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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.

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.

Evaluating the role of ivabradine in acute decompensated heart failure: A systematic review and meta-analysis.

BACKGROUND: Acute decompensated heart failure (ADHF) presents a significant global health challenge, with high morbidity, mortality, and healthcare costs. The current therapeutic options for ADHF are limited. Ivabradine, a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, has emerged as a potential therapy for ADHF by reducing the heart rate (HR) without negatively affecting myocardial contractility. However, the evidence regarding the efficacy and safety of ivabradine in patients with ADHF is limited and inconsistent. This meta-analysis aimed to evaluate the efficacy and safety of ivabradine for ADHF based on observational studies. METHODS: A systematic literature search was conducted following PRISMA guidelines to identify relevant observational studies comparing ivabradine with placebo in adult patients with ADHF. Data were pooled using a random-effects model, and heterogeneity was assessed. The risk of bias was evaluated using the Newcastle-Ottawa Scale. RESULTS: Four observational studies comprising a total of 12034 patients. Meta-analysis revealed that ivabradine significantly reduced all-cause mortality (RR: 0.66, 95 % CI: 0.49-0.89, p < 0.01) and resting HR (MD: -12.54, 95 % CI: -21.66-3.42, p < 0.01) compared to placebo. However, no significant differences were observed in cardiovascular mortality, hospital readmission for all causes, changes in LVEF, or changes in LVEDD. Sensitivity and publication bias assessments were conducted for each outcome. CONCLUSION: Ivabradine may be beneficial for reducing mortality and HR in patients with ADHF. However, its impact on other clinical outcomes such as cardiovascular mortality, hospital readmission, and cardiac function remains inconclusive. Further research, particularly well-designed RCTs with larger sample sizes and longer follow-up durations, are warranted.

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.

Hyperpolarization-activated cyclic nucleotide-gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation.

Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone-driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in cardiac pacemaker cells. However, in post-MI hearts, HCN can also be expressed ectopically in non-pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species-induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases.

The efficacy and safety of ivabradine hydrochloride in hemodialysis patients with chronic heart failure.

INTRODUCTION: There is little evidence for ivabradine hydrochloride in patients undergoing hemodialysis. METHODS: In this open-label prospective interventional trial of hemodialysis patients with chronic heart failure, during 12 weeks of treatment, changes in Heart rate (HR), frequency of dialysis-related hypotension were examined, and we investigated health-related quality of life (HR-QOL) and adverse effects. RESULTS: 18 patients from 6 facilities were enrolled in the study. HR significantly decreased over time, from 87 ± 12.61/min at baseline to 75.85 ± 8.91/min (p = 0.0003), and systolic blood pressure also increased significantly (p < 0.0001). The frequency of dialysis-related hypotension was markedly reduced (p = 0.0001). The HR-QOL survey showed significant improvements in Social Functioning among others (p = 0.0178). No specific adverse events occurred. CONCLUSION: Ivabradine hydrochloride improved dialysis-related hypotension. Furthermore, the HR-QOL improvement effect were suggested. These results demonstrated the safety and effectiveness of ivabradine hydrochloride.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

AIMS: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. METHODS AND RESULTS: This multicentre, single-arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment-emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor-neprilysin inhibitor (ARNI) or beta-blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP changed by -331.9 ng/L (-1238.6, -134.0) and -1113.8 ng/L (-2202.0, -297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta-blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta-blocker subgroups (21.9-35.6%). CONCLUSIONS: Ivabradine treatment reduced HR and improved cardiac function and health-related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta-blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.

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.

Ivabradine could not decrease mitral regurgitation triggered atrial fibrosis and fibrillation compared with carvedilol.

BACKGROUND: Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta-blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta-blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. METHODS AND RESULTS: Using a novel echo-guided mini-invasive surgery, MR was created in 12-weeks-old Sprague-Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two-week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR-induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR-induced chamber dilatation (end-systolic volume and end-diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end-systolic pressure-volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01). CONCLUSIONS: Although both ivabradine and carvedilol, at least in part, mitigated MR-induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR-induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings.

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.