Ivabradine and AF: Coincidence, Correlation or a New Treatment?
Abdelnabi Mahmoud,Ahmed Ashraf,Almaghraby Abdallah,Saleh Yehia,Badran Haitham
Arrhythmia & electrophysiology review
Ivabradine is a heart rate-lowering agent that inhibits pacemaker funny current (I). It has been approved by the European Medicines Agency and the US Food and Drug Administration for patients with stable angina and heart failure (HF). AF is a common issue especially in ischaemic heart disease and HF patients. In contrast to experimental findings and a limited number of clinical trials that demonstrate the emerging role of ivabradine for heart rate control in AF or maintenance of sinus rhythm, there is accumulating contradictory data indicating that there is, in fact, an increased incidence of new-onset AF among people who are taking ivabradine in clinical practice. This article reviews the most recent evidence highlighting the diversity of data in relation to the use of ivabradine and the onset of AF and whether it has a legitimate role in AF treatment and the maintenance of sinus rhythm.
Efficacy of medical and ablation therapy for inappropriate sinus tachycardia: A single-center experience.
Shabtaie Samuel A,Witt Chance M,Asirvatham Samuel J
Journal of cardiovascular electrophysiology
BACKGROUND:Effective therapy for inappropriate sinus tachycardia (IST) remains challenging with high rates of treatment failure and symptom recurrence. It is uncertain how effective pharmacotherapy and procedural therapy are long-term, with poor response to medical therapy in general. METHODS:We retrospectively reviewed all patients with the diagnosis of IST at a tertiary academic medical center from 1998 to 2018. We extracted data related to prescribing patterns and symptom response to medical therapy and sinus node modification (SNM), assessing efficacy and periprocedural complication rates. RESULTS:A total of 305 patients with a formal diagnosis of IST were identified, with 259 (84.9%) receiving at least one prescription medication related to the condition. Beta-blockers were the most commonly used medication (n = 245), with a majority of patients reporting no change or worsening of symptoms, and poor response was seen to other medication classes. Improvement was seen significantly more often with ivabradine than beta blockers, though the sample size was limited (p = .003). Fifty-five patients (18.0% of all IST patients), mean age 32.0 ± 9.1 years, underwent a SNM procedure, with an average of 1.8 ± 0.9 procedures per patient. Acute symptomatic improvement (<6 months) was seen in 58.2% of patients. Long-term complete resolution of symptoms was seen in 5.5% of patients, modest improvement in 29.1%, and no long-term benefit was seen in 65.5% of patients. CONCLUSIONS:Among all medical therapies, there were high rates of treatment failure or symptom worsening in over three-quarters of patients in our study. Ivabradine was most beneficial, though the sample size was small. While most patients receiving SNM ablation for IST perceive an acute symptomatic improvement, almost two-thirds of patients have no long-term improvement, and resolution of symptoms is quite rare. AV node ablation with pacemaker implantation following lack of response to SNM offered increased success, though the sample size was limited.
The rationale for repurposing funny current inhibition for management of ventricular arrhythmia.
Chakraborty Praloy,Rose Robert A,Nair Krishnakumar,Downar Eugene,Nanthakumar Kumaraswamy
Management of ventricular arrhythmia in structural heart disease is complicated by the toxicity of the limited antiarrhythmic options available. In others, proarrhythmia and deleterious hemodynamic and noncardiac effects prevent practical use. This necessitates new thinking in therapeutic agents for ventricular arrhythmia in structural heart disease. Ivabradine, a funny current (I) inhibitor, has proven safety in heart failure, angina, and inappropriate sinus tachycardia. Although it is commonly known that funny channels are primarily expressed in the sinoatrial node, atrioventricular node, and conducting system of the ventricle, ivabradine is known to exert effects on metabolism, ion homeostasis, and membrane electrophysiology of remodeled ventricular myocardium. This review considers novel concepts and evidence from clinical and experimental studies regarding this paradigm, with a potential role of ivabradine in ventricular arrhythmia.
Implications of Doppler Echocardiography-guided Heart Rate Modulation Using Ivabradine.
Hori Masakazu,Imamura Teruhiko,Narang Nikhil,Kinugawa Koichiro
Internal medicine (Tokyo, Japan)
Objective Heart rate modulation therapy using ivabradine reduces both morbidity and mortality in patients with systolic heart failure. However, the target heart rate for this patient population remains to be elucidated. Methods In this prospective observational study, we included patients with heart failure and a reduced ejection fraction who received 5.0 mg/day of ivabradine for three days. At baseline and three days later, the overlap length between E-wave and A-wave using trans-mitral Doppler echocardiography, as well as the cardiac output using AESCLONE mini, were simultaneously measured. The associations between Δ overlap length and Δ cardiac output were then investigated. Results Eight patients [77 (53, 87) years old, 2 men] were included. The heart rate decreased from 81 (69, 104) bpm down to 64 (57, 79) bpm (p=0.012). The overlap length increased in four patients and decreased in the other four patients. During the time period of ivabradine therapy, patients who had a greater decrease in overlap length had a greater increase in cardiac output (r=0.84, p=0.009). Conclusion Decreases in the overlap length between E-wave and A-wave by Doppler echocardiography were associated with an increase in the cardiac output while on ivabradine therapy. The implications of Doppler echocardiography-guided heart rate modulation therapy targeting a minimal overlap length therefore require further evaluation in larger, prospective studies.
Impact of left bundle branch block on heart rate and its relationship to treatment with ivabradine in chronic heart failure.
Reil Jan-Christian,Robertson Michele,Ford Ian,Borer Jeffrey,Komajda Michel,Swedberg Karl,Tavazzi Luigi,Böhm Michael
European journal of heart failure
AIMS:Left bundle branch block (LBBB) increases morbidity and mortality in heart failure (HF). Heart rate reduction with ivabradine improves outcomes in patients with systolic HF. Therefore, we aimed to analyse the impact of LBBB on outcomes in patients with systolic HF as a function of heart rate, and the relationship between LBBB and the effect of treatment with ivabradine. METHODS AND RESULTS:Patients from the SHIFT (n = 6505) were divided into groups with (n = 912) or without (n = 5593) LBBB at baseline, and according to tertiles of heart rate (70-73, 74-80, and ≥81 b.p.m.). The effect of LBBB, heart rate, and ivabradine on the primary endpoint (cardiovascular death or HF hospitalization) and other endpoints was analysed. LBBB was associated with increases in the primary endpoint by 65%, cardiovascular mortality by 49%, HF hospitalization by 86%, and all-cause mortality by 49% (all P < 0.001). No interaction appeared between the impact of heart rate on outcomes and presence of LBBB (P = 0.83 for the primary endpoint); thus LBBB increases risk for all heart rates. No interaction was apparent in the effect of ivabradine with LBBB or without LBBB. Ivabradine did not increase the prevalence of bradycardia in patients with LBBB. CONCLUSION:LBBB increases risk in HF patients with heart rates ≥70 b.p.m. in sinus rhythm, unmodulated by heart rate. Ivabradine was safe in LBBB. Its effect was directionally similar to that in patients without LBBB, but did not reach statistical significance, possibly due to lack of power to test this effect because of the small number of LBBB patients.
Ivabradine: potential clinical applications in critically ill patients.
De Santis Vincenzo,Vitale Domenico,Santoro Anna,Magliocca Aurora,Porto Andrea Giuseppe,Nencini Cecilia,Tritapepe Luigi
Clinical research in cardiology : official journal of the German Cardiac Society
It has been extensively demonstrated that an elevated heart rate is a modifiable, independent risk factor for cardiovascular events. A high heart rate increases myocardial oxygen consumption and reduces diastolic perfusion time. It can also increase ventricular diastolic pressures and induce ventricular arrhythmias. Critical care patients are prone to develop a stress induced cardiac impairment and consequently an increase in sympathetic tone. This in turn increases heart rate. In this setting, however, heart rate lowering might be difficult because the effects of inotropic drugs could be hindered by heart rate reducing drugs like beta-blockers. Ivabradine is a new selective antagonist of funny channels. It lowers heart rate, reducing the diastolic depolarization slope. Moreover, ivabradine is not active on sympathetic pathways, thus avoiding any interference with inotropic amines. We reviewed the literature available regarding heart rate control in critical care patients, focusing our interest on the use of ivabradine to assess the potential benefits of the drug in this particular setting.
COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine.
O'Sullivan Jenna Stephanie,Lyne Andrew,Vaughan Carl J
BMJ case reports
A 22-year-old woman was referred with exertional dyspnoea and chest tightness 3 weeks following a diagnosis of COVID-19. Evaluation revealed a resting sinus tachycardia and criteria for postural orthostatic tachycardia syndrome were met. After non-pharmacological interventions failed to yield symptomatic improvement, ivabradine was commenced. This intervention was followed by a substantial improvement in the patient's exercise tolerance and energy levels and an objective reduction in supine and standing heart rate.
The Risk of Atrial Fibrillation With Ivabradine Treatment: A Meta-analysis With Trial Sequential Analysis of More Than 40000 Patients.
Tanboğa İbrahim Halil,Topçu Selim,Aksakal Enbiya,Gulcu Oktay,Aksakal Emrah,Aksu Uğur,Oduncu Vecih,Ulusoy Fatih Rıfat,Sevimli Serdar,Kaymaz Cihangir
Recent trials reported that risk of atrial fibrillation (AF) is increased in patients using ivabradine compared with controls. We performed this meta-analysis to investigate the risk of AF association with ivabradine treatment on the basis of data obtained from randomized controlled trials (RCTs). We searched PubMed, EMBASE, Scopus, and the Cochrane Library for RCTs that comprised >100 patients. The incidence of AF was assessed. We obtained data from European Medicines Agency (EMA) scientific reports for the RCTs in which the incidence of AF was not reported. We used trial sequential analysis (TSA) to provide information on when we had reached firm evidence of new AF based on a 15% relative risk increase (RRI) in ivabradine treatment. Three RCTs and 1 EMA overall oral safety set (OOSS) pooled analysis (included 5 RCTs) were included in the meta-analysis (N = 40 437). The incidence of AF was 5.34% in patients using ivabradine and 4.56% in placebo. There was significantly higher incidence of AF (24% RRI) in the ivabradine group when compared with placebo before (RR: 1.24, 95% confidence interval: 1.08-1.42, P = 0.003, I 1980 = 53%) and after excluding OOSS (RR: 1.24, 95% confidence interval: 1.06-1.44, P = 0.008). In the TSA, the cumulative z-curve crossed both the traditional boundary (P = 0.05) and the trial sequential monitoring boundary, indicating firm evidence for ≥15% increase in ivabradine treatment when compared with placebo. Study results indicate that AF is more common in the ivabradine group (24% RRI) than in controls.
Emerging role of ivabradine for rate control in atrial fibrillation.
Turley Sarah L,Francis Kerry E,Lowe Denise K,Cahoon William D
Therapeutic advances in cardiovascular disease
Control of ventricular rate is recommended for patients with paroxysmal, persistent, or permanent atrial fibrillation (AF). Existing rate-control options, including beta-blockers, nondihydropyridine calcium channel blockers, and digoxin, are limited by adverse hemodynamic effects and their ability to attain target heart rate (HR). Ivabradine, a novel HR-controlling agent, decreases HR through deceleration of conduction through I ('funny') channels, and is approved for HR reduction in heart failure patients with ejection fraction less than 35% and elevated HR, despite optimal pharmacological treatment. Because I channels were thought to be expressed solely in sinoatrial (SA) nodal tissue, ivabradine was not investigated in heart failure patients with concomitant AF. Subsequent identification of hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4), the primary gene responsible for I current expression throughout the myocardium, stimulated interest in the potential role of ivabradine for ventricular rate control in AF. Preclinical studies of ivabradine in animal models with induced AF demonstrated a reduction in HR, with no significant worsening of QT interval or mean arterial pressure. Preliminary human data suggest that ivabradine provides HR reduction without associated hemodynamic complications in patients with AF. Questions remain regarding efficacy, safety, optimal dosing, and length of therapy in these patients. Prospective, randomized studies are needed to determine if ivabradine has a role as a rate-control treatment in patients with AF.
Ivabradine reduced ventricular rate in patients with non-paroxysmal atrial fibrillation.
Wongcharoen Wanwarang,Ruttanaphol Adisai,Gunaparn Siriluck,Phrommintikul Arintaya
International journal of cardiology
BACKGROUND:It has been shown that I channels can be found in AV node, apart from the sinus node. Previous animal studies showed that I inhibitor resulted in the rate-dependent reduction in AV node conduction during atrial fibrillation (AF). Therefore, we aimed to examine the effect of ivabradine on ventricular rate in patients with non-paroxysmal AF. METHOD:This study was a prospective randomized, double blind, placebo-controlled study. Ivabradine, 5mg twice a day (n=21), or placebo (n=11) was administered for 1month to adult patients with non-paroxysmal AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and 1month, as assessed by 24-hour Holter. RESULTS:The baseline characteristics did not differ between ivabradine and placebo groups (mean age was 59.7±13.3years, male 62.5%). Mean 24-hour ventricular rate at baseline was comparable between 2 groups. We found that ivabradine significantly decreased mean ventricular rate from 86.0±10.9beats/min to 79.2±9.6beats/min (p<0.001). In contrast, no significant change in ventricular rate was observed in placebo group (84.3±11.2 vs. 82.9±9.9beats/min, p=0.469). The effect of ivabradine on rate reduction was significantly greater than placebo (6.9±6.3 vs. 1.4±6.0beats/min, p=0.024). No drug-related adverse effects were observed in both groups. CONCLUSION:We demonstrated that ivabradine significantly decreased ventricular rate during AF compared to placebo. Therefore, ivabradine can be a potential treatment to improve ventricular control in patients with non-paroxysmal AF. Due to the small sample size, larger studies are needed to confirm this effect of ivabradine.
Effective suppression of atrial fibrillation by ivabradine: Novel target for an established drug?
Frommeyer Gerrit,Sterneberg Magdalena,Dechering Dirk G,Ellermann Christian,Bögeholz Nils,Kochhäuser Simon,Pott Christian,Fehr Michael,Eckardt Lars
International journal of cardiology
BACKGROUND:Ivabradine is an inhibitor of mixed Na-K-currents and routinely administered in chronic heart failure. Clinical studies reported divergent trends regarding proarrhythmic and antiarrhythmic effects in atrial fibrillation (AF). METHODS AND RESULTS:In 12 isolated rabbit hearts AF was induced in 7 of 12 hearts (13 episodes) under baseline conditions by a standardized protocol employing atrial burst pacing. Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Monophasic action potential recordings showed a decrease of atrial action potential duration (aAPD,-37ms, p<0.05) and atrial effective refractory period (aERP;-39ms, p<0.05) after infusion of both acetycholine (1μM) and isoproterenol (1μM) as compared with baseline. This led to induction of AF in 11 of 12 hearts (124 episodes). Simultaneous infusion of ivabradine (3μM) led to a significant reduction of AF (6 of 11 hearts, 63 episodes). Ivabradine induced an increase of aAPD (+9ms) and aERP (+30ms, p<0.05) leading to a marked increase of atrial post-repolarization refractoriness (aPRR), defined as the difference of aERP and aAPD (+21ms, p<0.05). Results were compared to 10 rabbits treated with flecainide. Flecainide treatment also induced a significant increase of aPRR and resulted in induction of AF in 6 of 10 hearts (58 episodes) while 9 of 10 hearts were inducible during sole treatment with acetylcholine and isoproterenol (129 episodes). CONCLUSION:In the present experimental study, administration of ivabradine reduced inducibility of AF and therefore may represent a supplemental therapeutic option in AF. Of note, its antiarrhythmic efficacy was comparable to the established agent flecainide.
Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.
Li Yao-Dong,Ji Yu-Tong,Zhou Xian-Hui,Jiang Tao,Hong Yi-fan,Li Jin-Xin,Xing Qiang,Xiong Jian,Yusufuaji Yueerguli,Tang Bao-Peng
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND:Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS:Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS:As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS:Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.
Acute ivabradine treatment reduces heart rate without increasing atrial fibrillation inducibility irrespective of underlying vagal activity in dogs.
Uemura Kazunori,Inagaki Masashi,Zheng Can,Kawada Toru,Li Meihua,Fukumitsu Masafumi,Sugimachi Masaru
Heart and vessels
Ivabradine, a bradycardic agent, has been shown to stably reduce patient's heart rate (HR) in the setting of acute cardiac care. However, an association between atrial fibrillation (AF) risk and acute ivabradine treatment remains a controversial clinical issue, and has not been thoroughly investigated. Bradycardia and abnormal atrial refractoriness induced by ivabradine treatment may enhance vulnerability to AF induction, especially when vagal nerve is concurrently activated. We aimed to experimentally investigate the effects of acute ivabradine treatment with/without concurrent vagal activation on AF inducibility. In 16 anesthetized dogs, cervical vagal nerves were prepared for electrical stimulation (VS). AF induction rate (AFIR) was determined by atrial burst pacing. HR, atrial action potential duration (APD), atrial effective refractory period (ERP), and AFIR were obtained consecutively at baseline, during delivery of VS (VS alone), after intravenous injection of ivabradine 0.5 mg/kg (n = 8, ivabradine group) or saline (n = 8, saline group), and again during VS delivery (drug+VS). In the ivabradine group, ivabradine alone significantly lowered HR compared to baseline, while ivabradine+VS significantly lowered HR compared to VS alone. Contrary to expectations, there were no significant differences in trends of APD, temporal dispersion of APD, ERP, and AFIR between ivabradine and saline groups. Irrespective of whether ivabradine or saline was injected, VS significantly shortened APD and ERP, and increased AFIR. Interestingly, although bradycardia in response to ivabradine injection was more intense than that to VS alone, AFIR was significantly lower after ivabradine injection than during VS alone. We conclude that, despite its intense bradycardic effect, acute ivabradine treatment does not increase AF inducibility irrespective of underlying vagal activity. This study may constitute support for the safety of using ivabradine in the setting of acute cardiac care.
hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine.
Journal of the American Heart Association
BACKGROUND:Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN-channels. This study investigated the propensity of ivabradine to interact with KCNH2-encoded human Ether-à-go-go-Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia. METHODS AND RESULTS:Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Ih ERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time-dependent characteristics of Ih ERG block were consistent with preferential gated-state-dependent channel block. Inhibition was partially attenuated by the N588K inactivation-mutant and the S624A pore-helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK-based homology model of hERG, the 2 aromatic rings of the drug could form multiple π-π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea-pig Langendorff-perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve. CONCLUSIONS:Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits Ih ERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design.
Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope.
Sutton Richard,Salukhe Tushar V,Franzen-McManus Ann-Christine,Collins Andrea,Lim Phang Boon,Francis Darrel P
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
AIMS:Ivabradine, an I(f) current blocker, has shown promising results in treatment of postural orthostatic tachycardia syndrome (POTS). There is a subgroup of vasovagal syncope (VVS) patients, who demonstrate sinus tachycardia before collapse on tilt testing mimicking some features of POTS. These patients may also respond to ivabradine therapy. University Hospital Syncope Clinic where ivabradine was prescribed in a prospective fashion on humanitarian grounds between October 2008 and December 2011. METHODS AND RESULTS:Twenty-five patients of mean age 33±years presenting syncope in all and palpitation in 23, duration 9±years underwent tilt testing with reproduction of usual symptoms including tachycardia preceding collapse. Ivabradine was prescribed in doses of 5-20 mg/day, mean 10.7 mg, as once or twice daily medication. The response to treatment was classified as deterioration in none, no change in 5, improvement in 10, and symptoms abolished in 8 patients. Side effects were minimal; one patient required discontinuation. CONCLUSION:In this pilot study of ivabradine, in patients with VVS, of patients who demonstrated sinus tachycardia before collapse on tilt, 72% reported a marked benefit or complete resolution of symptoms. The drug was well tolerated. A randomized controlled trial against placebo is justified.
Inappropriate sinus tachycardia-symptom and heart rate reduction with ivabradine: A pooled analysis of prospective studies.
Mathew Sunil T,Po Sunny S,Thadani Udho
BACKGROUND:Inappropriate sinus tachycardia (IST) is debilitating despite available treatment. Off-label use of ivabradine for IST prompted this systematic analysis of existing data quality and sample size estimates for adequately powered studies. OBJECTIVE:To determine clinical efficacy of ivabradine in IST from pooled prospective studies. METHODS:Analysis included ivabradine studies for IST participants without structural heart disease and with follow-up of ≥2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by various data instruments used in each study. Studies were assessed for quality using validated checklists. Sample sizes were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. RESULTS:Nine studies met criteria, culminating in 145 patients pooled. Most patients were women (≥70%). Studies were small and not adequately powered, and all reported a decrease in maximum or mean resting heart rate or both, with complete or considerable amelioration of symptoms with ivabradine. Most studies had moderate quality with excellent consistency of study quality and narrow limits of agreement between the quality checklists. Sample size estimates for adequately powered studies with various placebo effects and comparisons with β-blockade are reported. CONCLUSIONS:Ivabradine effectively reduces heart rate and symptoms in IST, but no study was adequately powered to account for the expected placebo effect on symptoms. A multicenter, randomized, placebo-controlled, active, comparative study with a β-blocker is needed for confirmation. This is especially relevant given the ivabradine's potential teratogenic effect, as many IST patients are females of childbearing potential.
Advances in the management of heart failure: the role of ivabradine.
Müller-Werdan Ursula,Stöckl Georg,Werdan Karl
Vascular health and risk management
A high resting heart rate (≥70-75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, ) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class "IIa" = weight of evidence/opinion is in favor of usefulness/efficacy: "should be considered"; level of evidence "B" = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5-7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication "HF with reduced EF" together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF.
Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.
Mesirca Pietro,Alig Jacqueline,Torrente Angelo G,Müller Jana Christina,Marger Laurine,Rollin Anne,Marquilly Claire,Vincent Anne,Dubel Stefan,Bidaud Isabelle,Fernandez Anne,Seniuk Anika,Engeland Birgit,Singh Jasmin,Miquerol Lucile,Ehmke Heimo,Eschenhagen Thomas,Nargeot Joel,Wickman Kevin,Isbrandt Dirk,Mangoni Matteo E
The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.
Ivabradine preserves dynamic sympathetic control of heart rate despite inducing significant bradycardia in rats.
Kawada Toru,Shimizu Shuji,Uemura Kazunori,Hayama Yohsuke,Yamamoto Hiromi,Shishido Toshiaki,Nishikawa Takuya,Sugimachi Masaru
The journal of physiological sciences : JPS
Ivabradine is a selective bradycardic agent that inhibits hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. HCN channels play a key role in mediating the positive chronotropic response to sympathetic nerve stimulation (SNS). We examined whether ivabradine would interfere with dynamic sympathetic control of heart rate (HR). The effect of intravenous ivabradine (2 mg/kg, n = 7) or metoprolol (10 mg/kg, n = 6) on the transfer function from SNS to HR was examined in anesthetized rats. Ivabradine preserved the asymptotic dynamic gain of the HR transfer function and nearly doubled the asymptotic dynamic gain of the transfer function from SNS to the R-R interval. In contrast, metoprolol abolished dynamic sympathetic control of HR. Preserved dynamic sympathetic control of HR, with coexisting bradycardia, may contribute to some of the beneficial effects of ivabradine previously reported in clinical application.
The Pore-Lipid Interface: Role of Amino-Acid Determinants of Lipophilic Access by Ivabradine to the hERG1 Pore Domain.
Perissinotti Laura,Guo Jiqing,Kudaibergenova Meruyert,Lees-Miller James,Ol'khovich Marina,Sharapova Angelica,Perlovich German L,Muruve Daniel A,Gerull Brenda,Noskov Sergei Yu,Duff Henry J
Abnormal cardiac electrical activity is a common side effect caused by unintended block of the promiscuous drug target human -related gene (hERG1), the pore-forming domain of the delayed rectifier K channel in the heart. hERG1 block leads to a prolongation of the QT interval, a phase of the cardiac cycle that underlies myocyte repolarization detectable on the electrocardiogram. Even newly released drugs such as heart-rate lowering agent ivabradine block the rapid delayed rectifier current I, prolong action potential duration, and induce potentially lethal arrhythmia known as torsades de pointes. In this study, we describe a critical drug-binding pocket located at the lateral pore surface facing the cellular membrane. Mutations of the conserved M651 residue alter ivabradine-induced block but not by the common hERG1 blocker dofetilide. As revealed by molecular dynamics simulations, binding of ivabradine to a lipophilic pore access site is coupled to a state-dependent reorientation of aromatic residues F557 and F656 in the S5 and S6 helices. We show that the M651 mutation impedes state-dependent dynamics of F557 and F656 aromatic cassettes at the protein-lipid interface, which has a potential to disrupt drug-induced block of the channel. This fundamentally new mechanism coupling the channel dynamics and small-molecule access from the membrane into the hERG1 intracavitary site provides a simple rationale for the well established state-dependence of drug blockade. SIGNIFICANCE STATEMENT: The drug interference with the function of the cardiac hERG channels represents one of the major sources of drug-induced heart disturbances. We found a novel and a critical drug-binding pocket adjacent to a lipid-facing surface of the hERG1 channel, which furthers our molecular understanding of drug-induced QT syndrome.
Ivabradine in Management of Heart Failure: a Critical Appraisal.
Orasanu Gabriela,Al-Kindi Sadeer G,Oliveira Guilherme H
Current heart failure reports
Elevated resting heart rate has been linked to poor outcomes in patients with chronic systolic heart failure. Blockade of funny current channel with ivabradine reduces heart rate without inotropic effects. Ivabradine was recently approved by US Food and Drug Administration for patients with stable, symptomatic chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35 %, who are in sinus rhythm with resting heart rate (HR) ≥ 70 bpm and either are on maximally tolerated doses of beta-blockers, or have a contraindication to beta-blockers. This article will review and evaluate the data supporting the use of ivabradine in patients with HF and explore its mechanisms and physiologic effects.
Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study.
Ekman Inger,Chassany Olivier,Komajda Michel,Böhm Michael,Borer Jeffrey S,Ford Ian,Tavazzi Luigi,Swedberg Karl
European heart journal
AIMS:Heart failure (HF) has a major impact on health-related quality of life (HQoL). The aim was to evaluate whether heart rate (HR) reduction with ivabradine can translate into increased HQoL in parallel to a reduction of primary outcomes in SHIFT. METHODS AND RESULTS:In symptomatic patients with systolic HF treated with recommended background therapy, HQoL was assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) containing the following dimensions: overall summary score (OSS) and clinical summary score (CSS), analysed at baseline, and 4, 12, and 24 months, and last post-baseline visit. A total of 1944 patients (968 ivabradine, 976 placebo) were evaluated. At 12 months, incidence of clinical events (cardiovascular death or hospital admission for HF) was inversely associated with KCCQ scores. Ivabradine reduced HR by 10.1 bpm (placebo-corrected, P < 0.001) and improved KCCQ by 1.8 for CSS and 2.4 for OSS (placebo-corrected, P = 0.02 and P < 0.01, respectively); these changes were associated with the change in HR for both CSS (P < 0.001) and OSS (P < 0.001). The relationship was found in both allocation groups though the changes were more pronounced in the ivabradine group. Health-related quality of life at follow-up was better preserved in the ivabradine group compared with placebo; poorest outcomes were seen in the placebo group with lowest KCCQ scores (<50). CONCLUSION:In patients with systolic HF, low HQoL is associated with an increased rate of cardiovascular death or hospital admission for HF. Reduction in HR with ivabradine is associated with improved HQoL. The magnitude of HR reduction is related to the extent of improvement in HQoL.
Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias.
Frommeyer Gerrit,Weller Jan,Ellermann Christian,Bögeholz Nils,Leitz Patrick,Dechering Dirk G,Kochhäuser Simon,Wasmer Kristina,Eckardt Lars
Basic & clinical pharmacology & toxicology
The I channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 μM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 μM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 μM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine.
Intravenous ivabradine versus placebo in patients with low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery: a phase 2 exploratory randomized controlled trial.
Nguyen Lee S,Squara Pierre,Amour Julien,Carbognani Daniel,Bouabdallah Kamel,Thierry Stéphane,Apert-Verneuil Caroline,Moyne Aurélie,Cholley Bernard
Critical care (London, England)
BACKGROUND:Low cardiac output syndrome (LCOS) is a severe condition which can occur after cardiac surgery, especially among patients with pre-existing left ventricular dysfunction. Dobutamine, its first-line treatment, is associated with sinus tachycardia. This study aims to assess the ability of intravenous ivabradine to decrease sinus tachycardia associated with dobutamine infused for LCOS after coronary artery bypass graft (CABG) surgery. METHODS:In a phase 2, multi-center, single-blind, randomized controlled trial, patients with left ventricular ejection fraction below 40% presenting sinus tachycardia of at least 100 beats per minute (bpm) following dobutamine infusion for LCOS after CABG surgery received either intravenous ivabradine or placebo (three ivabradine for one placebo). Treatment lasted until dobutamine weaning or up to 48 h. The primary endpoint was the proportion of patients achieving a heart rate (HR) in the 80- to 90-bpm range. Secondary endpoints were invasive and non-invasive hemodynamic parameters and arrhythmia events. RESULTS:Nineteen patients were included. More patients reached the primary endpoint in the ivabradine than in the placebo group (13 (93%) versus 2 (40%); P = 0.04). Median times to reach target HR were 1.0 h in the ivabradine group and 5.7 h in the placebo group. Ivabradine decreased HR (112 to 86 bpm, P <0.001) while increasing cardiac index (P = 0.02), stroke volume (P <0.001), and systolic blood pressure (P = 0.03). In the placebo group, these parameters remained unchanged from baseline. In the ivabradine group, five patients (36%) developed atrial fibrillation (AF) and one (7%) was discontinued for sustained AF; two (14%) were discontinued for bradycardia. CONCLUSION:Intravenous ivabradine achieved effective and rapid correction of sinus tachycardia in patients who received dobutamine for LCOS after CABG surgery. Simultaneously, stroke volume and systolic blood pressure increased, suggesting a beneficial effect of this treatment on tissue perfusion. TRIAL REGISTRATION:European Clinical Trials Database: EudraCT 2009-018175-14 . Registered February 2, 2010.
Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression.
Wang Juan,Yang Yan-Min,Li Yang,Zhu Jun,Lian Hong,Shao Xing-Hui,Zhang Han,Fu Yi-Cheng,Zhang Lian-Feng
Journal of cardiovascular electrophysiology
INTRODUCTION:Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on I current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. METHODS AND RESULTS:We investigated both the I current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the I current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the I current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform I loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01). CONCLUSION:IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating I gain-of-function.
Ivabradine-Induced Torsade de Pointes in Patients with Heart Failure Reduced Ejection Fraction.
Jang Ji-Hun,Kwon Sung Woo,Lee Man-Jong,Ko Kyu-Yong,Park Jin-Hee,Yoon Gwang-Seok,Choi Seong-Huan,Beak Yong-Soo,Park Sang-Don,Shin Sung-Hee,Woo Seong-Ill,Kim Dae-Hyeok,Kwan Jun
International heart journal
Ivabradine is a selective inhibitor of the sinoatrial node "funny" current, prolonging the slow diastolic depolarization. As it has the ability to block the heart rate selectively, it is more effective at a faster heart rate. It is recommended for the treatment of heart failure reduced ejection fraction in the presence of beta-blocker therapy for the further reduction of the heart rate. However, previous reports have shown the association of Torsade de pointes (TdP) with concurrent use of ivabradine and drugs resulting in QT prolongation or blockage of the metabolic breakdown of ivabradine. In this article, we report two cases of patients with heart failure reduced ejection fraction who developed TdP after ivabradine use. Our report highlights the need to exercise caution with the administration of ivabradine in the presence of a reduced repolarization reserve, such as QT prolongation or metabolic insufficiency.
Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy.
Tardif Jean-Claude,O'Meara Eileen,Komajda Michel,Böhm Michael,Borer Jeffrey S,Ford Ian,Tavazzi Luigi,Swedberg Karl,
European heart journal
AIMS:The SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF). METHODS AND RESULTS:Eligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ≤35%], were in sinus rhythm, and had resting heart rate ≥70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203). Treatment with ivabradine reduced LVESVI (primary substudy endpoint) vs. placebo [-7.0 ± 16.3 vs. -0.9 ± 17.1 mL/m(2); difference (SE), -5.8 (1.6), 95% CI -8.8 to -2.7, P< 0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (-7.9 ± 18.9 vs. -1.8 ± 19.0 mL/m(2), P= 0.002) and LVEF (+2.4 ± 7.7 vs. -0.1 ± 8.0%, P< 0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03-2.56, P= 0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates. CONCLUSION:Ivabradine reverses cardiac remodelling in patients with HF and LV systolic dysfunction.
Clinical and Electrophysiological Correlates of Incessant Ivabradine-Sensitive Atrial Tachycardia.
Banavalikar Bharatraj,Shenthar Jayaprakash,Padmanabhan Deepak,Valappil Sanjai Pattu,Singha Sinam Inaoton,Kottayan Anju,Ghadei Milan,Ali Muzaffar
Circulation. Arrhythmia and electrophysiology
BACKGROUND:Incessant focal atrial tachycardia (FAT), if untreated, can lead to ventricular dysfunction and heart failure (tachycardia-induced cardiomyopathy). Drug therapy of FAT is often difficult and ineffective. The efficacy of ivabradine has not been systematically evaluated in the treatment of FAT. METHODS:The study group consisted of patients with incessant FAT (lasting >24 hours) and structurally normal hearts. Patients with ventricular dysfunction as a consequence of FAT were not excluded. All antiarrhythmic drugs were discontinued at least 5 half-lives before the initiation of ivabradine. Oral ivabradine (adults, 10 mg twice 12 hours apart; pediatric patients: 0.28 mg/kg in 2 divided doses) was initiated in the intensive care unit under continuous electrocardiographic monitoring. A positive response was defined as the termination of tachycardia with the restoration of sinus rhythm or suppression of the tachycardia to <100 beats per minute without termination within 12 hours of initiating ivabradine. RESULTS:Twenty-eight patients (mean age, 34.6±21.5 years; women, 60.7%) were included in the study. The most common symptom was palpitation (85.7%) followed by shortness of breath (25%). The mean atrial rate during tachycardia was 170±21 beats per minute, and the mean left ventricular ejection fraction was 54.7±14.3%. Overall, 18 (64.3%) patients responded within 6 hours of the first dose of ivabradine. Thirteen of 18 ivabradine responders subsequently underwent successful catheter ablation. FAT originating in the atrial appendages was a predictor of ivabradine response compared with those arising from other atrial sites (P=0.046). CONCLUSIONS:Ivabradine-sensitive atrial tachycardia constitutes 64% of incessant FAT in patients without structural heart disease. Incessant FAT originating in the atrial appendages is more likely to respond to ivabradine than that arising from other atrial sites. Our findings implicate the funny current in the pathogenesis of FAT.
Baseline intrinsic heart rate and response to ivabradine treatment in patients with inappropriate sinus tachycardia.
Kaczmarek Krzysztof,Klingenheben Thomas,Poddebska Izabela,Urbanek Irmina,Wranicz Jerzy K,Cygankiewicz Iwona,Ptaszyński Pawel
Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc
BACKGROUND:Treatment with ivabradine became a new therapeutic alternative for patients with inappropriate sinus tachycardia (IST). The aim was to determine a relation between intrinsic heart rate (IHR) and response to ivabradine treatment. METHODS:Twenty-seven patients (mean age 37 ± 11; 23 women) with symptomatic IST despite medical treatment were recruited into the study. Resting ECG, 24-hr ECG monitoring (24hECG), exercise treadmill test, and symptoms evaluation were performed initially and after 60 days on ivabradine. IHR was acquired at baseline after pharmacological autonomic blockade. RESULTS:Nineteen patients (70%) were classified as abnormal IHR group (AIHR) while eight showed normal IHR (NIHR). No significant differences in ECG parameters were found between NIHR and AIHR subgroups, while baseline exercise capacity was higher in AIHR patients (10.9 vs. 9.5 METs, p < .05). Ivabradine treatment resulted in significant reduction in resting heart rate, average 24hECG heart rate, improvement in exercise capacity and reduction of symptoms in both subgroups. Nevertheless, favorable influence of ivabradine was significantly more exaggerated in AIHR subgroup (HR 116 vs. 90 bpm, av. HR 98 vs. 79 bpm, 10.9 vs. 13.6 METS, EHRA score 3.1 vs. 1.1, p < .001 for all) than in NIHR patients (HR 112 vs. 98 bpm, av. HR 97 vs. 88 bpm, 9.5 vs. 11.1 METs, EHRA score 3.1 vs. 1.9; p < .05 for all). CONCLUSIONS:Intrinsic heart rate may be useful in predicting response to ivabradine in patients with IST. More intense response to ivabradine in patients with AIHR may be attributed to different pathophysiological mechanisms underlying IST in AIHR and NIHR groups.
Ivabradine as a stabilising anti-arrhythmic agent for multifocal atrial tachycardia.
Cohen Mitchell I,Cohen Jordan A,Shope Connor,Stollar Lauren,Collazo Lucas
Cardiology in the young
Multifocal atrial tachycardia has certain electrocardiographic similarities to atrial fibrillation. The mechanism of atrial fibrillation is heterogenous but in some cases may arise from a single ectopic driver with fibrillatory conduction to the rest of the atria. This has led to the speculation that multifocal atrial tachycardia may have a similar mechanistic unifocal site that disperses through the atrium in a fibrillatory pattern. Ivabradine has been reported to be efficacious in an adult with paroxysmal atrial fibrillation as well as in children with junctional or ectopic atrial tachycardias. This is the first report of successfully using ivabradine, a novel anti-arrhythmic If blocking agent, to convert multifocal atrial tachycardia in a 5-month-old critically ill infant to a pattern indicating a single ectopic atrial focus. This allowed the patient's single atrial focus to be ablated with return to sinus rhythm and decannulation from ventriculoarterial extracorporeal membrane oxygenation. This case suggests that multifocal atrial tachycardia may arise from a single automatic focus with downstream fibrillatory conduction to the atria.
Ivabradine is an effective antiarrhythmic therapy for congenital junctional ectopic tachycardia-induced cardiomyopathy during infancy: Case studies.
Ergul Yakup,Ozturk Erkut,Ozgur Senem,Ozyurt Abdullah,Cilsal Erman,Guzeltas Alper
Pacing and clinical electrophysiology : PACE
Junctional ectopic tachycardia (JET) is a rare form of arrhythmia that is most commonly seen during infancy. JET is continuous and incessant, characterized by persistently high heart rates that may result in impaired cardiac function and tachycardia-induced cardiomyopathy. Despite the availability of multiple antiarrhythmic treatments, including flecainide and amiodarone, management of JET is generally very difficult. Catheter ablation has a high risk of atrioventricular block and it may require the placement of a pacemaker. Ivabradine, also known as a cardiac pacemaker cell inhibitor, is a new-generation antiarrhythmic used to treat sinus tachycardia and angina pectoris in adult patients. In this article, we present three cases of subjects with infantile congenital JET who were admitted to our clinic with a tachycardia-induced cardiomyopathy. The age of the subjects ranged from 52 days to 10 months. Although the cases of tachycardia could not be controlled by multiple antiarrhythmics, including a combination of amiodarone and flecainide combined with either propranolol or digoxin, they were rapidly converted into sinus rhythm with an ivabradine treatment of 0.1-0.2 mg/kg/day. No cardiac or other side effects were observed during ivabradine treatment, and left ventricular functions and rhythms improved within 24 hours. These three cases therefore provide hope that ivabradine may be a suitable standard initial treatment for congenital JET. However, additional research is needed to confirm the validity of these results in other circumstances.
Intravenous ivabradine augments the dynamic heart rate response to moderate vagal nerve stimulation in anesthetized rats.
Kawada Toru,Yamamoto Hiromi,Uemura Kazunori,Hayama Yohsuke,Nishikawa Takuya,Sugimachi Masaru
American journal of physiology. Heart and circulatory physiology
Ivabradine is a selective bradycardic agent that reduces the heart rate (HR) by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels. Although its cardiovascular effect is thought to be minimal except for inducing bradycardia, ivabradine could interact with cardiovascular regulation by the autonomic nervous system. We tested whether ivabradine modifies dynamic characteristics of peripheral vagal HR control. In anesthetized Wistar-Kyoto rats ( = 7), the right vagal nerve was sectioned and stimulated for 10 min according to a binary white noise sequence with a switching interval of 500 ms. The efferent vagal nerve stimulation (VNS) trials were performed using three different rates (10, 20, and 40 Hz), and were designated as V, V, and V, respectively. The transfer function from the VNS to the HR was estimated before and after the intravenous administration of ivabradine (2 mg/kg). Ivabradine increased the asymptotic dynamic gain in V [from 3.88 (1.78-5.79) to 6.62 (3.12-8.31) beats·min·Hz, < 0.01, median (range)] but not in V or V. Ivabradine increased the corner frequency in V [from 0.032 (0.026-0.041) to 0.064 (0.029-0.090) Hz, < 0.01] and V [from 0.040 (0.037-0.056) to 0.068 (0.051-0.100) Hz, < 0.01] but not in V. In conclusion, ivabradine augmented the dynamic HR response to moderate VNS. At high VNS, however, ivabradine did not significantly augment the dynamic HR response, possibly because ivabradine reduced the baseline HR and limited the range for the bradycardic response to high VNS. Ivabradine is considered to be a pure bradycardic agent that has little effect on cardiovascular function except inducing bradycardia. The present study demonstrated that ivabradine interacts with the dynamic vagal heart rate control in a manner that augments the heart rate response to moderate-intensity efferent vagal nerve stimulation.
Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions.
Koncz István,Szél Tamás,Bitay Miklós,Cerbai Elisabetta,Jaeger Kristian,Fülöp Ferenc,Jost Norbert,Virág László,Orvos Péter,Tálosi László,Kristóf Attila,Baczkó István,Papp Julius Gy,Varró András
European journal of pharmacology
Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V(max)), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V(max) block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V(max) block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V(max) from inactivation (τ=41-46 ms) observed in control, a second slow component for recovery of V(max) was expressed (offset kinetics of V(max) block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.
Atrial Fibrillation After Coronary Artery Bypass Surgery: Can Ivabradine Reduce Its Occurrence?
Abdel-Salam Zainab,Nammas Wail
Journal of cardiovascular electrophysiology
INTRODUCTION:We compared the efficacy of perioperative ivabradine, bisoprolol, or both for prevention of postoperative atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS:We enrolled 740 consecutive patients scheduled for elective CABG with/without valve surgery. Patients were assigned to 1 of 3 protocols: ivabradine given perioperatively (48 hours preoperatively, then 1 week postoperatively) 5 mg bid for 24 hours, then 7.5 mg bid thereafter in patients who can tolerate (group 1, n = 212); bisoprolol given perioperatively 5 mg bid (group 2, n = 288); or both drugs given perioperatively (ivabradine as before + bisoprolol 5 mg once daily) (group 3, n = 240). Cardiac rhythm was continuously monitored for 15 days postoperatively by ambulatory event recorder. Clinical follow-up for the occurrence of arrhythmias was performed for the next 15 days. The primary endpoint was the incidence of AF at 30-day follow-up. Mean age was 56.5 ± 8.9 years (30.5% females). All patients completed 30-day follow-up. AF occurred in 10.4%. The 3 groups were matched for most baseline characteristics, echocardiographic and angiographic data (P > 0.05 for all). The incidence of AF was significantly lower in group 3 (4.2%), compared with group 1 (15.5%), and group 2 (12.2%), (P < 0.001 both). The duration of stay in the intensive care unit was shorter in group 3 versus group 1 and 2 (P < 0.001 both). CONCLUSION:In patients undergoing elective CABG, adding ivabradine to β-blockers during the perioperative period was associated with reduced incidence of AF at 30-day follow-up, compared with either medication alone.
Ivabradine vs metoprolol in patients with acute inferior wall myocardial infarction-"Expanding arena for ivabradine".
Priti Kumari,Ranwa Bhanwar L,Gokhroo Rajendra K,Kishore Kamal,Bisht Devendra Singh,Gupta Sajal
BACKGROUND:Atrioventricular (AV) blocks are of concern with the use of beta blockers in inferior wall myocardial infarction (MI). Ivabradine lowers heart rate with a lesser risk of AV blocks. OBJECTIVES:To compare ivabradine with metoprolol in acute inferior wall MI in terms of feasibility, tolerability, and efficacy. METHODS:It was a prospective double-blind single-center randomized controlled study. Of 1032 patients with acute inferior wall MI, 468 eligible patients were randomized in 1:1 manner to ivabradine (group A) and metoprolol (group B). Intention to treat analysis of 426 patients (group A-232 and group B-232) was performed. The primary endpoint was 30-day incidence of major adverse cardiovascular events including death, reinfarction, complete heart block (CHB), and heart failure. Secondary endpoints included 30 days incidence of recurrent angina, readmission, first- or second-degree AV block, and tachyarrhythmias. RESULTS:Both the drugs decreased the mean heart rate to 62.22±2.95 (group A) vs 62.53±3.59 (group B) beats per minute (P=0.33). Ejection fraction improved in both the groups (5.15±1.93% in group A vs 5.52±2.18% in group B, P=0.065). The two groups did not differ significantly in their primary endpoints in terms of death (group A=1.72% vs group B=1.72%, OR=1.00, 95% CI=0.25-4.05, P=1.00), reinfarction (group A=0.86% vs group B=0.86%, OR=1.00, 95% CI=0.14-7.16, P=1.00), heart failure (group A=4.31% vs group B=2.59%, OR=1.70, 95% CI=0.61-4.75, P=0.31), or CHB (0% vs 2.59%, OR=0.07, 95% CI=0.00-1.34, P=0.08). There were no significant differences in the secondary endpoints of recurrent angina, readmission, and tachyarrhythmias except for more first- and second-degree AV blocks with metoprolol (12.93% vs 2.59%, OR=5.59, 95% CI=2.28-13.72, P=0.0002). CONCLUSIONS:Ivabradine is well tolerated and equally effective as metoprolol in acute inferior wall ST elevation myocardial infarction patients for lowering the heart rate with lesser risk of AV blocks.
Ivabradine Aggravates the Proarrhythmic Risk in Experimental Models of Long QT Syndrome.
Frommeyer Gerrit,Weller Jan,Ellermann Christian,Leitz Patrick,Kochhäuser Simon,Lange Philipp S,Dechering Dirk G,Eckardt Lars
Ivabradine has recently been demonstrated to have antiarrhythmic properties in atrial fibrillation. The aim of the present study was to assess the electrophysiologic profile of ivabradine in an experimental whole-heart model of long-QT-syndrome. In 12 isolated rabbit hearts long-QT-2-syndrome (LQT2) was simulated by infusion of D,L-sotalol (100 µM). 12 rabbit hearts were treated with veratridine (0.5 µM) to mimic long-QT-3-syndrome (LQT3). Sotalol induced a significant prolongation of QT-interval (+ 40 ms, p < 0.01) and action potential duration (APD, + 20 ms, p < 0.01). Similar results were obtained in veratridine-treated hearts (QT-interval: +52 ms, p < 0.01; APD: + 41 ms, p < 0.01). Of note, both sotalol (+ 26 ms, p < 0.01) and veratridine (+ 42 ms, p < 0.01) significantly increased spatial dispersion of repolarisation. Additional infusion of ivabradine (5 µM) did not change these parameters in sotalol-pretreated hearts but resulted in a further significant increase of QT-interval (+ 26 ms, p < 0.05) and APD (+ 49 ms, p < 0.05) in veratridine-treated hearts. Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) or polymorphic ventricular tachycardias (VT) resembling torsade de pointes in 6 of 12 sotalol-treated hearts (56 episodes) and 6 of 12 veratridine-treated hearts (73 episodes). Additional infusion of ivabradine increased occurrence of polymorphic VT. Ivabradine treatment resulted in occurrence of EAD and polymorphic VT in 9 of 12 sotalol-treated hearts (212 episodes), and 8 of 12 veratridine-treated hearts (155 episodes). Treatment with ivabradine in experimental models of LQT2 and LQT3 increases proarrhythmia. A distinct interaction with potassium currents most likely represents a major underlying mechanism. These results imply that ivabradine should be employed with caution in the presence of QT-prolongation.
Cardiac pacemaker channel (HCN4) inhibition and atrial arrhythmogenesis after releasing cardiac sympathetic activation.
Chobanyan-Jürgens Kristine,Heusser Karsten,Duncker David,Veltmann Christian,May Marcus,Mehling Heidrun,Luft Friedrich C,Schröder Christoph,Jordan Jens,Tank Jens
Clinical trials and studies with ivabradine implicate cardiac pacemaker channels (HCN4) in the pathogenesis of atrial arrhythmias. Because acute changes in cardiac autonomic tone predispose to atrial arrhythmias, we studied humans in whom profound cardiac sympathetic activation was rapidly relieved to test influences of HCN4 inhibition with ivabradine on atrial arrhythmias. We tested 19 healthy participants with ivabradine, metoprolol, or placebo in a double blind, randomized, cross-over fashion on top of selective norepinephrine reuptake inhibition with reboxetine. Subjects underwent combined head up tilt plus lower body negative pressure testing followed by rapid return to the supine position. In the current secondary analysis with predefined endpoints before data unblinding, continuous finger blood pressure and ECG recordings were analyzed by two experienced cardiac electrophysiologists and a physician, blinded for treatment assignment. The total atrial premature activity (referred to as atrial events) at baseline did not differ between treatments. After backwards tilting, atrial events were significantly higher with ivabradine compared with metoprolol or with placebo. Unlike beta-adrenoreceptor blockade, HCN4 inhibition while lowering heart rate does not protect from atrial arrhythmias under conditions of experimental cardiac sympathetic activation. The model in addition to providing insight in the role of HCN4 in human atrial arrhythmogenesis may have utility in gauging potential atrial pro-arrhythmic drug properties.
Ivabradine in Post-operative Junctional Ectopic Tachycardia (JET): Breaking New Ground.
Krishna Mani Ram,Kunde Mohammed Farooq,Kumar Raman Krishna,Balaji Seshadri
Junctional ectopic tachycardia (JET) is the commonest tachyarrhythmia in the early post-operative period in children undergoing open-heart surgery. It frequently leads to hemodynamic instability and needs to be managed aggressively. Amiodarone is the first-line agent along with non-pharmacological interventions. We report our initial experience with the use of Ivabradine in post-operative JET. A retrospective case records review of children with post-operative JET during the period from June 2018 to May 2019 was performed. Eight patients with post-operative JET were treated with Ivabradine during this period. The first patient was initially treated with Amiodarone. All eight patients responded to Ivabradine. The initial response was rate control permitting overdrive pacing. One patient had recurrence of JET 10 h after Ivabradine and after return to sinus rhythm. Amiodarone was administered along with the second dose of Ivabradine resulting in remission to sinus rhythm. Ivabradine appears to be an effective alternative to Amiodarone in children with post-operative JET based on our initial clinical experience.
Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.
Fontenla Adolfo,López-Gil María,Tamargo-Menéndez Juan,Matía-Francés Roberto,Salgado-Aranda Ricardo,Rey-Blas Juan Ramón,Miracle-Blanco Ángel,Mejía-Martínez Elena,Pastor-Fuentes Agustín,Toquero-Ramos Jorge,Arias Miguel Ángel,Montilla Isabel,Gómez de la Cámara Agustín,Arribas Fernando,
Revista espanola de cardiologia (English ed.)
INTRODUCTION AND OBJECTIVES:Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS:A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS:New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS:The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION:http://www.clinicaltrials.gov. Identifier: NCT03718273.
Ivabradine Versus Amiodarone in the Management of Postoperative Junctional Ectopic Tachycardia: A Randomized, Open-Label, Noninferiority Study.
Arvind Balaji,Kothari Shyam S,Juneja Rajnish,Saxena Anita,Ramakrishnan Sivasubramanian,Gupta Saurabh Kumar,Chowdhury Ujjwal K,Devagourou Velayoudam,Talwar Sachin,Hote Milind P,Rajashekar Palleti,Sahu Manoj Kumar,Singh Sarvesh Pal
JACC. Clinical electrophysiology
OBJECTIVES:This study sought to compare the efficacy of ivabradine and amiodarone in the management of postoperative junctional ectopic tachycardia (JET) after cardiac surgery in children. BACKGROUND:JET is a serious arrhythmia occurring in children after cardiac surgery and requires aggressive management. Amiodarone has been conventionally used in its treatment. Recent studies have reported the utility of ivabradine in this regard. METHODS:In this open-label randomized controlled trial, 94 children (age ≤18 years) who developed postoperative JET were allocated to receive either amiodarone or ivabradine. The primary endpoint was restoration of normal sinus rhythm. RESULTS:Sinus rhythm was achieved in 43 out of the 46 patients (93.5%) in the amiodarone group and 46 out of the 48 patients (95.8%) in the ivabradine group (mean difference of treatment effect: 2.3%; 95% confidence interval: -6.7% to 11.5%). The median (interquartile range) time taken to achieve sinus rhythm conversion was similar in both the groups: 21.5 (17-30.2) hours versus 22 (13.4-38.5) hours (p = 0.36)]. The time taken to rate control of JET was significantly less in the amiodarone group: median 7.0 (5.5-9.5) hours versus 8.0 (5.8-10.8) hours (p = 0.02)]. No drug-related adverse events were observed in the ivabradine group. CONCLUSIONS:Oral ivabradine is not inferior to intravenous amiodarone in converting postoperative JET to sinus rhythm. There was no difference in time taken to sinus rhythm conversion between the groups, although the rate control was earlier in patients who received amiodarone. Monotherapy with ivabradine may be considered as an alternative to amiodarone in the management of postoperative JET. (Comparison of Two Drugs, Ivabradine and Amiodarone, in the Management of Junctional Ectopic Tachycardia, an Abnormality in Cardiac Rhythm in Patients Under 18 years Who Undergo Cardiac Surgery: CTRI/2018/08/015182).
The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia.
Bueno-Levy Hanna,Weisbrod David,Yadin Dor,Haron-Khun Shiraz,Peretz Asher,Hochhauser Edith,Arad Michael,Attali Bernard
Frontiers in pharmacology
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressed-provoked ventricular arrhythmia. CPVT is treated by β-adrenergic receptor blockers, Na channel inhibitors, sympathetic denervation, or by implanting a defibrillator. We showed recently that blockers of SK4 Ca-activated K channels depolarize the maximal diastolic potential, reduce the heart rate, and attenuate ventricular arrhythmias in CPVT. The aim of the present study was to examine whether the pacemaker channel inhibitor, ivabradine could demonstrate anti-arrhythmic properties in CPVT like other bradycardic agents used in this disease and to compare them with those of the SK4 channel blocker, TRAM-34. The effects of ivabradine were examined on the arrhythmic beating of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) from CPVT patients, on sinoatrial node (SAN) calcium transients, and on ECG measurements obtained from transgenic mice model of CPVT. Ivabradine did neither prevent the arrhythmic pacing of hiPSC-CMs derived from CPVT patients, nor preclude the aberrant SAN calcium transients. In contrast to TRAM-34, ivabradine was unable to reduce the ventricular premature complexes and ventricular tachyarrhythmias in transgenic CPVT mice. In conclusion, ivabradine does not exhibit anti-arrhythmic properties in CPVT, which indicates that this blocker cannot be used as a plausible treatment for CPVT ventricular arrhythmias.
Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?
Oknińska Marta,Paterek Aleksandra,Zambrowska Zuzanna,Mackiewicz Urszula,Mączewski Michał
Journal of clinical medicine
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.
Antiarrhythmic properties of ivabradine in an experimental model of Short-QT- Syndrome.
Frommeyer Gerrit,Weller Jan,Ellermann Christian,Kaese Sven,Kochhäuser Simon,Lange Philipp S,Dechering Dirk G,Eckardt Lars
Clinical and experimental pharmacology & physiology
The I channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether-a-go-go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short-QT-syndrome. Twelve rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an I channel opener, was infused (1 μmol/L). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (-32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; -22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; -20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 μmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post-repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short-QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR.
Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias.
Ng Fu Siong,Shadi Iqbal T,Peters Nicholas S,Lyon Alexander R
Journal of molecular and cellular cardiology
Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia-reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8min followed by 10min of reperfusion: (1) Control n=10; (2) 1μM of ivabradine perfusion n=10; (3) 1μM of ivabradine+5Hz atrial pacing throughout ischaemia-reperfusion n=5; (4) 1μM of ivabradine+5Hz pacing only at reperfusion; (5) 100μM of ivabradine was used as a 1ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n=5; 5Hz pacing n=5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195±11bpm vs. control 272±14bpm, p<0.05) and at reperfusion (168±13bpm vs. 276±14bpm, p<0.05) was associated with reduced reperfusion ventricular fibrillation (VF) incidence (20% vs. 90%, p<0.05). Pacing throughout ischaemia-reperfusion abolished the protective effects of ivabradine (100% VF), whereas pacing at reperfusion only partially attenuated this effect (40% VF). Ivabradine, given as a bolus at reperfusion, did not significantly affect VF incidence (80% VF). Optical mapping experiments showed a delay to ischaemia-induced conduction slowing (time to 50% conduction slowing: 10.2±1.3min vs. 5.1±0.7min, p<0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7±4.3min vs. 14.5±0.6min, p<0.05). Ivabradine administered throughout ischaemia and reperfusion reduced reperfusion VF incidence through HRR. Heart rate during ischaemia is a major determinant of reperfusion arrhythmias. Heart rate at reperfusion alone was not a determinant of reperfusion VF, as neither a bolus of ivabradine nor pacing immediately prior to reperfusion significantly altered reperfusion VF incidence. This anti-arrhythmic effect of heart rate reduction during ischaemia may reflect slower development of ischaemia-induced electrophysiological changes.
Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat.
Mackiewicz Urszula,Gerges Joseph Y,Chu Sandy,Duda Monika,Dobrzynski Halina,Lewartowski Bohdan,Mączewski Michał
Journal of cellular physiology
Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24 h after non-reperfused MI in the rat. ECG was recorded for 24 h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty-five minutes and twenty-four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca(2+) handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI + Ivabradine rats. MI resulted in (1) increase of Ca(2+) sensitivity of ryanodine receptors 24 h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (IF) in LV cardiomyocytes 24 h after MI, and (3) dispersion of MAP duration both 45 min and 24 h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca(2+)-leak from sarcoplasmic reticulum, upregulation of IF current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI.
Comparative efficacy of ivabradine versus beta-blockers in patients with mitral stenosis in sinus rhythm: systematic review and meta-analysis.
Ghadimi Nashmil,Kaveh Sara,Shabaninejad Hossein,Lijassi Alaadine,Mehr Ali Zahed,Hosseinifard Hossein
International journal of clinical pharmacy
Background Patients with mitral valve stenosis have increased heart rate. HR reduction is known as an important treatment and therapy strategy for patients with mitral valve stenosis. Aim of the review The aim of this systematic review and meta-analysis was to compare the efficacy of ivabradine versus beta-blockers in patients with mitral stenosis in sinus rhythm. Methods Randomized controlled trials were searched in Cochrane Library, PubMed, Web of Science, CRD, Scopus, and Google Scholar with no start time limitation and ending June 2018. Risk of bias across was assessed by the Cochrane Risk of Bias Assessment tool. Fixed effects models were used to combine the results and the mean difference with a 95% confidence interval. This meta-analysis was performed using Meta Package in R software. Results Five studies entered meta-analysis. The total number of patients treated with ivabradine and beta-blockers was 178 and 178 respectively. The results showed that the mean of maximum HR and HR at rest was lower at about 5.03 units and upper 4.32 units respectively with use of ivabradine compared with the use of beta-blockers. These values were statistically significant. Conclusion It seems that the efficacy of ivabradine is good in comparison with betablockers, but it still requires more clinical trials.
Initiation of ivabradine in cardiogenic shock.
Chiu Michael H,Howlett Jonathan G,Sharma Nakul C
ESC heart failure
AIMS:Ivabradine is a selective sinus node inhibitor indicated in patients with symptomatic chronic heart failure on stable guideline-recommended heart failure therapy including appropriate doses of beta-blockers. The use in cardiogenic shock remains off label and has been considered a contraindication due to the theoretical risk of attenuating compensatory tachycardia. Tachycardia, especially in the context of inotropic therapy, may be deleterious, resulting in increased myocardial oxygen consumption and reduction in diastolic filling. As ivabradine does not have negative inotropic action, it may present a potential means to manage tachycardia in cardiogenic shock. We present a case series of four patients with cardiogenic shock started on ivabradine who were unable to tolerate beta-blockers. METHODS AND RESULTS:Five patients identified with cardiogenic shock defined as a severe reduction in cardiac index (<2.0 L/min/m ) and elevated filling pressures on inotropic therapy were started on ivabradine in patients with sinus tachycardia [heart rate (HR) >100] who were intolerant to beta-blockers. Each patient had a cardiac magnetic resonance imaging, echocardiogram, and coronary angiogram for determination of aetiology. Invasive haemodynamics via pulmonary artery catheterization were measured during initiation and titration of ivabradine (baseline, 6, 12, 24, and 48 h after ivabradine administration) with continuous telemetry monitoring for any dysrhythmia or bradyarrhythmias. All patients tolerated ivabradine initiation, and at 24 h, an observed decrease in HR (106 ± 6.8 vs. 91.6 ± 6.4 b.p.m., P = 0.04), pulmonary arterial occlusion pressure (30.4 ± 4.8 vs. 24 ± 5.1 mmHg, P = 0.04), and right atrial pressure (16.8 ± 6.2 vs. 9 ± 4.3 mmHg, P = 0.0002). An improvement was observed in mixed venous oxygen saturation (SvO ) (51 ± 8.8 vs. 64.8 ± 5.3%, P < 0.04), stroke volume (37.2 ± 7.6 vs. 49.2 ± 12.9 mL, P < 0.04), and right and left ventricular stroke work index (Table 1). No significant changes were observed with mean arterial pressure (73.4 ± 7.5 vs. 75.8 ± 5.0 mmHg, P = 0.81) and thermodilution-derived cardiac index (1.7 ± 0.2 vs. 2.5 ± 0.7 L/min/m , P = 0.58). Inotropic support was weaned successfully in three of five patients (88 ± 30 h) with subsequent titration of beta-blocker therapy. Two patients improved clinically but ultimately required left ventricular assist device implantation. All patients were discharged alive from hospital at 17 ± 7.9 days following ivabradine initiation. CONCLUSIONS:In our small non-randomized series of patients in cardiogenic shock, ivabradine was safely used to reduce HR in patients previously intolerant of beta-blockade. There are limited data surrounding the use of ivabradine in cardiogenic shock, and future studies should be undertaken to determine the optimal HR in humans with cardiogenic shock and whether systematic limitation of peak HR may improve outcomes.
Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy.
Kohli Utkarsh,Aziz Zaid,Beaser Andrew D,Nayak Hemal M
Pacing and clinical electrophysiology : PACE
Conventional treatment strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT) include avoidance of strenuous exercise and competitive sports, drugs such as ß-blockers and flecainide and, cervical sympathectomy. An implantable cardioverter-defibrillator (ICD) has been utilized if the response to these strategies is inadequate; however, ICD use in CPVT patients, in addition to usual complications, is associated with an increased risk of life-threatening electrical storm. Ivabradine is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 generated funny current (I ), which has been shown to be efficacious in suppression of inappropriate sinus tachycardia, junctional tachycardia, atrial tachycardia, and ventricular ectopy in humans. We report an 18-year-old male with a severe CPVT phenotype refractory to flecainide, nadolol, and sympathectomy who exhibited suppression of ventricular arrhythmias after initiation of ivabradine. These findings are of importance as ivabradine could be an important add-on therapy in CPVT patients who are drug refractory or are unable to continue conventional therapies at the recommended doses.
Efficacy of ivabradine to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia.
Vaksmann Guy,Klug Didier
Pacing and clinical electrophysiology : PACE
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal hereditary disease characterized by complex ventricular arrhythmias provoked by exercise or emotional stress and by a high mortality rate in young individuals. Nadolol alone or in combination with flecainide is the most effective therapy. However, compliance to treatment is often low due to side effects. We report two patients with CPVT in whom side effects of treatment prompted discontinuation of flecainide or nadolol and in whom ivabradine was successfully added to therapy. In these two patients, ivabradine in combination with nadolol or flecainide was well tolerated and successfully suppressed nonsustained polymorphic ventricular tachycardia and couplets. Thus, ivabradine could limit the use of implantable cardioverter-defibrillators or left cardiac sympathetic denervation in CPVT patients with uncontrollable ventricular arrhythmias.
Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?
Marciszek Mariusz,Paterek Aleksandra,Oknińska Marta,Zambrowska Zuzanna,Mackiewicz Urszula,Mączewski Michał
Cardiac arrhythmias are a major source of mortality and morbidity. Unfortunately, their treatment remains suboptimal. Major classes of antiarrhythmic drugs pose a significant risk of proarrhythmia, and their side effects often outweigh their benefits. Therefore, implantable devices remain the only truly effective antiarrhythmic therapy, and new strategies of antiarrhythmic treatment are required. Ivabradine is a selective heart rate-reducing agent, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, currently approved for treatment of coronary artery disease and chronic heart failure. In this review, we focus on the clinical and basic science evidence for the antiarrhythmic and proarrhythmic effects of ivabradine. We attempt to dissect the mechanisms behind the effects of ivabradine and indicate the focus of future studies.
Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat.
Marciszek Mariusz,Paterek Aleksandra,Oknińska Marta,Mackiewicz Urszula,Mączewski Michał
Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. Thus we investigated effects of ivabradine, a presumably specific bradycardic agent versus metoprolol, a β-blocker, at doses offering the same heart rate (HR) reduction, on ventricular arrhythmias in the acute non-reperfused MI in the rat. Immediately after MI induction a single dose of ivabradine/ metoprolol was given. ECG was continuously recorded and ventricular arrhythmias were analyzed. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca handling was assessed. Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. Both drugs reduced QTc prolongation and decreased sensitivity of ryanodine receptors in isolated cardiomyocytes, but otherwise had no effect on Ca handling, velocity of conduction or repolarization. We did not find any effects of potential I inhibition by ivabradine in this setting. Thus Ivabradine is an equally effective antiarrhythmic agent as metoprolol in early MI in the rat. It could be potentially tested as an alternative antiarrhythmic agent in acute MI when β-blockers are contraindicated.
The bradycardic agent ivabradine decreases conduction velocity in the AV node and in the ventricles in-vivo.
Amstetter Daniel,Badt Florian,Rubi Lena,Bittner Reginald E,Ebner Janine,Uhrin Pavel,Hilber Karlheinz,Koenig Xaver,Todt Hannes
European journal of pharmacology
Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles. Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine-induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo.
Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias.
Mert Kadir Uğur,Mert Gurbet Özge,Morrad Bektas,Tahmazov Senan,Mutlu Fezan,Çavuşoglu Yüksel
BACKGROUND:Indirect evidences suggest that the If blocker ivabradine may exert an antiarrhythmic effect in ventricular myocardium in heart failure (HF) patients by inhibiting spontaneous depolarisations, but the clinical relevance of this mechanism is not known. Dobutamine (DOB) has been known to increase heart rate and the incidence of cardiac arrhythmias. AIM:In this study, we evaluated the effects of ivabradine on DOB-induced ventricular arrhythmias and compared them with those of beta-blocker (BB) therapy. METHODS:Patients with decompensated HF requiring inotropic support, left ventricular ejection fraction < 35%, and in sinus rhythm were included in the study (ivabradine group - 29 patients, control group - 29 patients, BB group - 15 patients). All patients underwent Holter recording for 6 h before the initiation of DOB infusion. Following baseline recording, DOB was administered at incremental doses of 5, 10, and 15 μg/kg/min, with 6-h steps. Holter monitoring was continued during 18 h of DOB infusion and analysed for the median number of ventricular premature contractions (VPC), ventricular couplets, episodes of non-sustained ventricular tachycardia, and total ventricular arrhythmias in each step of the study protocol. RESULTS:The positive chronotropic effect of incremental DOB doses was blunted by beta-blockade and was totally abolished by ivabradine. The median number of VPCs, ventricular couplets, and total ventricular arrhythmias significantly increased with incremental doses of DOB in the control group (p = 0.018) and, to a lesser extent, in the ivabradine group (p = 0.015). In the BB group the absolute VPCs numbers were smaller than in the control or the ivabradine group, with the on-ivabradine VPCs numbers falling between those seen in control and BB groups. A numeric increase in VPCs with incremental DOB doses occurred in the BB group but did not reach statistical significance (p > 0.05), consistent with a protective effect of beta-blockade. Ivabradine reduced VPCs by 43% at 5 μg/kg/min DOB and by 38% at 10 μg/kg/min DOB against the control group (VPCs median 256 vs. 147 and 251 vs. 158) in the absence of significant differences at 15 μg/kg/min DOB between the control and ivabradine groups (overall p > 0.05). Thus, ivabradine administered without background beta-blockade attenuated the arrhythmogenic effect of increasing doses of DOB in the low and moderate DOB dose but not in the high DOB dose. CONCLUSIONS:In patients with decompensated HF, ivabradine appears to reduce the incidence of VPCs in response to low and medium DOB dose. Whether the anti-arrhythmic effect of ivabradine is additive to the anti-arrhythmic effect of beta-blockade requires further investigation; this should also determine the clinical significance of ventricular arrhythmia attenuation with ivabradine.