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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. [ABSTRACT FROM AUTHOR]

The author discusses a study by S. A. Shabtaie and colleagues which provided a review on the outcome results of a series of consecutive patients with inappropriate sinus tachycardia (IST) referred to the authors' center between 1998 and 2018. Topics include symptoms in patients with IST, mechanisms that are potentially responsible for increased heart rate in patients with IST, and therapies that have been investigated for the treatment of IST.

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 If current and hyperpolarization‐activated cyclic nucleotide gated (HCN) channel overexpression. Methods and Results: We investigated both the If 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 If current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the If 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 (V1/2: 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 If 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 If gain‐of‐function. [ABSTRACT FROM AUTHOR]

Ivabradine in Postoperative Atrial Fibrillation 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. [ABSTRACT FROM AUTHOR]

Ivabradine in Atrial Tachycardia Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18-year-old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity. [ABSTRACT FROM AUTHOR]

Effects of Ivabradine and Ryanodine on Cardiac Pacemakers. Introduction: It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly If) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca2+ release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity. Methods and Results: Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1-3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca2+ release or If, respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl2. In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol-accelerated automaticity. In PF depolarized with BaCl2, ivabradine decreased BaCl2-induced automatic rate while ryanodine had no effect. Conclusion: In canine SN, If contributes to both basal automaticity and β-adrenergic-induced rate acceleration while the ryanodine-inhibited Ca clock appears more involved in β-adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on If. Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN-like responses to inhibition of membrane and Ca clocks. (J Cardiovasc Electrophysiol, Vol. 23, pp. 650-655, June 2012) [ABSTRACT FROM AUTHOR]

Effects of Ivabradine on Pulmonary Veins. Introduction: Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (If). The aim of this study was to investigate the pharmacological effects of ivabradine on the pulmonary vein (PV) cardiomyocytes. Methods and Results: Whole-cell patch-clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the If and intracellular calcium ( Ca 2+i) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Ivabradine (0.3, 3, 10, and 30 μM) concentration dependently decreased the spontaneous activity by 6 ± 3%, 32 ± 6%, 49 ± 5%, and 85 ± 4%, and decreased the If by 35 ± 8%, 47 ± 9%, 62 ± 5%, and 65 ± 7%, respectively, in PV cardiomyocytes. The decreased extent of the PV beating rate or If by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC50 of the spontaneous activity and If induced by ivabradine were 9.5 and 3.5 μM, respectively. Moreover, ivabradine (30 μM, but not 3 μM) decreased the Ca 2+i transient in the PV cardiomyocytes and ivabradine (30 μM) decreased the L-type calcium current in the PV cardiomyocytes. Conclusion: Ivabradine decreased the Ifs and Ca 2+i transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity. (J Cardiovasc Electrophysiol, Vol. 23, pp. 200-206, February 2012) [ABSTRACT FROM AUTHOR]

Ablate and Pace for POTS. A 42-year-old woman with postural tachycardia syndrome (POTS) was admitted to our hospital with severe palpitations, light-headedness, and syncope. Several drugs had been administered previously, but all had been discontinued due to intolerable adverse effects or limited efficacy. One of the drugs, the If current inhibitor ivabradine, effectively slowed the patient's heart rate and relieved the symptoms, but was discontinued due to allergy. After unsuccessful sinus node ablation, atrioventricular node ablation and dual chamber pacemaker implantation was performed, which dramatically improved her symptoms and eliminated syncope. Atrioventricular node ablation could modify the cardiac autonomic balance and thereby suppressed the excessive orthostatic sympathetic activity. (J Cardiovasc Electrophysiol, Vol. pp. 1-4) [ABSTRACT FROM AUTHOR]

Introduction: It has been speculated that pacemaker current (I f) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I f inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I f in atrial myocytes. Methods and Results: Using patch-clamp technique, we studied effects of ivabradine on I f present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I f inhibition with an IC50 at steady state of 2.9 μM. Time constant of block development (Tauon) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 μM) was not modified in the presence of cAMP (10 μM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected. Conclusions: Ivabradine inhibits I f current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I f recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f-channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed. [ABSTRACT FROM AUTHOR]

The article presents Atrial fibrillation (AF) to be the most sustained cardiac arrhythmia which leads to cardiac morbidity and mortality. It discusses the agents available for pharmacologic management of AF and states that such agents have a limitation of suboptimal efficacy and proarrhythmic risk. It focuses on the use of rhythm control medical treatment for the patients suffering with paroxysmal and persistent AF.

Potential New Indication for Ivabradine Ivabradine is a new antiarrhythmic agent with direct inhibition of the pacemaker (If) current. It has been used extensively to decrease sinus rate in the treatment of cardiac failure, and also in a single case of atrial ectopic tachycardia in a child. Here we report the case of a 3-year-old girl with congenital junctional ectopic tachycardia (JET), resistant to conventional antiarrhythmic medications, who was successfully treated with ivabradine. We suggest that ivabradine can be an effective treatment for junctional automatic tachycardias and can be considered as a new line of therapy for this incessant form of tachycardia. [ABSTRACT FROM AUTHOR]

Ivabradine has been shown to be effective in reducing sinus rate. Here we report of a case where ivabradine reduced the rate of a focal atrial tachycardia relieving patient's symptoms and reversing tachycardiomyopathy. (J Cardiovasc Electrophysiol, Vol. 22, pp. 340-342, March 2011) [ABSTRACT FROM AUTHOR]

Ivabradine in IST. We present a case of a 49-year-old man with inappropriate sinus tachycardia and ventricular dysfunction. The conventional treatment (ace-inhibitor and beta-blockers) was not well tolerated by the patient, so Ivabradine, a specific inhibitor of If current in the sinus node, was started. After 3 months of using this medication, we observed an improvement of ejection fraction and quality of life. (J Cardiovasc Electrophysiol, Vol. pp. 815-817, July 2010) [ABSTRACT FROM AUTHOR]

In this article the author discusses the role that enhanced automaticity plays in atrial fibrillation, the role a cardiac current called the funny current (If) plays in pacemaker functioning and the article "Chronic Atrial Fibrillation Alters the Functional Properties of If in the Human Atrium" by F. Stillitano et al. in the issue. She is supportive of several points which are raised in Stillitano et al.'s article and of suppressing lf in patients with atrial tachycardia and atrial fibrillation.

Introduction: Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF., Methods and Results: Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine's reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF., Conclusion: Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility., (© 2014 Wiley Periodicals, Inc.)

Introduction: The mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of If are plausible., Methods and Results: In anesthetized pigs, we compared the effects of dronedarone to the prototypical If inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated. Cumulative doses of dronedarone (0.5 mg/kg, i.v., and 5.0 mg/kg, i.v.; plasma level: 80 ± 16.1 nM) progressively reduced heart rate (P < 0.02) without changes in MAP or contractility as assessed by LV dP/dt (N = 6). Ivabradine (0.5 mg/kg, i.v.) similarly reduced heart rate (P < 0.01) without change in MAP (N = 6). Diltiazem (0.8 mg/kg, i.v.) reduced heart rate and MAP and decreased contractility (N = 6). Dronedarone blunted phenylephrine's alpha-receptor-mediated increase in MAP but did not alter the marked beta-adrenergic receptor (BAR)-mediated increase in heart rate induced by isoproterenol. When dronedarone injection was preceded by ivabradine, no further decrease in heart rate or change in MAP was observed (N = 6)., Conclusions: Dronedarone reduced heart rate without affecting MAP or contractility, effects that differ from L-type calcium channel blockade. Dronedarone did not antagonize BAR stimulation, and its heart-rate lowering effects were eliminated by prior administration of ivabradine. Thus, dronedarone's bradycardic action is likely due to inhibition of If and not to blockade of either L-type calcium channels or BAR., (© 2013 Wiley Periodicals, Inc.)

Introduction: It has been speculated that pacemaker current (I(f)) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I(f) inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I(f) in atrial myocytes., Methods and Results: Using patch-clamp technique, we studied effects of ivabradine on I(f) present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I(f) inhibition with an IC50 at steady state of 2.9 microM. Time constant of block development (Tau(on)) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 microM) was not modified in the presence of cAMP (10 microM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected., Conclusions: Ivabradine inhibits I(f) current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I(f) recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f-channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed.