Specific and selective If inhibition: expected clinical benefits from pure heart rate reduction in coronary patients
1Department of Cardiology, University of Ferrara, Ferrara, Italy
2Cardiovascular Research Center IRCCS, Salvatore Maugeri Foundation, Gussago, Brescia, Italy
* Corresponding author: Chair of Cardiology, University of Ferrara, Corso Giovecca, 203, 44100 Ferrara, Italy. Tel: +39 0532 202143; fax: +39 0532 241885. E-mail address: fri{at}dns.unife.it
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Abstract |
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 Top Abstract IntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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Heart rate is increasingly being considered as a prognostic factor in cardiovascular disease, and the need to measure and control heart rate in all coronary patients is clear. When comparisons of heart rate and life expectancy are adjusted for body weight in mammals, it appears that life span is pre-determined by the basic energetics of living cells. This inverse relationship between heart rate and life expectancy reflects an epiphenomenon in which heart rate is a marker for, or a determinant of, metabolic rate and energetic needs. The heart rate is controlled by the If current, which plays a central role as a pacemaker in the sinoatrial node. Ivabradine, the first representative of a new class of exclusive heart rate-reducing agents, selectively inhibits the If current in the sinoatrial node. The direct electrophysiological consequence of this inhibition is a reduction in the slope of the diastolic depolarization curve and a decrease in heart rate. Pharmacological inhibition of the If current with ivabradine has been shown to preserve coronary vasodilatation upon exercise, i.e. myocardial perfusion, with no negative inotropic effects and maintenance of cardiac contractility. Ivabradine also protects the myocardium during ischaemia, improves left ventricular function in congestive heart failure, and reduces remodelling subsequent to myocardial infarction. Pure heart rate reduction by specific and selective If inhibition decreases oxygen demand and improves myocardial energetics, and so we can expect distinct clinical benefits from long-term heart rate reduction in patients with chronic ischaemic disease.
Key Words: Heart rate • Cardiovascular risk • If current • Ivabradine • Cellular energetic needs
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Introduction |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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The relationship between resting heart rate and cardiovascular risk has been demonstrated in a number of large-scale epidemiological studies including the Chicago epidemiological study,1 the Framingham Heart Study,2 and the National Health and Nutrition Examination Survey (NHANES) I Follow-up Study.3 These studies all reported a correlation between elevated resting heart rate and both cardiovascular and all-cause mortalities.
A recently published long-term follow-up study has provided us with strong confirmation that heart rate is an independent risk factor for all-cause and cardiovascular mortalities, using data from nearly 25 000 patients who underwent coronary arteriography for the presence of suspected or proven coronary artery disease (CAD).4 Patients with a resting heart rate between 77 and 82 b.p.m. had a significantly higher risk of all-cause mortality (hazard ratio, HR: 1.16; 95% confidence interval, CI: 1.04–1.28) than patients with heart rate 
62 b.p.m. Moreover, the increased risk was observed independently of other cardiovascular risk factors (age, sex, presence of diabetes or hypertension, body mass index, ejection fraction, and treatment with ß-blocker). This study places heart rate as a prognostic factor in cardiovascular disease and highlights the need to measure and control heart rate in all coronary patients.
These epidemiological results are also supported by data from clinical trials. It has been reported that heart rate reduction improves survival after myocardial infarction5 and reduces mortality in patients with congestive heart failure.6 Moreover, much of the anti-ischaemic effect of ß-blockade can be eliminated by the suppression of its heart rate-reducing effect using atrial pacing,7 a result that emphasizes the independent role of heart rate and the value of any therapeutic strategy to reduce it.
Variations in heart rate can also affect the symptoms of CAD. For example, the symptom of chest pain in stable angina is often triggered by elevated heart rate due to physical or emotional stress, which then aggravates myocardial ischaemia. An increase in heart rate also precedes episodes of asymptomatic or silent myocardial ischaemia. Indeed, the efficacy of some anti-anginal drugs has been related to their efficacy in reducing heart rate.8
Thus, heart rate is an important therapeutic target, and the purpose of the present article is to anticipate the expected benefits from pure heart rate reduction by If inhibition.
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Principles of heart rate regulation: the role of the If current |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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There is spontaneous electrical pacemaking activity in many regions of the heart, including the sinoatrial node, the atrioventricular node, the bundle of His, and the Purkinje fibres. Under normal physiological conditions, the intrinsic rhythm is fastest in the sinoatrial node, which therefore determines the overall heart rate. At the resting potential, the cells are hyperpolarized; the pacemaker cells at the sinoatrial node then generate a slow diastolic depolarization, which drives the membrane voltage towards a threshold level, in preparation for the next action potential. These regular action potentials propagate through the heart and trigger myocardial ventricular contraction: the heartbeat.
Four ionic currents work in concert to produce the spontaneous diastolic depolarization: (i) the decay of the outward potassium current (IK) which was activated during the previous action potential; (ii) the activation of the time-dependent inward current If; and (iii) activation of two calcium currents, ICaL (long-lasting) and ICaT (transient). The If current was discovered in 1979 by Brown et al.9 The authors named it as ‘funny’ current (If) because, funnily enough, this net-inward mixed Na+/K+ current is slowly activated on hyperpolarization. The If current determines the slope of the diastolic depolarization curve towards the threshold level (approximately –40 mV in humans), which, in turn, controls the time interval between the successive action potentials and therefore plays a central role in the process of pacemaking.
The f channels responsible for the If current are HCN (hyperpolarization-activated, cyclonucleotide-gated) ion channels. There are four distinct isoforms of the HCN channels (HCN1–HCN4), which vary in terms of their properties and their distribution in the different tissues.10 HCN channels are expressed in the heart, retina, and brain. The isoform found in the heart is the HCN4 channel, which is active in the sinoatrial node. HCN4 channels are also found in the atrioventricular node and the Purkinje fibres, but these are not active under normal physiological conditions, although they operate under pathological conditions such as heart failure and cardiac hypertrophy. The sinoatrial node is densely innervated by both adrenergic and cholinergic branches of the autonomic nervous system, which thereby controls the chronotropic state of the heart. Sympathetic ß-adrenergic stimulation accelerates the pacemaker, whereas parasympathetic cholinergic vagal stimulation slows the heart rate.
The prospect of inhibiting the If current is clearly attractive in the search for a pharmacological means of reducing heart rate. This target sets such agents aside from conventional heart rate-reducing drugs, which can cause debilitating cardiovascular and non-cardiovascular side effects. For example, ß-blockers reduce heart rate, but also have negative inotropic effects and do not preserve myocardial contractility. Their use is also limited because of contraindications, such as in cases of atrioventricular block and in asthmatics.
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The If inhibitor ivabradine as a tool for specific and selective heart rate reduction |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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Awareness that ß-blockade in addition to heart rate reduction depresses contractility and unmasks ß-adrenergic coronary vasoconstriction has prompted the development of selective If inhibitors.
The first of this series of compounds is alinidine, a clonidine derivative and ULFS-49, a benzazepinone derivative. However, alinidine showed a negative inotropic action.11 ULFS-49 proved to be a selective bradycardic agent but resulted in frequent adverse events; for these reasons, none of the aforementioned compounds were ever developed further for clinical use. The only currently available, selective bradycardic agent that has been developed for clinical use is ivabradine.
Ivabradine has been shown to inhibit, in a concentration-dependent manner, If current in various experimental settings. Ivabradine is selective throughout two-thirds of its If inhibition curve, whereas other currents become marginally affected at concentrations at which If inhibition saturates.
Ivabradine binds specifically to the f channels on the intracellular side of the plasma membrane of the pacemaker cells in the sinoatrial node, thereby inhibiting the If current. The direct electrophysiological consequence of this inhibition is a reduction in the slope of the diastolic depolarization curve, leading to an increase in the time interval between successive action potentials and, therefore, a decrease in heart rate.12
This has been confirmed experimentally in in vitro studies in rabbit sinoatrial node cells,13,14 using the patch-clamp technique to investigate the inhibition of the If current by ivabradine. Ivabradine is an open-channel blocker: it inhibits the f channel in the open phase upon depolarization and is relieved by the channel upon hyperpolarization in the closing phase.13 The inhibition of the channel also appears to be current-dependent, suggesting that ivabradine is more active at higher heart rates. The inhibition is dose-dependent and selective for the pacemaker f channels.14
Slight inhibition of L-type Ca2+ channels (18%) was observed with 10 µm (60 times the therapeutic dose in the same animal blood) of ivabradine, whereas it has no effect on T-type Ca2+ channels. The relative lack of effect of ivabradine on the L-type Ca2+ current suggests the absence of negative inotropy induced by ivabradine. No significant effect on Na+ or K+ currents by ivabradine was reported.
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Expected clinical benefit from pure heart rate reduction |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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There are several potential benefits of heart rate reduction at cellular and body level.
Heart rate as determinant of life span: experience from the animal kingdom
In the animal kingdom, an inverse relationship has been observed between heart rate and life expectancy. This concept has been summarized in an outstanding editorial from Levine,15 which states that smaller animals have higher heart rates and shorter life span than larger animals (Figure 1).
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The explanation is provided in part by a biophysical imperative in which the ratio of heat loss (a function of body surface area) to heat production (a function of body mass) increases as body size is reduced.
Azbel16 stresses the concept that smaller animals have higher heart rates and shorter life span than larger animals, with a 35-fold difference in heart rate and a 20-fold difference in life span and suggests that life expectancy is pre-determined by basic energetics of living cells and that the inverse relationship between longevity and heart rate reflects an epiphenomenon in which heart rate is a marker or a determinant for metabolic rate and energetic requirements.
Although the fact that the total number of heartbeats per lifetime is constant has been demonstrated only in mammals, there is good reason to believe that this holds true throughout the entire animal kingdom. Thus, a giant (Galapagos) tortoise with a heart rate of 6 b.p.m. and a life expectancy of 177 years will produce 5.6x108 beats per lifetime,17 which is similar to the figure obtained for a rat (6.3x108) with a heart rate of 240 b.p.m. and a life expectancy of about 5 years.
Heart rate controls the body's metabolic activity
By adjusting its rate, the heart can control both the temperature and the energy requirements of the whole body. The heart is able to send ‘messages’ and ‘talk’ to most cells of the body through the circulatory system, mainly with the help of the endothelium. The ‘language’ chosen by the heart could be the ‘heart rate,’ via the intensity and frequency of shear stress so exerting an important regulatory role on endothelial function and vascular tone.18 The endothelium responds to shear stress by releasing nitric oxide and other vasoactive compounds, regulating the degree of vasodilation and thus the amount of blood and oxygen available to peripheral muscles. The metabolic rate is dependent on the physical activity, which in turn is related to, and likely determined by, heart rate itself. Regression analysis on a logarithmic scale between body mass and metabolic rate among animals yields a straight line with the same slope as that between body mass and heart rate.19 Therefore, there is a close link between temperature, metabolism, and heart rate, and the question is which is the primary control among these parameters? If heart rate determines the metabolic rate, it follows that a relationship between heart rate and life span exists in the entire animal kingdom including man.
Heart rate as the ‘life’ pacemaker
Whether heart rate reduction would bring about a prolongation of life span is not yet known for certain in man. Coburn et al.20 tested this hypothesis experimentally by feeding mice with digoxin and reported that treated mice had a slower heart rate and lived significantly longer than control mice. However, because of various confounding factors, such as lower body weight in treated mice, it was impossible to establish a clear cause-and-effect relationship.
Humans, with a mean heart rate of 70 b.p.m. and a life expectancy of 80 years, are an exception to the relationship between heart rate and life expectancy shown in mammals, as their life expectancy is higher than that predicted by their heart rate. It has been estimated that a decrease in heart rate from 70 to 60 b.p.m. would further increase life expectancy from 80 to 93.3 years in humans.17 It is an established fact, however, that in the general population, the risk of death from all causes, including cardiovascular disease, augments as resting heart rate increases. Several clinical studies have demonstrated that heart rate is an important risk factor for cardiovascular morbidity and mortality, not only among patients with established heart disease21 or well-known cardiovascular risk factors such as hypertension22 but also in the general population.2
Heart rate reduction reduces myocardial energy expenditure
Adenosine triphosphate (ATP) is the primary source of energy in the heart and is used for electrical excitation, contraction, relaxation, and recovery of the resting electrochemical gradients across membranes.
Even though the heart may suddenly increase its output up to six-fold, thus requiring a huge amount of energy, unlike other tissues, it only stores low quantities of ATP, just sufficient to support a few beats. However, the low ATP levels in the heart are counterbalanced by a higher level of creatine phosphate which permits availability of ATP from the adenosine diphosphate, through a phosphorylation reaction catalyzed by creatine kinase.23
In the heart, ATP is synthesized in the mitochondria from a variety of aerobic substrates.24 At rest, ATP is also generated from fatty acid ß-oxidation (60–70%) and carbohydrate catabolism (30%) including exogenous glucose and lactate catabolism. Amino acids and ketone bodies are utilized as substrates, however, less frequently.
In man, the heart beats a total of an average of 100 800 cycles per day. This figure corresponds to 36.8x106 cycles per year and 29x108 heartbeats in a lifetime (80 years on average). The heart produces and consumes 
30 kg of ATP every day, i.e. nearly 11 000 kg/year and 880 000 kg in a lifetime. It follows that the cost of each heartbeat is 300 mg of ATP. Slowing the heart rate by 10 b.p.m. would result in a saving of 5 kg of ATP every day. To produce ATP, the myocardium needs oxygen, which is used by the mitochondria during oxidative phosphorylation. Azbel has calculated that in all animals, the basal oxygen consumption/body atom is 10 molecules of oxygen/lifetime, which, referred to heart rate, corresponds to 10–8 molecules of oxygen per heartbeat.18 Surprisingly, the total number of heartbeats per lifetime calculated with these data (10x108) is similar to the mean value observed among mammals (7.3x108).
Even though these calculations are based on simplified figures, they point to the pivotal role of heart rate reduction at the cellular level. Because oxygen delivery in the heart mainly occurs during diastole, through the coronary flow, it is clear that the deleterious consequences resulting from conditions in which the heart is damaged and oxygen delivery is impaired, such as ischaemic heart disease and certain types of heart failure, will be improved when agents that decrease heart rate are administered.25–28 Because heart rate is a major determinant of oxygen consumption and metabolic demand, heart rate reduction would be beneficial (Figure 2).
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Heart rate reduction improves perfusion of the ischaemic myocardium
Often under ischaemic conditions, stenotic coronary arteries are connected via collaterals to intact or less severely stenotic arteries. This causes a typical redistribution of coronary flow with a possible steal phenomenon. Any increase in heart rate would be deleterious as it will further reduce diastolic perfusion, increase stealing from the ischaemic zone, and impairing the flow at the ischaemic obstruction, which, in turn, further compromises coronary flow. Reduction of heart rate under these circumstances is therefore highly beneficial.
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Main pharmacological results for heart rate reduction with ivabradine |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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The effect of ivabradine in improving coronary perfusion has been investigated in resting and exercising conscious dogs and compared with the ß-blocker propranolol.29 Ivabradine reduced resting and exercising heart rate in a dose-dependent manner and preserved coronary artery vasodilatation during exercise without any negative inotropic effects. In contrast, for the same heart rate reduction, propranolol caused vasoconstriction of the coronary arteries and a negative inotropic effect. The same study showed that ivabradine did not alter the increased cardiac output and stroke volume upon exercise, which were significantly decreased by propranolol. Finally, this study proved that the coronary and systemic effects of ivabradine were exclusively due to its effect as a reducer of heart rate as they were abolished by atrial pacing.29 Therefore, ivabradine reduces heart rate, preserves coronary vasodilatation upon exercise, i.e. myocardial perfusion, with no negative inotropic effects and maintenance of cardiac contractility.
Ivabradine's anti-ischaemic properties also effectively ensure a better cardiac recovery upon reperfusion. In a recent study in our laboratories, we have shown that administration of ivabradine preserves tissue ATP levels in the isolated perfused rabbit heart during ischaemia and reperfusion.30 This cardioprotection is dependent on ivabradine's heart rate-lowering activity because it disappears upon atrial pacing and it is dose-dependent. These results confirm previously reported studies in another experimental model.31
The protection of the ischaemic myocardium by heart rate reduction has been tested for ivabradine and atenolol in an animal model of exercise-induced ischaemia and stunning.31 Ivabradine and atenolol reduced heart rate to the same extent at rest and during exercise.
During exercise, ivabradine improved left ventricular wall thickening and reduced the subsequent myocardial stunning compared with saline. The ß-blocker also improved left ventricular wall thickening, but had no effect during recovery (Figure 3). The effect of ivabradine disappeared upon atrial pacing, proving that it is solely due to ivabradine's heart rate-reducing properties31 and can be linked to the improvement in myocardial contractility.
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Ivabradine has also been shown to improve left ventricular function in congestive heart failure and reduce remodelling subsequent to myocardial infarction.32 In post-myocardial infarction rats, heart rate reduction with ivabradine decreased left ventricular collagen density and increased left ventricular capillary density, without modifying left ventricular weight, indicating that heart rate reduction improves left ventricular function, increases stroke volume, and preserves cardiac output (Figure 4). This improvement in cardiac function was related not only to the heart rate reduction per se but also to the modification of the extracellular matrix and the function of the myocytes as a result of the long-term reduction in heart rate.32 These observations have been tested clinically with ivabradine in CAD patients with left ventricular dysfunction (ejection fraction <40%) with promising results.33 These results may be linked to modifications of left ventricular structure.
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), 1 (
), 3 (
), or 10 (
) mg/kg per day (n=8–19 per group). Asterisk denotes P<0.05 vs. untreated CHF. Reproduced from Mulder et al.Increased heart rate and haemodynamic forces may play a role in plaque disruption. Plaque rupture is the main pathophysiological mechanism underlying acute coronary syndromes and the progression of coronary atherosclerosis.10 The role of haemodynamic forces, i.e. heart rate, has been investigated in 106 patients who underwent two coronary angiographic procedures within 6 months.34 This study identified positive associations between plaque rupture, left ventricular muscle mass >270 g, and a mean heart rate >80 b.p.m. and a negative association with heart rate-reducing medication.
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Conclusion |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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We can expect a number of clinical benefits from pure heart reduction in coronary patients. Pure heart rate reduction by specific and selective If inhibition decreases oxygen demand and improves myocardial energetics; it increases diastolic perfusion time and preserves myocardial contractility and coronary vasodilatation during exercise. Ivabradine also protects the myocardium in acute ischaemic conditions and has favourable sustained remodelling properties in the long term. There is clinical proof of the anti-anginal and anti-ischaemic effects of ivabradine in stable angina.35,36 Pure heart rate reduction with chronic treatment with ivabradine is therefore of clear clinical benefit in patients with chronic ischaemic disease.
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References |
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TopAbstractIntroductionPrinciples of heart rate...The If inhibitor ivabradine...Expected clinical benefit from...Main pharmacological results for...ConclusionReferences |
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