Mechanisms of Myocardial Ischemic Injury, Healing, and Remodeling

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.