ß-blockers, myocardial ischaemia and collateral circulation

M Sato*, S.E Harding and P.A Poole-Wilson

Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK

* Corresponding author: Dr M. Sato, Imperial College London, London, UK
E-mail address: m.sato{at}imperial.ac.uk

This editorial refers to "Heart rate reduction during exercise-induced myocardial ischemia and stunning" by X. Monnet et al. on page 579, and "Coronary collateral perfusion in patients with coronary artery disease: effect of metoprolol" by M. Billinger et al. on page 565.1

ß-blockers are established as standard first-line therapy for both stable and unstable angina pectoris having been introduced to the clinical setting in the mid-1960s. This class of drug is effective in alleviating the symptoms of angina but has never been shown to impact on mortality in patients with chronic stable angina. Several large clinical trials have shown ß-blockers to reduce mortality when used in patients after myocardial infarction and more recently in heart failure.1–3 The recently published COMET trial demonstrated mortality benefit of carvedilol (a nonselective ß-blocker and {alpha}-antagonist) compared to metoprolol tartrate (a selective ß1-blocker) in heart failure.4 Thus over recent years the focus of interest has moved from the treatment of ischaemic heart disease to the use of ß-blocker in chronic heart failure.

This issue of European Heart Journal reports two studies of the possible deleterious effects of particular ß-blockers on two aspects of clinical relevance to ischaemic heart disease, namely coronary collateral flow under controlled occlusion of the coronary artery,5 and the impact on ischaemic and stunned myocardium.6 In the first study,5 the effect on coronary collaterals of a second generation selective ß1-blocker, metoprolol tartrate, was investigated. Natural bypass of coronary arteries is defined as anastomotic connections without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries. Since collateral circulation has a cardioprotective effect as an alternative blood supply to avoid and/or delay myocardial damage when the original vessels are occluded, it has been recognised that factors with the potential to affect coronary collateral blood flow may play an important role in determining myocardial vulnerability and eventually prognosis for patients with coronary arterial disease. In this clinical study, including 25 patients with one or two vessel disease and collateral arteries,5 collateral blood flow velocity during PTCA balloon occlusion, was measured using ultrathin Doppler angioplasty guidewires. This is a reliable and authenticated method. The degree of collateral flow assessed by angiographic grade of collateral filling (Rentrop’s score: 0=none to 3=complete filling via collateral) on the distal side of the coronary stenosis was not affected by intravenous injection of adenosine (140µg/kg/min) and metoprolol (5mg iv). Collateral Flow Index (post-stenotic blood flow velocity during PTCA/baseline flow velocity prior to PTCA) significantly decreased from 0.25 to 0.16 during 3rd PTCA with 5mg i.v. metoprolol. Despite conflicting results from experimental studies, this clinical result is consistent with a previous clinical study using propranolol.7 Since the Doppler flow velocity time integral during coronary angioplasty is the most accurate index of coronary collateral blood flow, it is now clear that these first and second generation ß-blockers decrease coronary collateral blood flow. Nevertheless, there remain several important questions to be answered. First, the precise mechanism of the reduction in coronary collateral flow after the administration of ß-blocker remains unknown. The authors indicate that the mechanism may be an increase in coronary collateral resistance or a reduction in oxygen demand associated with a decrease in rate-pressure product.5 Theoretically, the factors that affect collateral blood flow to the ischaemic area include: (1) the driving pressure, (2) heart rate, (3) resistance in the donor artery, (4) number and diameter of collateral vessels and (5) resistance in the microcirculation of the ischaemic area which is under metabolic and hormonal control. The decrease in heart rate and negative inotropic effects produced by ß-blockers favour collateral flow because of the increase in the diastolic filling interval, the reduction of extravascular compressive forces, and decreased shortening compression in the ischaemic area. ß-blockers are also known to have some actions expected to decrease collateral flow, such as reduced oxygen consumption and increased resistance in the microcirculation of the ischaemic area consequent on autoregulatory mechanisms. The second and possibly more pressing question, is whether the reduction in collateral blood flow by ß-blockers has the potential to affect clinical outcome of patients with coronary heart disease. In this study, despite the significant reduction of collateral blood flow after intravenous metoprolol administration, there was no increase in the number of patients with anginal pain. The earlier study using propranolol reported that ST- segment shift during PTCA was significantly smaller after propranolol administration even in the condition of the decrease in collateral coronary flow.7 Hence, the negative effect of ß-adrenergic blockade on collateral flow has the potential for causing harm in the ischaemic area, but benefit from an anti-ischaemic effect due to improvement of the oxygen supply-demand balance. To date, there is no study reporting the effect of ß-blockers such as carvedilol on collateral circulation. The effect of carvedilol is difficult to predict, because of the mixed of ß1, ß2and {alpha}- adrenoceptor blocking effects and reported NO and endothelin release.8,9

The second pre-clinical study6 reports a comparison of the effect on stunned myocardium between ivabradine (Procoralan), a new class of heart rate-lowering agents, and the ß-blocker, atenolol. Myocardial stunning is defined as the prolonged but reversible contractile dysfunction which follows an episode of acute ischaemia, despite the return of normal blood flow. In this study, regional contractility (i.e., left ventricular wall thickening (Wth)) in canine exercise-induced stunned myocardium models, was measured by sonomicrometery technique. This method is invasive, but is the most reliable measurement for detecting a deterioration of contractile function. When atenolol was administered before ischaemia induced by exercise, the ß-blocker showed a similar effect on the reduction in heart rate to ivabradine, but a better impact on Wth in the ischaemic area compared with ivabradine (17±4% cf Ivabradine; 10±3%). In contrast, the depression of regional contractility after exercise (stunned myocardium) recovered after 3h in the ivabradine group, whereas in the atenolol group contractility remained unchanged at lower level during exercise and recovered to the baseline level only after 6h. This trend was distinguished more clearly when agents were administered after the induction of stunning. The authors conclude that the timing of ß-blocker administration may play a crucial role in the treatment for stunned myocardium and selective heart rate reduction without negative inotropic effects by ivabradine may be better as a first choice for angina pectoris. As the authors elegantly demonstrate, the reduction in heart rate is a major, independent factor involved in cardioprotective effects and the effect of Ivabradine is purely due to the heart rate reduction. Once more, several unanswered questions remain. First, negative inotropic effects of ß-blockers may not be harmful to the ischaemic heart. From a clinical standpoint, angina is unlikely to deteriorate into acute heart failure without myocardial infarction or severe ventricular arrhythmias. In this study, the administration of drug after the induction of stunning appeared to be critical to showing a difference between the two drugs. Ivabradine consistently shortened the recovery time for contractility back to the baseline level. The atenolol group eventually showed similar post-stunning to that of pre-administration at 6h after the induction of stunning, (if the effect of atenolol to depress basal wall thickening by 18±4% per se is taken into account). Second, the precise mechanism of prolonged recovery of the contractility in stunned myocardium, despite a good blood supply in the ischaemic area due to a ß-blocker remains unknown. It is certain that myocardial stunning per se is a multifactorial process involving complex intracellular mechanisms and the precise pathogenesis of myocardial stunning is still not established. Alterations in Ca2+handling, probably Ca2+overload, play a significant role in large mammals10 and may be modified by ß-blockers. Lastly, it is uncertain whether the delayed recovery of regional contractility by ß-blockers is clinically meaningful or negligible when these agents are administered to patients with significant coronary disease, but not infarction and heart failure. In other words, which is more important to treat patients with angina, better blood flow in the ischaemic area or short-term recovery of the contractility of stunning myocardium? If repeated stunning leads to a longer lasting reduction in the function of the heart, it may cause chronic contractile dysfunction and some of the rather non-specific symptoms, such as tiredness and exhaustion, which often afflict people with coronary heart disease. As the authors mention, ivabradine could provide a potent anti-ischaemic effect. However, in the clinical setting, where repetitive myocardial stunning and hibernation may co-exist,10 treatment with ß-blockers is indicated.

Despite a number of unanswered questions, both the pre-clinical and clinical studies of ß-blockers in this issue are unquestionably important and significant steps forward in understanding the precise mechanism of these agents. Cardiologists should always bear the possibility of harm from the negative effects of ß-blockers in ischaemic heart disease in mind, but at this time ß-blockers should be considered in all patients with angina at an appropriate dose, unless specifically contraindicated.

Footnotes

1 Doi: 10.1016/j.ehj.2003.10.010, 10.1016/j.ehj.2004.02.003. Back

References

  1. Bohm M, Maack C, Wehrlen-Grandjean M et al. Bisoprolol und perioperative Komplikationen chirurgischer Eingriffe bei chronischer Herzinsuffizienz Cardiac Insufficiency Bisoprolol Study II (CIBIS II)). Z Kardiol. 2003;92(8):668–676.[CrossRef][Medline]
  2. Janosi A, Ghali J, Herlitz J et al. Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: experiences from MERIT-HF. Am Heart J. 2003;146(4):721–728.[CrossRef][Medline]
  3. Krum H, Roecker E, Mohacsi P et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA. 2003;289(6):712–718.[Abstract/Free Full Text]
  4. Poole-Wilson P, Swedberg K, Cleland J et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362(9377):7–13.[CrossRef][Medline]
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  6. Monnet X, Colin P, Ghaleh B et al. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J. 2004;25:579–586.[Abstract/Free Full Text]
  7. Kyriakides Z, Kolettis T, Antoniadis A et al. Beta-adrenergic blockade decreases coronary collateral blood flow in patients with coronary artery disease. Cardiovasc Drugs Ther. 1998;12(6):551–559.[CrossRef][Medline]
  8. Brehm B, Bertsch D, von Falloris J et al. Beta-blockers of the third generation inhibit endothelin-1 liberation, mRNA production and proliferation of human coronary smooth muscle and endothelial cells. J Cardiovasc Pharmacol. 2000;36(5 Suppl :1):S401–S403.[Medline]
  9. Khattar R. Effects of ACE-inhibitors and beta- blockers on left ventricular remodeling in chronic heart failure. Minerva Cardioangiologica. 2003;51(2):143–154.[Medline]
  10. Kim S, Depre C, Vantner S. Novel mechanism mediating stunned myocardium. Heart Fail Rev. 2003;8:145–153.

Related articles in EHJ:

Heart rate reduction during exercise-induced myocardial ischaemia and stunning
Xavier Monnet, Patrice Colin, Bijan Ghaleh, Luc Hittinger, Jean-François Giudicelli, and Alain Berdeaux
EHJ 2004 25: 579-586. [Abstract] [Full Text]  

Coronary collateral perfusion in patients with coronary artery disease: effect of metoprolol
Michael Billinger, Lorenz Raeber, Christian Seiler, Stephan Windecker, Bernhard Meier, and Otto M. Hess
EHJ 2004 25: 565-570. [Abstract] [Full Text]  




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