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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: permissions@oupjournals.org

Editorial

If inhibition: from pure heart reduction to treatment of stable angina

Michal Tendera*

Third Department of Cardiology, Silesian School of Medicine, Ziolowa 47, 40-635 Katowice, Poland

* Corresponding author. Tel: +48 32 2523930; fax: +48 32 202 3060. E-mail address: mtendera{at}kardio3.katowice.pl

Heart rate: prognostic role in health and disease

Population studies have shown that accelerated resting heart rate is associated with increased all-cause and cardiovascular mortalities.1–4 Moreover, there is an increasing body of evidence that tachycardia is not merely an indicator of an increased mortality, but actually contributes to a worse prognosis. Several potential mechanisms may be involved in this process. It appears that all living creatures have a limited number of heartbeats in their lifetime.5 In the cardiovascular system, a high heart rate may promote development of atherosclerotic lesions and induce cardiomyopathy and arrhythmias.

In patients with coronary artery disease, the relationship between heart rate and mortality is even more established. In a large recently published study6 conducted in patients with established or suspected coronary atherosclerosis, heart rate at rest was an independent factor predicting survival. In this group, increased heart rate not only induces ischaemia but also predisposes to plaque rupture, and therefore, triggers acute coronary events, which are mostly responsible for mortality in patients with ischaemic heart disease.

Role of elevated heart rate in ischaemic heart disease

Heart rate, together with the contractility and left ventricular loading conditions, is a key determinant of myocardial oxygen consumption. Acceleration of heart rate by exercise or pacing is frequently used in clinical practice to induce myocardial ischaemia. Also in everyday life, it triggers most ischaemic events.7–9

However, the association between heart rate and ischaemia goes far beyond this simple mechanism.

The influence of accelerated heart rate on the development of atherosclerosis is known from animal experiments. Beere et al.10 examined lesion size and maximum coronary stenosis in two groups of monkeys: one group with a sham procedure, the other group with sinus node ablation. Both groups received atherogenic diet, but severity of coronary lesions was much smaller in animals with low heart rate due to ablation. In addition, in man, a positive association between heart rate and development of atherosclerosis was found. In a group of young myocardial infarction survivors, coronary lesions were significantly more extensive in those with high heart rates.11 In addition, in the SHEP program (Systolic Hypertension in the Elderly Program),12 there was an apparent association between heart rate and atherosclerotic lesions in the carotid arteries. Accelerated atherogenesis resulting from increased heart rate may be due to both mechanical and metabolic factors. Increased vascular wall stress may result in endothelial injury, with greater permeability of the endothelium and easier penetration of lipids into the vessel wall. High heart rate can also reflect the presence of increased sympathetic tone, which may additionally cause elevated blood pressure and metabolic abnormalities.

Heart rate acceleration can also increase the risk of an acute coronary syndrome. In a study involving patients with repeat coronary angiography, Heidland and Strauer13 found an association between plaque disruption and heart rate >80 b.p.m. In another study14 conducted in a large group of patients with stable angina, heart rate, together with increasing age and male gender, was an independent predictor of new coronary events.

An increased propensity for acute coronary events in patients with tachycardia may be caused by excessive mechanical stress to the atherosclerotic plaque, which increases its probability of rupturing.

The results of several studies indicate that faster heart rates are associated with increased probability of sudden cardiac death.15,16 Patients with tachycardia may be more prone to develop malignant ventricular arrhythmias simply because they have severe ischaemia. However, other mechanisms may also play a role. For example, slow conduction observed in the diseased myocardium is more pronounced with shorter cycle length, which can promote re-entry.

In the presence of an acute coronary syndrome, heart rate also proves useful as a prognostic factor. Heart rate on admission for acute myocardial infarction is predictive of both short- and long-term mortalities.17–19 This is true even after correction for the infarct size. In addition, heart rate elevation may increase the extent of myocardial injury.

Stable angina: magnitude of the problem, current treatment, and unmet needs

Ischaemic heart disease remains the leading cause of mortality and morbidity and continues to be a major burden on public health. Stable angina pectoris is a common manifestation of cardiac ischaemia. It occurs more frequently in men. Its prevalence increases with age in both genders, from 2–5% in men aged 45–54 to 11–20% in those aged 65–74. In women, the respective values increase from 0.5–1 to 10–14%. Over the age of 75, the prevalence of angina in men and women is almost equal.20,21 It is estimated that in countries with high ischaemic heart disease rates, the total number of persons with angina may be as high as 30–40 thousand per million of the total population.21 In a substantial proportion of patients, angina causes an important limitation of everyday activities and impairs their quality of life. Thus, stable angina pectoris is common and may be debilitating.

Mortality in patients with stable angina is estimated at 2–3% per year.22,23 This means that in the majority of patients, risk of death may be only moderately increased when compared with age-matched healthy subjects. However, prognosis in patients with chronic angina is not uniform. It depends on several factors, including underlying coronary anatomy, left ventricular function, and comorbidities. Identification of high-risk patients who can benefit from therapy aimed at improving prognosis is of the utmost importance. In low-risk patients, the main aim of treatment is to eliminate symptoms and improve health-related quality of life.

The introduction of surgical and percutaneous myocardial revascularization has dramatically changed the treatment of patients with ischaemic heart disease. Revascularization offers effective relief of symptoms and in patients with extensive ischaemia, like those with left main or triple-vessel disease, it improves prognosis. Effective restoration of adequate coronary flow, either surgical or percutaneous, does not obviate the need for medical treatment. Medical therapy is necessary to prevent subsequent events and to treat residual or recurrent ischaemia. In addition, not all patients with chronic ischaemia require revascularization. Medical treatment is still recommended as the first-line strategy to control symptoms.21

Beta-blockers, calcium-channel blocking agents, and nitrates have been the mainstay of medical therapy of chronic angina for a long time. Although these drugs can also improve oxygen supply, they predominantly act by decreasing myocardial oxygen demand. Contractility, systolic wall tension, and heart rate are the most important determinants of this demand.

Heart rate is relatively easy to change, and therefore, its reduction is often targeted. In the presence of ischaemia, heart rate reduction may restore the balance between myocardial oxygen supply and demand. Slowing of heart rate not only decreases oxygen demand but also improves myocardial perfusion through prolongation of diastole. Beta-blockers and some calcium-channel blockers act, at least partly, through this mechanism.

Beta-blockers are most often recommended as primary therapy because, in addition to symptomatic relief, they have been found to reduce mortality and reinfarction, at least in post-infarction patients.24 In several patients, target doses of beta-blockers cannot be reached because of adverse effects: fatigue, lethargy, insomnia, worsening claudication, or erectile dysfunction in men. In addition, beta-blockers are contraindicated in some patients, including those with reversible airways obstruction, atrioventricular conduction defects, decompensated heart failure, symptomatic peripheral vascular disease, brittle diabetes, or history of severe depression.

Some calcium-channel blockers, such as verapamil or diltiazem, can also slow the heart rate, but their effect is difficult to predict, and the data on their clinical benefit are rather scanty. Therefore, there is an evident need for another class of drugs that could attain this effect administered alone or in combination with other agents.

Concept of If inhibition

The pacemaker (If) current plays a central role in heart rate control.25 This makes it an interesting target for a pharmacological intervention.

Inhibition of the If current results in heart rate reduction, with no other effects on the heart. This bradycardic effect has a clear potential to reduce ischaemia.

Ivabradine is a selective and specific If current inhibitor26,27 that has been used to test this novel therapeutic concept.

As opposed to beta-blockers, ivabradine has no negative inotropic action. It also has no impact on atrioventricular nodal conduction. In an experimental model, it decreased exercise-induced ECG changes to the same extent as propranolol but was able to better preserve systolic function in the ischaemic area.28 Ivabradine was also shown to be superior to beta-blockade in the setting of myocardial stunning, where it was capable of improving contractility.29 In addition, ivabradine is devoid of the relative alpha2-stimulating effect, which is responsible for the coronary vasoconstriction seen with beta-blockers.

In humans, ivabradine significantly slows heart rate at rest and at peak exercise.29

It proved to be a safe and effective anti-anginal and anti-ischaemic agent in patients with stable angina. In a double-blind, placebo-controlled study, it produced a dose-dependent prolongation of total exercise time and time to development of ischaemia.30

Ivabradine proved to be equivalent to the beta-blocker atenolol31 and to the calcium-channel blocker amlodipine32 in prolonging total exercise time, as well as the time to the onset of angina and to 1 mm ST-segment depression. It was also equally effective as these standard drugs in preventing spontaneously reported angina attacks.

This supplement is focused on the concept of If current inhibition as a new therapeutic modality in patients with ischaemic heart disease. The paper by Steg and Himbert33 addresses the current options in the treatment of patients with stable angina, as well as the unmet needs and therapeutic opportunities. It is emphasized that a new class of drugs, the If current inhibitors, is a welcome addition to the existing therapeutic armamentarium.

In the article by Ferrari et al.,34 the impact of heart rate reduction in patients with coronary artery disease is discussed, with the emphasis on If current inhibition.

Tardif35 discusses the benefits of If current inhibition, and Borer36 provides an overview of the results of the clinical development program of ivabradine, the first representative of this class to be used in clinical practice in patients with stable angina. It is the most extensive program for this indication, including more than 5000 patients.

Fox37 emphasizes other potential clinical applications of If inhibition, such as prevention of post-infarction remodelling, treatment of inappropriate sinus tachycardia, and heart failure, both due to systolic and diastolic left ventricular dysfunction.

The data presented in this supplement indicate that the prevalence of ischaemic heart disease is still high. Despite an important reduction in mortality, mainly as a result of improved primary and secondary prevention, there are still important unmet needs in the treatment of the disease. New pharmacological agents are needed to alleviate the symptoms, increase exercise tolerance, and improve quality of life. In this context, the novel selective and specific If inhibitor ivabradine appears to be an effective and safe treatment of stable angina through exclusive heart rate reduction. Other potential indications for its use are also being explored.

References

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