Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176

Comprehensive Review

Cardiac Contractility Modulation for Heart Failure: Current and

Future Directions
Daniel C. Pipilas, MD a, b, Alan Hanley, MB, BCh, BAO a, b, c, Jagmeet P. Singh, MD, PhD a, b, c,
Theofanie Mela, MD a, b, c, *
a b
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; c Demoulas Center for
Cardiac Arrhythmias, Massachusetts General Hospital, Boston, Massachusetts

A B S T R A C T

Cardiac contractility modulation (CCM) is a Food and Drug Administration-approved device-based therapy for patients with heart failure. The system delivers
biphasic electric stimulation to the ventricular myocardium during the absolute refractory period to augment left ventricular contraction. CCM therapy
promotes acute and chronic changes at the cellular level, leading to favorable remodeling throughout the myocardium. CCM improves quality of life, New
York Heart Association class, left ventricular ejection fraction, peak oxygen uptake, and the composite end point of cardiovascular death and heart failure
hospitalizations. This review will focus on the biological basis, indications, and evidence for CCM, as well as the future applications of this technology.

Introduction Guideline-directed medical therapy is the cornerstone of therapy for

patients with HFrEF and has improved substantially in the past 3 de-
Heart failure (HF) is a complex clinical syndrome that currently af- cades leading to improved morbidity and mortality in this population.5
fects an estimated 6 million adults in the United States, with that These medications target adverse neurohormonal activation that occurs
number expected to rise in the coming decades.1,2 HF is a leading as a result of HF and add cumulative benefit to survival. Prospective
cause of mortality and is projected to cost at least $70 billion annually in data in patients with HFmrEF is less robust, and similarly, only
the United States by 2030.3 HF can arise from numerous underlying sodium-glucose cotransporter-2 (SGLT2) inhibitors are shown to
pathophysiologic processes that impact cardiac structure or function.4 decrease hospitalizations and cardiovascular mortality in the HFpEF
Three major HF classifications exist and are defined by left ventricular population.6
ejection fraction (LVEF): heart failure with a reduced ejection fraction In addition to medical therapy, disease-modifying device-based
(HFrEF, LVEF
40%), heart failure with mildly reduced ejection fraction therapies that target the cardiac conduction system improve outcomes
(HFmrEF, LVEF 41%-49%), and heart failure with a preserved ejection in select patients with HFrEF. Although implantable cardioverter-
fraction (HFpEF, 50%).5 Patients with HF are further characterized by defibrillator (ICD) therapy is indicated in HFrEF patients for primary
American Heart Association (AHA) and American College of Cardiology and secondary prevention of sudden cardiac death, these devices do
(ACC) guideline stage (A-D), which helps characterize the severity of the not modify the disease substrate and thus will not be addressed here.
underlying disease state, and by New York Heart Association (NYHA) Normal electrical activation of the heart is uniform, and rapid, and
classification (I-IV) which delineates the extent of HF symptoms.5 facilitates coordinated contraction of the right and left ventricular (LV)
Treatment modalities for patients with HF include medications, myocardium. In HFrEF, structural and mechanical changes lead to
device-based therapies, and transplantation, but there exists substan- conduction system disease that alters this uniformity and can lead to
tial heterogeneity in treatment options available to individual patients ventricular dyssynchrony and progressive adverse remodeling. CRT,
within these categories owing both to the breadth of disease processes also termed biventricular pacing, facilitates simultaneous pacing of the
that cause clinical HF and patient characteristics (eg, age, patient right and left ventricles via leads placed in the right ventricular (RV)
comorbidities, LVEF, QRS-complex width). septum and coronary sinus. CRT has been shown to reverse deleterious

Abbreviations: CCM, cardiac contractility modulation; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart
failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; LTCC, L-type calcium channel; LVEF, left ventricular ejection fraction; MLWHFQ, Minnesota Living with
Heart Failure Questionnaire; PPM, permanent pacemaker; VO2, myocardial oxygen consumption.
Keywords: cardiac contractility modulation; cardiac devices; cardiomyopathy; electrophysiology; heart failure.
* Corresponding author: tmela@mgh.harvard.edu (T. Mela).

https://doi.org/10.1016/j.jscai.2023.101176
Received 1 August 2023; Received in revised form 30 August 2023; Accepted 6 September 2023
2772-9303/© 2023 The Author(s). Published by Elsevier Inc. on behalf of Society for Cardiovascular Angiography and Interventions Foundation. This is an open access article under the
CC BY license (http://creativecommons.org/licenses/by/4.0/).
2 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176

cellular, tissue, and organ-level dysfunction that occurs in HF by results in distorted intracellular calcium handling and impairs force
inducing molecular, genetic, and functional changes.7,8 At the organ production and relaxation.28 Over time, metabolic stress, inflammation,
level, CRT restores ventricular synchrony, and has been shown to altered ion channel expression, reduced function of contractile pro-
improve mortality, hospitalizations, symptoms, and quality of life in teins, and deleterious gene expression lead to progressive myocardial
patients with HFrEF and HFmrEF who have a wide QRS (150 ms), and dysfunction and worsening of clinical HF. Impaired calcium handling
select patients with QRS duration between 120 to 149 ms or those with occurs via several mechanisms including downregulation of genes
a high pacing burden (eg, patients with atrial fibrillation [AF] who un- related to calcium cycling, upregulation of myocardial fetal and stretch
dergo atrioventricular nodal ablation).5,9 In patients with HF and QRS response genes, reduced L-type calcium channel (LTCC) activity,
duration <130 ms, CRT is not recommended and may increase mor- decreased sarcoplasmic reticulum calcium uptake and release, and
tality.10 These strict indications limit who is eligible for CRT and thus enhanced clearance of calcium by the sodium-calcium exchange pro-
only a subset of patients with HFrEF meet criteria for CRT.11,12 tein 1.17 These cellular changes correspond with progressive ventricular
Furthermore, roughly 30% of patients respond poorly to CRT and derive dilation, eccentric and concentric hypertrophy, tissue fibrosis, and
minimal benefit.13,14 electrical and mechanical dyssynchrony at the organ level, leading to
Neuromodulation via baroreceptor activation is an additional further remodeling.
device-based therapy that is Food and Drug Administration (FDA)- The mechanism by which CCM improves functional status is likely
approved to treat patients with HFrEF and is indicated in patients who related to changes in calcium handling and correction toward more
are not candidates for CRT.15 Baroreceptor activation therapy targets normal myocardial gene expression and calcium regulation, and over
autonomic imbalance and has shown improvement in exercise capacity time these effects occur throughout the ventricular myocardium and
and quality of life, but there is limited data on mortality and hospitali- contribute to reverse LV remodeling.19 Early preclinical studies first
zations. Despite the widespread availability of CRT and the growing use demonstrated that high-amplitude CCM pulses applied to ferret hearts
of neuromodulation, many patients are not eligible for these treatments during the absolute refractory period increased the amplitude and
and are left without options for device-based therapy. Thus, significant decreased the time-to-peak values of cytoplasmic calcium currents.20
gaps in treatment options exist for patients with HFrEF and HFmrEF These changes correlated with changes in muscle contraction. Several
with narrow QRS on optimal medical therapy (OMT), as well as those mechanisms have been proposed for the increase in cytoplasmic cal-
with HFpEF. Accruing evidence suggests that these populations may cium with CCM, which include an increased activation and duration of
derive benefit from CCM. opening of ryanodine receptors, increased calcium influx via LTCC, and
In 1969, it was shown that excitatory stimulation applied during the increased calcium influx into the sarcoplasmic reticulum via the sarco-
absolute refractory period augments myocardial contraction.16 This plasmic reticulum calcium adenosine-triphosphatase-2a (SERCA2a).17
observation served as the basis for the development of CCM therapy in In 1 study of canines with chronic HF, 1 hour of CCM therapy resulted in
HF to augment systole and provide a positive inotropic effect to failing upregulation of LTCC and improved calcium-induced calcium release.22
hearts.17,18 The CCM system uses standard pacing electrodes to deliver In addition to short-term effects related to calcium handling,
high-voltage, nonexcitatory impulses during the absolute refractory long-term CCM therapy upregulates genes related to calcium cycling
period and is implanted in a procedure similar to permanent pacemaker and handling, reduces fetal gene expression, and results in reverse
(PPM) and ICD insertions.19 Initial studies in preclinical HF models remodeling at the tissue level.29-31 One study of biopsy specimens
showed improvement in cardiac contractile parameters and ventricular from patients with HF receiving CCM therapy for 3 months showed
function,20-22 and early human studies showed improvement in LVEF, increased expression of SERCA2a, phospholamban, and RyR2, indi-
symptoms, and functional status.23. CCM has been studied in the HF cating favorable changes in gene expression.31 The global effect of
population for over 2 decades, and this therapy is the subject of sig- CCM on LV contractility and reverse remodeling was shown in a study
nificant interest for the treatment of all patients with HF regardless of by Yu et al, in which 30 patients undergoing CCM therapy for 3
LVEF and QRS duration. The device was first approved for use in Europe months demonstrated reduced LV end-systolic volume, improvement
in 2016. Two seminal clinical trials, FIX-HF-524 and FIX-HF-5C,25 later in LVEF, and global improvement in myocardial contraction by
resulted in the 2019 breakthrough FDA approval of the Optimizer Smart real-time 3-dimensional echocardiography.30 Despite these positive
System CCM device (Impulse Dynamics Inc) for patients with NYHA inotropic effects, myocardial oxygen demand does not seem to in-
class III HF with LVEF of 25% to 45%. This review will summarize the crease with CCM,31-33 perhaps because CCM acts through mecha-
physiologic basis for CCM, technical aspects of the therapy, and avail- nisms independent of cyclic adenosine monophosphate and
able evidence for use in HF patients (Central Illustration). improves the relationship between oxygen consumption and
myocardial workload.17

Physiologic mechanism of action of cardiac contractility

modulation Device description and technical considerations

This section will highlight major insights into the physiologic ratio- Several CCM systems have been developed, but as of 2023, the
nale for cardiac contractility modulation (CCM) therapy. Mechanisms Optimizer Smart system and the Optimizer Smart Mini system are the
underlying the benefit of CCM are multifactorial. In general, an acute only 2 devices that are FDA-approved. The Optimizer system consists of
effect on cellular calcium handling and influence on gene expression a pulse generator unit implanted subcutaneously in the upper chest wall
lead to regional and global improvement in myocardial contractility and 2 ventricular leads embedded in the RV septum. The 2 leads are
without an increase in myocardial oxygen demand. referred to as the RV lead, defined by the earliest ventricular sensed
At the cellular level, contraction of the myocardium begins with event, and the local sense (LS) lead. Note that earlier CCM technology
plasma membrane depolarization, resulting in calcium entering the required an atrial lead, but the safety and efficacy of a system consisting
cytosol from extracellular and intracellular stores.26 This influx of cal- of only ventricular leads was demonstrated in the FIX-HF-5C2 study;
cium leads to muscle contraction through subsequent binding of cal- thus, systems containing atrial leads will not be described here.34 The
cium ions to troponin, resulting in the sliding of contractile proteins Optimizer device is similar in size to a dual-chamber PPM and is
actin and myosin.27 The magnitude and duration of this rise in intra- recharged on a weekly basis by the patient with an estimated longevity
cellular calcium is a major regulator of the force of myocardial of 15 to 20 years before replacement is required. The CCM system
contraction.27 In failing hearts, adverse neurohormonal activation provides therapy for 5 to 12 hours each day (programmed at physician
 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176 3

discretion) in 1-hour intervals dispersed evenly over 24 hours. Of note, 164 patients with <35% and NYHA class II or III symptoms on OMT
longer duration of therapy has not been shown to improve outcomes.35 underwent placement of a CCM pulse generator and either received
The implantation procedure of these devices is similar to that of a CCM for 3 months followed by sham treatment for 3 months, or sham
dual-chamber PPM and the complications of device insertion and overall treatment for 3 months followed by CCM for 3 months.42 During the
complication rate are similar to those of PPM and ICD insertions.25,34,36 A first 3 months, peak myocardial oxygen consumption (VO2) increased in
detailed guide to the CCM implantation was published in 2017 by both groups, but during the second phase, peak VO2 decreased in the
Kuschyk et al and outlines the insertion procedure, testing protocol, and group switched to sham and increased in the group switched to CCM.
special considerations.37 Briefly, the procedure is typically performed in a Quality of life by MLWHFQ trended better with treatment during the
sterile, fluoroscopy-enabled electrophysiology laboratory or operating first 3 months, increased during the second 3 months in the group
room.36 Site selection in the left or right upper chest wall depends on the switched to sham, and decreased further in patients switched from
presence of a pre-existing PPM or ICD (usually in the left chest wall), and sham to active CCM. Overall, the group that switched from sham (first 3
the Optimizer system is implanted on the contralateral side. Vascular months) to CCM (second 3 months) had statistically significant im-
access is obtained via the axillary and/or subclavian veins for insertion of 2 provements in MLWHFQ and peak VO2 compared to the group
guide wires that will be used to guide the leads into the RV septum. The switched from CCM to sham. The study was underpowered to detect
leads should be at least 2 cm apart and inserted into the septomarginal differences in mortality or HF admissions, but the improvement in
trabeculations in the inferior portion of the septal RV outflow tract. Prior to functional status observed with CCM therapy confirmed prior obser-
extending the fixation screws at the tip of the leads, an adequate ven- vation and formed the basis for further prospective investigation.
tricular waveform should be confirmed as excellent sensing is a priority to The subsequent FIX-HF-5 study was then conducted in a larger cohort
ensure appropriate device function. Blunt dissection is used to construct of 428 patients with LVEF
35%, NYHA class III/IV symptoms despite
a pocket in the prepectoral area. Leads are secured into the pocket, and OMT, ineligibility for CRT, and QRS duration of <130 ms.24 Patients were
further programming and testing are conducted. randomized to receive OMT plus CCM (n ¼ 215) vs OMT alone (n ¼ 213).
Proper programming of the device is critical to ensure delivery of The primary end point of the trial was an improvement in ventilatory
CCM stimulation at precisely the right time in each cardiac cycle. anaerobic threshold in the CCM group, which was not met. However, the
Inadvertent firing could result in unintended ventricular pacing or OMT plus CCM group demonstrated improved quality of life by
arrhythmia generation.38 The 2 leads are programmed to sense ven- MLWHFQ, NYHA class, and peak VO2 at 6 months, and at 12 months
tricular activation events in time with respect to one another. Once a there was comparable all-cause mortality and hospitalizations satisfying a
ventricular event is detected by the RV lead, the local sense alert win- prespecified noninferiority safety end point. A prespecified subgroup
dow is opened which represents the delay between the sensed RV analysis revealed that LVEF 25% was a predictor of increased efficacy of
event and the sensed local sense event. The length of this window is CCM in the FIX-HF-5 cohort,53 prompting the follow-up study FIX-HF-5C.
programmable and tells the device how to discriminate between In this randomized trial, 160 symptomatic HF patients with NYHA class
normal beats and abnormal beats (eg, premature ventricular contrac- III/IV symptoms, LVEF 25% and
45%, and QRS <130 ms were ran-
tions). Normal beats that fall within the local sense alert window result in domized to OMT plus CCM or continue OMT alone.25 At a mean 24
CCM delivery, which is usually 30 to 40 ms after the QRS complex. weeks of follow-up, CCM therapy was associated with increased peak
Although the energy delivered by CCM is several times greater than the VO2, and improvement in NYHA functional class, 6-minute walk test, and
energy delivered by a pacemaker (~7.5V), myocardial depolarization MLWHFQ score. In addition, a composite end point of cardiovascular
does not occur because the CCM stimulus is delivered during the ab- death and HF hospitalizations was reduced. Interestingly, in a pre-
solute refractory period. Following the completion of testing, the specified subgroup analysis of patients with LVEF 35%, a more signifi-
pocket is closed in layers. cant benefit was derived compared to those with LVEF 25% but
Certain technical concerns must be considered in patients under- <35%.25 The results of FIX-HF-5 and FIX-HF-5C ultimately led to the
going insertion of an Optimizer system. First, if a patient has another device gaining FDA breakthrough status in 2019.54 The more recent
implanted cardiac device in place such as an ICD, it is critical to test for FIX-HF-5C2 study enrolled 60 patients with NYHA III/IV symptoms and
device-device interactions. The large voltage signal delivered by the LVEF 25% and <45% who were not eligible for CRT to test the efficacy
CCM can be inappropriately interpreted as a ventricular arrhythmia by and safety of a 2-lead (2 ventricular leads, no atrial lead) Optimizer sys-
an ICD. Similarly, in patients with PPM, it is critical to ensure that CCM tem.34 Results demonstrated comparable device function between the
pulses do not inhibit RV pacing. Furthermore, in patients with 2-lead and 3-lead system and similar improvement in peak VO2 and
indwelling devices, insertion of 2 additional leads through the tricuspid NYHA class compared to FIX-HF-5C controls. Two important benefits of
valve may worsen tricuspid regurgitation and may increase infection the 2-lead system were highlighted in this work. First, lead-related
risk. Importantly, it is also possible for patients to experience chest adverse events were significantly decreased and second, this system
discomfort given the large electrical current delivered via CCM. relied solely on sensing from the ventricular leads, allowing CCM therapy
Therefore, it is important to test the therapy while the patient is awake to be delivered to patients with AF.
before securing the leads. If a patient experiences chest discomfort, the In 2020, Giallauria et al performed a comprehensive individual pa-
leads must be repositioned. Finally, patients with mechanical tricuspid tient data meta-analysis of all randomized trials, and the non-
valves or lack of adequate venous access (eg, venous occlusion) are not randomized FIX-HF-5C2 included 861 patients and pooled analysis
eligible for CCM given issues with lead placement. showed that CCM significantly improved peak VO2, 6-minute walk test
distance, and quality of life by MLWHFQ.55 Results were similar in a
sensitivity analysis excluding the 60 patients from FIX-HF-5C2. The
Clinical efficacy and available evidence discussion of CCM devices was first included in the European Society of
Cardiology HF Guidelines in 201656 and is mentioned in the 2022
CCM has been studied extensively in the HF population ACC/AHA Guidelines for the Management of HF.5
(Table 1).24,25,30,34,35,39-51 In 2004, the observational FIX-HF-3 study In summary, clinical trials both randomized and nonrandomized
demonstrated encouraging safety and efficacy results in 23 patients have demonstrated that CCM therapy in patients with HFrEF and
with improvement in LVEF, quality of life by Minnesota Living with HF HFmrEF in addition to OMT improves peak VO2, 6-minute walk test,
Questionnaire (MLWHFQ)52 score, and an increased 6-minute walk NYHA functional class, and quality of life. The patients who seem to
test.39 This gave way to the first randomized study, FIX-HF-4, which was benefit most are those with LVEF between 25% and 45% and NYHA
published in 2008.42 In this randomized, double-blind, crossover study class II-III.25,29 A positive effect of CCM on cardiovascular outcomes
 4
Table 1. Selected studies of cardiac contractility modulation.
Study n Follow-up Clinical question Randomized Comparison group Primary outcome Additional findings
(Yes/No)

Stix et al,39 2004 23 8 wk Feasibility of CCM in patients with No Baseline LVEF increased from 22  7% to 28  8%, P ¼ .0002 MLWHFQ and 6MWT also improved
(FIX-HF-3) LVEF
35% and NYHA III significantly
Neelagaru et al,40 49 6 mo Pilot study for FIX-HF-5 in patients Yes Control Primary safety end point met, no difference in survival Nonsignificant improvement in 6MWT and
2006 on OMT with LVEF
35% and free of any hospitalization (HR, 0.47; 95% CI, 0.16- peak VO2 in treatment compared to control
NYHA III-IV 1.40)
agele et al,41 2008
N€ 16 3 mo Assess CCM in CRT nonresponders No Baseline CCM implantation is feasible in CRT nonresponders, Significant increase in NYHA class and LVEF
on OMT with NYHA III-IV no electrical interference events between CRT and following CCM implantation
CCM

D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176
Borggrefe et al,42 164 6-mo Efficacy of CCM in patients with Yes Active treatment vs Improved peak VO2 on treatment (0.52  1.39 mL/kg/ —
2008 (FIX-HF-4) crossover (3 LVEF
35% and NYHA II, III, IV sham min; 95% CI, 0.04-0.99; P ¼ .032) and MLWHFQ on
mo of CCM) treatment (2.93  8.01, ;95% CI, 0.29-5.56; P ¼ .03 on
treatment)
Yu et al,30 2009 30 3 mo Effect of CCM on LV function using No Baseline Reduction in LVESV by 11.5  10.5% and increased Significant improvement in 6MWT and NYHA
echocardiography LVEF by 4.8  3.6% (P < .001 for both) class noted with CCM
Schau et al,62 2011 54 Median Retrospective analysis of mortality No — No difference in survival between CCM patients —
survival 33.1 in patients undergoing CCM (median death rate 18.4% per y; 95% CI, 11%-24%)
mo and predicted survival by SHFM (mean 1-y mortality
18.4%; 95% CI, 14.3%-20.1%)
Kadish et al,24 2011 428 6 mo CCM plus OMT to CCM alone Yes Control No change in ventilatory anaerobic threshold with Significant improvement in peak VO2 and
(FIX-HF-5) CCM (4.5 mL/kg/min; 95% CI, 2.4-11.5; P ¼ .314) MLWHFQ in CCM over OMT
Kuschyk et al,43 81 34 mo Single-center analysis of efficacy of No Baseline Lower observed 1-y mortality rate vs predicted rate Significant increase in LVEF, mean NYHA class,
2015 CCM derived from MAGGIC score (5.2% vs 18.4%; P < and mean peak VO2
.001), nonsignificant trend in 3-y mortality rate (29.5%
vs 40%)
Kloppe et al,44 2016 68 Mean follow- Survival in CCM patients with No — Survival at 1, 2, and 5 y was lower with CCM than —
up of 4.5 y NYHA II or II and QRSd
130 ms predicted by SHFM (0% vs 6.1, 3.5% vs 11.8%, and
14.2% vs 27.7%, respectively; P ¼ .007)
Liu et al,45 2016 82 6y Case-control study of survival after No — All-cause mortality was lower in CCM group vs control —
CCM vs OMT in HF patients with (39% vs 71%; P ¼ .001)
LVEF
40%
Kloppe et al,35 2016 19 6 mo Effect of varying duration of CCM (5 Yes Difference between No significant differences clinically or statistically in —
vs 12 h) groups (12h vs 5h) MLWHFQ, NYHA, peak VO2, 6MWT, or LVEF
between groups
oger et al,46 2017
R€ 48 6 mo Comparison of CCM delivery via 2- Yes Change in each Reduction in NYHA class (0.70.5 vs 0.90.7; P < Peak VO2 improvement in both groups was not
lead system vs 1-lead system group compared to .05) and MLWHFQ (14  20 vs 1622; P < .05) significant
baseline
Müller et al,47 2017 143 6, 12, 18, and Prospective registry evaluating the No Baseline Improvement in MLWHFQ, NYHA class, and LVEF at Overall survival at 24 mo was 86.4% (95% CI,
24 mo effect of CCM on outcomes by 24 mo (P < .001 for all) 79.3-91.2)
LVEF subgroup
Abraham et al,25 160 6 mo Confirm CCM efficacy in patients Yes Control Increase in peak VO2 of 0.84 mL/kg/min (95% Composite decrease in CV death and HF
2018 (FIX-HF-5C) with LVEF between 25% and 45% in Bayesian credible interval 0.123 to 0.1552) hospitalizations (10.8% to 2.9%; P ¼ .048)
patients with NYHA III-IV
Kuschyk et al,48 17 6 mo Efficacy of CCM in CRT No Baseline Increase in peak VO2 (1.1  1.6 mL/kg/min; P ¼ .03) Mean NYHA class and 6MWT also significantly
2019 nonresponders and MLWHFQ (16  6; P < .01) improved
(continued on next page)
 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176 5

including mortality and hospitalizations is suggested by some ran-

questionnaire; LVEF, left ventricular ejection fraction; MAGGIC, Meta-Analysis Global Group in Chronic Heart Failure; LVESV, left ventricular end systolic volume; MLWHFQ, Minnesota Living With Heart Failure Questionnaire;
6MWT, 6-minute walk time; CCM, cardiac contractility modulation; CRT, cardiac resynchronization therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; KCCQ, Kansas City Cardiomyopathy
Estimated survival was significantly better than
predicted at 1 and 3 y in the entire cohort. HF
domized trials and retrospective studies,25,43–45,49 but requires veri-

Survival significantly better than predicted by

hospitalizations significantly decreased in the

Decreased CCM-related adverse events with
2-lead system compared with 3-lead system
SHFM in patients with LVEF 35-45 (88% vs
fication and further study in prospective, randomized controlled
trials.

Future directions
(0% vs 8%; P ¼ .03)
Additional findings

Accruing evidence suggests that CCM may fill the gap in device-
74.7%; P ¼ .046)

overall cohort.
based HF therapy for patients with HFrEF and HFmrEF who are not
candidates for CRT or are CRT nonresponders. The available evidence
comes from modestly sized trials with relatively short duration of follow-
up, and it remains unknown whether there is an improved benefit over
—

longer time periods and whether CCM increases LVEF, exerts effects on
Improvement in MLWHFQ, NYHA class, and LVEF at

Improvement in MLWHFQ, NYHA class, and LVEF at

reverse remodeling, and improves cardiovascular outcomes. Impor-

Improvement in KCCQ score (18  16.6; P < .001)

tantly, increases in peak VO2 have been shown to improve clinical

Increase in peak VO2 of 1.72 mL/kg/min (95%

outcomes in HF patients,57 and it is possible that the improvement in

peak VO2 with CCM may signify that better cardiovascular outcomes
will be observed in larger prospective studies.
Bayesian credible interval 1.02-2.42)

Technological advances are likely to increase the feasibility,

compatibility, and safety profile of CCM in HF patients, especially those
who require additional indwelling cardiac devices (eg, PPM or ICD). One
24 mo (P < .001 for all)

NYHA, New York Heart Association; OMT, optimal medical therapy; SHFM, Seattle Heart Failure Model; VO2, myocardial oxygen consumption.

randomized study of 48 patients assessed the safety and efficacy of CCM

3 y (P < .001 for all)

therapy delivered through 1 vs 2 leads and showed similar improvement

Primary outcome

in NYHA class, MLWHFQ score, and Peak VO2.46 Decreasing the number
of leads required may reduce the risk of infection and tricuspid regur-
gitation as well as venous occlusion. Furthermore, combination devices
may further reduce the need for multiple leads, indwelling generators,
and procedures. Recently, the first combined CCM-ICD device (Opti-
mizer Integra CCM-D system) was implanted,58 and a multicenter trial
Comparison group

(INTEGRA-D) investigating this therapy is enrolling.

Control group of

Baseline (overall

Recently, a pilot study (CCM-HFpEF) was conducted in 47 patients

FIX-HF-5C

with HFpEF and NYHA class II or III symptoms demonstrated an

Baseline

Baseline
cohort)

improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ)

summary score,51,59 suggesting that the benefits of CCM may extend to
the growing population of patients with HFpEF. The ongoing AIM
HIGHer Clinical Trial (NCT 05064709) is a prospective, multicenter
Randomized

randomized controlled trial in patients with LVEF 40% and
60% and
(Yes/No)

is expected to enroll 1500 participants with an estimated completion

No

No

No

No

date in 2026, and will lend valuable insight into the role of CCM in this
population.60 In addition, a recent review by Riccardi et al expands
patients with HF and an EF
45%.

Pilot study of CCM in patients with

upon the rationale and role of CCM in patients with HFpEF, highlighting
Safety and efficacy of 2-lead CCM

Registry of patients with CCM by

LVEF (
25%, 26%-34%, 35%)
Prospective registry of CCM in

the potential impact of CCM therapy on calcium homeostasis, reverse

remodeling, and favorable clinical outcomes after CCM therapy in
patients with HFpEF.61
HFpEF (LVEF 50%)

Accruing evidence suggests that CCM may be beneficial among

Clinical question

patients with HF across a broad range of LVEF. However, the mechanism

through which CCM exerts its beneficial effects remains incompletely
understood and is an area for future study. In addition, despite evidence
system

that CCM improves outcomes such as quality of life, NYHA class, and
peak VO2, much of the data comes from meta-analyses and secondary
end points of randomized controlled trials. More studies are needed to
6, 12, 18, and

determine whether CCM therapy improves long-term outcomes

Follow-up

including mortality, cardiovascular death, and HF hospitalizations.

24 mo
6 mo

6 mo
3y

Conclusion
140

503
60

47
n
Table 1 (continued )

CCM represents a unique device-based therapy for patients with

Wiegn et al,34 2020

2021 (CCM-REG)
Anker et al,49 2019

Linde et al,51 2022

HF. There is robust evidence to suggest improved quality of life and

(CCM-REG25-45)

(CCM-HFpEF)
Kuschyk et al,50
(FIX-HF-5C2)

functional status with CCM, and future trials are needed to confirm
benefits on mortality, hospitalization, and the use of CCM in patients
with HFpEF. CCM should be considered in patients with HFrEF and
Study

HFmrEF who have a narrow QRS complex and are symptomatic despite
OMT.
6 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176

Central Illustration.
Cardiac contractility modulation. Device specifications for the Optimizer Smart Mini device, clinical benefits, potential mechanisms, and approved indications are shown.
Acknowledgement: Giorgio A. Medranda, MD, constructed the final Central Illustration.

Declaration of competing interest 2. Mohebi R, Chen C, Ibrahim NE, et al. Cardiovascular disease projections in the
United States based on the 2020 census estimates. J Am Coll Cardiol. 2022;80(6):
565–578. https://doi.org/10.1016/j.jacc.2022.05.033
Theofanie Mela reports the following disclosures: Medtronic 3. Heidenreich PA, Fonarow GC, Opsha Y, et al. Economic issues in heart failure in the
speaker honoraria and consultation fees, Biotronik speaker honoraria United States. J Card Fail. 2022;28(3):453–466. https://doi.org/10.1016/
and consultation fees, and Abbott consultation fees. The other authors j.cardfail.2021.12.017
4. Schwinger RHG. Pathophysiology of heart failure. Cardiovasc Diagn Ther. 2021;
have no outside interests to disclose. 11(1):263–276. https://doi.org/10.21037/cdt-20-302
5. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the
management of heart failure: A report of the American College of Cardiology/
Funding sources American Heart Association joint committee on clinical practice guidelines.
Circulation. 2022;145(18):e895–e1032. https://doi.org/10.1161/CIR.00000000000
01063
This research did not receive any specific grant from funding 6. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved
agencies in the public, commercial, or not-for-profit sectors. ejection fraction. N Engl J Med. 2021;385(16):1451–1461. https://doi.org/10.1056/
NEJMoa2107038
7. Zweier JL, Chen CA, Talukder MA. Cardiac resynchronization therapy and
Ethics statement and patient consent reverse molecular remodeling: importance of mitochondrial redox signaling.
Circ Res. 2011;109(7):716–719. https://doi.org/10.1161/CIRCRESAHA.111.
253864
The research reported here has adhered to the relevant ethical 8. Sharif ZI, Galand V, Hucker WJ, Singh JP. Evolving cardiac electrical therapies for
guidelines. advanced heart failure patients. Circ Arrhythm Electrophysiol. 2021;14(4),
e009668. https://doi.org/10.1161/CIRCEP.120.009668
9. Jaffe LM, Morin DP. Cardiac resynchronization therapy: history, present status, and
References future directions. Ochsner J. 2014;14(4):596–607.
1. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics—2021 10. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-resynchronization therapy in
update. Circulation. 2021;143(8):e254–e743. https://doi.org/10.1161/CIR.000000 heart failure with a narrow QRS complex. N Engl J Med. 2013;369(15):
0000000950 1395–1405. https://doi.org/10.1056/NEJMoa1306687
 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176 7

11. García-Pinilla JM, Jim enez-Navarro MF, Anguita-S 

anchez M, Martínez-Martínez A, reduced ejection fraction. J Clin Med. 2022;11(19):5866. https://doi.org/10.3390/
Torres-Calvo F. How many patients admitted for heart failure are eligible for jcm11195866
cardiac resynchronization therapy? Analysis of the Andalusian heart failure registry 34. Wiegn P, Chan R, Jost C, et al. Safety, performance, and efficacy of cardiac
(RAIC) study. Rev Esp Cardiol (Engl Ed). 2007;60(1):38–44. https://doi.org/ contractility modulation delivered by the 2-lead Optimizer Smart System: the FIX-
10.1016/S1885-5857(07)60104-2 HF-5C2 study. Circ Heart Fail. 2020;13(4):e006512. https://doi.org/10.1161/
12. European Society of Cardiology (ESC). European Heart Rhythm Association (EHRA), CIRCHEARTFAILURE.119.006512
Brignole M, et al. 2013 ESC guidelines on cardiac pacing and cardiac 35. Kloppe A, Mijic D, Schiedat F, et al. A randomized comparison of 5 versus 12 hours
resynchronization therapy: the task force on cardiac pacing and resynchronization per day of cardiac contractility modulation treatment for heart failure patients: a
therapy of the European Society of Cardiology (ESC). Developed in collaboration preliminary report. Cardiol J. 2016;23(1):114–119. https://doi.org/10.5603/
with the European Heart Rhythm Association (EHRA). Europace. 2013;15(8): CJ.a2015.0073
1070–1118. https://doi.org/10.1093/europace/eut206 36. Abi-Samra F, Gutterman D. Cardiac contractility modulation: a novel approach for
13. Wijesuriya N, Elliott MK, Mehta V, et al. Pacing interventions in non-responders to the treatment of heart failure. Heart Fail Rev. 2016;21(6):645–660. https://doi.org/
cardiac resynchronization therapy. Front Physiol. 2023;14, 1054095. https://doi.org/ 10.1007/s10741-016-9571-6
10.3389/fphys.2023.1054095 37. Kuschyk J, Kloppe A, Schmidt-Schweda S, Bonnemeier H, Rousso B, R€ oger S.
14. Daubert C, Behar N, Martins RP, Mabo P, Leclercq C. Avoiding non-responders to Cardiac contractility modulation: A technical guide for device implantation. Rev
cardiac resynchronization therapy: a practical guide. Eur Heart J. 2017;38(19): Cardiovasc Med. 2017;18(1):1–13. https://doi.org/10.3909/ricm0825
1463–1472. https://doi.org/10.1093/eurheartj/ehw270 38. Hesselson AB. Cardiac contractility modulation: A technical review. J Innov Card
15. Duncker D, Bauersachs J. Current and future use of neuromodulation in heart Rhythm Manag. 2022;13(10):5205–5218. https://doi.org/10.19102/icrm.2022.13102
failure. Eur Heart J Suppl. 2022;24(Supplement E):E28–E34. https://doi.org/ 39. Stix G, Borggrefe M, Wolpert C, et al. Chronic electrical stimulation during the
10.1093/eurheartjsupp/suac031 absolute refractory period of the myocardium improves severe heart failure. Eur
16. Wood EH, Heppner RL, Weidmann S. Inotropic effects of electric currents. I. Positive Heart J. 2004;25(8):650–655. https://doi.org/10.1016/j.ehj.2004.02.027
and negative effects of constant electric currents or current pulses applied during 40. Neelagaru SB, Sanchez JE, Lau SK, et al. Non-excitatory, cardiac contractility
cardiac action potentials. II. Hypotheses: calcium movements, excitation- modulation electrical impulses: feasibility study for advanced heart failure in
contraction coupling and inotropic effects. Circ Res. 1969;24(3):409–445. https:// patients with normal QRS duration. J Card Fail. 2006;12(6):S74. https://doi.org/
doi.org/10.1161/01.res.24.3.409 10.1016/j.cardfail.2006.06.251
17. Lyon AR, Samara MA, Feldman DS. Cardiac contractility modulation therapy in 41. N€agele H, Behrens S, Eisermann C. Cardiac contractility modulation in non-
advanced systolic heart failure. Nat Rev Cardiol. 2013;10(10):584–598. https:// responders to cardiac resynchronization therapy. Europace. 2008;10(12):
doi.org/10.1038/nrcardio.2013.114 1375–1380. https://doi.org/10.1093/europace/eun257
18. Burkhoff D, Shemer I, Felzen B, et al. Electric currents applied during the refractory 42. Borggrefe MM, Lawo T, Butter C, et al. Randomized, double blind study of non-
period can modulate cardiac contractility in vitro and in vivo. Heart Fail Rev. 2001; excitatory, cardiac contractility modulation electrical impulses for symptomatic heart
6(1):27–34. https://doi.org/10.1023/a:1009851107189 failure. Eur Heart J. 2008;29(8):1019–1028. https://doi.org/10.1093/eurheartj/ehn020
19. Tsch€ ope C, Kherad B, Klein O, et al. Cardiac contractility modulation: mechanisms 43. Kuschyk J, Roeger S, Schneider R, et al. Efficacy and survival in patients with cardiac
of action in heart failure with reduced ejection fraction and beyond. Eur J Heart Fail. contractility modulation: long-term single center experience in 81 patients. Int J
2019;21(1):14–22. https://doi.org/10.1002/ejhf.1349 Cardiol. 2015;183:76–81. https://doi.org/10.1016/j.ijcard.2014.12.178
20. Mohri S, Shimizu J, Mika Y, et al. Electric currents applied during refractory period 44. Kloppe A, Lawo T, Mijic D, Schiedat F, Muegge A, Lemke B. Long-term survival with
enhance contractility and systolic calcium in the ferret heart. Am J Physiol Heart cardiac contractility modulation in patients with NYHA II or III symptoms and normal
Circ Physiol. 2003;284(4):H1119–H1123. https://doi.org/10.1152/ajpheart.003 QRS duration. Int J Cardiol. 2016;209:291–295. https://doi.org/10.1016/
78.2002 j.ijcard.2016.02.001
21. Brunckhorst CB, Shemer I, Mika Y, Ben-Haim SA, Burkhoff D. Cardiac contractility 45. Liu M, Fang F, Luo XX, et al. Improvement of long-term survival by cardiac
modulation by non-excitatory currents: studies in isolated cardiac muscle. Eur J contractility modulation in heart failure patients: A case-control study. Int J
Heart Fail. 2006;8(1):7–15. https://doi.org/10.1016/j.ejheart.2005.05.011 Cardiol. 2016;206:122–126. https://doi.org/10.1016/j.ijcard.2016.01.071
22. Imai M, Rastogi S, Gupta RC, et al. Therapy with cardiac contractility modulation 46. R€oger S, Said S, Kloppe A, et al. Cardiac contractility modulation in heart failure
electrical signals improves left ventricular function and remodeling in dogs with patients: randomized comparison of signal delivery through one vs. two ventricular
chronic heart failure. J Am Coll Cardiol. 2007;49(21):2120–2128. https://doi.org/ leads. J Cardiol. 2017;69(1):326–332. https://doi.org/10.1016/j.jjcc.2016.06.015
10.1016/j.jacc.2006.10.082 47. Müller D, Remppis A, Schauerte P, et al. Clinical effects of long-term cardiac
23. Pappone C, Augello G, Rosanio S, et al. First human chronic experience with cardiac contractility modulation (CCM) in subjects with heart failure caused by left
contractility modulation by nonexcitatory electrical currents for treating systolic ventricular systolic dysfunction. Clin Res Cardiol. 2017;106(11):893–904. https://
heart failure: mid-term safety and efficacy results from a multicenter study. doi.org/10.1007/s00392-017-1135-9
J Cardiovasc Electrophysiol. 2004;15(4):418–427. https://doi.org/10.1046/j.1540- 48. Kuschyk J, N€ agele H, Heinz-Kuck K, et al. Cardiac contractility modulation treatment
8167.2004.03580.x in patients with symptomatic heart failure despite optimal medical therapy and
24. Kadish A, Nademanee K, Volosin K, et al. A randomized controlled trial evaluating cardiac resynchronization therapy (CRT). Int J Cardiol. 2019;277:173–177. https://
the safety and efficacy of cardiac contractility modulation in advanced heart doi.org/10.1016/j.ijcard.2018.10.086
failure. Am Heart J. 2011;161(2):329–337.e1. https://doi.org/10.1016/j.ahj.2010. 49. Anker SD, Borggrefe M, Neuser H, et al. Cardiac contractility modulation improves
10.025 long-term survival and hospitalizations in heart failure with reduced ejection
25. Abraham WT, Kuck KH, Goldsmith RL, et al. A randomized controlled trial to fraction. Eur J Heart Fail. 2019;21(9):1103–1113. https://doi.org/10.1002/ejhf.1374
evaluate the safety and efficacy of cardiac contractility modulation. JACC Heart 50. Kuschyk J, Falk P, Demming T, et al. Long-term clinical experience with cardiac
Fail. 2018;6(10):874–883. https://doi.org/10.1016/j.jchf.2018.04.010 contractility modulation therapy delivered by the Optimizer Smart system. Eur J
26. Katz AM. Molecular and cellular basis of myocardial contractility. In: Rosendorff C, Heart Fail. 2021;23(7):1160–1169. https://doi.org/10.1002/ejhf.2202
ed. Essential Cardiology: Principles and Practice. Springer; 2013:19–30. https:// 51. Linde C, Grabowski M, Ponikowski P, Rao I, Stagg A, Tsch€ ope C. Cardiac
doi.org/10.1007/978-1-4614-6705-2_2 contractility modulation therapy improves health status in patients with heart
27. Eisner DA, Caldwell JL, Kistamas K, Trafford AW. Calcium and excitation- failure with preserved ejection fraction: a pilot study (CCM-HFpEF). Eur J Heart
contraction coupling in the heart. Circ Res. 2017;121(2):181–195. https://doi.org/ Fail. 2022;24(12):2275–2284. https://doi.org/10.1002/ejhf.2619
10.1161/CIRCRESAHA.117.310230 52. Minnesota Living with HEART FAILURE® Questionnaire (MLHFQ) available from
28. Azevedo PS, Polegato BF, Minicucci MF, Paiva SAR, Zornoff LAM. Cardiac Technology Commercialization. Accessed June 14, 2023. https://license.umn.edu/
remodeling: concepts, clinical impact, pathophysiological mechanisms and product/minnesota-living-with-heart-failure-questionnaire-mlhfq
pharmacologic treatment. Arq Bras Cardiol. 2016;106(1):62–69. https://doi.org/ 53. Abraham WT, Nademanee K, Volosin K, et al. Subgroup analysis of a randomized
10.5935/abc.20160005 controlled trial evaluating the safety and efficacy of cardiac contractility
29. Borggrefe M, Mann DL. Cardiac contractility modulation in 2018. Circulation. modulation in advanced heart failure. J Card Fail. 2011;17(9):710–717. https://
2018;138(24):2738–2740. https://doi.org/10.1161/CIRCULATIONAHA.118. doi.org/10.1016/j.cardfail.2011.05.006
036460 54. Impulse Dynamics. Impulse Dynamics receives FDA approval for breakthrough
30. Yu CM, Chan JYS, Zhang Q, et al. Impact of cardiac contractility modulation on left Optimizer® Smart System delivering CCMTM therapy for treatment of heart failure.
ventricular global and regional function and remodeling. JACC Cardiovasc Imaging. March 21, 2019. Accessed June 14, 2023. https://impulse-dynamics.com/blog
2009;2(12):1341–1349. https://doi.org/10.1016/j.jcmg.2009.07.011 /2019/03/21/impulse-dynamics-receives-fda-approval-for-breakthrough-optimizer-
31. Butter C, Rastogi S, Minden HH, Meyh€ ofer J, Burkhoff D, Sabbah HN. Cardiac smart-system-delivering-ccm-therapy-for-treatment-of-heart-failure/.
contractility modulation electrical signals improve myocardial gene expression in 55. Giallauria F, Cuomo G, Parlato A, Raval NY, Kuschyk J, Stewart Coats AJ.
patients with heart failure. J Am Coll Cardiol. 2008;51(18):1784–1789. https:// A comprehensive individual patient data meta-analysis of the effects of cardiac
doi.org/10.1016/j.jacc.2008.01.036 contractility modulation on functional capacity and heart failure-related quality of
32. Goliasch G, Khorsand A, Schütz M, et al. The effect of device-based cardiac life. ESC Heart Fail. 2020;7(5):2922–2932. https://doi.org/10.1002/ehf2.12902
contractility modulation therapy on myocardial efficiency and oxidative 56. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and
metabolism in patients with heart failure. Eur J Nucl Med Mol Imaging. 2012; treatment of acute and chronic heart failure: the Task Force for the diagnosis and
39(3):408–415. https://doi.org/10.1007/s00259-011-1977-8 treatment of acute and chronic heart failure of the European Society of
33. Masarone D, Kittleson MM, De Vivo S, et al. The effects of device-based cardiac Cardiology (ESC)Developed with the special contribution of the Heart Failure
contractility modulation therapy on left ventricle global longitudinal strain and Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–2200. https://
myocardial mechano-energetic efficiency in patients with heart failure with doi.org/10.1093/eurheartj/ehw128
8 D.C. Pipilas et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101176

57. Swank AM, Horton J, Fleg JL, et al. Modest increase in peak VO2 is 60. Impulse dynamics. Assessment of CCM in HF With Higher Ejection Fraction (AIM
related to better clinical outcomes in chronic heart failure patients. Circ HIGHer). ClinicalTrials.gov identifier: NCT05064709. Accessed May 2, 2023.
Heart Fail. 2012;5(5):579–585. https://doi.org/10.1161/CIRCHEARTFAILURE. https://classic.clinicaltrials.gov/ct2/show/NCT05064709
111.965186 61. Riccardi M, Sammartino AM, Adamo M, et al. Cardiac contractility modulation: an
 Impulse Dynamics announces first implantation of combined CCM and
58. Malpass E. effective treatment strategy for heart failure beyond reduced left ventricular
ICD device. Cardiac Rhythm News. May 18, 2023. Accessed June 14, 2023. ejection fraction? Heart Fail Rev. 2023;28(5):1141–1149. https://doi.org/10.1007/
https://cardiacrhythmnews.com/impulse-dynamics-announces-first-implantation-of- s10741-023-10315-4
combined-ccm-and-icd-device/. 62. Schau T, Seifert M, Meyh€ ofer J, Neuss M, Butter C. Long-term outcome of cardiac
59. Spertus JA, Jones PG, Sandhu AT, Arnold SV. Interpreting the Kansas City contractility modulation in patients with severe congestive heart failure. Eur Eur
cardiomyopathy questionnaire in clinical trials and clinical care: JACC state-of- Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card
the-art review. J Am Coll Cardiol. 2020;76(20):2379–2390. https://doi.org/ Cell Electrophysiol Eur Soc Cardiol. 2011;13(10):1436–1444. https://doi.org/
10.1016/j.jacc.2020.09.542 10.1093/europace/eur153