Cardiovascular Research Advance Access originally published online on May 16, 2008
Cardiovascular Research 2008 79(1):5-6; doi:10.1093/cvr/cvn109
Published by Oxford University Press on behalf of the European Society of Cardiology 2008
Heart-rate reduction and β-blockade in early post-infarction cardiac remodelling
Cardiology Division, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA
* Corresponding author. Tel: +1 301 295 3601; fax: +1 301 295 3557. E-mail address: rgoldstein{at}usuhs.mil
Soon after acute myocardial infarction, the heart may experience extensive changes in function, structure, tissue architecture, and biochemical properties collectively known as cardiac remodelling. Many of the deleterious changes can be attenuated by treatment with β-adrenergic blocking agents1–3 or with alternative drugs that reduce post-infarction heart rate without interrupting β-adrenergic signalling.4,5 In a study appearing in this issue of Cardiovascular Research,6 M
czewski and Mackiewicz employed a rat model to elucidate the benefits of post-infarction β-blockade by comparing effects of heart-rate reduction without β-blockade (using ivabradine) and effects observed when the same reduction in heart rate was combined with β-blocking action (using metoprolol). Drug treatment was begun 24 h after coronary ligation and halted 48 h before final measurements. Thus, outcomes reflected drug manipulation of early remodelling after the acute ischaemic insult, and measurements identified effects persisting after drug washout and dissipation of immediate drug actions on heart rate and β-receptors.
Heart-rate reduction appeared impressively beneficial for haemodynamic function, even in the absence of concomitant β-blockade: improvement in contractility (ejection fraction and +dP/dt) and filling pressures (left ventricular end-diastolic pressures and lung congestion) were equivalent in rats receiving ivabradine and those receiving metoprolol. The authors quite reasonably ascribed these benefits to enhanced coronary perfusion and reduced metabolic demand accompanying lower heart rates. Less frequent systolic wall stress may also have played a role. These haemodynamic benefits were accompanied by more ominous developments in cardiac structure relative to untreated rats—persistent left ventricular (LV) dilation and increased LV hypertrophy (greater heart weight and wall thickness). The former could have reflected augmented LV filling volume with slower heart rate and the latter a reaction to dilating forces, perhaps partly mediated by vascular endothelial growth factor. Despite favourable haemodynamics after 8 weeks of treatment, this LV dilation and hypertrophy could ultimately lead to heart failure and arrhythmias. A comparison of ivabradine and metoprolol after a longer treatment period might have arrived at different conclusions regarding the relative effect of the two drugs on cardiac performance.
With metoprolol treatment, haemodynamic benefits were accompanied by a reduction in LV dimensions and no further increment in infarct-related LV hypertrophy. The favourable actions of β-blockade on LV loading conditions and mediators of hypertrophy in post-infarct hearts (cited by the authors) represented benefits of β-blockade for cardiac structure that supplemented and enhanced the actions of heart-rate reduction. The study also examined other important aspects of myocardial function. Myocyte Ca2+ handling showed striking differences: metoprolol treatment was associated with greater increases in amplitude of the systolic Ca2+ transient relative to ivabradine, a unique rise in the Ca2+ content of the sarcoplasmic reticulum (SR), and unique suppression of both increased sarcolemmal Na+–Ca2+ exchanger (NCX) activity and excessive Ca2+ sensitivity of ryanodine receptors following acute myocardial infarction. While the long-term significance of these changes was not demonstrated, greater abundance of intracellular storage and systolic release of Ca2+ likely contributed to increased contractile reserve for the post-infarction myocardium. Although action potentials were not evaluated in this study, suppression of post-infarct rises in NCX activity may have improved electrical stability following infarction: enhanced extrusion of Ca2+ (exchanging three Na+ for each Ca2+) results in an inward current that may disrupt orderly repolarization and favour early as well as delayed afterdepolarizations. Destabilization of repolarization may promote ventricular ectopy, inhomogeneous impulse conduction, and ventricular fibrillation.7,8 Suppression of Ca2+ extrusion by NCX may have also played a role in augmented SR Ca2+ storage. Excessive post-infarction sensitivity of ryanodine receptors—mediators of systolic Ca2+ release from SR—led to inappropriate Ca2+ release in diastole. Metoprolol-mediated reversal of this excessive sensitivity may have further contributed to electrical stability.
Recent publications demonstrated that activation of β-adrenergic mechanisms results in increased phosphorylation of key regulatory sites that raises NCX activity and ryanodine receptor sensitivity.9,10 The calcium effects in Mczewski and Mackiewicz's metoprolol-treated rats were consistent with persistent decrement in basal phosphorylation at these regulatory sites. When metoprolol was halted, β-adrenergic mechanisms—including activation of protein kinase A—were unlikely to exhibit direct attenuation 48 h later. Study findings suggest a lasting effect, possibly a sustained phosphatase activity, after withdrawal of the β-blocker. Caution is appropriate, however, to avoid over-interpretation. In the absence of experiments to test the responsiveness of calcium handling to stimulation of the β-adrenergic system—which would indirectly assess the state of phosphorylation—no conclusions can be reached.
Mczewski and Mackiewicz's study focused on LV structure and calcium handling, suggesting a number of potentially beneficial changes with β-blocker after myocardial infarction. These deserve further exploration in suitable experimental models. However, there are many other possible mechanisms for benefit with β-blockade (Table 1). Within myocytes, these include prevention of apoptosis and transformation of heavy-chain myosin to the less effective foetal form as well as preservation or restoration of myofilaments and elements of the cytoskeleton such as structured dystrophin. β-blockade may also retard deleterious changes in the extracellular matrix that occur with cardiac remodelling. In addition, β-blockade is likely to suppress potential toxic excesses of circulating neuroendocrine mediators such as angiotensin II and vasopressin and favour increase in possibly beneficial mediators such as nitric oxide or prostacyclin.
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While M
czewski and Mackiewicz's study provides significant insights regarding the potential advantages of β-blockade, the study also offers an important message regarding the likely value of heart-rate reduction during postinfarction recovery. There are many differences between the rodent model and human therapeutics; concepts relating to therapy must be confirmed in a clinical setting. Nevertheless, the potential benefit of heart-rate reduction should not be overlooked in managing patients after myocardial infarction: appropriate heart-rate reduction should be a consideration when shaping treatment regimens (with or without β-blockers), and conditions preventing this heart-rate reduction should be removed or ameliorated. Conflict of interest: none declared.
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The views expressed in this editorial are solely those of the authors and do not represent the opinions of the Uniformed Services University of the Health Sciences or the United States Department of Defense.
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