Evolution of Concepts Regarding Mechanisms of Myocardial Infarction
Historical Perspective
The scientific study of the mechanisms of myocardial infarction (MI) occurred surprisingly recently. Heberden published his strikingly contemporary description of angina pectoris in 1772. The very first article in the predecessor of the New England Journal of Medicine , published in 1812, described a North American case of angina pectoris that came to autopsy. The author, John Warren, concluded that because the coronary arteries were enlarged, they were “not essentially connected with angina pectoris; and, therefore…not the cause of the disease.” In contrast, British observers previously proposed an association between “ossification” of the coronary arteries and angina pectoris based on anecdotal autopsy observations.
Although physicians from the time of Morgangni and Corvisart and the great nineteenth century German pathologists described cardiac aneurysms or “fatty degeneration,” the link among angina pectoris, coronary artery disease, and MI came together only at the beginning of the 20th century. The Russian physicians Obrastzow and Straschesko articulated the connection between coronary thrombosis and prolonged angina pectoris. In 1912, James Herrick described the survival of individuals with coronary thrombosis, a situation that was previously considered invariably fatal. Samuel A. Levine, a cardiologist at Boston’s Peter Bent Brigham Hospital (currently Brigham and Women’s Hospital), in his 1929 monograph on “Coronary Thrombosis” reviewed the connection between coronary artery disease and MI. Levine published a report of two cases of coronary thrombosis, including one diagnosed antemortem in 1918 that clearly connected this pathological finding with MI ( Figure 4-1 ). The advent of electrocardiography in the early part of the 20th century also helped clarify the entity of MI by providing a noninvasive method of detection of myocardial injury, ischemia, and infarct. Herrick’s 1942 monograph on the history of cardiology highlighted the confusion that previously prevailed with regard to the acute coronary syndromes (ACS) and their pathogenesis. He stated, “It was long before it was realized that the Ariadne thread that guided one through the maze of angina pectoris, infarct, rupture, certain forms of pericarditis, and of acute and chronic heart failure was disease of the coronary artery.”
As late as the 1970s, controversy still brewed regarding the causality of coronary thrombosis in MI. The ascendancy of selective coronary arteriography heightened interest in coronary vasospasm as a pathogenic process that led to myocardial ischemia. The introduction of calcium channel blockers as pharmacologic tools to treat vasospasm spurred this interest. The advent of fibrinolytic agents and their success in restoring coronary flow in some patients with ST-elevation MI (STEMI) brought thrombosis to the forefront as a pathological mechanism for MI.
In evaluating the current state of knowledge put forth in this chapter, readers should reflect that this history illustrates the degree to which pathophysiological constructs depend on the tools of the time, and how concepts evolve as new methodologies emerge. Today’s tools likely similarly constrain our vision, and the synthesis we provide here will doubtless require revision as we learn more.
The Concept of Mutability of Myocardial Infarction: Oxygen Supply and Demand Balance, Reperfusion, and Remodeling
As late as the 1970s, most regarded MI as an “all or none” event. Individuals transitioned from apparent good health or stable angina to acute MI suddenly, as if struck by lightning. Treatment focused on symptom relief and did not encompass efforts to modify the infarction, then considered completed at presentation. In the late 1950s to 1960s, rigorous physiologic investigations delineated the factors that determine the myocardial requirements for oxygen. This area of inquiry provided a scientific basis for conceiving of myocardial ischemia as an imbalance between oxygen supply and demand. Some of the determinants of oxygen requirements seemed modifiable. The frequency, force of contraction (inotropic state), and afterload contributed to myocardial oxygen demand. This recognition led to the exploration of carotid sinus stimulation and intervention that reduced blood pressure and heart rate as a treatment for angina pectoris. Implantation of a carotid sinus nerve stimulator could provide relief from angina pectoris. These early efforts represented pioneering developments in device therapy.
The introduction of β-adrenergic blocking agents in the 1960s provided a pharmacologic tool for manipulating myocardial oxygen requirements (see Chapter 13 ). Blocking β-adrenergic stimuli could both lower heart rate and reduce the force of contraction of the left ventricle, which are two key determinants of myocardial oxygen requirements. Experimental studies in dogs with coronary artery ligation affirmed the concept that interventions that decreased myocardial oxygen requirements could limit myocardial injury following coronary artery ligation as determined by electrocardiographic, histologic, and biochemical criteria (see also Chapter 24 ). If performed with sufficient haste, coronary artery reperfusion could mitigate the consequences of coronary artery ligation in dogs.
These observations affirmed the principle of mutability of the consequences of a given coronary occlusion. Further physiologic studies on experimental MI conducted in rats disclosed a previously unrecognized aspect of the myocardial response to coronary artery ligation: expansive geometric remodeling (see Chapter 36 ). Following ligation of the left anterior descending coronary artery, the left ventricular cavity of rat hearts showed regional expansion. This consequence of coronary artery ligation also proved mutable. Pioneering observations showed that interruption of the renin-angiotensin system, as affected by administration of angiotensin-converting enzyme inhibitors, could reduce the expansive remodeling in the left ventricles of rats following coronary artery ligation. Clinical pilot observations affirmed the translatability of these results. Ultimately, large-scale clinical trials confirmed improvement in long-term outcomes in patients treated with interventions that interrupted the renin-angiotensin-aldosterone axis.
These brief summaries of bodies of work conducted in the 1970s and 1980s reveal how recent concepts regarding the mutability of MI emerged. The experimental findings, which were rapidly reduced to practice, ushered in the era of reperfusion achieved first by biologically derived fibrinolytic agents (e.g., streptokinase), thrombolytic agents derived through recombinant DNA technology (e.g., tissue plasminogen activator), and were followed by fibrinolytic agents (see Chapter 15 ). Percutaneous intervention to achieve reperfusion and “salvage” infarcting myocardium came in successive waves—percutaneous balloon angioplasty, bare metal stents, drug-eluting stents, and currently, bioabsorbable stents (see Chapter 17 ). This entire revolution in our fundamental understanding of the relationship between coronary artery occlusion and MI, the recognition of its mutability, and the translation to clinical practice occurred in a compressed time scale, only over the last three or four decades. Built on a burgeoning scientific foundation, the treatment of MI has transformed from mere symptomatic relief to pharmacologic and mechanical interventions that modify the disease and its downstream consequences, including arrhythmias and the development of heart failure (see Chapter 13 ).
New Insights into the Mechanisms of Coronary Thrombosis
Understanding of the mechanisms of coronary thrombosis that most often lead to MI has evolved hand-in-hand with the evolution of our concepts with regard to MI. Chapter 3 reviews in detail the current state of the pathophysiology of coronary artery thrombosis, as do authoritative reviews.
Pathological Findings During the Evolution and Healing of Myocardial Infarction
The traditional concept of the cellular sequence of events in myocardial infarction focused primarily on myocyte injury, death, and “replacement fibrosis,” which are the formation of granulation tissue, provisional scar, and ultimately, a fully healed scar. Morphologic appearance characterized various stages of myocyte injury ( Figure 4-2 and Table 4-1 ). During the first 12 hours, myocyte necrosis occurs, accompanied by edema manifested microscopically by an increased spacing between sarcomere bundles. After 12 to 24 hours, neutrophils accumulate, myocytes die, and contraction bands appear. In the ensuing days, myocyte death continues, and mononuclear phagocytes begin to engulf the remains of dying cells, particularly near the border zone of the infarct. After the first week, granulation tissue begins to form, characterized by neoangiogenesis and extracellular matrix accumulation. After several weeks, a well-organized collagenous extracellular matrix replaces the functioning myocardium in the center of the infarct.
| MONOCYTE SUBTYPE | Proteolysis | Phagocytosis | Inflammation | Fibrosis | Angiogenesis |
|---|---|---|---|---|---|
| Ly6C high CD14 ++ CD16 − | High | High | High | Less | Less |
| Ly6C low CD14 + CD16 + | Less | Less | Less | More | More |
In the current era, many patients with ACS undergo reperfusion, altering this classical sequence of events that characterizes infarct healing. Reperfusion can salvage myocardial tissue in a manner that depends on the time of reestablishing blood flow following the onset of ischemia (see Chapter 13 ). Reperfused regions of infarcts can show accentuation of hemorrhage. Reperfusion can also hasten the death of irreversibly injured myocytes and accentuate contraction band formation. Even when intervention reestablishes epicardial flow, microvascular dysfunction can cause distal microvascular occlusion, yielding the “no reflow” phenomenon (see Chapter 24 ).
The Current Era: The Role of Inflammation in the Evolution and Healing of Myocardial Infarction
The remarkable revolutions in understanding and treating MI, as recounted previously, emerged from application of classical physiologic and pharmacologic concepts and investigations. These advances, which were predicated primarily on approaches to realign a mismatch between oxygen supply and demand, accorded little weight to the response of the myocardial tissue itself. The cardiovascular community expended strenuous efforts to comprehend and modify either coronary artery perfusion or the oxygen requirements of the heart muscle. This undertaking focused on aspects of myocardial intermediary metabolism, and the regulation of the force and frequency of cardiac contraction, but largely relegated the myocardium itself to the role of bystander. Moreover, although the cardiac myocyte received detailed attention from physiologic and biochemical investigators, the other cellular constituents of the heart, with the possible exception of the endothelial cells, received relatively little attention from clinical investigators.
The last decade witnessed the dawning of an increased interest in the response of myocardial tissue to ischemic injury viewed through the lens of inflammation. The balance of this chapter reviews some of these more recent observations and concepts. Perhaps the study and clinical translation of the principles elucidated in this work will provide a platform for future advances in mitigating MI, as classical physiologic and pathological studies allowed in previous years.
Inflammatory Response to Myocardial Infarction
The first forays implicating inflammation in MI depended on careful clinical observations and classical pathological investigation. Samuel Levine in his 1929 monograph on “Coronary Thrombosis” stated, “In the great majority of acute cases of coronary thrombosis, there quickly develops a fever and leukocytosis.” He deduced “…that infarcted tissue…probably liberates toxic products that produce leukocytosis and fever,” whereas he remarked that “the leukocyte count is apt to run hand in hand with the fever.” He further noted “…a distinct increase in the polymorphonuclear ratio, which rises to 80% and sometimes even to 90%….” His careful clinical observations led him to conclude “the presence of a leukocytosis is one of the most constant findings in coronary thrombosis.”
Following Levine’s astute clinical observations, pathologists at the Boston City Hospital formally studied the sequence of inflammatory cell appearance in the infarcting myocardium based on histopathological study of human hearts postmortem. They established the well-defined sequence of microscopic changes in the previously described infarct region. In the first hours to days following presentation, polymorphonuclear leukocytes accumulated in the infarcting myocardium. After several more days, mononuclear phagocytes predominated. In the second and subsequent weeks following presentation, fibroblasts and “connective tissue” appeared ( Figure 4-3A ). These findings, together with the clinical observations that documented peripheral leukocytosis in patients who experienced MI, called attention to the potential role of inflammatory cells in MI.
Early studies also supported the involvement of inflammation in acute MI by monitoring biomarkers of the acute phase response. In particular, C-reactive protein elevation, recognized in the mid-20th century, indicated that an inflammatory state ensued following MI. Only recently have investigations suggested that inflammation may not merely follow MI as a consequence, but that inflammatory processes may modulate the tissue response to ischemic injury as discussed in the following.
In the 1980s and 1990s, many studies of ischemia–reperfusion injury focused on the recruitment of leukocytes as a potential therapeutic target, including inhibition of leukocyte adhesion molecules. Yet, these studies focused little on the effector functions of various classes of leukocytes in different phases of myocardial ischemic injury, nor did they address the origins of leukocytes that accumulate in the infarcting myocardium.
Inflammatory Cells and Infarct Healing
Experimental studies have deepened our understanding of the participation of inflammatory mechanisms in myocardial ischemic injury. Traditionally, such inquiries focused on the acute inflammatory response mediated by polymorphonuclear leukocytes. More recent studies have called attention to the participation of mononuclear phagocytes that participate not only acutely, but also in the more chronic phases of healing of myocardial injury. This work has shown that the normal myocardium possesses a resident population of these mononuclear cells, indicating a role in ongoing immune surveillance or other unknown functions.
Role of Specific Leukocyte Classes
Inflammation biologists have increasingly recognized the functional diversity of various leukocyte classes. In particular, monocytes, which are key responders to tissue injury that participate in repair processes, exist in various states that express varied palettes of mediators and functions. The polarization of leukocyte function into subsets often shows clearer demarcation in mice than in humans. In mice, a particularly proinflammatory subset of monocytes expresses high levels of a surface marker denoted as Ly-6C. Human cells with a high concentration of a cell surface marker known as CD14, with low levels of CD16, resemble the Ly-6C high monocyte subset in mice. Human monocytes that have low surface amounts of CD14 and higher concentrations of CD16 may resemble the Ly-6C low population of monocytes in mice. Table 4-2 shows the characteristics of the proinflammatory subsets of monocytes and macrophages.
