Meta-analysis of Traditional Chinese Medicine combined with Ivabradine in the Treatment of Chronic Heart Failure

Objective:To systemically evaluate clinical efficacy and safety of traditional Chinese medicine(TCM)combined with ivabradine(IVA)in the treatment of chronic heart failure(CHF).Method:We searched China National Knowledge Infrastructure(CNKI)datebase,Wanfang datebase,Chinese Scientifific Journal Database(VIP)datebase,PubMed,Conchrane Library and EMbase database to enroll the random control trials(RCTs)of TCM combined with IVA treating CHF.Meta-analysis was performed by Review Manager 5.3 software.Results:A total of 10 RCTs involving 960 patients were included.The results of Meta-analysis showed that compared with control group,the experimental group could improve the efficiency of cardiac function improvement[RR=1.19,95%CI(1.12,1.27),P<0.00001],increase left ventricular ejection fraction[MD=4.36,95%CI(2.88,5.83),P<0.0001]and reduce heart rate[MD=-8.21,95%CI(-12.08,-4.34),P<0.00001],the incidence of adverse reactions was similar between two groups[RR=1.00,95%CI(0.62,1.61),P=1.00].Conclusion:Traditional Chinese medicine combined with ivabradine has significant efficacy and good safety in improving cardiac function,improving left ventricular ejection fraction and reducing heart rate in the treatment of chronic heart failure.

Increased heart rate and atherosclerosis: Potential implications of ivabradine therapy

Despite all the therapeutic advances in the field of cardiology, cardiovascular diseases, and in particular coronary artery disease, remain the leading cause of death and disability worldwide, thereby underlining the importance of acquiring new therapeutic options in this field. A reduction in elevated resting heart rate (HR) has long been postulated as a therapeutic approach in the management of cardiovascular disease. An increased HR has been shown to be associated with increased progression of coronary atherosclerosis in animal models and patients. A high HR has also been associated with a greatly increased risk of plaque rupture in patients with coronary atherosclerosis. Endothelial function may be an important link between HR and atherosclerosis. An increased HR has been shown experimentally to cause endothelial dysfunction. Inflammation plays a significant role in the pathogenesis and progression of atherosclerosis. In the literature, there is data that shows an association between HR and circulating markers of vascular inflammation. In addition, HR reduction by pharmacological intervention with ivabradine (a selective HR-lowering agent that acts by inhibiting the pacemaker ionic current If in sinoatrial node cells) reduces the formation of atherosclerotic plaques in animal models of lipid-induced atherosclerosis. The aim of this editorial is to review the possible role of ivabradine on atherosclerosis.

Ivabradine in the treatment of systolic heart failure- A systematic review and meta-analysis

AIM To perform a systematic-review and meta-analysis to compare outcomes of ivabradine combined with betablocker to beta-blocker alone in heart failure with reduced ejection fraction(HFr EF).METHODS We searched PubM ed, Cochrane, EMBASE, CINAHL and Web of Science for trials comparing ivabradine + betablocker to beta-blocker alone in HFr EF. We performed a systematic-review and meta-analysis of published literature. Primary end-point was combined end point of cardiac death and hospitalization for heart failure.RESULTS Six studies with 17671 patients were included. Mean follow-up was 8.7 ± 7.9 mo. Combined end-point of heart failure readmission and cardiovascular death was better in ivabradine + beta-blocker group compared to beta-blocker alone(RR: 0.93, 95%CI: 0.79-1.09, P = 0.354). Mean difference(MD) in heart rate was higher in the ivabradine + beta-blocker group(MD: 6.14, 95%CI: 3.80-8.48, P < 0.001). There was no difference in all cause mortality(RR: 0.98, 95%CI: 0.89-1.07, P = 0.609), cardiovascular mortality(RR: 0.99, 95%CI: 0.86-1.15, P = 0.908) or heart failure hospitalization(RR: 0.87, 95%CI: 0.68-1.11, P = 0.271). CONCLUSION From the available clinical trials, ivabradine + betablocker resulted in a significantly greater reduction in HRcoupled with improvement in combined end-point of heart failure readmission and cardiovascular death but with no improvement in all cause or cardiovascular mortality. Given the limited evidence, further randomized controlled trials are essential before widespread clinical application of ivabradine + beta-blocker is advocated for HFrEF.

Ivabradine tolerability in heart failure

The Systolic Heart failure treatment with the I( inhibitor ivabradine Trial (SHIFT, n = 6505) evaluated patients with symptomatic chronic heart failure (CHF), in sinus rhythm with resting heart rate ≥70 beats/min and left ventricular ejection fraction (LVEF)≤ 35%, average age 60 ± 11 years[1].

Effect of ivabradine in the treatment of acute exacerbation of chronic obstructive pulmonary disease with heart failure

Objective: To observe the effectiveness and safety of ivabradine in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and heart failure. Methods:Patients who were admitted to hospital with AECOPD during the period from August 2017 to July 2018. Then those both had heart failure with reduced ejection fraction(HFrEF) and a resting heart rate>70 beats/min were enrolled. A total of 86 cases were screened and completed, which were randomly divided into two groups for treatment. The control group(41 cases) received standard treatments, such as oxygen, anti-infection, anti-spasmodic, hormone, diuretic, ACEI/ARB, recombinant human brain natriuretic peptide (rhBNP), etc. The bisoprolol was given 2.5~5 mg orally once a day to control heart rate, and the test group(45 cases) was further treated with ivabradine 2.5~5 mg orally twice a day on the basis of the control group. The average heart rate, cardiac function, lung function, and 6-minute walking test were compared between the two groups. Results: After treatment, the average heart rate of the test group was lower than the control group, and the heart rate control rate(<70 beats/min%) of the test group was superior to the control group. The level of N-terminal B-type natriuretic peptide(NT-proBNP) in test group was significantly lower than that in control group. The distance of the 6-minute walking test in e test group was significantly longer than that in control group. Conclusion: Ivabradine combined with bisoprolol could help patients with AECOPD and heart failure to further reduce the heart rates, improve heart function and exercise tolerance. Moreover, the therapeutic safety was acceptable during the short term.

Effects of ivabradine on Notch and NF-kappa B signaling pathway in myocardial cells of rats with myocardial infarction

Objective:To investigate the effects of ivabradine on Notch and NF-kappa B signaling pathway in myocardial cells of rats with myocardial infarction.Methods: The model of myocardial infarction was established by ligating the left anterior descending coronary artery. The surviving rats were randomly divided into model group (MI group,n=8) and treatment group (IVA group,n=8). Rats with the same location but without ligation of the left anterior descending coronary artery were used as control group (CON group,n = 8). IVA was administered for 28 d. Hemodynamic and cardiac function indexes of all rats were measured: heart rate (HR), systolic pressure (SBP), diastolic pressure (DBP), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and maximum rate of increase and decrease of left ventricular internal pressure (+dp/dt);left ventricular mass index, left ventricular cross-sectional diameter and infarct area;The expression of Notch signaling pathway components mRNA (Notch-1, Dll-4, Hes-1) in rat cardiomyocytes was detected by PT-PCR, and the expression of DICD-1 and P65 protein was detected by western-blot. One-way ANOVA was used for comparison between groups, and SNK was used for comparison between groups.Results: SBP, DBP, MAP, LASP, LVEDP and (+dp/dt) in MI group were lower than those in control group (P<0.05), while IVA was higher than those in MI group (P<0.05). Left ventricular mass index and left ventricular sectional diameter in MI group were significantly higher than those in control group (P<0.05), but lower than those in IVA group (P<0.05). The expression of Notch-1 in MI group was significantly higher than that in control group (P<0.05), but lower than that in IVA group (P<0.05). There was no significant difference in the expression of Dll-4 and Hes-1 mRNA between the three groups (P>0.05). The expression levels of NICD-1 and P 65 in MI group were significantly higher than those in CON group (P<0.05), but lower than those in IVA group (P<0.05). Conclusion: IVA may improve cardiac function and inhibit ventricular remodeling in rats with myocardial infarction through Notch and NF-kappa B signaling pathways.

CHANGES IN NEUROPEPTIDES AFTER MUSIC EXPOSURE 429Cardioprotective effect of ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injuryinduced in H9c2 cell

Post-resuscitation myocardial dysfunction(PRMD)is the most severe myocardial ischemia-reperfusion injury(MIRI)and is characterized by difficult treatment and poor prognosis.Research has shown the protective effects of the rational use of ivabradine(IVA)against PRMD,however,the molecular mechanisms of IVA remain unknown.In this study,an ischemia-reperfusion injury(IRI)model was established using hypoxic chambers.The results demonstrated that pretreatment with IVA reduced IRI-induced cytotoxicity and apoptosis.IVA attenuated mitochondrial damage,eliminated excess reactive oxygen species(ROS),suppressed IRI-induced ATP and NAD+,and increased the AMP/ATP ratio.We further found that IVA increased the mRNA levels of sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)and upregulated the expression levels of phosphorylated AMP-activated protein kinase(p-AMPK)/AMPK,SIRT1,and PGC-1αproteins.Interestingly,no change in AMPK mRNA levels was observed.Cardiomyocyte energy metabolism significantly changed after IRI.The aim of this study was to demonstrate the cardioprotective effect of Ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injury-induced in H9c2 cell.

Ivabradine—The Final Crusader for Postoperative Junctional Ectopic Tachycardia, a Case Report with Literature Review

Background: Junctional ectopic tachycardia (JET) is one troublesome supraventricular arrhythmia in postoperative pediatric cardiac surgical patients. Unless treated timely and effectively it may lead to morbidity and even mortality. Aim: To understand the role of Ivabradine in the treatment of JET in postoperative pediatric cardiac surgical patients. Case: We present a postoperative case of complete repair of Tetralogy of Fallot who was in normal sinus rhythm in the preoperative period and developed JET 4 hours later in postoperative period which was persistent despite measures to optimize the internal milieu of the body and conventional antiarrhythmics, that was successfully treated with Ivabradine at a dose of 0.05 mg/kg/12 hourly. Conclusion: Ivabradine can be used to successfully treat postoperative JET in cases ofrefractory to other antiarrhythmic drugs like Digoxin and Amiodarone.

New Developments in Anti-Anginal Therapy: Roles of Ivabradine, Allopurinol and of Agents Modifying Myocardial Metabolism

Over the last 20 years, it has emerged that, while surgical revascularisation of extensive ischaemic heart disease may have prognostic advantages, the main issues considered regarding individual management are usually those of symptomatic improvement only. The major impetus towards invasive intervention is therefore failure of prophylactic anti-anginal therapy. On the other hand, many patients, especially the elderly, now present the clinical problem of ongoing angina without residual invasive options. There is an ongoing need for more effective anti-anginal therapies. Of the currently available major classes of prophylactic anti-anginal agents, neither nitrates, β-blockers nor calcium antagonists generally produce marked improvements in exercise duration. Three areas of new therapeutic development in anti-anginal therapy are worthy of note. These involve the sinus node inhibitor ivabradine, high dose allopurinol (xanthine oxidase inhibitor) and a new class of “metabolic modulators” represented by perhexiline, trimetazidine and probably ranolazine. The current review addresses the therapeutic potential of these agents. Notably, all of these “new” drugs are potentially suitable for management of angina in the setting of impaired left ventricular systolic function, and they may also be utilized in patients with angina independent of the presence of coronary disease (for example in hypertrophic cardiomyopathy). The current evidence for efficacy and potential future development in this area are reviewed.

Simultaneous determination of ivabradine and N-desmethylivabradine in human plasma and urine using a LC-MS/MS method: application to a pharmacokinetic study

A sensitive and specific liquid-chromatography tandem mass spectrometry(LC-MS/MS)assay has been developed and validated for the simultaneous quantification of ivabradine and its active metabolite N-desmethylivabradine in human plasma and urine.The assay employed a single liquid–liquid extraction of the analytes from plasma and urine samples,and diazepam was used as internal standard(IS).The chromatographic separation was achieved on a Diamonsil C18 column(150 mm4.6 mm,5 mm,Dikma)using a mixture of methanol and aqueous 5 mM ammonium acetate buffer containing 0.2%formic acid(80:20,v/v)as mobile phase.The assay for ivabradine and N-desmethylivabradine in plasma showed good linearity(r≥0.99)over the ranges 0.1013–101.3 ng/mL and 0.085–25.5 ng/mL,respectively.The assay for ivabradine and N-desmethylivabradine in urine showed good linearity(r≥0.99)over the ranges 10.13–6078 ng/mL and 8.5–850 ng/mL,respectively.The intra-and inter-day accuracy and precision values were found to be within the assay variability limits(RSD<15%)in accordance with FDA guidelines.The methods were successfully used for evaluating the pharmacokinetic properties of ivabradine and N-desmethylivabradine in human plasma and urine in Chinese healthy volunteers.

HCN4与心律失常相关性及其抑制剂研究进展

超级化激活环核苷酸门控通道4(HCN4)与心脏起搏运动有关,它可以通过控制心率来调节人体正常的生理功能。研究发现,心律失常的原因之一是HCN4通道功能丧失或获得。该综述总结了关于HCN4通道突变的一些研究,旨在进一步证实HCN4与心律失常之间的相关性。此外,一种新兴的HCN4抑制剂伊伐布雷定(Ivabradine)在临床上有着广泛的研究,主要用途是稳定心绞痛或心力衰竭患者的心率,该综述也将对Ivabradine的临床研究做一阐述。

Safety of ivabradine, a heart rate lowering drug: a systematic review and meta-analysis

As a novel heart rate lowing agent, ivabradine can reduce the heart rate by inhibiting the If （pacemaker） current in the sinoatrial node without affecting blood pressure or left ventricular systolic function. However, the safety of ivabradine remains controversial. In the present work, we aimed to assess any risk of cardiovascular mortality, bradycardia, phosphenes and atrial fibrillation associated with the ivabradine administration by recta-analysis. Studies were retrieved from PubMed, EMBASE, MEDLINE, Web of Science, Cochrane, www.clinicaltrials.gov web site and related conferences. Randomized controlled trials comparing ivabradine with comparators were identified and analyzed. Two reviewers independently extracted relevant information from the eligible trials and processed the data. This recta-analysis was performed by using Review Manager （5.3） and Stata （14.1） software. Moreover, sensitivity analysis and publication bias of the included studies were evaluated. A total of 12 randomized controlled trials meeting the inclusion criteria were included. Results of the meta-analysis revealed that there was no significant difference between ivabradine group and control groups in cardiovascular mortality （RR = 0.97, 95% CI： 0.89-1.06, P = 0.49）. While the administration of ivabradine was associated with a significant increase in the incidence of bradycardia （RR = 3.90, 95% CI： 2.47-6.17, P〈0.00001） and phosphenes （RR = 4.95, 95% CI： 3.24-7.55, P〈0.00001） as well as atrial fibrillation （RR = 1.24, 95% CI： 1.07-1.43, P = 0.003）. High quality of the included studies was confirmed by quality assessment. No publication bias was observed, and sensitivity analysis confirmed that the obtained results were stable. In conclusion, the meta-analysis proved that the use of ivabradine was associated with a significant increase in the risk of bradycardia, phosphenes and atrial fibrillation. Therefore, clinicians need to take these risks into account when using ivabradine in treatment.

Effects of ivabradine on the levels of HIF-1α and VEGF in serum of rabbit with acute myocardial infarction

The study aimed to investigate the effects of ivabradine on the levels of hypoxia-inducible factor-lalpha （HIF-1α） and VEGF in serum of rabbit with acute myocardial infarction （AMI）. Methods AMI model was established by ligating the left anterior descending branch of the coronary artery in New Zealand white rabbits. Twenty five rabbits were randomly divided into 4 groups： sham-operated （S）, myocardial-infarction （M） with bisoprolol treatment （M ＋ B） and ivabradine-treated （I ＋ M）. The medical treatment began immediately after infarction and continued for 3 weeks. Serum of each rabbit was obtained at the following time points （24 h before the operation, 24 h, 3 d, 1 week, 2 weeks and 3 weeks after the operation）. ELISA was used to measure the levels of HIF-1α and VEGF of each sample. ECG and heart rates （before and after treatment） were analyzed. Results Baseline heart rate showed no significant differences between the 3 infarcted groups （M, M ＋ B, M ＋ I）. Three weeks later the heart rates were significantly lower in group M ＋ B and group M ＋ I than in group M. However, there was no statistic difference between the two drug-treated groups （P = 0.848）. The levels of HIF-1α and VEGF in groups M, M ＋ B and M ＋ I） increased significantly compared with group S （P 〈 0.01）. The productions of HIF-1α and VEGF were lower in group M ＋ B and group M ＋ I compared with group M （P 〈 0.01）. There was no statistical difference between the group M ＋ B and group M ＋ I （P 〉 0.05）, and the correlative analysis revealed that the production of HIF-1α was positively correlated with that of VEGF （r = 0.732, P 〈 0.01）. Conclusion Ivabradine can reduce heart rate and meanwhile decrease the serum levels of HIF-1α and VEGF after AMI.

Recent Research Advances in Ivabradine and Its Cardiovascular Effects

Elevated heart rate is a major risk factor for cardiovascular diseases. The inhibitor of funny current （I （f） ）, a hyperpolarization-activated cyclic nucleotide-gated channel current, ivabradine is a new agent selectively reducing heart rate devoid of other cardiovascular effects, which has come into the market in Europe for more than 3 years. It has been approved that pure heart rate reduction by ivabradine can improve myocardial ischernia, endothelial function and myocardial contractile function. Long-term administration will not increase all-cause mortality. Its therapeutic value in stable coronary artery disease has been verified in clinical practice, while in other fields of cardiovascular diseases still needs more evidence-based medical research. This article is a review about its recent research advances in experimental and clinical studies.