The Patent Infarct-Related Artery Hypothesis
The open artery hypothesis: Potential mechanisms of action

https://doi.org/10.1016/S0033-0620(00)70006-5Get rights and content

Abstract

The postinfarction period is one of intense dynamic activity because the cardiovascular system undergoes a number of adaptive responses attempting to maintain cardiac output. These homeostatic responses contribute to the processes involved in postinfarction ventricular remodeling and involve acute, chronic, systemic, and local reactions. Almost immediately, neurohormones are activated that alter hemodynamic load, and, later, stimulate myocyte hypertrophy, while locally, inflammatory processes clear necrotic debris, reorganize the extracellular matrix, and orchestrate scar formation. Where the initial cardiac insult is sufficiently large (eg, necrosis of more than 40% of left ventricular mass), remodeling responses are exaggerated and may become maladaptive, contributing to the poor long-term prognosis associated with myocardial infarction. Although several studies have shown clear benefits after neurohormonal modulation and/or manipulation of ventricular loading forces in the postinfarction setting, relatively few studies have investigated the potential merits of a patent infarct-related artery during postinfarction ventricular remodeling. In particular, the salutary effects of late revascularization of previously occluded vessels remains controversial. Thus, though this issue remains speculative, our present practice must be governed by circumstantial evidence and hypothetical arguments. This article discusses the potential mechanisms whereby late reperfusion of an infarcted myocardial region may benefit long-term prognosis. Copyright © 2000 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 42, No. 6 (May/June), 2000: pp 419-438

Section snippets

Late infarct-related artery reperfusion and infarct expansion

Infarct expansion, defined by Hutchins and Bulkley11 as “an acute dilatation of and thinning of the area of infarction not explained by additional myocardial necrosis,” forms one of the earliest morphological sequelae of postinfarction ventricular remodeling. Although the precise mechanisms leading to infarct expansion are unknown, it seems likely that extracellular matrix remodeling including the breakdown of intercellular collagen struts is implicated (see later). The cellular basis of

Collagen breakdown

The myocardium consists of a tough 3-dimensional scaffold of type 1 and type III collagen fibers.22 Within this framework is a finer lattice of fibronectin to which parenchymal components and latent metalloprotinases (MMPs) are anchored.23 The geometric alignment of the extracellular matrix is responsible for much of the tensile strength and elasticity of the myocardium.22 Disruption of the matrix (which occurs after myocardial infarction) leads to a vulnerable segment of softened tissue liable

Inflammation and late reperfusion

The relationship between inflammation and infarct healing is interesting and may account for some of the favorable effects associated with delayed reperfusion. After infarction, endothelial cells play a crucial role in the regional inflammatory response.24 Inflammatory mediators (eg, bradykinin, prostaglandins, and chemokines) are released, endothelial cell permeability is increased, and the interstitium becomes edematous.32 The result includes recruitment of phagocytes that lyse and clear

Mechanical effects associated with late reperfusion

In addition to promoting an acute inflammatory response and local edema, reperfusion of an infarct-related coronary artery with blood at an arterial perfusion pressure increases tissue turgor. It is possible, therefore, that engorgement of the coronary vascular tree can have a scaffolding effect on the vulnerable infarcted bed, which increases tissue stiffness, to resist early infarct expansion.

The effect of reperfusion on tissue stiffness has been investigated in a canine study involving left

Global ventricular dilatation and late reperfusion

In the first few days after myocardial infarction, infarct expansion accounts for most of the geometric changes and increases in left ventricular chamber volume.15 Initially, ventricular dilatation can be considered beneficial because it maintains stroke volume through the Frank Starling mechanism. At the same time, however, the dilating ventricle also proves detrimental because it exerts further demands on the surviving myocardium through increases in wall tension (Fig 5).16 Despite

The arrhythmic substrate and late reperfusion

The electrical substrate of the myocardium is altered after myocardial infarction.50 Electrically neutral scar tissue, for example, predisposes to reentrant arrhythmias,51 while in other areas, automaticity is increased.51 Analysis of 24-hour Holter recordings taken approximately 11 days after myocardial infarction from patients participating in the Multicentre Post-Infarction Programme, for example, revealed that at least 11% of patients had runs of nonsustained ventricular tachycardia.52

Autonomic function and late reperfusion

The relationship between autonomic tone and postinfarction arrhythmogenesis may be another mechanism by which late reperfusion of an infarct-related artery may favorably influence prognosis.63 The sympathetic system is among the first of the neurohormones to be activated after infarction.64 In the initial postinfarction period, increased intracellular cyclic AMP (through activation of myocyte adrenoceptors) results in positive chronotropic and inotropic effects that help maintain cardiac

Conclusion

In patients receiving reperfusion therapy late, and in which the opportunity for myocardial salvage has been missed, there still appear to be additional mechanisms of benefit. Caution, however, must be exercised when interpreting the results of experimental studies examining the open artery hypothesis. In animals, the open artery hypothesis can be tested in its purest sense. The clinical situation, however, is more complex, often with acute-on-chronic coronary artery occlusion in the presence

Acknowledgements

Z.R.Y. and M.S.M. are funded in part by the British Heart Foundation.

The magnetic resonance images in Fig 4 were kindly provided by Dr N. Bellenger and Dr D. Pennell (MRI Unit, The Royal Brompton and Harefield Hospitals).

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      Reperfusion of ischemic myocardium may help deliver blood products necessary for clearing necrotic cells and formation of healthy scar tissue. IRA patency may also provide a scaffolding function for collateral circulation to develop and allow perfusion to peri-infarct myocardium in hibernation.26 Despite these putative benefits, randomized trials have reached mixed conclusions regarding the benefits of late reperfusion.

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      Left ventricular ESV is a sensitive measure of post-infarction LV remodeling and one of the most powerful predictors of long-term prognosis after MI (13). Furthermore, attenuation of post-infarction LV dilation is thought to be an important contributing mechanism to the open artery hypothesis (2). The Open Artery Trial was therefore designed to compare LV ESV between the two study groups of patients at highest risk of adverse LV remodeling (transmural anterior MI).

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      Our previous results also suggest that late reperfusion has a preventive effect on LV dilatation without infarct size reduction.5 These preventive effects of late reperfusion on LV dilatation could be explained by the proposed mechanism as suggested by previous published reports.3,20,21 In contrast, the long-term beneficial effect of very late reperfusion has not been demonstrated in either animal models or in clinical settings.

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    Address reprint requests to Professor Michael S. Marber, PhD, FRCP, FACC, Department of Cardiology, The Rayne Institute, St Thomas' Hospital, Kings College London, London, SE1 7EH, United Kingdom; e-mail: [email protected].

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