Cardiac Contractility Modulation Therapy for Heart Failure – First Romanian Experience

Aim: The purpose of this study is to present the ﬁ rst Romanian case-series of patients with heart failure with reduced ejection fraction (HFrEF), supported with the newest generation of cardiac contractility modulation (CCM) device. Methods and results: Sixteen patients (15 men), aged 66.6±7.49 years, were supported with OPTIMIZER® smart IPG CCMX10 device and followed-up for an average duration of 385.75±326.32 days. The etiology of HF was ischemic in 13 patients (81%), 8 patients (50%) had atrial ﬁ brillation, mean creatinine clearance value was 55.8±13.87 ml/min, and 5 patients (31,2%) had diabetes mellitus. All patients were supported with an implanted cardio verter-deﬁ brillator (ICD), while 5 patients (31.2%) had cardiac resynchronization therapy (CRT) on top. The pharma cological treatment has been optimized in all patients. Six months after implantation, the LVEF has increased from 25.93%±6.21 to 35.5%±4.31 (p=0.00002), NYHA class improved from 3.18±0.4 to 1.83±0.38 (p<0.0001), and exercise tolerance evaluated with 6-minute walking test (6MWT) increased (from 321.87±70.63m to 521.41±86.43m; p<0,00001). Three patients (18,7%) died during the follow-up period after 48, 108 and 545 days (one non-cardiac death). Cardiac contractile therapy is a feasible, safe, and useful therapy for patients with HFrEF whose symptomatology is not improved with optimal standard therapy.


INTRODUCTION
Optimal treatment of heart failure (HF) includes, in addition to pharmacological treatment, implantable devices dedicated to correcting cardiac asynchronism and preventing sudden death 1 .
If ICDs had a favorably impact on sudden cardiac death 2,3 , devices dedicated for CRT still have notable defi ciencies with a signifi cant proportion of patients remaining symptomatic (about 30%, so-called "nonrespoders") 4 .
In addition, CRT is not suitable for about 70% of patients with HFrEF (patients with QRS ≤130 msec), meaning that most of these patients cannot be benefi ciaries of this kind of non-pharmacological therapy 5 .
Here, CCM therapy comes to cover a remarkable gap. Unlike a pacemaker or a defi brillator, the CCM device is designed to modulate the strength of the cardiac muscle rather than the rhythm, and it is applicable for patients with HF with functional NYHA class II to IV, reduced or mid-range (up to 45%) LVEF, and low range of ventricular ectopic beats (less than 10.000 per day). The modulation of the myocytes' contraction strength is made by the generation of non-excitatory high voltage impulses (between 4.0V and 7.5 V according to patient's tolerance, higher voltages being preferred). The stimulation train generally consists of two biphasic pulses having a total duration of 20.5-22.5 msec. Even though it is technically possible, the therapy is not required to be provided for 24 hours a day, thus it is provided at regular intervals throughout the day, for a total of 7 to 12 hours.
This novel device enhances cardiac contractility through a variety of processes [6][7][8] . They primarily involve: (1) acute alterations in intracellular calcium handling, due to up-regulation of L-type calcium channels and to an improved calcium uptake into the sarcoplasmic reticulum, (2) chronic alterations in the expression and phosphorylation of important calcium regulators, and (3) the most important mechanism seems to be related with reversal of the fetal maladaptative myocyte gene program associated with HF and normalizes expression of key sarcoplasmic reticulum Ca (2+) cycling and stretch response genes.
The device was fi rst created and designed for patients with sinus rhythm (SR) with a narrow QRS, but it was later modifi ed and adapted to be suitable for patients with atrial fi brillation (AF) as well as for nonresponders to CRT (patients with a wider QRS). THE AIM of this paper is to present the evolution of the fi rst series of patients in Romania who have benefi ted from the implant of a CCM device on top of the optimal standard pharmacological treatment, covering not only a proper medication, but also the recommended implantable devices (ICDs and CRT-Ds).

METHOD
Sixteen patients with clinically signifi cant symptomatic HFrEF (e.g., NYHA Class III or IV) despite an appropriate therapy for chronic HF (diuretic, beta-blocker, and ACE-inhibitor/ ARB and devices ICD or CRT-D), were supported with the latest generation CCM device-OPTIMIZER ® SMART IPG CCMX 10 (Impulse Dynamics (USA) Inc. Orangeburg, NY, USA).
All the patients had an initial evaluation before the implantation procedure consisted in the assessment of the NYHA functional class, medication, and an echocardiographic evaluation of the heart (including cavities measurements, LVEF and left ventricle volumes, mitral regurgitation, and tricuspid regurgitation), acquired with a Vivid 7 machine (GE Healthcare). Blood samples for routine analysis were also taken. A six-minute walk test (6MWT) was performed at the baseline and at least once during the 6-month follow-up assessments. The devices already implanted (implantable cardioverter-defi brillators (ICDs) or cardiac-resynchronization and defi brillators CRT-Ds) were interrogated. Other potential uncorrected causes of HF (e.g., treatable coronary lesions and frequent ventricular ectopy) were evaluated before the implant.
The details related to CCM device implantation were described elsewhere 9 .
Active CCM treatment was programmed to be delivered daily for at least 7 h, in equally spaced-out intervals throughout the day, with a voltage between 5 and 7.5 V, on one or two channels, according to the patient's tolerability, and to aim for at least a 40% CCM therapy delivery.
The ECG aspect of the CCM delivery in a patient with sinus rhythm is depicted in Figure 1.
Statistics: Student's t-test for matched pairs was used to determine whether differences in clinical and hemodynamic data were signifi cant. The mean and standard deviation is used to express all data.

RESULTS
A total of 16 subjects were supported with an Optimizer IPG device between November 2018 and May 2021. The mean follow-up time was 385.75±326.3 (15-896) days. The baseline characteristics of the enrolled patients are depicted in Table 1.
The mean age was 66.5±7.49 year and 15 patients were male. The etiology of HF was ischemic in 13 patients (81%) and non-ischemic in 3 patients (19%). History of previous myocardial infarction was recorded in 7 patients (43.7%) and 11 patients have had revascularization therapy (aorto-coronary by-pass in 4 patients and percutaneous angioplasty with stent implantation in 8 patients). One patient had both therapies. One third of patients had diabetes mellitus (5 patients), and hypertension was present in 3 patients. All off the patients had chronic kidney disease (7 patients stage two and 9 patients stage three) with mean creatinine clearance of 55.8±13.87 ml/min. Half of the patients had history of atrial fi brillation (AF), and two of them were in AF at the moment of device implantation. Five Three patients (18.7%) died during the follow-up period at 48, 108 and 545 days after the CCM implantation. The fi rst patient died of a severe cardio-renal syndrome with decreasing renal function and severe hyponatremia, and the second died of a non-cardiac cause (angiocolitis with septic shock). The third patient developed severe hypothyroidism as a result of autoimmune thyroiditis, was treated with corticotherapy, became decompensated, and died of irreversible cardiac pulmonary edema due to late hospital presentation in the context of COVID-19 pandemia.

DISCUSSIONS
Despite breakthroughs in pharmaceutical and nonpharmacological therapy during the previous decades, HF treatment has remained challenging. Although device therapy has shown to be effective, a considerable number of patients with HF continue to be sympto-patients were previously provided with CRT-D, and all the rest had ICDs.
The medical treatment was optimized, beta-blockers and mineralocorticoids antagonists were administered to all patients, and renin-angiotensin inhibitors in 14 patients (87.5%).
Six months after implantation, the LVEF has increased from 25.93%±6.21 to 35.5%±4.31 (p=0.00002), NYHA class improved from 3.18±0.4 to 1.83±0.38  increased exercise tolerance and quality of life, as well as fewer HF hospitalizations, as compared to patients who did not get CCM [10][11][12][13] . Further trials supported the earlier fi ndings, demonstrating that CCM improves peak oxygen consumption (VO 2 ), 6MWT distance, and quality of life [as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ)], and symptoms (NYHA class). Clinical advantages were found to be greater in a group of persons with an LVEF of 35% to 45% [14][15] .
Two other studies suggested that patients with a LVEF of 25% to 45% percent benefi t the most with CCM 16,17 , but more recent real-world trials revealing an even more dramatic effect in a subgroup of patients with an ejection fraction of 35 to 45 percent 18 .
CCM therapy was, for the fi rst time, included in the European Society of Cardiology's (ESC) 2016 guidelines for the diagnosis and treatment of acute and chronic heart failure being indicated for selected patients 1 .
Very recently, the long-term effects of cardiac contractility modulation delivered by the Optimizer Smart system were evaluated in a prospective registry (CCM-REG). The study included the highest number of patients (503) from 51 European centers, followed for the longest time (3 years), and spanning the widest range of LVEF. Many patients were having AF. Patients with atrial fi brillation (AF) and normal sinus rhythm were studied in three terciles of LVEF (25%, 26-34%, and >35%). Cardiac contractility modulation therapy matic despite optimal treatment, and only one-third of these patients may benefi t from CRT therapy.
In this fi eld, CCM represents an emergent therapy whose effi cacy and safety was fi rst evaluated in a small number of clinical trials, with results suggesting  increased functional status, quality of life, LVEF (even in those with LVEF <25%), and lowered heart failure hospitalization rates as compared to patients' past histories 19 . The therapy may also seem to have a positive impact on survival.
The delivery of CCM therapy to patients who are considered non-responders to CRT is an intriguing element. Concerns were raised regarding the effi cient CCM impulses delivery in patients with particularly wide QRS interval, as well as regarding the number of leads inside the patient's heart. An older version of the CCM device-OPTIMIZER III (a three-lead model (one atrial and two ventricular leads))-was evaluated, showing that the association of these devices appears feasible, but with some calculated risks, primarily related to various complications (e.g., lead dislodgement and arrhythmias) 20 . Another trial showed that the peak VO 2 , as well as exercise tolerance rose, while the LVEF trended upwards, and quality of life (assessed with the Minnesota Living with Heart Failure Questionnaire) improved 21 .
One third of our patients were supported with a CRT-D device, having a large QRS interval. The CCM therapy has been associated with good results even in these patients. Figure 2 illustrates the chest X-ray, while Figure 3 illustrates the ECG in such a patient.
The CCM therapy was previously contraindicated for patients with chronic or long-standing persistent atrial fi brillation or fl utter, but a new product version -the OPTIMIZER ® SMART IPG CCMX10 was deve-loped, allowing the atrial sensor lead to be removed if desired. This arrangement lowers lead-related problems (e.g., dislodgement, perforation, cardiac injury, mechanical obstruction of the superior caval vein, fracture, and infection), shortens the surgery, and provides a therapeutic advantage. The new model allows CCM therapy delivery on patients with permanent atrial fi brillation, which formerly was considered a contraindication for the previous generation of OPTI-MIZER ® devices. First experience in heart failure patients with reduced ejection fraction and permanent atrial fi brillation was published in 2014 22 .
One half of patients included in our series have had history of AF, two patients were in AF at the implantation as this condition was permanent. The rest of the patients experienced many episodes of paroxysmal AF during the follow-up perioded, with little infl uence on CCM therapy delivery. Figure 3 illustrates the ECG aspect of CCM delivery in a patient having AF.
Our small series of patients was very heterogenous and included patients with wide range of LVEF (between 15% and 35%), non-responders to CRT therapy, as well as patients with AF history. The results were in line with most published data in the fi eld.

LIMITATIONS
We just presented a summary of our fi ndings from a small group of patients who were followed for varying lengths of time. We recognize that the NYHA classification is a highly subjective assessment of HF, and that