Future perspectives of If inhibition in various cardiac conditions
Director of Cardiology, Royal Brompton & National Heart and Lung Hospital, Sydney Street, London SW3 6NP, England
* Corresponding author. Tel: (44) 207 351 86 26; fax: (44) 207 351 86 29. E-mail address: d.curcher{at}rbh.nthames.nhs.uk
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Abstract |
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Heart rate (HR) is a major determinant of myocardial oxygen consumption and myocardial perfusion in patients with ischaemic heart disease. Large epidemiological studies have demonstrated that high resting HR is a strong predictor of total and cardiovascular mortality in the healthy population and in patients with hypertension, in patients with metabolic syndromes, in the elderly, and in patients with coronary artery disease (CAD). HR modulation with beta-blockers has shown favourable effects on post-myocardial infarction mortality in correlation with their HR-lowering actions. In this regard, because of their pharmacological action, inhibitors of the sinus pacemaker If current, agents that exclusively reduce HR, may be of particular importance as antianginal agents, and have potential utility in reducing morbidity and mortality in cardiovascular disorders in patients with CAD and in patients with heart failure. Sinus tachyarrhythmias are a heterogeneous group of disorders that are often difficult to manage. A pure HR reduction may be a novel way of treatment for these patients.
Key Words: Heart rate • Ivabradine • Coronary artery disease • Congestive heart failure • If inhibition • Sinus node inhibitor
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Introduction |
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Epidemiological studies indicate that heart rate (HR) is inversely proportional to life expectancy and that a rapid HR is a risk factor for future hypertension, atherosclerosis, and cardiovascular morbidity and mortality.1,2
HR modulation may improve survival in certain clinical conditions such as post-myocardial infarction and chronic heart failure (CHF). These observations are based on the results of the large-scale Chicago epidemiological studies,3 the Framingham study,4 and the National Health and Nutrition Examination Survey (NHANES) I Follow-Up Study5, which investigated the correlation between elevated resting HR and both cardiovascular and all-cause mortalities. Moreover, the association is not limited to those with an obviously elevated HR and a graded increase in risk has been suggested for HRs 
>60 b.p.m.
These studies find further support in clinical trials in patients treated with HR-reducing agents, which demonstrate improved survival after myocardial infarction6 and reduced mortality in patients with CHF.7 Indeed, there is evidence that much of the anti-ischaemic benefit of beta-blockade can be eliminated by the suppression of its HR effect using atrial pacing, both in conscious dogs8 and in patients with angina pectoris.9 Together, these trials provide clear evidence that the reduction in mortality is directly related to the pharmacological reduction in HR.
HR is determined by spontaneous electrical pacemaker activity in the sinoatrial node. Cardiac pacemaker cells generate the spontaneous slow diastolic depolarization, which drives the membrane voltage away from a hyperpolarized level towards the threshold level for initiating a subsequent action potential and generating a rhythmic action potential that propagates through the heart and triggers myocardial contraction. The If current is an ionic current that determines the slope of the diastolic depolarization, which in turn controls the heart rate.
Ivabradine is the first specific HR-lowering agent to have a complete clinical development for stable angina pectoris. Ivabradine specifically inhibits cardiac pacemaker cell f-channels by entering and binding to a site in the channel pore from the intracellular side. Ivabradine is selective for the If current and exerts significant inhibition of this current and HR reduction at concentrations that do not affect other cardiac ionic currents. This activity translates into pure HR reduction, which reduces myocardial oxygen demand and simultaneously improves oxygen supply, by prolonging diastole,10 preserving coronary vasodilation during exercise and thus allowing increased coronary flow and myocardial perfusion.11 Ivabradine lowers HR without any negative inotropic or lusitropic effect, thus preserving ventricular contractility.
Ivabradine was shown to reduce resting HR without modifying any major electrophysiological parameters that are not related to HR. In patients with left ventricular (LV) dysfunction, ivabradine reduced resting HR without altering myocardial contractility.12 Thus, pure HR lowering can be achieved in the clinic as a result of specific and selective If current inhibition.
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Potential relevance of pure HR reduction in coronary artery disease |
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Resting HR is a strong predictor of cardiovascular morbidity and mortality, particularly in patients with unstable angina or acute myocardial infarction.
A recent study analysing13 initial (day 1) hospital admission and delayed (days 2–3) HRs in over 10 000 patients with acute coronary syndromes enrolled in a large clinical trial of an oral glycoprotein IIb/IIIa inhibitor showed significant 30-day and 10-month mortality among patients with higher initial and delayed HRs. A number of possible reasons have been proposed to explain this and, clinically, tachycardia at rest is an adverse finding. Sinus tachycardia can reflect overactive sympathetic activity. It can be experimentally demonstrated that relatively high HRs can amplify atherogenesis and endothelial dysfunction selectively in the coronary vessels and that low HRs can exert a sparing effect.
A classic experiment14 in cynomolgus monkeys fed with a high-cholesterol diet for 6 months showed that after sinus node ablation by electrocautery to reduce HR, coronary atheroma was twice as severe in the animals with higher HRs which underwent a sham surgical procedure compared with those which had the ablation performed (55.9 vs. 26.1% stenosis in the two groups; P<0.002). Similar findings were also seen with further work in carotid vessels. In both sets of experiments, the animals did not significantly differ in blood pressure, serum lipids, or body weight.
In a study15 in 56 patients who had experienced a myocardial infarction before the age of 45 and who underwent two coronary angiograms within a period of 4–7 years, the progression of disease was predicted independently by HR. When patients were divided into high and low HR groups (by median value of minimum HR), coronary atherosclerosis progression was two times higher in the high HR group.
A further retrospective study examined the relationship between bradycardia and the development of coronary collateral vessels on angiography in patients with obstructive coronary artery disease (CAD). Patel et al.16 observed that a larger number of patients with HR 
50 b.p.m. had significantly greater development of collateral vessels (decreasing the ischaemic burden) when compared with control patients with HRs 
60 b.p.m. (P<0.001). The presence of collaterals was independent of the history of angina or use of beta-blockers.
Another retrospective angiographic study17 examined 53 of 106 patients who underwent two coronary angiograms within 6 months. These patients had initially smooth stenoses, but developed plaque disruption by the time of the second angiogram. They were compared with 53 control patients with smooth stenoses without angiographic plaque disruption. Logistic regression analysis identified positive associations between plaque disruption, LV muscle mass >270 g, and a mean HR >80 b.p.m. and a negative association with the use of beta-blockers (Table 1).
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This association again indicates how haemodynamic forces may play a critical role in the process of plaque disruption.
A further study has shown that high HR is strongly associated with high arterial rigidity, reduced distensibility, and elevated pulse-wave velocity, all of which are associated with myocardial infarction and cardiac death.18
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Potential relevance of pure HR reduction in CHF |
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HR is markedly elevated during CHF, most probably due to increased and persistent sympathetic overdrive, manifested by increased cardiac norepinephrine spillover and plasma norepinephrine levels. Increases in HR and plasma norepinephrine are correlated with reduced HR variability, which is related to prognosis, especially sudden death. Increased myocardial oxygen requirement and sympathetic activity cause direct cytotoxic effects on myocytes and accelerate apoptosis: they may therefore contribute significantly to pathological ventricular remodelling.19
Enhanced HR also influences the incremental elastic modulus in the large arteries and is therefore associated with increased stiffness of peripheral and central arteries. This may contribute to the loading condition of the heart and further contributes to the energy requirement of the heart and coronary risk.
A number of well-conducted randomized controlled trials have demonstrated the efficacy of beta-blocking agents in patients with chronic systolic heart failure.20,21 There is growing evidence that the impact of HR reduction is of particular importance in the improvement of the prognosis in this population.
Ivabradine was investigated in a rat model of heart failure to determine the effects of long-term HR reduction on LV function and remodelling.22 The study showed that in animals that had experienced long-term (90 days) HR reduction following randomization to ivabradine, LV function was improved with an increased stroke volume relative to placebo resulting in a preservation of cardiac output.
The investigators noted that the improvement in LV function was probably related not only to HR reduction but also to modifications of LV structure and/or myocyte properties as suggested by the decrease in LV collagen density and the increase in capillary density without any modification of LV weight, which persisted for at least 3 days after interruption of the treatment with ivabradine.
One can only speculate about the mechanisms that contribute to the modification of myocardial structure and LV function. HR lowering associated with ivabradine possibly augments coronary perfusion, thus preventing the development of endothelial dysfunction associated with local hypoxia and the production of cytokine and free radicals. Similarly, it is unknown whether such changes occur in clinical use. However, preliminary findings from a trial23 suggest that myocardial contractility improves in patients with heart failure treated with ivabradine 10 mg twice daily over 3 months, as evidenced by a trend towards a decrease in LV volumes and an increase in ejection fraction. Trials are planned to confirm related therapeutic benefits.
Patients with congestive heart failure may benefit from HR reduction both through the decrease in myocardial oxygen needs and the increase in oxygen supply (the prolongation of the diastole improves myocardial perfusion). In addition, with the constant ageing of the general population, diastolic heart failure represents an increasingly frequent cause of chronic cardiac failure. The therapeutic management of these patients is complex because only few studies were conducted in this population and therefore therapeutic recommendations remain largely speculative (Task Force of the European Society of Cardiology). Because excessive tachycardia has deleterious consequences on diastolic function, HR reduction is important to achieve. However, the negative lusitropic effect of beta-blockers may represent a disadvantage in this setting. The absence of deleterious effects on systolic and diastolic function and on blood pressure places ivabradine in a unique position to control HR in such unstable patients. Colin et al.10 examined LV relaxation in response to saline infusion, ivabradine or atenolol in dogs at rest and during exercise. Under saline, HR increased from 108 to 220 b.p.m. and the relaxation time constant (
BF) decreased from 22 to 14 ms. Both ivabradine and atenolol significantly limited the increase in HR during exercise to 150 b.p.m. Concomitantly, atenolol prevented the decrease in BF (23 ms), whereas ivabradine did not (15 ms, Table 2).
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Ivabradine limited the exercise-induced tachycardia without simultaneously altering the exercise-induced acceleration rate of the LV relaxation; in contrast, for the same level of limitation in HR during exercise, atenolol prevent the acceleration rate of the ventricular relaxation.
Vasoactive and inotropic agents often need to be initiated in patients with LV dysfunction and inadequate tissue perfusion. Dobutamine can precipitate inappropriate tachycardia and may exacerbate hypotension in some patients. Dopamine also acts directly on myocardial beta1-adrenergic receptors and indirectly releases norepinephrine. Tachycardia induced by the infusion of dobutamine or dopamine may aggravate myocardial ischaemia. Ivabradine may play a crucial role in the management of these patients, limiting unnecessary tachycardia without preventing positive inotropic effects and hence improving myocardial perfusion and haemodynamic parameters in heart failure or cardiogenic shock.
There is experimental evidence, in a rat model of myocardial stunning caused by a sequence of ischaemia-reperfusion, that the concomitant use of dobutamine and ivabradine prevents the tachycardia generated by dobutamine without altering mean arterial pressure or the recovery in LV wall thickening and LV fractional shortening obtained with dobutamine (V. Richard, personal communication).
An optimal HR is also desirable in patients with an intra-aortic balloon pump, which is commonly used in patients with cardiogenic shock, and ivabradine may be helpful.
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Potential relevance for pure HR reduction in sinus tachyarrhythmias |
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Sinus tachyarrhythmias are a heterogeneous group of disorders including normal sinus tachycardia, inappropriate sinus tachycardia, postural orthostatic syndrome, and sinus node re-entry tachycardia. Over the last few years, considerable progress has been made in deciphering and classifying the various forms; nevertheless, such arrhythmias often provoke much concern clinically, other than triggering the need to investigate a potential cause. Their management can be a challenge, and yet, in practice, remains generally limited to the use of beta-blockers and bradycardic calcium channel blockers while accumulating evidence suggests that the negative inotropic and hypotensive effects of these agents may exacerbate patient symptoms.24 Thus, the absence of these two properties with specific HR-lowering agents such as ivabradine may lead to a very exciting potential development as a treatment of these disorders.
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Conclusion |
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Ivabradine, a selective If current inhibitor, offers exciting therapeutic possibilities for a number of extremely common cardiac conditions. The ability of medications such as ivabradine to decrease HR or to limit its increase without exerting any negative inotropic effect could constitute a major advance, both in CAD and congestive heart failure. There is considerable epidemiological as well as experimental evidence of a relationship between resting HR and the development and evolution of coronary atherosclerosis; in addition, in post-myocardial infarction controlled trials of beta-blockers, a strong correlation has been observed between the reduction in baseline HR and the reduction in long-term mortality. The favourable effect of HR lowering in CAD might be partly linked to the observed relationship between elevated HR and coronary plaque rupture. As in CAD, the favourable effect of beta-blockers on long-term outcome in patients with CHF caused by systolic dysfunction appears largely, although probably not solely, mediated by the reduction in HR achieved with beta-blocking agents. Ivabradine might prove particularly useful in this setting, in which all observational studies have shown that in the real world, only a minority of patients were treated with beta-blocking agents. Ivabradine might also have important potential in diastolic heart failure, which remains a therapeutic puzzle for cardiologists, as well as in patients with acute heart failure treated with sympathomimetic agents such as dobutamine.
In addition, HR reduction with ivabradine may be a very attractive alternative for successful management of sinus tachyarrhythmias.
Future studies will be needed to determine whether ivabradine fulfils part, or all, of these promising perspectives.
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References |
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  M. Tendera Editorial: If inhibition: from pure heart reduction to treatment of stable angina Eur. Heart J. Suppl., September 1, 2005; 7(suppl_H): H3 - H6. [Full Text] [PDF]
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