[Short-term efficacy and safety of cardiac contractility modulation in patients with heart failure].

Objective: To investigate the short-term efficacy and safety of cardiac contractility modulation (CCM) in patients with heart failure. Methods: This was a cross-sectional study of patients with heart failure who underwent CCM placement at the First Affiliated Hospital of Xinjiang Medical University from February to June 2022. With a follow-up of 3 months, CCM sensation, impedance, percent output, and work time were monitored, and patients were compared with pre-and 3-month postoperative left ventricular ejection fraction (LVEF) values, and 6-minute walk test distance and New York Heart Association (NYHA) cardiac function classification, and the occurrence of complications was recorded. Results: CCM was successfully implanted in all 9 patients. Seven(7/9) of them were male, aged (56±14) years, 3 patients had ischaemic cardiomyopathy and 6 patients had dilated cardiomyopathy. At 3-month postoperative follow-up, threshold was stable, sense was significantly lower at follow-up than before (right ventricle: (16.3±7.0) mV vs. (8.2±1.1) mV, P<0.05; local sense: (15.7±4.9) mV vs. (6.7±2.5) mV, P<0.05), and impedance was significantly lower at follow-up than before (right ventricle (846±179) Ω vs. (470±65) Ω, P<0.05, local sense: (832±246) Ω vs. (464±63) Ω, P<0.05). The CCM output percentage was (86.9±10.7) %, the output amplitude was (6.7±0.4) V, and the daily operating time was (8.6±1.0) h. LVEF was elevated compared to preoperative ((29.4±5.2) % vs. (38.3±4.3) %, P<0.05), the 6-minute walk test was significantly longer than before ((96.8±66.7)m vs. (289.3±121.7)m, P<0.05). No significant increase in the number of NYHA Class Ⅲ-Ⅳ patients was seen (7/9 vs. 2/9, P>0.05). The patient was not re-hospitalised for worsening heart failure symptoms, had no malignant arrhythmic events and experienced significant relief of symptoms such as chest tightness and shortness of breath. No postoperative complications related to pocket hematoma, pocket infection and rupture, electrode detachment, valve function impairment, pericardial effusion, or cardiac perforation were found. Conclusions: CCM has better short-term safety and efficacy in patients with heart failure.

Mathematical analysis of left ventricular elastance with respect to afterload change during ejection phase.

Since the left ventricle (LV) has pressure (Plv) and volume (Vlv), we can define LV elastance from the ratio between Plv and Vlv, termed as "instantaneous elastance." On the other hand, end-systolic elastance (Emax) is known to be a good index of LV contractility, which is measured by the slope of several end-systolic Plv-Vlv points obtained by using different loads. The word Emax originates from the assumption that LV elastance increases during the ejection phase and attains its maximum at the end-systole. From this concept, we can define another elastance determined by the slope of isochronous Plv-Vlv points, that is Plv-Vlv points at a certain time after the ejection onset time by using different loads. We refer to this elastance as "load-dependent elastance." To reveal the relation between these two elastances, we used a hemodynamic model that included a detailed ventricular myocyte contraction model. From the simulation results, we found that the isochronous Plv-Vlv points lay in one line and that the line slope corresponding to the load-dependent elastance slightly decreased during the ejection phase, which is quite different from the instantaneous elastance. Subsequently, we analyzed the mechanism determining these elastances from the model equations. We found that instantaneous elastance is directly related to contraction force generated by the ventricular myocyte, but the load-dependent elastance is determined by two factors: one is the transient characteristics of the cardiac cell, i.e., the velocity-dependent force drops characteristics in instantaneous shortening. The other is the force-velocity relation of the cardiac cell. We also found that the linear isochronous pressure-volume relation is based on the approximately linear relation between the time derivative of the cellular contraction force and the cellular shortening velocity that results from the combined characteristics of LV and aortic compliances.

Right ventricular preload and afterload challenge induces contractile dysfunction and arrhythmia in isolated hearts of dystrophin-deficient male mice.

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes hypoventilation and elevated afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-min sustained RV preload/afterload challenge to isolated hearts of wild-type (Wt) and dystrophic (Dmdmdx-4Cv) mice at both young (2-6 month) and middle-age (8-12 month) to test the hypothesis that the dystrophic RV is susceptible to dysfunction with elevated load. Young dystrophic hearts exhibited greater pressure development than wild type under baseline (Langendorff) conditions, but following RV challenge exhibited similar contractile function as wild type. Following the RV challenge, young dystrophic hearts had an increased incidence of premature ventricular contractions (PVCs) compared to wild type. Hearts of middle-aged wild-type and dystrophic mice had similar contractile function during baseline conditions. After RV challenge, hearts of middle-aged dystrophic mice had severe RV dysfunction and arrhythmias, including ventricular tachycardia. Following the RV load challenge, dystrophic hearts had greater lactate dehydrogenase (LDH) release than wild-type mice indicative of damage. Our data indicate age-dependent changes in RV function with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall dysfunction and arrhythmia.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H1-Histamine Receptor on the Heart.

There is a debate on whether H1-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H1-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H1-histamine receptors (H1-TG) and compared these findings with those in littermate wild-type mice (WT). In H1-TG mice, we studied the presence of H1-histamine receptors by autoradiography of the atrium and ventricle using [3H]mepyramine. The messenger RNA for human H1-histamine receptors was present in the heart from H1-TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H1-histamine receptor in cardiac cells from H1-TG. We noted that histamine (1 nM-10 µM) in paced (1 Hz) left atrial preparations from H1-TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H1-TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H1-TG were attenuated by the H1-histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H1-histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H1-histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H1-histamine receptor to contribute to the clarification of the controversy on whether H1-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H1-histamine receptors first decrease and then raise contractile force in the mammalian heart but exert solely negative chronotropic effects.

The carbon monoxide prodrug oCOm-21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

Utilization of the genetically encoded calcium indicator Salsa6F in cardiac applications.

Calcium signaling is a critical process required for cellular mechanisms such as cardiomyocyte contraction. The inability of the cell to properly activate or regulate calcium signaling can lead to contractile dysfunction. In isolated cardiomyocytes, calcium signaling has been primarily studied using calcium fluorescent dyes, however these dyes have limited applicability to whole organs. Here, we crossed the Salsa6f mouse which expresses a genetically encoded ratiometric cytosolic calcium indicator with a cardiomyocyte specific inducible cre to temporally-induce expression and studied cytosolic calcium transients in isolated cardiomyocytes and modified Langendorff heart preparations. Isolated cardiomyocytes expressing Salsa6f or Fluo-4AM loaded were compared. We also crossed the Salsa6f mouse with a floxed Polycystin 2 (PC2) mouse to test the feasibility of using the Salsa6f mouse to measure calcium transients in PC2 heterozygous or homozygous knock out mice. Although there are caveats in the applicability of the Salsa6f mouse, there are clear advantages to using the Salsa6f mouse to measure whole heart calcium signals.

Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

INTRODUCTION: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). METHODS: Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. RESULTS: Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). CONCLUSION: These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Myosin folding boosts solubility in cardiac muscle sarcomeres.

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected > 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility.

Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.

Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4 °C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3 weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.

Influence of Power-Weighted Center of Echo Signal Within Window Function on Local Strain Rate Distribution in Left Ventricular Wall.

OBJECTIVE: The deviation of the power-weighted center of the echo signal from the geometric center within the velocity estimation window for calculating strain rate (SR) causes an estimation error. This study aimed to confirm whether an erroneous multilayer pattern in the SR distribution of the left ventricular wall could be corrected by considering the power-weighted center of the echo signal. METHODS: The SR distributions were measured locally in the transmural direction around the pre-ejection and early diastolic phases in healthy volunteers. The estimation error related to the power-weighted center of the echo signal was corrected using a previously proposed method, and the effectiveness of the correction was confirmed based on the accuracy of the estimated myocardial displacement. RESULTS: The SR distribution in early diastole was observed as multilayers of low- and high-amplitude negative SRs. However, this multilayer pattern disappeared after correction. In the pre-ejection phase, multilayers of positive and negative SRs were observed in the SR distributions with and without correction. This correction was sufficiently effective in accurately tracking the local peak of the echo signal. CONCLUSION: The multilayer pattern of low- and high-amplitude positive or negative SRs is caused by estimation errors related to the power-weighted center of the echo signal. The multilayer pattern of positive and negative SRs might not be caused by these errors and might relate to the actual change in myocardial thickness because the estimation errors do not convert the negative (positive) SR to positive (negative) in a homogeneous negative (positive) SR distribution.

Geometry and length control of 3D engineered heart tissues using direct laser writing.

Geometry and mechanical characteristics of the environment surrounding the Engineered Heart Tissues (EHT) affect their structure and function. Here, we employed a 3D tissue culture platform fabricated using two-photon direct laser writing with a high degree of accuracy to control parameters that are relevant to EHT maturation. Using this platform, we first explore the effects of geometry based on two distinct shapes: a rectangular seeding well with two attachment sites, and a stadium-like seeding well with six attachment sites that are placed symmetrically along hemicylindrical membranes. The former geometry promotes uniaxial contraction of the tissues; the latter additionally induces diagonal fiber alignment. We systematically increase the length of the seeding wells for both configurations and observe a positive correlation between fiber alignment at the center of the EHTs and tissue length. With increasing length, an undesirable thinning and "necking" also emerge, leading to the failure of longer tissues over time. In the second step, we optimize the stiffness of the seeding wells and modify some of the attachment sites of the platform and the seeding parameters to achieve tissue stability for each length and geometry. Furthermore, we use the platform for electrical pacing and calcium imaging to evaluate the functional dynamics of EHTs as a function of frequency.

Medical therapy of cardiogenic shock: Contemporary use of inotropes and vasopressors.

Cardiogenic shock is a primary cardiac disorder that results in both clinical and biochemical evidence of tissue hypoperfusion and can lead to multi-organ failure and death depending on its severity. Inadequate cardiac contractility or cardiac power secondary to acute myocardial infarction remains the most frequent cause of cardiogenic shock, although its contribution has declined over the past two decades, compared with other causes. Despite some advances in cardiogenic shock management, this clinical syndrome is still burdened by an extremely high mortality. Its management is based on immediate stabilization of haemodynamic parameters so that further treatment, including mechanical circulatory support and transfer to specialized tertiary care centres, can be accomplished. With these aims, medical therapy, consisting mainly of inotropic drugs and vasopressors, still has a major role. The purpose of this article is to review current evidence on the use of these medications in patients with cardiogenic shock and discuss specific clinical settings with indications to their use.

Elevated levels of alcohol dehydrogenase aggravate ethanol-evoked cardiac remodeling and contractile anomalies through FKBP5-yap-mediated regulation of ferroptosis and ER stress.

Alcohol intake provokes severe organ injuries including alcoholic cardiomyopathy with hallmarks of cardiac remodeling and contractile defects. This study examined the toxicity of facilitated ethanol metabolism in alcoholism-evoked changes in myocardial morphology and contractile function, insulin signaling and various cell death domains using cardiac-selective overexpression of alcohol dehydrogenase (ADH). WT and ADH mice were offered an alcohol liquid diet for 12 weeks prior to assessment of cardiac geometry, function, ER stress, apoptosis and ferroptosis. Alcohol intake provoked pronounced glucose intolerance, cardiac remodeling and contractile anomalies with apoptosis, ER stress, and ferroptosis, the effects were accentuated by ADH with the exception of global glucose intolerance. Hearts from alcohol ingesting mice displayed dampened insulin-stimulated phosphorylation of insulin receptor (tyr1146) and IRS-1 (tyrosine) along with elevated IRS-1 serine phosphorylation, the effect was augmented by ADH. Alcohol challenge dampened phosphorylation of Akt and GSK-3ß, and increased phosphorylation of c-Jun and JNK, the effects were accentuated by ADH. Alcohol challenge promoted ER stress, FK506 binding protein 5 (FKBP5), YAP, apoptosis and ferroptosis, the effects were exaggerated by ADH. Using a short-term ethanol challenge model (3 g/kg, i.p., twice in three days), we found that inhibition of FKBP5-YAP signaling or facilitated ethanol detoxification by Alda-1 alleviated ethanol cardiotoxicity. In vitro study revealed that the ethanol metabolite acetaldehyde evoked cardiac contractile anomalies, lipid peroxidation, and apoptosis, the effects of which were mitigated by Alda-1, inhibition of ER stress, FKBP5 and YAP. These data suggest that facilitated ethanol metabolism via ADH exacerbates alcohol-evoked myocardial remodeling, functional defects, and insulin insensitivity possibly through a FKBP5-YAP-associated regulation of ER stress and ferroptosis.

Non-contact assessment of cardiac physiology using FO-MVSS-based ballistocardiography: a promising approach for heart failure evaluation.

Continuous monitoring of cardiac motions has been expected to provide essential cardiac physiology information on cardiovascular functioning. A fiber-optic micro-vibration sensing system (FO-MVSS) makes it promising. This study aimed to explore the correlation between Ballistocardiography (BCG) waveforms, measured using an FO-MVSS, and myocardial valve activity during the systolic and diastolic phases of the cardiac cycle in participants with normal cardiac function and patients with congestive heart failure (CHF). A high-sensitivity FO-MVSS acquired continuous BCG recordings. The simultaneous recordings of BCG and electrocardiogram (ECG) signals were obtained from 101 participants to examine their correlation. BCG, ECG, and intracavitary pressure signals were collected from 6 patients undergoing cardiac catheter intervention to investigate BCG waveforms and cardiac cycle phases. Tissue Doppler imaging (TDI) measured cardiac time intervals in 51 participants correlated with BCG intervals. The BCG recordings were further validated in 61 CHF patients to assess cardiac parameters by BCG. For heart failure evaluation machine learning was used to analyze BCG-derived cardiac parameters. Significant correlations were observed between cardiac physiology parameters and BCG's parameters. Furthermore, a linear relationship was found betwen IJ amplitude and cardiac output (r = 0.923, R2 = 0.926, p < 0.001). Machine learning techniques, including K-Nearest Neighbors (KNN), Decision Tree Classifier (DTC), Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), and XGBoost, respectively, demonstrated remarkable performance. They all achieved average accuracy and AUC values exceeding 95% in a five-fold cross-validation approach. We establish an electromagnetic-interference-free and non-contact method for continuous monitoring of the cardiac cycle and myocardial contractility and measure the different phases of the cardiac cycle. It presents a sensitive method for evaluating changes in both cardiac contraction and relaxation in the context of heart failure assessment.

Regulation of myocardial contraction as revealed by intracellular Ca2+ measurements using aequorin.

Of the ions involved in myocardial function, Ca2+ is the most important. Ca2+ is crucial to the process that allows myocardium to repeatedly contract and relax in a well-organized fashion; it is the process called excitation-contraction coupling. In order, therefore, for accurate comprehension of the physiology of the heart, it is fundamentally important to understand the detailed mechanism by which the intracellular Ca2+ concentration is regulated to elicit excitation-contraction coupling. Aequorin was discovered by Shimomura, Johnson and Saiga in 1962. By taking advantage of the fact that aequorin emits blue light when it binds to Ca2+ within the physiologically relevant concentration range, in the 1970s and 1980s, physiologists microinjected it into myocardial preparations. By doing so, they proved that Ca2+ transients occur upon membrane depolarization, and tension development (i.e., actomyosin interaction) subsequently follows, dramatically advancing the research on cardiac excitation-contraction coupling.

The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart.

AIMS: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic ß-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. METHODS: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and α1A-AR knockout mice and defined the effects of chronic ß-AR activation and myocardial infarction on selected mitochondrial functions. RESULTS: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The ß-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. CONCLUSIONS: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Cardiac contractility modulation in patients with heart failure - A review of the literature.

Experimental in vivo and in vitro studies showed that electric currents applied during the absolute refractory period can modulate cardiac contractility. In preclinical studies, cardiac contractility modulation (CCM) was found to improve calcium handling, reverse the foetal myocyte gene programming associated with heart failure (HF), and facilitate reverse remodeling. Randomized control trials and observational studies have provided evidence about the safety and efficacy of CCM in patients with HF. Clinically, CCM therapy is indicated to improve the 6-min hall walk, quality of life, and functional status of HF patients who remain symptomatic despite guideline-directed medical treatment without an indication for cardiac resynchronization therapy (CRT) and have a left ventricular ejection fraction (LVEF) ranging from 25 to 45%. Although there are promising results about the role of CCM in HF patients with preserved LVEF (HFpEF), further studies are needed to elucidate the role of CCM therapy in this population. Late gadolinium enhancement (LGE) assessment before CCM implantation has been proposed for guiding the lead placement. Furthermore, the optimal duration of CCM application needs further investigation. This review aims to present the existing evidence regarding the role of CCM therapy in HF patients and identify gaps and challenges that require further studies.