Effects Of Ivabradine Research Articles

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

Effect of ivabradine in heart failure: a meta-analysis of heart failure patients with reduced versus preserved ejection fraction.

In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646beats/min) and HFpEF (-11.434beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p= 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p< 0.001) when compared with placebo (p< 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment.

PD27-07 BEDSIDE TO BENCHTOP RESEARCH UNCOVERS THE FUNCTIONAL ROLE OF HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED GATED (HCN) CHANNELS IN AGING BLADDER PHENOTYPE

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (PD27)1 Sep 2021PD27-07 BEDSIDE TO BENCHTOP RESEARCH UNCOVERS THE FUNCTIONAL ROLE OF HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED GATED (HCN) CHANNELS IN AGING BLADDER PHENOTYPE Nishant Singh, Irina Zabbarova, Anthony Kanai, Christopher Chermansky, Naoki Yoshimura, and Pradeep Tyagi Nishant SinghNishant Singh More articles by this author , Irina ZabbarovaIrina Zabbarova More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Christopher ChermanskyChristopher Chermansky More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Pradeep TyagiPradeep Tyagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002020.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aging bladder phenotype in detrusor overactivity, detrusor underactivity or detrusor hyperactivity with impaired contractility patients is characterized by detrusor instability with or without the loss of bladder volume sensitivity. Since separate studies reported age related downregulation of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in mouse and human bladder, we examined the functional significance of age related reduction in HCN activity with multiple oral dosing of FDA approved HCN blocker, Ivabradine. METHODS: Aged male Fisher 344 rats (n=15) and young rats of both genders (n=15) were left untreated or treated daily with oral gavage of either vehicle or Ivabradine 6mg/kg (n=5) for 7 days prior to assessing nocturnal urination followed by awake cystometry on 7th day and quantitative RT-PCR and Western blot of HCN subtypes of untreated aged and young rats. RESULTS: Untreated aged aged rats (n=10) voided nearly double the volume of individual voids of young rats at night time (0.82±0.22 mL vs 0.41±0.12 mL, p<0.05), which was confirmed by a significant increase (p<0.05) in the micturition volume threshold (VT) in awake cystometry of aged rats. Increase in VT of aged rats coincided with a doubling of non-voiding contraction (NVC) frequency (p<0.05) while maximum voiding pressure (MVP) did not change with age. The age- related alterations in cystometry parameters correlated with the significant downregulation of cAMP sensitive HCN1and HCN2 subtype (40%) and the upregulation of cAMP insensitive HCN3 (60%) subtype. Ivabradine treatment significantly increased the VT (p<0.005), NVC frequency (p<0.001) and MVP (p<0.0001) in young and aged rats to different extents. CONCLUSIONS: A critical role for the altered bladder expression of HCN subtypes in the manifestation of aging bladder phenotype is supported by the dramatic changes in the bladder function following pharmacological blockade of HCN channels in young rats. The dramatic effect of Ivabradine on VT and MVP of aged rats in this bedside to benchtop research provides a basis for the therapeutic benefit of Ivabradine on detrusor underactivity of a male patient (Int Urol Nephrol, 40: 333, 2008). Source of Funding: NIA- AG062971 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e446-e446 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nishant Singh More articles by this author Irina Zabbarova More articles by this author Anthony Kanai More articles by this author Christopher Chermansky More articles by this author Naoki Yoshimura More articles by this author Pradeep Tyagi More articles by this author Expand All Advertisement Loading ...

The Functional Role of Hyperpolarization Activated Current (I f) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study.

The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.

Effectiveness of enteral ivabradine for heart rate control in septic shock: A randomised controlled trial.

Persistent tachycardia in patients with septic shock predicts poor outcome. This study sought to investigate the effect of the cardiac pacemaker current inhibitor ivabradine on heart rate and cardio-circulatory function in patients with septic shock. After informed consent, 60 patients with septic shock and persistent tachycardia (heart rate >95 /minute) were prospectively randomly assigned to receive either standard therapy for septic shock (group S) or standard therapy along with enteral ivabradine (group I) for the initial 96 hours after enrolment. Primary outcome was the difference in heart rate between the two groups during the first 96 hours. Secondary outcomes included the effect of ivabradine on haemodynamic, oxygenation, myocardial function and organ function parameters, incidence of adverse events and 30-day overall survival. Heart rate was lower in group I compared to group S (median difference in area under the curve -25.6 (95% confidence intervals -31.4 to -15.9) /minute; P <0.001). Vasopressor requirements, blood lactate levels, Sequential Organ Failure Assessment scores and E/e' ratio were lower in group I compared to group S. Stroke volume index and ejection fraction were higher in group I while cardiac index and oxygen delivery parameters were maintained similar to group S. There was no difference in 30-day mortality or in the incidence of serious adverse events. Enteral ivabradine is effective in reducing heart rate, and improving haemodynamic parameters and cardiac function in patients with septic shock and persistent tachycardia, without increasing the incidence of adverse events.

The association between ivabradine and adverse cardiovascular events in acute decompensated HFrEF patients.

AimsIvabradine has been used in patients who have chronic heart failure (HF) with reduced ejection fraction (HFrEF) and concomitant sinus heart rate ≥70 bpm. This administration for acute HFrEF remains a concern. This study used a real‐world multicentre database to investigate the effects of ivabradine among patients with acute decompensated HFrEF before discharge.Methods and resultsThis study retrospectively identified patients with acute decompensated HFrEF who were administered ivabradine at discharge from two multicentre HF databases. Propensity score matching was performed to adjust for confounders. Cardiovascular mortality, all‐cause mortality, and recurrent HF rehospitalization risks were then compared between those with and without ivabradine treatment. After 1:2 propensity score matching, 876 patients (age, 60.7 ± 14.6 years; female, 23.2%; left ventricular ejection fraction, 28.2% ± 7.8%; and heart rate at discharge, 84.3 ± 13.8 bpm) were included in the final analysis, including 292 and 584 patients with and without ivabradine treatment at discharge, respectively. No significant differences were observed in baseline characteristics between the two groups. At 1 year follow‐up, patients in the ivabradine group had significantly lower heart rates (77.6 ± 14.7 vs. 81.1 ± 16.3 bpm; P = 0.005) and lower HF severity symptoms (New York Heart Association Functional class, 2.1 ± 0.7 vs. 2.3 ± 0.9; P < 0.001) than those from the non‐ivabradine group. Ivabradine users had significantly lower risks of 1 year cardiovascular mortality (5.8 vs. 12.2 per 100‐person year; P = 0.003), all‐cause mortality (7.2 vs. 14.0 per 100‐person year; P = 0.003), and total HF rehospitalization (42.3 vs. 72.6 per 100‐person year; P < 0.001) than non‐ivabradine users. Following multivariate analysis, the predischarge prescription of ivabradine remained independently associated with lower 1 year all‐cause mortality (hazard ratio, 0.45; 95% confidence interval, 0.28–0.74; P = 0.002) and cardiovascular mortality (hazard ratio, 0.41; 95% confidence interval, 0.24–0.72; P = 0.002).ConclusionsThe current study findings suggest that ivabradine treatment is associated with reduced risks of cardiovascular mortality, all‐cause mortality, and HF rehospitalization within 1 year among patients with acute decompensated HFrEF in real‐world populations.

The Effect of Ivabradine on Hospitalization of Heart Failure Patients: A Retrospective Cohort Study.

Background:Ivabradine is recommended in heart failure (HF) patients to reduce cardiovascular death and hospitalization due to worsening of HF symptoms.Aims and Objectives:To study the effect of Ivabradine in addition to guideline-directed medical therapy (GDMT) in a group of HF patients with HR more than 70 bpm, HF with reduced ejection fraction (HFrEF) left ventricular ejection fraction (LVEF ≤ 40%), and New York Heart Association class II-IV.Methods:The study was conducted at Heart Hospital, Hamad Medical Corporation, Qatar. HF patients with age > 18 years, LVEF ≤40%, on GDMT, and HR of ≥70 bpm were included. The study population was divided into two groups: ivabradine group and non-ivabradine group. The primary outcomes were risk, number and length of hospitalizations due to worsening HF, and cardiovascular mortality. The secondary outcome was all-cause mortality. Baseline characteristics were collected at enrollment. Study outcomes were compared in the two groups by applying Chi-square and Fisher's exact tests. Logistic regression model was applied to assess both hospitalizations and cardiovascular mortality.Results:A total of 111 patients were studied, 37 (33.94%) ivabradine group and 74 (66.67%) non-ivabradine group. Risk of hospitalization was lower in Ivabradine group compared to non-Ivabradine group (odds ratio: 0.43, 95% confidence interval [CI]: 0.16–1.015, P = 0.094). Average length of hospitalization in ivabradine and non-ivabradine groups was 12.54 and 8.91 days, respectively (incidence rate ratio [IRR]: 1.63, 95% CI: 0.79–3.38, P = 0.187). Compared to non-ivabradine, ivabradine patients had lower number of hospitalizations (IRR: 1.13, 95% CI: 0.61–2.11, P = 0.694). Death rate in both ivabradine and non-ivabradine groups was 3.Conclusions:Ivabradine along with GDMT reduces the risk of hospitalization due to worsening HF symptoms. Ivabradine had no significant effect on cardiovascular mortality and all-cause mortality. HFrEF non-Arabs patients have lower risk, number and length of hospitalization, and mortality compared to Arabs.

Abstract P184: Cardioprotective Effects Of Ivabradine After Coronary Revascularization: A Systematic Review

Background: The perioperative management of cardiac risk for patients undergoing coronary revascularization has mostly centered around beta-blockers (BB). Ivabradine is a much newer drug that has been approved for stable angina and heart failure not fully controlled by BB. Emerging evidence suggests that it may have cardioprotective effects in high-risk cardiac patients. The objective of this study was to summarize the evidence on the use and effects of ivabradine in coronary revascularization patients. Methods: We performed a systematic review using the PubMed, EMBASE, and Google Scholar databases for studies published between 2010 and 2020. Two independent investigators reviewed studies reporting information on ivabradine use following coronary revascularization. We excluded articles written in languages other than English. Results: Eleven studies met our inclusion criteria, including a total of 3,847 patients (1994 with percutaneous coronary intervention [51.8%], 1680 with coronary artery bypass graft [43.7%], and 173 with other type of intervention [4.5%]). The studies were from seven different countries: Egypt, France, Germany, Greece, Italy, Romania, and Spain. The mean age ranged from 56.5 to 74.3. Males accounted for 70.9% of the patients, resulting in an M:F ratio of 1.4:1. For studies that compared the use of ivabradine to placebo/control, the latter being defined as standard medical therapy that either did or did not include BB, the results showed that the use of ivabradine resulted in significant reduction of heart rate, decreased number of angina attacks, lower nitrate consumption, improvement in quality of life, and increased cardiac index. Studies that compared the effects of ivabradine monotherapy to BB monotherapy showed that the former was associated with a higher rate of atrial fibrillation, but an overall better quality of life as measured by the EuroQol questionnaire. When combined therapy with ivabradine and BB was compared to BB monotherapy, the former was associated with a significant increase in diastolic function, improvement in left ventricular ejection fraction, and a decrease in incidence of arrhythmias. Eight of the eleven studies reported adverse events related to ivabradine use, the most frequent being bradycardia (range: 0 to 7.1%), phosphenes (range: 0 to 0.3%), and blurred vision (range: 0 to 0.2%). Conclusions: This study demonstrates that ivabradine may be used alone or in addition to BB to reduce adverse cardiac events and improve the quality of life in patients undergoing coronary revascularization. However, there is no evidence that ivabradine is superior to BB when used alone. Further studies are needed to determine the optimal medical management for patients undergoing coronary revascularization.

Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats.

Background: The complex interactions that exist between the pacemaker current, I f, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the I f blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to in situ and in vitro parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for I f, was also evaluated. Methods: Sympathetic and parasympathetic heart rate variability parameters and right atrial HCN(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to in situ electrical stimulation of the vagus nerve (2–20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10−9–10−6 mol/L) was also assessed in these later rats. Results: Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, in situ vagus nerve stimulation induced progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher right atrial HCN4 expression (p = 0.02). Conclusion: Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in situ vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term I f blockade may protect against excessive bradycardia induced by acute vagal activation.

Effect of ivabradine on heart rate, functional capacity and pulmonary artery pressure in patients of COPD with cor pulmonale

We studied the effects of heart rate reduction by ivabradine to the ongoing therapy in patients with chronic obstructive pulmonary disease (COPD) and cor pulmonale.100 patients of COPD with cor pulmonale with sinus heart rate ≥ 90 bpm were randomly assigned to either ivabradine 5 mg twice daily (50 patients) or placebo (50 patients) alongwith standard therapy. Assessment was done at baseline and after 6 months which included 6 min walk test (6MWT), dyspnea scoring by modified borg scale, Lung function test by forced expiratory volume in 1 s (FEV1) and pulmonary artery systolic pressure (PASP) by echocardiogram. The drug group showed a significant reduction in heart rate from 95.1 ± 8.2 bpm to 71.1 ± 6.2 bpm (p < 0.001). This group also showed significant improvement in 6-min walk distance and dyspnea on modified Borg scale (p < 0.001) at 6 months follow up. However no significant difference was found between both groups regarding PASP or FEV1 at 6 months.

Efficacy of ivabradine in HIV-associated dilated cardiomyopathy.

Ivabradine is a pure heart rate-lowering drug that acts directly on the sinus node and does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization. Ivabradine is used in the treatment of adults with New York Heart Association (NYHA) class II-IV chronic heart failure (CHF) with systolic dysfunction, in sinus rhythm, with a heart rate of ≥75 beats per minute (bpm). This report describes the beneficial effect of ivabradine on clinical parameters in a HIV-infected patient with dilated cardiomyopathy presenting with NYHA class III CHF symptoms. Ivabradine improved functional capacity and left ventricular (LV) systolic function in our patient with HIV-related dilated cardiomyopathy and CHF. This report also lists the summaries of potential clinically significant interaction, likely to require additional monitoring, alteration of drug dosage or timing of administration, between ivabradine and antiretroviral drugs.

Synergistic effects of ivabradine and metformin in the treatment of concomitant chronic heart failure and diabetes mellitus by regulating the activity of the H19/miR-423-5p/HCN4 axis

IntroductionIn this study, the molecular mechanisms underlying the therapeutic effect of metformin (MET) and ivabradine (IBD) in the treatment of concomitant chronic heart failure (CHF) and diabetes mellitus (DM) were investigated.Material and methodsBasic and cardiac indexes were measured to study the therapeutic effect of MET and IBD. Real-time PCR, IHC assays, in-silicon analysis, luciferase assays, real-time PCR and Western blot assays were conducted to clarify the molecular mechanisms underlying the interaction between MET and IBD.ResultsMET administration restored the normal values of general/cardiac indexes in CHF rats. The abnormal values of echocardiographic indexes in CHF rats with STZ-induced DM were all corrected by a certain degree after the MET administration. Moreover, the injection of STZ up-regulated the expression of plasma NE/BNP-45, while the IBD administration reduced the levels of NE/BNP-45 in CHF rats. Furthermore, the administration of MET also reduced the NE level in CHF rats, indicating that both MET and IBD can exert a therapeutic effect on CHF rats. Additionally, in-silicon analysis and luciferase assays verified the role of H19 and HCN4 as target genes of miR-423-5p. In fact, the transfection of MET or H19 siRNA1/2 into HL-1 and H9C2 cells down-regulated the levels of H19 and HCN4 while increasing the level of miR-423-5p.ConclusionsMET reduces H19 expression via inducing methylation of its promoter, and the inhibited H19 expression suppresses HCN4 expression by up-regulating miR-423-5p expression. As a result, the suppressed expression of HCN4 reduces heart rate and exhibits a therapeutic effect in the treatment of concomitant CHF and DM.

Hemodynamic Effect of Ivabradine in Young Girl with Acute Heart Failure

<h3>Introduction</h3> Few data are currently available on the use of Ivabradine in children with heart failure (HF). This medication has recently proved to be useful in decreasing heart rate (HR) and in improving left ventricular (LV) function in pediatric population with chronic HF. No data are reported in case of advanced HF and/or in acute phase. <h3>Case Report</h3> We report a case of a 12-year-old girl affected by dilated/LV non-compaction cardiomyopathy and Wolf-Parkinson-White syndrome (WPWS) and presenting with acute HF admitted to Intensive care. At admission, she presented with clinical signs of inadequate perfusion (vasoconstriction, pallor, sweating, cool extremities) and pulmonary rales (cold-wet phenotype). The pro-NT-BNP was 10650 pg/ml. Echocardiography demonstrated a markedly dilated LV with severe systolic dysfunction (LVEF 17%) and a mildly dilated left atrium and moderate-severe mitral insufficiency. The right ventricle was quite normal with mild tricuspid insufficiency with normal PSVD. Intravenously medical treatment was started with dopamine [6 mcg/kg/min], milrinone [0,5 mcg/kg/min], furosemide. After dopamine weaning, the patient was still tachycardic and echocardiography confirmed EF of 14%. Ivabradine was started at 2,5 mg twice a day in PICU setting. After introduction of ivabradine we observed an acute reduction of heart rate from 97 to 70 bpm in 24 h. The hourly hemodynamic monitoring with MOST care ® showed an increase of Cardiac Index from 2.0 (at baseline) to 3.0 after 24 h and an increase of Stroke volume from 35 ml to 60 ml after 24 h. No changes in blood pressure were reported [figure 1] <h3>Summary</h3> Our case suggests that in children with advanced HF and markedly depressed LV function, the acute administration of ivabradine is well tolerated. Ivabradine seems a favourable approach for treatment of children with advanced heart failure, effective in reduction of HR, able to increase stroke volume and cardiac output. Further studies are required to assess the feasibility and efficacy of this drug.

Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta-analysis of randomized controlled trials.

Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta‐analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta‐blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = −9.57; 95% CI ‐11.15, −8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = −3.73; 95% CI ‐4.25, −3.21, LVESV; MD = −17.00, 95%CI ‐29.65, −4.35, LVEDD; MD = −1.43, 95%CI ‐2.78, −0.08, LVEDV; MD = −14.75, 95%CI ‐34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI ‐10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.

Ivabradine and Blood Pressure Reduction: Underlying Pleiotropic Mechanisms and Clinical Implications

Elevated heart rate (HR) is a well-recognized but somewhat neglected risk factor among the healthy population and various cardiovascular pathologies (1). High HR is fraught with a spate of detrimental cardiovascular consequences including immense myocardial oxygen demand in reduced diastolic perfusion time (2) and low, oscillatory vascular shear stress with high tensile stress triggering endothelial dysfunction (3). Although beta-blockers (BBs) are considered to be the cornerstone treatment of elevated HR in various cardiovascular pathologies, they are associated with negative inotropy, a number of side effects, and undesirable metabolic actions limiting their usage (4, 5). Thus, new approaches to HR reduction are being continuously sought out. The inhibition of the If current in the sinoatrial node (SAN) seems to offer a promising approach to the reduction of elevated HR. Indeed, the SAN's pacemaker cells are inherently capable of cyclic variations of the resting membrane potential necessary for spontaneous depolarization. The SAN's spontaneous slow diastolic depolarization is administered by a mixed sodium/potassium inward current, known as an If current, through the “funny” (f)-channel (6). Structurally, the f-channel belongs to hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and is activated by both hyperpolarization in the diastolic voltage range and intracellular cyclic adenosine monophosphate (7). Ivabradine selectively inhibits the If current, thus reducing the steepness of SAN's diastolic depolarization, ensuing diastole prolongation without affecting action potential duration or inducing negative inotropy (7, 8). Several studies have assessed ivabradine's efficacy in clinical settings. In the SHIFT study, the investigation of 6,558 patients with systolic heart failure (HF) during a median 22.9 month follow-up period revealed that the addition of ivabradine to an established HF therapy significantly reduced the primary composite endpoint of hospital admission for worsening HF or cardiovascular death. Considering the results of the SHIFT study, ivabradine is recommended for patients with systolic HF and HR above 70 bpm despite an evidence-based optimal medical therapy (with or without BB) to reduce the composite endpoint of hospitalization and mortality (9, 10). The BEAUTIFUL study comprised 10,917 systolic HF patients with HR above 70 bpm suffering from stable coronary artery disease (CAD), and the primary endpoint was a composite of cardiovascular death and hospital admission for acute myocardial infarction or HF. Although neither the primary endpoint nor the cardiovascular death rate improved, ivabradine reduced the secondary endpoints of hospital admissions for myocardial infarction and coronary revascularization (11). However, in the SIGNIFY study involving 19,102 patients with stable CAD but without HF, ivabradine did not reduce the compound primary endpoint of cardiovascular death and myocardial infarction (12). Hypertension, however, is a substantially different condition, and data regarding ivabradine's effect on peripheral blood pressure (BP) in a hypertensive population are scanty. Yet ivabradine's interference with central BP (CBP) was indicated in several studies. Lopatin and Vitale (13) reviewed five studies analyzing ivabradine's effect on CBP in patients with CAD: two studies reported a neutral effect, while in two other studies and in one study, ivabradine decreased and increased CBP, respectively. In 12 normotensive patients with stable CAD and HR ≥ 70 bmp, a 3 week ivabradine treatment reduced brachial systolic and diastolic BP, while the HR reduction did not increase central aortic BP (14). Moreover, in patients with arterial hypertension and CAD treated with ivabradine, the increase in HR between resting conditions and early recovery post exercise showed a trend toward correlation with the radial augmentation index (15). Besides ivabradine's HR-reducing action, which is considered to be a principal mechanism of its benefit, ivabradine exerts a number of pleiotropic effects, some of which may partly be HR independent (16, 17) and some of which are still emerging.

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

BackgroundPostural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited. ObjectivesThis study investigated the effect of ivabradine (selective blocker of the Ifunny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test. MethodsIn total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month. ResultsThe average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine. ConclusionIvabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.

Using Tissue Doppler and Speckle Tracking Echocardiography to Assess if Ivabradine Improves Right Ventricular Function.

ObjectiveTo evaluate the mid-term effects of ivabradine on right ventricular functions in patients with heart failure.MethodsA prospective study was conducted on 52 patients who had heart failure in normal sinus rhythm (59% male, age: 64.76 ±12.49 years). Right ventricular functions were measured at baseline, after one month and one year by conventional and tissue Doppler echocardiography imaging. The parameters, right ventricular (RV) longitudinal strain (LS), RV systolic longitudinal strain rate (LSRs), RV early diastolic longitudinal strain rate, and late diastolic longitudinal strain rate, were evaluated by apical four-chamber grayscale imaging through the free wall of RV in accordance with the automated function imaging protocol.ResultsDuring the follow-up, the pulmonary artery systolic pressure (PASP), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI), E peak, and A peak values were similar to the basal values. While comparing the basal values of the global longitudinal systolic strain (GLS), LS, LSRs, longitudinal strain rate diastolic early filling (LSRe), and longitudinal strain rate diastolic late filling (LSRa), there were no differences in the first month but a significant increase was observed on one-year follow-up (p<0.001).ConclusionAt the one-year follow-up, the heart failure patients who were given ivabradine treatment showed an improvement in the right ventricular function assessed by the new echocardiographic techniques.

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR-133a.

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

Effect of ivabradine on left ventricular diastolic function of patients with heart failure with preserved ejection fraction -IVA-PEF study-

BackgroundHigh resting heart rate (HR) is a known marker of cardiovascular outcomes for heart failure (HF) patients. Ivabradine is a new class of HR lowering drug and a specific inhibitor of the If current in the sinoatrial node. Ivabradine substantially and significantly reduces major risks associated with HF when added to guideline-based treatment for left ventricular (LV) ejection fraction ≤35% and HR ≥70 bpm in sinus rhythm. On the other hand, HF with preserved ejection fraction (HFpEF) currently accounts for roughly half of all HF cases and usually presents as LV diastolic dysfunction. However, the association between HR reduction and LV diastolic function for HFpEF patients remains uncertain. Methods/designThis investigation into the effect of IVAbradine on left ventricular diastolic function of patients with heart failure with Preserved Ejection Fraction (IVA-PEF) is a multicenter, prospective, uncontrolled, open-label, single assignment, and an interventional single-arm study to investigate the effect of ivabradine on LV diastolic function of HFpEF patients. The key inclusion criterion is HFpEF with resting HR ≥75bpm in sinus rhythm. After completed informed consent forms are obtained, patients will be given 5 mg/day of ivabradine during the study. LV diastolic function is assessed in terms of mitral inflow E and mitral e’ annular velocities (E/e’). The primary endpoint will be defined as a change in E/e′ between baseline and 3 months after the start of administration of ivabradine. ConclusionThe findings of our trial may provide a new perspective on ivabradine for the treatment of HFpEF.

Effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: A pilot test.

ObjectiveTo investigate the effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST‐segment elevation myocardial infarction (STEMI).MethodsA total of 66 STEMI patients with sinus rhythm and the resting heart rate ≥80 bpm after successful emergency PCI were included. The patients in the test group were treated with ivabradine combined with metoprolol at 12 hr after PCI, while the control group was given only metoprolol orally. Their resting heart rate was controlled to <70 bpm at discharge and followed for 180 days. Heart rate and blood pressure were measured regularly. Echocardiogram was performed. N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high sensitivity troponin T, high sensitivity troponin I, and high sensitivity C‐reactive protein were measured. The major adverse cardiovascular events during hospitalization and follow‐up period were recorded.ResultsCompared with the control group, the heart rate of the test group decreased significantly (p < .05). Compared with the control group, the left ventricular end‐diastolic volume and left ventricular end‐systolic volume were significantly decreased while left ventricular ejection fraction was significantly increased in the test group at 90 days after operation. NT‐proBNP of the test group was significantly lower than that of the control group at 7 days after operation (p < .05).ConclusionFor STEMI patients, early use of ivabradine combined with standard therapy such as β‐blocker after successful reperfusion can achieve effective heart rate control, with great safety and tolerance. But the effect of ivabradine on left ventricular remodeling is uncertain.