REVIEW

CURRENT
OPINION The emerging role of cardiac contractility
modulation in heart failure treatment
Ikeotunye R. Chinyere, Mahesh Balakrishnan, and Mathew D. Hutchinson

Purpose of review
Heart failure often progresses despite optimal medical and device therapies, and advanced mechanical
circulatory support has limited availability and substantial associated morbidity. Cardiac contractility
modulation (CCM) provides nonexcitatory stimulation to ventricular myocardium which increases cardiac
contractility without increasing oxygen demand. This review describes the emerging role of CCM in heart
failure treatment.
Recent findings
The FIX-HF-5C2 study demonstrated similar safety and efficacy profile of the two-lead Optimizer device in
comparison with the prior three-lead system, thereby decreasing procedural complexity and minimizing
endocardial hardware. The FIX-HF-5C trial underscored the benefit of CCM in patients with mild-moderate
left ventricular dysfunction (ejection fraction, 25–45%) with New York Heart Association (NYHA) Class III
symptoms. The summarized randomized trial data show consistent improvements in peak VO2, 6-min walk
distance, and NYHA functional class with CCM. Future trials are planned to determine the role of CCM in
heart failure patients with preserved ejection fraction, obligate ventricular pacing, and atrial arrhythmias.
Summary
Nonexcitatory extracellular electric potentials can facilitate inotropic improvements in the failing heart. The
mechanism of CCM does not increase myocardial oxygen consumption and has been shown to mitigate
heart failure symptoms, decrease hospitalizations, and work in synergy with guideline-directed therapy for
heart failure.
Keywords
congestive heart failure, heart contractility, medical devices

INTRODUCTION advanced mechanical support is limited, with only

Heart failure is a significant public health burden,
affecting approximately 6 million Americans today
[1,2]. Risk factors for heart failure, including coro-
nary artery disease, diabetes, obesity, and hyperten-
sion are increasingly prevalent. Optimal medical
therapy for heart failure targeting neurohumoral
pathways has reduced the mortality and morbidity
associated with heart failure, decreased hospitaliza-
tions, and improved quality of life in many patients.
However, despite these advancements, heart failure-
related mortality remains high with an estimated
10-year survival of 35% [3].
Advanced heart failure, defined as severe symp-
toms despite optimal medical and device therapy,
affects up to 25% of heart failure patients [4,5].
Treatments for such patients are limited to palliative
inotrope therapy, mechanical circulatory support,
or cardiac transplantation [6]. Inotropes increase
mortality and the risk of life-threatening arrhyth-
mias, with less than 40% 1-year survival. Access to
3000 left ventricular (LV) assist devices and cardiac
transplants performed annually [7]. Although cardiac
conduction abnormalities are present in one-third of
heart failure patients, cardiac resynchronization ther-
apy (CRT) is currently indicated in a minority of such
patients and has shown a consistent lack of response
in 30% of implanted patients [8]. Therefore, many
patients with advanced heart failure lack effective
treatment options, committing them to progressive
and intractable symptoms. The purpose of this review
Division of Cardiovascular Medicine, University of Arizona College of
Medicine – Tucson, Tucson, Arizona, USA
Correspondence to Mathew D. Hutchinson, MD, Director, Cardiac
Electrophysiology, Sarver Heart Center, Division of Cardiovascular Med-
icine, University of Arizona College of Medicine – Tucson, 1501 North
Campbell Avenue, Room 4142B, Tucson, AZ 85724, USA.
Tel: +1 520 626 8615; e-mail: MathewHutchinson@shc.arizona.edu
Curr Opin Cardiol 2022, 37:30–35
DOI:10.1097/HCO.0000000000000929

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 Cardiac contractility modulation in heart failure Chinyere et al.
KEY POINTS
 CCM therapy consists of nonexcitatory stimulation of
ventricular myocardium resulting in increased
contractile force without a concomitant increase in
myocardial oxygen demand.
 CCM improves calcium handling in the failing ventricle
and alters adverse gene expression seen in heart
failure patients.
 CCM is delivered via a cardiovascular implantable
electronic device that is similar in design to a
traditional pectoral pacemaker system however the
pulse generator is recharged transcutaneously.
 Several randomized trials have shown modest
improvements in peak VO2, NYHA functional class, 6-
min walk test distance, and quality of life indices in
CCM-treated patients; these improvements appear to be
most consistent in patients with severe heart failure
symptoms and left ventricular ejection fraction between
25 and 45%.
is to discuss the emerging role of cardiac contractility
modulation (CCM) in contemporary heart failure
management.
PHYSIOLOGY OF CARDIAC
CONTRACTILITY MODULATION IN HEART
FAILURE
The technique of CCM is based upon early ex vivo
observations that delivering monophasic currents to
canine ventricular myocardium during mechanical
systole, but after completion of the absolute refrac-
tory period, produced a propagated depolarization
of the ventricles without a second cardiac contrac-
tion [9]. This prolonged action potential duration
and increased both LV pressure and myocardial
contractile force [10]. These effects occurred imme-
diately upon initiation of stimulation and resolved
rapidly after its cessation. The early effects of
CCM on ventricular myocardium were ascribed to
improved calcium handling. Supporting this
hypothesis was the observation that treatment with
ryanodine or L-type calcium channel blockade
mitigated the CCM effect on contractility [11]. Sub-
sequent in vivo studies in a canine ischemic heart
failure model demonstrated that dogs treated with
CCM had a persistent increase in levels of SERCA-2a
and phosphorylated phospholamban at 3 months;
these levels were similar to those seen in control
animals [12]. Similar findings were demonstrated
in humans with systolic heart failure [13]. The
CCM-treated dogs also had sustained improvement
in LV function, decreased LV end-diastolic pressure,
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Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
and improvement in the degree of adverse LV
remodeling. Importantly, no proarrhythmic effect
was seen with CCM delivery. Invasive studies in
both canine models and human heart failure have
also shown no effect of CCM on myocardial oxygen
consumption [14,15].
OPTIMIZER DEVICE DESIGN AND
IMPLANTATION
Delivery of CCM is achieved through direct cardiac
stimulation with a cardiovascular implantable elec-
tronic device (CIED) known as the Optimizer Smart
system (Impulse Dynamics USA, Orangeburg, New
York). The Optimizer technology has undergone sev-
eral iterations since its conception nearly 2 decades
ago. The current device consists of a pulse generator
and two active fixation IS-1 bipolar pacing leads. The
device is implanted in a similar fashion as traditional
pacemakers and defibrillators, although a right pec-
toral approach is typically utilized due to the presence
of contemporaneous implanted devices (Fig. 1).
The original Optimizer design included a dedi-
cated third lead for atrial sensing, however the more
contemporary design eliminated the need for atrio-
ventricular timing. The subsequent FIX-HF-5C2 study
showed no decrease in CCM delivery with the two-
&
lead compared with the three-lead system [16 ]. The
Optimizer device delivers two biphasic pulses at up to
7.5 V and 20 ms total duration to the right ventricular
septum during its absolute refractory period. CCM
therapy is delivered up to 12 h a day. In contrast to
other CIEDs, the Optimizer pulse generator requires
manual transcutaneous recharging by the patient.
The battery voltage at full charge is approximately
4.1 V, and recharging is recommended at or below
3.5 V. Routine recharging is done weekly and requires
approximately 1 h to complete.
CLINICAL EVIDENCE FOR CARDIAC
CONTRACTILITY MODULATION THERAPY
Several clinical trials have outlined the benefits of
CCM in heart failure patients (Table 1). FIX-HF-3 was
a small observational study from 2004 that included
25 patients with drug refractory New York Heart
Association (NYHA) Class III heart failure with LV
ejection fraction 35% or less, in sinus rhythm with
QRS duration less than 140 ms, and on optimal
medical therapy [17]. Two-dimensional echocardiog-
raphy was used to measure the LV ejection fraction
(LVEF) at baseline and at least 12 h after CCM stimu-
lation. NYHA functional class, Minnesota Living
with Heart Failure Questionnaire score (MLWHFQ),
6-min walk test (6MWT), ventricular ectopy and
CCM-associated symptoms were also monitored.
www.co-cardiology.com 31
Arrhythmias

FIGURE 1. Optimizer smart system dimensions and implantation. (a) The optimizer smart device consists of a rechargeable
pulse generator and two active fixation IS-1 bipolar endocardial pacing leads affixed to the right ventricular septum. (b) The
optimizer mini charger permits weekly transcutaneous recharging of the pulse generator. (c) Anteroposterior chest radiograph
showing typical right pectoral location of optimizer pulse generator and leads. A contemporaneous left pectoral single
chamber implantable defibrillator is also present. (d) A 12-lead ECG taken during cardiac contractility modulation delivery.
Images (c) and (d) courtesy of George Yesenosky, MD.

LVEF improved from 22  7 to 28  8% (P ¼ 0.0002),
MLWHFQ improved from 43  22 to 25  18%
(P ¼ 0.001) and the 6MWT increased from 411  86
to 465  81 m (P ¼ 0.02) in these patients after 8 weeks
of CCM therapy. Two patients suffered sudden death
during follow-up, neither occurring during CCM
stimulation. 35% reported intermittent mild sensa-
tions with CCM signal application. A small subse-
quent randomized pilot study of 49 patients showed a
nonsignificant increase in 6MWT, peak VO2, and
aerobic threshold at 6 months [18].
FIX-HF-4 (2008) was a larger randomized trial
that sought to evaluate the safety and efficacy of
CCM [19]. It was a multicenter, randomized, double
blind, crossover design which included 164 patients
with NYHA Class II to IV heart failure with LVEF or
less 35%, peak oxygen uptake (peak VO2) between
10 and 20 ml O2/min/kg on optimal medical ther-
apy. A total of 178 patients underwent attempted
device implantation however 12 were withdrawn
due to lack of acute effect of CCM on dP/dtmax.
Two patients died within 1 week of device implan-
tation. The remaining 164 patients were random-
ized to either active or sham CCM therapy. The
device was programmed to deliver CCM signals
for seven 1-h periods spaced equally over a day in
the treatment group and turned off in the sham
group for the first 12 weeks. Subsequently, all par-
ticipants were crossed over to the other treatment
group. The primary endpoints included change in
peak VO2 and MLWHFQ at 12 and 24 weeks. Overall,
there was a significant increase in peak VO2
[0.52  1.39 O2/kg/min, P ¼ 0.032 (0.04–0.99)] and
MLWHFQ [2.93  8.0, P ¼ 0.030 (0.29–5.56)] on
treatment compared with sham. There was an initial
increase in peak VO2, MLWHFQ and 6MWT at
12 weeks in both treatment and sham groups, how-
ever patients who were switched to sham during
phase 2 of the trial had a significant decline in all
three indices. There was no significant difference
between groups in number of serious adverse events,
arrhythmia or other Holter parameters.

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 Table 1. Summary of outcomes in pivotal trials cardiac contractility modulation
Study name/type Study cohort Study design Clinical endpoints Results Adverse events

1. FIX-HF-3 [17] Inclusion criteria: Delivery of two biphasic, square-wave 1. LVEF LVEF improved from 22  7 to Two sudden deaths:
Multicenter observational -Ischemic and nonischemic signals of up to 7.73 V during the 2. NYHA classification 28  8% (P ¼ 0.0002) Ventricular
study (2004) cardiomyopathy absolute refractory period, 3 h/day 3. MLWHFQ Quality of life improved from Fibrillation and
Sample size ¼ 25 -HFrEF  35% on OMT  4 weeks between 7 p.m. and 10 p.m. 4. 6MWT 43  22 to 25  18% Asystole. Neither
-Sinus rhythm with QRS < 140 ms CCM signal generator (optimizer II 5. CCM-associated (P ¼ 0.001) during CCM
-NYHA class III device) symptoms 6MWT increased from 411  86 to therapy
Exclusion criteria: 8-week follow-up 6. Ventricular ectopy 465  81 m (P ¼ 0.02) Mild sensations in
-Sustained ventricular tachycardia 35% of cohort.
-Coronary revascularization within 3 Lead repositioning
months required in 1
-Patients eligible for CRT patient
2. FIX-HF-4 [19] Inclusion criteria: Randomized to 2 groups, 2–4 weeks 1. VO2 peak VO2 peak increased significantly in No significant
Multicenter, randomized, -Ischemic and nonischemic after optimizer system implant 2. MLWHFQ the therapy group compared differences between
double blind, cardiomyopathy Group 1: CCM signals delivered for 3. NYHA class with the sham group; the cohorts in the
crossover study (2008) -HFrEF  35% on OMT seven 1 h periods spaced equally 4. 6MWT 0.52  1.39 O2/kg/min number or types of
Sample size ¼ 164 -NYHA class  II over the day 5. Safety (t ¼ 2.16, P ¼ 0.032, 95% CI adverse events.
-VO2 peak: 10–20 ml O2/kg/min Group 2: device programmed to ‘OFF’ 0.04–0.99) No significant
Exclusion criteria: Phase 1: 12 weeks MLWHFQ-score also improved difference between
-AFib Phase 2: 12 weeks (participants significantly compared with the cohorts in
-Frequent ectopy crossed over to opposite treatment sham; 2.93  8.01 m (t ¼ 2.20, arrhythmias or other
-MI (<3 months) group) P ¼ 0.03, 95%CI 0.29–5.56) Holter parameters
-Clinically significant angina Data assessed with t-test No change in LVEF in either group
-HF requiring IV medication (<1 month) Similar improvement in NYHA class
-Eligible for CRT in both groups
3. FIX-HF-5 [20] Inclusion criteria: Randomized to OMT vs. OMT and Efficacy: No significant difference in CCM was non inferior
Prospective randomized -Ischemic and nonischemic CCM 1. Ventilatory anaerobic ventilatory anaerobic threshold to OMT for safety
controlled trial (2011) cardiomyopathy Optimizer system delivered CCM threshold (primary) between the two groups endpoints
Sample size ¼ 428 -Age  18 years signals for five 1 h periods 2. VO2 peak CCM significantly improved pVO2

0268-4705 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved.
-HFrEF  35% on OMT þ ICD, if indicated spaced equally throughout the day 3. MLWHFQ (6 months) by 0.65 ml/kg/min (P ¼ 0.024)
-Sinus rhythm, QRS <130 ms 12-month follow-up Safety: CCM improved MLWHFQ by 9.7
-NYHA class III, IV 1. All-cause mortality and points (P ¼ 0.0001) compared
-Baseline peak VO2  9 ml O2/kg/min hospitalizations with OMT
Exclusion criteria: (12 months)
-Hospitalized within 30 days of enrollment 2. Adverse events
-Inotrope dependence
->8900 PVCs/day on Holter
-Permanent AFib
-MI or CABG within 90 days
-PCI within 30 days
4. FIX-HF-5C [22] Inclusion criteria: Randomized to OMT vs. OMT and Efficacy: CCM significantly Composite of
Prospective randomized -Ischemic and nonischemic CCM 1. VO2 peak (primary) improved: cardiovascular
controlled trial (2018) cardiomyopathy Optimizer system delivered CCM 2. MLWHFQ 1. VO2 peak by 0.084 ml/kg/min death and HF
Sample size ¼ 160 -Age  18 years signals for five 1-h periods spaced 3. NYHA class (95% Bayesian credible interval: hospitalizations was
-HFrEF  25% and 45% on OMT þ ICD, equally throughout the day 4. 6MWT 0.123–1.552) reduced from 10.8
if indicated 2 Cardiopulmonary stress tests Safety: 2. MLWHFQ to 2.9% by CCM
-Sinus rhythm, QRS < 130 ms (averaged) were performed for each 1. All-cause mortality 3. NYHA class
-NYHA class III, IV patient at baseline and at the 12- 2. Cardiac mortality

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

and 24-week follow-up visits 3. All-cause hospitalization
Data assessed with Bayesian repeated 4. Cardiac hospitalization
measures linear modeling 5. HF hospitalization
6. Adverse events

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6MWT, 6-min walk test; AFib, atrial fibrillation; CABG, coronary artery bypass graft; CCM, cardiac contractility modulation; CI, confidence intervals; CRT, cardiac resynchronization therapy; HF, heart failure; HFrEF,
heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; IV, intravenous; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MLWHFQ, Minnesota Living with Heart Failure
Questionnaire; NYHA, New York Heart Association; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.
Cardiac contractility modulation in heart failure Chinyere et al.

33
Arrhythmias
The FIX-HF-5 trial (2011) was designed to assess
longer term outcomes in CCM treated patients in a
larger randomized controlled trial [20]. A total of
428 patients with NYHA Class III or IV heart failure,
LVEF 35% or less despite medical therapy with a
baseline peak VO2 of at least 9 ml O2/kg/min were
randomized to optimal medical therapy alone vs.
optimal medical therapy and CCM therapy. All
patients were in sinus rhythm and were not candi-
dates for CRT (QRS < 130 ms). Cardiopulmonary
exercise testing, MLWHFQ, 6MWT, NYHA func-
tional class, echocardiograms, and 24-h Holter mon-
itoring were performed at baseline, 3, and 6 months.
Patients randomized to the CCM group underwent
Optimizer device implantation and CCM signal
delivery for five 1-h periods spaced equally through-
out the day. The primary efficacy endpoint was
improvement in ventilatory anaerobic threshold
(VAT), and secondary efficacy endpoints included
peak VO2 and MLWHFQ. The primary safety end-
point was a composite of all-cause mortality and
hospitalization at 50 weeks. At 24 weeks, VAT
decreased 0.14 ml/kg/min in both CCM and medical
therapy cohorts. At 50 weeks, CCM treated patients
had a 9.3% higher response rate than medical ther-
apy patients (P ¼ 0.027). Although the peak VO2
increased by 0.65 ml/kg/min in the CCM group,
the proportion of patients deemed responders was
not statistically higher at 24 weeks. The study met its
primary safety endpoint. Notably, 95% of study
participants had implantable defibrillators present
during the study and the mean LVEF was 26% in
both groups.
A subgroup analysis of the FIX-HF-5 study
showed improved treatment effects on both primary
and secondary endpoints in the cohort of patients
with relative ejection fraction preservation (25–45%)
[21]. This observation prompted the FIX-HF-5C trial
(2018) which enrolled 160 patients in a prospective
randomized control trial with Bayesian statistical
analysis [22]. The primary efficacy endpoint of peak
VO2 was significantly higher in CCM treated patients
at 24 weeks (15.04 vs. 14.20 ml O2/kg/min, probabil-
ity of superiority 0.989) which was statistically sig-
nificant. Secondary endpoints of MLWHFQ and
NYHA functional class were also improved in the
CCM group. The treatment effects were more pro-
nounced in the subgroup of patients with LVEF
between 35 and 45%. Survival free of cardiac death
and heart failure hospitalization was reduced by 73%
(from 10.8 to 2.9%) in the CCM therapy group. No
significant difference in adverse events was noted
between the treatment groups.
The CCM-REG is a prospective European registry
including 51 centers, and recently reported 2-year
follow-up data in 503 patients with CCM devices
34 www.co-cardiology.com
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
[23]. Patients were stratified into tertiles of LVEF.
There was a consistent and significant improvement
in NYHA functional class, MLWHFQ, and LVEF in
each tertile. The improvement in ejection fraction
was most pronounced in the cohort with LVEF 25%
or less and was independent of atrial rhythm. CCM
treatment was also associated with a significant
decrease in hospitalization rate at 2 years. The
observed mortality rates at 2 and 3 years were sig-
nificantly lower in CCM-treated patients with LVEF
more than 25% compared with predictive models.
FUTURE STUDIES
Further studies are needed to determine the potential
benefit of CCM in patients with permanent atrial
fibrillation or ongoing ventricular pacing. The effect
of CCM in patients who are nonresponders to
CRT was evaluated in a multicenter, treatment only,
feasibility study of 17 patients [24]. Quality of life
(MLWHFQ) and exercise tolerance (change in peak
VO2) were determined at baseline and at 24 weeks.
CCM therapy showed sustained improvement in
quality of life, peak VO2 (1.1  1.6 ml/kg/min,
P ¼ 0.03), NYHA functional class, and a nonsignifi-
cant improvement in LVEF (2.9  5.8%, P ¼ 0.08).
CCM-HFpEF (NCT03240237) is an ongoing pilot
study to determine the safety and efficacy of CCM
in 60 patients with LVEF at least 50% and NYHA Class
II or III symptoms. Future studies will examine the
feasibility of delivering CCM through a single ventric-
ular lead, which may permit both CCM and defibril-
lation therapy to be delivered through a single lead.
CONCLUSION
In summary, CCM is a disruptive technology that
adds a novel treatment pathway in patients with
severe heart failure. In the United States, CCM is
currently indicated to improve quality of life, func-
tional capacity, and 6MWT distance in patients with
LVEF 25–45% and NYHA Class III heart failure
despite guideline directed medical therapy. Patients
must be in sinus rhythm and lack indication for
CRT. CCM requires a motivated patient given the
need to manually recharge the device. Considering
the high prevalence of contemporaneous CIED
implants in eligible patients, careful risk benefit
analysis is required due to an elevated risk of infec-
tion and lead-related complications.
Acknowledgements
None.
Financial support and sponsorship
None.
Volume 37  Number 1  January 2022
 Cardiac contractility modulation in heart failure Chinyere et al.
Conflicts of interest
There are no conflicts of interest.
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