Top

Published in:

23-02-2024 | Heart Failure

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

Authors: George Bazoukis, Athanasios Saplaouras, Polyxeni Efthymiou, Andronicos Yiannikourides, Tong Liu, Konstantinos P. Letsas, Michael Efremidis, Konstantinos Lampropoulos, Sotirios Xydonas, Gary Tse, Antonis A. Armoundas

Published in: Heart Failure Reviews | Issue 3/2024

Abstract

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

Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ (1997) Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276:800–806CrossRefPubMed

Armoundas AA, Wu R, Juang G, Marban E, Tomaselli GF (2001) Electrical and structural remodeling of the failing ventricle. Pharmacol Ther 92:213–230CrossRefPubMed

Iyer V, Heller V, Armoundas AA (1985) Altered spatial calcium regulation enhances electrical heterogeneity in the failing canine left ventricle: Implications for electrical instability. J Appl Physiol 2012(112):944–955

Armoundas AA, Rose J, Aggarwal R, Stuyvers BD, O’Rourke B, Kass DA, Marban E, Shorofsky SR, Tomaselli GF, William BC (2007) Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 292:H1607–H1618CrossRefPubMed

Armoundas AA, Hobai IA, Tomaselli GF, Winslow RL, O’Rourke B (2003) Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circ Res 93:46–53CrossRefPubMedPubMedCentral

Katz AM (2011) Physiology of the Heart, 5th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins Health

Akar FG, Wu RC, Juang GJ, Tian Y, Burysek M, Disilvestre D, Xiong W, Armoundas AA, Tomaselli GF (2005) Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure. Am J Physiol Heart Circ Physiol 288:H2887–H2896CrossRefPubMed

Rose J, Armoundas AA, Tian Y, DiSilvestre D, Burysek M, Halperin V, O’Rourke B, Kass DA, Marban E, Tomaselli GF (2005) Molecular correlates of altered expression of potassium currents in failing rabbit myocardium. Am J Physiol Heart Circ Physiol 288:H2077–H2087CrossRefPubMed

Akar FG, Wu RC, Deschenes I, Armoundas AA, Piacentino V 3rd, Houser SR, Tomaselli GF (2004) Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. Am J Physiol Heart Circ Physiol 286:H602–H609CrossRefPubMed

10.

Wood EH, Heppner RL, Weidmann S (1969) Inotropic effects of electric currents. I. Positive and negative effects of constant electric currents or current pulses applied during cardiac action potentials. II. Hypotheses: calcium movements, excitation-contraction coupling and inotropic effects. Circ Res 24:409–45CrossRefPubMed

11.

Roger S, Schneider R, Rudic B, Liebe V, Stach K, Schimpf R, Borggrefe M, Kuschyk J (2014) Cardiac contractility modulation: first experience in heart failure patients with reduced ejection fraction and permanent atrial fibrillation. Europace 16(8):1205–1209. https://doi.org/10.1093/europace/euu050CrossRefPubMed

12.

Kuschyk J, Kloppe A, Schmidt-Schweda S, Bonnemeier H, Rousso B, Roger S (2017) Cardiac contractility modulation: a technical guide for device implantation. Rev Cardiovasc Med 18:1–13CrossRefPubMed

13.

Merchant FM, Sayadi O, Sohn K, Weiss EH, Puppala D, Doddamani R, Singh JP, Heist EK, Owen C, Kulkarni K, Armoundas AA (2020) Real-time closed-loop suppression of repolarization alternans reduces arrhythmia susceptibility in vivo. Circ Arrhythm Electrophysiol 13:e008186CrossRefPubMedPubMedCentral

14.

Sayadi O, Puppala D, Ishaque N, Doddamani R, Merchant FM, Barrett C, Singh JP, Heist EK, Mela T, Martinez JP, Laguna P, Armoundas AA (2014) A novel method to capture the onset of dynamic electrocardiographic ischemic changes and its implications to arrhythmia susceptibility. J Am Heart Assoc 3:e001055CrossRefPubMedPubMedCentral

15.

Merchant FM, Sayadi O, Puppala D, Moazzami K, Heller V, Armoundas AA (2014) A translational approach to probe the proarrhythmic potential of cardiac alternans: a reversible overture to arrhythmogenesis? Am J Physiol Heart Circ Physiol 306:H465–H474CrossRefPubMed

16.

Armoundas AA, Weiss EH, Sayadi O, Laferriere S, Sajja N, Mela T, Singh JP, Barrett CD, Kevin Heist E, Merchant FM (2013) A novel pacing method to suppress repolarization alternans in vivo: implications for arrhythmia prevention. Heart Rhythm 10:564–572CrossRefPubMed

17.

Burkhoff D, Shemer I, Felzen B, Shimizu J, Mika Y, Dickstein M, Prutchi D, Darvish N, Ben-Haim SA (2001) Electric currents applied during the refractory period can modulate cardiac contractility in vitro and in vivo. Heart Fail Rev 6:27–34CrossRefPubMed

18.

Sabbah HN, Haddad W, Mika Y, Nass O, Aviv R, Sharov VG, Maltsev V, Felzen B, Undrovinas AI, Goldstein S, Darvish N, Ben-Haim SA (2001) Cardiac contractility modulation with the impulse dynamics signal: Studies in dogs with chronic heart failure. Heart Fail Rev 6:45–53CrossRefPubMed

19.

Mohri S, He KL, Dickstein M, Mika Y, Shimizu J, Shemer I, Yi GH, Wang J, Ben-Haim S, Burkhoff D (2002) Cardiac contractility modulation by electric currents applied during the refractory period. Am J Physiol Heart Circ Physiol 282:H1642–H1647CrossRefPubMed

20.

Butter C, Wellnhofer E, Schlegl M, Winbeck G, Fleck E, Sabbah HN (2007) Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption. J Card Fail 13(2):137–142. https://doi.org/10.1016/j.cardfail.2006.11.00421CrossRefPubMed

21.

Goliasch G, Khorsand A, Schutz M, Karanikas G, Khazen C, Sochor H, Schmidinger H, Wolzt M, Graf S (2012) The effect of device-based cardiac contractility modulation therapy on myocardial efficiency and oxidative metabolism in patients with heart failure. Eur J Nucl Med Mol Imaging 39(3):408–415. https://doi.org/10.1007/s00259-011-1977-8CrossRefPubMed

22.

Tschope C, Kherad B, Klein O, Lipp A, Blaschke F, Gutterman D, Burkhoff D, Hamdani N, Spillmann F, Van Linthout S (2019) Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond. Eur J Heart Fail 21:14–22CrossRefPubMed

23.

Kloppe A, Mijic D, Schiedat F, Bogossian H, Mugge A, Rousso B, Lemke B (2016) A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report. Cardiol J 23(1):114–119. https://doi.org/10.5603/CJ.a2015.0073CrossRefPubMed

24.

Pappone C, Rosanio S, Burkhoff D, Mika Y, Vicedomini G, Augello G, Shemer I, Prutchi D, Haddad W, Aviv R, Snir Y, Kronzon I, Alfieri O, Ben-Haim SA (2002) 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 90:1307–1313CrossRefPubMed

25.

Pappone C, Augello G, Rosanio S, Vicedomini G, Santinelli V, Romano M, Agricola E, Maggi F, Buchmayr G, Moretti G, Mika Y, Ben-Haim SA, Wolzt M, Stix G, Schmidinger H (2004) First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol 15(4):418–427. https://doi.org/10.1046/j.1540-8167.2004.03580.xCrossRefPubMed

26.

Zhang Q, Chan YS, Liang YJ, Fang F, Lam YY, Chan CP, Lee AP, Chan KC, Wu EB, Yu CM (2013) Comparison of left ventricular reverse remodeling induced by cardiac contractility modulation and cardiac resynchronization therapy in heart failure patients with different QRS durations. Int J Cardiol 167(3):889–893. https://doi.org/10.1016/j.ijcard.2012.01.066CrossRefPubMed

27.

Kuschyk J, Nagele H, Heinz-Kuck K, Butter C, Lawo T, Wietholt D, Roeger S, Gutterman D, Burkhoff D, Rousso B, Borggrefe M (2019) Cardiac contractility modulation treatment in patients with symptomatic heart failure despite optimal medical therapy and cardiac resynchronization therapy (CRT). Int J Cardiol 277:173–177. https://doi.org/10.1016/j.ijcard.2018.10.086CrossRefPubMed

28.

Yucel G, Fastner C, Hetjens S, Toepel M, Schmiel G, Yazdani B, Husain-Syed F, Liebe V, Rudic B, Akin I, Borggrefe M, Kuschyk J (2022) Impact of baseline left ventricular ejection fraction on long-term outcomes in cardiac contractility modulation therapy. Pacing Clin Electrophysiol 45(5):639–648. https://doi.org/10.1111/pace.14478CrossRefPubMed

29.

Yu CM, Chan JY, Zhang Q, Yip GW, Lam YY, Chan A, Burkhoff D, Lee PW, Fung JW (2009) Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling. JACC Cardiovasc Imaging 2(12):1341–1349. https://doi.org/10.1016/j.jcmg.2009.07.011CrossRefPubMed

30.

Anker SD, Borggrefe M, Neuser H, Ohlow MA, Roger S, Goette A, Remppis BA, Kuck KH, Najarian KB, Gutterman DD, Rousso B, Burkhoff D, Hasenfuss G (2019) Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur J Heart Fail 21(9):1103–1113. https://doi.org/10.1002/ejhf.1374CrossRefPubMed

31.

Kuschyk J, Falk P, Demming T, Marx O, Morley D, Rao I, Burkhoff D (2021) Long-term clinical experience with cardiac contractility modulation therapy delivered by the Optimizer Smart system. Eur J Heart Fail 23(7):1160–1169. https://doi.org/10.1002/ejhf.2202CrossRefPubMed

32.

Kuschyk J, Roeger S, Schneider R, Streitner F, Stach K, Rudic B, Weiss C, Schimpf R, Papavasilliu T, Rousso B, Burkhoff D, Borggrefe M (2015) Efficacy and survival in patients with cardiac contractility modulation: Long-term single center experience in 81 patients. Int J Cardiol 183:76–81. https://doi.org/10.1016/j.ijcard.2014.12.178CrossRefPubMed

33.

Liu M, Fang F, Luo XX, Shlomo BH, Burkhoff D, Chan JY, Chan CP, Cheung L, Rousso B, Gutterman D, Yu CM (2016) Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case-control study. Int J Cardiol 206:122–126. https://doi.org/10.1016/j.ijcard.2016.01.071CrossRefPubMed

34.

Muller D, Remppis A, Schauerte P, Schmidt-Schweda S, Burkhoff D, Rousso B, Gutterman D, Senges J, Hindricks G, Kuck KH (2017) Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction. Clin Res Cardiol 106(11):893–904. https://doi.org/10.1007/s00392-017-1135-9CrossRefPubMedPubMedCentral

35.

Schau T, Seifert M, Meyhofer J, Neuss M, Butter C (2011) Long-term outcome of cardiac contractility modulation in patients with severe congestive heart failure. Europace 13(10):1436–1444. https://doi.org/10.1093/europace/eur153CrossRefPubMed

36.

Fastner C, Yuecel G, Rudic B, Schmiel G, Toepel M, Burkhoff D, Liebe V, Kruska M, Hetjens S, Borggrefe M, Akin I, Kuschyk J (2021) Cardiac contractility modulation in patients with ischemic versus non-ischemic cardiomyopathy: Results from the MAINTAINED observational study. Int J Cardiol 342:49–55. https://doi.org/10.1016/j.ijcard.2021.07.048CrossRefPubMed

37.

Yao J, Gao J, Yan JF, Fang S (2023) Cardiac contractility modulation and subcutaneous defibrillator (S-ICD): first experience with simultaneous implantation. Pacing Clin Electrophysiol 46:1595–1598CrossRefPubMed

38.

Roger S, Rudic B, Akin I, Shchetynska-Marinova T, Fastenrath F, Tulumen E, Liebe V, El-Battrawy I, Baumann S, Kuschyk J, Borggrefe M (2018) Long-term results of combined cardiac contractility modulation and subcutaneous defibrillator therapy in patients with heart failure and reduced ejection fraction. Clin Cardiol 41(4):518–524. https://doi.org/10.1002/clc.22919CrossRefPubMedPubMedCentral

39.

Trolese L, Faber T, Gressler A, Steinfurt J, Stuplich J, Jordan E, Bode C, Zehender M, Hilgendorf I (2021) Device interaction between cardiac contractility modulation (CCM) and subcutaneous defibrillator (S-ICD). J Cardiovasc Electrophysiol 32:3095–3098CrossRefPubMed

40.

Fastenrath F, Roger S, Akin I, Borggrefe M, Kuschyk J (2016) Combined implantation of dual-chamber ICD and optimizer through a persistent left superior vena cava. Anatol J Cardiol 16:138–140PubMedPubMedCentral

41.

Linde C, Grabowski M, Ponikowski P, Rao I, Stagg A, Tschope C (2022) Cardiac contractility modulation therapy improves health status in patients with heart failure with preserved ejection fraction: A pilot study (CCM-HFpEF). Eur J Heart Fail 24(12):2275–2284. https://doi.org/10.1002/ejhf.2619CrossRefPubMed

42.

Ansari U, Overhoff D, Burkhoff D, Fastner C, Yucel G, Roger S, Rudic B, Liebe V, Borggrefe M, Akin I, Kuschyk J, Papavassiliu T, Tulumen E (2022) Septal myocardial scar burden predicts the response to cardiac contractility modulation in patients with heart failure. Sci Rep 12(1):20504. https://doi.org/10.1038/s41598-022-24461-6CrossRefPubMedPubMedCentral

43.

Stix G, Borggrefe M, Wolpert C, Hindricks G, Kottkamp H, Bocker D, Wichter T, Mika Y, Ben-Haim S, Burkhoff D, Wolzt M, Schmidinger H (2004) Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J 25(8):650–655. https://doi.org/10.1016/j.ehj.2004.02.027CrossRefPubMed

44.

Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati M, Pieske B, Misier AR, Curnis A, Bocker D, Remppis A, Kautzner J, Stuhlinger M, Leclerq C, Taborsky M, Frigerio M, Parides M, Burkhoff D, Hindricks G (2008) Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur Heart J 29:1019–1028. https://doi.org/10.1093/eurheartj/ehn020CrossRefPubMed

45.

Neelagaru SB, Sanchez JE, Lau SK, Greenberg SM, Raval NY, Worley S, Kalman J, Merliss AD, Krueger S, Wood M, Wish M, Burkhoff D, Nademanee K (2006) Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm 3(10):1140–1147. https://doi.org/10.1016/j.hrthm.2006.06.031CrossRefPubMed

46.

Kadish A, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R, Goldstein S, Mika Y, Burkhoff D, Abraham WT (2011) A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am Heart J 161(2):329–337 e321–322. https://doi.org/10.1016/j.ahj.2010.10.025CrossRefPubMed

47.

Abraham WT, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R, Goldstein S, Mika Y, Burkhoff D, Kadish A, Investigators F-H- and Coordinators (2011) Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. J Card Fail 17:710–7. https://doi.org/10.1016/j.cardfail.2011.05.006CrossRefPubMed

48.

Abraham WT, Kuck KH, Goldsmith RL, Lindenfeld J, Reddy VY, Carson PE, Mann DL, Saville B, Parise H, Chan R, Wiegn P, Hastings JL, Kaplan AJ, Edelmann F, Luthje L, Kahwash R, Tomassoni GF, Gutterman DD, Stagg A, Burkhoff D, Hasenfuss G (2018) A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation. JACC Heart Fail 6:874–883. https://doi.org/10.1016/j.jchf.2018.04.010CrossRefPubMed

49.

Wiegn P, Chan R, Jost C, Saville BR, Parise H, Prutchi D, Carson PE, Stagg A, Goldsmith RL, Burkhoff D (2020) Safety, performance, and efficacy of cardiac contractility modulation delivered by the 2-lead optimizer smart system: The FIX-HF-5C2 study. Circ Heart Fail 13(4):e006512. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006512CrossRefPubMed

50.

Roger S, Said S, Kloppe A, Lawo T, Emig U, Rousso B, Gutterman D, Borggrefe M, Kuschyk J (2017) Cardiac contractility modulation in heart failure patients: Randomized comparison of signal delivery through one vs. two ventricular leads. J Cardiol 69(1):326–332. https://doi.org/10.1016/j.jjcc.2016.06.015CrossRefPubMed

51.

Giallauria F, Vigorito C, Piepoli MF, Stewart Coats AJ (2014) 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. Int J Cardiol 175:352–357CrossRefPubMed

52.

Giallauria F, Cuomo G, Parlato A, Raval NY, Kuschyk J, Stewart Coats AJ (2020) A comprehensive individual patient data meta-analysis of the effects of cardiac contractility modulation on functional capacity and heart failure-related quality of life. ESC Heart Fail 7:2922–2932CrossRefPubMedPubMedCentral

53.

Mando R, Goel A, Habash F, Saad M, Ayoub K, Vallurupalli S, Maskoun W (2019) Outcomes of cardiac contractility modulation: a systematic review and meta-analysis of randomized clinical trials. Cardiovasc Ther 2019:9769724CrossRefPubMedPubMedCentral

54.

Witte K, Hasenfuss G, Kloppe A, Burkhoff D, Green M, Moss J, Peel A, Mealing S, Durand Zaleski I, Cowie MR (2019) Cost-effectiveness of a cardiac contractility modulation device in heart failure with normal QRS duration. ESC Heart Fail 6:1178–1187CrossRefPubMed

55.

Hesselson AB (2022) Cardiac contractility modulation: a technical review. J Innov Card Rhythm Manag 13:5205–5218CrossRefPubMedPubMedCentral

56.

Vartanian K, Franco M, Busse N, Bidzhoian S, Hamdan T, von Schwarz ER (2022) Improved physical function after cardiac contractility modulation therapy in 10 patients with chronic heart failure. Tex Heart Inst J 49(6):e227905https://doi.org/10.14503/THIJ-22-7905CrossRef

57.

Kloppe A, Lawo T, Mijic D, Schiedat F, Muegge A, Lemke B (2016) Long-term survival with cardiac contractility modulation in patients with NYHA II or III symptoms and normal QRS duration. Int J Cardiol 209:291–295. https://doi.org/10.1016/j.ijcard.2016.02.001CrossRefPubMed

Title: Cardiac contractility modulation in patients with heart failure — A review of the literature
Authors: George Bazoukis
Athanasios Saplaouras
Polyxeni Efthymiou
Andronicos Yiannikourides
Tong Liu
Konstantinos P. Letsas
Michael Efremidis
Konstantinos Lampropoulos
Sotirios Xydonas
Gary Tse
Antonis A. Armoundas
Publication date: 23-02-2024
Publisher: Springer US
Keywords: Heart Failure
Cardiac Resynchronization Therapy
Cardiac Resynchronization Therapy
Cardiac Resynchronization Therapy
Cardiac Resynchronization Therapy
Published in: Heart Failure Reviews / Issue 3/2024
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-024-10390-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2024

Heart failure with mildly reduced and preserved ejection fraction: A review of disease burden and remaining unmet medical needs within a new treatment landscape

Latest pharmaceutical approaches across the spectrum of heart failure

Durable ventricular assist device in adult patients with single ventricle: a systematic literature review

Incremental diagnostic and prognostic utility of left atrial deformation in heart failure using speckle tracking echocardiography

Kinin-kallikrein system: New perspectives in heart failure

Stem cell-based therapies for heart failure management: a narrative review of current evidence and future perspectives