Cardiac contractility modulation (CCM) in chronic heart failure: mechanistic insights and clinical implications
|Take Home Messages|
In patients with chronic heart failure (CHF) that have persistence of symptoms despite optimal medical therapy (OMT) and prolonged QRS duration, cardiac resynchronisation therapy (CRT) has been shown to improve symptoms and quality of life.(1) Significantly, it also reduces hospitalisations and confers mortality benefit.(2) However, around 30% of cohorts treated with CRT are confirmed to be nonresponders.(3) In addition, 60% of heart failure sufferers have normal QRS duration(4), and benefits of CRT do not extend to those with normal or marginally increased QRS duration in whom outcomes may be worsened.(5) There is therefore the potential to diversify therapeutic options in this cohort.
What is the underlying physiology in CCM?
Cardiac contractility modulation (CCM) refers to electrical impulses delivered during the absolute refractory period (ARP) of the action potential, around 30ms after onset of QRS complex. It incorporates biphasic, bipolar signals administered for a duration of 20ms, with energy levels that are 50-100 fold that of a standard pacemaker impulse. They are typically administered for 5-12 hours on a daily basis. The shorter duration appears comparable in effectiveness(6), is more efficacious in reducing battery drain and enables eligibility of patients with frequent ectopy burden who may otherwise be excluded.
Impulses do not elicit a new action potential and the electro-mechanical impulse is unaffected (i.e. ‘non-excitatory’). Treatment has been shown to alter acute haemodynamics (contractility) as measured by dP/dt max, but significantly, without a concurrent increase in myocardial oxygen consumption (MVO2).(7) This phenomenon is analogous with CRT whereby haemodynamic and clinical benefits are derived without augmenting energy requirements. Although the natural history of CHF relates to a gradual prolongation in QRS duration, it has been shown to remain constant during CCM albeit over a 2 year follow-up period.(8)
The implantation procedure is in many ways comparable to that of a transvenous pacemaker system. CCM therapy is provided by a pacemaker-like generator (OPTIMIZER III, IMPULSE Dynamics) that is attached to two standard active fixation leads. These are placed along the mid-septal wall with an anatomical separation distance of at least 2cm. The proposed target zone are the septo-parietal trabeculations situated in the inferior portion of the septal right ventricular outflow tract (RVOT). Adequate sensing parameters are prioritised above the capture thresholds. A separate right atrial lead is positioned via active fixation to sequence with atrial activation.
What are the cellular mechanisms?
CCM exerts multiple effects at cellular and molecular levels, with acute benefits relating to alterations in calcium handling that enhance contractile performance. Both systolic and diastolic ventricular dysfunction are associated with alterations in cellular calcium homeostasis.(9) CCM has been shown to upregulate L-type calcium channels resulting in augmentation of intracellular calcium influx during the subsequent membrane depolarisation. There is also concurrent uptake into the sarcoplasmic reticulum via sarcoplasmic reticulum calcium-ATPase 2a (SERCA2a) receptors, thus improving calcium-triggered calcium release via ryanodine receptors (RyR2).(10) Analysis of endomyocardial biopsies from subjects with CHF after 3 months has shown increased expression of SERCA2a and RyR2, suggesting that CCM therapy normalises defective expression and reverts to the foetal gene programme.(11) These acute contractile effects are additive to those of CRT, as they arise from different mechanisms.
Animal models have shown that within minutes of signal delivery, there is a local shift in myocardial gene expression of key calcium cycling and stretch response components.(12) Interestingly, this alteration is also exhibited in remote sites such as the left ventricular free wall after chronic therapy.(13) This phenomenon may relate to diffuse changes in gene expression as a consequence of global effects on ventricular haemodynamics, or via direct transmission through gap junctions. Results broadly correlate with human studies using tissues derived from myocardial biopsies.(14) Importantly, this was associated with improvements in peak oxygen consumption (VO2) and subjective assessment of quality of life (QoL).(11) Data from animal studies also indicates that chronic CCM monotherapy increases left ventricular ejection fraction (LVEF) and reduces fibrotic burden(12), which may relate to normalised expression of matrix metalloproteinases.(15)
What do clinical trials suggest?
FIX-HF3 was the first study to assess clinical effectiveness of CCM therapy, though it was unblinded and observational.(16) In patients with drug-refractory New York Heart Association (NYHA) class III CHF and narrow QRS duration, improvements were observed at 2 month follow-up in LVEF, 6-minute walk, NYHA functional class and QoL scores as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ). This was succeeded by the first, randomised, double-blinded crossover study in patients with severe left ventricular dysfunction (LVSD) quantified as LVEF < 35%, and NYHA class II/III (FIX-HF4).(17) Peak VO2 increased comparably in the two groups at 3 month follow-up, suggestive of a potential placebo effect, but there was a statistically significant improvement at the end of the treatment period (i.e. 6 months) which correlated with QoL assessment.
The FIX-HF5 study explored sicker cohorts (NYHA III/IV) for a 6 month period, though the study was unblinded due to ethical concerns.(18) It was the largest clinical trial of CCM to date, performed across 50 centres in the USA. The primary endpoint of ventilatory anaerobic threshold (VAT) did not differ, though peak VO2 and QoL scores were improved. Notably, the use of VAT as a measure of exercise tolerance is disputable as patients with CHF cannot typically exert themselves sufficiently to reach the required threshold for lactate production. An exploratory subgroup analysis observed significant treatment benefits in those with LVEF of 25-45% , which has been subsequently verified by a prospective, confirmatory RCT.(20)
A meta-analysis in 2014 incorporated individual patient data from 3 studies and 641 participants.(21) Overall, CCM was suggested to exert modest yet statistically significant benefits on peak VO2, 6-minute walk and QoL. This data is aligned with haemodynamic assessments of CCM therapy, with one study exhibiting an improvement in LVEF by 5% and reduction in end-diastolic volume (EDV) by 12mls after 3 months, suggestive of reverse remodelling.(22) This response is comparable to that of CRT in patients with mild QRS prolongation.(23)
The effect of CCM on survival remains to be established. A case-control study with a 6 year follow-up period has shown a reduction in all-cause mortality, and particularly in subcohorts with LVEF of 25-40%.(24) Similar results have been presented from a retrospective study in cohorts with NYHA II/III symptoms, with mortality reductions at 1, 2 and 5 years when compared with predicted survival using the Seattle Heart Failure Model (SHFM).(25) The CCM-REG registry has now provided long-term outcome data from a real-world perspective for up to 3 years, and results are suggestive of a sustainable impact of CCM on functional capacity, QoL and mortality.(26)
What is the future of CCM?
European Society of Cardiology (ESC) guidelines for the treatment of CHF stipulate that “the evidence is considered insufficient to support specific guideline recommendations for CCM”.(27) However, it “may be considered in selected patients with CHF” and is approved for clinical use in some European Union (EU) countries, China, India, Australia and Brazil. Nonetheless, many uncertainties remain. The magnitude of derived haemodynamic benefit is likely to rely on precise septal positioning, which confers procedural complexity. It is unclear whether effects are dependent upon underlying aetiology of cardiomyopathy, analogous to the DANISH trial that observed an absence of mortality benefit in patients with non-ischaemic CHF that received prophylactic implantable cardioverter-defibrillators (ICD).(28)
Around 25% of patients with CHF have co-existent atrial fibrillation, and those with permanent dysrhythmia may be challenging due to the loss of atrial sensing. However, newer versions of the device appear to incorporate algorithms to circumvent this limitation.(29) The role of CCM in patients with non-severe LVSD and preserved ejection fraction (HFpEF) is yet to be elucidated. However, preliminary studies in the latter group have suggested positive findings, which may relate to upregulation of the cardiac protein titin which is involved in early diastolic recoil and late distensibility of cardiomyocytes.(30) Lastly, a rigorous cost-benefit analysis of CCM therapy needs to be conducted. One economic evaluation has estimated gain in quality-adjusted life years (QALY) of 5.26 compared to 4.00 for OMT. This equates to a cost per QALY of around £16,000 which is comparable with the derived benefit from CRT/ICD devices and below the designated threshold of £20-30,000 utilised in the UK.(31)
In summary, CCM offers a novel therapeutic option for patients with symptomatic, severe CHF that are ineligible for CRT based on QRS duration. Early studies in both animals and humans suggest positive effects on myocardial dynamics and reversal of the typical maladaptive gene profile that exists in CHF. However, further mechanistic insights and clarification of effects on long-term morbidity and mortality are necessitated before CCM can be considered part of the routine device armamentarium to treat patients with CHF.
- Bristow, M.R., et al., Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med, 2004. 350(21): p. 2140-50.
- Moss, A.J., et al., Cardiac-resynchronization therapy for the prevention of heartfailure events. N Engl J Med, 2009. 361(14): p. 1329-38.
- Abraham, W.T., et al., Cardiac resynchronization in chronic heart failure. N Engl J Med, 2002. 346(24): p. 1845-53.
- Shenkman, H.J., et al., Congestive heart failure and QRS duration: establishing prognosis study. Chest, 2002. 122(2): p. 528-34.
- Shah, R.M., et al., Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval </=130 ms: insights from a meta-analysis. Europace, 2015. 17(2): p. 267-73.
- Kloppe, A., et al., A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report. Cardiol J, 2016. 23(1): p. 114-9.
- Butter, C., et al., 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, 2007. 13(2): p. 137-42.
- Roger, S., et al., Long term impact of cardiac contractility modulation on QRS duration. J Electrocardiol, 2014. 47(6): p. 936-40.
- Lompre, A.M., et al., Ca2+ cycling and new therapeutic approaches for heart failure. Circulation, 2010. 121(6): p. 822-30.
- Lyon, A.R., M.A. Samara, and D.S. Feldman, Cardiac contractility modulation therapy in advanced systolic heart failure. Nat Rev Cardiol, 2013. 10(10): p. 584- 98.
- Butter, C., et al., Cardiac contractility modulation electrical signals improve myocardial gene expression in patients with heart failure. J Am Coll Cardiol, 2008. 51(18): p. 1784-9.
- Imai, M., 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(21): p. 2120-8.
- Morita, H., et al., Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure. J Card Fail, 2003. 9(1): p. 69-75.
- Winter, J., K.E. Brack, and G.A. Ng, Cardiac contractility modulation in the treatment of heart failure: initial results and unanswered questions. Eur J Heart Fail, 2011. 13(7): p. 700-10.
- Rastogi, S., et al., Effects of chronic therapy with cardiac contractility modulation electrical signals on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure. Cardiology, 2008. 110(4): p. 230-7.
- Stix, G., et al., Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J, 2004. 25(8): p. 650-5.
- Borggrefe, M.M., et al., Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur Heart J, 2008. 29(8): p. 1019-28.
- Kadish, A., et al., A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am Heart J, 2011. 161(2): p. 329-337.e1-2.
- Abraham, W.T., 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(9): p. 710-7.
- Abraham, W.T., et al., A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation. JACC Heart Fail, 2018. 6(10): p. 874-883.
- Giallauria, F., et al., 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, 2014. 175(2): p. 352-7.
- Yu, C.M., et al., Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling. JACC Cardiovasc Imaging, 2009. 2(12): p. 1341-9.
- Zhang, Q., et al., 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, 2013. 167(3): p. 889- 93.
- Liu, M., et al., Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case-control study. Int J Cardiol, 2016. 206: p. 122-6.
- Kloppe, A., et al., Long-term survival with Cardiac Contractility Modulation in patients with NYHA II or III symptoms and normal QRS duration. Int J Cardiol, 2016. 209: p. 291-5.
- Anker, S.D., et al., Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur J Heart Fail, 2019.
- Ponikowski, P., et al., 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, 2016. 37(27): p. 2129-2200.
- Kober, L., et al., Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med, 2016. 375(13): p. 1221-30.
- Roger, S., et al., Cardiac contractility modulation: first experience in heart failure patients with reduced ejection fraction and permanent atrial fibrillation. Europace, 2014. 16(8): p. 1205-9.
- Tschope, C., et al., Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF. Int J Cardiol, 2016. 203: p. 1061-6.
- Rohde, L.E., et al., Cost-effectiveness of heart failure therapies. Nat Rev Cardiol, 2013. 10(6): p. 338-54.