伊伐布雷定治疗心力衰竭的基础和临床研究进展

伊伐布雷定是高度特异性的If离子通道阻滞剂,通过抑制If电流降低窦房结节律,减慢心率,而对心内传导系统、心肌收缩力以及血流动力学无明显影响。很多基础和临床研究表明,伊伐布雷定能改善心力衰竭患者临床症状、提高生活质量、降低病死率及心血管事件发生率。     

伊伐布雷定在快速性心律失常治疗中的研究进展

伊伐布雷定是一种新型减慢心率药物,对快速性心律失常有潜在的治疗作用。伊伐布雷定特异性地抑制起搏电流(If),降低窦房结节律,对不适当窦性心动过速及体位性心动过速综合征的治疗有一定的作用。伊伐布雷定能降低心肌细胞自发动作电位的频率,减慢房室结的传导速度,可能减少心房颤动的发生并且控制心室率,其临床疗效观察存在不一致性,其疗效有待观察。伊伐布雷定通过抑制超极化激活环核苷酸门控通道(HCN)通道介导的If增加,其可能减少室性心律失常的发生率,降低心室颤动阈值,其临床疗效有待验证。     

伊伐布雷定临床与药学实践专家共识

心率是心血管疾病的独立危险因子,心率增快不仅易引起心肌缺血,也会加速动脉粥样硬化、心律失常和心力衰竭(心衰)等疾病的进程.伊伐布雷定(Ivabradine)是首个窦房结If电流选择特异性抑制剂,具有单纯减慢心率的作用,对心肌收缩力和心脏传导无明显影响.伊伐布雷定最早于2005年在欧洲被批准上市,于2015年在我国被批准...     

伊伐布雷定在快速性心律失常中的应用

伊伐布雷定是一种特殊的起搏电流(If)抑制剂,可用于降低心率,并具有潜在的抗心律失常作用。伊伐布雷定能降低由If引起的细胞自律性以及抑制房室结的传导速度,具有潜在的预防与治疗心房颤动和控制心房颤动心室率的作用。伊伐布雷定抑制HCN通道和If,对室性心律失常有一定的治疗作用。伊伐布雷定可抑制窦房结内的If,降低窦房结节律,从而稳定心率。伊伐布雷定目前的治疗价值尚缺乏大规模临床研究的证据支持,还需进一步深入研究。     

伊伐布雷丁在心血管疾病中的现状与进展

降低心率可能成为心血管疾病治疗的新靶标,伊伐布雷定可通过特异性地抑制If起搏电流通过降低窦房结节律而减慢心率,目前在心血管疾病领域取得了一定的进展,现对其临床应用进行综述。     

伊伐布雷定治疗稳定性心绞痛的研究进展

心率增快是心血管疾病的重要危险因素,也是导致心绞痛发作的重要原因。伊伐布雷定是一种I(f)电流通道抑制剂,能有效减慢稳定性心绞痛患者心率,进而减低心肌耗氧量、改善临床症状、减少心绞痛发作次数。但目前关于伊伐布雷定能否改善稳定性心绞痛患者远期预后及提高患者生活质量等方面的研究仍存在争议。本文从伊伐布雷定作用机制、相关临床证据及不良反应等方面进行综述,以探讨伊伐布雷定治疗稳定性心绞痛的可行性。     

If电流抑制剂伊伐布雷定在心血管疾病中的临床应用进展

伊伐布雷定通过选择性抑制超极化激活环核苷酸门控阳离子通道(HCN)介导的I_f电流,降低窦房结4期自动去极化速率而减慢心率。此外,伊伐布雷定还能通过降低心率来改善心肌能量供应,预防心脏重构并改善远期预后,目前在心力衰竭、冠心病心绞痛和不适当窦性心动过速三方面具有明确的治疗作用。本文仅就伊伐布雷定的电生理作用特点及其在临床应用中的重要研究进展作扼要介绍。     

If电流抑制剂一伊伐布雷定

伊伐布雷定作为目前临床上唯一的If 电流抑制剂,通过选择性作用于窦房结上高表达的HCN4通道减慢心率。大量的临床研究表明,它对冠心病、心力衰竭、心律失常等疾病具有明确治疗效果,能够提高患者预后及生存质量。伊伐布雷定无负性肌力、负性传导作用,对支气管平滑肌、血压无干扰,为B受体阻滞剂及钙离子拮抗剂禁用的患者提供了新的选择,为心血管疾病的治疗提供了更广阔的前景。     

伊伐布雷定减慢心率的研究现状

心率是心血管疾病的主要危险因子。I(f)离子通道抑制剂伊伐布雷定是一类选择性减慢心率的新药,在欧洲已上市3年余,现对其实验及临床研究的现状进行一综述:伊伐布雷定选择性抑制I(f)电流,减慢心率而没有其他心血管效应,单纯减慢心率可改善心肌缺血、内皮功能和心肌收缩功能,长期应用不会增加全因死亡率。其在稳定型冠心病患者中的治疗价值已被证实,但在其他心血管疾病中的应用还需更多的循证医学支持。     

伊伐布雷定在冠心病患者中的应用进展

心率过快缩短心肌血流灌注时间,加剧心肌供氧不足和耗氧过多的不平衡,不利于冠心病患者的病情控制。伊伐布雷定可特异性减慢窦性心率,且对心肌收缩、房室传导、支气管平滑肌无影响,相比于β受体阻滞剂,在冠心病的应用具备一定的优势。现阶段临床研究表明,伊伐布雷定可降低稳定性冠心病患者心率,具有一定的抗心肌缺血、缓解胸痛的作用;对于合并慢性心力衰竭者,还可改善心室重构和远期临床转归;伊伐布雷定在急性冠状动脉综合征中可能具有潜在的临床应用价值,但其长期应用的安全性和有效性仍待观察和验证。     

伊伐布雷定在心血管疾病中应用的研究进展

伊伐布雷定为特异性的 I f通道阻滞剂，通过调节窦房结的起搏，发挥特有电生理学作用，可减慢心率但不影响心肌收缩力、心内传导、心室复极等，因其不良反应少，安全性高，目前不仅被广泛应用于慢性稳定性心衰、冠心病等疾病，而且最新临床及动物试验证实，伊伐布雷定药物的应用在不断的拓展，一些临床不良反应也得到进一步证实，该文就其近年来在心血管疾病中的新的应用进展予以综述。     

伊伐布雷定在心血管疾病中的研究进展

伊伐布雷定为首个特异性心脏起搏电流抑制剂,具有特异性降低心率的作用,相关的动物实验及大规模临床研究也日益增多。现对伊伐布雷定在心血管疾病中的研究进展进行综述。     

Implication of Ivabradine in Up-titrating Beta-blocker in a Patient with Advanced Heart Failure

Titration of beta-blockers is a gold-standard therapy in patients with heart failure and a reduced ejection fraction but is sometimes challenging to administer, given symptomatic hypotension. Ivabradine is a recently introduced selective I_f channel inhibitor that purely reduces the heart rate. We encountered a patient with advanced heart failure in whom a beta-blocker could not be up-titrated given his symptomatic hypotension. Following the initiation of ivabradine, an increase in blood pressure due to heart rate optimization, probably via an improvement in the cardiac output, allowed for the further up-titration of carvedilol, followed by a successful clinical course. Ivabradine might be a novel therapeutic tool to facilitate the up-titration of beta-blockers in patients with heart failure and hypotension.     

Potential New Indication for Ivabradine: Treatment of a Patient with Congenital Junctional Ectopic Tachycardia

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

Novel drugs for heart rate control in heart failure

In patients with heart failure, increased sympathetic activity is associated with a positive chronotropic stimulation leading to accelerated resting heart rate. Elevated heart rate (HR) is a risk factor for cardiovascular events, both in the general population and in patients with heart failure. Ivabradine is a pure HR-lowering agent, and it does not affect myocardial contractility, blood pressure, intracardiac conduction, or ventricular repolarization. In clinical trials such as BEAUTIFUL, CARVIVA HF, SHIFT, and INTENSIFY in patients with systolic left ventricular dysfunction, heart rate reduction with ivabradine brought positive outcomes. However, the results of the recent meta-analysis are rather neutral. In a diabetes mouse model of heart failure with preserved ejection fraction (HFpEF), selective heart rate reduction by I_f inhibition improved vascular stiffness, left ventricular (LV) contractility, and diastolic function. However, EDIFY (Effect of ivabradine in patients with heart rate with preserved ejection fraction) trial show that the use of ivabradine in patients with HFpEF is not supported. The further clinical trials investigating the use of ivabradine in heart failure should be carried out.     

Heart rate and its reduction in chronic heart failure and beyond

Heart rate (HR) is associated with cardiovascular outcomes in all the stages of the cardiovascular continuum as well as in patients with pulmonary, cerebrovascular, and renal disease, sepsis, cancer, and erectile dysfunction. In patients with cardiovascular disease, but also in the general population, increased HR represents an important indicator of mortality with each acceleration of HR over 70 b.p.m. increasing the risk. In patients in sinus rhythm with chronic heart failure with reduced ejection fraction (HFrEF), a HR >70 b.p.m. increased the risk of hospitalization, and >75 b.p.m. the risk of cardiovascular death as shown in the Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT). Reducing HR with ivabradine by 11 b.p.m. (placebo‐controlled) reduced the primary composite endpoint (cardiovascular death and hospitalization for worsening heart failure). Ivabradine was well tolerated showing benefit irrespective of age or diabetes status, and also in the presence of low systolic blood pressure and severe heart failure (SHIFT trial). Therefore, HR qualifies as a modifiable risk factor in heart failure. In patients with stable coronary disease, HR is a risk marker but HR reduction with ivabradine does not improve outcomes. The role of selective HR lowering remains unclear in patients with pulmonary, renal, cerebrovascular, and other diseases, as the potential benefit of interventions on HR has not been explored in these conditions. Future studies should scrutinize if HR reduction improves outcomes, defining HR as a potential risk factor and therapeutic target in other conditions beyond heart failure.     

Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta‐analysis of randomized controlled trials

Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta‐analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta‐blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = −9.57; 95% CI ‐11.15, −8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = −3.73; 95% CI ‐4.25, −3.21, LVESV; MD = −17.00, 95%CI ‐29.65, −4.35, LVEDD; MD = −1.43, 95%CI ‐2.78, −0.08, LVEDV; MD = −14.75, 95%CI ‐34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI ‐10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.     

Efficacy of Ivabradine in a Case of Inappropriate Sinus Tachycardia and Ventricular Dysfunction

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

Cardiac Arrhythmias and the Autonomic Nervous System

Cardiac Arrhythmias and the Autonomic Nervous System. The multiple facets of cardiac arrhythmias and their relationship with the autonomic nervous system can be investigated by studying the spontaneous heart rate behavior through ambulatory ECG recordins, an approach that complements the limitations of invasive electrophysiologic investigations. Information obtained from heart rate behavior is more reliable in the absence of structural heart disease and ventricular hypertrophy/failure, during which compensatory mechanisms involving the autonomic nervous system tend to limit reflex changes in heart rate. Thus, in such situations, less marked sinus rhythm variations preceding the arrhythmia onset do not imply a more limited influence of the autonomic nervous system, and the sensitivity of the electrophysiologic substrate may otherwise vary. These two factors may combine to form the basis of the adrenergic paradox¹¹ that implies that the more marked the autonomic nervous system dependence of tachyarrhythmias, the less obvious its evidence. Assessment of the QT interval dynamicity may also allow one to evaluate the modulation of autonomic neural effects on the ventricular tissues. Finally, it may be difficult to distinguish clearly autonomic nervous system dependence from rate dependence: the latter frequently conditions the behavior of the trigger whereas the former mainly concerns the electrophysiologic substrate. There are many examples of the importance of the autonomic nervous system as a determinant of cardiac arrhythmias. In the atrium, either limb of the autonomic nervous system, particularly the parasympathetic limb, can generate atrial fibrillation. The absence of structural heart disease defines pure electrophysiologic substrates responsible for benign forms of ventricular tachycardia as welt as potentially lethal tachyarrhythmias of the long QT syndrome and its variants. In both, the role of the autonomic nervous system is essential, although the therapeutic consequences are crucial only in the latter. In the presence of heart disease and, in particular, heart failure, the autonomic nervous system behavior is more difficult to assess than in the absence of structural heart disease. This does not mean that its role is less crucial. In this situation the beneficial effects of beta blockers may be as important as in normal hearts although physicians should be more cautious when heart failure is present.     

Efficacy of ivabradine in patients with stable angina and comorbid chronic obstructive pulmonary disease

We investigated impact of ivabradine on exercise capacity and quality of life in patients with stable angina and comorbid chronic obstructive pulmonary disease during treatment with -blockers. Ivabradine with -blockers reduced heart rate, increased exercise capacity and improved angina more effective than -blockers only. Quality of life associated with angina increased in patients with stage I and II chronic obstructive pulmonary disease. Addition of ivabradine to -blockers for 2 month did not produce adverse respiratory effects.