3 Coronary Heart Disease Syndromes: …extras.springer.com/2007/978-1-84628-715-2/fscommand/...667...

6 67

Coronary Heart Disease Syndromes: Pathophysiology and Clinical Recognition

James T. Willerson, Attilio Maseri, and Paul W. Armstrong

Key Points

• Atherosclerotic plaque fi ssuring or ulceration generally cause the development of the acute coronary artery disease syndromes.

• Vulnerable or “unstable” atherosclerotic plaques have temperature and pH heterogeneity, thin fi brous caps, infl ammatory cells primarily macrophages, and activated T cells on their surface, and an adjacent lipid pool. Some patients have multiple unstable atherosclerotic plaques simultaneously.

• Several serum markers when elevated help identify patients at increased risk for future vascular events, including C-reactive protein (CRP), CD40SL, pregnancy-associated protein, serum amyloid protein (SAP), brain natriuretic peptide (BNP), vascular cell adhesion mole-cule (VCAM), intracellular adhesion molecule (ICAM), and interleukin-6.

• Unstable angina and non-ST segment elevation myocar-dial infarction (NSTEMI) are associated with atheroscle-rotic plaque fi ssuring or ulceration, adherence of platelets at the same sites, the accumulation of thromboxane A2, serotonin, adenosine diphosphate (ADP), thrombin, tissue factor, oxygen-derived free radicals, and endothelin promoting growth of the thrombus and dynamic vaso-constriction with transient (unstable angina or NSTEMI)

or permanent coronary artery occlusion (ST segment elevation MI, STEMI).

• The functional absence or diminished effect of nitric oxide (NO), tissue-type plasminogen activator (t-PA), and prostacyclin at sites of vascular injury contributes to dynamic thrombosis, vasoconstriction, fi broprolifera-tion, and infl ammation at sites of coronary artery athero-sclerosis and plaque fi ssuring and ulceration.

• Unstable angina, NSTEMI, and STEMI represent a con-tinuum of thrombosis and vasoconstriction in that unstable angina is often caused by transient and recurrent coronary artery thrombosis and vasoconstric-tion, NSTEMI by slightly more prolonged but still usually transient thrombosis and vasoconstriction or subtotal coronary artery occlusion, and STEMI by prolonged and usually permanent coronary artery occlusion.

• Power failure complications of MIs occur in patients with ≥40% irreversible damage to the left ventricle (LV) and include cardiogenic shock, medically refractory con-gestive heart failure (CHF), and medically refractory arrhythmias.

• Even with relatively small MIs, mechanical problems, such as acute mitral regurgitation (MR), ventricular septal defects (VSDs), and ventricular aneurysms may lead to shock and CHF.

30

Stable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668Variant Angina (“Prinzmetal’s Angina”). . . . . . . . . . . . . 670Unstable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672

Vulnerable or Unstable Atherosclerotic Plaque . . . . . . . 672Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . 677Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691

CAR030.indd 667CAR030.indd 667 11/24/2006 11:31:00 AM11/24/2006 11:31:00 AM

6 6 8 c h a p t e r 3 0

Stable Angina

Pathophysiology

The coronary heart disease syndromes are listed in Table 30.1.

Angina pectoris is the clinical term used to describe chest discomfort resulting from a relative oxygen defi ciency in heart muscle. Heberden1 named this entity when he identifi ed a “disorder of the breast marked with strong and peculiar symptoms and considerable for the kind of danger belonging to it” associated with a “strangling and anxiety,” which he suggested should be called “angina pectoris.” This description was enlarged on by Herrick2 in 1912. Angina is usually described by the patient as a left precordial tightness or ache provoked by exercise or emotion and relieved by rest. Many patients deny they have pain, but when questioned closely, they identify chest tightness, chest pressure, or ache associated with effort, emotion, and/or cold exposure. Angina occurs when oxygen demand exceeds supply.3–7 Most indi-viduals with angina have underlying atherosclerotic coro-nary artery disease (CAD) (Figs. 30.1 and 30.2).

However, angina may also develop in some patients with ventricular hypertrophy, left ventricular (LV) outfl ow obstruc-

tion, severe aortic valvular regurgitation or stenosis, cardio-myopathy, or dilated ventricle(s) in whom severe coronary artery stenoses are not present. The explanation for angina when CAD is not present is that even normal coronary arter-ies may not adequately supply hypertrophied, dilated, or failing heart muscle with oxygen. On occasion, limited coro-nary vasodilator reserve may explain angina, especially in some patients with severe ventricular hypertrophy associ-ated with LV outfl ow obstruction, including valvular aortic

TABLE 30.1. Coronary heart disease syndromes

Stable angina pectorisUnstable angina pectorisVariant angina (“Prinzmetal’s angina”)Acute myocardial infarctionNon-Q wave or non-ST elevation (usually nontransmural infarcts)Q wave or ST elevation (usually transmural myocardial infarcts)

A

B

FIGURE 30.1. (A) A typical atherosclerotic plaque in which plaque has ruptured, leading to the development of coronary artery throm-bosis. Such a patient may or may not have had angina at effort before the plaque rupture and thrombosis, and may have abruptly devel-oped severe chest pain and a myocardial infarction (MI) with plaque rupture and coronary artery thrombosis. (B) The neointimal prolif-eration occurring with restenosis after coronary artery angioplasty,

leading to coronary artery luminal diameter narrowing and the need for some additional revascularization procedure is shown. Patients who develop coronary heart disease after cardiac transplan-tation also demonstrate this same alteration in their coronary arter-ies (i.e., neointimal proliferation). Native atheromas have substantial fi broproliferative alterations as well.

FIGURE 30.2. Typical narrowing and occlusion of the coronary artery by atherosclerosis in patients with unstable angina and MI. In many other patients, the severity of the left anterior descending coronary artery stenosis is less than that demonstrated in this right anterior oblique projection of the left coronary artery by coronary arteriography.


c oron a ry h e a rt di s e a s e s y n drom e s 6 6 9

stenosis and hypertrophic obstructive cardiomyopathy, and in patients with poorly controlled systemic arterial hyper-tension.8,9 Coronary artery vasoconstriction occurring with exercise or stress may also be a contributing factor.10,11 Most humans without coronary heart disease or ventricular hyper-trophy do not develop angina with effort or stress, probably because the heart is protected from an important imbalance between oxygen supply and demand by other factors that limit physical activity, such as dyspnea and fatigue.

The predisposing pathologic alteration in coronary arter-ies responsible for angina is atherosclerosis, atherothrombo-sclerosis, and neointimal fi brous proliferation (Fig. 30.3; see also Figs. 30.1 and 30.2). The term atherothrombosclerosis describes the relative importance of each of its components, including atherosclerosis, thrombosis, and fi brosclerosis, in the development of the process that has long been called atherosclerosis, but in fact often includes evidence of throm-bosis in the progressive atherosclerotic plaque. Embolic ath-erosclerotic debris and platelet aggregates may contribute to distal coronary artery occlusion and limitation of coronary fl ow reserve (Fig. 30.3). Severe narrowing of the lumen of the coronary artery results in a decreased ability to deliver oxygen, especially when oxygen demand in the heart is increased, as with increases in heart rate, contractile state, or myocardial wall tension, or a combination of these.3–7 Therefore, stable and relatively predictable angina may develop during exercise, cold exposure, or emotional stress or after eating a large meal. Angina may also occur because of extracardiac infl uences. In particular, severe anemia or carbon monoxide exposure reduces the amount of oxygen delivered to the heart and may result in angina under condi-tions that would otherwise be well tolerated. Increases in systemic arterial pressure and consequent dilatation of the heart may result in angina. Increases in heart rate or con-tractile state, as with hyperthyroidism, pheochromocytoma, and exogenous administration or release of catecholamines, may also lead to angina. Cold exposure decreases oxygen delivery by causing coronary artery vasoconstriction and increases systemic blood pressure, ventricular wall tension, and oxygen demand.

Physical Examination/Bedside Findings

The fi ndings on physical examination in the patient with stable angina pectoris are highly variable. Sometimes, there are no localizing or suggestive physical fi ndings. Alterna-tively, associated risk factors, such as systemic arterial hypertension, hyperlipidemia, valvular heart disease, heart failure, or peripheral atherosclerosis may result in a specifi c physical fi nding, such as elevated blood pressure, a promi-nent fourth heart sound (S4), an accentuated aortic closure sound, a paradoxically split second heart sound (S2) [systemic arterial hypertension, during an episode of angina or with left bundle branch block (LBBB)], reduced peripheral pulse (i.e., carotid, femoral, or lower extremity pulse with or without bruit over the artery), murmur of aortic stenosis or mitral insuffi ciency (the most commonly associated valvular heart diseases with CAD), or a third heart sound (S3) with heart failure or rapid fi lling of the ventricle, such as occurs with moderately severe and severe aortic or mitral insuffi -ciency. The patient with coronary heart disease and stable angina may or may not have an enlarged heart, frequent

t-PAPGI2

EDRF

Platelet aggregation

Plateletattachment at site

of endothelialcell injury

Transient plateletaggregation

Mechanicalobstruction

Vasoconstriction

Mechanicalobstruction

Vasoconstriction

Release of mediators

Thromboxane A2Serotonin

Adenosine diphosphate

Thrombin

Platelet-activating factorOxygen-derivedfree radicalsTissue factorEndothelin

PGI2EDRF

+ –

FIGURE 30.3. Schematic diagram suggests probable mechanisms responsible for the conversion from chronic coronary heart disease to acute coronary artery disease syndromes. In this scheme, endo-thelial injury, generally at sites of atherosclerotic plaques and usually plaque ulceration or fi ssuring, is associated with platelet adhesion and aggregation and the release and activation of selected mediators, including thromboxane A2, serotonin, adenosine diphosphate, plate-let-activating factor, thrombin, oxygen-derived free radicals, and endothelin. Local accumulation of thromboxane A2, serotonin, platelet-activating factor, thrombin, adenosine diphosphate, and tissue factor promotes platelet aggregation. Thromboxane A2, sero-tonin, thrombin, and platelet activating factor are vasoconstrictors at sites of endothelial injury. Therefore, the conversion from chronic stable to acute unstable coronary heart disease syndromes is usually associated with endothelial injury, platelet aggregation, accumula-tion of platelet and other cell-derived mediators, further platelet aggregation, and vasoconstriction, with consequent dynamic nar-rowing of the coronary artery lumen. In addition to atherosclerotic plaque fi ssuring or ulceration, other reasons for endothelial injury include fl ow shear stress, hypertension, immune complex deposition and complement activation, infection, and mechanical injury to the endothelium as it occurs with coronary artery angioplasty, stents, and after heart transplantation. Injured endothelial cells have reduced amounts of the normally present vaso protective substances that when present prevent thrombosis, vasoconstriction, and infl am-mation, nitric oxide (NO), tissue-type plasminogen activator (t-PA), and prostacyclin (PGI2).

or complex ventricular premature beats, S4, murmur of mitral insuffi ciency, S3 moist rales, and peripheral vascular disease.

The electrocardiogram (ECG) may be normal, but it often shows ST-T-wave changes, usually ST depression and T-wave fl attening or inversion during angina. On occasion, ST-T-wave depression or inverted T waves persist for weeks or longer, presumably refl ecting chronic ischemia. The ECG


670 c h a p t e r 3 0

may also show ventricular ectopic beats or evidence of a prior Q wave myocardial infarction (MI). An echocardiogram may be normal at rest or may show regional or global wall motion abnormalities, including reduced left ventricular ejection fraction or increased LV dimensions (“ischemic cardiomyopa-thy”), consistent with myocardial ischemia or infarction, or mitral insuffi ciency. Chest x-ray may show a normal-sized or enlarged heart with or without heart failure. On occasion, the patient has coronary artery calcifi cation on the chest x-ray.

Rapid-speed computed tomography (CT) [or electron beam CT (EBCT)] often identifi es coronary artery calcifi ca-tion. Several studies12–16 have shown that coronary calcium assessment using fl uoroscopy or EBCT imaging has a sensi-tivity for signifi cant angiographic stenoses comparable with that of exercise tests when used in symptomatic patients, but the specifi city is lower. Symptomatic patients with coronary calcium have at least a fourfold increased risk of death or infarction compared with those with no calcifi cation. The fl uoroscopic fi nding of at least one calcifi ed coronary artery or the EBCT identifi cation of a coronary calcium score exceeding 100 has been shown to be predictive of the pres-ence of advanced coronary plaque and stenosis. In general, greater degrees of calcifi cation in coronary arteries are con-sistent with greater amounts of atherosclerotic plaque and more advanced coronary luminal diameter narrowing. An advantage of an assessment of coronary artery calcium is that it can be done irrespective of the patient’s ability to exercise and regardless of the presence or absence of resting electrocardiographic abnormalities. However, a valuable fi nding in the symptomatic patient is a negative EBCT study for coronary calcium. The negative predictive value of such a calcium scan for signifi cant stenosis of a major coronary artery is greater than 90%. Thus, EBCT scanning might be an appropriate fi rst test in individuals with atypical cardiac symptoms in whom the likelihood for ischemic disease is considered to be small by the responsible physician. Patients with a zero or very low calcium score (i.e., <10) may generally be reassured and further testing directed at noncardiac eti-ologies of chest pain. On the other hand, if the calcium score is consistent with moderate or severe atherosclerotic plaque development, additional cardiac evaluation, including stress testing ideally with perfusion or functional evaluation, may be indicated. We must keep in mind individual variation, however, and even in the absence of coronary artery calcifi -cation, one may have coronary heart disease as the cause of one’s chest pain. We do not recommend routine screening of patients for coronary calcifi cation.

Asymptomatic individuals differ from symptomatic patients in that the risk of subsequent morbid events is rela-tively small. Data are not conclusive regarding the ability of coronary calcifi cation in asymptomatic individuals to predict short-term coronary artery risks.12 Figure 30.4 demonstrates, however, that prevalence/risk relationships decrease with age. Although serious overprediction may occur in the young, overprediction is only moderate in the elderly. It should be stressed, however, that extensive coronary artery calcifi ca-tion does not necessarily indicate the presence of a signifi -cant coronary artery stenosis, and some patients with very advanced coronary calcium scores have no signifi cant coro-nary artery stenosis or functional abnormality on stress perfusion or LV functional analysis.

Hemodynamic monitoring typically shows increases in mean pulmonary capillary wedge pressure during angina pectoris. With the onset of myocardial ischemia, the initial hemodynamic change in the left ventricle is a decrease in myocardial compliance and an increase in stiffness. This results in a sharp increase in mean pulmonary capillary wedge pressure during angina, with a return to baseline as the angina resolves. The change in compliance is followed by ST-T wave changes on the ECG, a decline in regional systolic wall thickening, and fi nally, the development of chest pain, with this entire sequence occurring within a few seconds.

Variant Angina (“Prinzmetal’s Angina”)

Patients with variant angina pectoris (“Prinzmetal’s angina”) have angina at rest, often in the early morning hours, associ-ated with ST-segment elevation on the ECG and the presence of coronary artery spasm that causes focal obliteration of a coronary artery lumen (Fig. 30.5).17,18

In the early descriptions of typical angina, Latham19 and Osler20 suggested that this entity was due to periodic spasm of a large coronary artery. Subsequently, however, clinical studies with anatomic correlations suggested that fi xed ath-erosclerotic CAD was responsible for typical angina and MI. In 1959, Prinzmetal and coworkers21 revived interest in coronary arterial spasm when they described a group of indi-viduals with “variant angina.” The clinical features of this syndrome are distinctly different from those of typical angina.17,21–48 First, the patients described by Prinzmetal and coworkers usually had chest pain at rest rather than with physical exertion or emotional stimulation. Second, the epi-sodes of pain tended to recur at roughly the same time(s) each day, often during the early morning hours, awakening the patient from sleep. Third, the patient with variant angina usually had ST-segment elevation on the ECG recorded during chest pain (Fig. 30.5). Fourth, the episodes of chest pain were sometimes accompanied by atrioventricular block or ven-

Ca

prev

alen

ce/e

vent

ris

k ra

tio Ca prevalence/event risk

10-Yearevent risk

Age (years)25

0

2

4

6

8

10

12

35 45 55 65 750%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Ca prevalence

Ca prevalence; event risk

FIGURE 30.4. Coronary artery calcium (Ca) prevalence, 10-year event risk, and prevalence/risk ratio in asymptomatic men. Event risk and calcium prevalence are plotted against the right axis, and prevalence/risk ratio is plotted against the left axis. Prevalence/risk curve decreases with age, demonstrating serious overprediction in the young and moderate overprediction in the elderly.


c oron a ry h e a rt di s e a s e s y n drom e s 671

tricular ectopic activity, and occasionally, the patients had transient ventricular tachycardia. Finally, the chest discomfort of variant angina was quickly relieved by nitro-glycerin, after which the ST-segment elevation resolved. Prinzmetal’s patients did not undergo selective coronary arte-riography, but Prinzmetal and coworkers hypothesized that patients with variant angina had severe proximal stenoses of one or more large coronary arteries in which spasm occurred periodically. Since the original description of variant angina by Prinzmetal and coworkers, many observers21–32 have con-

fi rmed the existence of this syndrome and have shown the presence of coronary artery spasm at sites of fi xed coronary artery stenosis and in regions of the coronary vasculature where no obvious stenosis exists. In patients with clinically active coronary artery spasm, variant angina can often be induced by ergonovine maleate.33–43 Other maneuvers that have been used to produce coronary artery spasm in suscep-tible patients include hyperventilation with the administra-tion of an alkaline buffer, cold pressor testing, and the administration of methacholine, a parasympath omimetic agent, acetylcholine, or serotonin.38,41–48 We have speculated that endothelial or adventitial injury, often in association with coronary artery stenosis, leads to the accumulation of platelets and white blood cells, mononuclear cells, including mast cells, and T cells, and the release of humoral mediators, including serotonin, thromboxane A2, prostaglandin D2, thrombin, leukotrienes, platelet-activating factor, endothe-lin, or histamine, which singly or in combination may cause coronary artery spasm (see Figs. 30.3 and 30.5).49–58 Exposure of tissue factor59 and accumulation of local inhibitors of thrombolysis, such as the endogenous inhibitor of tissue plasminogen activator (PAI-1),60 and activation of procoagu-lant factors, such as factors X and Xa (Fig. 30.6),61 may also

During chest pain

Baseline recording Just before chest pain

B After nitroglycerin

Normalizationof ECG

ST segmentelevation

A Arterial spasm

Channel 2

Channel 1

Channel 2

Channel 1

A B

C D

With pain relidf

FIGURE 30.5. Top: (Inset A) Focal obliteration of the coronary artery lumen caused by coronary artery spasm at a spot marked by the arrows. (Inset B) The associated ST-segment elevation that occurs with coronary artery spasm (A–D) Continuous 24–hour Holter recording in a patient with coronary artery spasm before chest pain (A,B), as chest pain begins (B), during chest pain (C), and with pain relief (D). The T wave prominence and ST-segment eleva-tion that occur with coronary artery spasm are demonstrated. Bottom: (D) Resolution of the coronary artery spasm after adminis-tration of nitroglycerin. (Inset) Normalization of the electrocardio-gram (ECG).

VII VIIaTF

IX

VIIa/TF

VIIIa

IXa

XaX

PL

XI

XII

HKPK

XIIa

VIII

Va

Th

V

XIa

HK

Ca2+

Ca2+

PL

PL

Fibrinogen

Fibrinpolymer

Fibrinmonomer

XIIIa XIII

Cross-linkedfibrinpolymer

Ca2+

FIGURE 30.6. Schematic representation of the role of tissue factor (TF), factors IX, X, XI, XII, and VIII in the formation of thrombin (Th) and the subsequent role of thrombin in the formation of fi brin. HK, high-molecular-weight; PK, prekallikrein; PL, phospholipids; PT, prothrombin.


67 2 c h a p t e r 3 0

contribute to the development of thrombosis. This is espe-cially likely to be true when endothelial injury decreases vascular concentrations of the endogenous inhibitors of infl ammation, thrombosis, and vasoconstriction, nitric oxide, tissue plasminogen activator, and/or prostacyclin (see Fig. 30.3).53–55 It also seems highly likely that the endothe-lium-derived vasoconstrictor, endothelin, is responsible for coronary artery constriction or spasm in some patients (Fig. 30.3).53–55 Local plaque and systemic increases in catechol-amine concentrations also contribute to the development of plaque thrombosis and vasoconstriction.

Unstable Angina

Pathophysiology

Angina occurring in a crescendo pattern, with limited physi-cal activity or at rest, is known as unstable angina. The chest discomfort is typically milder than that occurring with acute MI, being described as recurrent chest or epigastric “tightness” or “pressure” and as usually “not severe” in character. Typically, the episodes of angina last less than 30 minutes; they may or may not be associated with nausea. On occasion, however, unstable angina is associated with more severe and prolonged chest pain or nausea, making its clini-cal differentiation from acute MI at the bedside diffi cult. In these situations, serial ECGs and measurement of serum creatine kinase (CK) and its relatively specifi c cardiac isoen-zyme, CK-MB, and of troponin I or T are needed to distin-guish unstable angina from acute MI. While unstable angina and non-ST segment elevation myocardial infarction (NSTEMI) both lead to ST segment fl attening or depression and T-wave fl attening or inversion (Fig. 30.7), increases in troponin I or T or of CK-MB identify the presence of myo-cardial necrosis.

Unstable angina is usually caused by a primary decrease in coronary blood fl ow and myocardial oxygen delivery occurring as a consequence of atherosclerotic plaque fi ssur-ing or ulceration.59–70 The atherosclerotic plaque fi ssuring or ulceration is followed by platelet adhesion and aggregation at the site of plaque disruption and transient thrombosis or subtotal coronary artery occlusion with dynamic vasocon-striction. Platelet adhesion occurs by platelet attachment to exposed collagen and to von Willebrand binding sites largely through platelet glycoprotein Ib receptors. Thrombosis and vasoconstriction are promoted by the local accumulation of powerful promoters of platelet aggregation and vasoconstric-tion at these same sites, including thromboxane A2, sero-tonin, adenosine diphosphate, platelet-activating factor (PAF), thrombin, oxygen-derived free radicals, tissue factor, and endothelin (see Fig. 30.3).49–58 All but endothelin promote thrombosis. Thromboxane A2, serotonin, PAF, and thrombin are also vasoconstrictors. Endothelin is a powerful vasocon-strictor. There is also a loss of the endogenous inhibitors of thrombosis and vasoconstriction, nitric oxide (NO), tissue-type plasminogen activator (t-PA), and prostacyclin at sites of vascular injury (Fig. 30.3).65–70

Unstable angina may also occur in the individual with a severe coronary artery stenosis or partially occluded coro-nary artery when myocardial oxygen demand is increased

by intense emotion, tachycardia, or systemic hypertension. Alternatively, unstable angina may occur as a result of a reduction in myocardial blood fl ow associated with severe and progressive coronary artery atherosclerosis or dynamic coronary artery constriction associated with coronary artery spasm.17,18

Vulnerable or Unstable Atherosclerotic Plaque

Pathophysiology

Figure 30.8 demonstrates the characteristics of the “vulner-able” unstable atherosclerotic plaque herein defi ned as one likely to ulcerate or fi ssure or otherwise promote platelet adherence and aggregation and vasoactive mediator accumu-lation leading to the development of thrombosis, dynamic

A

B

Subendocardial

(non-Q-wave) myocardial infarction

P P

R

R

TT

Electrocardiographic changes

of (non-Q-wave) myocardial infarction

Subendocardium

Subepicardium

Left ventricle

FIGURE 30.7. (A) Schematic diagram shows the location of myocardial necrosis with non-ST segment elevation myocardial infarction (NSTEMI) and a representation of the typical electrocar-diographic changes. (B) Typical electrocardiogram (ECG) in a patient with acute NSTEMI. With these infarcts, the ECG is unable to provide specifi c evidence of the presence of the infarct but ST-segment depression of varying magnitude and T-wave abnormali-ties, usually T-wave fl attening or inversion, often develop. The only evolution of the electrocardiographic abnormalities is a return to the normal pattern.


c oron a ry h e a rt di s e a s e s y n drom e s 67 3

Macrophages Degradation

of collagen

in fibrous

cap

Anatomy of 30% of fatal myocardial infarctions: Erosion

A

B

C

Anatomy of 60% of fatal myocardial infarctions: Rupture

EndotheliumThrombus

Thin fibrous cap

Diffuse intimal thickening

(dense collagen, sparse

smooth muscle cells)

Cholesterol,

old hemorrhage,

cell debris,

calcium

Macrophages

Proteaserelease

VCAMIntegrinreceptors

Oxidized LDL

FIGURE 30.8. (A) Potential mechanisms responsible for athero-sclerotic plaque fi ssuring and ulceration. Oxidized low-density lipo-protein (LDL) within the atherosclerotic plaque promotes the upregulation of vascular cell adhesion molecule (VCAM) and other integrins, resulting in the recruitment of infl ammatory cells, pri-marily monocytes-derived macrophages but including activated T cells and mast cells; subsequent protease release from the mononu-clear cells; and degradation of collagen in the fi brous cap, leading to its fi ssuring and ulceration. (B) Atherosclerotic plaque fi ssuring, leading to platelet adhesion and aggregation and thrombosis. (C) Atherosclerotic plaque ulceration and thrombosis.

Relative cell densityvs delta T (Celsius)12

10

8

6

4

00 1 2 3 4

Delta T (C)5

2

Rel

ativ

e ce

ll de

nsity

FIGURE 30.9. Relationship between temperature heterogeneity and infl ammatory cell presence in human carotid plaques removed at carotid endarterectomy.

Stable anginaControls

3

2.5

2

1.5

1

0.5

0Unstableangina

Acutemyocardialinfarction

Diff

eren

ce fr

om b

ackg

roun

d te

mpe

ratu

re (

°C)

FIGURE 30.10. Increased temperature of infarct-related plaques in patients with unstable angina and with acute MI compared with controls and with patients with stable angina.

vasoconstriction, and fi broproliferation. The morphologic characteristics of the unstable plaque include a thin fi brous cap, the presence of infl ammatory cells on or beneath the atherosclerotic plaque surface, and an adjacent lipid core. Casscells et al.71 have shown that such plaques in the human carotid artery have temperature heterogeneity with tempera-tures varying by 0.2° to 2°C in that part of the plaque where the infl ammation exists (Fig. 30.9). More recently, others have confi rmed these observations and shown the same tem-perature heterogeneity in vivo in human coronary arteries in patients with unstable angina and acute MI (Fig. 30.10).72 In vivo studies have shown that the temperature heterogeneity is more commonly in the 0.15° to 1°C range in the vulnerable atherosclerotic plaque. Maseri, Borst, and others73–75 have suggested that unstable atherosclerotic plaques may develop as part of widespread infl ammation and that a sub-stantial number of patients have multiple unstable plaques simultaneously.


674 c h a p t e r 3 0

1.00.3

A BAdm. Peak

valueAdm. Peak

valueAdm. Peak

valueAdm. Peak

value

2.03.04.05.06.07.0

C-R

eact

ive

prot

ein

(mg/

dL)

Ser

um a

myl

oid

a pr

otei

n (m

g/dL

)

8.09.0

10.011.012.0

2.50.3

5.07.5

10.012.515.017.520.022.525.027.530.0

Group 1 Group 2A Group 2B

Group 1 Group 2A Group 2B39.4 mg/dL

0.000 0.1 20.5 1 5 1510

Troponin T (ng/mL)

Pro

babi

lity

of d

eath

wih

in 3

0 da

ys

0.05

0.10

0.15

0.20

0.25

FIGURE 30.11. Plasma levels of C-reactive protein (A) and serum amyloid A protein (B) in patients with stable angina (group 1), in patients with unstable angina and levels of C-reactive protein <0.3 mg/dL on admission (Adm.) (group 2A), and in patients with unstable angina and levels of C-reactive protein ≥0.3 mg/dL on admission (group 2B). Circles, urgent coronary artery bypass or angioplasty; squares, cardiac death or MI. In one patient, the peak

value for serum amyloid A protein, which exceeded the values on the scale, is shown numerically and joined by a dashed line to the corresponding value on admission. The level of C-reactive protein is <0.3 mg/dL horizontal line in A) in 90% of normal subjects. The median normal level of serum amyloid A protein is 0.3 mg/dL (dashed horizontal line in B); 96% of normal subjects have levels of serum amyloid A protein <1.0 mg/dL.

FIGURE 30.12. Probability of death within 30 days according to the serum troponin T level at hospital admission. Dots represent simple estimates of mortality derived from ranges of the troponin T level that contained at least 70 patients.

FIGURE 30.13. Relative 30-day mortality risks in OPUS-TIMI 16 (A) and TACTICS-TIMI 18 (B) in patients stratifi ed by the number of elevated cardiac biomarkers.

Several studies have shown that patients with unstable angina, NSTEMI, and ST segment elevation MI (STEMI) with elevated serum C-reactive protein (CRP) levels at hospital dis-charge, elevations in serum troponin I or T at hospital admis-sion, or increases in serum interleukin-6 concentrations or of multiple biomarkers during their hospital admission have an increased risk of future coronary events, presumably refl ecting the importance of infl ammation in the instability of their unstable atherosclerotic plaques (Figs. 30.11 to 30.16).76–86,96 Increases in troponin I and T identify myocardial necrosis and possibly more extensive plaque instability, longer duration of platelet-derived thrombosis and vasoconstriction, and

p = .014

3.5

6

1.8

1

n = 67

0 1

No. of elevated cardiac biomarkers

2 3

n = 150 n = 155 n = 780

30-d

ay m

orta

lity

rela

tive

risk

1

2

3

4

5

6A

B

p = .0001

5.7

13

2.11

n = 504

0 1

No. of elevated cardiac biomarkers

2 3

n = 717 n = 324 n = 900

30-d

ay m

orta

lity

rela

tive

risk

2

4

8

6

10

12

14


c oron a ry h e a rt di s e a s e s y n drom e s 675

Cardiac troponin I (ng/mL)Risk ratio 95%confidenceinterval

Mor

talit

y at

42

days

(%

of p

atie

nts)

1.0 1.80.5−6.7

3.51.2−10.6

3.91.3−11.7

6.21.7−22.3

7.82.6−23.0_

0

1.0

831

0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 ≥9.00 to <0.4

174 148 134 50 67

1.7

3.4 3.7

6.0

7.5

1

2

3

4

5

6

7

8

FIGURE 30.14. The mortality incidence at 42 days in patients admitted to the hospital with unstable angina or NSTEMI (non-Q-wave MI) based on their initial cardiac troponin serum levels (nano-grams per milligram). The number of patients in each category is shown within each black bar.

FIGURE 30.16. Relative risks of future cardio-vascular events among those with calculated 10-year Framingham risks <10% (left) and between 10% and 20% (right).

predict the development of future coronary events, even in otherwise apparently healthy individuals. Figure 30.11 dem-onstrates that for patients with unstable angina and NSTEMIs with CRP values of 0.3 mg/dL or higher, there is an increased risk of future coronary events, including urgent coronary artery bypass surgery or angioplasty, cardiac death, or MI. Similar data have been provided for patients who have ele-vated serum fi brinogen values at hospital discharge.83

Several groups have shown the importance of increases in serum levels of troponin I as prognostic factors indicative of increased future risk for patients with ACS. Antman and colleagues,78 in a multicenter study of 1404 symptomatic patients, found a relation between mortality at 42 days and the serum cardiac troponin I levels at patient admission to the hospital (Fig. 30.14). The mortality rate at 42 days was signifi cantly higher in the 573 patients with cardiac troponin I levels of 0.4 ng/mL and greater than in the 831 patients with cardiac troponin I levels less than 0.4 ng/mL. For each increase of 1 ng/mL in the cardiac troponin I level, there was an associated signifi cant increase in the risk ratio for death,

FIGURE 30.15. Relative risks of future cardiovascular events across a full clinical range of high-sensitivity C-reactive protein (hsCRP) values. Black bars represent crude relative risks; gray bars, risk adjusted for FRS.

0<0.5

“Low risk” “Moderate risk” “High risk”

HsCRP (mg/l)

Rel

ativ

e ris

k of

futu

re c

ardi

ovas

cula

r ev

ents

0.5−1.0 1.0−2.0 2.0−3.0 3.0−4.0 4.0−5.0 5.0−10.010.0−20.0 >20

1

2

3

4

5

6

7

8

<0.5 0.5-<1.0 1.0-<3.0

hsCRP (mg/L)

3.0-<10.0 ≥10.0

0

1

2

3

4

Framingham 10-year risk <10%

Rel

ativ

e ris

k

Rel

ativ

e ris

k

Framingham 10-year risk 10% to 20%

5

<0.5 0.5-<1.0 1.0-<3.0

hsCRP (mg/L)

3.0-<10.0 ≥10.00

1

2

3

4

5

sometimes platelet emboli and occlusive disease of distal arter-ies (Figs. 30.12 and 30.13).78–86 Table 30.2 lists other biomarkers that have been shown to be predictive of future cardiovascular events (Figs. 30.14 and 30.15).87–95

It has also been shown by Sabatine et al.96 that elevations in serum troponin, CRP, and brain natriuretic peptide (BNP) each provide unique prognostic information in patients with acute coronary syndrome (ACS). A relatively simple multi-marker strategy that categorizes patients with ACS based on the number of elevated biomarkers at admission allows risk stratifi cation over a range of short- and long-term major cardiac events (Fig. 30.13).96

Berk and coworkers81 were among the fi rst to demon-strate an increase in CRP in patients with acute coronary heart disease syndromes. Subsequently, several studies, including those by Maseri and colleagues, demonstrated a poorer prognosis in patients with unstable angina who had increased serum CRP and serum amyloid-A protein values.82 Ridker and associates85 (Fig. 30.16) and Koenig and coworkers80 demonstrated that increases in serum CRP


676 c h a p t e r 3 0

after adjustment for baseline characteristics that were inde-pendently predictive of mortality, including ST-segment depression and age 65 years or older. Similar data have been provided for serum values of troponin T in patients with unstable coronary heart disease. Lindahl and associates77 found that the risk of cardiac events in these patients increased with increasing maximal levels of troponin T obtained in the initial 24 hours after admission. The lowest quartile (<0.06 μg/L) constituted a low-risk group, the second quartile (0.06 to 0.18 μg/L) an intermediate group, and the third highest quartile (≥0.18 μg/L) a relatively high-risk group with 4.3%, 10.5%, and 16% risk of either MI or cardiac death, or both, respectively. Biasucci and coworkers86 demonstrated an increased risk for future coronary events in patients whose serum interleukin-6 increased during hospital admission. Other serum markers that when elevated are associated with future vascular and myocardial events include CD40L, CD40, serum amyloid protein (SAP), pregnancy-associated protein, vascular cell adhesion molecule (VCAM), intercel-lular adhesion molecule (ICAM), and BNP (Table 30.2).96a

Stability of an atherosclerotic plaque depends largely on the structural integrity of its fi brous cap, which is composed primarily of extracellular matrix components rich in colla-gen. Available evidence supports a role for the release of matrix-degrading enzymes, that is, matrix metalloprotein-ases (MMPs) in the catabolism of the structural macromole-cules causing a dissolution of the fi brous cap of the plaque.97–103 The MMP family includes at least 19 structurally related, zincdependent enzymes that function at physiologic pH in the extracellular space. In addition, membrane-type (MT) metalloproteinases have been identifi ed that have the desig-nations MT1-MMP through MT4-MMP.

The MMPs have been broadly classifi ed into three main groups on the basis of substrate specifi city. They include the collagenases (MMP-1, -8, and -13) that degrade intact fi brillar collagens. The gelatinases (MMP-2 and -9) hydrolyze the denatured collagen fi bril and basement membrane collagen type IV. The stromelysins (MMP-3, -7, -10, and -11) have broad substrate specifi city. For some of the remaining MMPs, substrate specifi city has not yet been identifi ed.

Regulation of MMPs occurs at three levels: (1) control of the rate of gene transcription; (2) conversion of the inactive translational product, and inactive zymogen precursor, to the

active form; and (3) inactivation by a family of endogenous inhibitors known as tissue inhibitors of metalloproteinases (TIMPs).

Human peripheral blood monocytes produce little MMP, but differentiation into macrophages yields higher levels of MMP-9.97–103 Secretion of MMP-9 from macrophages can be induced by tumor necrosis factor-α, interleukin-1β, and CD40. Expression of collagenase (MMP-1) and stromelysin (MMP-3) in macrophages is regulated by certain bacterial products, including lipopolysaccharide (endotoxin) and yeast zymosan. Activated T lymphocytes may cause collagenase and stromelysin expression in the human monocytes-derived macrophages.

The MMPs are secreted from cells as inactive zymogens and require activation in the extracellular milieu before they are capable of degrading extracellular matrix molecules. Macrophage-derived reactive oxygen species activate MMP-2 and MMP-9 and thrombin activates MMP-2. The MMPs themselves, once processed from the zymogen to active form, can trigger activation of other members of the MMP family. Mast cells within atheroma may release serine proteinases that activate MMPs.

The endogenous inhibitors known as TIMPs help regu-late MMP activity under normal circumstances. Four TIMPs have been described thus far. They exhibit sequence homol-ogy and share domains of identical protein structures that consist of highly conserved N-terminal regions believed to be critical for inhibition of the enzyme.

The balance between MMP activities and their inhibi-tion by TIMPs is important in the maintenance of homeo-stasis for the extracellular matrix. Excessive MMP activity occurs in a number of disease states, including metastatic cancer, rheumatoid arthritis, and glomerulosclerosis. There is evidence that MMPs play a role in accelerated connective tissue turnover associated with degenerative diseases of vessels, including aortic aneurysms and vein graft stenoses, as well as migration of smooth muscle cells from the media to the intima after arterial injury.

Several of the MMPs and TIMPs have been found in atherosclerotic plaques,97–103 including MMP-1 (collagenase), MMP-9 (gelatinase B), and stromelysin-1 (MMP-3). Each of these has been found in the fi brous cap, the atherosclerotic lesions’ shoulders, and the base of the lipid core. MMP-7 (matrilysin) is found primarily in macrophages overlying the lipid core. A high expression of MMPs has also been detected in lipid-laden macrophages in experimental animal lesions.

Similarly, constitutive expression of TIMP-1 and -2 has been described in both normal and diseased arteries and TIMP-3 has been found in atheromas. Thus, the spatial dis-tribution of selected TIMPs within atheromas correlates with that described for MMP expression. Most of the MMPs and TIMPs in atheromas are in macrophages, thereby iden-tifying the macrophage as most likely a key participant in the regulation of the balance between synthesis and degrada-tion of extracellular matrix macromolecules in the athero-sclerotic plaque.

Available evidence suggests a probable role for metallo-proteinase release in excess of TIMP presence leading to degradation of collagen in the fi brous cap and the subsequent fi ssuring and ulceration that predisposes to unstable angina and acute MI (see Fig. 30.8). The proposed scheme includes

TABLE 30.2. Biomarkers to predict prognosis in patients with unstable angina and non-ST segment elevation myocardial infarction (NSTEMI)

C-reactive proteinBrain natriuretic peptide (BNP)CD40L and CD40MyeloperoxidasePregnancy-associated proteinSerum amyloid proteinVascular cell adhesion molecule (VCAM)Intercellular adhesion molecule (ICAM)Interleukin-6Asymmetric dimethylarginineTroponinsPhospholipase A2



the oxidation of low-density lipoprotein (LDL) within the plaque and the chemoattractant infl uence of oxidized LDL and other oxidation products to promote the expression of selected adhesion molecules, including VCAM and ICAM and the subsequent recruitment of monocyte-derived macrophages, activated T lymphocytes, and mast cells within the plaque. The release of selected MMPs in excess of their TIMP concentrations locally degrades plaque colla-gen within the fi brous cap and leads to fi ssuring and ulcer-ation of the atherosclerotic plaque. One anticipates future clinical trials with inhibitors of selected MMPs, but the redundancy within the system, that is, the number of MMPs and other proteases within plaques that are nonmetalloen-zymes, may make effective inhibition of these plaque-degrading enzymes diffi cult. Other approaches to inhibiting infl ammation and the recruitment of monocytes-derived macrophages that may be protective of atherosclerotic plaques include inhibiting macrophage homing to unstable atherosclerotic plaques using inhibitors of VCAM and ICAM104 or of antioxidants; inhibitors of selected cytokines, especially tumor necrosis factor-α; nitric oxide donors; inhibitors of nuclear factor κB (NF-κB); and marked lipid lowering with the use of medications capable of providing marked reductions in serum cholesterol and LDL, most espe-cially statins.

Acute Myocardial Infarction

Acute MI occurs when there are severe reductions in coro-nary blood fl ow and myocardial oxygen delivery for more than 20 minutes. The infarct begins on the inner wall or subendocardium of the heart and is confi ned there in the fi rst 30 minutes to 2 hours (Fig. 30.7; non-Q wave or NSTEMI); these are generally subendocardial infarcts. If the coronary artery thrombosis is transient or does not cause complete coronary artery occlusion, the infarct usually remains largely confi ned to the subendocardium (or mid-wall of the heart) and a non-Q wave or NSTEMI develops. However, if the coro-nary artery occlusion is sustained for longer periods, the myocardial necrosis progresses vertically outward toward the epicardium in the next 2 to 3 hours [“Q wave” or ST elevation infarct (STEMI)] (Fig. 30.17).

Herrick2 described acute MI caused by coronary artery thrombosis in 1912. Subsequently, the role of coronary artery thrombosis in causing MI was debated77 until studies by DeWood and colleagues105 demonstrated by coronary arteri-ography that coronary artery thrombosis is virtually always the cause of acute Q wave or STEMIs. Buja and Willerson106 confi rmed the association between thrombosis of the infarct-related coronary artery and the development of acute Q wave or STEMI by detailed clinicopathologic correlations. Ninety percent or more of STEMIs have prolonged occlusive coro-nary artery thrombosis in the infarct-related coronary artery.105–107

As noted above, STEMIs are usually caused by persistent thrombotic occlusion of a coronary artery resulting in sus-tained reductions in coronary blood fl ow and myocardial oxygen availability. Occasionally, increases in myocardial oxygen demand above the ability of a stenotic coronary artery to delivery oxygen cause MI, often NSTEMI. Such

increases in oxygen demand occur in some patients with CAD who have severe systemic arterial hypertension, sus-tained tachycardia, or both. Alternatively, sustained reduc-tions in myocardial oxygen delivery associated with severe systemic arterial hypotension may lead to MI, again usually NSTEMI. Approximately 30% of patients with NSTEMI have an occlusive thrombus in the infarct-related artery.106,108,109 Nevertheless, in most patients with NSTEMI, transient coronary artery occlusion, initiated by platelet aggregation and with associated vasoconstriction most prob-ably lasting more than 30 minutes and up to 2 hours, is present (see Figs. 30.3 and 30.7).

Local accumulation of endothelin causes marked vasoconstriction; serotonin, adenosine diphosphate, throm-bin, and endothelin are mitogens, and they likely contribute to subsequent local fi broproliferation with increases in the neointima, further narrowing the lumen of the endo-thelium-injured coronary artery.110 In 30% (or more) of patients with unstable angina and NSTEMIs, there is a rapid anatomic progression in the severity of the coronary luminal diameter narrowing, most likely associated with the inclusion of organized thrombus within the plaque and the fi broproliferation that follows plaque fi ssur-ing and ulceration.110 Reductions in fi brinolytic capability at sites of vascular endothelial injury associated with decreases in vascular tissue concentrations of prostacyclin, tissue plasminogen activating factor, and nitric oxide undoubtedly contribute to coronary artery thrombosis, vasoconstriction, and fi broproliferation at these same sites (see Fig. 30.3).33–35

We have suggested that unstable angina, NSTEMI, and STEMI represent a continuum pathophysiologically.53–55 The process begins with coronary endothelial injury, usually atherosclerotic plaque ulceration or fi ssuring. The degree of coronary artery stenosis where plaque ulceration or fi ssuring occurs may be mild or severe. Approximately half of the coronary stenoses where plaque fi ssuring or ulceration occurs are sites of less than 50% luminal diameter nar-rowing.111 We have suggested that when the platelet-fi brin thrombus and associated severe vasoconstriction persist for periods of less than 20 minutes and often recur, the clinical syndrome of unstable angina develops.53–55 However, when the reduction in coronary blood fl ow and oxygen delivery to the heart is more prolonged, lasting 30 minutes to 1 to 2 hours, a NSTEMI occurs. When the period of inadequate myocardial oxygen delivery persists for more than 2 hours, STEMI results (see Fig. 30.3).53–55 When unsta-ble angina and acute MI are viewed in this manner, it is easy to appreciate that patients with unstable angina and NSTEMI have “aborted” Q wave MIs, and therefore, they remain at risk for new infarction and its consequences in the ensuing 6 weeks.106,108,112–115 The risk for renewed unstable angina and MI persists until the endothelial injury is repaired. Other causes of endothelial injury may also lead to this same sequence of events, including endothelial injury associated with systemic arterial hypertension, fl ow shear stress, smoking, diabetes, infection, aging, immune complex deposition, substance abuse (e.g., cocaine), and the placement of a coronary artery catheter into a coronary artery, espe-cially with the interventional procedures of percutaneous transluminal coronary angioplasty (PTCA) and stent placement.53–55


67 8 c h a p t e r 3 0

A

C

Left ventricle

Subepicardium P R RT TP

P

P

R

Q QR

R

R

T

T

Electrocardiographic stages identifytransmural (Q-wave) myocardial infarction

T

T

P

P

Subendocardium

Transmural (Q-wave)myocardial infarction

II

III

aVR

aVL

aVF

I V1

V2

V2

02002

V1

V3r

V4r

V5r

V6r

400 msec

V3

V4

V5

V6

B

FIGURE 30.17. (A) Schematic diagram of the topographic location of myocardial necrosis with STEMI and the associated electrocar-diographic changes. (B) The sequential electrocardiographic altera-tions that document the development of a STEMI or Q-wave infarct, beginning with T-wave prominence (top), followed by hyperacute ST-segment elevation (middle), T-wave inversion, and the develop-ment of a signifi cant Q wave (0.04 seconds in duration) (bottom). (C) Atrial rhythm, rate 50 beats/min, Q waves in leads II, III, aVF and

V6 indicating conduction delay in the inferolateral wall, ST eleva-tion in leads II, III, aVF and 4–6, consistent with inferolateral infarc-tion infarction and right ventricular involvement. As shown by the right precordial leads, showing prominent ST segment elevation (V4r–V6r). ST depression in lead I suggests right coronary artery occlusion. Note also ST depression in leads aVR and aVL typical of acute inferior wall infarction.

Fissuring and ulceration of the plaque often (but not always) occur in the asymmetric portion or “shoulder region” with a thin fi brous cap that is lipid laden. Infl ammation at sites of thin fi brous plaques with adjacent lipid cores best predicts the vulnerable atherosclerotic plaque and one likely to fi ssure or ulcerate.59–69 Infl ammation is characterized in the unstable plaque by the accumulation of monocyte-derived macrophages, activated T cells, and mast cells. Most likely, proteases released from the infi ltrating mononuclear cells contribute to thinning of the fi brous cap through their deg-radation of collagen and subsequent atherosclerotic plaque fi ssuring and ulceration (Fig. 30.8).53,55,68,97–103,110–122

Physical Examination/Bedside Findings

The patient with unstable angina and NSTEMI and STEMI typically appears concerned. There may be no localizing fi nding or the patient may have an audible S4, cardiac enlarge-ment, congestive heart failure (CHF), acute mitral insuf-fi ciency, acute ventricular septal defect, or evidence of peripheral vascular disease.

The rest ECG between episodes of unstable angina may be normal or may show the same ST-T wave changes or prior MI found in patients with stable angina. However, often the ECG demonstrates ST-T wave changes during angina, usually



ST depression or T-wave fl attening or inversion in patients with unstable angina and NSTEMI, refl ecting alterations in myocardial perfusion of the “culprit” artery. Similar ECG changes occur in patients with unstable angina and NSTEMI, making it impossible to distinguish them electrocardio-graphically. On occasion, episodes of unstable angina and the development of NSTEMI are not associated with ST-T wave changes on the ECG, but this is unusual.

Echocardiographic fi ndings are highly variable, but they may include reversible or fi xed reductions in regional wall motion or global LV function abnormalities depending on the reversibility of ischemia, the presence of MI, and its size. In some patients, reductions in regional wall motion occur with episodes of rest angina and resolve as the angina resolves.

The chest x-ray also shows great variability in fi ndings from a normal-sized heart to cardiomegaly with CHF. Hemo-dynamic fi ndings are similar to those during angina in the patient with stable angina, that is, one expects to see an increase in mean pulmonary capillary wedge and left ven-tricular end-diastolic pressures that are dynamic and resolve as the angina disappears. Patients with angina may also develop transient mitral insuffi ciency secondary to mitral valve papillary muscle dysfunction.

Coronary artery spasm leads to abrupt and dynamic decreases in myocardial oxygen delivery (Fig. 30.5).17,18 With a primary decrease in coronary blood fl ow, there is no asso-ciation between the development of angina and exertion, and the majority of anginal episodes occur at limited activity and rest. These patients usually have little or no change in heart rate or blood pressure before the onset of pain. The pain occurs fi rst and may be followed later by increased blood pressure or heart rate.

In the patient with unstable angina, continuous electro-cardiographic monitoring often documents transient ST-segment change immediately before the onset of chest pain, either ST-segment elevation indicating transmural ischemia as a consequence of spasm in a major epicardial coronary artery or platelet-initiated transient coronary artery throm-bosis (see Figs. 30.3 and 30.5) or ST-segment depression.123–125 Most commonly, however, the patient with unstable angina has ST-segment depression when subendocardial ischemia develops. In some individuals, ST-segment alterations occur in the absence of chest pain; this is referred to as silent isch-emia.125 Silent ischemia has the same prognosis as painful episodes of ischemia (see Chapter 31).123–125

Clinical Recognition

History

The history is of utmost importance in the recognition of acute MI.1,2,126 Typically, the patient complains of severe chest or epigastric pain that lasts until analgesic medication is administered, usually 30 minutes or longer. The pain is often described as being retrosternal or left precordial, as a “heaviness,” “tightness,” or “like a weight on my chest,” and is often associated with nausea and diaphoresis. It may radiate to the back, neck, jaw, or left arm, particularly down its ulnar aspect. Occasionally, the pain exists only in the

back, jaw, left arm, or neck. The pain is usually described as the most severe the individual has ever experienced. It gradu-ally builds in severity, reaches a peak, and then recedes. Some patients with acute MIs have unstable angina for hours to days before their infarcts. It should be emphasized, however, that 10% to 20% of patients with diabetes mellitus who have MIs have “silent” (i.e., painless) ones.127–129 Silent MIs also occur in patients who develop CAD (trans-plant vasculopathy) after cardiac transplantation, occasion-ally in individuals with neuromyopathic abnormalities, and in some seemingly otherwise normal subjects. One should have a high index of suspicion in the patient who presents with new CHF, ventricular arrhythmias, hypotension, heart murmur of mitral insuffi ciency, systemic embolic events, or is resuscitated from sudden death, especially in the diabetic patient. Serial serum measurements of CK, CK-MB, and tro-ponin I or T and serial ECGs should be obtained in such patients.

Physical Examination

Patients with small MIs, particularly NSTEMIs, often have no detectable abnormality on physical examination. At the other extreme, patients with extensive damage to the left ventricle, usually those with anterior STEMIs with ≥40% irreversible injury of the LV mass, often develop “power-failure” complications of their infarcts, including cardio-genic shock, severe LV failure, or medically refractory arrhythmias (Fig. 30.18).130–134

Inspection and Palpation

The fi ndings on physical examination in patients with acute MI depend primarily on the extent of the myocardial damage. Most patients are in obvious discomfort and diaphoretic. Those with extensive myocardial damage develop a reduc-tion in systemic arterial blood pressure, ranging from mild to severe, including the development of cardiogenic shock. Cardiogenic shock is defi ned as hypotension resulting from extensive myocardial damage coexisting with evidence that the reduced blood pressure is inadequate for normal systemic perfusion, so that cool skin, mental confusion, and oliguria are usually present. Patients with extensive LV myocardial necrosis may also have an alternating pulse force (pulsus alternans) (Fig. 30.19) and frequent premature ventricular beats.

If second- or third-degree (complete) atrioventricular block with sinus rhythm is present, the patient will have intermittent “cannon” A waves in the jugular venous pulse (Fig. 30.20). Patients with atrial fi brillation do not have an A wave in the jugular venous pulse but instead have an irregularly irregular pulse. Those with important tricuspid insuffi ciency have prominent V waves in their jugular venous pulse (Fig. 30.21). Patients with right ventricular (RV) failure have an increased jugular venous pressure, and they may have hepatomegaly, right upper quadrant tenderness when acute hepatic congestion develops, ascites if the RV failure is severe, and peripheral or sacral edema.

With acute STEMI, a precordial “ectopic impulse” may sometimes be palpated over the left precordium, typically along the lower left sternal border or between the left sternal border and the apex. This impulse is caused by an increase


6 8 0 c h a p t e r 3 0

10

0Without Cardiogenic Shock During Life Cardiogenic Shock During Life

Recent

Group B Group A

Old

20

30

40

Myo

card

ial L

oss

(%)

50

60

70

80

90

FIGURE 30.18. Development of “power failure” complications of MI, including cardiogenic shock, occurs in patients with the most extensive myocardial necrosis from their infarcts.

ECG

Carotid

PCG-MA

PCG-AA

1 2 1 2

FIGURE 30.19. Heart sounds (top), carotid pulse tracing (middle), and electrocardiogram (ECG) (bottom). Pulsus alternans is shown as the alternating height in the pulse wave tracing in a woman with a dilated cardiomyopathy. AA, aortic area; MA, mitral area; PCG, phonocardiogram.

Jugularvenous pulse

A“Cannon”

A

VPB

JUG.PULSE

C

A

X

A

B

V

Y

H

1 A2P2

Fourth LSB(400 cps)

Second LSB(400 cps)

FIGURE 30.20. (A) Normal jugular (jug.) venous pulse confi gutation. Note the prominence of the A wave and that the X trough is deeper than the Y trough. Heart sounds and the ECG are shown (top). (B) A “cannon” A wave in the jugular venous pulse. Heart sounds are shown along with the ECG (top). LSB, left sternal border; VPB, ventricular premature beat.



in regional LV compliance within the area of injury, with a resultant systolic distention or bulging (dyskinesia) of the injured heart segment. Over hours to a few days after MI, the compliance of this region decreases (stiffness increases) and the systolic bulging is replaced by reduced (hypokinetic) or absent (akinetic) regional wall motion. If the systolic bulging persists, a ventricular aneurysm may be present.

Auscultation

S4’s are heard in most patients with acute and chronic CAD (Fig. 30.22), and they are usually soft and best heard with light application of the bell of the stethoscope over the middle and lower left precordium. S4 is caused by a more forceful atrial contraction against a ventricle whose compliance is reduced as a consequence of increased ventricular stiffness caused by the physiologic effects of CAD.

When the mitral valve apparatus is damaged, a murmur of mitral insuffi ciency may be audible. These murmurs have variable auscultatory characteristics; they may be ejection in quality, peaking in intensity in mid- to late systole, or they may be holosystolic (Fig. 30.23). Intermittent myocardial ischemia with transient dysfunction of the posterior papil-lary muscle of the mitral valve leads to a murmur of papillary muscle dysfunction typically associated with mild to moder-ate mitral insuffi ciency. The murmur of papillary muscle dysfunction usually begins after the fi rst heart sound (S1), peaks in mid- to late systole, and extends up to S2. It is heard at the cardiac apex and may radiate toward the left sternal border or into the axilla. If caused by intermittent myocar-dial ischemia, the murmur is transient. If caused by infarc-tion of the papillary muscle, the murmur is usually permanent. Rupture of a papillary muscle with acute MI causes severe mitral insuffi ciency and often a soft apical holosystolic murmur. However, sometimes no audible murmur occurs with a ruptured papillary muscle, even though severe mitral insuffi ciency develops. Acute mitral

v

v

v

v

vv

XX

Y

Y

Y

Y

Y

Y

aSEVERE

MODERATE

NORMAL

L R L R

A

B

1 2 3 1 2 3

a

a a

ac c

FIGURE 30.21. (A) The jugular venous pulse normally (bottom) and with moderate (middle) and severe tricuspid insuffi ciency (top). Note the marked prominence of the V wave with moderate and severe tricuspid insuffi ciency. The V wave correlates with the second heart sound (bottom, 2). The holosystolic murmur of tricuspid insuffi -ciency is also shown (bottom). Typically, it becomes louder along the lower left sternal border with inspiration. L and R, timing of left and right ventricular third heart sounds (3). Third heart sounds occur with moderately severe and severe valvular regurgitation, and those emanating from the right heart become louder with inspira-tion. (B) A preferred way to evaluate the jugular venous pulse wave-form is to examine the right external jugular vein as shown and simultaneously listen to the heart sounds, timing the A wave with the fi rst heart sound and the V wave with the second heart sound.

Carotid

Apex(25 cps)

Fifth lsb(25 cps)

SMS2

S4 S1 S3

FIGURE 30.22. Fourth heart sound (S4), third heart sound (S3), and a systolic ejection murmur (SM), representing mitral insuffi ciency. LSB, left sternal border; S1, fi rst heart sound; S2, second heart sound.


6 8 2 c h a p t e r 3 0

insuffi ciency occurs most commonly in patients with infe-rior or lateral STEMIs and in those with NSTEMIs.135–141 Similarly, those with inferior infarcts and structural damage to the tricuspid valve may develop tricuspid insuffi ciency.

Rupture of the interventricular septum occurs most com-monly in patients with acute anterior infarction, although it may also occur in the patient with an inferior MI (Fig. 30.24).142–151 The murmur caused by a ventricular septal defect (VSD) is located along the lower left sternal border, is holosystolic, and is often associated with a left sternal border systolic thrill. As pulmonary artery pressure and vascular resistance increase, the systolic murmur of a VSD becomes shorter, ultimately disappearing altogether with the develop-ment of severe pulmonary hypertension (Fig. 30.24). Func-tionally large acute VSDs (pulmonary to systolic blood fl ow of 1.5 to 1 or greater) should be closed usually by surgical intervention when CHF develops in the patient with MI; otherwise, rapidly progressive CHF and death may ensue. We recommend prompt coronary arteriography and repair of an acute VSD with the development of CHF.

A murmur of relative mitral or tricuspid insuffi ciency occurs in patients with LV or RV failure, respectively; it is the result of a spatial abnormality in the orientation of the papillary muscles of the mitral and tricuspid valves caused by marked dilatation of the left or right ventricle. The mitral and tricuspid insuffi ciency with these entities is usually mild or moderate and diminishes in severity with diuresis and unloading therapy.

Third heart sounds occur in patients with acute MIs who have ventricular fi lling pressures (LV end-diastolic pressures) of 15 mm Hg or greater and in those with moderately severe or severe mitral, aortic, or tricuspid valvular insuffi ciency (Fig. 30.22). S3’s are heard in patients with CHF and in those with rapid fi lling of the ventricles as a consequence of moder-ate or severe mitral, tricuspid, or aortic valve incompetence. S3’s may be rarely heard in some young individuals (i.e., those

PCG-PA

M1M1

M1SM

MDM

A2 A2

A2

P2 P2S3 S3

S3 M1 SMMDMOS

A2S3

PCG-MA

CAROTID

ECG

FIGURE 30.23. Use of two simultaneous phonocardiograms (PCGs) to identify heart sounds in the patient with mitral regurgitation. A loud holosystolic murmur (SM) is noted at both the pulmonary artery (PCG-PA) and the mitral area (PCG-MA). The aortic compo-nent of the second heart sound (A2) is masked by the latter part of the murmur, but it can be identifi ed as the widely transmitted sound immediately preceding the incisura of the carotid pulse tracing (arrow). In this patient, mixed mitral regurgitation and stenosis coexist and a mitral valve opening snap (OS) can be seen occurring slightly later than the second pulmonic heart sound (P2) in the cardiac cycle. A prominent third sound (S3) is seen in both PCG channels, and a mid-diastolic murmur (MDM) is present at the mitral area.

S2S2

S2S2

S2

S1S1

S1 S1 S1 E

22/11

A

PA

LSE

LSE

D 2 LICSE

B

C

FIGURE 30.24. The typical holosystolic murmur of a ventricular septal defect (VSD) and the infl uence of increasing pulmonary artery (PA) pressure on the murmur. (A) Murmur of a VSD with normal PA pressure. (B–E) The infl uence of increasing PA pressure on the murmur of a VSD shows that, with the development of severe pul-

monary hypertension, the murmur becomes shorter and ejection in timing. With severe pulmonary hypertension, the systolic murmur of a VSD disappears. E, ejection click; 2 LICS, second left intercostal spaces; LSE, lower sternal edge.



under 30 years of age) as a result of rapid fi lling of the ventricle.

S2 normally splits into two components with inspiration, the earlier aortic and the later pulmonary valve closure sound, because inspiration increases venous return to the right heart and delays pulmonary valve closure (Fig. 30.25). However, the second sound may be paradoxically split (i.e., wider splitting of the second sound during expiration) in the patient during angina pectoris, and in the patient with severe LV failure, systemic arterial hypertension, LBBB, or pacing from the right ventricle, and with the various forms of LV outfl ow obstruction, including valvular, supravalvular, and subvalvular aortic stenosis (see Fig. 30.24). The pulmonary closure sound is increased in intensity in the patient with moderately severe to severe pulmonary hypertension of any etiology.

A pericardial friction rub is detected in some patients with STEMIs and almost never in those with acute NSTEMIs. Patients with audible pericardial friction rubs are usually those with the largest MIs. If a large pericardial effusion develops, the heart sounds may be distant and the jugular venous pressure elevated. Cardiac tamponade results in the development of hypotension, pulsus paradoxus (reduction in systolic blood pressure during inspiration of more than 10 mm Hg), distant heart sounds, and an elevated jugular venous pressure. This is a life-threatening occurrence and requires the removal of the large pericardial effusion and emergent pericardiocentesis.

Bibasilar or more extensive moist rales develop in patients with LV failure. Pulmonary edema occurs with extensive MI, in those with myocardial ischemia superimposed on extensive previous MI, and in some who develop mechanical complications (acute VSDs, acute mitral insuffi ciency, or large ventricular aneurysms) as a complication of acute MI.

Myocardial Stunning and Hibernation

Transient myocardial ischemia followed by reperfusion may lead to protracted recovery of segmental ventricular func-tion, known as myocardial stunning. This is probably caused by cellular calcium overload and free radical generation.152–159 Stunned myocardial segments may contribute to the devel-

opment of CHF when the area of ischemia or infarction is large. Alternatively, persistent ischemia can lead to chronic depression of segmental ventricular function, known as myocardial hibernation, which may also contribute to CHF and can be reversed, thereby correcting severe CHF, in selected patients who undergo coronary artery revascularization.

Electrocardiographic Diagnosis

As indicated earlier, unstable angina and NSTEMIs have transient ST-T wave changes that are similar and include ST segment depression and T-wave fl attening or inversion in ECG leads refl ecting the myocardium perfused by the culprit coronary artery. With LBBB, acute anterior MI is not recog-nizable from the ECG, since the LBBB pattern simulates that of an anterior MI in the left precordial leads. However, if the LBBB pattern is otherwise altered by the presence of diminu-tive R-wave voltage, S waves, or initial Q waves in leads I, aVL, or V5 and V6, the patient may have had prior anterior and lateral MI. Inferior STEMIs can be recognized in the patient with LBBB because the evolution of Q waves in the inferior ECG leads is not altered by LBBB. Abnormal T-wave vectors reversed from the normal pattern in patients with LBBB, that is, inverted T waves in V1 to V3 or upright T waves in leads V4 to V6, may indicate anterior or lateral ischemia or infarction. In patients with prior STEMI, recognition of new injury in the same general regions of the left ventricle is dif-fi cult. Finally, with rapid electrocardiographic evolution of the MI, it may not be possible to differentiate old from new MI from the ECG alone. ST-segment elevation may also occur under other circumstances: (1) with normal early repo-larization; (2) with transient myocardial ischemia, as in Prinzmetal’s angina, or with ischemia in an area of previous MI; (3) in some individuals with chronic ventricular aneu-rysms (Fig. 30.26); (4) transiently after electrical cardiover-sion; (5) in the anterior precordial electrocardiographic leads in patients with LBBB; (6) in the anterior precordial leads in some patients with LV hypertrophy; and (7) in an occasional patient with hyperkalemia.

Although the ECG is useful in the recognition of STEMI, it does not enable one to recognize acute NSTEMI with cer-tainty. In these patients, the ECG usually demonstrates ST depression and T-wave inversion, and the only evolution is a return to baseline (Fig. 30.27; see also Fig. 30.7). Unfortu-nately, unstable angina, subendocardial ischemia, ventric-ular hypertrophy, tachycardia, severe emotion, electrolyte alterations (especially hypokalemia, hypomagnesemia, hypo-calcemia), and the use of certain medications (including cardiac glycosides) are often associated with similar electro-cardiographic changes. Indeed, bizarre and deeply inverted T-wave alterations occur in some patients with acute intra-cerebral hemorrhage. The only useful rule in the electrocar-diographic recognition of NSTEMI is that the deeper the ST-segment depression and the longer it lasts, the more likely is MI.

Serum Enzyme and Cardiac Intracellular Substance Changes

The relationship of changes in cardiac enzyme concentra-tions and other intracellular myocardial substances to the

L BBB

Normal

Expiration

A2 P2

2 21 1 2 2Inspiration

A2P2A2P2

A2P2

FIGURE 30.25. Normal and paradoxical splitting of the second heart sound are shown at top and bottom, respectively. The infl u-ence of the left bundle branch block (LBBB) to produce paradoxical splitting of the second heart sound is shown (bottom).


6 8 4 c h a p t e r 3 0

1 2 3

aVR

V1 V2 V3

V4 V5 V6

aVL aVF

FIGURE 30.26. Chest radiography (A) and corresponding ECG (B) refl ect a ventricular aneurysm. Note the high lateral bulge in the left ventricular silhouette in the chest x-ray and the persistent ST-segment elevation across the precordium (leads V1 through V6).

I

I

II

III

II III aVR

V1 V2 V3 V4 V5 V6

aVL aVF

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

03061

400 msec

A

B

FIGURE 30.27. (A) Electrocardiographic patterns seen with an acute NSTEMI. The T-wave inversion in leads II, III, and aVF and the ST-segment depression and T-wave inver-sion in the lateral precordial leads (leads V2 through V6) suggest the presence of NSTEMI. Lower: Sinus rhythm, combination of marked generalized, downloping ST depres-sion and ST elevation more in lead aVR (B) Provided by Hein J.J. Wellens and Anton Gorgels. aVR that in lead V1, indicating isch-emia or NSTEMI due to the left main stem stenosis or 3 vessel disease.



development of acute MI is shown in Figure 30.28. A previ-ously preferred enzymatic technique was the measurement of CK and, in particular, the myocardium-specifi c CK-MB isoenzyme, measured by spectrophotometry, fl uorometry, or radioimmunoassay.160–175 CK-MB usually increases in the sera of patients 2 to 3 hours after the onset of acute MI, reaches a peak at 10 to 12 hours, and returns to normal within 24 hours after the event in patients with small infarcts and in those who have reperfusion after endogenous throm-bolysis. In patients with large infarcts, and those who fail to experience reperfusion, CK and CK-MB often peak later (e.g., 18 to 24 hours after infarction) and return to normal 30 to 40 hours after the event. Stuttering infarcts, defi ned as repeated episodes of infarction with recurrent chest pain over hours to days, result in repeated elevations of serum CK and CK-MB.

Radioimmunoassay measurement of alterations in serum myoglobin concentration allows a slightly earlier recognition of acute MI, but there is no means to distinguish myoglobin release from the heart and skeletal muscle when both cardiac and skeletal muscle injury occur. Therefore, in the patient with skeletal muscle damage from trauma, intramuscular injection, recent surgery, cardioversion, heat exposure, con-sumption of alcohol in excess, or primary skeletal muscle disorders, determining the presence of MI is not possible by measurement of serum myoglobin levels. However, in the patient without skeletal muscle injury, measurement of serum myoglobin by radioimmunoassay provides a sensitive and rel-atively rapid means to detect MI within 1 to 2 hours of the event. Myoglobin is released from injured myocardial cells within 30 minutes to 2 hours of the event, peaks within 4 to 6 hours, and returns to normal values within 10 to 12 hours.

Radioimmunoassay measurement of alterations in the serum concentration of the light chain of myosin may also allow a relatively early and precise recognition of acute MI.166,167 Measurements of serum transaminase values were made in the past, but these are nonspecifi c and they are not relied on now for MI detection. Serial serum measurements

of lactic dehydrogenase (LDH) and LDH isoenzymes have also been used to recognize acute MI. There are fi ve LDH isoenzymes, and increases in LDH isoenzymes 1 and 2 are consistent with MI, such that when LDH-1 or -2 elevations represent more than 50% of the total, they are often indica-tive of an acute MI. Increases in LDH occur 18 to 30 hours after MI and usually return to normal within 48 to 72 hours. Therefore, LDH measurements allow the detection of some patients with MI who delay their hospital admission in whom it is not possible to rely on changes in CK and CK-MB for infarct detection. However, these are almost never used in contemporary practice.

Measurements of CK isoforms, as well as myoglobin, have proved useful in detecting reperfusion after thrombo-lytic therapy or release of an experimental coronary artery occlusion.169–173 The conversion of CK isoform from CKMM-1 to CKMM-2 in the peripheral circulation appears to correlate with successful reperfusion therapy. Staccato increases in serum myoglobin in the fi rst 4 to 6 hours after MI are indica-tive of reperfusion; rapid peaking of increases in serum CK and CK-MB (within 10 to 12 hours from symptom onset) are also often indicative of reperfusion of the MI.

Presently, the preferred marker of myocardial necrosis for detecting MI is a troponin. Three troponin subunits regulate muscle contraction by modulating the calcium-dependent interaction of actin and myosin: the tropomyosin-binding subunit T, the calcium-binding subunit C, and the actomyo-sin–adenosine triphosphatase (ATPase)-inhibiting subunit I. Troponin I exists in three isoforms: slow-twitch, fast-twitch, and cardiac. Cardiac troponin I (cTn-I) is the 26.5-kd isoform of the muscle subunit and is genetically and structurally distinct from that produced in extracardiac muscle.

Previous studies have shown that increases in cTn-I and cardiac troponin T (cTn-T) correlate with acute myocardial necrosis in the general population.168,174,175 Both substances are increased in the systemic circulation within 6 to 8 hours after acute MI or other forms of myocardial necrosis, and they may remain elevated for at least 2 to 3 days. However, in patients with renal failure, spurious cTn-T elevations and increases in CK-MB have been found.79 Studies have shown that cTn-I accurately predicts myocardial injury in patients with renal failure. Martin and coworkers79 evaluated 56 patients with acute or chronic renal failure or end-stage renal disease, assessing the sensitivity and specifi city of cTn-I for detecting myocardial injury in these patients. During a 6-month period, patients admitted with suspected MI were evaluated. These patients had end-stage renal disease, chronic or acute renal failure, and a mean age of 62 years. There were an equal number of males and females. Further cardiac testing, including echocardiography, stress testing, or arteri-ography, was performed at the discretion of the primary phy-sician. Increased cTn-I levels were associated with increased in-hospital mortality. The sensitivity and specifi city for CK-MB were 44% and 56%, respectively, whereas they were 94% and 100% for cTn-I. In this study, elevated cTn-I levels were associated with increased short-term mortality and an ability to risk-stratify patients with severe renal failure and myo-cardial injury. Troponin T values were slightly elevated in patients with renal disease, although not necessarily outside of the normal range. Troponin I values appeared to be more reliable in infarct detection in these patients.79

CK and CK-MB

WBCMyoglobin

ESRLDHTroponin I andTroponin T

Ele

vatio

n of

val

ue

2X

Normal0 2 4 6 8 10 12 24 48 72

Time (hrs)96 120

FIGURE 30.28. Typical changes in several substances measured in a patient with an evolving acute MI. Increases in serum myoglobin concentration are the earliest change indicative of MI. Note that the white blood cell count (WBC) rises early after infarction and that the serum creatine kinase (CK) and MB isoenzyme of CK (CK-MB) rise before the serum troponin I and T. The erythrocyte sedimenta-tion rate (ESR) and lactic dehydrogenase (LDH) rise relatively late after acute MI.


6 8 6 c h a p t e r 3 0

In patients with unstable angina and NSTEMI, elevations in CRP and troponin I or T identify patients who usually benefi t from interventional therapy, including PTCA and stent placement when the coronary anatomy allows or coro-nary artery revascularization when the coronary stenoses are very diffuse and severe.176

Myocardial Scintigraphy

Radionuclide myocardial scintigraphy techniques for identi-fi cation of acute MI can be useful.177–189 These techniques enable one to visualize the region(s) of acute MI (infarct-avid imaging technique) or to identify areas of nonreversibly decreased myocardial perfusion (myocardial perfusion imaging technique). The prototype infarct-avid imaging agent, technetium 99m (99mTc) stannous pyrophosphate, accumulates in irreversibly damaged myocardium 1 to 5 days after MI; its sensitivity in the detection of acute MIs of 3 g or larger is greater than 90% (Fig. 30.29).179,180,189

With successful reperfusion, MI may be detected within 2 to 3 hours of the event.184,185 An alternative to pyrophos-phate imaging is the use of an antimyosin antibody labeled

with technetium or iodine, which binds to myosin with myocyte membrane injury and MI.186–188 It has the same sen-sitivity in MI detection as pyrophosphate, but it does not accumulate in bone. However, neither of these approaches is used frequently now.

Thallium 201 (201Tl) and Tc-sestamibi are myocardial per-fusion imaging agents that accumulate in the myocardium in direct proportion to blood fl ow (Fig. 30.30).182,183

When used within 24 hours after acute MI, their sensi-tivities for infarct detection are approximately 90%. The size of the initial 201Tl or 99mTc-sestamibi defect after acute MI appears to have prognostic signifi cance, as do persistently abnormal pyrophosphate scintigrams,189 that is, ones that remain abnormal for 3 months or longer after MI. Large MIs, as detected by extensive perfusion defect or by pyrophosphate or antimyosin antibody uptake, and persistently abnormal pyrophosphate scintigrams, are associated with an increased risk for future coronary events and heart failure. 99mTc-sestamibi provides information similar to that of 201Tl, but

a 1b 1c

a 2b 2c

a 3b 3c

a 4b 4c

FIGURE 30.29. Various transmural MIs as evidenced by techne-tium 99m stannous pyrophosphate myocardial scintigraphy in the anterior, left anterior oblique, and left lateral imaging views. (1a–1c) Large “doughnut” anterolateral MI. (2a–2c) Inferior MI. (3a–3c) Inferolateral MI. (4a–4c) True posterior MI.

FIGURE 30.30. A thallium 201 myocardial scintigram from a patient with an acute MI in the anterior (Ant), left anterior oblique (LAO), and left lateral (LL) views. Only a portion of the interior and posterior wall of the heart are normally perfused. The anteroseptal and anterolateral aspects of the heart have marked decrease in thallium 201 perfusion, as shown by the straight arrows. RV, right ventricle (curved arrow).

Ant

LAO

RV

LL



also allows an evaluation of global and regional systolic func-tion, including systolic wall thickening.

In addition to these imaging techniques, the cardiovas-cular blood pool can be identifi ed with technetium-labeled erythrocytes to characterize the impact of acute MI on regional and global ventricular function by dynamic myocar-dial scintigraphy.190–193 This latter technique allows measure-ment of ventricular ejection fraction, ventricular volumes, regional wall motion, left-to-right shunts (i.e., VSDs), and valvular insuffi ciency, including mitral or tricuspid regurgi-tation and the identifi cation of ventricular aneurysms.

Two-dimensional (or three-dimensional) echocardio-graphic measurements can also be used to detect intramyo-cardial masses and to evaluate global and segmental ventric-ular functional alterations in patients with acute MI.194–198 Transthoracic and transesophageal two-dimensional echo-cardiography can also be used for detection of LV thrombi complicating acute MIs.196–198 Patients with acute anterior STEMIS more frequently develop LV mural thrombi acutely (10% to 40% of such individuals prior to development of reperfusion therapies), but probably less often with early reperfusion. This occurs more commonly in patients with acute STEMI than in those with NSTEMI. These patients have an increased risk for systemic embolic events, requiring that they receive anticoagulants unless there is some contra-indication. Echocardiography with Doppler, transthoracic and transesophageal, enables one to detect and estimate the severity of mitral insuffi ciency and VSDs, to identify ven-tricular aneurysms and pseudoaneurysms, and to assess the extent of wall motion abnormalities in patients with infarc-tion.199–206 Detection of these abnormalities is important, especially in patients with a low-output state, hypotension, or heart failure, since proper medical management or surgi-cal repair may save the patient’s life.

Pseudoaneurysms (false aneurysms) developing after MI (most commonly acute STEMIs) represent partial tears in the left ventricle and an immediate risk for complete rupture. They are distinguished from true aneurysms by demonstra-tion—on two-dimensional echocardiogram, angiography, radionuclide ventriculography, or magnetic resonance imaging (MRI)—of their communication with the true left ventricle by a narrow channel or neck. True LV aneurysms communicate with the LV cavity by an imperceptible pathway. False LV aneurysms rupture spontaneously and should be surgically corrected as soon as they are identifi ed. Patients at greatest risk for heart rupture after MI are those with systemic arterial hypertension who are experiencing their fi rst MIs and elderly patients. Blood pressure elevations should be prevented in patients with MIs to minimize this risk. When myocardial rupture occurs after MI, most patients die suddenly of exsanguinations or cardiac tamponade. A few develop tamponade with a sealing of the tear by a blood clot in the pericardial space. Although blood does not usually clot in the pericardial space, in the patient with extensive MI, it may clot as a consequence of the loss of segmental wall motion in the infarcted segment. Thus, continued bleeding is prevented, providing the observant physician an opportu-nity to recognize the development of an enlarging pericardial effusion with early tamponade and to intervene surgically to correct the tamponade and repair the myocardial rupture. It appears best to place these patients on cardiopulmonary

bypass and evacuate the pericardial fl uid/thrombosis while they are on bypass rather than attempting to treat the peri-cardial tamponade by pericardiocentesis before placing the patient on bypass. The classic fi nding in the patient with sudden myocardial rupture is the development of electrome-chanical dissociation (EMD), in which the patient loses blood pressure and becomes unresponsive but has continuing electrical activity on the ECG for the subsequent seconds to minutes. Electromechanical dissociation is not specifi c for myocardial rupture because it may also occur with a large anteroseptal infarct, pericardial tamponade of any etiology, and severe systemic hypoxemia or acidosis.

Differential Diagnosis

In theory, the differential diagnosis of acute NSTEMI and STEMI includes any cause of chest pain, cardiac arrhyth-mias, new systolic murmur of mitral insuffi ciency or VSD, heart failure, and sudden death. Important diagnostic considerations include (1) unstable angina, (2) Prinzmetal’s angina, (3) pericarditis, and (4) dissecting aortic aneurysm. Other diagnostic considerations, although less commonly presenting with pain classical for MI, include (1) peptic ulcer disease, (2) pancreatitis, (3) cholecystitis, (4) pulmonary embolic disease, (5) spontaneous pneumothorax, and (6) pneumonitis. Careful attention to history, physical examina-tion, relevant blood tests, ECGs, and noninvasive or invasive imaging test results usually enables one to make the correct diagnosis.

Estimation of Infarct Size

Accurate measurements of the extent of reversible and irre-versible cell damage can be useful in predicting prognosis and selecting optimal future therapy for patients. Ideally, such measurements should be relatively noninvasive, appli-cable early in the patient’s clinical course, capable of being repeated with reasonable frequency, able to provide quantita-tion of the extent of damage with various types of infarcts, and generally available. No perfect measurement of infarct size or of the extent of ischemic damage exists at present, although several methods have been used: (1) enzymatic indices of infarct size, most importantly, measurement of CK-MB enzyme release from the heart207; (2) scintigraphic measurements of infarct size, including infarct-avid scinti-graphic techniques (with 99mTc stannous pyrophosphate or antimyosin antibody)208–210 and myocardial perfusion tech-niques (201Tl or 99mTc-sestamibi and other technetium-based perfusion markers); (3) two-dimensional transthoracic or transesophageal echocardiography; and (4) dynamic myocar-dial scintigraphy to estimate abnormalities of global and segmental ventricular function, using either fi rst-pass or equilibrium techniques. Evaluation of global LV function with MRI and utilizing Gadolinium allows estimation of infarct size. Each of these techniques has its limitations, but each also provides important information concerning the location and relative size of an infarct.

Three-dimensional estimates of the extent of myocardial damage are needed for accurate scintigraphic measurements (single photon emission computed tomography) and with other imaging techniques, including three-dimensional


6 8 8 c h a p t e r 3 0

echocardiography and MRI. Distinction of reversibly (“viable” myocardium) and irreversibly injured myocardium can be made in patients by positron emission tomography (PET) imaging evaluation that combines estimates of myocardial perfusion (rubidium or other PET perfusion marker) and fl uo-rodeoxyglucose studies to identify reversibly injured myocar-dium as regions with reduced perfusion but persistent metabolic activity. Persistent metabolic activity is indicated by uptake and utilization of fl uorodeoxyglucose (indicative of reversible injury to the myocardium) even when perfusion is markedly reduced or absent. One may also demonstrate reversible wall motion abnormalities by echocardiography, radionuclide ventriculography, or MRI when potent inotropic stimuli, such as dobutamine, dopamine, or paired electrical stimulations, are used, or during low-level exercise 5 to 7 days after MI.211–220 Finally, the extent of myocardial scar may be identifi ed by MRI and estimated by a QRS scoring system.221,221a

Evaluation of Ventricular Function

Invasive and noninvasive techniques can be used to allow more precise characterization of ventricular function in patients with reduced systemic arterial blood pressure and uncertain LV functional status. Flow-directed catheters, such as the Swan-Ganz catheter, allow measurement of LV fi lling pressure without entering a systemic artery or the LV (Fig. 30.31).222

This balloon-tipped, fl ow-directed catheter can be placed in the pulmonary artery from a systemic vein (Fig. 30.31). The Swan-Ganz catheter is positioned in the pulmonary artery either with the aid of fl uoroscopy or with continuous pressure monitoring to identify the characteristic right atrial, RV, and pulmonary artery pressures. Once the catheter is in the pulmonary artery, the balloon is infl ated, facilitating the measurement of pulmonary capillary wedge pressure. In the absence of mitral valve disease, the mean pulmonary capillary wedge pressure is the same as the LV end-diastolic pressure (Fig. 30.31).

Measurement of LV fi lling pressure with the Swan-Ganz catheter enables one to differentiate hypotension caused by hypovolemia from cardiogenic shock and LV failure. Mean pulmonary capillary wedge pressures less than 12 mm Hg with hypotension occur with hypovolemia and those 15 mm Hg or higher are usually associated with cardiogenic shock and LV failure. In addition, cardiac output may be measured with the same catheter. The patient with an acute MI and shock should also have an indwelling arterial cannula placed to allow accurate measurement of and to detect moment-to-moment changes in systemic arterial pressure. The fl ow-directed pulmonary arterial catheter may also be utilized to help idealize mean pulmonary capillary wedge pressure either with volume infusion with normal saline when the patient is hypovolemic or by diuresis when the patient is hypervolemic to values of 15 to 18 mm Hg in the hypotensive patient.

Both LV and RV function after acute MI can be assessed noninvasively with either dynamic myocardial scintigraphy, echocardiography, or MRI. These methodologies facilitate measurement of ventricular ejection fraction, ventricular dimensions or volumes, and segmental wall motion. Two-dimensional echocardiography and transesophageal echocar-

diography with Doppler assessment facilitate the detection of LV thrombi, VSDs, and mitral insuffi ciency, as well as an estimation of their severity. Transesophageal echocardiogra-phy facilitates a more precise detection of small intracardiac thrombi than does transthoracic echocardiography. Three-dimensional echocardiography has been developed, and it may facilitate even more accurate characterization of sys-tolic function and detection of thrombi in the future.

Prognosis

Most patients with acute MIs who survive to reach the hos-pital and subsequently receive appropriate therapy for their MIs have a relatively uncomplicated course. However, some patients develop life-threatening complications during the fi rst 1 to 2 weeks, and others die (Table 30.3). During the early 1970s, more than 50% of patients died before reaching the hospital, primarily due to ventricular arrhythmias during the seconds or minutes after onset of chest pain. Since the

Ballooninflated

Proximallumen

RA

RA

SVC

PAThermistor and

distal lumen

I second

51015202530

mm Hg

A a

Cc

LA

PAW

V v

FIGURE 30.31. (A) Path taken by a Swan-Ganz catheter. The cath-eter is inserted into a systemic vein, threaded into the right heart, and positioned in the pulmonary artery (PA). In this location, pul-monary artery and pulmonary capillary wedge pressures and cardiac output may be measured. RA, right atrium; RV, right ventricle; SVC, superior vena cava. (B) The pulmonary artery wedge (PAW) pressure, and the A, C, and V waves in both the LA and PAW pressure wave forms.



late 1980s, emergency ambulance systems have achieved a 25% to 30% reduction in the incidence of death before hos-pitalization of patients with acute MIs and sudden cardiac arrest syndromes.223–225

Overall mortality in patients with acute MIs who reach the hospital ranges from 3% to 30%, depending on the popu-lation studied and the promptness and success of the therapy given in opening the infarct-related artery. In general, patients with anterior MIs have a higher mortality than those with inferior MIs, probably because of a greater loss of LV muscle.

Patients can be categorized into groups with differing prognoses on the basis of their initial hemodynamic mea-surements. Patients without LV failure and with a mean systolic arterial pressure of greater than 110 mm Hg, an average cardiac index greater than 2.5 L/min/m2, and a normal pulmonary capillary wedge pressure (or pulmonary artery diastolic pressure) have low mortality rates. Death in these patients is usually caused by a ventricular arrhythmia, later infarct extension, or a mechanical complication (e.g., myocardial, septal, or papillary muscle rupture).

A ruptured papillary muscle of the mitral valve leads to fulminant left heart failure with pulmonary edema and often hypotension, and the patient is typically unresponsive to diuretics and unloading interventions. This catastrophic event should be suspected when a patient with an inferior, lateral or NSTEMI abruptly develops fulminant left heart failure with a new apical murmur, often soft, of mitral insuf-fi ciency. On occasion, however, the severity of the LV failure is such that no murmur is generated. Prominent V waves are usually found in the pulmonary capillary wedge tracing by fl ow-directed catheter. An echocardiogram and Doppler eval-uation demonstrate severe mitral regurgitation and some-times a fl ail mitral leafl et. Ordinarily, the only chance for survival is immediate surgical repair or replacement of the mitral valve.

TABLE 30.3. Life-threatening complications of acute myocardial infarction

Ventricular arrhythmias (ventricular tachycardia, ventricular fi brillation or asystole)Extremely rapid atrial arrhythmias in association with extensive MI (atrial fl utter or atrial fi brillation)Heart block [second-degree (Mobitz II) or third-degree]Marked bradycardiaInfarction ≥40% of left ventricleExtensive RV infarctionAcute ventricular septal defectsAcute and severe mitral regurgitationSevere pulmonary edemaRupture of the heartSystemic and/or pulmonary emboliExtension of the MIMarkedly increased LV end-systolic volume after MIOccluded proximal LAD after anterior MI

* LAD, left anterior descending coronary artery; LV, left ventricular; MI, myocardial infarction; RV, right ventricular.

Papillary muscle dysfunction, mediated by ischemia with a transient apical systolic murmur or by infarction with a permanent apical systolic murmur, usually causes less severe mitral regurgitation, and the patient can generally be stabilized by unloading therapy with a diuretic and nitroprusside or, if needed, temporary intraaortic balloon support.

Chordae tendineae rupture is not usually caused by MI, but instead may lead to acute mitral regurgitation as a con-sequence of spontaneous rupture, in the Marfan syndrome patient, in some women with mitral valve prolapse, in patients with chest wall trauma, or secondary to trauma on the mitral valve apparatus of signifi cant valvular aortic insuffi ciency, with endocarditis, or as a consequence of acute rheumatic fever.

Acute VSDs occur primarily in the muscular septum and develop within 1 day to 2 weeks after MI, resulting in a new holosystolic murmur along the lower left sternal border, often associated with a systolic thrill in the same location and a signifi cant oxygen step-up between the right atrium and the right ventricle. The VSD places a pressure and volume load on the left and right ventricles and may result in sudden, or gradual, hemodynamic decompensation, with severe CHF, hypotension, and relentless hemodynamic deterioration. We believe that immediate surgical correction of a large VSD is indicated with the development of the earliest signs of hemo-dynamic deterioration (e.g., increased respiratory rate, tachy-cardia, hypotension). In the future, it may be possible to do this in the cardiac catheterization laboratory with a device, such as a “clam shell” occluder. Such patients are often placed on an intraaortic balloon and other unloading therapy and are usually taken to the cardiac catheterization suite for coronary arteriography and then to surgery to repair the VSD and bypass signifi cantly narrowed coronary arteries. In patients with large left-to-right shunts, 1.5 to 2.0 or greater, surgical closure of the VSD becomes mandatory to prevent the subsequent development of severe pulmonary artery hypertension. However, in the hemodynamically stable patient, VSD closure can be delayed for 4 to 6 weeks with resultant lowering of operative risk. Antibiotic prophylaxis against infective endocarditis with dental or sur-gical work is necessary in these patients, even after VSD closure.

Patients with cardiogenic shock and systolic arterial pressures of 80 mm Hg or less, decreased peripheral perfu-sion without a reversible cause, reduced mean cardiac index (<2 L/min/m2), and an increased pulmonary capillary wedge or pulmonary artery diastolic pressure (>25 mm Hg) have an increased mortality, unless the infarct-related artery can be opened by percutaneous coronary intervention (PCI) or emergent surgery within the fi rst 1 to 2 hours after the event.226 Percutaneous coronary intervention is capable of more rapid reperfusion than thrombolysis in desperately ill patients with MI and cardiogenic shock and, if the cardiac catheterization facility is available and an experi-enced team on site or close by, is the preferred means for providing rapid and potentially lifesaving reperfusion in these patients.227 Very early reperfusion, that is, within 2 hours, in patients with cardiogenic shock or severe heart failure by PCI may save the lives of more than half of these patients.227


6 9 0 c h a p t e r 3 0

Longer-term mortality after recovery from an initial MI is related to the presence of ventricular arrhythmias, the extent of myocardial damage, the age of the patient, and the LV end-systolic volume (Fig. 30.32). Persistent occlusion of the infarct-related artery, most especially the proximal left anterior descending coronary artery, is also associated with a reduced long-term survival (Fig. 30.33).

In general, if the patient is less than 50 years of age at the time of the initial MI, the annual mortality rate is approxi-mately 5% or less. If the patient is 50 years of age or older, the mortality rate is approximately doubled. If a patient sur-vives for 1 year after MI, there is a 75% chance of 5-year survival. If a patient survives for 5 years after MI, there is an approximately 50% or greater chance of 15-year survival. These numbers will improve in the coming years with exten-sive efforts at prevention of future coronary events, utilizing potent lipid-lowering, antioxidant, and antithrombotic thera-pies and with earlier reperfusion in patients with STEMI.

In-hospital and immediate posthospital complications are related directly to infarct size. When more than 40% of the LV muscle mass is irreversibly damaged and reperfusion is not accomplished by PCI or surgical revascularization within the fi rst 1 to 2 hours, one can expect power-failure complications, including cardiogenic shock, CHF, and medi-

cally refractory ventricular arrhythmias. Patients with small MIs (irrespective of the location) are less likely to experience such complications. However, a strategically located small MI may cause heart block, acute development of a VSD, or papillary muscle dysfunction or rupture resulting in acute mitral insuffi ciency. In addition, patients with multiple small MIs may ultimately develop cardiogenic shock, medi-cally refractory CHF, or medically refractory arrhythmias as a consequence of the cumulative muscle loss. Even a small MI may be associated with ventricular arrhythmias; there-fore, continuous electrocardiographic monitoring is neces-sary for at least 2 to 3 days after MI, irrespective of infarct size or clinical complications.

Accurate predictors of longer-term prognosis in patients with acute MI are needed. Serial CK measurements can be important prognostically, as patients with the largest MIs are most likely to experience cardiogenic shock, refractory CHF, or refractory ventricular arrhythmias; however, several hours to a few days are required to complete such measurements. Myocardial perfusion imaging, 201Tl, or 99mTc-sestamibi myocardial scintigraphy may be used at hospital admission to estimate the extent of the myocardial perfusion defect. Patients with the largest perfusion defects have a poorer prognosis during hospitalization and a higher mortality in the short-term follow-up. Similarly, patients with the most extensive ventricular functional abnormalities (as detected by radionuclide ventriculography, echocardiography, mag-netic resonance imaging, or angiography) and those with large anterior MIs may develop “pump failure” and impor-tant ventricular arrhythmias. Patients with anterior STEMIs who extend their infarction in hospital have increased mor-bidity and mortality.227–229

Patients with ventricular ejection fractions below 40% and those with similar ventricular dysfunction and complex ventricular ectopy (frequent ventricular premature beats, coupled ventricular premature beats, or short bursts of ven-tricular tachycardia) at the time of hospital discharge, and those with severe global and segmental ventricular dysfunc-tion or a reversible perfusion or function defect on low-level

100

90

70

80

100

90

70

80

50

60

100

Sur

viva

l (%

)

90

70

80

50

40

Years0 1 2 3 4 5 6 7

16

8 9 10

ESV ≥130 mL (n = 53)

16 ESV >130 mL (n = 53)

13 ESV ≥95 mL (n = 60)

23 ESV >95 mL (n = 60)

1221

EF ≥50%

ESV ≥55 mL (n = 186)ESV ≥55 mL (n = 1931)

EF 40 − 49%

EF <40%

60

0

5

10

15

20

25

Save Tami Weltyet ai

Kanderet ai

Eurcoop

Andersonmeta-

analysis

OpenClosed

Mor

talit

y (%

)

FIGURE 30.32. Actuarial survival curves for patients with low end-systolic volume (ESV) versus high ESV at various ejection frac-tions (EFs) after MI. In patients with left ventricular EF <50%, ESV plays a greater role in predicting survival than does left ven-tricular EF.

FIGURE 30.33. Mortality in patients with an open versus a closed infarct-related artery after MI. The presence of an open artery at discharge confers a signifi cant survival benefi t in the fi rst year after acute MI.



exercise or stress testing at the time of hospital discharge, have a relatively poor prognosis unless the infarct-related and other critically narrowed arteries can be better perfused by PCI or surgical therapy.

Remodeling of the Left Ventricle (“Infarct Expansion”)

Infarct expansion or remodeling of the infarct and peri-infarct regions refers to shape alterations in the infarct and peri-infarct areas that result from stress and strain alterations in the infarct and adjacent areas. Most likely, metalloproteinase release and alterations in myocardial wall stress related to the local infl uence of angiotensin and endothelin play a role in the remodeling process. The remodeling phenomenon causes changes in contractile patterns in the infarct and peri-infarct regions and dilatation of the heart over time.230–233a Infarct expansion or remodeling occurs primarily in patients with anterior STEMIs, in those with large MIs, in those with sys-temic arterial hypertension, in those with permanently occluded infarct-related arteries, and in older individuals. Infarct remodeling leads to increases in LV end-diastolic and end-systolic volumes and dimensions and decline in LV func-tion with a fall in LV ejection fraction in the several weeks to years after the infarct. Previous studies have demonstrated that angiotensin-converting enzyme inhibitors reduce the magnitude of the remodeling phenomenon and preserve LV function when administered hours to a few days after MI, especially in patients with anterior STEMIs.233–241 The same is likely to be true for the angiotensin receptor antagonists and the combination of angiotensin-converting enzyme inhibi-tors and angiotensin receptor antagonists. Revascularization with subsequent patency of the infarct-related artery also reduces the magnitude of post-MI remodeling. Inhibutors of matrix metalloproteinases are also being evaluated.233a

Infarct Extension

Infarct extension is the result of new MI hours to days after the original event, often associated with reocclusion of the infarct-related artery with a STEMI after thrombolytic therapy or PCI or as a consequence of increases in myocar-dial oxygen demand or relative decreases in LV regional oxygen availability, such as occur with tachycardia, severe systemic arterial hypertension, severe anemia, hypotension, or worsening CHF. Reductions in myocardial oxygen deliv-ery associated with hypotension or decreased substrate avail-ability as with hypoglycemia may extend MIs. Every effort should be made to prevent increases in myocardial oxygen demand and decreases in oxygen delivery in patients with CAD, especially those with MIs. Infarct extension is poorly tolerated hemodynamically in those with anterior and previ-ous MIs and seems to occur most commonly in those with NSTEMI and possibly in those with anterior STEMIs who are not treated with PCI or thrombolytic therapy.

Van Belle and colleagues,242 using coronary angioscopic techniques in patients with MIs, have shown that healing of the infarct-related coronary artery lesion requires more than 1 month and that an unstable yellow plaque with adherent thrombus is commonly present during that period. These fi ndings may help explain the risk for some patients with unstable angina and acute MIs to reocclude the culprit artery in this time period and the need to provide effective anti-

thrombotic therapy for at least several weeks after the event. Reclosure of the infarct-related artery is associated with a poor prognosis.

Summary

The acute coronary artery disease syndromes are usually caused by atherosclerotic plaque fi ssuring or ulceration. Patients with unstable angina and NSTEMI should be hospi-talized as an emergency in a coronary care unit. There, they should receive medications directed at preventing the stabi-lization and persistence of a thrombus and the associated vasoconstriction at the sites of fi ssured or ulcerated athero-sclerotic plaque(s) (see Chapter 27A). Patients with STEMI are treated by PCI or thrombolytic therapy acutely (see Chapters 40 and 44). There is a continuum from unstable angina to NSTEMI and STEMI that usually depends on the duration of severe coronary artery narrowing by dynamic thrombosis and vasoconstriction. When the thrombosis and associated vasoconstriction are transient and repetitive but developing and resolving within 5 to 15 to 20 minutes, one has unstable angina. When the thrombosis and associated vasoconstric-tion are more durable but persist for 30 minutes up to 2 hours before resolving, one has a NSTEMI. In some patients, a partially but not completely occlusive coronary thrombus, also causes unstable angina and NSTEMI. When the throm-bosis and associated vasoconstriction are more permanent, one has a STEMI.

Acute and longer term prognosis and best therapies, that is, medical versus interventional (PCI or coronary artery bypass graft) for patients with unstable angina and NSTEMI may be selected by measuring several biomarkers, including serum CRP, BNP, and troponin. Increases in CD40L, and CD40, serum amyloid protein, interleukin-6, myeloperoxi-dase, asymmetric dimethylarginine, VCAM, and ICAM also appear to identify patients at risk for adverse events in the future.

References

1. Heberden W. Some account of a disorder of the breast. Med Trans R Coll Phys II Lond 1786;59.

2. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912;59:2015.

3. Sarnoff SJ, Braunwald E, Welch GH Jr, Case RB, Stainsby WN, Macruz R. Hemodynamic determinants of oxygen consump-tion of the heart with special reference to the tension-time index. Am J Physiol 1958;192:148–156.

4. Rude RE, Izquierdo C, Buja LM, Willerson JT. Effects of ino-tropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the barbiturate-anesthe-tized dog. Circulation 1982;65:1321–1328.

5. Rude RE, Izquierdo C, Bush LR, Buja LM, Willerson JT. Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. II. Studies with dopamine and ouabain in the barbiturate-anesthetized dog. J Cardiovasc Pharmacol 1983;5:717–724.

6. Rude RE, Bush LR, Izquierdo C, Buja LM, Willerson JT. Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. III. Infl uences of basal heart rate. Am J Cardiol 1984;53:1688–1694.

7. Sonnenblick EH, Ross J Jr, Braunwald E. Oxygen consumption of the heart: newer concepts of its multifactorial determina-tion. Am J Cardiol 1968;22:328–336.


6 92 c h a p t e r 3 0

8. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve—a mechanism for angina pecto-ris in patients with aortic stenosis and normal coronary arter-ies. N Engl J Med 1982;307:1362–1366.

9. Marcus ML, Mueller TM, Eastham CL. Effects of short- and long-term left ventricular hypertrophy on coronary circula-tion. Am J Physiol 1981;241:H358–362.

10. Berkenboom GM, Abramowicz M, Vandermoten P, Degre SG. Role of alpha-adrenergic coronary tone in exercise-induced angina pectoris. Am J Cardiol 1986;57:195–198.

11. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayen-buehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pec-toris: reversibility by nitroglycerin. Circulation 1986;73:865–876.

12. Wexler L, Brundage B, Crouse J, et al. Coronary artery calci-fi cation: pathophysiology, epidemiology, imaging methods, and clinical implications. Circulation 1996;94:1175–1192.

13. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantifi cation of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–832.

14. Detrano R, Hsiai T, Wang S, et al. Prognostic value of coro-nary calcifi cation and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285–290.

15. Secci A, Wong N, Tang W, Wang S, Doherty T, Detrano R. Electron beam computed tomographic coronary calcium as a predictor of coronary events: comparison of two protocols. Circulation 1997;96:1122–1129.

16. Arad Y, Spadaro LA, Goodman K, et al. Predictive value of electron beam computed tomography of the coronary arteries. Circulation 1996;93:1951–1953.

17. Maseri A, Severi S, Nes MD, et al. “Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia; pathogenic mechanisms, estimated incidence and clinical and coronary arteriographic fi ndings in 138 patients. Am J Cardiol 1978;42:1019–1035.

18. Dalen JE, Ockene IS, Alpert JS. Coronary spasm, coronary thrombosis and myocardial infarction. Am Heart J 1982;104:1119–1124.

19. Latham P. Collected Works, vol 1. London: New Sydenham Society, 1876.

20. Osler W. The Lumleian lectures on angina pectoris. Lancet 1910;1:697.

21. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris. Am J Med 1959;27:375–388.

22. Hillis LD, Braunwald E. Coronary artery spasm. N Engl J Med 1978;299:695–702.

23. Silverman ME, Flamm MD Jr. Variant angina pectoris: ana-tomic fi ndings and prognostic implications. Ann Intern Med 1971;75:339–343.

24. Cheng TO, Bashour R, Kelser GA Jr, Weiss L, Bacos J. Variant angina of Prinzmetal with normal coronary arteriograms. A variant of the variant. Circulation 1973;47:476–485.

25. Wiener L, Kasparian H, Duca PR, et al. Spectrum of coronary arterial spasm: clinical, angiographic, and myocardial metabolic experience in 29 cases. Am J Cardiol 1976;38:945–955.

26. Dhurandhar RW, Watt DL, Silver MD, Trimble AS, Adelman AG. Prinzmetal’s variant form of angina with arteriographic evidence of coronary arterial spasm. Am J Cardiol 1972;30:902–905.

27. Oliva PB, Potts DE, Pluss RG. Coronary arterial spasm in Prinzmetal angina: documentation by coronary arteriogra-phy. N Engl J Med 1973;288:745–751.

28. Maseri A, Mimmo R, Chierchia S. Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest 1975;68:625.

29. Higgins CB, Wexler L, Silverman JF, Schroeder JS. Clinical and arteriographic features of Prinzmetal’s variant angina: documentation of etiologic factors. Am J Cardiol 1976;37:831–839.

30. Maseri A, Parodi O, Severi S, Pesola A. Transient transmural reduction of myocardial blood fl ow, demonstrated by thal-lium-201 scintigraphy, as a cause of variant angina. Circula-tion 1976;54:280–288.

31. McLaughlin PR, Doherty PW, Martin RP, Goris ML, Harrison DC. Myocardial imaging in a patient with reproducible variant angina. Am J Cardiol 1977;39:126–129.

32. Berman ND, McLaughlin PR, Huckell VF, Mahon WA, Morch JE, Adelman AG. Prinzmetal’s angina with coronary artery spasm: angiographic, pharmacologic, metabolic, and radionu-clide perfusion studies. Am J Med 1976;60:727–732.

33. Ricci DR, Orlick AE, Doherty PW, Cipriano PR, Harrison DC. Reduction of coronary blood fl ow during coronary artery spasm occurring spontaneously and after provocation by ergo-novine maleate. Circulation 1978;57:392–395.

34. Nelson C, Nowak B, Childs H, Weinrauch L, Forwand S. Provocative testing for coronary arterial spasm: rationale, risk, and clinical illustrations. Am J Cardiol 1977;40:624–629.

35. Schroeder JS, Bolen JL, Quint RA, et al. Provocation of coro-nary spasm with ergonovine maleate: new test with result in 57 patients undergoing coronary arteriography. Am J Cardiol 1977;40:487–491.

36. Curry RC Jr, Pepine CJ, Sabom MB, Feldman RL, Christie LG, Conti CR. Effects of ergonovine in patients with and without coronary artery disease. Circulation 1977;56:803–809.

37. Heupler FA, Proudfi t WL, Razavi M, Shirey EK, Greenstreet R, Sheldon WC. Ergonovine maleate provocative test for coro-nary arterial spasm. Am J Cardiol 1978;41:631–640.

38. Helfant R. Coronary arterial spasm and provocative testing in ischemic heart disease. Am J Cardiol 1978;41:787–789.

39. Buxton A, Goldberg S, Hirshfeld JW, et al. Refractory ergono-vine-induced coronary vasospasm: importance of intracoro-nary nitroglycerin. Am J Cardiol 1980;46:329–334.

40. Scherf D, Perlman A, Schlachman M. Effect of dihydroergo-novine on the heart. Proc Soc Exp Biol Med 1949;71:420.

41. Heupler FA Jr. Provocative testing for coronary arterial spasm: risk, method, and rationale. Am J Cardiol 1980;46:335–337.

42. Fester A. Provocative testing for coronary arterial spasm with ergonovine maleate. Am J Cardiol 1980;46:338–340.

43. Cipriano PR, Guthaner DF, Orlick AE, Ricci DR, Wexler L, Silverman JF. The effects of ergonovine maleate on coronary arterial size. Circulation 1979;59:82–89.

44. Endo M, Hirosawa K, Kaneko N, Hase K, Inoue Y. Prinzmet-al’s variant angina: coronary arteriogram and left ventriculo-gram during angina attack induced by methacholine. N Engl J Med 1976;294:252–255.

45. Yasue H, Horio Y, Imoto N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 1986;74:955–963.

46. Raizner AE, Chahine RA, Ishimori T, et al. Provocation of coronary artery spasm by the cold pressor test: hemodynamic, arteriographic, and quantitative angiographic observations. Circulation 1980;62:925–932.

47. Mudge GH Jr, Grossman W, Mills RM Jr, Lesch M, Braunwald E. Refl ex increase in coronary vascular resistance in patients with ischemic heart disease. N Engl J Med 1976;295:1333–1337.



48. Yasue H, Nagao M, Omote S, Takizawa A, Miwa K, Tanaka S. Coronary arterial spasm and Prinzmetal’s variant form of angina induced by hyperventilation and tris-buffer infusion. Circulation 1978;58:56–62.

49. Bush L, Campbell WB, Tilton GD, Buja LM, Willerson JT. Effects of the selective thromboxane synthase inhibitor, dazoxi ben, on cyclic fl ow variations in stenosed canine coro-nary arteries. Trans Assoc Am Physicians 1983;96:103–112.

50. Ashton JH, Ogletree ML, Michel IM, et al. Cooperative medi-ation by serotonin S2 and thromboxane A2/prostaglandin H2 receptor activation of cyclic fl ow variations in dogs with severe coronary artery stenoses. Circulation 1987;76:952–959.

51. Golino P, Ashton JH, Buja LM, et al. Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo: thromboxane A2 and serotonin are possible mediators. Circulation 1989;79:154–166.

52. Bush LR, Campbell WB, Kern K, et al. The effects of alpha 2–adrenergic and serotonergic receptor antagonists on cyclic blood fl ow alterations in stenosed canine coronary arteries. Circ Res 1984;55:642–652.

53. Willerson JT, Hillis LD, Winniford MD, Buja LM. Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes. J Am Coll Cardiol 1986;8:245–250.

54. Willerson JT, Campbell WB, Winniford MD, et al. Conversion from chronic to acute coronary artery disease: speculation regarding mechanisms. Am J Cardiol 1984;54:1349–1354.

55. Willerson JT, Golino P, Eidt JF, Campbell WB, Buja LM. Spe-cifi c platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications. Circulation 1989;80:198–205.

56. Hirsh PD, Hillis LD, Campbell WB, Firth BG, Willerson JT. Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. N Engl J Med 1981;304:685–691.

57. Eidt JF, Allison P, Noble S, et al. Thrombin is an important mediator of platelet aggregation in stenosed and endothelially injured canine coronary arteries. J Clin Invest 1989;84:18–27.

58. van den Berg EK, Schmitz JM, Benedict CR, Malloy CR, Wil-lerson JT, Dehmer GJ. Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology. Circulation 1989;79:116–124.

59. Constantinides P. Plaque fi ssuring in human coronary throm-bosis. J Atheroscler Res 1966;6:1.

60. Davies MJ, Thomas AC. Plaque fi ssuring—the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373.

61. Falk E. Plaque rupture with severe preexisting stenosis pre-cipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127–134.

62. Buja LM, Willerson JT. Clinicopathologic correlates of acute ischemic heart disease syndromes. Am J Cardiol 1981;47:343–356.

63. Davies MJ, Fulton WF, Robertson WB. The relation of coro-nary thrombosis to ischemic myocardial necrosis. J Pathol 1979;127:99–110.

64. Buja LM, Willerson JT. The role of coronary artery lesions in ischemic heart disease: insights from recent clinicopatho-logic, coronary arteriographic, and experimental studies. Hum Pathol 1987;18:451–461.

65. Buja LM, Tofe AJ, Kulkarni PV, et al. Sites and mechanisms of localization of technetium-99m phosphorus radiopharma-ceuticals in acute myocardial infarcts and other tissues. J Clin Invest 1977;60:724–740.

66. Davies JM, Thomas AC, Knapman PA, Hangartner JR. Intra-myocardial platelet aggregation in patients with unstable angina pectoris suffering sudden ischemic cardiac death. Circulation 1986;73:418–427.

67. Willerson JT, Hillis LD, Buja LM. Ischemic Heart Disease: Clinical and Pathophysiological Aspects. New York: Raven, 1982.

68. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogen-esis of coronary artery disease and the acute coronary syn-dromes. N Engl J Med 1992;326:242–250,310–318.

69. Fuster V, Lewis A. Mechanisms leading to myocardial infarc-tion: insights from studies of vascular biology. Connor Memo-rial Lecture. Circulation 1995;91:256.

70. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844–2850.

71. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infi ltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447–1451.

72. Stefanadis C, Diamantopoulos L, Vlachopoulos C, et al. Thermal heterogeneity within human atherosclerotic coro-nary arteries detected in vivo. A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–1971.

73. Pasterkamp G, Vink A, Borst C. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2001;344:527–528.

74. Buffon A, Biasucci L, Liuzzo G, D’Onofrio G, Crea F, Maseri A. Widespread coronary infl ammation in unstable angina. N Engl J Med 2002;347:5–12.

75. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922.

76. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratifi cation in acute myocardial ischemia. N Engl J Med 1996;335:1333–1341.

77. Lindahl B, Venge P, Wallentin L, for the FRISC Study Group. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circula-tion 1996;93:1651–1657.

78. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specifi c troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342–1349.

79. Martin GS, Becker B, Schulman G. Cardiac troponin-I accu-rately predicts myocardial injury in renal failure. Nephrol Dial Transplant 1998;13:1709–1712.

80. Koenig W, Sund M. Frölich M, et al. C-reactive protein, a sensitive marker of infl ammation, predicts future risk of cor-onary heart disease in initially healthy middle-aged men. Circulation 1999;99:237–242.

81. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reac-tive protein in “acute” coronary artery disease. Am J Cardiol 1990;65:168–172.

82. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein in severe angina. N Engl J Med 1994;331:417–424.

83. Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fi brinogen related antigens in patients with stable and unsta-ble coronary artery disease. N Engl J Med 1987;317:1361–1365.

84. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997;349:462–466.


6 9 4 c h a p t e r 3 0

85. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Infl ammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979.

86. Biasucci LM, Liuzzo G, Fantuzzi G, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the fi rst 2 days of hospi-talization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 1999;99:2079–2084.

87. Ridker PM, Rifai N, Clearfi eld M, et al. Measurement of c-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:1959–1965.

88. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–1021.

89. Conde I, Kleiman NS. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348:2575–2577.

90. Freedman JE. CD40 ligand—assessing risk instead of damage? N Engl J Med 2003;348:1163–1165.

91. Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348:1104–1111.

92. Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med 2001;345:1022–1029.

93. Valkonen V-P, Päivä H, Salonen JT, et al. Risk of acute coro-nary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001;358:2127–2128.

94. Brennan M-L, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595–1604.

95. Morrow DA, Cannon CP, Rifai N, et al. Ability of minor ele-vations of troponins I and T to predict benefi t from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction. JAMA 2001;286:2405–2412.

96. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratifi cation in non-ST elevation acute coro-nary syndromes. Simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002;105:1760–1763.

96a. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES, Califf R, Topol EJ, Simoons ML, Wallentin L. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease. Circulation 2003;10:275–281.

97. Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in the atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA 1991;88:8154–8158.

98. Nikkari ST, O’Brien KD, Ferguson M, et al. Interstitial colla-genase (MMP-1) expression in human carotid atherosclerosis. Circulation 1995;92:1393–1398.

99. Sukhova G, Schönbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnera-ble human atheromatous plaques. Circulation 1999;99:2503–2509.

100. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P. Enhanced expression of vascular matrix metallopro-teinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann N Y Acad Sci 1995;748:501–507.

101. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infi ltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775–778.

102. Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA 1991;88:8154–8158.

103. Rajavashisth TB, Xiao-Ping X, Jovinge S, et al. Membrane type I matrix metalloproteinase expression in human athero-sclerotic plaques. Evidence for activation by proinfl ammatory mediators. Circulation 1999;99:3103–3109.

104. Patel SS, Thiagarajan R, Willerson JT, Yeh ETH. Inhibition of α4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-defi cient mice. Circulation 1998;97:75–81.

105. DeWood MA, Spores J, Notshe R, et al. Prevalence of total coronary occlusion during the early hours of transmural myo-cardial infarction. N Engl J Med 1980;303:897–902.

106. Buja LM, Willerson JT. Clinicopathologic correlates of acute ischemic heart disease syndromes. Am J Cardiol 1981;47:343–356.

107. Chandler AB, Chapman I, Erhardt LR, et al. Coronary throm-bosis in myocardial infarction. Report of a workshop on the role of coronary thrombosis in the pathogenesis of acute myo-cardial infarction. Am J Cardiol 1974;34:823–833.

108. Gibson RS, Beller GA, Gheroghiade M, et al. The prevalence and clinical signifi cance of residual myocardial ischemia 2 weeks after uncomplicated non-Q wave infarction: a prospective natural history study. Circulation 1986;73:1186–1198.

109. Falk E. Unstable angina with fatal outcome: dynamic coro-nary thrombosis leading to infarction and/or sudden death. Circulation 1985;71:699–708.

110. Haft JI, Haik BJ, Goldstein JE, Brodyn NE. Development of signifi cant coronary artery lesions in areas of minimal disease. A common mechanism for coronary disease progres-sion. Chest 1988;94:731–736.

111. Little WC, Constantinescu M, Applegate RJ, et al. Can coro-nary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157–1166.

112. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990;336:827–830.

113. Lewis HD Jr, David JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983;309:396–403.

114. Freeman MR, Williams AE, Chisholm RJ, Armstrong PW. Intracoronary thrombus and complex morphology in unstable angina. Relation to timing of angiography and in-hospital cardiac events. Circulation 1989;80:17–23.

115. Sherman CT, Litvak F, Grundfest W, et al. Coronary angios-copy in patients with unstable angina pectoris. N Engl J Med 1986;315:913–919.

116. Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest 1991;64:5–15.

117. Hansson GK, Jonasson L, Seifert PS, Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis 1989;9:567–578.

118. Gerrity RG. The role of the monocytes in atherogenesis. I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol 1981;103:181–190.

119. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulation of T cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Arterio-sclerosis 1986;6:131–138.

120. Parthasarathy S, Printz DJ, Boyd D, Joy L, Steinberg D. Macrophage oxidation of low-density lipoprotein generates a



modifi ed form recognized by the scavenger receptor. Arteriosclerosis 1986;6:505–510.

121. Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ 2nd, Virmani R. Increased adventitial mast cells in a patient with coronary spasm. N Engl J Med 1985;313:1138–1141.

122. Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia: in vivo evidence for 5–lipoxy-genase activation. Circulation 1992;85:230–236.

123. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenb-lith G. Silent ischemia as a marker for early unfavorable out-comes in patients with unstable angina. N Engl J Med 1986;314:1214–1219.

124. Fleg JL, Gerstenblith G, Zonderman AB, et al. Prevalence and prognostic signifi cance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardi-ography in asymptomatic volunteers. Circulation 1990;81:428–436.

125. Weiner DA, Ryan TJ, McCabe CH, et al. Signifi cance of silent myocardial ischemia during exercise testing in patients with coronary artery disease. Am J Cardiol 1987;59:725–729.

126. Weisfeldt ML, Flaherty JR. Myocardial infarction. In: Willer-son JT, Sanders CA, eds. Clinical Cardiology. New York: Grune & Stratton, 1977:346–369.

127. Kannel WB, Abbott RD. Incidence and prognosis of unrecog-nized myocardial infarction. N Engl J Med 1984;311:1144–1147.

128. Younis LT, Byers S, Shaw L, Barth G, Goodgold H, Chaitman BR. Prognostic importance of silent myocardial ischemia detected by intravenous dipyridamole thallium myocardial imaging in asymptomatic patients with coronary artery disease. J Am Coll Cardiol 1989;14:1635–1641.

129. Weiner DA, Ryan TJ, McCabe CH, et al. Risk of developing an acute myocardial infarction or sudden coronary death in patients with exercise-induced silent myocardial ischemia. A report from the Coronary Artery Surgery Study (CASS) registry. Am J Cardiol 1988;62:1155–1158.

130. Page DL, Caulfi eld JB, Kastor JA, DeSanctis RW, Sanders CA. Myocardial changes associated with cardiogenic shock. N Engl J Med 1971;285:133–137.

131. Alonso DR, Scheidt S, Post M, Killip T. Pathophysiology of cardiogenic shock: quantifi cation of myocardial necrosis, clinical, pathologic, and electrocardiographic correlation. Cir-culation 1973;48:588–596.

132. Willerson JT, Curry GC, Watson JT, et al. Intraaortic balloon counterpulsation in patients in cardiogenic shock, medically refractory left ventricular failure, and/or recurrent ventricu-lar tachycardia. Am J Med 1975;58:183–191.

133. Platt MR, Willerson JT, Watson JT, et al. The use of AVCO intraaortic balloon circulatory assistance for patients with cardiogenic shock, severe left ventricular failure and refrac-tory, recurrent ventricular tachycardia. In: Norman JC, ed. Coronary Artery Medicine and Surgery: Concepts and Con-troversies. New York: Appleton-Century-Crofts, 1975:401–409.

134. Sehapayak GK, Watson JT, Curry GC, et al. Late development of intractable ventricular tachycardia after acute myocardial infarction. J Thorac Cardiovasc Surg 1974;67:818–825.

135. Austen WG, Sanders CA, Averill JH, Friedlich AL. Ruptured papillary muscle: report of a case with successful mitral valve replacement. Circulation 1965;32:597–601.

136. Nishimura RA, Schaff HV, Shub C, Gersh BJ, Edwards WD, Tajik AJ. Papillary muscle rupture complicating acute myo-cardial infarction: analysis of 17 patients. Am J Cardiol 1983;51:373–377.

137. Ballester M, Tasca R, Marin L, Rees S, Rickards A, McDonald L. Different mechanisms of mitral regurgitation in acute and

chronic forms of coronary heart disease. Eur Heart J 1983;4:557–565.

138. Barbour DJ, Roberts WC. Rupture of a left ventricular papil-lary muscle during acute myocardial infarction: analysis of 22 necropsy patients. J Am Coll Cardiol 1986;8:558–565.

139. Meister SG, Helfant RH. Rapid bedside differentiation of rup-tured interventricular septum from acute mitral insuffi -ciency. N Engl J Med 1972;287:1024–1025.

140. Coma-Canella I, Gamallo C, Onsurbe PM, Jadraque LM. Ana-tomic fi ndings in acute papillary muscle necrosis. Am Heart J 1989;118:1188–1192.

141. Come PC, Riley MF, Weintraub R, Morgan JP, Nakao S. Echo-cardiographic detection of complete and partial papillary muscle rupture during acute myocardial infarction. Am J Cardiol 1985;56:787–789.

142. Radford MJ, Johnson RA, Daggett WM Jr, et al. Ventricular septal rupture: a review of clinical and physiologic features and an analysis of survival. Circulation 1981;64:545–553.

143. Moore CA, Nygaard TW, Kaiser DL, Cooper AA, Gibson RS. Post infarction ventricular septal rupture: the importance of location of infarction and right ventricular function in deter-mining survival. Circulation 1986;74:45–55.

144. Bansal, Eng AK, Shakudo M. Role of two-dimensional echo-cardiography, pulsed, continuous wave and color fl ow Doppler techniques in the assessment of ventricular septal rupture after myocardial infarction. Am J Cardiol 1990;65:852–860.

145. Cummings RG, Reimer KA, Califf R, Hackel D, Boswick J, Lowe JE. Quantitative analysis of right and left ventricular infarction in the presence of postinfarction ventricular septal defect. Circulation 1988;77:33–42.

146. Mann JM, Roberts WC. Acquired ventricular septal defect during acute myocardial infarction: analysis of 38 unoperated necropsy patients and comparison with 50 unoperated nec-ropsy patients and comparison with 50 unoperated necropsy patients without rupture. Am J Cardiol 1988;62:8–19.

147. Edwards BS, Edwards WD, Edwards JE. Ventricular septal rupture complicating acute myocardial infarction: identifi ca-tion of simple and complex types in 53 autopsied hearts. Am J Cardiol 1984;54:1201–1205.

148. Jones MT, Schofi eld PM, Dark JF, et al. Surgical repair of acquired ventricular septal defects: determinants of early and late outcome. J Thorac Cardiovasc Surg 1987;93:680–686.

149. Norell MS, Gershlick AH, Pillai R, et al. Ventricular septal rupture complication myocardial infarction: is earlier surgery justifi ed? Eur Heart J 1987;8:1281–1286.

150. Miller DC, Stinson EB. Surgical management of acute mechanical defects secondary to myocardial infarction. Am J Surg 1981;141:677–683.

151. Lader E, Colvin S, Tunick P. Myocardial infarction compli-cated by rupture of both ventricular septum and right ven-tricular papillary muscle. Am J Cardiol 1983;52:423–424.

152. Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial functional and electrophysi-ological alterations after brief coronary occlusion in conscious dog. J Clin Invest 1975;56:978–985.

153. Bush LR, Buja LM, Tilton GD, et al. Effects of propranolol and diltiazem alone and in combination on the recovery of left ventricular segmental function after long-term reperfusion following temporary coronary occlusion in conscious dogs. Circulation 1985;72:413–430.

154. Ellis SG, Henschke CI, Sandor T, Wynne J, Braunwald E, Kloner RA. Time course of functional and biochemical recov-ery of myocardium salvaged by reperfusion. J Am Coll Cardiol 1983;1:1047–1055.

155. Braunwald E, Kloner RA. The stunned myocardium: pro-longed, postischemic ventricular dysfunction. Circulation 1982;66:1146–1149.


6 9 6 c h a p t e r 3 0

156. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;117:211–221.

157. Fedele FA, Gerwitz H, Capone RJ, Sharaf B, Most AS. Meta-bolic response to prolonged reduction of myocardial blood fl ow distal to a severe coronary artery stenosis. Circulation 1988;78:729–735.

158. Marban E. Myocardial stunning and hibernation: the physiol-ogy behind the colloquialisms. Circulation 1991;83:681–688.

159. Schaefer S, Schwartz GG, Gober JR, et al. Relationship between myocardial metabolites and contractile abnormali-ties during graded regional ischemia: phosphorus-31 nuclear magnetic resonance studies of porcine myocardium in vivo. J Clin Invest 1990;85:706–713.

160. Roberts R, Sobel BE, Parker CW. Radioimmunoassay of cre-atine kinase isoenzymes. Science 1976;194:855–857.

161. Roberts R, Sobel BE. Isoenzymes of creatine phosphokinase and diagnosis of myocardial infarction. Ann Intern Med 1973;79:741–743.

162. Willerson JT, Stone MJ, Ting R, et al. Radioimmunoassay of creatine kinase-B isoenzyme in human sera: results in patients with acute myocardial infarction. Proc Natl Acad Sci USA 1977;74:1711–1715.

163. Stone MJ, Willerson JT, Gomez-Sanchez CE, Waterman MR. Radioimmunoassay of myoglobin in human serum: results in patients with acute myocardial infarction. J Clinc Invest 1975;56:1334–1339.

164. Stone MJ, Waterman MR, Harimoto D, et al. Serum myoglo-bin level as diagnostic test in patients with acute myocardial infarction. Br Heart J 1977;39:375–380.

165. Gilkeson G, Stone MJ, Waterman M, et al. Detection of myoglobin by radioimmunoassay in human sera: its useful-ness and limitations as an emergency room screening test for acute myocardial infarction. Am Heart J 1978;95:70–77.

166. Trahern CA, Gere JB, Krauth GH, Bigham DA. Clinical assessment of serum myosin light chains in the diagnosis of acute myocardial infarction. Am J Cardiol 1978;41:641–645.

167. Knaw BA, Gold H, Fallon J, Haber E. Detection of serum cardiac myosin light chains in acute experimental myocar-dial infarction: radioimmunoassay of cardiac myosin light chains. Circulation 1978;58:1130–1136.

168. Katus HA, Remppis A, Newmann FJ, et al. Diagnostic effi -ciency of troponin T measurements in acute myocardial infarction. Circulation 1991;83:902–912.

169. Stone MJ, Waterman MR, Poliner LR, Templeton GH, Buja LM, Willerson JT. Myoglobinemia is an early and quantitative index of acute myocardial infarction. Angiology 1978;29:386–392.

170. Ellis AK, Little T, Masud AR, Liberman HA, Morris DC, Klocke FJ. Early noninvasive detection of successful reperfu-sion in patients with acute myocardial infarction. Circulation 1988;78:1352–1357.

171. Puleo PR, Perryman MB, Bresser MA, Rokey R, Pratt CM, Roberts R. Creatine kinase isoforms analysis in the detection and assessment of thrombolysis in man. Circulation 1987;75:1162–1169.

172. Abendschein D, Seacord LM, Nohara R, Sobel BE, Jaffe AS. Prompt detection of myocardial injury by assay of creatine kinase isoforms in initial plasma samples. Clin Cardiol 1988;11:661–664.

173. Mair J, Morandell D, Genser N, Lechleitner P, Dienstl F, Puschendorf B. Equivalent early sensitivities of myoglobin, creatine kinase MB mass, creatine kinase isoform ratios, and cardiac troponins I and T for acute myocardial infarction. Clin Chem 1995;41:1266–1272.

174. Adams JE III, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I: a marker with high specifi city for cardiac injury. Circulation 1993;88:101–106.

175. Cummins B, Auckland ML, Cummins P. Cardiac-specifi c troponin I radioimmunoassay in the diagnosis of acute myo-cardial infarction. Am Heart J 1987;113:1333–1344.

176. Cannon CP, Weintraub WS, Demopoulos LA, et al. Compari-son of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycopro-tein IIb/IIIa inhibitor tirofi ban. N Engl J Med 2001;344:1879–1887.

177. Bonte FJ, Parkey RW, Graham KD, Moore J, Stokely EM. A new method for radionuclide imaging of myocardial infarcts. Radiology 1974;110:473–474.

178. Willerson JT, Parkey RW, Stokely EM, et al. Infarct sizing with technetium-99m stannous pyrophosphate scintigraphy in dogs and man: the relationship between scintigraphic and precordial mapping estimates of infarct size in patients. Car-diovasc Res 1977;11:291–298.

179. Parkey RW, Bonte FJ, Meyer SL, et al. A new method for radio-nuclide imaging of acute myocardial infarction in humans. Circulation 1974;50:540–546.

180. Willerson JT, Parkey RW, Bonte FJ, Meyer SL, Atkins JM, Stokley EM. Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation 1975;51:1046–1052.

181. Wackers FJ III, Schoot JB, Sokole EB, et al. Noninvasive visu-alization of acute myocardial infarction in man with thal-lium-201. Br Heart J 1975;37:741–744.

182. Wackers FJ, Sokole EB, Samson G, et al. Value and limitations of thallium-201 scintigraphy in the acute phase of myocardial infarction. N Engl J Med 1976;295:1–5.

183. Silverman KJ, Becker LC, Bulkley BH, et al. Value of early thallium-201 scintigraphy for predicting mortality in patients with acute myocardial infarction. Circulation 1980;61:996–1003.

184. Wheelan K, Wolfe C, Corbett J, et al. Early positive techne-tium-99m stannous pyrophosphate images as a marker of reperfusion in patients receiving thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1985;56:252–256.

185. Parkey RW, Kulkarni PV, Lewis S, et al. Effect of coronary blood fl ow and site of injection on Tc-99m-PPi detection of early canine myocardial infarcts. J Nucl Med 1981;22:133–137.

186. Dec GW, Palacios I, Yasuda T, et al. Antimyosin antibody cardiac imaging: its role in the diagnosis of myocarditis. J Am Coll Cardiol 1990;16:97–104.

187. Johnson LL, Seldin DW, Becker LC, et al. Antimyosin imaging in acute transmural myocardial infarctions: results of a mul-ticenter clinical trial. J Am Coll Cardiol 1989;13:27–35.

188. Carrio I, Bernia L, Ballester M, et al. Indium-111 antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection. J Nucl Med 1988;29:1893–1900.

189. Buja LM, Poliner LR, Parkey RW, et al. Clinicopathologic study of persistently positive technetium-99m stannous pyro-phosphate myocardial scintigrams and myocytologic degen-eration after acute myocardial infarction. Circulation 1977;56:1016–1023.

190. Sanford CF, Corbett J, Nicod P, et al. Value of radionuclide ventriculography in the immediate characterization of patients with acute myocardial infarction. Am J Cardiol 1982;49:637–644.

191. Stokely EM, Parkey RW, Bonte FJ, Graham KD, Stone MJ, Wil-lerson JT. Gated blood pool imaging following technetium-99m phosphate scintigraphy. Radiology 1976;120:433–434.

192. Strauss HW, Zaret BL, Hurley PJ, Natarajan TK, Pitt B. A scintigraphic method for measuring left ventricular ejection fraction in man without cardiac catheterization. Am J Cardiol 1971;28:575–580.



193. Schelbert HR, Verba JW, Johnson AD, et al. Nontraumatic determination of left ventricular ejection fraction by radionu-clide angiography. Circulation 1975;51:902–909.

194. Nixon JV, Narahara KA, Smitherman TC. Estimation of myocardial involvement in patients with acute myocardial infarction by two-dimensional echocardiography. Circulation 1980;62:1248–1255.

195. Sheiban I, Casarotto D, Trevi G, et al. Two-dimensional echo-cardiography in the diagnosis of intracardiac masses: a pro-spective study with anatomic validation. Cardiovasc Intervent Radiol 1987;10:157–161.

196. Stratton JR, Resnick AD. Increased embolic risk in patients with left ventricular thrombi. Circulation 1987;75:1004–1011.

197. Spirito P, Bellotti P, Chiarella F, Domenicucci S, Sementa A, Vecchio C. Prognostic signifi cance and natural history of left ventricular thrombi in patients with acute anterior myocar-dial infarction: a two-dimensional echocardiographic study. Circulation 1985;72:774–780.

198. Schnittger I. Cardiac and extracardiac masses: echocardio-graphic evaluation. In: Marcus ML, Schelbert HR, Skorton DJ, et al., eds. Cardiac Imaging: A Comparison to Braunwald’s Heart Disease. Philadelphia: WB Saunders, 1991:511–537.

199. Pearlman AS, Otto CM. Quantifi cation of valvular regurgita-tion. Echocardiography 1987;4:271.

200. Pearson AC, Labovitz AJ, Mrosek D, Williams GA, Kennedy HL. Assessment of diastolic function in normal and hyper-trophied hearts: comparison of Doppler echocardiography and M-mode echocardiography. Am Heart J 1987;113:1417–1425.

201. Stein PD. Sabbah HN, Albert DE, Snyder JE. Continuous wave Doppler for the noninvasive evaluation of aortic blood veloc-ity and rate of change of velocity: evaluation in dogs. Med Instrum 1987;21:177–182.

202. Rokey R, Kuo LC, Zoghbi WA, Limacher MC, Quinones MA. Determination of parameters of left ventricular diastolic fi lling by pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985;71:543–550.

203. Loeppky JA, Greene ER, Hoekenga ED, Caprihan A, Luft UC. Beat-by-beat stroke volume assessment by pulsed Doppler in upright and supine exercise. J Appl Physiol 1981;50:1173–1182.

204. Aschenberg W, Schluter M, Kremer P, Schroder E, Siglow V, Bleifeld W. Transesophageal two-dimensional echocardiogra-phy for detection of left atrial appendage thrombus. J Am Coll Cardiol 1986;7:163–166.

205. Nellessen U, Daniel WG, Matheis G, Oelert H, Depping K, Lichtlen PR. Impending paradoxical embolism from atrial thrombus: correct diagnosis by transesophageal echocardiog-raphy and prevention by surgery. J Am Coll Cardiol 1985;5:1002–1004.

206. Lee W, Schiller NB. Transesophageal echocardiography in clinical cardiology. In: Marcus ML, Schelbert Hr, Skorton DJ, et al, eds. Cardiac Imaging: A Comparison to Braunwald’s Heart Disease. Philadelphia: WB Saunders, 1991:605–616.

207. Sobel BE, Bresnahan GF, Shell WE, Yoder RD. Estimation of infarct size in man and its relation to prognosis. Circulation 1972;46:640–648.

208. Jansen DE, Corbett JR, Wolfe CL, et al. Quantifi cation of myocardial infarction: a comparison of single photon emis-sion computed tomography with pyrophosphate to serial plasma CK-MB measurements. Circulation 1985;72:327–333.

209. Wolfe CL, Lewis SE, Corbett JR, Parkey RW, Buja LM, Willerson JT. Measurement of infarction fraction using single photon emission computed tomography. J Am Coll Cardiol 1985;6:145–151.

210. Corbett JR, Lewis SE, Wolfe CL, et al. Measurement of myocardial infarct size in patients by technetium pyrophos-

phate single photon tomography. Am J Cardiol 1984;54:1231–1236.

211. Corbett JR, Nicod PH, Huxley RL, Lewis SE, Rude RE, Willerson JT. Left ventricular functional alterations at rest and during submaximal exercise in patients with acute myo-cardial infarction. Am J Med 1983;74:577.

212. Corbett JR, Nicod P, Lewis SE, Rude RE, Willerson JT. Prog-nostic value of submaximal exercise radionuclide ventricu-lography after myocardial infarction. Am J Cardiol 1983;52:82A–91A.

213. Dehmer GJ, Lewis SE, Hillis LD, Corbett J, Parkey RW, Willerson, JT. Exercise induced alterations in left ventri-cular volumes and the pressure-volume relationship: a sensitive indicator of left ventricular dysfunction in patients with coronary artery disease. Circulation 1981;63:1008–1018.

214. Corbett J, Dehner GJ, Lewis SE, et al. The prognostic value of submaximal exercise testing with radionuclide ventriculog-raphy prior to hospital discharge in patients with recent myo-cardial infarction. Circulation 1981;64:535–544.

215. Pulido J, Doss J, Twieg D, et al. Submaximal exercise testing in patients following acute myocardial infarction: myocardial scintigraphic and electrocardiographic observations. Am J Cardiol 1978;42:19–28.

216. Gibson RS, Watson DD, Taylor GJ, et al. Prospective assess-ment of regional myocardial perfusion before and after coro-nary revascularization surgery by quantitative thallium-201 scintigraphy. J Am Coll Cardiol 1983;1:804–815.

217. Melin JA, Wijns W, Keyeux A, et al. Assessment of thallium-201 redistribution versus glucose uptake as predictors of via-bility after coronary occlusion and reperfusion. Circulation 1988;77:927–934.

218. Armstrong WF, O’Donnell J, Ryan T, Feigenbaum H. Effect of prior myocardial infarction and extent and location of coro-nary disease on accuracy of exercise echocardiography. J Am Coll Cardiol 1987;10:531–538.

219. Applegate RJ, Dell’Italia LJ, Crawford MH. Usefulness of two-dimensional echocardiography during low-level exercise testing early after uncomplicated acute myocardial infarc-tion. Am J Cardiol 1987;60:10–14.

220. Crawford MH, Petru MA, Amon KW, et al. Comparative value of 2–dimensional echocardiography and radionuclide angiog-raphy for quantitating changes in left ventricular performance during exercise limited by angina pectoris. Am J Cardiol 1984;53:42–46.

221. Shan K, Constantine G, Sivananthan M, Flamm SD. Role of cardiac magnetic resonance imaging in the assessment of myocardial viability. Circulation 2004;109:1328–1334.

221a. Anderson WE, Wagner NB, Lee KL, White AD, Yuschaj J, Behan VS, Selvester RH, Ideker RE, Wagner GS. Evaluation of a QRS scoring system for estimating myocardial infarct size. Identifi cation screening criteria for non-acute myocardial infarcts. Am J Card 1998;61(10):729–733.

222. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Cho-nette D. Catheterization of the heart in men with the use of a fl ow-directed balloon-tipped catheter. N Engl J Med 1970;283:447–451.

223. Cobb LA, Baum RS, Alvarez H III, Schaffer WA. Resuscitation from out-of-hospital ventricular fi brillation: 4 year follow-up. Circulation 1975;52 (Suppl III):223–235.

224. Liberthson RR, Nagel EL, Hirschman JC, Nussenfeld SR. Pre-hospital ventricular defi brillation: prognosis and follow-up course. N Engl J Med 1974;291:317–321.

225. Liberthson RR, Nagel EL, Hirschmann JC, Nussenfeld SR, Blackbourne BD, Davis JH. Pathophysiologic observations in prehospital ventricular fi brillation and sudden cardiac death. Circulation 1974;49:790–798.


6 9 8 c h a p t e r 3 0

226. Lee L, Bates ER, Pitt B, Walton JA, Laufer N, O’Neill WW. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by car-diogenic shock. Circulation 1988;78:1345–1351.

227. Rothkopf M. Boerner J, Stone MJ, et al. Detection of myocar-dial infarct extension by CK-B radioimmunoassay. Circula-tion 1979;59:268–274.

228. Muller JE, Rude RE, Braunwald E, et al. Myocardial infarct extension: incidence, outcome, and risk factors in the MILIS study. Ann Intern Med 1988;108:1–6.

229. Marmor A, Sobel BE, Roberts R. Factors presaging early recurrent myocardial infarction (“extension”). Am J Cardiol 1981;48:603–610.

230. Hammerman H, Schoen FJ, Braunwald E, Kloner RA. Drug-induced expansion of infarct: morphologic and func-tional correlates. Circulation 1984;69:611–617.

231. Eaton LW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. Regional cardiac dilatation after acute myocardial infarction. Recognition by two-dimensional echocardiography. N Engl J Med 1979;300:57–62.

232. McKay RG, Pfeffer MA, Pasternak RC, et al. Left ventricular remodeling after myocardial infarction. A corollary to infarct expansion. Circulation 1986;74:693–702.

233. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation. N Engl J Med 1988;319:80–86.

233a. Hudson MP, Armstrong PW, Ruzyllo W, Brum J, Cusmano L, Krzeski P, Lyon R, Quinones M, Theroux P, Sydlowski D, Kim HE, Garcia MJ, Jaber WA, Weaver D. Effect of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricu-lar remodeling after myocardia infarction: results of the PRE-vention of MI Early Remodeling (PREMIER) Trial. JACC in press.

234. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients

with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–691.

235. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–1435.

236. Hutchins GM, Bulkley BH. Infarct expansion versus exten-sion: two different complications of acute myocardial infarc-tion. Am J Cardiol 1978;41:1127–1132.

237. The Acute Infarction Ramipril Effi cacy (AIRE) Study Investi-gators. Effect of ramipril on mortality and morbidity of sur-vivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–828.

238. ISIS-4. A randomized factorial trial assessing early oral cap-topril, oral mononitrate, and intravenous magnesium sulfate in 58,050 patients with suspected acute myocardial infarc-tion. Lancet 1995;345:669–685.

239. Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell’ Infarto Miocardico Investigators. Six month effects of early treatment with lisinopril and transdermal glyceryl trinitrate singly and together withdrawn six weeks after acute myocar-dial infarction: the GISSI-3 trial. J Am Coll Cardiol 1996;27:337–344.

240. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor tran-dolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evalu-ations (TRACE) Study Group. N Engl J Med 1995;333:1670–1676.

241. Lindpaintner K, Ganten D. The cardiac renin-angiotensin system. Circ Res 1991;68:905–921.

242. Van Belle E, Lablanche JM, Bauters C, Renaud N, McFadden EP, Bertrand ME. Coronary angioscopic fi ndings in the infarct-related vessel within 1 month of acute myocardial infarction. Circulation 1998;97:26–33.


3 Coronary Heart Disease Syndromes: …extras.springer.com/2007/978-1-84628-715-2/fscommand/...667...

Documents

Transcript of 3 Coronary Heart Disease Syndromes: …extras.springer.com/2007/978-1-84628-715-2/fscommand/...667...