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

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

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

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

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

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

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

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

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

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

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

Feasibility of Short-Term Use of Ivabradine in Critical Ill Patients Who Have Atrial Fibrillation and Tachycardia.

Background: Ivabradine is approved for heart rate reduction in patients with stable symptomatic heart failure (HF). The United States Food and Drug Administration and Taiwan Central Health Insurance Agency approved the use of ivabradine for patients with chronic stable HF with sinus rhythm, but it has not yet been approved for patients with acute decompensated HF or with atrial fibrillation (AF). Objectives: To investigate whether short-term ivabradine use is feasible in critically ill patients with AF and rapid ventricular response (RVR). Methods: This study retrospectively analyzed 23 patients admitted to an intensive care unit with acute HF and AF-RVR who received ivabradine. All patients initially received a slow IV of amiodarone. Other medications for HF were prescribed according to current HF guidelines. The time taken for ivabradine to reduce HR to 80 beats per minute, referred to as "Time to 80," was measured in each patient. Results: Overall, 69.6 % (16/23) of the patients had New York Heart Association functional class IV HF. In addition, 60.9% (14/23) of the patients required endotracheal intubation and ventilatory support, with more than half receiving vasopressor treatment to manage hypotension. Five patients died during the study period. The surviving patients had a significantly shorter "Time to 80" compared to those who did not survive (p = 0.037). Conclusions: Adding ivabradine to standard treatment might be feasible for critically ill patients with AF and tachycardia. The finding that surviving patients had a shorter "Time to 80" duration than those who did not survive may have clinical implications. However, further investigations are needed to assess its clinical utility.

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

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

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

Dynamic accentuated antagonism of heart rate control during different levels of vagal nerve stimulation intensity in rats.

Accentuated antagonism refers to a phenomenon in which the vagal effect on heart rate (HR) is augmented by background sympathetic tone. The dynamic aspect of accentuated antagonism remains to be elucidated during different levels of vagal nerve stimulation (VNS) intensity. We performed VNS on anesthetized rats (n = 8) according to a binary white noise signal with a switching interval of 500 ms at three different stimulation rates (low-intensity: 0-10 Hz, moderate-intensity: 0-20 Hz, and high-intensity: 0-40 Hz). The transfer function from VNS to HR was estimated with and without concomitant tonic sympathetic nerve stimulation (SNS) at 5 Hz. The asymptotic low-frequency (LF) gain (in beats/min/Hz) of the transfer function increased with SNS regardless of the VNS rate [low-intensity: 3.93 ± 0.70 vs. 5.82 ± 0.65 (P = 0.021), moderate-intensity: 3.87 ± 0.62 vs. 5.36 ± 0.53 (P = 0.018), high-intensity: 4.77 ± 0.85 vs. 7.39 ± 1.36 (P = 0.011)]. Moreover, SNS slightly increased the ratio of high-frequency (HF) gain to the LF gain. These effects of SNS were canceled by the pretreatment of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated channels, in another group of rats (n = 6). Although background sympathetic tone antagonizes the vagal effect on mean HR, it enables finer HR control by increasing the dynamic gain of the vagal HR transfer function regardless of VNS intensity. When interpreting the HF component of HR variability, the augmenting effect from background sympathetic tone needs to be considered.

Physiological effects of ivabradine in heart failure and beyond.

Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection.

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

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

Ivabradine as a treatment option for junctional ectopic tachycardia in an adult female.

A Junctional ectopic tachycardia diagnosis was performed using two electrophysiological maneuvers in an adult female with a narrow-complex supraventricular tachycardia with a bystander AV-node slow pathway conduction, who previously underwent catheter ablation attempts for an atrio-ventricular nodal re-entrant tachycardia misdiagnosis. The first maneuver was atrial entrainment with an atrial-His-His-atrial response. The second was based on the response to a premature atrial complex delivered at different phases of the tachycardia cycle confirming that anterograde slow pathway conduction and retrograde fast pathway were not involved. Considering that verapamil, diltiazem, bisoprolol + flecainide, and nadolol were ineffective, we tried ivabradine with no sustained arrhythmias during 18-months.

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

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

Efficacy of Doppler echocardiography-guided ivabradine therapy.

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

Ivabradine in the treatment of non-paroxysmal junctional tachycardia with interference atrioventricular dissociation: A case report.

Ivabradine reduces the heart rate by selectively inhibiting the If current of the sinoatrial node, mainly for the treatment of chronic heart failure with decreased left ventricular systolic function and inappropriate sinus tachycardia, but the inhibitory effect on the atrioventricular node is rarely reported. The patient was admitted to hospital mainly because of intermittent chest pain for 7 years, which worsened for 10 days. Admission electrocardiogram (ECG) considered sinus tachycardia, with QS wave and T wave inversion in II, III, aVF, V3 R-V5 R, V4 -V9 leads, and non-paroxysmal junctional tachycardia (NPJT) with interference atrioventricular dissociation. After treatment with ivabradine the ECG returned to normal conduction sequence. NPJT with interference atrioventricular dissociation is a fairly rare electrocardiographic phenomenon. This case reports for the first time that ivabradine is used in the treatment of NPJT with interference atrioventricular dissociation. It is speculated that ivabradine has a potential inhibitory effect on the atrioventricular node.

Successful use of ivabradine in a 10-year-old patient with graft failure after heart transplantation.

We encountered a paediatric case of graft failure due to antibody-mediated rejection after heart transplantation in which ivabradine was effective. Inappropriate sinus tachycardia in denervated transplanted hearts is a good indication for ivabradine administration as beta-blockers have a limited efficacy. To our knowledge, this is the first report on the effectiveness of ivabradine in a paediatric heart transplant rejection case.

Cardiovascular therapeutics: A new potential for anxiety treatment?

Besides the well-recognized risk factors, novel conditions increasing cardiovascular morbidity and mortality are emerging. Undesirable emotions and behavior such as anxiety and depression, appear to participate in worsening cardiovascular pathologies. On the other hand, deteriorating conditions of the heart and vasculature result in disturbed mental and emotional health. The pathophysiological background of this bidirectional interplay could reside in an inappropriate activation of vegetative neurohormonal and other humoral systems in both cardiovascular and psychological disturbances. This results in circulus vitiosus potentiating mental and circulatory disorders. Thus, it appears to be of utmost importance to examine the alteration of emotions, cognition, and behavior in cardiovascular patients. In terms of this consideration, recognizing the potential of principal cardiovascular drugs to interact with the mental state in patients with heart or vasculature disturbances is unavoidable, to optimize their therapeutic benefit. In general, beta-blockers, central sympatholytics, ACE inhibitors, ARBs, aldosterone receptor blockers, sacubitril/valsartan, and fibrates are considered to exert anxiolytic effect in animal experiments and clinical settings. Statins and some beta-blockers appear to have an equivocal impact on mood and anxiety and ivabradine expressed neutral psychological impact. It seems reasonable to suppose that the knowledge of a patient's mood, cognition, and behavior, along with applying careful consideration of the choice of the particular cardiovascular drug and respecting its potential psychological benefit or harm might improve the individualized approach to the treatment of cardiovascular disorders.

Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice.

PURPOSE: Cardiac rupture is a fatal complication following myocardial infarction (MI). An increase in heart rate (HR) is reportedly an independent risk factor for cardiac rupture during acute MI. However, the role of HR reduction in cardiac rupture after MI remains to be fully elucidated. We aimed to evaluate the therapeutic efficacy of HR reduction with ivabradine (IVA) on post-MI cardiac rupture in mice. METHODS: We induced MI in mice by ligating the left anterior descending coronary artery. Subsequently, we subcutaneously implanted osmotic pumps filled with IVA solution or vehicle (Veh) in the surviving MI mice at 24 h postoperatively. We biochemically analyzed the myocardium on day 5, additionally observed the mice for 10 days, and analyzed the rates of cardiac rupture and non-cardiac rupture death, and survival after MI. RESULTS: HR was significantly lower in the IVA-treated mice, whereas blood pressure was comparable between the two groups. Compared to the Veh-treated mice, apoptosis was significantly reduced in the MI border zone in the IVA-treated mice. Although there were no differences in the infarct size of the surviving MI mice between the two groups, HR reduction with IVA significantly reduced cardiac rupture (rupture rate 26 and 8% in the Veh-treated and IVA-treated groups, respectively) and improved survival after MI. CONCLUSION: Our findings suggest that HR reduction with IVA prevents cardiac rupture after MI. This may be particularly effective in MI patients with a high HR who are either unable to adequately tolerate ß-blockers or whose HR remains high despite receiving ß-blockers.