Protection of Ivabradine Combined with Trimetazidine on Myocardial Injury after Percutaneous Coronary Intervention in Patients with Coronary Artery Disease Evaluated by Magnetic Resonance Image under Convolutional Neural Network.

Objective: To evaluate the myocardial protection of Ivabradine (IBD) combined with Trimetazidine (TMZ) in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI), magnetic resonance imaging (MRI) images under convolutional neural network (CNN) algorithm were used. Methods: A CNN artificial intelligence algorithm was proposed to process the image artifacts caused by undersampling magnetic resonance, so as to be used in the diagnosis and efficacy evaluation of myocardial injury. 120 patients with CAD after PCI were rolled into group A (TMZ treatment), group B (IBD treatment), and group C (IBD + TMZ combined treatment) randomly, with 40 patients in each group. All the patients were treated for two consecutive weeks and followed up for six months. Clinical indicators of patients in the two groups were observed, detected, and statistically analyzed. Results: The accuracy, sensitivity, specificity, and area under the curve (AUC) of MRI images based on CNN algorithm for the diagnosis of myocardial injury were 91.04%, 97.60%, 87.04%, and 96.43%, respectively. After treatment, the left ventricular end diastolic diameter (LVEDD), LVE diastolic volume (LVEDV), LVE systolic diameter (LVESD), and LVE systolic volume (LVESV) were greatly reduced in all groups after treatment, whereas the left ventricular ejection fraction (LVEF) increased considerably (P < 0.05). LVEDD, LVEDV, LVESD, and LVESV in group C were substantially inferior to those in groups A and B, and LVEF was remarkably superior to that in groups A and B (P < 0.05). After treatment, cTnI, hs-CRP, sICAM-1, ET-1, and MDA in three groups were greatly decreased (P < 0.05), while SOD was substantially increased (P < 0.05). After treatment, cTnI, hs-CRP, SICAM-1, ET-1, and MDA in group C were notably inferior to groups A and B (P < 0.05), while SOD was greatly higher (P < 0.05). Conclusion: MRI based on CNN had high application value in the diagnosis and efficacy evaluation of myocardial injury after PCI. For patients with CAD, IBD combined with TMZ after PCI can effectively play the role of anti-inflammatory and antioxidative damage and improve intradermal function.

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

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

Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

The efficacy of ivabradine in the treatment of acute myocardial infarction: A protocol for systematic review and meta-analysis.

BACKGROUND: Cardiovascular diseases have become a prominent threat to public health and quality of life. In recent years, some studies have reported that ivabradine can improve the cardiac function and prognosis of patients with acute myocardial infarction (AMI). Therefore, we perform a protocol for systematic review and meta-analysis to evaluate the efficacy of ivabradine for treating AMI. METHODS: This protocol of systematic review and meta-analysis has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols. We will search PubMed, Cochrane Library, Embase, Web of Science, and Medline databases for relevant studies. In addition, we will also collect 4 databases of China: China National Knowledge Infrastructure, China Biomedical Literature Database, China Science Journal Database, and Wan-fang Database. Risk of bias will be assessed using the Cochrane Handbook risk of bias assessment tool version (V.5.1.0). We will use STATA 16.0 software (Stata Corporation, College Station, TX) to perform data analysis. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: We hypothesized that ivabradine can reduce the resting heart rate and improve heart function in patients with AMI.

Nano-ivabradine averts behavioral anomalies in Huntington's disease rat model via modulating Rhes/m-tor pathway.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

Simultaneous Optimization of Oral and Transdermal Nanovesicles for Bioavailability Enhancement of Ivabradine Hydrochloride.

PURPOSE: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most ß-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally. MATERIALS AND METHODS: A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics. RESULTS: The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, -40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively. CONCLUSION: Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.

An Integrative Approach for Improved Assessment of Cardiovascular Safety Data.

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.

Long-term pharmacological torpor of rats with feedback-controlled drug administration.

The maintenance of pharmacological torpor and hypothermia (body temperature 28 °C - 33 °C) in rats for a week is presented. For this purpose, our laboratory has developed a device (BioFeedback-2) for the feed-back controlled multiple injections of small doses of a pharmacological composition that we created earlier. On the 7th day, the rat spontaneously come out of the pharmacological torpor, the body temperature returned to normal, and on the 8th day, the animal could consume food and water. The proposed approach for maintaining multi-day pharmacological torpor can be applied in medicine, as well as for protecting astronauts during long missions in space.

Practical instructions for using drugs in CT and MR cardiac imaging.

The progressive increase in numbers of noninvasive cardiac imaging examinations broadens the spectrum of knowledge radiologists are expected to acquire in the management of drugs during CT coronary angiography (CTCA) and cardiac MR (CMR) to improve image quality for optimal visualization and assessment of the coronary arteries and adequate MR functional analysis. Aim of this review is to provide an overview on different class of drugs (nitrate, beta-blockers, ivabradine, anxiolytic, adenosine, dobutamine, atropine, dipyridamole and regadenoson) that can be used in CTCA and CMR, illustrating their main indications, contraindications, efficacy, mechanism of action, metabolism, safety, side effects or complications, and providing advices in their use.

Effectiveness of point-of-care oral ivabradine for cardiac computed tomography.

BACKGROUND: Coronary CT angiography (CCTA) is increasing seen as a first line investigation in patients with suspected coronary artery disease. Heart-rate control improves the image quality and diagnostic accuracy of CCTA. Typically, beta-blockers are administered to induce sinus bradycardia. Sinus bradycardia may also be induced by ivabradine. We hypothesized that in a real-world population ivabradine would be an effective alternative to metoprolol at heart rate lowering for CCTA. METHODS: This was a retrospective analysis of consecutive patients who were exposed to an ivabradine-based (IB) versus a metoprolol-only (MO) protocol to achieve a target heart rate 65 and received heart-rate lowering medication: 1958 patients had MO, and 718 received IB protocol. Target heart rate of

Ivabradine improves survival and attenuates cardiac remodeling in isoproterenol-induced myocardial injury.

This study investigated whether ivabradine, a selective If current inhibitor reducing heart rate (HR), is able to improve survival and prevent left ventricular (LV) remodeling in isoproterenol-induced heart damage. Wistar rats were treated for 6 weeks: controls (n = 10), ivabradine (10 mg/kg/day orally; n = 10), isoproterenol (5 mg/kg/day intraperitoneally; n = 40), and isoproterenol plus ivabradine (n = 40). Isoproterenol increased mortality, induced hypertrophy of both ventricles and LV fibrotic rebuilding, and reduced systolic blood pressure (SBP). Ivabradine significantly increased survival rate (by 120%) and prolonged average survival time (by 20%). Furthermore, ivabradine reduced LV weight and hydroxyproline content in soluble and insoluble collagen fraction, reduced HR and attenuated SBP decline. We conclude that ivabradine improved survival in isoproterenol-damaged hearts.

Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method.

Ivabradine and its metabolite both demonstrate heart rate-reducing effect (If current inhibitors) and undergo CYP3A4 metabolism. The purpose of this study was to develop a joint parent-metabolite physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict the PK and PD of ivabradine and its metabolite following intravenous (i.v.) or oral administration (alone or co-administered with CYP3A4 inhibitors). Firstly, a parent-metabolite disposition model was developed and optimised using individual plasma concentration-time data following i.v. administration of ivabradine or metabolite within a Bayesian framework. Secondly, the model was extended and combined with a mechanistic intestinal model to account for oral absorption and drug-drug interactions (DDIs) with CYP3A4 inhibitors (ketoconazole, grapefruit juice). Lastly, a PD model was linked to the PBPK model to relate parent and metabolite PK to heart rate (HR) reduction. The disposition model described successfully parent-metabolite PK following i.v. administration. Following integration of a gut model, the PBPK model adequately predicted plasma concentration profiles and the DDI risk (92% and 85% of predicted AUC+inhibitor/AUCcontrol and Cmax+inhibitor/Cmaxcontrol for ivabradine and metabolite within the prediction limits). Ivabradine-metabolite PBPK model was linked to PD by using the simulated unbound parent-metabolite concentrations in the heart. This approach successfully predicted the effects of both entities on HR (observed vs predicted - 7.7/- 5.9 bpm and - 15.8/- 14.0 bpm, control and ketoconazole group, respectively). This study provides a framework for PBPK/PD modelling of a parent-metabolite and can be scaled to other populations or used for investigation of untested scenarios (e.g. evaluation of DDI risk in special populations).

A case of highly disabling orthostatic hypotension: when an integrated cardiac rehabilitation approach makes the difference.

SUMMARY: Orthostatic hypotension (OH) is a disabling condition accompanying several diseases. It has increased morbidity and mortality, and limited chances of treatment. We report a case of a patient with stable ischemic heart disease and severe OH unresponsive to usual care. A baseline 75° head-up tilt test (HUT) was positive for symptomatic OH, i.e. pre-syncope with a systolic arterial pressure drop of 35 mmHg. On top of optimal treatment, ivabradine was started. Symptoms improved within 24 hours. At a repeated HUT, the patient could tolerate the up-right position up to 25 minutes. He was able to undergo an individualized training program with further amelioration of quality of life. Thereafter, titration of ACE inhibitors became possible. Lasting benefits were present at a 6-month follow-up. To our knowledge, this is the first reported case of successful use of ivabradine to integrate cardiac rehabilitation for management of a highly disabling OH.

Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk-minimization measures.

PURPOSE: This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study. METHODS: This was a multinational (five European countries) chart review study with two study periods: pre-RMM and post-RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow-up, and no concomitant use of verapamil or diltiazem. RESULTS: Overall, 711 and 506 eligible patients were included in the pre-RMM and post-RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post-RMM period (70.6% and 78.4% in the pre- and post-RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow-up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007). CONCLUSIONS: The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris.

Ivabradine in Post-operative Junctional Ectopic Tachycardia (JET): Breaking New Ground.

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.

Intravenous ivabradine augments the dynamic heart rate response to moderate vagal nerve stimulation in anesthetized rats.

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 (n = 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 V0-10, V0-20, and V0-40, 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 V0-20 [from 3.88 (1.78-5.79) to 6.62 (3.12-8.31) beats·min-1·Hz-1, P < 0.01, median (range)] but not in V0-10 or V0-40. Ivabradine increased the corner frequency in V0-10 [from 0.032 (0.026-0.041) to 0.064 (0.029-0.090) Hz, P < 0.01] and V0-20 [from 0.040 (0.037-0.056) to 0.068 (0.051-0.100) Hz, P < 0.01] but not in V0-40. 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.NEW & NOTEWORTHY 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.

Clinical and Electrophysiological Correlates of Incessant Ivabradine-Sensitive Atrial Tachycardia.

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.

[Proportion of patients with heart failure in a specialized clinic eligible for novel therapies]. / Pacientes elegibles para las nuevas terapias de la insuficiencia cardíaca en un policlínico especializado.

BACKGROUND: Pharmacological treatment improves survival in patients with heart failure with reduced ejection fraction. The use of sacubutril/valsartan and ivabradine has been recently approved and incorporated in the latest guidelines. AIM: To identify candidates eligible for these therapies among patients treated in a heart failure clinic, considering the inclusion criteria for the PARADIGM-HF and SHIFT trials. MATERIAL AND METHODS: Cross-sectional study on 158 patients aged 62 ± 11 years (67% male) with heart failure and reduced ejection fraction, with at least three months of follow-up and without decompensation. The percentage of patients complying for the inclusion criteria for the PARADIGM-HF y SHIFT trials was determined. RESULTS: In 37%, the etiology of heart failure was ischemic, 49% were in functional class I, their ejection fraction was 33 ± 11% and their median Pro-brain natriuretic peptide was 800 pg/mL. Ninety five percent were treated with vasodilators, 97% with beta-blockers and 82% with aldosterone antagonists. Using PARADIGM-HF and SHIFT criteria, 11 patients (7%) were eligible for sacubitril / valsartan and 21 patients (13.3%) for ivabradine. Among the main causes of non-eligibility for sacubitril / valsartan were being functional class I (48.7%) and not achieving a stable dose of enalapril ≥ 20 mg / day or losartan ≥ 100 mg / day (24.7%). In the case of ivabradine, apart from those in functional class I, the absence of sinus rhythm and a heart rate < 70 / min when receiving a maximal tolerated dose of beta-blockers, were present in 22%. CONCLUSIONS: A low percentage of our patients were eligible for these therapies. Among the causes that explain these results were clinical stability, a high percentage of patients in functional class I and being in a disease modifying treatment.

Pharmacokinetic profile of ivabradine hemisulfate sustained-release tablets administered in Chinese healthy volunteers: An open-label, randomized, single-dose, three-period crossover study.

We aimed to determine the pharmacokinetics and safety of three single oral doses (5, 10 and 15 mg) of ivabradine hemisulfate sustained-release tablets in healthy Chinese volunteers. A total of 12 volunteers (six males and six females) were randomized to receive a single oral dose of ivabradine hemisulfate sustained-release tablets 5, 10 or 15 mg, with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 48 h after drug administration, and the concentrations of ivabradine and N-desmethyl ivabradine were determined by HPLC-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis. After administering single doses of 5, 10 and 15 mg, the mean maximum concentration (Cmax ) levels of ivabradine were 4.36, 7.29 and 12.62 ng/mL, and the mean area under the curve from time 0 to 48 h (AUC0-48 ) values were 55.66, 101.16 and 182.09 h·ng/mL, respectively. The mean Cmax levels of N-desmethyl ivabradine were 1.05, 2.03 and 3.16 ng/mL, and the mean AUC0-48 values were 20.61, 39.44 and 65.72 h·ng/mL, respectively. The median time of maximum concentration (Tmax ) levels of ivabradine and N-desmethyl ivabradine were 5 h for all three doses tested. The pharmacokinetic properties of ivabradine hemisulfate sustained-release tablets were linear at doses from 5 to 15 mg. Ivabradine hemisulfate sustained-release tablet appears to be well tolerated in these healthy volunteers.

Initiation of ivabradine in cardiogenic shock.

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/m2 ) 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 (SvO2 ) (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/m2 , 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.