Pathobiology of Ischemic Heart Disease: Past, Present and Future

    Pathobiology of Cardiovascular Diseases: Past, Present And Future Perspectives L. Maximilian Buja, Richard S. Vander Heide PII: DOI: Reference:

S1054-8807(16)30001-1 doi: 10.1016/j.carpath.2016.01.007 CVP 6905

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Cardiovascular Pathology

Received date: Accepted date:

10 January 2016 28 January 2016

Please cite this article as: Buja L. Maximilian, Heide Richard S. Vander, Pathobiology of Cardiovascular Diseases: Past, Present And Future Perspectives, Cardiovascular Pathology (2016), doi: 10.1016/j.carpath.2016.01.007

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PATHOBIOLOGY OF CARDIOVASCULAR DISEASES: PAST, PRESENT AND FUTURE PERSPECTIVES (CVP 25TH ANNIVERSARY SPECIAL ARTICLE)

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L. Maximilian Buja, MDa and Richard S. Vander Heide, MD, PhDb

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PATHOBIOLOGY OF ISCHEMIC HEART DISEASE: PAST, PRESENT AND FUTURE

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Department of Pathology and Laboratory Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas b

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Department of Pathology, Louisiana State Health Science Center, New Orleans, Louisiana

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ACCEPTED MANUSCRIPT ABSTRACT

This review provides a perspective on knowledge of ischemic heart disease (IHD) obtained from the

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contemporary era of research which began in the 1960ies and has continued to the present day.

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Important discoveries have been made by basic and translational scientists and clinicians. Pathologists have contributed significantly to insights obtained from experimental studies and clinicopathological

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studies in humans. The review also provides a perspective for future directions in research in IHD aimed

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at increasing basic knowledge and developing additional therapeutic options for patients with IHD.

KEY WORDS

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Myocardial Ischemia, myocardial infarction, preconditioning, postconditioning, stunning, hibernation, mitochondria

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ACCEPTED MANUSCRIPT INTRODUCTION

Ischemic heart disease (IHD) has been a leading cause of morbidity and mortality of long-standing in

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industrialized countries, and IHD is increasingly prevalent in countries with emerging economies (1).

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Investigation over decades has led to increasing knowledge of the pathogenesis of IHD which has served as the basis for more effective treatment and salvage of patients with this condition (2). These

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discoveries have been made by basic and translational scientists and clinicians. Pathologists have contributed significantly along the pathway of discovery by providing insights gained from experimental

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studies and clinicopathological studies in humans.

Ischemic heart disease results from the interaction of alterations in the coronary arteries and

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myocardium. Clinically, patients present with an acute coronary syndrome (ACS) – angina pectoris, sudden cardiac death, acute myocardial infarction (AMI) – or chronic ischemic heart disease. This review takes a comprehensive approach to ischemic heart disease while emphasizing the response of

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the myocardium to ischemic stress. The history of this field is one of basic discoveries leading to optimism and enthusiasm for the development of new therapeutic approaches for amelioration of acute

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IHD followed by periods of retrenchment after inconclusive or negative results from clinical trials. However, there have been three major accomplishments that have led to significant improvement in

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morbidity and mortality from IHD: first, is the introduction of electrophysiological monitoring leading to prompt treatment of arrhythmias in hospitalized patients, second, the demonstration that routine use

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of beta blockers, aspirin and other medications can improve survival (without necessarily salvaging ischemic myocardium), and third, the introduction of procedures to provide prompt opening of an occluded coronary artery leading to reperfusion of the ischemic myocardium and significant myocardial salvage (3). BASIC PATHOBIOLOGY OF CORONARY ARTERY DISEASE Atherosclerosis of the aorta and its major distributing branches, including the coronary arteries, develops as a response of the arterial wall to chronic, repetitive, multifactorial injury (4, 5). The disease is initiated by perturbation of the endothelium and is mediated by inflammation with selective expression of adhesion molecules favoring the accumulation of platelets, monocytes and lymphocytes on and in the lesion-prone regions. Local accumulation of low density lipoprotein and its oxidation is essential for the development of the characteristic lesion of established atherosclerosis, the 3

ACCEPTED MANUSCRIPT atherosclerotic plaque (the lipid theory of atherosclerosis). Atherosclerotic plaques are localized areas of intimal thickening with an endothelial lining and a content consisting of variable combinations of foam cells derived from macrophages and vascular smooth muscle cells, extracellular lipid, fibrous tissue and

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collections of macrophages and lymphocytes. Such plaques are usually vascularized by ingrowth of vasa

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vasora. At intermediate stages of coronary atherosclerosis, the coronary lumen is preserved by outward displacement of the media due to a process of positive remodeling (Glagov phenomenon) (6, 7).

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However, growth of atherosclerotic plaques eventually leads to progressive narrowing of the coronary lumen.

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The asymptomatic progression of coronary atherosclerosis is frequently interrupted by a stochastic event involving erosion of the endothelial lining of a coronary plaque, or rupture of the surface lining of

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a plaque, which triggers platelet aggregation and thrombosis and often results in rapid occlusion of the coronary lumen, manifest clinically as an ACS (8-10). Certain lesions, including thin-cap fibroatheromas (TCFA), are predisposed to these stochastic thrombotic events (11). They are considered to be

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vulnerable plaques. An active research effort has been ongoing to develop one or more advanced diagnostic imaging techniques for the identification of vulnerable plaques at risk for producing ACS (12,

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13).

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For decades, pathologists have investigated the pathogenesis of coronary thrombosis and the role of coronary thrombosis in the pathogenesis of AMI (14). Pathologists provided the key insights linking

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coronary plaque erosion or rupture to the development of coronary thrombosis, and they characterized the varying types of lesions, including TCFA, which are prone to develop arterial thrombosis. Pathologists also have raised provocative questions regarding the relationship of coronary thrombosis to the development of ACS, including the question of whether the coronary thrombus is a cause or a consequence of AMI (14). This question was definitively answered by clinical studies which showed that thrombi can be recovered from coronary arteries within the earliest stages of the evolution of AMI (15). Studies published recently in this journal have provided more detail regarding the evolution of coronary thrombi (16-18). Intrinsic to the confusion regarding the role of coronary thrombosis in ACS was a lack of understanding of the relationship of sudden cardiac death to AMI. Thus, clarifying the role of coronary thrombosis in ACS also provided insight into the cause of sudden cardiac death (19). It is now clear that sudden cardiac death is a result of ventricular dysrhythmia frequently devolving into ventricular fibrillation 4

ACCEPTED MANUSCRIPT followed by cardiac arrest, i.e., a phenomenon of dysfunction of the electrical heart (20, 21). There are at least three routes to sudden cardiac death: 1) ischemia induced by a perturbation in a coronary artery with rapid development of ventricular fibrillation; 2) arrhythmia occurring in the setting of an early stage

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AMI associated with a coronary thrombosis; 3) so-called primary ventricular arrhythmia not associated

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with new onset ischemia and related to a cardiomyopathy or channelopathy (19). Regarding the first route, experimental studies have confirmed that transient episodes of platelet aggregation short of

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permanent thrombosis can lead to recurrent episodes of impaired coronary blood flow and myocardial ischemia (22, 23).

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There has been an evolution in thinking regarding the relationship of coronary atherosclerosis and ACS. The traditional paradigm has been that the clinical horizon of acute ischemic heart disease is reached

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when coronary atherosclerosis has progressed to multiple foci of severe luminal narrowing. A more recent view is that an acute ischemic event is not closely linked to the severity of coronary atherosclerosis but rather is triggered by the development of instability and thrombosis of a vulnerable

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plaque which is frequently non-stenotic (24). A contrary view is that an individual patient may have multiple vulnerable plaques, that instability and thrombosis of a vulnerable plaque may or may not

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trigger an acute ischemic event, and that the total burden of atherosclerotic disease is important in

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determining the development of an ACS (25). In summary, pathologists have contributed significantly to refining our understanding of the role of

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vulnerable and unstable plaques in the development of ACS (11, 26, 27). These insights include: 1) the presence of prominent macrophage-rich inflammatory infiltrates near the surface of TCFA; 2) equal probability of plaque rupture at central and shoulder regions of vulnerable plaques; 3) thrombosis at the proximal margin of vulnerable plaques generating the false impression that unstable plaques undergoing thrombosis are non-stenotic when in fact the central regions are stenotic; 4) the natural history of coronary plaques characterized by changes in morphological features over time; and 5) natural history of TCFA characterized by recurrent episodes of instability, rupture, thrombosis, and subsequent organization and healing. Also, pathologists have pointed out that no single feature, including inflammation, is clearly predictive of an individual vulnerable plaque becoming unstable and undergoing thrombosis leading to an ACS. This is an area for future research.

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ACCEPTED MANUSCRIPT BASIC PATHOBIOLOGY OF MYOCARDIAL ISCHEMIC INJURY The contemporary era of basic research on the pathobiology of myocardial ischemic injury began with

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the publication of experimental findings regarding the effects of temporary coronary occlusion on

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canine myocardium by the pathologist, Robert Jennings and colleagues (28). Subsequently, Keith Reimer, Robert Jennings and colleagues produced leading work and publications documenting the ultrastructural and biochemical features of myocardial ischemic injury (29-31). Other pathologists and

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experimentalists also contributed early on to the development of a large body of knowledge in this area

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(32, 33).

In 1977-79, Reimer, Jennings and associates published very important experimental results regarding the time course of progression of myocardial ischemic injury to completed infarction within a defined

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myocardial bed at risk subtending an occluded coronary artery. In canine experiments, irreversible injury was shown to begin at about 20 minutes in the ischemic subendocardium and papillary muscle

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and then to extend into the mid-myocardium by about 60-90 minutes followed by completed transmural infarction by 3 to 4 hours (34, 35). A more rapid evolution to competed infarction was found

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in animals without collateral circulation, such as the pig, compared to dogs which exhibit variable amounts of subepicardial collateral blood flow. Clinical studies have confirmed that the time course in

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most patients is similar to that seen in the canine experiments. Ischemic cardiomyocyte injury is characterized by progressive membrane damage with a variable degree

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of cell swelling (28-33). Ischemic membrane damage has been shown to progress from discrete alterations in specific membrane pumps and ion channels to an intermediate stage of less selective and increasing membrane permeability with more severe ionic disturbances including increased influx of calcium ions to a final stage of membrane rupture (33). The membrane damage is mediated by activation of phospholipases and proteases and accumulation of toxic metabolites. This pattern of cell injury fits the general description of cell injury and death centered on cell swelling designated as oncosis (36-38). In the 1980’s a major paradigm shift occurred with the recognition of apoptosis as an important mode of cell injury and death (33, 36). Cell death due to apoptosis is characterized morphologically by cell shrinkage with intact plasma membrane, at least in isolated cell preparations, and biochemically by caspase activation and discrete double-stranded DNA breaks. Reports appeared implicating apoptosis as a major mode of myocardial ischemic injury (39). However, published evidence documenting the classic morphological features of apoptosis in ischemic cardiomyocytes is lacking. Nevertheless, 6

ACCEPTED MANUSCRIPT cardiomyocytes have been demonstrated to contain the molecular mechanisms to activate apoptotic pathways as well as pathways leading to progressive membrane damage (38). This has led to the

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terminal events 9are dominated by oncotic ultrastructure (37, 38).

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conclusion that cardiomyocyte ischemic injury and death is a hybrid form of cell injury in which the

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IMPORTANCE OF INFARCT SIZE

Autopsy studies performed by pathologists have been essential for advancement of understanding of

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IHD and have repeatedly yielded important insights uniquely available by this foundational procedure in medicine (40, 41). In spite of the many negative impacts on the autopsy, it remains as important today

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as ever. Two seminal autopsy studies confirmed a quantitative relationship between the extent of myocardial infarction and the severity of symptoms and prognosis in patients with ACS (42, 43). Specifically, loss of 40% or more of left ventricular myocardium due to a single large infarct or the

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cumulative effects of multiple small infarcts correlated with the development of intractable ventricular arrhythmias and/or cardiogenic shock with an associated high mortality rate (42, 43). Other studies

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linked the basic pathobiology of myocardial infarction to the mechanisms of scintigraphic detection and sizing of myocardial infarcts with the imaging agents’ technetium-99m pyrophosphate and thallium-201

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(44, 45). These studies have provided a pathobiological basis for further development of imaging

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modalities for the detection and quantitation of ischemic and infarcted myocardium (46, 47). Survival after relatively large infarcts was found to initiate a process of sustained pathological remodeling in the surviving myocardium leading to progressive cardiac dysfunction and heart failure manifest clinically as ischemic cardiomyopathy (ICMP) (48-50). While there is variability in the understanding and use of the term, ICMP, this entity is best understood as a form of advanced heart disease which is initiated by complications of coronary atherosclerosis but which progresses due to the effects of pathological remodeling independent of the status of the coronary arteries, which often have been subject to intervention (49). Ventricular remodeling is a complex process involving hypertrophy of cardiomyocytes, persistent cardiomyocyte cell death, inadequate replacement of dead and/or dying cardiomyocytes by precursor cells, changes in the microvasculature and connective tissue matrix, and geometric enlargement of the ventricular cavity placing increased stress on the ventricular wall (Law of LaPlace) (48). ICMP is the leading cause of advanced heart failure which requires ventricular assist device placement or orthotopic heart transplantation for survival. A similar phenomenon of ventricular 7

ACCEPTED MANUSCRIPT remodeling also is operative in the progression of heart failure in non-ischemic cardiomyopathies which

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collectively constitute the other leading category of heart disease requiring advanced therapy (50).

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INITIAL EXPLORATION OF LIMITING INFARCT SIZE

Based on seminal autopsy findings regarding the importance of infarct size in the morbidity and

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mortality associated with myocardial infarction, an influential call was made to accelerate research to develop approaches to limit infarct size (51). This led to a flurry of experimental studies in the 1970’s

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and 1980’s aimed at developing pharmacological therapies to limit myocardial infarct size (52). Many of these experimental studies yielded positive results indicating that reduction of myocardial damage was possible with a variety of agents, including free radical scavengers, calcium channel blocking agents,

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beta adrenergic blockers, and hyperosmolar agents (52). However, increasing concern about variability in reported results led to an effort to further characterize and standardize experimental models,

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including anesthetized and conscious animal preparations (53-55). A major dichotomy then became apparent between positive results of these pharmacological approaches in limiting myocardial infarct

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size in experimental animal models and equivocal results with these agents on limitation of infarct size in human clinical trials. Nevertheless, certain pharmacological agents, including aspirin and beta

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adrenergic blockers were shown to have positive effects on morbidity and mortality and have become standard of care in patients with ACS (56). BASIC PATHOBIOLOGY OF MYOCARDIAL REPERFUSION While pharmacological approaches for limitation of infarct size were yielding equivocal results, other studies showed unequivocally that timely reperfusion salvages previously ischemic myocardium (57-61). However, reperfusion also results in some degree of reperfusion injury which can include postreperfusion dysfunction (stunning), arrhythmias, lethal reperfusion injury of a population of marginally viable myocytes, and vascular damage leading to the no reflow phenomenon in the central core of the ischemic region. Reperfusion injury is mediated by a combination of a reoxygenation-induced burst of oxygen and nitrogen-derived free radicals and reactive lipid molecules coupled with an influx of ionic calcium leading to activation of degradative pathways by calcium-mediated proteases, including the

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ACCEPTED MANUSCRIPT calpains (58-61). Pharmacological approaches to ameliorate reperfusion damage have been widely proposed (62). The spectrum of the severity of sub-lethal to lethal injury is determined by a dose effect which in turn is related to the severity of injury and the timing of reperfusion. When reperfusion is

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achieved after 1 to 2 hours of severe ischemia, the effect is to convert a potentially transmural infarct

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into a subendocardial infarct with salvage of the mid- and subepicardial myocardium (63). An important concept has been advanced that the combination of pharmacological agents with reperfusion has the

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potential to reduce reperfusion damage and salvage more myocardium than with reperfusion alone (60, 61).

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CLINICAL REPERFUSION THERAPY

Coronary artery bypass graft (CABG) surgery for chronic ischemic heart disease became an accepted and

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frequently performed procedure beginning in the 1960’s (64-66). CABG surgery also was applied successfully to patients with unstable coronary disease and more selectively to patients with evolving

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AMI (64-66).

The era of coronary reperfusion for acute ischemic heart disease began in the 1980’s with reports of

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successful clinical trials of thrombolytic therapy for treatment of patients early in the course of acute myocardial infarction (67). The agent of choice became tissue plasminogen activating factor (tPA).

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Following an early clinical trial in Italy, a series of TIMI trials (Thrombolysis in Myocardial Infarction) were conducted in the United States, which were initially focused on thrombolysis but later expanded to

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other aspects of AMI (68). Currently, patients with unstable angina pectoris and early AMI are treated by percutaneous coronary intervention (PCI) protocols involving coronary stenting with or without thrombolytic therapy. The basic studies have emphasized that the timeliness of reperfusion is critically important to achieve maximum salvage of myocardium. As a result, referral hospitals have established AMI units with systems in place to facilitate optimal “door to balloon” times and a goal of reperfusion within 90 minutes of onset of symptoms. In 1977, the cardiologist, Andreas Gruentzig, introduced percutaneous transluminal coronary angioplasty (PTCA) (69). PTCA is based on the concept that expansion of a catheter-based balloon under pressure will dilate an obstructed coronary artery and, while some amount of “controlled injury” may occur, patency of the vessel will be restored (70). It is highly unlikely that PTCA would have been conceived by a pathologist given that pathologists developed models of atherosclerosis using ballooninduced endothelial denudation of arteries (4). Given the characteristic response of arteries to pressure9

ACCEPTED MANUSCRIPT induced injury with endothelial denudation, the high incidence of rapidly developing coronary restenosis was a biological inevitability. Coronary restensosis served as a stimulus for other creative cardiologists to develop coronary stenting, first with bare-metal stents and then with drug-eluting stents. Drug-

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eluting stents reduced the incidence of restenosis which continued to occur with bare-metal stents.

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However drug-eluting stents were found to be prone to delayed thrombosis once anti-thrombotic therapy is discontinued. This can be explained by the fact that the anti-proliferative agents retard the

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proliferation of myofibroblasts but also retard the healing and regrowth of endothelium placing the stented site at higher risk for thrombosis (70-73).

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PCI has been shown to improve the outcome and survival of patients with ST-segment elevation, transmural AMI (STEMI) and non-ST-segment elevation, subendocardial AMI (NSTEMI). PCI also has

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been shown to reduce symptoms but not to improve the long-term survival of patients with stable IHD (74).

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MYOCARDIAL STUNNING AND HIBERNATION

IHD can be associated with two forms of hypo-contractile but viable myocardium. Myocardial stunning

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refers to myocardium that is salvaged by timely reperfusion but has transiently impaired contractile function that recovers spontaneously over time and is due primarily to reversible injury produced by

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oxygen-based radicals (75-78). Hibernating myocardium refers to myocardium with chronically reduced contractile function associated with a local reduction in myocardial perfusion capacity (79-82). Over

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time, the hypo-perfused cardiomyocytes can develop degenerative changes. However, in contrast to stunned myocardium, contractile function can be immediately restored by reperfusion of the affected vessel by CABG or PCI. It is important in patients with IHD to determine whether identified dyskinetic segments of myocardium represent foci of irreversible scar or hibernating myocardium which can be salvaged by reperfusion. Diagnostic imaging is currently used to guide clinical decision making and intervention (46, 47). ISCHEMIC PRECONDITIONING Inn 1986, Murry, Reimer and Jennings described the phenomenon they coined as ischemic preconditioning (IP) (83-87). Murry and colleagues observed that repeated brief periods of reversible ischemia conferred a marked degree of cardioprotection to the same myocardial region subsequently subjected to a prolonged lethal period of severe ischemia. This protection was characterized by a 10

ACCEPTED MANUSCRIPT slower rate of early ATP depletion and lactate accumulation and a delay in the onset of irreversible injury and infarction. Importantly, they subsequently showed that IP and myocardial stunning were independent phenomena, indicating that the protection of IP was not simply the result of reduced

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contractile function (86). Due to the reproducibility across nearly all animal models, IP became a topic

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of extensive investigation (87-90). Several substitute triggers of IP have been identified as a result of these investigations including small autocoids, such as adenosine and bradykinin, which are released

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during the brief periods of ischemia, as well as other small molecules, including opioids. These autocoids have been shown to activate G protein- coupled receptors which subsequently activate other downstream signaling pathways that modulate mitochondrial function and initiate the mediator phase.

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To date, however, the ultimate effector of the cardioprotective effect has yet to be definitively

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identified.

When the interval between the ischemic preconditioning protocol and the prolonged coronary occlusion is extended to greater than one hour, the cardioprotective effect of IP ”disappears” for a period of about

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24 hours. However, after 24 hours, a cardioprotective effect reappears but at a lower level of effectiveness. This phenomenon is known as the “second window of protection” (SWOP) and is thought

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to be mediated by gene activation and subsequent protein production during the dormant phase (88-

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90).

More recently, other forms of cardioprotection associated with modification of ischemia and

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reperfusion times have been identified. If reperfusion is produced gradually rather than by sudden opening, the amount of reperfusion injury is reduced. This phenomenon was called “post-conditioning” (PC) (91). If ischemia is produced in an organ remote from the heart, typically by transient ischemia of skeletal muscle, the rate of myocyte death is slowed resulting in smaller myocardial infarcts. This phenomenon has been called “remote preconditioning” (RP) (92). RP appears to result from the production of a soluble substance in the remote ischemic region which reaches the myocardium via the circulation and exert effects similar to those seen in classical IP. NEW INSIGHTS INTO PATHOBIOLOGY WITH A FOCUS ON MITOCHONDRIA The biochemical and ultrastructural changes occurring in cardiac mitochondria during the evolution of myocardial ischemic injury are well documented (93). Recent studies have provided a heightened awareness of the central role of the mitochondria in ischemic injury, reperfusion injury and IP (94-96). Mitochondria have been found to have mechanisms that mediate irreversible injury (death channels) 11

ACCEPTED MANUSCRIPT and others that mediate cardioprotection (salvage pathway) (96). The mitochondrial death channels include the mitochondrial permeability transition pore (mPTP) and the mitochondrial apoptosis channel (mAC). The mPTP is a voltage-dependent channel that is regulated by calcium and oxidative stress. The

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function of the mPTP is influenced by three proteins: the voltage-dependent anion channel (VDAC), the

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adenine nucleotide translocator (ANT) and cyclophilin D (CypD). These proteins span the inner and outer mitochondrial membranes and provide a path from the mitochondrial matrix to the cytoplasm.

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The opening of the mPTP (without cytochrome c release) results in the immediate loss of the electrical potential difference across the inner membrane with resultant cessation of ATP synthesis, influx of solute, and mitochondrial swelling (96). The mAC mediates the intrinsic pathway of apoptosis and is

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highly regulated by the Bcl-2 family of proteins. A central event in many forms of apoptosis is mitochondrial outer-membrane permeabilization (MOMP), which is produced by activation of the mAC

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with release of cytochrome c and activation of the effector pathway of apoptosis (96). Preservation of mitochondrial function and ATP production is the ultimate mechanism for the protective

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effect of IP, PC, and RP. The induced signaling cascade leads to the opening of potassium channels in the mitochondrial membrane and maintenance of the mPTP and the electrical potential of the inner

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mitochondrial membrane. Recently, reperfusion has been found to activate a series of potentially cardioprotective signaling pathways which together have been termed the “reperfusion injury salvage

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kinase” (RISK) pathway (60, 61, 97).

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RECENT CLINICAL TRIALS OF PRESERVATION OF ISCHEMIC MYOCARDIUM The identification of pre, post, and remote conditioning as well as the rediscovery of the central role of mitochondria in ischemia/reperfusion injury have generated new interest in exploring approaches to salvage myocardium and reduce or eliminate reperfusion injury using pharmacological and pathophysiological approaches (98-103). Cyclosporine was selected as a prototype for pharmacologicalinduced cardioprotection since cyclosporine inhibits the formation and opening of the mPTP by binding to CypD. In a proof-of-concept trial involving 58 patients and published in 2008, cyclosporine administered as a 2.5 mg/kg intravenous bolus at the time of PCI was found to reduce AMI size compared to placebo (104). Other small pilot studies using IP reported positive results. This led to the formation of an NIH-sponsored consortium for preclinical assessment of cardioprotective therapies (CAESAR) (105-107). Recently, however, several larger multicenter trials have reported lack of protective effect with cyclosporine and remote ischemic preconditioning (108-112). These negative results 12

ACCEPTED MANUSCRIPT highlight the difficulties of translating basic knowledge of pathobiology into effective clinical therapy and the need for continuing effort in that regard (113).

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MYOCARDIAL REPAIR AND REGENERATION

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Based on initial experimental studies in rodents indicated that exogenous stem cells can regenerate infarcted myocardium, clinical trials of stem cell therapy in patients were begun in the USA, Europe and

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elsewhere (48, 114-117). Myocardial regeneration has not been reproducibly confirmed in subsequent experimental work in rodents and large animal models. Nevertheless, clinical trials have continued with

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stem cells as the hypothesis has evolved into stem cells promoting myocardial repair by paracrine mechanisms (114-117). The trials have now included not only autologous stem cells but packaged preparations of allogeneic stem cells despite evidence that allogeneic stem cells gain immunogenicity in

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vivo (115). Systematic analysis has indicated that: 1) stem cell therapy has the capability to produce moderate improvement in global heart function in patients with acute myocardial infarction, although

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the interpretation of the outcome is complicated by substantial heterogeneity in design of the published studies and 2) stem cell therapy has had modest effects in patients with chronic heart failure (118-120).

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Increasingly, major impediments are being recognized, including ineffective homing of adult stem cells or pluripotential stem cells to the heart and lack of differentiation of these cells into functioning

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cardiomyocytes. At some point in the near future, a collective decision is needed as to whether the objective outcomes warrant continuation of clinical trials based on administration of exogenous stem

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cells on the current major scale. New paradigms and strategies are needed based on deeper understanding of the fundamental biology. One such attractive potential alternative therapeutic strategy involves stimulation of endogenous mechanisms of repair and regeneration (121-122). FUTURE DIRECTIONS Our contemporary understanding of the pathobiology of ischemic heart disease is the result of decades of basic science and clinical research. As in other fields of science, the basis for further progress begins with the identification of gaps in knowledge of the basic pathobiology of ischemic heart disease and the focus of research to gain the missing knowledge (Table 1). While prevention of IHD continues to be a goal of public health, IHD will remain a major clinical problem into the future. Basic and translational studies have clearly indicated that progress in reducing the extent of ischemic injury and reperfusion injury coupled with modulation of ventricular remodeling in surviving myocardium are of paramount importance in further reducing the morbidity and mortality of symptomatic IHD. However, the 13

ACCEPTED MANUSCRIPT difficulties in translating knowledge of basic pathobiology into new and more effective clinical approaches to salvage of ischemic myocardium and controlling remodeling remain daunting. Nevertheless, there is reason for cautious optimism that further progress can be made to reduce the

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morbidity and mortality of acute IHD and to reduce the burden of chronic ischemic heart failure. ACKNOWLEDGEMENTS

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None.

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ACCEPTED MANUSCRIPT Table 1. Major Knowledge Gaps and Future Research Directions for Ischemic Heart Disease

Gap – Reliable clinical identification of vulnerable plaques leading to ACS and understanding of

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the underlying initiating mechanisms are inadequate.

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Research Direction – Continued work is needed on non-invasive methods for distinguishing

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different types of plaques and identifying initiating mechanisms in clinical situations.

Gap – Successive generations of coronary stents have resulted in long-term patency of previously stenotic segments of coronary arteries; however, segments with drug-eluting stents

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are subject to late thrombosis and atherosclerosis.

Research Direction – Develop new strategies to retard intimal thickening due to proliferation of

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myofibroblasts and to promote endothelial regeneration.

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Gap – The progression from reversible to irreversible cardiomyocyte injury involves oncotic and apoptotic pathways, but the complex interactions are not fully understood. Research Direction – Further define these pathways while investigating possible targets for

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therapeutic interventions.

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Gap – While components of the trigger phase of ischemic preconditioning have been well established, the ultimate effector of the protective effect of preconditioning has not been

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determined.

Research Direction – Continue to investigate biochemical and molecular mechanisms of the mediator/effector phase of ischemic preconditioning.

Gap – While experimental studies have provided evidence that a number of pharmacological agents and pathophysiological interventions can exert protective effects on the evolution of myocardial infarction, application of these approaches in clinical trials have yielded generally equivocal results, including the most recent trials combining pharmacological agents and conditioning protocols. Research Direction – Continue to refine the design of clinical trials with the aim of extending proof of principle into practical clinical application for improvement in morbidity and mortality of patients with IHD. 30

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Gap – While advances in the last 50 years have resulted in major reduction in the morbidity and

chronic ischemic heart disease requiring advanced therapies.

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mortality from ACS, there has been a progressive increase in the incidence of patients with

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Research Direction – Since progression of chronic heart failure is caused by progressive pathological remodeling of the myocardium, further research is needed to gain a better

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understanding of pathological remodeling and to develop approaches to modulating its development and progression.

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Gap – While a rationale for cell-based therapy for salvage and repair of ischemic myocardium and reversal of chronic heart failure has been advanced, the clinical trials of such therapy have

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yielded only modest results particularly in relationship to consideration of return on investment. Research Direction – Develop new paradigms with a stronger experimentally grounded basis for

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continuation of cell-based therapeutic interventions.

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ACCEPTED MANUSCRIPT Funding

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ACCEPTED MANUSCRIPT

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Highlights The basic pathobiology of the relationship between unstable coronary lesions and acute coronary syndromes is discussed A synthesis is provided of the major components of the response of myocardium to ischemic injury, including: basic mechanisms of cardiomyocyte injury, determinants of myocardial infarct size, pathological remodeling, effects of reperfusion, conditioning, stunning and hibernation. The evolution of approaches to salvage of ischemic myocardium is reviewed. The status of cell-based therapy for repair of damaged myocardium is analyzed. Gaps in current knowledge are discussed in relationship to ongoing directions in research in ischemic heart disease.

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