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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The role of heart rate and the benefits of heart rate reduction in acute myocardial ischaemia

Gerd Heusch* and Rainer Schulz

Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany

* Corresponding author. Tel: +49 201 723 4480; fax: +49 201 723 4481. E-mail address: gerd.heusch{at}uk-essen.de


   Abstract
Top
 Abstract
Introduction
 Quantitative relation of...
 Distribution of perfusion and...
 Effects of heart rate...
 Beta-adrenergic blockade in...
 Selective heart rate-reducing...
 References
 
In myocardial ischaemia, detailed analyses of experimental data show that regional myocardial blood flow and contractile function are reduced proportionately—this being contrary to the common notion that the underlying pathological mechanism is a supply/demand imbalance. Such perfusion–contraction matching is maintained at an increased heart rate. In the normal myocardium, metabolic regulation prevails and tachycardia results in an increased coronary blood flow. In post-stenotic myocardium that has an exhausted dilator reserve, a reduction in diastolic duration prevails, and coronary blood flow is decreased with tachycardia. In the presence of collaterals, both metabolic vasodilation of the normal microcirculation and reduced diastolic duration act in concert to decrease collateral perfusion pressure and collateral flow into the post-stenotic coronary microcirculation. Tachycardia results from sympathetic activation and activation of beta-adrenoceptors. Accordingly, beta-adrenergic blockers have been used to treat patients with stress-induced myocardial ischaemia. The benefits of heart rate reduction by beta-blockade are in part counterbalanced by unmasked alpha-adrenergic coronary vasoconstriction. Selective heart rate-reducing agents can decrease heart rate without unmasking alpha-adrenergic coronary vasoconstriction. They improve the blood flow distribution into the ischaemic myocardium and, as a consequence, improve regional myocardial function. Ivabradine is the only clinically available selective heart rate-reducing agent, and it exerts anti-ischaemic actions in patients with chronic stable angina.

Key Words: Heart rate • Coronary blood flow • Myocardial ischaemia • Steal phenomenon


   Introduction
Top
 Abstract
 Introduction
Quantitative relation of...
 Distribution of perfusion and...
 Effects of heart rate...
 Beta-adrenergic blockade in...
 Selective heart rate-reducing...
 References
 
It appears to be common wisdom that myocardial ischaemia is characterized by an imbalance between oxygen supply and demand1 and that an increased heart rate contributes to such an imbalance by both decreasing supply and increasing demand.

However, this view is too simplistic—if not incorrect—largely, because other than cardioplegic arrest, in which heart rate is of no importance, it does not adequately consider the regional nature of myocardial ischaemia2 in most clinical scenarios.


   Quantitative relation of perfusion and contraction in normal and ischaemic myocardium
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 Abstract
 Introduction
 Quantitative relation of...
Distribution of perfusion and...
 Effects of heart rate...
 Beta-adrenergic blockade in...
 Selective heart rate-reducing...
 References
 
The gold standard for the measurement of regional myocardial blood flow is the microsphere technique,3,4 and for the measurement of regional contractile function, it is sonomicrometry.5

In the normal heart, increases in contractile function are associated with increased metabolism, and the increased metabolic demands are met, to a smaller extent, by increased oxygen extraction, and to a larger extent, by an increase in the myocardial blood flow.6,7 The mechanisms/mediators of such metabolic coronary dilation are still unclear;6 however, this is clearly a situation involving perfusion–contraction matching,8 in which alterations in contractile function are the cause of alterations in blood flow.

A reverse causal relationship, i.e. increases in myocardial blood flow causing increases in contractile function, does not exist in the normal beating heart.9 Upon acute coronary artery inflow reduction, contractile function in the ischaemic region is rapidly decreased.10 As soon as a steady state has developed (2–3 min) that permits the measurement of regional myocardial blood flow with the microsphere technique, a consistent—almost linear—relation between the reduced regional myocardial blood flow and contractile function is apparent (Figure 1).11,12


Figure 1
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  		Figure 1 Linear relationship between normalized (as a fraction of baseline) regional myocardial systolic wall thickening and normalized (as a fraction of that in remote control myocardium) myocardial blood flow, i.e. perfusion–contraction matching. Reproduced from Gallagher et al.12

 
The relationship between ischaemic regional myocardial blood flow and contractile function varies with the haemodynamic situation. There is a higher blood flow for a given level of function during exercise than at rest.11 However, when myocardial blood flow is normalized for heart rate, i.e. expressed as blood flow per beat rather than blood flow per minute, and is thus related to the same temporal reference as contractile function, i.e. a single cardiac cycle, the relationships at rest and during exercise11 and those at different heart rates13,14 are superimposable.

When equating such perfusion–contraction matching in acutely ischaemic myocardium with an energetic supply–demand balance, several limitations must be considered. On the supply side, in addition to blood flow, changes in myocardial oxygen extraction and anaerobic glycolytic metabolism may also contribute to supply. In terms of demand, regional wall excursion may underestimate the regional metabolic demand when the ischaemic myocardium still develops wall tension, and indeed, even dyskinetic myocardium has a surprisingly high oxygen consumption.15–18

The mechanisms/biochemical signals that underlie the rapid development of perfusion–contraction matching in acutely ischaemic myocardium are still entirely unclear.


   Distribution of perfusion and contraction between ischaemic and non-ischaemic myocardium
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 Introduction
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 Distribution of perfusion and...
Effects of heart rate...
 Beta-adrenergic blockade in...
 Selective heart rate-reducing...
 References
 
Although collaterals certainly have a cardioprotective function,19,20 they can also be the underlying morphological substrate for aggravation of myocardial ischaemia when steal phenomena occur.

In the presence of flow-limiting coronary stenosis, flow into the ischaemic terminal vascular bed is the sum of coronary arterial inflow through the stenosis and collateral inflow from adjacent non-ischaemic, or less-ischaemic, regions (Figure 2). Collateral inflow is dependent on the pressure gradient between the origin of collaterals in the intact donor vessels and their orifice into the ischaemic recipient vessels. When the dilator reserve of the ischaemic recipient vessels is fully exhausted and flow is therefore pressure-dependent, any dilation of the non-ischaemic donor terminal vascular bed during enhanced metabolic demand21 or in response to dilator agents22–25 will decrease the driving pressure gradient across the collaterals and, as a consequence, will decrease collateral flow. This phenomenon has been termed collateral steal.26 A similar situation occurs with respect to the transmural distribution of myocardial blood flow when the subendocardial autoregulatory reserve is exhausted, but some subepicardial autoregulatory reserve persists.27 The dilation of subepicardial vessels during enhanced metabolic demand will then compromise subendocardial perfusion,28 a phenomenon termed transmural steal. The transmural steal phenomenon can be considered the major cause of the preferential subendocardial manifestation of myocardial ischaemia and infarction. The presence of a well-developed collateral circulation often maintains sufficient blood flow to the post-stenotic myocardium at rest, but steal phenomena contribute to the precipitation of myocardial ischaemia during exercise.29–31


Figure 2
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  		Figure 2 Collateral (left) and transmural (right) steal phenomena. P1 is the pressure at the origin of collaterals, P2 the pressure at the orifice of collaterals into the ischaemic terminal vascular bed, F1 the flow through the stenosis, and F2 the collateral blood flow. Any dilation of the normal terminal vascular bed will decrease P1, and as a consequence, the P1–P2 gradient and also finally F2. Increased heart rate decreases microvascular resistance and pressure at the origin of collaterals in normal myocardium (left), but increases microvascular resistance and pressure at the orifice of collaterals in post-stenotic myocardium (right). The driving pressure gradient for collateral blood flow (P1–P2) is reduced by two-thirds. Reproduced from Heusch and Yoshimoto.21

 
Regional myocardial ischaemia also has an impact on the non-ischaemic myocardium. During acute coronary artery occlusion, the ischaemic region is surrounded by a narrow zone of normally perfused myocardium with depressed systolic wall thickening or segment shortening.32 This depressed contractile function in the immediate border zone surrounding the ischaemic region is attributed to more or less well-defined mechanical ‘tethering’ between non-ischaemic and ischaemic myocardial fibres.33 From a diagnostic point of view, such a dysfunctional border zone leads to the overestimation of the ischaemic region. A dysfunctional non-ischaemic border zone may not only extend laterally from an ischaemic region during complete coronary occlusion, but also overlie the ischaemic inner myocardial layers during non-transmural ischaemia.

Although lateral and transmural tethering create a non-ischaemic dysfunctional border zone in the immediate vicinity of the ischaemic region, more remote non-ischaemic regions are characterized by enhanced contractile function.34 Whether an increase in remote non-ischaemic zone function can be considered as compensatory, in that it acts to preserve global left ventricular (LV) function,35–37 is not completely clear, as a major part of non-ischaemic zone hyperfunction occurs during isovolumic systole and does not contribute to ejection.38


   Effects of heart rate on perfusion and contraction in normal and ischaemic myocardium
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 Abstract
 Introduction
 Quantitative relation of...
 Distribution of perfusion and...
 Effects of heart rate...
Beta-adrenergic blockade in...
 Selective heart rate-reducing...
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Increases in heart rate increase the number of cardiac cycles per time frame and thus also increase the energy/oxygen demand per time frame. In addition, in some species—possibly including humans—increases in heart rate increase the myocardial inotropic state through a force–frequency effect.39 With an intact coronary circulation, metabolic vasodilation serves to increase coronary blood flow to match the increased oxygen demand, as myocardial oxygen extraction is near maximal at baseline and can only be increased by a small amount. At the same time, by increasing the oxygen demand, increases in heart rate also shorten diastolic duration and thus the time interval of the cardiac cycle, in which almost all of the coronary blood flow occurs.40,41 In an intact coronary circulation, metabolic vasodilation is powerful enough to overcome the limited coronary blood flow resulting from reduced diastolic duration, such that the increased oxygen demand is adequately matched; thus, increases in heart rate are associated with proportionately increased myocardial oxygen consumption. However, in the presence of a severe coronary stenosis, when the autoregulatory capacity of the coronary circulation is exhausted in order to maintain a normal coronary blood flow at baseline, any further increase in heart rate—or more precisely any further reduction in diastolic perfusion time42—compromises coronary blood flow such that it is actually reduced at higher heart rates.

In the setting of regional myocardial ischaemia, in which a severely stenotic coronary artery is connected via collaterals with an intact or less severely affected coronary artery, a typical redistribution/steal scenario develops, as outlined earlier. Metabolic vasodilation of the more or less intact coronary microcirculation decreases collateral perfusion pressure, and as a consequence, collateral blood flow into the post-stenotic coronary microcirculation,21 i.e. ischaemia, is precipitated (Figure 2).

In addition to such steal phenomena, the haemodynamic severity of a coronary stenosis is increased at higher heart rates because of increased turbulence, and this effect acts to further compromise coronary inflow.43


   Beta-adrenergic blockade in regional myocardial ischaemia
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Selective heart rate-reducing...
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Exercise and excitement are characterized by sympathetic activation, and beta-adrenergic mechanisms contribute to myocardial ischaemia through an unfavourable redistribution of coronary blood flow away from the ischaemic subendocardium, i.e. through a collateral as well as a transmural steal mechanism (discussed earlier). Beta-adrenergic blockade decreases heart rate at rest and attenuates the exercise-induced increases in heart rate, LV dP/dt, and function of the non-ischaemic myocardium. As a consequence, the increases in blood flow to the non-ischaemic myocardium and the post-stenotic subepicardium are attenuated. However, the subendocardial blood flow of the ischaemic myocardium is increased, i.e. there is a reversal of the steal phenomenon, thus resulting in improved regional myocardial function.44 The haemodynamic severity of a dynamic coronary stenosis is reduced by beta-adrenergic blockade. The beta-adrenergic blockade–induced autoregulatory decrease in flow to non-ischaemic regions results in an increase in post-stenotic coronary perfusion pressure. Increased perfusion pressure, in turn, reduces stenotic resistance, thus finally improving blood flow to ischaemic regions.45 The beneficial effects of beta-adrenergic blockade in exercise-induced myocardial ischaemia are almost exclusively due to the attenuation of the increase in heart rate. When this reduction in heart rate is prevented by atrial pacing, ischaemic regional myocardial blood flow and function are even reduced when compared with the untreated situation, possibly because of an unmasking of alpha-adrenergic constriction in the ischaemic coronary microcirculation.30,46 The disadvantage of beta-adrenergic blockade in reducing the inotropic state is well appreciated; however, the importance of alpha-adrenergic coronary vasoconstriction in patients with stable angina or patients undergoing coronary interventions47–50 has thus far been largely neglected or underestimated.


   Selective heart rate-reducing agents in regional myocardial ischaemia
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The appreciation that beta-adrenergic blockade not only reduces heart rate but also reduces the myocardial inotropic state and unmasks alpha-adrenergic coronary vasoconstriction has prompted the development of selective heart rate-reducing agents. Selective heart rate-reducing agents are chemically distinct compounds; the first drug to be advocated in the early 1980s as a selective heart rate-reducing agent was alinidine. Alinidine's promotion as a selective heart rate-reducing agent coincided with the detection of the sinoatrial pacemaker current, If, by DiFrancesco and Ojeda.51,52 This If current subsequently became the target of all selective heart rate-reducing agents, including the clonidine derivative alinidine, the benzazepinones ULFS-49 and ivabradine, and others.53,54 In conscious, chronically instrumented dogs with a coronary stenosis, alinidine reduced heart rate both at rest and during treadmill exercise. The ischaemic contractile dysfunction that developed during exercise was attenuated, but this was at the expense of a significant negative inotropic effect, both at rest and during exercise.55 In addition, in anaesthetised pigs, alinidine decreased heart rate, caused a favourable redistribution of myocardial blood flow into the post-stenotic subendocardium, and attenuated ischaemic contractile dysfunction but again at the expense of a negative inotropic action.56 Alinidine has also been used in patients with acute myocardial infarction and appears to be safe,57 but it is without effect in terms of myocardial salvage and arrhythmias.58

ULFS-49 has also been shown to decrease heart rate, both at rest and during exercise, in conscious, chronically instrumented dogs with a coronary stenosis. Post-stenotic subendocardial blood flow was additionally improved31 and ischaemic contractile dysfunction attenuated, and these beneficial effects were achieved in the absence of negative inotropic actions.31,59 Subsequently, the mechanism of the beneficial action of ULFS-49 in acute myocardial ischaemia was analysed in more detail, and plots of contractile function versus subendocardial blood flow were established in anaesthetised pigs. When expressed in the conventional terms of blood flow per minute, ULFS-49 improved regional systolic wall thickening for any given subendocardial blood. However, when blood flow was expressed as blood flow per cardiac cycle, and thus normalized for the same time frame as contractile function (discussed earlier), the flow–function relationships at different heart rates became superimposable, indicating that ULFS-49's beneficial effect on ischaemic regional myocardial blood flow and function was indeed entirely mediated through heart rate reduction.13 With ULFS-49, a more favourable blood flow distribution into the LV subendocardium occurred not only from the LV subepicardium, but also from the right ventricle, i.e. reverse transmural and interventricular steal phenomena occurred.60 Given these beneficial effects on ischaemic myocardial blood flow and its distribution, it is not surprising that ULFS-49 also decreased infarct size during more prolonged ischaemia in anaesthetised pigs, as did atenolol; however, contractile function was better preserved with ULFS-49 than with atenolol.61 Despite its favourable anti-ischaemic profile, ULFS-49 was never developed further for clinical use.

The only currently available, selective heart rate-reducing agent that has approval for clinical use is ivabradine (S 16257). In conscious, chronically instrumented dogs, ivabradine causes a dose-dependent reduction in heart rate both at rest and during exercise, and—in contrast to propranolol—exerts its effects without any negative inotropic action. In addition, ivabradine only slightly attenuates the epicardial coronary artery diameter increase that occurs during exercise, whereas propranolol actually reduces the epicardial diameter, thus unmasking alpha-adrenergic coronary vasoconstriction (Figure 3).62 Accordingly, ivabradine prolongs diastolic duration (thereby increasing perfusion) and reduces myocardial oxygen consumption (demand).63,64 In chronically instrumented dogs with a coronary stenosis, ivabradine again reduced heart rate at rest and during treadmill exercise and improved post-stenotic subendocardial blood flow and contractile function; these beneficial effects during exercise-induced ischaemia were followed by attenuation of post-ischaemic contractile dysfunction, i.e. stunning, and the attenuation of both ischaemic and post-ischaemic contractile functions was lost when the reduction in heart rate was eliminated by atrial pacing. In contrast, although beta-blockade with atenolol also attenuated ischaemic contractile dysfunction, it did not attenuate post-ischaemic stunning; in addition, atenolol reduced non-ischaemic wall function.65,66 The attenuation of ischaemic contractile dysfunction with reduced heart rate by ivabradine was confirmed in conscious pigs during treadmill exercise, who also displayed less ST-segment shift, similar to the effects of propranolol but without its negative inotropic action.67 It appears that in animal experiments, ivabradine fulfils all the criteria for selectively decreasing heart rate without a negative inotropic action and without unmasking alpha-adrenergic coronary vasoconstriction. In a recent study using a chronic coronary occlusion model in rabbits, ivabradine reduced infarct size and mortality as much as metoprolol, resulting in less remodelling and better preservation of LV function.68 Ivabradine's detailed effects on the flow–function relationship (perfusion–contraction match) and on the infarct size with reperfusion have yet to be determined.


Figure 3
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  		Figure 3 Increases in epicardial coronary artery diameter with increasing intensity of exercise with placebo (open circles) are only slightly attenuated with ivabradine (closed circles), whereas with propranolol (open squares), epicardial coronary artery diameter is decreased. Reproduced from Simon et al.62

 
Initial clinical data on patients with chronic stable angina treated with ivabradine have recently become available. In a double-blind, placebo-controlled prospective trial, patients receiving ivabradine had prolonged time to 1 mm ST-segment depression (Figure 4) and angina while carrying out exercise testing during 3 months of use, without any rebound effect during drug withdrawal.69 These findings were also confirmed in a larger trial, and non-inferiority to atenolol was demonstrated.70 In a rat model of post-myocardial infarction remodelling and heart failure, ivabradine reduced end-systolic volume, but not end-systolic LV volume, thus increasing stroke volume and preserving cardiac output.71 Also in patients with LV dysfunction, ivabradine reduced heart rate without any appreciable negative inotropic effect.72


Figure 4
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  		Figure 4 Changes in time to 1 mm ST-segment depression during exercise in patients with chronic stable angina. Reproduced from Borer et al.69

 
In conclusion, increases in heart rate are of major importance in the precipitation of myocardial ischaemia, predominantly through an unfavourable blood flow redistribution away from the ischaemic subendocardium. Selective reduction of heart rate by ivabradine accordingly attenuates both the reduction in regional myocardial blood flow and contractile function, importantly, not at the expense of a negative inotropic action or an unmasked alpha-adrenergic coronary vasoconstriction.

Conflict of interest: none declared.


   References
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 Quantitative relation of...
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