Novel Therapeutic Strategies in IHD with Reduced EF: History
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Contributor:
Sabina Andreea Leancă
,
Irina Afrăsânie
,
Daniela Crișu
,
Iulian Theodor Matei
,
Ștefania Teodora Duca
,
Alexandru Dan Costache
,
Viviana Onofrei
,
Ionuţ Tudorancea
,
Ovidiu Mitu
,
Minerva Codruța Bădescu
,
Lăcrămioara Ionela Șerban
,
Irina Iuliana Costache

Ischemic heart disease (IHD) continues to be the most common cause of heart failure (HF). Traditional HFrEF therapies, which include beta-blockers, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA), have extensive data from clinical trials to support their beneficial effect in patients with IHD and HFrEF, translated into improvements in survival and ventricular remodeling and function. The treatment of HF with reduced EF (HFrEF) has been innovated by the introduction of novel pharmacological therapies and device strategies which have been demonstrated to ameliorate the prognosis of HFrEF patients

  • heart failure
  • ischemic heart disease
  • myocardial infarction

1. Pharmacologic Therapies

1.1. Angiotensin Receptor Neprilysin Inhibitor

ARNI is a dual regulator that inhibits the RAAS as well as the breakdown of physiologically active natriuretic peptides and several other vasoactive substances, including bradykinin. The rise in circulating natriuretic peptides caused by neprilysin inhibition leads to vasodilatation, natriuresis, and lowering of intracardiac pressures, while blocking the angiotensin receptors type 1 exerts antiproliferative, antihypertrophic, and antifibrotic effects, all of these mechanisms promoting favorable ventricular remodeling [1][2][3]. The beneficial effect of the first drug in this therapeutic class, sacubitril/valsartan, has been proven by the PARADIGM-HF trial. This study included symptomatic patients with New York Heart Association (NYHA) class II, III, or IV HF and an LV EF of 40% or less, that were randomized to receive either sacubitril/valsartan or enalapril in addition to standard therapy. IHD was the etiology of HF in 59.9% of the patients from the sacubitril/valsartan group and in 60.1% of the patients from the enalapril group. The results of the trial showed that sacubitril/valsartan was superior to enalapril in decreasing the risk of death from cardiovascular causes or hospitalization for HF, which was reduced by 20% and 21%, respectively. The beneficial effect of sacubitril/valsartan was independent of the etiology of HF, whether ischemic or non-ischemic [4][5]. The compelling results of this trial led to the European Society of Cardiology (ESC) recommendation to replace ACEI or ARB therapy with sacubitril/valsartan in patients with HFrEF who remain symptomatic under optimal therapy [6].
Considering the tremendous benefits of ARNI in the management of HFrEF, including the ischemic etiology, several trials sought to investigate the potential role of sacubitril/valsartan in acute MI. The SAVE-STEMI trial evaluated the safety and efficacy of ARNI compared to ramipril in 200 patients with STEMI after undergoing primary percutaneous coronary intervention. The primary endpoint of major adverse cardiac events (MACE) representing a composite of cardiac death, MI, and HF hospitalizations was similar between groups at 30 days, while at 6 months, it was significantly reduced with sacubitril/valsartan, mainly driven by the reduction in HF hospitalizations. In addition, at 6 months, sacubitril/valsartan was associated with a significantly greater improvement in LV EF, LV end-diastolic diameter (LVEDD), and LV end-systolic diameter (LVESD) [7].
A subsequent trial that further evaluated the benefits of ARNI in MI was the PARADISE-MI trial, which included 5661 patients with acute MI with reduced LV EF of less than 40%, pulmonary congestion associated with the index acute MI, or both. The patients were randomly assigned to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or an HF episode (requiring outpatient management or hospitalization). During a mean observation period of 22 months, a primary-outcome event occurred in 11.9% of patients in the sacubitril-valsartan group and in 13.2% of patients in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; p = 0.17), leading to the conclusion that sacubitril-valsartan was not superior to ramipril in reducing the incidence of cardiovascular death or incident HF in patients with acute MI [8]. However, the PARADISE-MI echocardiographic substudy, which evaluated the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling, revealed several benefits of the combination therapy. Although there was no significant difference in terms of change in LV EF or left atrial volume between groups, patients from the sacubitril/valsartan group had less increase in LVEDV. In addition, they had a greater decline in LV mass index, an increase in lateral tissue Doppler velocity, and a decrease in tricuspid regurgitation peak velocity compared to patients from the ramipril group. These results demonstrated that sacubitril/valsartan is associated with less increase in LV dimensions and with improved diastolic function in patients with acute MI [9].
A recent meta-analysis which included 13 studies evaluated the efficacy of ARNI in reducing MACE and improving LV remodeling in patients with acute MI complicated with HF. The results showed that treatment with sacubitril-valsartan improved LV EF and decreased the LV remodeling parameters (LVEDD, LVESVI, and LVEDVI) to a greater proportion compared to the control group. In addition, sacubitril/ valsartan was associated with lower levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and with a greater increase in exercise capacity. Moreover, it further reduced the incidence of adverse cardiovascular events and the rate of HF rehospitalization compared to ACEI/ARB without significantly reducing the incidence of cardiac death or MI recurrence [10].

1.2. Sodium-Glucose Co-Transporter-2 Inhibitors

SGLT2 inhibitors are therapeutic agents originally designed for the treatment of type 2 diabetes (T2D) which exert their hypoglycemic effect by inhibiting glucose reabsorption in the proximal convoluted tubule, subsequently promoting glycosuria and lowering plasmatic glucose levels [11][12][13]. More recently, SGLT2 inhibitors were demonstrated to exert cardioprotective effects, although their exact mechanisms are not fully understood. Several hypotheses to explain these effects were generated, such as decreased preload and afterload due to natriuresis and reduction in blood pressure, improvement in cardiac energy metabolism and coronary endothelial function, increased cardiomyocyte autophagy and lysosomal activity, reduced oxidative stress and inflammation, and increased erythropoiesis with subsequent augmentation of the blood oxygen supply [14][15][16].
The tremendous cardiac benefits of SGLT2 inhibitors emerged for the first time from the major cardiovascular safety trials of these drugs, such as DECLARE-TIMI 58 and EMPA-REG OUTCOME, which showed that SGLT2 inhibitors therapy was associated with remarkable improvements in cardiovascular outcomes, including a reduction in mortality and HF hospitalization [17][18].
Later, the effects of dapagliflozin in HF were studied in the DAPA-HF trial, which included patients with HF with a reduced EF of 40% or less, regardless of the presence of T2D. In this trial, dapagliflozin reduced the risk of HF hospitalization and cardiovascular death with similar efficacy in patients with or without diabetes [19]. Similar results were obtained in the EMPEROR-Reduced trial, in which empagliflozin reduced the combined risk of cardiovascular death and hospitalization for HF by 25% in patients with HFrEF. Additionally, SGTL2 inhibitors appear to be more effective than vericiguat and comparable to ARNI in preventing HF hospitalization [14][19][20]. Both of these trials included more than half of the patients with an ischemic etiology of HF, and post hoc subgroup analysis showed similar outcomes in patients with or without ischemic HF [21].
Considering the categorical benefits of SGLT2 inhibitors in cardiovascular mortality and HF prognosis, several studies were designed to evaluate the impact of these drugs on cardiac function and remodeling. The SUGAR-DM-HF trial included patients with NYHA class II to IV HF, LV EF ≤ 40%, and T2D or prediabetes, that were randomly assigned to receive empagliflozin or placebo. After 36 weeks of treatment, empagliflozin significantly reduced the LVESVI and LVEDVI (assessed with cardiac magnetic resonance) compared to placebo, suggesting that SGLT2 inhibitors promote LV reverse remodeling, which might explain their benefits on cardiovascular mortality and HF hospitalizations [22]. Another study, the EMPA-HEART CardioLink-6, which included patients with T2D and coronary artery disease (CAD), demonstrated that a 6-month treatment with empagliflozin was associated with a reduction of the LV mass index, assessed by cardiac magnetic resonance [18][22]. Several hypotheses have been proposed to explain the anti-remodeling effects of SGLT2 inhibitors. Preclinical data suggest that SGLT2 inhibitors might reduce cardiac inflammation decreasing the macrophage inflammatory response, which will subsequently reduce the ECM turnover, preventing or ameliorating cardiac remodeling. In addition, SGLT2 inhibitors suppress pro-fibrotic markers, such as type 1 collagen and MMPs, and attenuate TGF-β1-induced fibroblast activation, thus reducing myocardial fibrosis [23][24].
As SGLT2 inhibitors appear to exert pleiotropic cardiovascular effects, their role in acute myocardial ischemia was evaluated in several trials. The EMMY trial included 476 patients with acute MI that were randomized to receive empagliflozin or placebo 3 days after interventional coronary revascularization. The primary outcome was represented by the change in NT-proBNP value after 26 weeks, while secondary outcomes included changes in echocardiographic parameters. The results showed a significantly greater reduction of NT-proBNP in the empagliflozin group. In addition, markers of ventricular remodeling such as LV EF, LVESV, LVEDV, and LV filling pressures improved with a greater magnitude in patients with empagliflozin therapy. These results suggest that the early initiation of the SGTL2 inhibitors in the treatment of acute MI could be beneficial for the prevention or attenuation of LV remodeling [25][26]. Other ongoing trials will provide, in the future, the necessary data to conclude the efficacity of SGLT2 inhibitors in the prevention of HF after acute MI. The EMPACT-MI trial (NCT04509674) will evaluate whether empagliflozin compared to placebo can lower the risk of HF and death in patients with acute MI and new onset LV systolic dysfunction or signs and symptoms of pulmonary congestion [27]. The DAPA-MI trial (NCT04564742) will offer information about the efficacity of dapagliflozin compared to placebo in the prevention of HF hospitalization or CV death in patients with acute MI and evidence of impaired LV systolic function. An important aspect related to these two trials is that the DAPA-MI trial will randomize only patients without a known diagnosis or evidence of T2D, while EMPACT-MI will include both diabetic and non-diabetic patients [27][28]. The PRESTIGE-AMI (NCT04899479) and EMPRESS MI (NCT05020704) trials will evaluate the potential role of SGLT2 inhibitors in reducing infarct size and preventing the occurrence of LV remodeling in patients with acute MI [15]. All of these studies are of great interest since myocardial remodeling after MI continues to represent a major cause of HF progression, despite timely coronary revascularization.

1.3. Selective Cardiac Myosin Activators

Impaired myocardial contractility is the central pathogenic process leading to HFrEF development, and therapeutic strategies which increase myocardial contraction should have a positive therapeutic impact. However, traditional inotropic drugs were not demonstrated to be beneficial for chronic administration in HFrEF, and they have been linked to an increased risk of morbidity and mortality due to increased myocardial oxygen consumption and myocyte toxicity as a consequence of intracellular calcium overload [29]. Omecamtiv mecarbil is the first drug from the class of selective cardiac myosin activators, which boosts myocardial force production by modulating the function of the sarcomere without affecting the intracellular calcium accumulation. The central mechanism of omecamtiv mecarbil is to activate myosin by accelerating the rate of adenosine triphosphate (ATP) hydrolysis to adenosine diphosphate (ADP) and phosphate, subsequently increasing the number of strong actin–myosin interactions, which result in augmented myocyte contraction with increased ventricular force generation and systolic ejection time [29][30][31][32].
The COSMIC-HF study was a phase 2 clinical trial that evaluated the pharmacokinetics and impact on the ventricular remodeling of orally administered omecamtiv mecarbil in patients with HFrEF. After 20 weeks of treatment, omecamtiv mecarbil compared to placebo was associated with increased systolic ejection time and stroke volume and improvements in LVESD and LVEDD, suggesting a beneficial effect of omecamtiv mecarbil on cardiac function and LV remodeling [33][34]. In addition, patients from the omecamtiv mecarbil group presented lower plasma concentrations of NT-proBNP and decreased heart rate values, suggesting that the enhancement of systolic function can minimize myocardial wall stress and possibly sympathetic activation, which might contribute to the favorable remodeling effect of this drug. This trial included a significant proportion of patients with IHD (65%), which suggests that omecamtiv mecarbil promotes positive ventricular remodeling in patients with HFrEF with an ischemic etiology as well [33][34].
The GALACTIC-HF phase 3 trial evaluated the cardiovascular outcomes of omecamtiv mecarbil compared to placebo in patients with symptomatic HF and an EF of less than 35%. The results showed that patients who received omecamtiv mecarbil had a lower incidence of a composite of HF events or cardiovascular death compared to placebo. In addition, NT-proBNP had lower values in the omecamtiv mecarbil group, and the clinical benefit was greater among patients with LVEF ≤ 28% and systolic blood pressure ≤ 100 mm Hg. Half of the included patients had ischemic HF. There were no considerable differences between groups regarding the occurrence of cardiac ischemic events and ventricular arrhythmias [32][35][36]. Despite the aforementioned positive effects of omecamtiv mecarbil in HFrEF patients, the recently published results of the METEORIC-HF trial showed that omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo [37].
There is no data in the literature specifically analyzing the role of omecamtiv mecarbil in the management of acute or chronic IHD. Scarce evidence coming from experimental studies suggests that omecamtiv mecarbil could have cardioprotective properties against I/R injury [38].

1.4. Soluble Guanylate Cyclase Stimulators

Soluble guanylate cyclase (sGC) stimulators emerge as a valuable treatment option in patients with impaired LV systolic function. HFrEF is associated with decreased cyclic guanosine monophosphate (cGMP) production, which promotes myocardial dysfunction and abnormal vasomotor regulation. cGMP deficiency is caused by altered nitric oxide (NO)-sGC-cGMP pathway signaling, due to decreased levels of NO in the context of the endothelial dysfunction state, which characterizes HFrEF [39]. By directly stimulating sGC independent of NO, these drugs increase cGMP production and subsequently improve myocardial and vascular function [40][41][42].
Vericiguat is an oral sGC stimulator approved for the treatment of HFrEF, following the results of the VICTORIA trial. This phase III trial included patients with EF < 45% and a history of recent episodes of HF decompensation and showed that vericiguat added to standard therapy is associated with a lower incidence of the primary composite outcome of cardiovascular death or HF hospitalization compared to placebo added to standard therapy [39]. A post hoc study showed that IHD defined as previous MI, surgical, or percutaneous coronary revascularization, was the etiology of HFrEF in more than half of the included patients. In addition, it showed that patients with coronary artery disease benefited as well from vericiguat therapy, as they had a lower primary outcome of cardiovascular death and HF hospitalization compared to patients with CAD from the placebo group [43].
The potential effect of vericiguat on ventricular remodeling was evaluated in the VICTORIA echocardiographic substudy, in which echocardiographic evaluation was performed at baseline and after 8 months of therapy in the two groups of patients with vericiguat and placebo therapy, respectively. The results failed to demonstrate a superior effect of vericiguat compared to placebo on ventricular function and dimensions. Although treatment with vericiguat significantly improved LV EF and LVESVI after 8 months, it did not show an additional significant effect on LV EF or LVESVI compared to placebo [44]. However, when interpreting these results, one should take into consideration the particularities of the patients included in the VICTORIA trial, as they were older, less stable, and had higher NT-proBNP levels compared to the patients included in the other HF trials such as PARADIGM-HF and DAPA-HF, which demonstrated positive effects on the ventricular remodeling [44]. In addition, only 15% of patients enrolled in the VICTORIA trial were simultaneously receiving treatment with sacubitril/valsartan, only 60% were receiving guideline-based triple medical therapy, and no data was provided regarding the administration of SGLT2 inhibitors. Whether vericiguat would have a more pronounced positive effect on ventricular remodeling if added to optimal HF therapy including sacubitril/valsartan and SGLT2 inhibitors, and in a more specific group, with less unstable patients, are questions that merit to be addressed in future studies [40][41][42].
Currently, there are no trials evaluating the effects of sGC stimulators on cardiac remodeling and HF development in patients with acute MI. However, data coming from experimental studies suggest a potential beneficial effect of sGC stimulators on ventricular remodeling after acute MI. In this regard, a study showed that riociguat administration in mice after 30 min of occlusion of the left anterior descending artery (LAD) followed by reperfusion therapy, resulted in a reduction of the infarct size and prevented the further development of HF. The beneficial effect was persistent, as the LV systolic function was preserved at 28 days after the ischemic event [45][46]. Similarly, another study evaluated the effects on the cardiac remodeling of ataciguat compared to either placebo, ramipril, or a combination of both in rats, with the initiation of therapy 10 days after acute MI. After 9 weeks, ataciguat administration was associated with lower LVESV and LVEDV and improved systolic and diastolic function compared to placebo or ramipril. In addition, these effects were potentiated when ataciguat was added to the ACEI. At a cellular level, ataciguat was demonstrated to reduce mitochondrial oxidative stress production, cardiomyocyte hypertrophy, interstitial collagen accumulation, and fibrosis development [47][48]. These results suggest a potential protective role of sGC stimulators against cardiac fibrosis and maladaptive ventricular remodeling in chronic IHD, which could be further explored in future research.

2. Device Therapy in HF

2.1. Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is a valuable therapeutic resource in the management of patients with HFrEF and wide QRS complex that remain symptomatic despite guideline-directed medical therapy (GDMT). Biventricular pacing improves intraventricular and interventricular synchrony and increases diastolic filling time, which overall translates into improved cardiac performance and amelioration of symptoms [49]. Multiple randomized clinical trials demonstrated the beneficial effects of CRT. Response to therapy was defined by clinical measures (improvements in NYHA class, quality of life, or 6 min walk test), LV reverse remodeling parameters (improvements in LV EF, LVESV, LVEDV, and mitral regurgitation), or by outcome measures, including reductions in HF hospitalizations, and mortality [49]. Response rates have varied across studies, depending on the criteria utilized to define response to therapy. As such, response rates were higher when clinical measures were used, while remodeling and outcomes indicators were associated with lower rates of response. In addition, clinical response was not always accompanied by improved ventricular remodeling or survival. Among 20 to 40% of patients with CRT remain unresponsive, which has been attributed to factors such as IHD with extensive myocardial scarring, atrial fibrillation or atrial conduction delay, severe ventricular dilatation, or mitral regurgitation [50][51].
Patients with IHD represented over 50% of the patients included in every trial evaluating CRT, except for CARE-HF, in which IHD was the etiology of HF in 36% of the patients [52]. The trials which particularly addressed the effect of CRT on ventricular remodeling will be presented below.
The CARE-HF trial included patients with symptomatic HF NYHA class III or IV, prolonged QRS, and a reduced LV EF < 35%, which were randomized to receive CRT plus optimal medical therapy, and standard HF therapy alone. The primary endpoint was a composite of death from any cause or an unplanned hospitalization for a major cardiovascular event. After a mean period of follow-up of 29.4 months, the primary endpoint was significantly lower in the CRT group compared to the group with medical therapy alone (39% vs. 55%). In addition, CRT was associated with clinical response, attributed to improved symptoms and quality of life, and with LV reverse remodeling, measured as a reduction in LVESVI, and in the area of the mitral regurgitant jet, or an increase in the LV EF [53].
The MIRACLE trial was among the first to show the clinical benefits of CRT. It included patients with NYHA class III or IV, LV EF of 35% or less, and a QRS duration of 130 msec or more, that were randomized in a CRT group and a control group with the maintenance of conventional HF therapy in both groups. Patients with IHD represented 58% of the total number of included patients [52][54]. The primary endpoints were the NYHA functional class, quality of life, and the distance walked in six minutes, which were significantly improved in the CRT group compared to the control group. The extent of the effect of CRT on the primary endpoints was not influenced by the etiology of HF, whether ischemic or nonischemic. In addition, CRT enhanced cardiac performance and promoted ventricular remodeling, evaluated as an increase in the LV EF and a reduction in the end-diastolic LV dimension and the area of the mitral regurgitant jet [54].
MADIT-CRT was another trial that included patients with ischemic HF (NYHA class I or II) and nonischemic HF (NYHA class II only), an LV EF of 30% or less, and a QRS duration of 130 msec or more. Patients with IHD represented 55% of the total included patients. They were randomized to receive CRT plus an implantable cardioverter-defibrillator (ICD) or an ICD alone. The primary endpoint was death from any cause or a nonfatal HF event. The results showed that CRT-ICD was superior to ICD alone, as it reduced the risk of death or HF events by 34%. In addition, CRT was demonstrated to favor LV reverse remodeling, as the LV volumes were reduced and the EF was increased to a greater amount in patients with a CRT-ICD compared with those with an ICD only [55]. However, when assessing the response to CRT by the etiology of HF, it appeared that patients with non-IHD had a greater clinical benefit compared to patients with IHD, with a reduction in the risk of HF or death of 44% and 34%, respectively. Moreover, the echocardiographic response to CRT was of smaller magnitude in patients with IHD compared to patients with non-IHD, with reductions in LVESV of 29 ± 14% vs. 37 ± 16%, and in LVEDV of 18 ± 10% vs. 24 ± 12%, respectively [56].
The REVERSE trial included patients with mildly symptomatic HF (NYHA class I or II) and a LV EF ≤ 40% who received a CRT device and were randomly assigned to active CRT (CRT-ON) or control (CRT-OFF) for 12 months. The results showed that patients from the CRT-ON group had a lower risk of HF hospitalization, as the worsened HF clinical response was lower in this group compared to the CRT-OFF group. In addition, patients who had active CRT had greater improvement in the LVESVI and other markers of ventricular remodeling. Notably, the improvement in LVESVI in CRT-ON patients was 3 times greater in the nonischemic group than in patients with IHD [57].
Sub-analysis of the trials presented above showed that indeed, CRT is associated with a greater LV reverse remodeling in nonischemic HF, compared to the ischemic etiology. Integrating data from the MADIT-CRT trial, seven factors were identified to predict echocardiographic response to CRT with defibrillation (CRT-D): female sex, nonischemic origin, left bundle-branch block (LBBB), QRS ≥ 150 msec, prior hospitalization for HF, LVEDVI ≥ 125 mL/m2 and left atrial volume < 40 mL/m2 [58]. However, new strategies are emerging to improve the ventricular remodeling response to CRT in IHD. In line with this, using two-dimensional speckle tracking imaging for LV lead position to the site of the latest activation has been associated with significantly greater reverse remodeling compared to the CRT procedure without echocardiographic guidance [59]. Moreover, sequential biventricular pacing with optimization of interventricular pacing interval (V-V) was demonstrated to improve ventricular systolic performance with a greater increase in LV EF compared to conventional simultaneous stimulation, and to a greater extent in patients with IHD compared to patients with non-IHD [52][60].
Considering the compelling data from clinical trials, current European and American guidelines recommend CRT with a class I indication in patients with symptomatic HF despite optimal medical therapy, with reduced ejection fraction (LV EF < 35%), and a QRS with LBBB morphology and a duration ≥ 150 msec [61][62].

2.2. Baroreflex Activation Therapy

Sympathetic overactivation is a major contributor to the progression of HF and ventricular maladaptive remodeling. Baroreflex activation therapy (BAT) emerges as a novel therapeutic approach in HFrEF, consisting in carotid baroreceptor stimulation, which subsequently decreases the sympathetic hyperreactivity and augments the parasympathetic tone, rebalancing the cardiac autonomic modulation [63][64]. BAT with Barostim Neo, an implantable system composed of a pulse generator and a carotid sinus lead that delivers electrical impulses to the carotid artery baroreceptors, has recently been evaluated in the phase III BeAT-HF trial. This study included patients with symptomatic HF NYHA class II or III, a LV EF ≤ 35%, and no Class I indication for CRT. The patients were randomized to receive either BAT plus optimal medical therapy or optimal medical therapy alone. The results showed that patients from the BAT group had significant improvements in quality of life, exercise capacity, and NT-proBNP levels, which led to the Food and Drug Administration (FDA) Barostim Neo approval in this category of patients [65].
While IHD was the etiology of HF in 66% of the included patients, there is no specific data regarding the particular response to BAT of patients with ischemic cardiomyopathy. Furthermore, the LV EF and dimensions were not endpoints in the BeAT-HF trial, therefore there is no data regarding the possible LV remodeling in the BAT group [65]. However, given the fact that BAT decreases sympathetic hyperreactivity, which is an aggravating factor of ventricular remodeling, and that it is associated with the lowering of NT-proBNP values, it would be interesting to assess in future trials whether BAT promotes or augments LV remodeling.

2.3. Cardiac Contractility Modulation (CCM)

Cardiac contractility modulation (CCM) is a device-based treatment that involves delivering relatively high-voltage precisely timed electric pulses to the right ventricle (RV) septal wall for 30–40 milliseconds after cardiomyocyte activation, during the absolute refractory period of the action potential. CCM is provided by the implantable OPTIMIZER system, composed of a generator that delivers electrical signals through the two right ventricular leads [66]. The physiological mechanisms of CCM involve increasing cytosolic calcium, which strengthens sarcomeric contractions, increasing ventricular force production but without augmentation of myocardial oxygen consumption [67][68].
While these studies included a significant proportion of patients with ischemic etiology of HF, there are no available data from these trials regarding the particular response to CCM in this subgroup of patients. Recently, the MAINTAINED observational retrospective study compared the long-term effects of CCM therapy in patients with IHD versus non-IHD. After 5 years of CCM, the entire cohort had improvements in LV EF and LVEDD, but non-IHD patients showed a significantly greater augmentation of LV EF and RV systolic function, although these parameters were similarly reduced at baseline in both groups. This finding might suggest that patients with non-IHD manifest a greater functional improvement in response to CCM therapy than IHD patients [69]. The results of another observational study which included symptomatic patients with an LV EF < 35% despite OMT showed that CCM was associated with a similar LV reverse remodeling to CRT for patients with a mildly prolonged QRS, while the similarity was less strong when compared to CRT for patients with a very wide QRS [70]. Further randomized studies are needed to evaluate whether patients with IHD have a similar response to CCM as those with non-IHD, and to what extent.

3. Cell Therapy

Despite significant progress in the pharmaceutical and device therapy of HF and the strategies of coronary revascularization in acute or chronic myocardial ischemia, a substantial proportion of patients still develop adverse ventricular remodeling, which ultimately leads to ischemic HF. As the therapeutic resources for advanced HF are limited to ventricular assist devices and heart transplantation, the finding of new therapeutic strategies for these patients is of major importance. Stem cell regeneration medicine represents a novel potential HF therapy, currently still under research, that aims to promote myocardial regeneration and repair [71]. Several mechanisms have been proposed to explain the beneficial effect of stem cell therapy in HF. While initially it was hypothesized that transplanted stem cells could promote myocardial tissue regeneration, subsequent studies demonstrated that inoculated cells do not engraft in the myocardium and do not differentiate in cardiomyocytes [72]. A considerable body of evidence later suggested that the clinical benefits of transplanted cells do not involve myogenesis but are rather related to their endocrine and paracrine effects, which activate pathways that further lead to a reduction in inflammation, attenuation of cardiac fibrosis, and promotion of cardiomyocyte survival and angiogenesis, all of these mechanisms acting in concert to improve the cardiac function [73].
Clinical trials utilized different types of stem cell populations to evaluate their regenerative capacity. First-generation stem cells include bone marrow-derived mononuclear cells (BM-MNCs), which were the most extensively used in clinical trials, due to their relatively easy procedure of isolation and the associated low costs. BM-MNCs include hematopoietic stem cells, endothelial progenitor cells, and a small fraction of mesenchymal stem cells (MSCs) [74]. MSCs are another type of first-generation stem cells and they are found in various tissues such as the bone marrow, the adipose tissue, and the umbilical cord matrix and blood. MSCs exert powerful paracrine actions, as they produce a large variety of cardioprotective factors which counteract inflammation, and apoptosis and stimulate angiogenesis, representing a preferred type of stem cells in clinical trials [73][74]. Research subsequently shifted towards second-generation cell therapy, which includes c-kit-positive cardiac stem cells (CSCs), cardiac progenitor cells (CPCs), and cardiosphere-derived cells (CDCs), which are isolated and expanded from cardiac tissue obtained by endomyocardial biopsy and are thought to possess increased regeneration capacity by the stimulation of endogenous cardiomyocytes or paracrine signaling [73][74][75].

This entry is adapted from the peer-reviewed paper 10.3390/life13041000

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