Pharmacological management of heart failure: a patient-centered approach.

INTRODUCTION: Heart failure (HF) is a global health challenge that requires a multidisciplinary approach. Despite recent advances in pharmacological and interventional therapy, morbidity and mortality in these patients remain high. For this reason, and because of its interplay with other cardiovascular and non-cardiovascular diseases, HF represents a major area of research, with new trials being published every year and international guidelines constantly updated. AREAS COVERED: The authors review the current status and possible future developments in HF pharmacotherapy. EXPERT OPINION: The treatment of HF has made significant advances in recent years, and the current recommendations are based on large outcome trials. This has led to significant reductions in both mortality and morbidity, but the death rate remains unacceptably high. In this context, a patient-centered approach that considers comorbidities and specific clinical scenarios when dosing HF medication is essential. Prevention of hospital admissions for cardiac decompensation is of utmost importance in patients with HF as is the enablement of activities of daily living, an endpoint which has only recently been incorporated into major HF trials.

Differential effects of myosin activators on myocardial contractile function in non-failing and failing human hearts.

The second-generation myosin activator danicamtiv (DN) has shown improved function compared to the first generation myosin activator omecamtiv mecarbil (OM) in non-failing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared to OM persists in remodeled failing myocardium remain unknown. Therefore, this study aimed to investigate the differential contractile response to myosin activators in non-failing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses, and loaded shortening velocity were analyzed at submaximal [Ca2+] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca2+-sensitivity of force generation were determined by incubating myocardial preparations at various [Ca2+]. The inherent impairment in force generation and cross-bridge behavior sensitized failing myocardium to the effects of myosin activators. Specifically, increased Ca2+-sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared to donor myocardium. Although these effects were less pronounced with DN compared to OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting.

Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.

Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (ß-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of µmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.5) or half-maximal (pCa 5.75) calcium activation, both under control conditions (15 °C; equimolar DMSO; contaminant inorganic phosphate [Pi] ~170 µM) and in the presence of 5 mM [Pi]. The activation state and OM concentration within the contractile lattice were rapidly altered by fast solution switching, demonstrating that the effect of OM was rapid and fully reversible with dose-dependent and myosin isoform-dependent features. In MyHC-7 ventricular myofibrils, OM increased submaximal and maximal Ca2+-activated isometric force with a complex dose-dependent effect peaking (40% increase) at 0.5 µM, whereas in MyHC-6 atrial myofibrils, it had no effect or-at concentrations above 5 µM-decreased the maximum Ca2+-activated force. In both ventricular and atrial myofibrils, OM strongly depressed the kinetics of force development and relaxation up to 90% at 10 µM [OM] and reduced the inhibition of force by inorganic phosphate. Interestingly, in the ventricle, but not in the atrium, OM induced a large dose-dependent Ca2+-independent force development and an increase in basal ATPase that were abolished by the presence of millimolar inorganic phosphate, consistent with the hypothesis that the widely reported Ca2+-sensitising effect of OM may be coupled to a change in the state of the thick filaments that resembles the on-off regulation of thin filaments by Ca2+. The complexity of this scenario may help to understand the disappointing results of clinical trials testing OM as inotropic support in systolic heart failure compared with currently available inotropic drugs that alter the calcium signalling cascade.

Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

New Pharmacotherapeutic Classes for the Management of Heart Failure: A Narrative Review.

Heart failure (HF) is a syndrome characterized by the heart failing to pump blood to the body at a rate proportional to its needs. HF is a public health burden globally and one of the leading causes of hospitalizations in adults. While many classes of drugs have been introduced for the treatment of HF, not every drug may be well-tolerated by patients. In this narrative review, we describe a few of the newer classes of medications proposed to be efficacious in treating acute and chronic HF. We focus on vericiguat, omecamtiv mecarbil, ularitide, and serelaxin, and thoroughly examine their efficacy and safety profiles while summarizing the clinical trials of the drugs. There is a need for more long-term studies comparing the efficacy of these medications to the conventional ones.

Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.

Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking curative therapies. In this study, we examined a cohort of ten NEM2 patients, each with unique pathogenic variants, aiming to understand their impact on mRNA, protein, and functional levels. Results show that pathogenic truncation variants affect NEB mRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with pathogenic splicing variants that are expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with either relatively normal or markedly reduced nebulin. We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a pathogenic duplication variant in nebulin that resulted in a four-copy gain in the triplicate region of NEB and a much larger nebulin protein and longer TFL. Additionally, we investigated the effect of Omecamtiv mecarbil (OM), a small-molecule activator of cardiac myosin, on force production of type 1 muscle fibers of NEM2 patients. OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin. In summary, this study indicates that post-transcriptional or post-translational mechanisms regulate nebulin expression. Moreover, we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from pathogenic splicing variants. Significantly, our findings highlight the potential of OM treatment to improve skeletal muscle function in NEM2 patients, especially those with large reductions in nebulin levels.

Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future.

Heart failure, a prevailing global health issue, imposes a substantial burden on both healthcare systems and patients worldwide. With an escalating prevalence of heart failure, prolonged survival rates, and an aging demographic, an increasing number of individuals are progressing to more advanced phases of this incapacitating ailment. Against this backdrop, the quest for pharmacological agents capable of addressing the diverse subtypes of heart failure becomes a paramount pursuit. From this viewpoint, the present article focuses on Omecamtiv Mecarbil (OM), an emerging chemical compound said to exert inotropic effects without altering calcium homeostasis. For the first time, as a review, the present article uniquely started from the very basic pathophysiology of heart failure, its classification, and the strategies underpinning drug design, to on-going debates of OM's underlying mechanism of action and the latest large-scale clinical trials. Furthermore, we not only saw the advantages of OM, but also exhaustively summarized the concerns in sense of its effects. These of no doubt make the present article the most systemic and informative one among the existing literature. Overall, by offering new mechanistic insights and therapeutic possibilities, OM has carved a significant niche in the treatment of heart failure, making it a compelling subject of study.

Mechanical and signaling responses of unloaded rat soleus muscle to chronically elevated ß-myosin activity.

It has been reported that muscle functional unloading is accompanied by an increase in motoneuronal excitability despite the elimination of afferent input. Thus, we hypothesized that pharmacological potentiation of spontaneous contractile soleus muscle activity during hindlimb unloading could activate anabolic signaling pathways and prevent the loss of muscle mass and strength. To investigate these aspects and underlying molecular mechanisms, we used ß-myosin allosteric effector Omecamtiv Mekarbil (OM). We found that OM partially prevented the loss of isometric strength and intrinsic stiffness of the soleus muscle after two weeks of disuse. Notably, OM was able to attenuate the unloading-induced decrease in the rate of muscle protein synthesis (MPS). At the same time, the use of drug neither prevented the reduction in the markers of translational capacity (18S and 28S rRNA) nor activation of the ubiquitin-proteosomal system, which is evidenced by a decrease in the cross-sectional area of fast and slow muscle fibers. These results suggest that chemically-induced increase in low-intensity spontaneous contractions of the soleus muscle during functional unloading creates prerequisites for protein synthesis. At the same time, it should be assumed that the use of OM is advisable with pharmacological drugs that inhibit the expression of ubiquitin ligases.

Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights.

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome.

Pharmacological Treatment of Heart Failure: Recent Advances.

BACKGROUND: Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the body. The pharmacological management of heart failure has been revolutionized over the past decade with novel treatments. OBJECTIVE: The aim of the review is to highlight the recent pharmacological advances in the management of heart failure. RESULTS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i), iron carboxymaltose, finerenone, omecamtiv mecarbil, and vericiguat have been shown to reduce hospitalization for heart failure. However, only SGLT2i, vericiguat, and omecamtiv mecarbil have been shown to reduce cardiovascular death. Finerenone has been shown to reduce cardiovascular events and renal adverse outcomes in patients with diabetes and kidney disease. Currently, only SGLT2i has been studied in patients beyond the heart failure with reduced ejection fraction population. CONCLUSION: The current quadruple therapy in the treatment of heart failure has demonstrated a reduction in the hospitalization of patients and a decrease in mortality associated with the condition. Individualized heart failure therapy research have shown some benefit in select heart failure patients. Further research on novel therapies will help improve heart failure patient outcomes.

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator.

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

Advances in the Management of Heart Failure with Reduced Ejection Fraction; The Role of SGLT2is, ARNI, Myotropes, Vericiguat, and Anti-inflammatory Agents: A Mini-review.

Heart failure with reduced ejection fraction (HFrEF) has been associated with poor prognosis, reduced quality of life, and increased healthcare expenditure. Despite tremendous advances in HFrEF management, reduced survival and a high rate of hospitalization remain unsolved issues. Furthermore, HFrEF morbidity and economic burden are estimated to increase in the following years; hence, new therapies are constantly emerging. In the last few years, a series of landmark clinical trials have expanded our therapeutic armamentarium with a ground-breaking change in HFrEF-related outcomes. Sodium-glucose co-transporter 2 inhibitors (mainly dapagliflozin and empagliflozin) have already revolutionized the management of HFrEF patients via a significant reduction in cardiovascular mortality and heart failure hospitalizations. Furthermore, vericiguat and omecamtiv mecarbil have emerged as promising and novel disease-modifying therapies. The former restores the impaired cyclic guanosine monophosphate pathway, and the latter stimulates cardiac myosin without marked arrhythmogenesis. Both vericiguat and omecamtiv mecarbil have been shown to reduce heart failure admissions. Sacubitril/valsartan is an established and effective therapy in HFrEF patients and should be considered as a replacement for angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs). Lastly, inflammasome activity is implicated in HFrEF pathophysiology, and the role of anti-inflammatory agents in HFrEF trajectories is readily scrutinized, yet available therapies are ineffective. This mini-review summarizes the major and most recent studies in this field, thus covering the current advances in HFrEF therapeutics.

Omecamtiv mecarbil augments cardiomyocyte contractile activity both at resting and systolic Ca2+ levels.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca2+ -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included. METHODS: Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca2+ -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations. RESULTS: SL was reduced by about 23% or 9% in the presence of 1 µM OM or 1 µM EMD in the absence of electrical stimulation, whereas 1 µM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 µM EMD or 1 µM Levo to about 152%, but only to about 128% in the presence of 0.03 µM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1 µM Levo had no effects on contraction durations. One-micromole Levo, but not 1 µM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca2+ transient amplitudes were unaffected by all treatments. CONCLUSIONS: Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca2+ -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca2+ -sensitizing effect.

Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.

Phospholamban (PLN) is a major regulator of cardiac contractility, and human mutations in this gene give rise to inherited cardiomyopathies. The deletion of Arginine 14 is the most-prevalent cardiomyopathy-related mutation, and it has been linked to arrhythmogenesis and early death. Studies in PLN-humanized mutant mice indicated an increased propensity to arrhythmias, but the underlying cellular mechanisms associated with R14del-PLN cardiac dysfunction in the absence of any apparent structural remodeling remain unclear. The present study addressed the specific role of myofilaments in the setting of R14del-PLN and the long-term effects of R14del-PLN in the heart. Maximal force was depressed in skinned cardiomyocytes from both left and right ventricles, but this effect was more pronounced in the right ventricle of R14del-PLN mice. In addition, the Ca2+ sensitivity of myofilaments was increased in both ventricles of mutant mice. However, the depressive effects of R14del-PLN on contractile parameters could be reversed with the positive inotropic drug omecamtiv mecarbil, a myosin activator. At 12 months of age, corresponding to the mean symptomatic age of R14del-PLN patients, contractile parameters and Ca2+ transients were significantly depressed in the right ventricular R14del-PLN cardiomyocytes. Echocardiography did not reveal any alterations in cardiac function or remodeling, although histological and electron microscopy analyses indicated subtle alterations in mutant hearts. These findings suggest that both aberrant myocyte calcium cycling and aberrant contractility remain specific to the right ventricle in the long term. In addition, altered myofilament activity is an early characteristic of R14del-PLN mutant hearts and the positive inotropic drug omecamtiv mecarbil may be beneficial in treating R14del-PLN cardiomyopathy.

KCCQ total symptom score, clinical outcome measures, and adverse events associated with omecamtiv mecarbil for heart failure with reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Omecamtiv mecarbil (OM) is a direct myosin activator that augments left ventricular systolic function. This review compares OM to placebo by evaluating its effect on clinical outcomes and adverse events in patients with heart failure with reduced left ventricular ejection fraction. METHODS AND RESULTS: A literature search of multiple databases for randomized controlled trials (RCTs) investigating OM versus placebo was undertaken. Six RCTs comprising 9596 patients were included. Use of OM was associated with a reduced risk of stroke (RR: 0.69; 95% CI 0.52-0.92). There was no significant mean difference (MD) change in the KCCQ total symptom score (MD: 1.82, 95% CI - 1.33 to 4.97), all-cause death (RR: 1.00; 95% CI 0.93-1.07), hospital readmissions (RR: 0.96; 95% CI 0.90-1.03), myocardial infarction (RR: 1.05; 95% CI 0.83-1.33), cardiovascular death (RR: 1.01; 95% CI 0.92-1.10), heart failure (HF) events (RR: 0.95; 95% CI 0.89-1.02), or a composite of cardiovascular death or HF events (RR: 0.97; 95% CI 0.93-1.02). In addition, OM was associated with an increased risk of dizziness (RR: 1.25; 95% CI 1.04-1.50) and hypotension (RR: 1.17; 95% CI 1.01-1.36). Other adverse events including ventricular tachyarrhythmias, (RR: 0.95; 95% CI 0.82-1.11), supraventricular tachyarrhythmias and atrial fibrillation/flutter (RR: 0.73; 95% CI 0.46-1.18), dyspnea (RR: 1.00; 95% CI 0.86-1.18), and acute renal injury (RR: 0.88; 95% CI 0.60-1.27) were not significant. CONCLUSION: OM is generally well tolerated. We identified a reduced risk of stroke with use of OM. However, there was no improvement in other clinical outcomes or quality of life. Study protocol was registered in PROSPERO international prospective register of systematic reviews (CRD42022348423).

Altered Left Ventricular Rat Gene Expression Induced by the Myosin Activator Omecamtiv Mecarbil.

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) α and γ, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta (Cacna1c) in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility.

Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity.

Modulation of sarcomere contractility represents a new therapeutic opportunity for the treatment of heart failure by directly targeting the thick and thin filament proteins of the sarcomere to increase cardiac muscle contraction. This study compared the effect of 2 small molecules (M and T) that selectively alter myosin thick filament (M) or troponin thin filament (T) activity on overall cardiac muscle mechanics. This study revealed key differences related to the mechanism utilized by M and T to increase contractile force generation and suggests that targeting different proteins within the sarcomere may result in differentiating therapeutic profiles.

Detection of soluble suppression of tumorigenicity 2 and N-terminal B-type natriuretic peptide in a rat model of aortic regurgitation: differential responses to omecamtiv mecarbil.

OBJECTIVES: Both N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and soluble isoform of ST2 (sST2) have been identified as biomarkers of heart failure. We evaluated the plasma levels of NT-proBNP and sST2 in a rat model of severe aortic valve regurgitation (AR) and correlated these findings with echocardiographic measurements. We also examined the impact of omecamtiv mecarbil (OM) on these parameters. METHODS: The plasma levels of NT-proBNP and sST2 were measured in 18 rats both before and 2 months after surgical induction of AR, and at these same time points, in six rats assigned to a sham-procedure control group. Plasma biomarkers were then measured again after infusion of OM or placebo in rats with AR (n=8 and 10, respectively) and OM alone in the sham control rats (n=6). Echocardiographic measurements were collected before and 2 months after induction of AR. RESULTS: Our results revealed increased levels of plasma NT-proBNP (219 ± 34 pg/mL vs. 429 ± 374 pg/mL; p<0.001) in rats with AR at day 7 after infusion of placebo, whereas plasma levels of sST2 were higher in this cohort after infusion of either OM or placebo. We identified a significant positive correlation between plasma sST2 with posterior wall thickness in diastole (r=0.34, p<0.05) and total body weight (r=0.45, p<0.01) in rats with surgically induced AR. CONCLUSIONS: Because sST2 increased markedly, whereas NT-proBNP remained unchanged, when OM was administered, we hypothesize that sST2 has a distinct capability to detect deleterious effects of passive muscle tension, not reliably assessed by NT-proBNP, in the setting of AR.