Approaches to Improving Cardiac Structure and Function During and After an Acute Myocardial Infarction

Abstract

While progress has been made in improving survival following myocardial infarction, this injury remains a major source of mortality and morbidity despite modern reperfusion therapy. While one approach has been to develop therapies to reduce lethal myocardial cell reperfusion injury, this concept has not translated to the clinics, and several recent negative clinical trials raise the question of whether reperfusion injury is important in humans undergoing reperfusion for acute ST segment elevation myocardial infarction. Therapy aimed at reducing myocardial cell death while the myocytes are still ischemic is more likely to further reduce myocardial infarct size. Developing new therapies to further reduce left ventricular remodeling after the acute event is another approach to preserving structure and function of the heart after infarction. Such therapy may include chronic administration of pharmacologic agents and/or therapies developed from the field of regenerative cardiology, including cellular or non-cellular materials such as extracellular matrix. The optimal therapy will be to administer agents that both reduce myocardial infarct size in the acute phase of infarction as well as reduce adverse left ventricular remodeling during the chronic or healing phase of myocardial infarction. Such a dual approach will help optimize the preservation of both cardiac structure and function.

Myocardial infarction remains a major source of mortality and morbidity, despite recent treatment advances. The purpose of this brief editorial is to review the major options for improving cardiac structure and function following a myocardial infarction, during both the acute phase of the infarction and the chronic or healing phase of the infarction. While one approach is reduction in acute myocardial infarct size by reducing the damage to myocardial cells while they are ischemic, emphasis over the last several years has been on attempts to limit reperfusion injury. Based upon data from our own laboratory as well as several recent negative clinical trials, we question the importance of attempting to reduce reperfusion injury as an approach to limiting myocardial infarct size. The concept of reperfusion injury as a viable target to help reduce myocardial cell death in the acute throes of a myocardial infarction may be coming to an end. Salvaging tissue during the acute ischemic phase of infarction and preventing adverse left ventricular remodeling during the chronic phase of infarction remain viable therapeutic approaches.

Acute Phase

There is no question that early, complete, and persistent reperfusion of the occluded coronary artery (percutaneous coronary interventions or thrombolysis) has been shown in a host of experimental and clinical studies to limit the size of the myocardial infarction. Adjunctive pharmacologic or other therapies, together with reperfusion, may further limit myocardial infarct size. These therapies must be administered within a matter of hours of onset of chest pain in order to be effective. Some therapies might work by limiting additional ischemic damage, if they are present while the coronary artery is still occluded; some therapies are believed to reduce lethal reperfusion injury if on board during reperfusion only; and some adjunctive therapies may work by a combined reduction in both ischemic and reperfusion injury. In our experience, there have been few agents that reduced myocardial infarct size above and beyond reperfusion, and in our laboratory, nearly all had to be present during some phase of the ischemic insult to demonstrate a benefit. In our models which involve experimental animal studies, ischemic preconditioning, ¹ remote ischemic preconditioning, ^2,3 cardiac hypothermia, ^4,5 and certain beta blockers ⁶ have reduced myocardial infarct size above and beyond reperfusion itself. In general, agents that we have administered only at the time of reperfusion or after reperfusion has already been instituted do not significantly reduce myocardial infarct size more than reperfusion alone. For example, we have observed that therapeutic hypothermia, when on board during the period of ischemia, consistently and significantly reduces myocardial infarct size. However, when the hypothermia is induced after reperfusion has already been instituted, it fails to reduce myocardial infarct size (but it will reduce the extent of the no-reflow phenomenon ⁷ ). We fully appreciate that many laboratories suggest that reperfusion injury plays a large role in causing myocardial cell death. We are less convinced of this, based on data from our own laboratory as well as data emerging from clinical trials. Many clinical trials have failed to show a benefit from adjunctive therapy given only at reperfusion. Often, there have been discrepancies between findings in the animal laboratory and findings in the clinical trials. We have described potential reasons for these discrepancies in previous reviews. ⁸ However, a very few adjunctive therapies have shown a positive benefit in clinical trials when instituted after reperfusion has occurred, including inducing hyperoxemia ⁹ and atrial natriuretic peptide. ¹⁰ There are some clinical trials suggesting that adjunctive therapy reduces infarct size above and beyond reperfusion alone, but these may include an element of cardioprotection that occurs during ischemia. Examples are adenosine infusion, ¹¹ remote ischemic conditioning which has now been shown to improve myocardial salvage in several separate clinical trials, ^{12 –14} hypothermia for anterior infarctions, when the core temperature is reduced to 35°C or less prior to reperfusion, ¹⁵ exenitide, ¹⁶ and a few others. But most of the clinical studies in which therapy was administered only at the time of reperfusion have failed to show a further reduction in myocardial infarct size, including 2 recent large studies with the mitochondrial permeability pore inhibitor, cyclosporine A. ^17,18 Studies that have attempted to reduce the inflammation associated with reperfusion have also failed. Attempts to inhibit the function of white blood cells have failed in clinical trials. ⁸ In addition, anti-inflammatory agents given during the acute phase of infarction may inhibit the healing phase of infarction and worsen left ventricular remodeling. ^19,20 Furthermore, there is a lack of data showing that agents that reduce myocardial infarct size in patients necessarily reduce adverse clinical outcomes.

At the present time, early and complete reperfusion of the occluded coronary artery remains the only accepted clinical approach to reducing myocardial infarct size. In the past, we used to think that “the ball game was over” after the first 24 hours of coronary occlusion, and in fact, in the setting of an acute myocardial infarction, nearly all the cells that are going to die are probably dead by 6 to 12 hours, unless coronary collateral flow is very high. However, the ultimate state of cardiac structure and function after myocardial infarction depends upon a number of factors, besides simply the size of the infarction.

Chronic or Healing Phase

In the healing phase following a myocardial infarction, the necrotic, noncontracting tissue thins and stretches, leading to myocardial infarct expansion. Myocardial infarct expansion begins as early as 48 hours to 1 week after infarction. Infarct expansion is associated with regional left ventricular dilatation, global left ventricular dilatation, and eventually eccentric (lengthwise) hypertrophy of the noninfarcted walls of the ventricle, processes that extend from weeks to months after the acute infarction. This entire process has been called postinfarction left ventricular remodeling and its presence is a negative prognosticator after myocardial infarction. ²¹ Large areas of no-reflow contribute to adverse left ventricular remodeling, as the microvascular obstruction that occurs following reperfusion of a patent epicardial coronary artery can impede healing by limiting access of macrophages to the infarcted tissue and hence interfere with the removal of necrotic debris as well as limiting access to the necrotic areas of factors and substances needed for adequate healing. The degree of left ventricular dilatation following myocardial infarction is one of the most powerful predictors of death 1 year after a myocardial infarction. What are some of the ways that postinfarct remodeling can be limited or treated? Adverse remodeling can be limited by first reducing myocardial infarct size. Our group and others have shown that early reperfusion reduces infarct size, and this results in less adverse postinfarction left ventricular remodeling. But even if reperfusion is instituted in a timely manner, some remodeling may occur. Therapies such as the chronic administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers reduce left ventricular remodeling (Figure 1). These benefits may occur by reducing afterload or contractility of the noninfarcted myocardium, with less adverse paradoxical systolic bulging. While these types of agents have become standard therapy for treating postinfarction left ventricular dysfunction, they reduce adverse clinical outcomes by about 20% to 25%, indicating that there is a large residual need for additional and more effective therapies. In an experimental rat model of myocardial infarction, chronic therapy with the mitochondrial-targeting agent, Bendavia, preserved genes related to mitochondrial function, prevented left ventricular dilation, and sustained left ventricular ejection fraction. ²² In addition, chronic administration of Bendavia reduced apoptosis within the noninfarcted border zone on either side of the infarct scar. Besides pharmacologic therapy for adverse left ventricular remodeling, another approach is to treat the infarcts or scars with cell therapy. Such therapy might include cells that build a “brick and mortar” sheet of muscle as we have previously observed when injecting neonatal cardiomyocytes, ²³ fetal cardiomyocytes, ²⁴ and immature cardiomyocytes derived from embryonic stem cells into the region of the scar. ²⁵ In this case, the cells added bulk to the thin scar, reduced left ventricular wall stress, and reduced paradoxical systolic bulging of the infarct, which reduced infarct expansion. In addition, cardiomyocytes derived from embryonic stem cells or induced pluripotent cells can form electrical connections with surrounding host myocardial cells and contribute to active contraction. Other cell types, such as those derived from endogenous adult cardiac stem cells or cardiospheres ²⁶ and bone marrow derived mesenchymal stem cells, ²⁷ appear to exert a paracrine effect that might aid healing, enhance angiogenesis, or recruit viable myocardium to the injured area of the heart. Finally, noncellular material injected into an infarct scar “bulks-up” the infarcted wall and may act as a thickener that prevents paradoxical systolic bulging and in so doing improves forward cardiac output. ²⁸ In addition, by thickening the infarcted wall, overall wall stress is lowered.

Figure 1.

The schematic shows the effects of various therapies on left ventricular structure following a myocardial infarction. Each circular drawing represents a cross-section through the mid-left ventricle. The inner circle represents the left ventricular cavity, and the space between the inner and outer circle represents the left ventricular wall. Following a proximal coronary artery occlusion, the anterior wall becomes ischemic (shown here as the hatched risk zone from about 4 o’clock to 8 o’clock on the circle) as shown on the far left. If no therapy is given and the infarct follows its natural history (top row), a large portion of the ischemic risk zone will go on to die (infarct) as shown by the large black area within the risk zone in the drawing in the upper left. Over weeks, the infarcted area stretches and thins (infarct expansion) and then regional and global dilatation of the left ventricular cavity occurs. After months the left ventricular cavity progressively dilates, and there is continued thinning of the scar. Eccentric (length wise) hypertrophy occurs in the noninfarcted portions of the left ventricle. These processes are considered to be a part of adverse left ventricular remodeling that occurs postmyocardial infarction. The type of ventricle shown in the upper right is associated with a poor prognosis including death and systolic heart failure. The second row shows the consequences of administering a therapy to reduce myocardial infarct size in the acute phase (hours) of infarction. Such therapy might include early reperfusion, ischemic preconditioning, remote conditioning, therapeutic hypothermia, adenosine infusion, or other therapies. Reducing infarct size will allow tissue salvage within the risk zone (usually viable myocardium that is salvaged within the risk zone but in the outer half of the ventricular wall) and limits but does not prevent left ventricular remodeling. The third row shows the effects of giving therapy to reduce adverse remodeling of the left ventricle without first reducing myocardial infarct size. Chronic administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers started too late to reduce infarct size will reduce myocardial infarct expansion, left ventricular dilatation, and eccentric hypertrophy. The scar will be large, but thick and remodeling minimized. The fourth row shows optimal treatment with therapy to acutely reduce myocardial infarct size as well as therapy to reduce remodeling. This is the ultimate way to preserve cardiac structure and function following a myocardial infarction. Early therapy reduces infarct size resulting in a large zone of salvaged myocardium within the ischemic risk zone, shown here overlying the infarct. The chronic administration of agents to reduce remodeling allows the scar to shrink down and prevents dilatation of the left ventricle so that the end result (circle shown in the bottom right) is a small subendocardial scar, thick previously ischemic wall with mainly salvaged tissue, and a nondilated left ventricle void of eccentric hypertrophy.

Optimal therapy aimed at improving ultimate cardiac structure and function following an acute myocardial infarction will reduce myocardial infarct size as well as limit adverse left ventricular remodeling (Figure 1). While early reperfusion therapy with angioplasty/stents or thrombolysis and antiremodeling therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or beta blockers have improved outcomes for acute myocardial infarctions, inhospital mortality is still in the order of 5%, and 1 year mortality in some registries is as high as 13%. In addition, about one-quarter of patients who have had a myocardial infarction develop heart failure. Therefore, there is still a need to better treat the structural and functional abnormalities that occur after a myocardial infarction. New therapies are needed to further limit initial myocardial infarct size and enhance healing after infarction. It is likely that these therapies will be aimed at further protection of myocardium during the phase of ischemia and further attempts to reduce left ventricular remodeling after infarction. We think it is unlikely that agents given after reperfusion has occurred will further salvage myocardial cells. However, we do think that therapies such as late hypothermia, started after reperfusion, have the potential to limit no-reflow and therefore improve healing of the infarct.