Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current

Two distinct intracellular mechanisms have been proposed to affect the firing rate of cardiac pacemaker cells: one involves modulation of the I(f) current by the second messenger cAMP, and one relies upon disruption or alteration of SR Ca2+ transients during activity. Although both mechanisms are necessary for proper automaticity and autonomic rate control, the specific contribution of each to pacemaking is still debated. We investigated if the two processes can be separated based on potentially different effects on action potential characteristics during rate modulation. To identify specific I(f)-mediated effects, we used the selective I(f) blocker ivabradine and found that ivabradine (3 microM) slows rate (-16.2%) by selectively reducing (-31.9%) the steepness of early diastolic depolarization (EDD). On the other hand ryanodine (3 microM), used to evaluate the effects of abolishment of SR Ca2+ transients, slowed rate (-31.3%) by depolarizing the take-off potential (TOP, 18.1%) without affecting EDD. We therefore used these two parameters to identify I(f)-based or SR Ca2+ transients-based processes and analyzed the effects on action potential's characteristics of Rp-cAMPs (50 microM), a membrane permeable cAMP analogue directly activating f-channels; we found that Rp-cAMPs accelerates rate by increasing EDD (+42.3%) without modifying TOP. Finally, rate modulation was achieved by muscarinic (ACh 0.01 microM) or beta-adrenergic (Iso 1 microM) stimulation; in both cases, rate changes were associated with modifications of EDD (ACh, -29.3% and Iso, +47.6%) and not of TOP. We conclude that rate-related changes in the EDD induced by autonomic agonists are mediated by I(f) and not by processes involving SR Ca2+ transients.     

Ivabradine -- the first selective sinus node I(f) channel inhibitor in the treatment of stable angina

Heart rate, a major determinant of angina in coronary disease, is also an important predictor of cardiovascular mortality. Lowering heart rate is therefore one of the most important therapeutic approaches in the treatment of stable angina pectoris. To date, beta-blockers and some calcium-channel antagonists reduce heart rate, but their use may be limited by adverse reactions or contraindications. Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node controlled by the I(f) current. Ivabradine is the first specific heart rate-lowering agent that has completed clinical development for stable angina pectoris. It is selective for the I(f) current, lowering heart rate at concentrations that do not affect other cardiac ionic currents. Specific heart-rate lowering with ivabradine reduces myocardial oxygen demand, simultaneously improving oxygen supply. Ivabradine has no negative inotropic or lusitropic effects, preserving ventricular contractility, and does not change any major electrophysiological parameters unrelated to heart rate. Randomised clinical studies in patients with stable angina show that ivabradine effectively reduces heart rate, improves exercise capacity and reduces the number of angina attacks. It has superior anti-anginal and anti-ischaemic activity to placebo and is non-inferior to atenolol and amlodipine. Ivabradine therefore offers a valuable approach to lowering heart rate exclusively and provides an attractive alternative to conventional treatment for a wide range of patients with confirmed stable angina.     

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 I_f (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 meta-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 informationfrom the eligible trials and processed the data. This meta-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.     

7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂革-2-酮的制备

目的合成抗心绞痛的新药伊伐布雷定的关键中间体7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂--2-酮。方法以3,4-二甲氧基苯乙酸为原料,经卤化、酰化、环合、烷基化、碘取代等反应制得目标化合物。结果五步反应总收率为63.6%,产物经MS1、HNMR确证结构。结论所用工艺路线具有原料易得、操作简便、收率较高的特点,适用于该中间体的放大制备。     

Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate‐lowering properties

Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta‐blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co‐morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent.     

伊伐布雷定联合左西孟旦治疗慢性心力衰竭的临床研究

目的探讨伊伐布雷定联合左西孟旦治疗慢性心力衰竭的临床疗效。方法选取2017年1月—2018年1月在焦作市第二人民医院进行治疗的80例慢性心力衰竭患者,根据用药差别分为对照组和治疗组,每组各40例。对照组患者给予左西孟旦注射液,先以12μg/kg初始剂量静脉推注,推注10 min,然后以微量泵持续泵入,泵入速度0.1μg/(kg·min),持续泵入24 h。治疗组在对照组基础上口服盐酸伊伐布雷定片,5 mg/次,2次/d。两组均治疗2周后进行效果比较。观察两组的临床疗效,比较两组治疗前后心功能指标、6 min步行距离(6WMT)、GQOLI-74评分、血清学指标和心肌纤维化标志物的变化情况。结果治疗后,对照组和治疗组的总有效率分别是75.0%、95.0%,两组比较差异具有统计学意义(P0.05)。治疗后,两组左心室射血分数(LVEE)、6WMT、GQOLI-74评分均较治疗前显著升高,而左心室收缩末内径(LVEDD)、左心室收缩末容量(LVESV)、左心室舒张末内径(LVESD)均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);治疗后,治疗组LVEE、6WMT、GQOLI-74评分高于对照组,而LVEDD、LVESV、LVESD低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清N-末端B型利钠肽前体(NT-proBNP)、可溶性晚期糖基化终产物受体(sRAGE)、心肌肌钙蛋白T(cTnT)、高迁移率族蛋白B1(HMGB1)、金属蛋白酶9(MMP-9)、β-内啡肽(β-EP)、Ⅰ型胶原交联羧基末端肽(ICTP)、Ⅲ型前胶原氨基末端肽(PIIINP)、结缔组织生长因子(CTGF)、透明质酸(HA)、层连蛋白(LA)水平均显著下降,同组治疗前后比较差异有统计学意义(P0.05);治疗后,治疗组这些血清学指标和心肌纤维化标志物指标均显著低于对照组,两组比较差异具有统计学意义(P0.05)。结论伊伐布雷定联合左西孟旦治疗慢性心力衰竭具有较好的临床疗效,可有效改善患者心功能,降低血清细胞因子水平,延缓心肌纤维化进展,促进患者运动耐量提高,有利于改善患者生活质量,具有一定的临床推广应用价值。     

伊伐布雷定联合美托洛尔治疗稳定型心绞痛的临床研究

目的探讨盐酸伊伐布雷定片联合酒石酸美托洛尔片治疗稳定型心绞痛的临床疗效。方法选取2019年9月—2020年4月天津市第二医院收治的84例稳定型心绞痛患者为研究对象。所有患者均口服酒石酸美托洛尔片,25 mg/次,2次/d。治疗4周后静息心率70次/min的患者为对照组(34例),对照组继续口服酒石酸美托洛尔片,25 mg/次,2次/d。静息心率≥70次/min的患者继续口服上述剂量酒石酸美托洛尔片的基础上口服盐酸伊伐布雷定片,5mg/次,2次/d,根据患者心率变化调整用药量,最大耐受度7.5 mg/次,2次/d。治疗12周后心率70次/min的患者为治疗组(38例)。两组患者均连续治疗12周。观察两组的临床疗效,比较两组静息和最大运动量时心率、心绞痛发作情况和生活质量评分。结果治疗后,治疗组总有效率为92.11%,高于对照组的79.41%,两组总有效率比较差异有统计学意义(P0.05)。治疗后,两组静息心率、最大运动量时心率均较治疗前明显降低,差异有统计学意义(P0.05);治疗后,治疗组最大运动量时心率较对照组降低更显著,差异有统计学意义(P0.05)。治疗后,两组患者发作频率、持续时间、硝酸甘油消耗量均较治疗前显著下降,差异有统计学意义(P0.05),且治疗组发作频率、持续时间、硝酸甘油消耗量较对照组下降更显著,差异具有统计学意义(P0.05)。治疗后,两组西雅图心绞痛量表(SAQ)中各维度评分较治疗前均显著升高,差异有统计学意义(P0.05),且治疗组SAQ中除对疾病的认识外,其他各维度评分均显著高于对照组,差异有统计学意义(P0.05)。结论盐酸伊伐布雷定片联合酒石酸美托洛尔片治疗稳定型心绞痛疗效良好,可能明显降低患者的心率,改善患者的心绞痛发作情况,保护心脏功能,提高患者的生活质量。     

伊伐布雷定在心血管疾病中的研究新进展

伊伐布雷定为首个特异性心脏起搏电流抑制剂,具有特异性减慢心率的作用,且在减慢心率的同时不影响心脏收缩功能。目前很多临床研究证实,伊伐布雷定对冠心病、快速型窦性心律失常、心力衰竭、心肌梗死等有明确的疗效。现对伊伐布雷定药理机制及其在临床应用中的研究新进展进行综述。     

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction

Aims

In the SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF.

Methods and results

The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days.

Conclusion

Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.