium

Alterations of myocardial contractility and energetics were examined in cardiac hypertrophy induced by different types of cardiac overload. Myocardial contractility was estimated by isometric contraction of isolated left ventricular papillary muscles. Myocardial energetics were assessed from ventricular myosin isoenzyme patterns obtained by pyrophosphate gel electrophoresis. Cardiac hypertrophy was induced by endurance swim-training and sustained pressure-overload by abdominal aortic constriction or volume-overload created by an arteriovenous shunt. In swim-trained hypertrophied myocardium, isometric developed tension (T) and dT/dtmax showed a tendency to increase and response of dT/dtmax to isoproterenol increased significantly as compared with sedentary rats. Training shifted the left ventricular myosin isoenzyme pattern toward VM-1, which has the highest ATPase activity. In pressure- or volume-overloaded myocardium, dT/dtmax decreased significantly and mechanical response to isoproterenol also decreased (or tended to decrease in volume-overloaded hearts) as compared with the respective sham-operated controls. In pressure- or volume-overloaded hearts, left ventricular myosin isoenzyme pattern shifted toward VM-3, which has the lowest ATPase activity. These results indicate that alterations in myocardial contractility, mechanical catecholamine responsiveness and myocardial energetics in hypertrophied myocardium do not always display the same trend, but are greatly influenced by the causes or duration of cardiac overload.     

Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

We assessed the feasibility of cardiac contractility modulation (CCM) by electric currents applied during the refractory period in patients with heart failure (HF). Extracellular electric currents modulating action potential and calcium transients have been shown to potentiate myocardial contractility in vitro and in animal models of chronic HF. CCM signals were biphasic square-wave pulses with adjustable amplitude, duration, and time delay from sensing of local electric activity. Signals were applied to the left ventricle through an epicardial vein (in 12 patients) or to the right ventricular (RV) aspect of the septum endocardially (in 6 patients). Simultaneous left ventricular (LV) and aortic pressure measurements were performed using a Millar catheter (Millar Instruments, Houston, Texas). Hemodynamics during RV temporary dual-chamber pacing was regarded as the control condition. Both LV and RV CCM stimulation increased dP/dt_max to a similar degree (9.1 ± 4.5% and 7.1 ± 0.8%, respectively; p <0.01 vs controls), with associated aortic pulse pressure changes of 10.3 ± 7.2% and 10.8 ± 1.1% (p <0.01 vs controls). Regional systolic wall motion assessed quantitatively by color kinesis echocardiography was markedly enhanced near the CCM electrode, and the area of increased contractility involved 4.6 ± 1.2 segments per patient. In 6 patients with HF with left bundle branch block, CCM signals delivered during biventricular pacing (BVP) produced an additional 16.1 ± 3.7% increase in dP/dt_max and a 17.0 ± 7.5% increase in pulse pressure compared with BVP alone (p <0.01). CCM stimulation in patients with HF enhanced regional and global measures of LV systolic function, regardless of the varied delivery chamber or whether modulation was performed during RV pacing or BVP.     

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.     

Myocardial contractility and ventricular myosin isoenzymes as influenced by cardiac hypertrophy and its regression

Summary Changes in myocardial contractility and ventricular myosin isoenzymes were examined during pressure-overloaded cardiac hypertrophy in rats. Effects of regression of cardiac hypertrophy were also examined. Cardiac hypertrophy was induced by abdominal aortic constriction in 7-week-old male Wistar rats. Regression of cardiac hypertrophy was obtained by opening the aortic band. Myocardial contractility was estimated by measuring isometrically developed tension and maximum rate of tension rise (+dT/dtmax) in isolated left-ventricular papillary muscles perfused with Tyrode solution (32°C, pH 7.4, bubbled with 95% O₂·5% CO₂, stimulation frequency: 0.2 Hz). Left-ventricular myosin isoenzymes were separated by pyrophosphate gel electrophoresis and the isoenzyme pattern was determined by densitometry. Isometrically developed tension (T) in hypertrophic myocardium remained unchanged, but ±dT/dtmax decreased as compared with hearts of normal rats. Decreased ±dT/dtmax recovered near to the level in normal rats by regression of cardiac hypertrophy. Leftventricular myosin isoenzyme pattern shifted towards VM-3 in hypertrophied myocardium and shifted again toward VM-1 by regression of cardiac hypertrophy. In conclusion, myocardial contractility and ventricular myosin isoenzymes were changed in pressure-overloaded hypertrophy in rats and these changes were reversible to a normal level by regression of cardiac hypertrophy.     

Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure

Background

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM.

Methods and Results

The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO₂, or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO₂ did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus −0.54 ± 1.83 mL kg⁻¹ min⁻¹ in OMT (P = .03) and pVO₂ increased by 0.34 ± 3.11 in CCM versus −0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks.

Conclusions

The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%.     

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.     

Does Contractility Modulation Have a Role in the Treatment of Heart Failure?

Cardiac resynchronization therapy (CRT) is an established therapy for patients with systolic dysfunction, QRS duration greater than 120 ms, and New York Heart Association (NYHA) class III or IV symptoms. However, most patients with heart failure have QRS duration below 120 ms and 30% or more of CRT recipients are nonresponders. Cardiac contractility modulation (CCM) signals are nonexcitatory electrical impulses applied during the absolute refractory period that are intended to enhance contractile strength independent of QRS duration. Myocardial biopsy studies suggest that modulation of protein phosphorylation and gene expression underlie the mechanisms by which CCM exerts its effects. Two prospective randomized studies have investigated the impact of CCM on exercise tolerance and quality of life in patients with chronic heart failure. These studies have included predominantly patients with NYHA class III heart failure with QRS duration below 130 ms. This review summarizes results of these clinical studies and outlines additional studies underway to further clarify the role of CCM in the treatment of heart failure.