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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 2  |  Issue : 1  |  Page : 29-33

The efficacy and safety of cardiac contractility modulation in patients with nonischemic cardiomyopathy: Chinese experience


1 State Key Laboratory of Cardiovascular Disease, Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
2 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
3 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Disease, Ministry of Education, Beijing 100029, China
4 Department of Cardiology, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
5 Department of Cardiology, Anhui Provincial Hospital, Hefei 230001, Anhui, China

Date of Web Publication19-Jun-2017

Correspondence Address:
Shu Zhang
State Key Laboratory of Cardiovascular Disease, Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJHR.IJHR_13_16

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  Abstract 

Background: Cardiac contractility modulation (CCM) has been used in patients with heart failure and normal QRS duration to improve exercise tolerance and quality of life. The safety and efficacy of CCM have been previously tested in moderate to severe heart failure patients with various etiologies in the western population. However, limited data are available on the safety and efficacy of CCM in Chinese patients with dilated cardiomyopathy and heart failure.
Methods: Eight patients with dilated cardiomyopathy were prospectively enrolled to receive CCM implants from 5 hospitals in China. All patients had the New York Heart Association (NYHA) functional class III and IV heart failure, with left ventricular ejection fraction (LVEF) ≤35%, and QRS ≤ 120 ms. All patients were followed up at the 3rd and 6th month. Evaluation included the NYHA functional class, 6-min hall walk test (6MHW), Minnesota Living with Heart Failure (MLWHF) Questionnaire, and CCM parameters.
Results: CCM was successfully implanted in all eight patients (50 ± 11 years, 6 men), and no device-related complications were observed in all patients at 3- and 6-month follow-up besides one patient voluntarily received heart transplantation at the 2nd month after CCM implantation and died from intracerebral hemorrhage during the perioperative period. Compared with baseline, the NYHA functional class (ΔNYHA: −1.0–−3.0, P= 0.016), the MLWHF quality of life scores (ΔMLWHF: −21.1 ± 17.5, P= 0.019), and 6MHW (Δ6MHW: 207.4 ± 202.5 m, P= 0.035) were significantly improved at 3-month follow-up. No significant change was observed in LVEF (ΔLVEF: −0.5%, 95% CI: −2.0%–12%, P= 0.813). All of these evaluations at 6-month follow-up were similar to those observed at 3-month, and no further improvement were observed from 3- to 6-month follow-up in the NYHA functional class (ΔNYHA 0; 0–1.0, P= 0.999), 6MHW (Δ6MHW: 39.2 ± 70.4 m, P= 0.231), MLWHF quality of life score (ΔMLWHF: 2.7 ± 3.9, P= 0.158), and LVEF (ΔLVEF: 2.0%, 95% CI: −2.0%–7.0%, P= 0.313).
Conclusions: CCM might be a new choice of device treatment for Chinese patients with nonischemic cardiomyopathy and heart failure if they have normal QRS duration.

Keywords: Cardiac contractility modulation, dilated cardiomyopathy, heart failure


How to cite this article:
Hua W, Fan X, Su Y, Zhou Y, Zou J, Yan J, Li X, Ding L, Niu H, Zhang S. The efficacy and safety of cardiac contractility modulation in patients with nonischemic cardiomyopathy: Chinese experience. Int J Heart Rhythm 2017;2:29-33

How to cite this URL:
Hua W, Fan X, Su Y, Zhou Y, Zou J, Yan J, Li X, Ding L, Niu H, Zhang S. The efficacy and safety of cardiac contractility modulation in patients with nonischemic cardiomyopathy: Chinese experience. Int J Heart Rhythm [serial online] 2017 [cited 2017 Nov 19];2:29-33. Available from: http://www.ijhronline.org/text.asp?2017/2/1/29/208456


  Introduction Top


Patients with advanced chronic heart failure (CHF) may be refractory to optimal standard medication therapy. Although cardiac resynchronization therapy enhances cardiac pump function and reduces hospitalizations and mortality in CHF patients with the evidence of biventricular contractile desynchronization (QRS duration ≥120 ms),[1] it benefits little for CHF patients with normal QRS duration.[2] Cardiac contractility modulation (CCM) is a new electrical device-based approach developed for the treatment of CHF.[3] CCM signals, which are relatively high-voltage electrical impulses applied to the myocardium during the absolute refractory period, have been demonstrated to enhance systolic function of the failing myocardium.[3] Previous randomized, controlled studies, the FIX-HF-4, FIX-HF-5 I and II phase study, have demonstrated the efficacy and safety of CCM in western patients with CHF and indications (viz., left ventricular ejection fraction [LVEF] ≤35%, New York Heart Association [NYHA] class III or IV symptoms with QRS duration ≤120 ms).[4],[5],[6] Patients receiving CCM implant demonstrate better exercise tolerance, improved NYHA functional class and quality of life without increasing myocardial oxygen consumption.[5],[6] In studies with long-term follow-up (6 years), CCM has been testified for the improvement of long-term survival and reduction of re-hospitalization rate, especially in those with EF ≥ 25%–40%.[7]

However, few data are available on CCM use in Chinese patients. We, therefore, conducted a prospective, multicenter study to enroll 8 patients from 5 hospitals in China to investigate the efficacy and safety of CCM in Chinese patients at 3- and 6-month follow-up.


  Methods Top


Patients and device implantation

Patients were recruited from five university teaching hospitals from December 2014 to January 2016. Subjects who were on optimal HF medications at least for 3 months, in NYHA class III–IV HF with LVEF ≤35% and electrocardiograph QRS ≤120 ms were included, and patients with permanent atrial fibrillation, coronary artery disease, the expectation of survival for <1 year were excluded. Finally, 8 CHF patients with nonischemic cardiomyopathy were enrolled (50 ± 11 years, 75% men). Written informed consents were obtained from each participator. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki, and this study was approved by the ethical committees of local hospital in each center.

The implantation procedure was performed as the protocol published before.[3],[5] All subjects received Optimizer System implantation (OPTIMIZER IVs IPG, Motorika Medical, Israel) by an experienced electrophysiological physician under local anesthesia. Three standard pacing leads were inserted through the subclavian vein. Atrial active-fixation lead (TENDRIL™ ST 1888TC-52, St. Jude, US) was placed at the right atrial appendage for sensing the P-wave, and the other two ventricular leads (TENDRIL™ ST 1888TC-58, St. Jude, US) were secured into the middle of and lower part of the right ventricular septum, respectively. The generator was inserted into a subcutaneous pocket formed in the right subclavicular area. Once incision was closed, the Optimizer IV was programed to deliver impulses only when atrial sensed signal was followed by ventricular signal occurring at a prespecified interval (70–398 ms). The impulse was delivered during several 1 h periods spread throughout the day for 7–8 h/day.

Endpoints and follow-up

The primary safety endpoint was composited of all-cause death and hospitalization due to symptomatic heart failure, and the secondary safety endpoint was the procedure and device-related adverse events, including heart failure exacerbation, documented severe ventricular arrhythmia, pericardial effusion, local/systemic infection, or optimizer lead dislodgment.[5],[6] The primary efficacy endpoints were changes in NYHA functional class; 6-min hall walk test (6MHW); Minnesota Living with Heart Failure (MLWHF) Questionnaire and LVEF.[8] Patients were assessed at the baseline, 3rd and 6th month of follow-up, for the evaluation of device functional status and patients' cardiac function. All adverse events were adjudicated by an independent Clinical Events Adjudication Committee and evaluation during follow-up was conducted by physicians who were blinded to CCM implants.

Statistical analysis

All continuous data were expressed as the mean ± standard deviation (SD). Paired t-test or Wilcoxon matched-pairs signed rank test was used when appropriate for comparisons of continuous variables between baseline and follow-up data. Comparison of categorical data was performed by Pearson Chi-square test. Two-sided P< 0.05 was considered statistically significant. All statistical analyses were performed using SPSS statistic software (version 21.0; SPSS Inc., Chicago, IL, USA) and figures were performed using GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA).


  Results Top


Patients' characteristics

Patients' baseline characteristics were summarized in [Table 1]. All the patients were nonischemic cause for CHF and 6 (75%) of them were NYHA functional class III patients, QRS duration and LVEF of the patients enrolled were 105.7 ± 17.8 ms and 26.4% ±7.4%, respectively. At baseline, the mean MLWHF was 39.4 ± 20.0 and 6MHW was 264.0 ± 145.8 m.
Table 1: Baseline clinical characteristics of patients who received cardiac contractility modulation (n=8)

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The safety of cardiac contractility modulation during follow-up

Optimal medication treatment was prescribed at least 3 months for all patients. One patient voluntarily received heart transplantation at the 2nd month after CCM implantation even though her exercise tolerance was improved and had no complication related to CCM. Unfortunately, the patients died from intracerebral hemorrhage during the perioperative period. ICD were implanted in 3 patients (37.5%) before or after the procedure. Except for the patient receiving heart transplantation, all patients were followed up and included in the analysis. No patients experienced heart failure exacerbation, documented severe ventricular arrhythmia, pericardial effusion, local infection, or lead dislodgment.

The efficacy of cardiac contractility modulation at 3- and 6-month follow-up

Compared to the baseline, exercise tolerance improved significantly at 3-month follow-up. As shown in [Figure 1], MLWHF quality of life score had a reduction of 21.1 in average (ΔMLWHF quality of life score: −21.1 ± 17.5, P= 0.019) and NYHA functional class decreased 1.0 class (ΔNYHA functional class: −1.0–−3.0, P= 0.016). The 6MHW was increased by 207.4 m in average (Δ6MHW 207.4 ± 202.5 m, P= 0.035). However, LVEF was not significantly improved at 3-month follow-up (ΔLVEF: −0.5%, −2.0%–12%, P= 0.813).
Figure 1: Baseline and 3-month status of patients receiving cardiac contractility modulation treatment. (a) MLWHF quality of life score between baseline and 3-month follow-up; (b) NYHA functional class between baseline and 3-month follow-up; (c) 6MHW between baseline and 3-month follow-up; (d) LVEF between baseline and 3-month follow-up. MLWHF: Minnesota Living with Heart Failure; NYHA: New York Heart Association; 6MHW: 6 min hall walk; LVEF: left ventricular ejection fraction. *P <0.05 compared with the baseline.

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As shown in [Figure 2], similar significantly functional improvement was observed at 6-month follow-up compared to the baseline in seven patients (ΔNYHA functional class: −1.0, −1.0–−3.0, P= 0.031; ΔMLWHF score: −19.5 ± 18.1, P= 0.046; Δ6MHW: 274.8 ± 208.4 m, P= 0.023, respectively). No significant change was observed in LVEF (5.9%, −1.9%–10.7%, P= 0.125). However, no further improvement was observed in all the parameters (ΔMLWHF quality of life score: 2.7 ± 3.9, P= 0.158; ΔNYHA functional class: 0, 0–1.0, P= 0.999; Δ6MHW: 39.2 ± 70.4 m, P= 0.231; ΔLVEF: 2.0%, −2.0%–7.0%, P= 0.313) as compared with the evaluation at 3-month follow-up [Figure 3].
Figure 2: Baseline and 6-month status of patients receiving cardiac contractility modulation treatment. (a) MLWHF quality of life score between baseline and 6-month follow-up; (b) NYHA functional class between baseline and 6-month follow-up; (c) 6MHW between baseline and 6-month follow-up; (d) LVEF between baseline and 6-month follow-up. MLWHF: Minnesota Living with Heart Failure; NYHA: New York Heart Association; 6MHW: 6 min hall walk; LVEF: left ventricular ejection fraction. *P < 0.05 compared with the baseline.

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Figure 3: Status at the baseline, 3- and 6-month of patients receiving cardiac contractility modulation treatment. (a) MLWHF quality of life score among baseline, 3- and 6-month follow-up; (b) NYHA functional class among baseline, 3- and 6-month follow-up; (c) 6MHW among baseline, 3- and 6-month follow-up; (d) LVEF among baseline, 3- and 6-month follow-up; MLWHF: Minnesota Living with Heart Failure; NYHA: New York Heart Association; 6MHW: 6 min hall walk; LVEF: left ventricular ejection fraction.

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  Discussion Top


The main finding in this prospective, multicenter study is that the safety and efficacy of CCM were confirmed in Chinese population. Patients with dilated cardiomyopathy and moderate to severe heart failure demonstrated improved exercise tolerance and life quality on the base of optimal medical therapy after receiving CCM implantation. The benefits maintained from 3- to 6-month follow-up. Our results indicate that CCM could be safely used in Chinese patients with heart failure and normal QRS as an effect treatment to improve exercise tolerance.

This study demonstrates the short-term benefit of CCM in mainland Chinese CHF patients. No lead dislodgment reported in our study during 6-month follow-up, similar to the reports in previous studies.[5],[6] Our results were also consistent with the prior observation [7],[9] that improvement in symptoms and function was observed after CCM treatment. The exercise tolerance improvement seemed to be obvious in our study as compared with that in previously studies.[5],[6],[10] However, different results could be observed in different studies due to our small sample size, racial differences, and different baseline characteristics. Recent studies showed that CCM could result in significant improvement in patients with LVEF 25%−40%, but not in patients with LVEF <25%.[7],[11] Our results confirmed these findings that CHF patients with moderate cardiac dysfunction may benefit more from CCM treatment because our patients with baseline mean LVEF >25% showed relatively high improvement in exercise tolerance parameters.

The mechanism by which CCM signals enhance contractile performance of the failing heart is still unclear. Underlying molecular mechanisms may involve the modulation of cardiomyocyte Ca 2+ fluxes through the enhancement of the L-type voltage-dependent Ca 2+ entry,[12] Na +-Ca 2+ mediated Ca 2+ entry,[13] cardiac phospholamban phosphorylation and sarcoplasmic reticulum Ca 2+ ATPase (SERCA2A) activity,[14] independent of the elevation of intracellular cAMPs.[15] Indeed, CCM could increase the cardiac contractility without increasing oxygen consumption. Furthermore, animal and clinical trials have demonstrated the benefits of CCM on the failing heart.[5],[7],[16] Most previous clinical trials demonstrate good safety and tolerance and better life quality during short-term follow-up. Recently, a case–control study showed a significant improvement of long-term survival and a reduction in heart failure hospitalizations after 6 years of CCM treatment, especially in CHF patients with EF ≥25%−40%.[7] However, the long-term effect of CCM on mortality and morbidity in patients with CHF and normal QRS still needs to be confirmed in large sample and long-term follow-up clinical trials. Furthermore, the accurate mechanisms of CCM on cardiac function also need extensive research.

The main limitation was the small sample size in the present study which due to limited use of CCM in China. However, our preliminary results of safety and efficacy of CCM treatment provided a basis for the further use of CCM in Chinese patients. Second, because all patients enrolled in our study were nonischemic cardiomyopathy, the effect of CCM treatment in patients with ischemic cardiomyopathy remains unclear and needs further study. Finally, our study just observed exercise tolerance parameters during relatively short-term follow-up, and both investigators and patients were not blind to testing of exercise tolerance. Therefore, the long-term benefit of CCM treatment should be verified in a relatively large sample double-blind study with a long-term follow-up.

CCM is associated with significant improvement in exercise tolerance and good safety in Chinese patients with heart failure and normal QRS duration. A large sample of patients with different heart functional classifications and various etiologies still need to be conducted to verify the long-term effect of CCM.

Financial support and sponsorship

This study was supported by the grant from National Natural Science Foundation of China to Dr. Wei Hua (No. 81570370).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49.  Back to cited text no. 1
    
2.
Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J, et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395-405.  Back to cited text no. 2
    
3.
Pappone C, Rosanio S, Burkhoff D, Mika Y, Vicedomini G, Augello G, et al. Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2002;90:1307-13.  Back to cited text no. 3
    
4.
Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati M, Pieske B, et al. Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur Heart J 2008;29:1019-28.  Back to cited text no. 4
    
5.
Abraham WT, Burkhoff D, Nademanee K, Carson P, Bourge R, Ellenbogen KA, et al. 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. Am Heart J 2008;156:641-8.e1.  Back to cited text no. 5
    
6.
Neelagaru SB, Sanchez JE, Lau SK, Greenberg SM, Raval NY, Worley S, et al. Nonexcitatory, cardiac contractility modulation electrical impulses: Feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm 2006;3:1140-7.  Back to cited text no. 6
    
7.
Liu M, Fang F, Luo XX, Shlomo BH, Burkhoff D, Chan JY, et al. Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case-control study. Int J Cardiol 2016;206:122-6.  Back to cited text no. 7
    
8.
Goldsmith RL, Mueller GM, Arwady MA, Burkhoff D. Optimizing exercise protocols for heart failure trials. J Am Coll Cardiol 2004;43:A169.  Back to cited text no. 8
    
9.
Kuschyk J, Roeger S, Schneider R, Streitner F, Stach K, Rudic B, et al. Efficacy and survival in patients with cardiac contractility modulation: Long-term single center experience in 81 patients. Int J Cardiol 2015;183:76-81.  Back to cited text no. 9
    
10.
Yu CM, Chan JY, Zhang Q, Yip GW, Lam YY, Chan A, et al. Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling. JACC Cardiovasc Imaging 2009;2:1341-9.  Back to cited text no. 10
    
11.
Abraham WT, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, et al. Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. J Card Fail 2011;17:710-7.  Back to cited text no. 11
    
12.
Zhao Z, Wen H, Fefelova N, Allen C, Baba A, Matsuda T, et al. Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: Predominant by Ca waves or Ca currents? Am J Physiol Heart Circ Physiol 2012;302:H1636-44.  Back to cited text no. 12
    
13.
Imai M, Rastogi S, Gupta RC, Mishra S, Sharov VG, Stanley WC, et al. Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure. J Am Coll Cardiol 2007;49:2120-8.  Back to cited text no. 13
    
14.
Mohri S, Shimizu J, Mika Y, Shemer I, Wang J, Ben-Haim S, et al. Electric currents applied during refractory period enhance contractility and systolic calcium in the ferret heart. Am J Physiol Heart Circ Physiol 2003;284:H1119-23.  Back to cited text no. 14
    
15.
Lyon AR, Samara MA, Feldman DS. Cardiac contractility modulation therapy in advanced systolic heart failure. Nat Rev Cardiol 2013;10:584-98.  Back to cited text no. 15
    
16.
Mohri S, He KL, Dickstein M, Mika Y, Shimizu J, Shemer I, et al. Cardiac contractility modulation by electric currents applied during the refractory period. Am J Physiol Heart Circ Physiol 2002;282:H1642-7.  Back to cited text no. 16
    


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