ST-Elevation Myocardial Infarction: Pathophysiology and Clinical Evolution

Acute Coronary Syndromes

Plaque disruption or erosion exposes thrombogenic core and matrix material to the blood that then produce an extensive thrombus in the infarct-related artery (see Fig. 37.1 ). An adequate collateral network that prevents necrosis from occurring can result in clinically silent episodes of coronary occlusion; in addition, many plaque ruptures are asymptomatic if the thrombosis is not occlusive. Characteristically, completely occlusive thrombi lead to extensive injury to the ventricular wall in the myocardial bed subtended by the affected coronary artery ( Fig. 37.4 ). Infarction alters the sequence of depolarization ultimately reflected as changes in the QRS-T complex. The most characteristic change in QRS that develops in most patients with STEMI is the evolution of Q waves in leads that interrogate the infarct zone. In a minority of patients with ST elevation, no Q waves develop but other abnormalities in the QRS complex occur frequently, such as diminution in R wave height and notching or splintering of the QRS (see Chapter 14 ). Patients who have ischemic symptoms without ST elevation are initially diagnosed as suffering either from unstable angina or, with evidence of myocardial necrosis, from NSTEMI.

Patients with persistent ST-segment elevation are candidates for reperfusion therapy (either catheter-based or if unavailable, pharmacologic) to restore flow in the occluded epicardial infarct-related artery. ^, Thus the 12-lead ECG remains at the center of the initial decision pathway for the management of patients with suspected ACS in order to distinguish between patients with ST elevation and those without it.

Gross Pathologic Findings

Gross alterations in the myocardium appear 6 to 12 hours after the onset of necrosis ( Fig. 37.6 ), but a variety of histochemical stains can identify zones of necrosis after only 2 to 3 hours. Subsequently, the infarcted myocardium undergoes a sequence of gross pathologic changes ( Fig. 37.7 ). Within hours of death from MI, the presence of an infarct can often be detected by immersing slices of myocardium in triphenyltetrazolium chloride (TTC), which turns noninfarcted myocardium a brick-red color due to preserved lactate dehydrogenase activity while the infarcted area remains unstained ( Fig. 37.8 ). An MI can often be identified at 12 to 24 hours as a red-blue area of discoloration caused by edema and extravasated blood. By day 7, an infarct is rimmed by a zone of granulation tissue as it eventually evolves into a fibrous scar.

On gross inspection, MI falls into two major types: transmural infarcts, in which myocardial necrosis involves the full thickness (or almost full thickness) of the ventricular wall, and subendocardial (nontransmural) infarcts, in which the necrosis involves the subendocardium, the intramural myocardium, or both, without extending all the way through the ventricular wall to the epicardium ( Fig. 37.9 ).

Occlusive coronary thrombosis appears to be much more common when the infarction is transmural and localized to the distribution of a single coronary artery (see Fig. 37.4 ). Nontransmural infarctions, however, frequently occur in the presence of severely narrowed but still patent coronary arteries, when the infarcted region has sufficient collateral circulation, or if the artery is only transiently occluded. Patchy nontransmural MI may arise secondary to fibrinolysis or PCI of an originally occlusive thrombus, with restoration of blood flow before the wavefront of necrosis has extended from the subendocardium across the full thickness of the ventricular wall ( eFig. 37.2 ).

Ultrastructural and Microscopic Findings of Ischemia

Ultrastructural changes appear within several minutes after the onset of ischemia. If reperfusion occurs, these early changes can reverse. Irreversible damage usually requires a reduction of flow to less than 10% of normal for 20 to 30 minutes. Disruption of the sarcolemma membrane is the earliest manifestation of myocyte necrosis, thus allowing the release of intracellular macromolecules (e.g., CKMB, troponin, myoglobin) into the microvasculature and lymphatics.

Histologic evaluation of MI reveals various stages of the acute injury and healing processes (see Figs. 37.6 and 37.7 and eTable 37.2 ). In experimental infarction, the earliest ultrastructural changes in cardiac muscle after ligation of a coronary artery, noted within 20 minutes, is a reduction in the size and number of glycogen granules, myofibrillar relaxation, intracellular edema, and swelling and distortion of the transverse tubular system, sarcoplasmic reticulum, and mitochondria. Changes after 60 minutes of occlusion include myocyte swelling, swelling and internal disruption of mitochondria, development of amorphous (flocculent) aggregation and margination of nuclear chromatin, and relaxation of myofibrils. After 20 minutes to 2 hours of ischemia, the changes in some cells become irreversible.

Patterns of Myocardial Necrosis

Current Concepts of the Cellular Events During Myocardial Infarction and Healing

Classic studies defined the sequence of cellular events that occur during human MI by careful histologic studies. ^, Accumulation of granulocytes characterized the first days following MI, then mononuclear phagocytes accumulated in the infarct in tissue. Granulation tissue characterized by neovascularization and accumulation of extracellular matrix (fibrosis) followed. Experimental work in mice has delineated a sequence of accumulation of subpopulations of mononuclear phagocytes. The first wave, occurring during days 1 to 3 after coronary ligation, consists of a proinflammatory subset of monocytes characterized by high proteolytic and phagocytic capacity and elaboration of proinflammatory cytokines. During a later phase (days 3 to 7), less inflammatory monocytes predominate and produce the angiogenic mediator vascular endothelial growth factor (VEGF) and the fibrogenic mediator transforming growth factor beta (TGF-β) ( Fig. 37.10 ). This highly orchestrated sequential recruitment of subpopulations of monocytes probably plays an important role in myocardial healing. The granulocytes arriving on the scene of ischemic injury function as “first responders.” They serve to initiate and amplify the acute local inflammatory response. The reactive oxygen species that they elaborate may contribute to endothelial damage, reperfusion injury, and the clinical phenomenon of “no-reflow.” Experimental evidence in mice using single cell gene expression analysis discloses considerable functional diversity in the granulocyte populations that localize in acutely ischemic tissue. The first wave of proinflammatory and phagocytically active mononuclear cells constitutes a “demolition crew” that can clear necrotic debris and pave the way for the second wave of less inflammatory monocytes, which contribute to healing by promoting the formation of granulation tissue ( Fig. 37.11 ). These “repair” monocyte/macrophages elaborate a palette of mediators that stimulate angiogenesis and extracellular matrix production by surviving myocardial stromal cells. New microvessels and fibrosis are key constituents of granulation tissue, and these processes furnish the foundation for myocardial scar formation, ventricular remodeling, and infarct healing.

The elucidation of this tightly orchestrated response to myocardial ischemic injury provides new perspectives on the pathophysiology of infarction, suggesting novel therapeutic targets to “tune” this local inflammatory response in any way that can favor salutary myocardial healing and prevent the adverse remodeling of the infarcted left ventricle associated with ischemic cardiomyopathy and poor outcomes. Experimental work has provided considerable new insight in this regard ( Fig. 37.12 ). Sympathetic nervous activation caused by the pain and anxiety associated with the ACS can have far-reaching effects on the inflammatory response in addition to the well-recognized hemodynamic alterations produced by catecholamines. Beta-adrenergic stimulation can mobilize leukocyte progenitor cells from the bone marrow. Some of these cells can feed extramedullary hematopoiesis in the spleen. This “emergency hematopoiesis” can provide the leukocytes that participate in myocardial healing. In mice, mobilization of a preformed pool of proinflammatory monocytes from the spleen depends in part on the role of angiotensin in signaling. This experimental observation may provide a mechanistic understanding of the ability of angiotensin-converting enzyme (ACE) inhibitors to combat adverse remodeling of the ischemic left ventricular (LV) myocardium. In addition to catecholamines, proinflammatory cytokines released during ACS can promote hematopoiesis and amplify the inflammatory response in the evolving infarct. In mice, interleukin (IL)-1β can mobilize precursors of leukocytes from the bone marrow. Inhibition of this proinflammatory cytokine does not change the size and experimental infarction but limits the decrement in contractile function in the infarcted ventricle. This example illustrates how modulation of the inflammatory response in ischemic myocardium might influence the healing process.

Another insight bolstered by experimental work is the concept that inflammation in the myocardium can ignite inflammatory activity in remote atherosclerotic plaques, predisposing them to disrupt and provoke thrombosis. Such “echoes” of myocardial inflammation in plaques themselves may explain some of the early recurrent coronary events in patients with ACS. Moreover, this observation provides some mechanistic understanding of clinical observations that coronary atherosclerotic plaques remote from the culprit lesion exhibit inflammatory activation not only in the non–infarct-related artery, but also in other arterial beds, such as the carotid circulation. In mice, dampened leukocyte recruitment follows second infarction in a different territory. Thus, altered inflammatory responses, perhaps due to epigenetic changes, or “trained immunity” can also accompany a recurrent ACS. ^,

Although much of the information in Fig. 37.12 emerged from murine experiments, imaging observations in humans lend credence to their clinical applicability. Uptake of the glucose analogue ¹⁸ F-deoxyglucose (FDG) monitors metabolic activity. Patients with ACS show increased uptake of FDG in bone marrow and in the spleen compared to stable patients. These observations support the clinical translatability of the mouse experiments that revealed bone marrow activation following coronary artery ligation and boosted inflammatory processes in the spleen. Indeed, those with increased splenic FDG uptake appear to have a greater risk for recurrent events. Thus a “cardiosplenic axis” of inflammatory signaling likely operates in humans and mice, furnishing new mechanistic insight into the pathogenesis of MI and uncovering novel therapeutic targets.

Modification of Pathologic Changes by Reperfusion

Early reperfusion of the myocardium evolving from ischemia to infarction (i.e., within 15 to 20 minutes) can prevent necrosis. Beyond this early stage, the number of salvaged myocytes—and therefore the amount of salvaged myocardial tissue (area of necrosis/area at risk)—relates directly to the duration of coronary artery occlusion, the level of myocardial oxygen consumption, and collateral blood flow (see Fig. 37.9 ). Reperfused infarcts typically show a mixture of necrosis, hemorrhage within zones of irreversibly injured myocytes, coagulative necrosis with contraction bands, and distorted architecture of cells in the reperfused zone ( eFig. 37.3 ). Reperfusion of infarcted myocardium accelerates the washout of leaked intracellular proteins, thereby producing an exaggerated and early peak value of substances such as cardiac-specific troponin T and I or the MB fraction of creatine kinase (CK-MB) (see later).

While all patients who achieve reperfusion as soon as possible to preserve viable, but at risk, myocardium, the reperfusion of tissue perfusion can induce arrhythmias and potential for “reperfusion injury,” which has been estimated to account for up to 50% of the ultimate infarct size. The physiology of reperfusion injury is likely multifactorial and includes release of cytotoxic mitochondrial content, myocyte hypercontractility due to Ca ²⁺ excess, reactive oxygen species, leukocyte aggregation, and platelet and complement activation. Pathologic findings of reperfusion injury include widespread myocardial hemorrhage and contraction bands.

Coronary Anatomy and Location of Infarction

Approximately 90% of STEMI cases will have a total occlusion of the infarct-related vessel on initial angiogram. Spontaneous fibrinolysis of the thrombotic occlusion can occur in the period following the onset of MI and may account for some of the cases when no thrombosis is identified, but STEMI without any angiographically evident coronary disease is an increasingly recognized separate entity discussed below.

A STEMI with transmural necrosis typically occurs distal to an acutely totally occluded coronary artery with thrombus superimposed on an eroded or ruptured plaque (see Fig. 37.4 ). Yet, total occlusion of a coronary artery does not always cause MI. Collateral blood flow and other factors, such as the level of myocardial metabolism, presence and location of stenoses in other coronary arteries, rate of development of the obstruction, and quantity of myocardium supplied by the obstructed vessel, all influence the viability of myocardial cells distal to the occlusion.

Studies of patients in whom STEMI ultimately develops after having undergone coronary angiography at some time before its occurrence have helped clarify the extent of coronary disease before infarction. Although high-grade stenoses more frequently lead to STEMI than do less obstructive lesions, STEMI can result from sudden thrombotic occlusion at the site of disruption of previously noncritically stenosed plaque. When collateral vessels perfuse an area of the ventricle, an infarct may occur at a distance from a coronary occlusion. For example, following gradual obliteration of the lumen of the right coronary artery (RCA), collateral vessels arising from the left anterior descending coronary artery (LAD) can keep the inferior wall of the left ventricle viable. Later, an occlusion of LAD may cause infarction of the distal inferior wall.

Collateral Circulation in Acute Myocardial Infarction

Patients with occlusive CAD frequently have a particularly well-developed coronary collateral circulation, especially those with reduction of the luminal cross-sectional area by more than 75% in one or more major vessels; patients with chronic hypoxia, as occurs in severe anemia, chronic obstructive pulmonary disease (COPD), and cyanotic congenital heart disease; and those with LV hypertrophy ( Fig. 37.5 and Chapter 36 ).

The magnitude of coronary collateral flow is a principal determinant of the infarct size. Indeed, patients with abundant collateral vessels may have totally occluded coronary arteries without evidence of infarction in the distribution of that artery; thus, survival of myocardium distal to such occlusions depends largely on collateral blood flow. ^, Even if the collateral perfusion existing at the time of coronary occlusion does not prevent infarction, it may still confer benefit by preventing the formation of LV aneurysms. The presence of a high-grade stenosis (90%), possibly with periods of intermittent total occlusion, probably permits the development of collateral vessels that remain only as potential conduits until a total occlusion occurs or recurs. Total occlusion then brings these channels into full operation. Patients with angiographic evidence of collateral formation have improved angiographic and clinical outcomes after MI.

Myocardial Infarction with Nonobstructive Coronary Arteries

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is defined as the evidence of MI (positive cardiac biomarker and corroborative clinical evidence of infarction due to ischemia) with angiographically normal or near-normal coronary arteries (the absence of obstructive CAD on angiography [i.e., no coronary artery stenosis ≥50%] in any potential infarct-related artery), and no other explanation for the presentation. It is estimated to be present in 5% to 10% of patients presenting with MI. The term MINOCA encompasses a variety of vascular and myocardial conditions that until recently, were poorly defined using standard electrocardiographic, angiographic, and imaging modalities. With greater sensitivity in techniques such as intravascular imaging (e.g., intravascular ultrasound [IVUS] and optical coherence tomography [OCT]) and magnetic resonance imaging (MRI), the underlying causes of MINOCA can be identified in a majority of patients. Coronary artery spasm, plaque erosion or rupture, and coronary dissection are common MINOCA etiologies affecting the epicardial arteries, as are plaque erosion and plaque rupture not discerned by standard angiography, whereas the two most common myocardial or microvascular mimickers of MI are acute myocarditis (see Chapter 55 ) and acute stress (takotsubo) cardiomyopathy. In one study of 301 women with MINOCA, an ischemic etiology was identified in 63.8% of women, a nonischemic etiology in 20.7%, and no mechanism in just 15.5% ( eFig. 37.4 ). Based on these findings, MINOCA can include thrombotic-mediated ischemia and infarcts (Type 1 MI) or oxygen supply and demand mismatch infarcts (type 2 MI).

Compared to patients with atherosclerotic-mediated MI, patients with MINOCA tend to be younger, and more often female, black Maori or Pacific race, or Hispanic, with relatively few coronary risk factors except a history of cigarette smoking. One third of patients with MINOCA present with STEMI. Usually, they have no history of angina pectoris before the infarction. These patients do not generally have a prodrome before infarction, but the clinical, laboratory, and electrocardiographic features of STEMI otherwise resemble those present in the overwhelming majority of patients with STEMI, who have classic obstructive atherosclerotic CAD. MINOCA should not be considered a final diagnosis per se, but rather a descriptive concept, or “working diagnosis” that should prompt more extensive evaluation to elucidate the underlying etiologies, which may then lead to distinct treatments such as antiplatelet therapy, statins, calcium channel blockers, or inhibitors of renin-angiotensin-aldosterone system (RAAS) based on the ultimate diagnosis ( Fig. 37.13 ).

In general, patients who have survived STEMI without evidence of significant CAD have a smaller infarct sizes better long-term outlook than those with atherosclerotic-mediated STEMI; in-hospital mortality is approximately 60% lower, and 1-year mortality, 40% lower. However, the subsequent risk for patients presenting with MINOCA is largely based on the underlying etiology and comorbidities and more recent observation.al data suggest the outcomes are similar to patients with atherosclerotic MI. ^{, ,}

Nonatherosclerotic Causes of Acute Myocardial Infarction

Numerous pathologic processes other than atherosclerosis can involve the coronary arteries and result in STEMI (see Table 37.3 ).

Embolic/Thrombotic coronary arterial occlusions can result from embolization into a coronary artery. The causes of coronary embolism are numerous: infective endocarditis and nonbacterial thrombotic endocarditis (see Chapter 80 ), prolapsed mitral valve, or myxoma, mural thrombi, prosthetic valves, neoplasms, air introduced at cardiac surgery, and calcium deposits from manipulation of calcified valves at surgery. In situ thrombosis of coronary arteries can occur secondary to chest wall trauma or hypercoagulable states.

Spontaneous coronary artery dissection (SCAD), once thought to be a relatively rare event, is identified more frequently now with greater utilization of intracoronary imaging and may account for 25% to 33% of MIs in women younger than 50 years old. ^, The prevalence is much lower in men. The underlying cause is felt to be a medial dissection or rupture in the vasa vasorum, often in the setting of some physical or emotional stress in patients with some predisposition, that leads to intramural hemorrhage and subsequent coronary occlusion by the hematoma itself or a dissection flap. Initial triage and evaluation of patients with suspected SCAD should follow standard ACS algorithms. A clear dissection flap and thrombosis may be visible at angiography, but often there is only an intramural hematoma, which can be mistaken for vasospasm or an atherosclerotic plaque unless intracoronary imaging is used. SCAD is categorized angiographically into three or four types based on the lesion characteristics ( eFig. 37.5 ). Revascularization strategies for SCAD diverge from standard ACS recommendations. Conservative management with oral and IV antithrombotic therapy alone is recommended if coronary flow is preserved because of high rates of PCI-related complications. Revascularization with PCI or coronary artery bypass grafting (CABG) should be considered for occlusive lesions with ongoing ischemia, shock, or associated arrhythmias, recognizing a higher risk of complications.

Rarer causes include syphilitic aortitis, which can produce marked narrowing or occlusion of one or both coronary ostia, whereas Takayasu arteritis can result in obstruction of the coronary arteries. Necrotizing arteritis, polyarteritis nodosa, mucocutaneous lymph node syndrome (Kawasaki disease), systemic lupus erythematosus (see Chapter 97 ), and giant cell arteritis can cause coronary occlusion. Therapeutic levels of mediastinal radiation can result in coronary arteriosclerosis with subsequent infarction. MI can also result from coronary arterial involvement in patients with amyloidosis (see Chapter 53 ), Hurler syndrome, pseudoxanthoma elasticum, and homocystinuria. Cocaine can cause MI in patients with normal coronary arteries, preexisting MI, documented CAD, or coronary artery spasm (see Chapter 84 ).

Additional causes MI in the setting of normal-appearing coronary arteries include (1) CAD in vessels too small to be visualized on coronary arteriography or coronary arterial thrombosis with subsequent recanalization; (2) a hematologic disorder (e.g., polycythemia vera, cyanotic heart disease with polycythemia, sickle cell anemia, disseminated intravascular coagulation, thrombocytosis, thrombotic thrombocytopenic purpura) causing in situ thrombosis in the presence of normal coronary arteries; and (3) anatomic variations, such as anomalous origin of a coronary artery, coronary arteriovenous fistula, or a myocardial bridge.

Stress (Takotsubo) Cardiomyopathy

Acute stress cardiomyopathy, also termed transient LV apical ballooning syndrome or takotsubo cardiomyopathy, typically involves transient wall motion abnormalities involving the LV apex and midventricle ( Fig. 37.14 ), although other patterns have been reported, including “reverse” takotsubo pattern. ^, This syndrome occurs in the absence of obstructive epicardial CAD and can mimic STEMI, but should not be considered a subtype of MINOCA as it has a specific pathophysiology that likely reflects neurocardiogenic myocardial stunning. With greater recognition, its incidence is rising to 15 to 30 cases per 100,000 per year. Typically, an episode of physical or psychological stress precedes the development of takotsubo cardiomyopathy, although some cases lack an evident precipitant. More than half of patients presenting with takotsubo cardiomyopathy have an active or history of a neurologic or psychiatric disorder, potentially linking neurologic-mediated vasoconstriction. Initial ECGs demonstrate substantial and often diffuse ST-segment elevation, prompting, when coupled with the typical (frequently severe) chest discomfort, the appropriate immediate referral for coronary angiography.

The proposed diagnostic criteria typically include the presence of transient regional wall motion abnormalities, frequent (but not required) preceding stressful trigger, absence of culprit CAD lesion, abnormal electrocardiographic and biomarker findings, absence of myocarditis or pheochromocytoma, and recovery of ventricular function over subsequent weeks or months ( eTable 37.3 ). One proposed ECG algorithm for differentiating stress cardiomyopathy from STEMI found that different patterns of ST elevations across the different coronary territories could distinguish stress cardiomyopathy from ACS with excellent specificity. However, this observation requires validation and should not preclude urgent catheterization to exclude acute thrombotic lesions. A clinical score (InterTAK Diagnostic Score) assigns points for female sex, physical or emotional trigger, absence of ST-segment depression, known neurologic or psychiatric disorder, and QTc prolongation that can provide good specificity for stress myopathy or ACS in patients with high and low score, respectively.

ETABLE 37.3

Diagnostic Criteria for Stress Cardiomyopathy According to Heart Failure Association of the European Society of Cardiology, Mayo Clinic Criteria, and InterTAK Diagnostic Criteria

From Medina de Chazal H, Del Buono MG, Keyser-Marcus L, et al. Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review. J Am Coll Cardiol . 2018;72(16):1955–1971.

Heart Failure Association–European Society of Cardiology Criteria

1. Transient regional wall motion abnormalities of left ventricle or right ventricle myocardium, which are frequently, but not always, preceded by a stressful trigger (emotional or physical).

2. The regional wall motion abnormalities usually ∗ extend beyond a single epicardial vascular distribution, and often result in circumferential dysfunction of the ventricular segments involved.

3. The absence of culprit atherosclerotic coronary artery disease, including acute plaque rupture, thrombus formation, and coronary dissection or other pathologic conditions to explain the pattern of temporary LV dysfunction observed (e.g., hypertrophic cardiomyopathy, viral myocarditis).

4. New and reversible electrocardiography abnormalities (ST-segment elevation, ST-segment depression, LBBB, † T wave inversion, and/or QTc prolongation) during the acute phase (3 months).

5. Significantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase.

6. Positive but relatively small elevation in cardiac troponin measured with conventional assay (i.e., disparity between the troponin level and the amount of dysfunctional myocardium present). ‡

7. Recovery of ventricular systolic function on cardiac imaging at follow-up (3–6 months). §

International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)

1. Patients show transient || left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or midventricular, basal, or focal wall motion abnormalities. Right ventricular involvement can be present. Besides these regional wall motion patterns, transitions between all types can exist. The regional wall motion abnormality usually extends beyond a single epicardial vascular distribution; however, rare cases can exist where the regional wall motion abnormality is present in the subtended myocardial territory of a single coronary artery (focal Takotsubo syndrome). ¶

2. An emotional, physical, or combined trigger can precede the Takotsubo syndrome event, but this is not obligatory.

3. Neurologic disorders (e.g., subarachnoid hemorrhage, stroke/transient ischemic attack, or seizures) as well as pheochromocytoma may serve as triggers for Takotsubo syndrome.

4. New ECG abnormalities are present (ST-segment elevation, ST-segment depression, T wave inversion, and QTc prolongation); however, rare cases exist without any ECG changes.

5. Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain natriuretic peptide is common.

6. Significant coronary artery disease is not a contradiction in Takotsubo syndrome.

7. Patients have no evidence of infectious myocarditis. ¶

8. Postmenopausal women are predominantly affected.

Revised Mayo Clink Criteria

1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular midsegments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always present #

2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture ∗∗

3. New electrocardiographic abnormalities (either ST-segment elevation and/or T wave inversion) or modest elevation in cardiac troponin

4. Absence of pheochromocytoma or myocarditis

BNP , B type natriuretic peptide; LBBB , left bundle branch block; LV , left ventricular; NT-proBNP , N-terminal pro-B-type natriuretic peptide.

∗ Acute, reversible dysfunction of a single coronary territory has been reported.

† Left bundle branch block may be permanent after Takotsubo syndrome but should also alert clinicians to exclude other cardiomyopathies. T wave changes and QTc prolongation may take many weeks to months to normalize after recovery of LV function.

‡ Troponin-negative cases have been reported but are atypical.

§ Small apical infarcts have been reported. Bystander subendocardial infarcts have been reported, involving a small proportion of the acutely dysfunctional myocardium. These infarcts are insufficient to explain the acute regional wall motion abnormality observed.

|| Wall motion abnormalities may remain for a prolonged period of time or documentation of recovery may not be possible. For example, death before evidence of recovery is captured.

¶ Cardiac magnetic resonance imaging is recommended to exclude infectious myocarditis and diagnosis confirmation of Takotsubo syndrome.

# There are rare exceptions to these criteria, such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory.

∗∗ It is possible that a patient with obstructive coronary atherosclerosis may also develop stress cardiomyopathy. However, this is very rare in our experience and in the published data, perhaps because such cases are misdiagnosed as an acute coronary syndrome. In both of the above circumstances, the diagnosis of stress cardiomyopathy should be made with caution, and a clear stressful precipitating trigger must be sought.

The etiology of stress cardiomyopathy is not clear, but neurally activated or circulating catecholamine-mediated microvascular dysfunction, as well as myocardial stunning and injury, play important roles. Neuroimaging suggests increased blood flow in the hippocampus, brainstem, and basal ganglia in patients with stress cardiomyopathy. Central activation of these areas stimulates activation of brainstem noradrenergic neurons and other stimulatory neuropeptides, which with intense stress, may induce direct toxic effects on the epicardial and microvascular function. Elevated levels of circulating catecholamines (as opposed to neurally mediated stimulation) may lead to similar dysfunction. Most patients with stress cardiomyopathy will recover ventricular function rapidly, although more than 20% of patients do suffer inhospital complications, including heart failure (HF), arrhythmias, and death, at rates similar to patients with ACS. ^{, ,}

Systolic Function

On interruption of antegrade flow in an epicardial coronary artery, the zone of myocardium supplied by that vessel immediately loses its ability to shorten and perform contractile work ( Fig. 37.15 ). Four abnormal contraction patterns develop in sequence: (1) dyssynchrony, or dissociation of the time course of contraction of adjacent segments, (2) hypokinesis, or a reduction in the extent of shortening, (3) akinesis, or cessation of shortening, and (4) dyskinesis, paradoxical expansion, and systolic bulging. Hyperkinesis of the remaining normal myocardium initially accompanies dysfunction of the infarct. The early hyperkinesis of the noninfarcted zones probably results from acute compensation, including increased activity of the sympathetic nervous system and the Frank-Starling mechanism. A portion of this compensatory hyperkinesis is ineffective work because contraction of the noninfarcted segments of myocardium causes dyskinesis of the infarct zone. The increased motion of the noninfarcted region subsides within 2 weeks of infarction, during which some degree of recovery often occurs in the infarct region as well, particularly if reperfusion of the infarcted area occurs and myocardial stunning diminishes.

Patients with STEMI may also have reduced myocardial contractile function in noninfarcted zones. This finding may result from previous obstruction of the coronary artery supplying the noninfarcted region of the ventricle and loss of collaterals from the freshly occluded infarct-related vessel, a condition termed ischemia at a distance . Conversely, the development of collaterals before STEMI occurs may allow greater preservation of regional systolic function in an area of distribution of the occluded artery and improvement in the LV ejection fraction (EF) early after infarction (see Fig. 37.5 ). ^,

If a sufficient quantity of myocardium undergoes ischemic injury (see Fig. 37.9 ), LV pump function becomes depressed; cardiac output, stroke volume, blood pressure (BP), and peak dP/dt decline; and end-systolic volume increases. The degree to which end-systolic volume increases is perhaps the most powerful hemodynamic predictor of mortality following STEMI. Paradoxical systolic expansion of an area of ventricular myocardium further decreases LV stroke volume. ^, As necrotic myocytes slip past each other, the infarct zone thins and elongates, especially in patients with large anterior infarcts, thereby leading to expansion of the infarct (see later). In some patients a vicious circle of dilation begetting further dilation ensues. Inhibitors of the RAAS can limit the degree of ventricular dilation, which depends closely on infarct size, patency of the infarct-related artery, and RAAS activation, even in the absence of symptomatic LV dysfunction. With time, edema and ultimately fibrosis via mechanisms previously discussed (see Fig. 37.7 ) increase the stiffness of the infarcted myocardium back to and beyond preinfarct values. Increasing stiffness in the infarcted zone of myocardium improves LV function because it prevents paradoxical systolic wall motion (dyskinesia).

The likelihood of clinical symptoms developing correlates with specific parameters of LV function. The earliest abnormality is ventricular stiffness in diastole (see later), which occurs with infarcts involving only a small portion of the left ventricle. When the abnormally contracting segment exceeds 15% of the myocardium, the EF may decline, and LV end-diastolic pressure and volume may increase. The risk for the development of physical signs and symptoms of LV failure also increases in proportion to increasing areas of abnormal LV wall motion. Clinical HF accompanies areas of abnormal contraction exceeding 25%, and loss of more than 40% of the LV myocardium usually leads to cardiogenic shock, often fatal.

Unless extension of the infarct occurs, some improvement in wall motion takes place during the healing phase, with recovery of function occurring in initially reversibly injured (stunned) myocardium (see Fig. 37.9 and eFig. 37.2 ). Regardless of the age of the infarct, patients who continue to demonstrate abnormal wall motion involving 20% to 25% of the left ventricle will probably manifest hemodynamic signs of LV failure, with its attendant poor prognosis for long-term survival.

Diastolic Function

The diastolic properties of the left ventricle change in ischemic and infarcted myocardium (see Chapter 46, Chapter 47, Chapter 51 ). These alterations are associated with a decrease in the peak rate of decline in LV pressure (peak—dP/dt), an increase in the time constant of the fall in LV pressure, and an initial rise in LV end-diastolic pressure. Over several weeks, end-diastolic volume increases, and diastolic pressure begins to fall toward normal. As with impairment of systolic function, the magnitude of the diastolic abnormality appears to relate to the size of the infarct.

Circulatory Regulation

Patients with STEMI have an abnormality in circulatory regulation. The process begins with an anatomic or functional obstruction in the coronary vascular bed that results in regional myocardial ischemia and, if the ischemia persists, in MI. If the infarct is sufficiently large, it depresses overall LV function such that LV stroke volume declines and filling pressure increases. In the setting of acute MI, the relative reduction in stroke volume may be greater when compared to the reduction in EF because the ventricle has not dilated. A marked depression in LV stroke volume ultimately lowers aortic pressure and, together with increased LV end-diastolic pressure, further reducing coronary perfusion pressure. This condition may intensify myocardial ischemia and thereby initiate a vicious cycle (see Fig. 37.15 ), leading to cardiogenic shock, which occurs in 5% to 8% of patients with STEMI. ^,

Local myocardial injury leads to systemic inflammation due to the release of cytokines that contribute to the vasodilation and decreased systemic vascular resistance. The inability of the left ventricle to empty normally also increases left-sided preload; that is, it dilates the well-perfused, normally functioning portion of the left ventricle. This compensatory mechanism tends to restore stroke volume to normal levels, but at the expense of a reduced EF. Dilation of the left ventricle also elevates ventricular wall tension, because Laplace law dictates that at any given arterial pressure, the dilated ventricle must develop higher wall tension. This increased afterload not only depresses LV stroke volume but also elevates myocardial oxygen consumption, which in turn intensifies the myocardial ischemia. When regional myocardial dysfunction is limited and the function of the remainder of the left ventricle is normal, compensatory mechanisms—especially hyperkinesis of the nonaffected portion of the ventricle and an appropriate increase in heart rate—sustain overall LV function. Ventricular dilation also exacerbates functional mitral regurgitation due to tethered chordae and poor coaptation of the leaflets. If a large portion of the left ventricle ceases to function, pump failure ensues.

Infarct Expansion

An increase in the size of the infarcted segment, known as infarct expansion , is defined as “acute dilation and thinning of the area of infarction not explained by additional myocardial necrosis.” Infarct expansion results from a combination of slippage between muscle bundles, which reduces the number of myocytes across the infarct wall, disruption of normal myocardial cells, and destruction of extracellular matrix within the necrotic zone. Infarct expansion involves thinning and dilation of the infarct zone before the formation of a firm, fibrotic scar. The degree of infarct expansion appears to be related to preinfarction wall thickness, with existing hypertrophy possibly protecting against infarct thinning.

On a cellular level, the degree of expansion and worsening remodeling depends on the intensity of the inflammatory response to the necrotic cells. Suppression of cytokine expression and stimulation may minimize the degree of inflammation and thus final infarct size. ^{, , ,}

The apex, the thinnest region of the left ventricle, is particularly vulnerable to infarct expansion. Infarction of the apex secondary to LAD occlusion causes the radius of curvature at the apex to increase, thereby exposing this normally thin region to a marked elevation in wall stress.

Infarct expansion associates with both higher mortality and a higher incidence of nonfatal complications, such as HF and ventricular aneurysm. Infarct expansion is best recognized by elongation of the noncontractile region of the ventricle on echocardiography or CMR. When the expansion is severe enough to cause symptoms, the most characteristic clinical findings are deterioration of systolic function, new or worsening pulmonary congestion, and development of ventricular arrhythmias.