Preface
This supplement of the European Heart Journal addresses the role of If inhibition in the management of cardiovascular disease, based on the presentations made at a satellite symposium of the Annual Congress of the European Society of Cardiology this year in Vienna.
The role of heart rate (HR) is well established in the development and pathophysiology of myocardial ischaemia. In patients with coronary artery disease, most ischaemic episodes are triggered by an increase in HR which results in imbalance between myocardial oxygen delivery and consumption. Therefore, HR reduction has been considered as an important therapeutic principle to prevent ischaemia by reducing myocardial oxygen consumption and to improve myocardial perfusion by prolonging the diastolic interval. In addition to the beneficial effects of HR reduction for the prevention of ischaemia, a lower HR is associated with a more favourable prognosis. The association between accelerated resting HR and increased all-cause and cardiovascular mortalities has been found in general populations and among patients with myocardial infarction, chronic ischaemic heart disease, heart failure, hypertension, or diabetes. Experimental and clinical data suggest that haemodynamic forces, related to increased HR, may play an important role in vascular damage, favouring both development of atherosclerosis and plaque rupture and, therefore, triggering acute coronary events in patients with coronary artery disease.
In accordance with these findings, numerous clinical studies have demonstrated that ß-blockade, which decreases HR, has significant favourable clinical effects in patients with a history of acute myocardial infarction or heart failure. In this context, ivabradine, the first selective and specific If inhibitor, represents a major advance in the treatment of coronary artery disease. Unlike other pharmacological agents, ivabradine exerts a unique action on cardiac pacemaker activity, thus providing all the benefits of HR slowing without possibly counteractive or deleterious cardiovascular effects. In contrast to ß-blockade, selective HR reduction by ivabradine does not impair myocardial contractility, isovolumic ventricular relaxation, or coronary vasodilation, and therefore ensures the full benefit of prolonged diastole for coronary blood flow supply. Ivabradine's clinical efficacy has been clearly established by a series of randomized trials, which have robustly documented its anti-ischaemic and anti-anginal efficacy in comparison with atenolol or amlodipine.
Over and above the beneficial effects of HR reduction in the prevention of angina, ivabradine's indications may extend even further, in view of the evidence that lower HR is associated with a more favourable prognosis in patients with coronary artery disease or heart failure. In fact, this consideration helps define new directions for clinical research programmes. The value of ivabradine in reducing cardiovascular events in patients with coronary artery disease and left ventricular dysfunction is presently being tested in the ongoing large-scale BEAUTIfUL (MorBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study. Also, preliminary preclinical and clinical data suggest that ivabradine has beneficial effects on left ventricular structure and function, thus prompting its evaluation as an addition to modern multifaceted therapy of heart failure, in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIfT). These large-scale clinical trials will help to determine whether the clinical benefits of a pure HR-reducing agent, such as ivabradine, are much greater than prevention of ischaemia and extend to reduction of cardiovascular mortality and morbidity.
In the present issue of the European Heart Journal Supplements, a panel of experts presents a comprehensive overview of the clinical advantages of pure HR reduction with ivabradine as a new therapeutic modality in patients with coronary artery disease and highlights its promise in the management of cardiovascular patients.
A. Hjalmarson extensively reviews the evidence demonstrating that elevated HR is an independent risk factor for mortality and morbidity in cardiovascular disease, the pathogenetic mechanisms potentially involved in this connection between elevated HR and cardiovascular events, and the clinical importance of HR reduction. Taken together, these data suggest that HR should be considered as an important risk factor in cardiovascular disease.
The rationale for HR reduction as an important strategy in preventing ischaemia is described by G. Heusch, who illustrates the relationship between ischaemic regional myocardial blood flow and contractile function in the different haemodynamic situations and considers the effects of HR on this relationship in normal and ischaemic myocardium. He also discusses the advantages of pure HR reduction in comparison with ß-blockers and other HR-reducing agents.
The paper by P.G. Steg describes the rationale, design, and patient population of the ongoing large-scale BEAUTIfUL study, which will be the first major outcome trial of selective and specific HR reduction by ivabradine.
K. Swedberg reviews the potential beneficial effects of pure HR reduction on cardiac function and clinical outcome in patients with heart failure.
This issue of the European Heart Journal Supplement reviews the available evidence on ivabradine and its prospects in cardiology.
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