Structural determinants of ivabradine block of the open pore of HCN4.

HCN1-4 channels are the molecular determinants of the If/Ih current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.

Analysis of changes in the action potential morphology of the mouse sinoatrial node true pacemaker cells during ontogenetic development in vitro and in silico.

BACKGROUND: Maturation of the mouse is accompanied by the increase in heart rate. However, the mechanisms underlying this process remain unclear. We performed an action potentials (APs) recordings in mouse sinoatrial node (SAN) true pacemaker cells and in silico analysis to clarify the mechanisms underlying pre-postnatal period heart rate changes. RESULTS: The APs of true pacemaker cells at different stages had similar configurations and dV/dtmax values. The cycle length, action potential duration (APD90), maximal diastolic potential (MDP), and AP amplitude decreased, meanwhile the velocity of diastolic depolarization (DDR) increased from E12.5 stage to adult. Using a pharmacological approach we found that in SAN true pacemaker cells ivabradine reduces the DDR and the cycle length significantly stronger in E12.5 than in newborn and adult mice, whereas the effects of Ni2+ and nifedipine were significantly stronger in adult mice. Computer simulations further suggested that the density of the hyperpolarization-activated pacemaker сurrent (If) decreased during development, whereas transmembrane and intracellular Ca2+ flows increased. CONCLUSIONS: The ontogenetic decrease in IK1 density from E12.5 to adult leads to depolarization of MDP to the voltage range in which calcium currents are activated, thereby shifting the balance from the "membrane-clock" to the "calcium-clock."

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.

Detection of retinal dysfunction induced by HCN channel inhibitors using multistep light stimulus and long-duration light stimulus ERG in rats.

Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, has been reported to induce photosensitivity-related visual disturbances such as phosphene in humans. Ivabradine-induced visual disturbances are caused by inhibition of HCN channels in the retina, and the mechanisms have been verified using HCN channel knockout mice and electroretinography (ERG). However, in rats, classical ERG using single flash light stimulus with standard analyses of waveform amplitude and latency has not revealed abnormal retinal function after administration of ivabradine. To verify whether retinal dysfunction after ivabradine administration was detectable in rats, we performed ERG using multistep flash light stimulation at the time when plasma concentration of ivabradine was high. Furthermore, the mechanism of the change in the waveform that appeared after the b-wave was investigated. Ivabradine and cilobradine, a selective HCN channel inhibitor, were administered subcutaneously to rats at 4-40 mg/kg as a single dose, and flash or long-duration ERG recordings at each light stimulus luminance were conducted 1.5 h after administration. Plasma and retinal concentrations of both compounds were measured immediately after the ERG recordings. In the flash ERG, prolongation of a- and/or b-wave latencies were detected at each light stimulus, and dose-dependent waveform changes after the b-wave were recorded at the specific light stimulus luminance for both compounds. These ERG changes increased in response to increasing plasma and retinal concentrations for both ivabradine and cilobradine. In the long-duration light stimulus ERG, a change in the waveform of the b-wave trough and attenuation of the c-wave were recorded, suggesting that the feedback control in the photoreceptor cells may be inhibited. This study revealed that the retinal dysfunction by HCN channel inhibitors in rats can be detected by multistep light stimulus ERG. Additionally, we identified that the inhibition of feedback current and the sustained responses in the photoreceptor cells cause the retinal dysfunction of HCN channel inhibitors in rats.

Ivabradine Approved and Other Uses in Clinical Practice: A Systematic Review.

ABSTRACT: Heart rate (HR) stands as a prognostic indicator of cardiovascular disease and a modifiable risk factor in heart failure (HF). Medication intolerance can curtail the application of conventional HR-lowering ß-blockers to the optimum target dose. Ivabradine (IVA), a specific negative-chronotropic agent, selectively inhibits I f current in pacemaker cells of the sinoatrial node without depressing myocardial contractility or comprising hemodynamics. This review summarized ivabradine's clinical labeled and off-label uses and mechanism of action focusing on the clinical outcomes. PubMed was searched up to January 2024 using the main keywords of IVA, coronary artery disease (CAD), HF, postural tachycardia syndrome (POTS), and tachyarrhythmia. To comprehensively review IVA's clinical indications, mechanisms, and therapeutic effects, all studies investigating treatment with IVA in humans were included, comprising different types of studies such as randomized controlled trials and longitudinal prospective observational studies. After screening, 141 studies were included in our review. A large number of reviewed articles were allocated to heart failure with reduced ejection fraction and CAD, suggesting IVA as an alternative to ß-blockers in case of contraindications or intolerance. The beneficial effects of IVA as premedication for coronary computed tomography angiography, HR lowering in POTS, and inappropriate sinus tachycardia constituted most studies among off-label uses. The promising results have been reported on the efficacy of IVA in controlling HR, especially in patients with inappropriate sinus tachycardia or POTS. Owing to the unique mechanism of action, IVA has the potential to be used more frequently in future clinical practice.

Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

Bidirectional flow of the funny current (If) during the pacemaking cycle in murine sinoatrial node myocytes.

Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current (If) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2 to 5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that ß-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of If Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.

Ivabradine for congenital ectopic tachycardia in newborn.

INTRODUCTION: Congenital junctional ectopic tachycardia is a rare arrhythmia that occurs in patients without previous cardiac surgery. In this report, we wanted to present a 6-hour-old newborn with congenital junctional ectopic tachycardia resistant to conventional anti-arrhythmic medications, who was successfully treated with ivabradine and amiadarone combination. CASE: A six-hour-old newborn girl was hospitalised in neonatal ICU because transient tachypnoea of the newborn. She was tachycardic, and supraventricular tachycardia was noticed. There was no answer to the adenosine esmolol treatment; even synchronised direct cardioversion intravenous amiodarone was started. Junctional ectopic tachycardia was diagnosed. We have added propranolol to the treatment and followed patient for 2 days. On the fourth day, junctional ectopic tachycardia rhythm still persisted; therefore, ivabradine treatment was added to the treatment. On the following day, the heart rhythm was slowed to 110/min, and propranolol was stopped; intravenous amiodarone treatment was changed to the oral form. The rhythm turned into sinus; two days after starting ivabradine and oral amiodarone. CONCLUSION: Tachyarrhythmia originating in the atrioventricular node and atrioventricular junction including the bundle of His complex are junctional ectopic tachycardia. Congenital junctional ectopic tachycardia is rare, and it is mostly resistant to the conventional treatment.Ivabradine is a new anti-arrhythmic agent, used extensively to decrease sinus rate in the treatment of cardiac failure. Ivabradine may be an option for the resistant congenital ectopic tachycardia.

A Systematic Review and Meta-Analysis of Randomised Controlled Trials Assessing Clinical and Haemodynamic Outcomes of Ivabradine in Heart Failure With Reduced Ejection Fraction Patients.

BACKGROUND: Ivabradine, a pure bradycardic agent, can be given to heart failure reduced ejection fraction (HFrEF) patients with a sinus rhythm of ≥70 bpm on a maximum beta blocker dose, or when beta blockers are contraindicated. This study aimed to see how ivabradine affects the clinical and haemodynamic outcomes of HFrEF patients. METHODS: This systematic review and meta-analysis searched ClinicalTrials.gov, OpenMD, ProQuest, PubMed, and ScienceDirect for potential articles. All relevant data were extracted. For all pooled effects, the random effect model was applied. RESULTS: A total of 18,972 heart failure (HF) patients from nine randomised clinical trials (RCTs) were involved in this study. Ivabradine decreased the risk of HF mortality (RR 0.79; 95% CI 0.64-0.98; p=0.03) and HF hospitalisation (RR 0.80; 95% CI 0.65-0.97; p=0.03). Ivabradine was related to a greater reduction in heart rate (MD -12.21; 95% CI -15.47 - -8.96; p<0.01) and left ventricular ejection fraction (LVEF) improvement (MD 3.24; 95% CI 2.17-4.31; p <0.01) compared with placebo. Asymptomatic bradycardia (RR 4.25; 95% CI 3.36-5.39; p<0.01) and symptomatic bradycardia (RR 3.99; 95% CI 3.17-5.03; p<0.01) were higher in the ivabradine group. CONCLUSION: Ivabradine can reduce the risk of HF mortality and HF hospitalisation in HFrEF patients. Ivabradine also effectively reduces resting heart rate and improves LVEF. However, ivabradine is associated with a greater risk of symptomatic and asymptomatic bradycardia.

Ivabradine Alleviates Experimental Autoimmune Myocarditis-Mediated Myocardial Injury.

Ivabradine (IVA) reduces heart rate by inhibiting hyperpolarization-activated cyclic nucleotide-gated channels (HCNs), which play a role in the promotion of pacemaker activity in cardiac sinoatrial node cells. HCNs are highly expressed in neural and myocardial tissues and are involved in the modulation of inflammatory neuropathic pain. However, whether IVA exerts any effect on myocardial inflammation in the pathogenesis of heart failure is unclear. We employed single-cell RNA sequencing (scRNA-seq) in porcine cardiac myosin-induced experimental autoimmune myocarditis rat model to determine the effects and mechanisms of IVA. Lewis rats (n = 32) were randomly divided into the normal, control, high-dose-IVA, and low-dose-IVA groups. Heart rate and blood pressure were measured on days 0 and 21, respectively. Echocardiography was performed on day 22, and inflammation of the myocardium was evaluated via histopathological examination. Western blot was employed to detect the expression of HCN1-4, MinK-related protein 1 (MiRP1), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor-ß (TGF-ß). Furthermore, enzyme-linked immunosorbent assay was performed to measure serum IL-1, IL-6, and TNF-α. The relative mRNA levels of collagen I, collagen III, and α-smooth muscle actin (α-SMA) were determined via qRT-PCR. We found that IVA reduced the total number of cells infiltrated into the myocardium, particularly in the subset of fibroblasts, endocardia, and monocytes. IVA administration ameliorated cardiac inflammation and reduced collagen production. Results of the echocardiography indicated that left ventricular internal diameter at end-systole LVIDs increased whereas left ventricular ejection fraction and left ventricular fractional shortening decreased in the control group. IVA improved cardiac performance. The expression of HCN4 and MiRP1 protein and the level of serum IL-1, IL-6, and TNF-α were decreased by IVA treatment. In conclusion, HCNs and the helper proteins were increased in the profile of myocardial inflammation. HCNs may be involved in the regulation of myocardial inflammation by inhibiting immune cell infiltration. Our findings can contribute to the development of IVA-based combination therapies for the future treatment of cardiac inflammation and heart failure.

Efficacy and Tolerability of Ivabradine for Cardiomyopathy in Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.

Clinical Implications of Ivabradine in the Contemporary Era.

Ivabradine is a recently introduced inhibitor of the If ion channel, which exhibits the capacity to reduce heart rate while preserving hemodynamic stability. At present, ivabradine finds its clinical indication in patients suffering from heart failure with reduced ejection fraction and maintaining a relative sinus rhythm refractory to beta-blockers. To optimize heart rate control, it is recommended to pursue an aggressive up-titration of ivabradine. This approach may ameliorate tachycardia-induced hypotension by incrementally enhancing cardiac output and allow further up-titration of agents aimed at ameliorating heart failure, such as beta-blockers. Both the modulation of heart rate itself and the up-titration of agents targeting heart failure lead to cardiac reverse remodeling, consequently culminating in a subsequent reduction in mortality and morbidity. A novel overlap theory that our team proposed recently has emerged in recent times. Under trans-mitral Doppler echocardiography, the E-wave and A-wave closely juxtapose one another without any overlapping at the optimal heart rate. Employing echocardiography-guided ivabradine for heart-rate modulation to minimize the overlap between the E-wave and A-wave appears to confer substantial benefits to patients with heart failure. This approach facilitates superior cardiac reverse remodeling and yields more favorable clinical outcomes when compared to those patients who do not receive echocardiography-guided care. The next pertinent issue revolves around the potential expansion of ivabradine's clinical indications to encompass a broader spectrum of diseases. It is imperative to acknowledge that ivabradine may not yield clinically significant benefits in patients afflicted by heart failure with preserved ejection fraction, acute heart failure, sepsis, or stable angina. An important fact yet to be explored is the clinical applicability of ivabradine in patients with atrial fibrillation, a concern that beckons future investigation. In this review, the concept of overlap theory it introduced, along with its application to expand the indication of ivabradine and the overlap theory-guided optimal ivabradine therapy.

Effects of Ranolazine and Ivabradine on Pulmonary Microhemodynamics in Experimental Model of Pulmonary Thromboembolism.

We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.

Effect of ivabradine on structural and functional changes of myocardium and NT-proBNP levels in patients with stable coronary heart disease after coronary stenting.

OBJECTIVE: Aim: To investigate the effect of ivabradine on the hemodynamics and contractility of the myocardium and the features of NT-pro-BNP production in patients with stable ischemic heart disease after endovascular revascularization of the myocardium depending on the number of affected coronary arteries during 12 months of therapy. PATIENTS AND METHODS: Materials and Methods: The object of the study was 120 patients with stable coronary artery disease: angina pectoris of functional class III with heart failure IIA FC III with preserved and moderately reduced ejection fraction of the left ventricle, who underwent coronary artery stenting. The examined patients were randomized according to the number of affected coronary vessels and the method of treatment. RESULTS: Results: Ivabradine in patients with stable ischemic heart disease after 12 months of therapy had a significant beneficial effect on the structural and functional parameters of the myocardium (contributed to the reverse remodeling of the left ventricle), which did not depend on the number of stented coronary arteries (p<0.05). In patients with stented one coronary artery, all structural and functional indicators of the heart after 12 months of treatment reached the values of practically healthy individuals from the control group. The use of ivabradine in patients with stable ischemic heart disease with heart failure with preserved and intermediate ejection fraction of the left ventricle after coronary stenting made it possible to ensure the correction of a number of clinical and pathogenetic links of the disease, which generally contributed to the improvement of metric and volumetric parameters of the heart. CONCLUSION: Conclusions: Ivabradine made it possible to significantly increase the effectiveness of standard therapy, which was manifested by a faster recovery of the geometry and contractility of the left ventricle. Therefore, the use of ivabradine along with standard therapy was appropriate for such a contingent of patients. The management of patients with stable coronary heart disease should combine adequate (surgical and pharmacological) treatment of the underlying disease, further individual medication correction of symptoms and circulatory disorders inherent in coronary heart disease and heart failure.

[Research progress in the application of ivabradine in children with cardiovascular diseases]. / ä¼Šä¼å¸ƒé›·å®šåœ¨å„¿ç«¥å¿ƒè¡€ç®¡ç–¾ç— ä¸­çš„åº”ç”¨è¿›å±•.

Ivabradine, as a specific If current inhibitor, has been widely used in the treatment of chronic heart failure in adults due to its ability to reduce heart rate without affecting myocardial contractility and blood pressure. It has also shown good effects in various types of tachyarrhythmias. However, the application of ivabradine in pediatric cardiovascular diseases still faces many limitations. This article reviews the current research progress on the use of ivabradine in treating pediatric cardiovascular diseases both domestically and internationally, aiming to provide guidance for pediatric cardiologists. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 782-788.

Sex-specific differences in the efficacy of heart failure therapies: a meta-analysis of 84,818 patients.

Women have been historically underrepresented in clinical trials of heart failure (HF). We aimed to assess for sex differences in patient characteristics and the efficacy of guideline-directed medical therapy (GDMT) in HF. Systematic literature search for randomized controlled trials (RCTs) of GDMT reporting cardiovascular outcomes by sex in patients with HF. The primary outcome was the composite of cardiovascular death and hospitalization for HF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using inverse variance weighting and random effects meta-analysis. Twenty-six RCTs totaling 84,818 participants (27% women) were included. Women with HF were older, had higher New York Heart Association (NYHA) class, more hypertension and obesity, and higher mean left ventricular ejection fraction compared to men. There was evidence for most GDMT in reducing the primary outcome in women with HF with reduced ejection fraction (HFrEF) (angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker [RR 0.86, 95% CI 0.75-0.97], angiotensin-receptor blocker/neprilysin inhibitor (ARNI) [RR 0.77, 95% CI 0.62-0.94], beta-blocker [RR 0.67, 95% CI 0.51-0.89], ivabradine [RR 0.74, 95% CI 0.60-0.91], and sodium-glucose cotransporter-2 (SGLT2) inhibitors [RR 0.66, 95% CI 0.54-0.81]) and a non-significant trend for benefit with mineralocorticoid-receptor-antagonist (MRA) [RR 0.77, 95% CI 0.52-1.16]). Compared to men with HFrEF, GDMT reduced the primary outcome in women to a similar degree across all drug classes (ratio of RR 1.05, 95% CI 0.96-1.14). Despite differences in baseline characteristics and an underrepresentation of women in HF clinical trials, GDMT are as efficacious in women as compared to men in reducing cardiovascular events in HF.

Ivabradine in a 15-day-old male neonate with refractory focal atrial tachycardia.

Ivabradine is used to reduce heart rate in children with chronic heart failure and dilated cardiomyopathy, it has recently been used off-label to treat tachyarrhythmias such as ectopic atrial tachycardia and junctional ectopic tachycardia (JET) in children. We report a successful ivabradine experience in a male neonate with refractory focal atrial tachycardia (FAT).

Ivabradine monotherapy in pediatric patients with focal atrial tachycardia: a single-center study.

This study investigated the efficacy of ivabradine monotherapy in pediatric patients with focal atrial tachycardia (FAT). We prospectively enrolled 12 pediatric patients (7.5 ± 4.5 years; six girls) with FAT who were resistant to conventional antiarrhythmics and received ivabradine as monotherapy. Patients were classified as having tachycardia-induced cardiomyopathy (TIC) if they had a left ventricular ejection fraction (LVEF) of < 50% and a left ventricular end-diastolic dimension (LVDD) z-score of > 2 due to tachycardia. Oral ivabradine was initiated at 0.1 mg/kg every 12 h, increased to 0.2 mg/kg every 12 h if no restoration of stable sinus rhythm was observed after two doses, and discontinued after 48 h if neither rhythm nor heart rate control was observed. Of these patients, six (50%) had incessant atrial tachycardia, and 6 had frequent short episodes of FAT. Six patients were diagnosed with TIC, and their mean LVEF and mean LVDD z-score were 36.2 ± 8.7% (range, 27-48%) and 4.2 ± 1.7 (range, 2.2-7.3), respectively. Finally, six patients achieved either rhythm (n = 3) or heart rate control (n = 3) within 48 h of ivabradine monotherapy. One patient achieved rhythm/heart rate control with ivabradine at a dose of 0.1 mg/kg every 12 h, while the others achieved rhythm/heart rate control at a dose of 0.2 mg/kg every 12 h. Five patients received ivabradine monotherapy for chronic therapy, one (20%) of whom had FAT breakthrough 1 month after discharge, and metoprolol was added. Neither FAT recurrence nor adverse effect (with or without beta-blocker) was observed during a median follow-up of 5 months. CONCLUSION: Ivabradine is well-tolerated and may provide early heart rate control in pediatric FAT and can be considered early, especially in the presence of left ventricular dysfunction. Further investigations are deserved to confirm the optimal dose and long-term efficacy in this population. WHAT IS KNOWN: • Focal atrial tachycardia (FAT) is the most common arrhythmia associated with tachycardia-induced cardiomyopathy (TIC) in children, and the efficacy of conventional antiarrhythmic medications in the treatment of FAT is poor. • Ivabradine is currently the only selective hyperpolarization-activated cyclic nucleotide-gated (HCN) inhibitor, which can effectively low HR without negative effect on blood pressure or inotropy. WHAT IS NEW: • Ivabradine (0.1-0.2 mg/kg every 12 h) can effectively suppress focal atrial tachycardia in 50% of pediatric patients. • Ivabradine provides early control of heart rate and hemodynamic stabilization in children with severe left ventricular dysfunction due to atrial tachycardia within 48 h.

Efficacy of Doppler echocardiography-guided ivabradine therapy.

BACKGROUND: The purpose of this study was to evaluate the advantage of heart rate (HR) modulation using ivabradine referring Doppler echocardiography over the conventional ivabradine therapy without echocardiography guide in patients with systolic heart failure. METHODS: From October 2020, our institute updated the protocol of ivabradine therapy, in which HR was optimized to minimize the overlap between the two left ventricular inflow waves using Doppler echocardiography (echo-guided group). The degree of cardiac reverse remodeling at 3-month follow-up was compared between the echo-guided group and the conventional ivabradine therapy group treated before October 2020. RESULTS: A total of 28 patients (62 years old, 17 men) were included, and 18 patients were from echo-guided group. Left ventricular ejection fraction increased significantly in the echo-guided group (from 41% [28%, 49%] to 55% [37%, 66%], p = 0.007), whereas it remained unchanged in the conventional group (p = 0.333). Systolic blood pressure and the daily dose of carvedilol increased significantly only in the echo-guided group (p = 0.009 and p = 0.001, respectively). CONCLUSIONS: Among those with systolic heart failure, a Doppler echocardiography guide might be a promising therapeutic tool in modulating HR by ivabradine in facilitating reverse remodeling.