Basic and Bedside Electrocardiography, 1st Edition (2009)

Chapter 24. Acute Coronary Syndrome: Non-ST Elevation Myocardial Infarction and Unstable Angina

   Acute coronary syndrome: Acute coronary syndrome is usually from plaque rupture, resulting in varying degrees of myocardial ischemia. The electrocardiogram (ECG) provides useful information that cannot be obtained with other diagnostic procedures and is the most important modality in the initial management of patients with this disorder.

·   ECG findings: Patients with acute coronary syndrome can be classified according to their ECG presentation and include those with ST segment elevation and those without ST elevation.

o    ST elevation: Almost all patients with acute coronary syndrome with ST segment elevation will develop myocardial necrosis with increased cardiac troponins in the circulation. These patients have an occluded coronary artery with completely obstructed flow and are candidates for immediate reperfusion with a thrombolytic agent or with primary percutaneous coronary intervention (PCI). This was discussed in Chapter 23, Acute Coronary Syndrome: ST Elevation Myocardial Infarction.

o    Non-ST elevation: Patients with acute coronary syndrome without ST segment elevation usually have ST depression, T-wave inversion, or less-specific ST and T wave abnormalities. Some patients may not show any changes in the ECG. These patients will either have unstable angina with no evidence of myocardial necrosis or non-ST elevation myocardial infarction (MI) when evidence of myocardial necrosis is present. The presence or absence of myocardial necrosis is based on whether or not cardiac troponins are elevated in the circulation. Unstable angina and non-ST elevation MI have the same pathophysiology, similar ECG findings, similar clinical presentation, and similar management and are discussed together.

·   The ECG is also helpful in providing prognostic information in acute coronary syndrome based on the initial presentation.

·   Patients with acute coronary syndrome accompanied by ST segment elevation carries the highest risk of death during the acute phase.

·   Patients presenting with ST segment depression have the highest overall mortality over a period of 6 months.

·   Patients with isolated T wave inversion or those with no significant ECG abnormalities incur the lowest risk.

The Normal T Wave

·   The normal T wave: The T wave normally follows the direction of the QRS complex. Thus, in leads where the R waves are tall, the T waves are also tall. In leads where the S waves are deep and the R waves are small, as in leads III or aVL, the T waves may be flat or inverted. Determining the direction or axis of any wave in the ECG such as the QRS complex was previously discussed in Chapter 4, The Electrical Axis and Cardiac Rotation.

o    Frontal plane: In the frontal plane, the axis of the normal T wave is within 45° of the axis of the QRS complex (Figs. 24.1 and 24.2). This is also called the QRS/T angle, which is the angle formed between the axis of the QRS complex and that of the T wave. When this angle is increased, myocardial ischemia should be considered, although this is usually not a specific finding. The tallest T wave in the limb leads is approximately 5 mm but could reach up to 8 mm.

o    Horizontal plane: In the horizontal plane, the axis of the normal T wave is within 60° of the axis of the QRS complex. Calculation of the T-wave axis in the horizontal plane is usually not necessary, because the T waves are expected to be upright in most precordial leads other than V1 or V2. If the T waves are inverted in V1, V2, and also in V3, this is abnormal (Fig. 24.3), except in children and young adults. Because the precordial leads are closer to the heart than the limb leads, the T waves are taller in the precordial leads, especially V2-V4, and usually measure up to 10 mm but can reach up to 12 mm.

Figure 24.1: Axis of the T Wave in the Frontal Plane. If the axis of the QRS is 60°, the T wave should be within 45° (shaded) to the left or right of the axis of the QRS complex as shown.

·   The normal T wave:

o    In Figure 24.2, the axis of the T wave and QRS complex is almost 0°. Although the T wave is inverted in lead III (arrows), this is not abnormal because the axis of the T wave is within 45° of the axis of the QRS complex. In the horizontal plane, the T wave is inverted in V1 and upright in V2 to V6. This is also a normal finding.

o    In Figure 24.3, the T waves are inverted in V1, V2 and V3 (arrows). This is abnormal in adults. However, inversion of the T wave from V1 to V3 is entirely normal in children. This T-wave inversion may normally persist through adulthood in some patients and is called persistent juvenile pattern.

Abnormal T Waves

·   T waves: Figure 24.4 shows different examples of T waves, both normal and abnormal.

Figure 24.2: T Wave Axis in the Frontal Plane. Although the T waves are inverted in lead III (arrows), the axis of the T wave is within 45° of the axis of the QRS complex (QRS axis 0°, T wave axis -5°), thus the T wave inversion in lead III is expected. This is not an abnormal finding.

o    Normal T wave: A normal T wave is upright and asymmetric. The initial upstroke is inscribed slowly and the terminal downstroke is inscribed more rapidly (Fig. 24.4A).

o    Ischemic T waves: Figure 24.4B-D show typical ischemic T waves. Ischemic T waves are symmetrical. They are symmetrically tall when the ischemia is subendocardial and are deeply symmetrically inverted, measuring at least 2 mm when the ischemia is subepicardial or transmural. These T-wave abnormalities when accompanied by symptoms of myocardial ischemia may or may not be associated with troponin elevation.

o    Nonspecific T waves: The other T-wave abnormalities shown in Figure 24.4E-G are nonspecific. These include T waves that are inverted but are <2 mm in amplitude. They may nevertheless occur as the only ECG abnormality associated with acute myocardial ischemia and may or may not be associated with troponin elevation. It is also possible that the ECG may not show any definite abnormalities when there is myocardial ischemia.

·   Interpretation of any T-wave abnormality should always include all available clinical information because the T-wave abnormalities are not always from ischemia, even if they look typical for myocardial ischemia.

·   Abnormal T-wave changes from myocardial ischemia:When coronary blood flow is diminished or when myocardial oxygen demand exceeds blood supply, changes in the T waves are the earliest to occur. Electrocardiographically, changes confined to the T waves indicate myocardial ischemia, which may be subendocardial or transmural.

o    Subendocardial ischemia: Myocardial ischemia is subendocardial when it is localized to the subendocardial area. It is usually manifested in the ECG as peaking of the T waves over the area of ischemia.

o    Transmural ischemia: The ischemia is transmural or subepicardial when it involves the whole thickness of the myocardium. This is usually manifested in the ECG as deeply and symmetrically inverted T waves over the area of ischemia.

Figure 24.3: Persistent Juvenile Pattern. The electrocardiogram is from a 25-year-old asymptomatic female showing inversion of the T wave in V1 to V3 (arrows). This is a normal finding in children, which may normally persist to adulthood and is called persistent juvenile pattern.

·   Subendocardial ischemia: The typical pattern of subendocardial ischemia is the presence of tall and symmetrically peaked T waves (Fig. 24.5). The configuration of the T wave is similar to that of hyperkalemia except that in subendocardial ischemia, the base is usually broad and the QT interval is slightly prolonged. Peaking of the T waves is confined to the area of ischemia unlike hyperkalemia where peaking is generalized (Fig. 24.6). Peaking of the T waves may also occur in fluoride intoxication and left ventricular hypertrophy from volume overload such as aortic regurgitation. It can also occur as a normal finding (Fig. 24.7) or when there is a metabolic abnormality (Fig. 24.8) especially over the precordial transition zone V2 to V4. Thus, peaking of the T wave is not specific for myocardial ischemia.

·   Transmural ischemia: T waves that are symmetrically and deeply inverted may indicate transmural ischemia, which involves the whole thickness of the myocardium. In transmural or subepicardial ischemia, the T wave is pointed downward, often resembling an arrowhead. If the T wave is divided equally into two halves by drawing a perpendicular line at the middle of the T wave, the left half of the inverted T wave resembles the other half. The ST segment may or may not be depressed. The QTc may be slightly prolonged (Fig. 24.9). When acute symptoms of ischemia are also present, these T waves may or may not be associated with troponin elevation. When troponins are elevated in the circulation, non-ST elevation MI or more specifically a T-wave infarct is present; otherwise, the T wave changes are due to unstable angina.

Figure 24.4: T Waves. (A) Normal T wave. (B) Peaked T waves from subendocardial ischemia. (C) Classical deep T-wave inversion due to transmural ischemia. (D) Symmetrically but less deeply inverted T wave also due to transmural ischemia.(E) Shallow T-wave inversion (F) Biphasic T wave. (G) Low, flat, or isoelectric T wave. Although the T-wave configuration of B, C, and D suggests myocardial ischemia, these T-wave abnormalities may also be due to other causes.

·   Other causes of deep T-wave inversion: There are several other causes of deep and symmetrical T-wave inversion other than myocardial ischemia. These include hypertrophic cardiomyopathy especially the apical type, pericarditis, pulmonary embolism, mitral valve prolapse, metabolic conditions, electrolyte disorders, and effect of drugs such as tricyclic antidepressants and antiarrhythmic agents. It can also be due to noncardiac conditions such as cerebrovascular accidents or other craniocerebral abnormalities, peptic ulcer perforation, acute cholecystitis, and acute pancreatitis. It may even be a variant of normal especially in young African American males. Deep symmetrical inversion of the T wave, therefore, is not specific and does not necessarily imply that the T-wave abnormality is due to transmural myocardial ischemia.

o    Figure 24.10 is the initial ECG of a patient who presented with chest discomfort. There was deep and symmetrical T-wave inversion across the precordium. The cardiac troponins were elevated consistent with non-ST elevation MI or, more specifically, a T-wave infarct.

o    Figure 24.11 is the 12-lead ECG of a 37-year-old woman, without history of cardiac disease and is 6 months postpartum when she developed cerebral hemorrhage. Deep T-wave inversion is noted in the limb and precordial leads resembling transmural ischemia.

·   Secondary ST and T wave abnormalities: The abnormality in the T wave as well as the ST segment is secondary if it is caused by abnormal depolarization of the ventricles, as would occur when there is bundle branch block, ventricular hypertrophy, preexcitation of the ventricles, or when the rhythm is ectopic or induced by a ventricular pacemaker. These secondary ST and T-wave abnormalities are therefore associated with abnormal QRS complexes, unlike myocardial ischemia, which is a primary repolarization disorder. Figures 24.12 and 24.13are examples of secondary ST and T-wave abnormalities. In Figure 24.12, the T waves are inverted because of left ventricular hypertrophy; in Figure 24.13, from preexcitation of the ventricles.

Figure 24.5: Subendocardial Ischemia. Peaking of the T waves is confined to V1 to V4 consistent with subendocardial ischemia involving the anterior wall. Note also that the T waves are taller in V1 than in V6 and are biphasic in leads II, III, and aVF. Peaking of the T waves mark the area of ischemia and can occur as the initial manifestation of acute coronary syndrome before the onset of ST segment elevation.

Figure 24.6: Hyperkalemia. Peaking of the T waves from hyperkalemia (serum potassium = 6.6 mEq/L). In subendocardial ischemia, the abnormally peaked T waves are localized to the ischemic area. In hyperkalemia, peaking of the T waves is generalized (arrows).

Figure 24.7: Peaked T Waves. Routine electrocardiogram obtained from an asymptomatic middle-age male. Peaked T waves are present representing a normal variant. Peaked T waves are often associated with early repolarization. Potassium level was 3.8 mEq/L.

Figure 24.8: Giant T Waves. Twelve-lead electrocardiogram (ECG) of a 33-year-old alcoholic man showing giant T waves with prolonged QTc. The T waves are tall and peaked with a broad base. The cause of the ECG abnormality was thought to be due to alcohol or associated metabolic abnormality.

 

Figure 24.9: Transmural Myocardial Ischemia. The T-wave changes shown are typical of transmural ischemia. Ischemic T waves are deeply inverted, usually measuring >2 mm and resemble the tip of an arrowhead as shown in V3 to V6.

Mechanism of Normal and Abnormal T Waves

·   Normal myocardium: Because the Purkinje fibers are located subendocardially, depolarization of the myocardium is endocardial to epicardial in direction. A surface electrode overlying the myocardium will record a tall QRS complex. Although the epicardium is the last to be depolarized, it is the earliest to recover because it has the shortest action potential duration when compared to other cells in the myocardium. Because the direction of repolarization is epicardial to endocardial, this causes the T wave to be normally upright (Fig. 24.14A).

·   Myocardial ischemia: Myocardial ischemia may alter the direction of repolarization depending on the severity of the ischemic process. This will cause changes that are confined to the T waves.

Figure 24.10: T-Wave Inversion from non-ST Elevation MI. The T waves are symmetrically and deeply inverted in most leads. These electrocardiogram changes are associated with elevation of the cardiac troponins consistent with non-ST elevation myocardial infarction or, more specifically, a T-wave infarct.

·   Subendocardial ischemia: When myocardial ischemia is confined to the subendocardium, the direction of depolarization and repolarization is not altered and is similar to that of normal myocardium. The repolarization wave however is delayed over the area of ischemia causing the T wave to become taller and more symmetrical (Fig. 24.14B). These changes are confined to the ischemic area.

·   Transmural ischemia: When the whole thickness of the myocardium is ischemic, the direction of the repolarization wave is not only reversed that of normal but also travels slowly causing the T wave to be deeply and symmetrically inverted (Fig. 24.14C).

The ST Segment

·   The normal ST segment is isoelectric and is at the same level as the TP and PR segments. The ST segment is abnormal when it is elevated or depressed by ≥1 mm from baseline or the configuration changes into a different pattern. Electrocardiographically, alteration involving the ST segment indicates a more advance stage of myocardial ischemia and is called myocardial injury.

·   ST elevation: Acute coronary syndrome with ST elevation indicates that one of the three epicardial coronary arteries is totally occluded with TIMI 0 flow indicating no perfusion or antegrade flow beyond the point of occlusion. Thrombotic occlusion of the vessel lumen with ST segment elevation almost always results in cellular necrosis with elevation of the cardiac troponins in the circulation. ST elevation electrocardiographically indicates transmural or subepicardial injury, which involves the whole thickness of the myocardium.

Figure 24.11: T-Wave Inversion from Cerebrovascular Accident Hemorrhage. The electrocardiogram (ECG) is from a 37-year-old woman 6 months postpartum who developed a left occipital hemorrhage. Note that the T-wave inversion is deep and symmetrical in V2 to V6 and also in leads I, II, and aVF resembling transmural myocardial ischemia. Note the similarity of this ECG from that in Figure 24.10.

Figure 24.12: Secondary ST and T-Wave Abnormality. The electrocardiogram shows left ventricular hypertrophy. Tall R waves are present with downsloping ST depression and T wave-inversion (arrows). These ST-T changes are secondary to abnormal activation of the ventricles.

Figure 24.13: Secondary T-Wave Abnormality. Twelve-lead electrocardiogram showing preexcitation. The ST-T abnormalities (arrows) are secondary to abnormal activation of the ventricles.

 

Figure 24.14: (A) The T Wave Normal myocardium. Depolarization starts from endocardium to epicardium since the Purkinje fibers are located subendocardially. Repolarization is reversed and is epicardial to endocardial, thus the T wave and QRS complex are both upright. (B) Subendocardial Ischemia. The shaded portion represents the area of ischemia. The direction of depolarization and repolarization is similar to normal myocardium. After the repolarization wave reaches the ischemic area, the repolarization wave is delayed causing the T wave to be tall and symmetrical. (C) Transmural Ischemia. The direction of repolarization is reversed that of normal and is endocardial to epicardial resulting in deeply and symmetrically inverted T waves.

·   ST depression: ST depression from acute coronary syndrome electrocardiographically indicates subendocardial myocardial injury. Unlike ST elevation, which is almost always accompanied by cellular necrosis, ST depression may or may not be associated with troponin elevation. ST depression may be horizontal (Fig. 24.15A,B), downsloping (C,D), scooping (E), slow upsloping (F), or fast upsloping (G). Typical ST depression from subendocardial injury is usually horizontal (A,B), downsloping (C), or slow upsloping (F) accompanied by depression of the J point. These types of ST segment depression, however, may be caused by other conditions that may be cardiac or noncardiac and similar to T-wave inversion, are not specific for myocardial injury.

Figure 24.15: ST Segment Depression. (A, B) Horizontal ST depression. (C, D) Downsloping ST segment depression. (E)Scooping ST segment depression frequently from digitalis effect. (F) Slow upsloping ST segment depression. (G) Fast upsloping ST segment depression frequently a normal finding. (A, B, C, F) Typical ischemic ST depression. (D) Left ventricular strain frequently associated with left ventricular hypertrophy. Arrows indicate the J point.

·   The typical ST depression associated with acute coronary syndrome has a horizontal or downsloping configuration with depression of the J point of at least 1 mm as shown inFigures 24.15A-C, 24.16, and 24.17. Other types of ST segment depression are less specific.

·   Unlike ST elevation, ST depression from acute myocardial injury, even when accompanied by troponin elevation, is not an indication for thrombolytic therapy. It usually indicates multivessel coronary disease, including significant stenosis of the left main coronary artery.

Figure 24.16: ST Segment Depression. Horizontal ST depression is seen in leads I and II and horizontal to downsloping ST depression in V3 to V6 consistent with subendocardial injury. Serial troponins were not elevated and the patient's symptoms were consistent with unstable angina.

ST Segment Depression

·   ST depression in V1 to V3: Acute coronary syndrome with ST segment depression in the ECG is a contraindication to thrombolytic therapy. One exception is ST segment depression in V1 to V3, which may represent a true posterolateral ST elevation MI from total occlusion of the left circumflex coronary artery (Fig. 24.17). When ST segment depression is present in V1 to V3, special leads V7 to V9 should be recorded to exclude a true posterolateral MI, which represents a true ST elevation MI. This has been previously discussed inChapter 23, Acute Coronary Syndrome: ST Elevation Myocardial Infarction (see Fig. 23.26A,B). Because leads V7 to V9 are not routinely recorded, ST depression confined to V1 to V3 can be mistaken for non-ST elevation MI or unstable angina.

·   Occlusion of the left main coronary artery: Total occlusion of the left main coronary artery is usually fatal and most patients do not survive to reach a medical facility. Total or subtotal occlusion of the left main coronary artery will show diffuse ST segment depression in multiple leads especially V4 to V6 and in leads I, II, and aVL. Leads aVR and V1 show elevation of the ST segments with ST elevation in aVR > ST elevation in V1 (Fig. 24.18, arrows). Because these leads are not adjacent to each other, thrombolytic therapy is not indicated. This type of ST segment depression may also occur when there is severe triple vessel disease. These ECG changes indicate extensive myocardial injury that will require aggressive therapy including early coronary revascularization.

Figure 24.17: ST Segment Depression in the Anterior Precordial Leads. The ST depression in the anterior precordial leads may represent anterior subendocardial injury, although this may also represent a true ST elevation myocardial infarction involving the left ventricle posterolaterally.

·   Digitalis effect: The scooping type of ST depression, as shown in Figure 24.19, is usually from digitalis effect.

·   Secondary ST segment depression: Secondary ST depression from left ventricular hypertrophy with strain pattern is shown in Figure 24.20.

Mechanism of ST Elevation and ST Depression

·   Deviation of the ST segment as a result of myocardial ischemia has been ascribed to two different mechanisms namely systolic current of injury or diastolic current of injury.

Systolic Current of Injury

·   ST elevation and ST depression from systolic current of injury: When the myocardial cells are injured, the resting potential of injured cells is less negative compared with normal cells. A less negative resting potential will diminish the height, amplitude, and duration of the action potential (Fig. 24.21). This difference in the action potential between normal cells and injured cells creates a current of injury during electrical systole (phases 1-3 or ST segment and T wave in the ECG) that is directed toward the injured myocardium. Thus, if the injury is transmural or subepicardial, the injury current is directed subepicardially resulting in elevation of the ST segment in the recording ECG electrodes that overlie the area of injury (Fig. 24.21). If the injury is confined to the subendocardium, the current of injury is directed subendocardially, away from the recording electrodes, resulting in depression of the ST segment.

Figure 24.18: ST Depression from Subtotal Occlusion of the Left Main Coronary Artery. Twelve-lead electrocardiogram (ECG) shows atrial fibrillation and marked ST depression in multiple leads including V3 to V6 and leads I, II, aVL, and aVF. There is also elevation of the ST segment in leads V1 and aVR. The ST elevation in aVR is higher than the ST elevation in V1 (arrows). This type of ECG is frequently associated with subtotal occlusion of the left main coronary artery or its equivalent.

Figure 24.19: ST Segment Depression from Digitalis. (A) The ST depression in leads II and V6 (arrows) has a scooping or slow downsloping pattern. This type of ST depression is due to digitalis. (B) Leads II and V6 are magnified to show the ST depression.

Figure 24.20: Left Ventricular Hypertrophy: Twelve-lead electrocardiogram showing left ventricular hypertrophy (LVH) with downsloping ST depression from left ventricular strain. The J point is not depressed and the ST segments have a downsloping configuration with upward convexity (arrows). This type of LVH is usually seen in patients with hypertension and is often described as pressure or systolic overload.

 

Figure 24.21: Systolic Current of Injury. The upper row represents transmembrane action potentials before and after myocardial injury and the lower row the corresponding electrocardiogram (ECG). A change in resting potential from -90 to approximately -60 mV will occur when cells are injured. A less negative resting potential causes the amplitude and duration of the action potential to diminish when compared to normal cells. This difference in potential creates a current of injury during electrical systole (corresponding to phases 1-3 of the action potential equivalent to the ST segment and T wave in the ECG) between normal and injured myocardium. This current flows from normal myocardium toward the injured myocardium. Thus, if the injury is subepicardial or transmural, the current of injury is directed toward the overlying electrode resulting in ST elevation. (0 to 4 represent the different phases of the action potential.)

Figure 24.22: Diastolic Current of Injury. The yellow shaded areas in the upper and lower diagrams represent electrical diastole showing a change in resting potential from -90 to -60 mV after myocardial injury. Because the resting potential of injured cells is less negative, the cells are relatively in a state of partial depolarization. Thus, the extracellular membrane of the injured cells is more negative (less positive) compared with that of normal myocardium causing a diastolic current of injury directed away from the injured myocardium. This diastolic current of injury causes the TQ segment to be displaced downward away from the overlying electrode. When all cells are discharged during systole, the potential gradient between injured and normal cells is diminished, shifting the electrocardiogram baseline to its original position, resulting in apparent ST elevation.

 

Figure 24.23: ST Segment Depression. When there is subendocardial injury, the ST segment is depressed because the baseline is shifted upward away from the injured subendocardium toward the direction of the recording electrode. See text.

Diastolic Current of Injury

·   Apparent ST segment elevation from diastolic current of injury: The resting potential of injured myocardial cells is less negative compared with normal cells. This difference in potential occurs during phase 4, which corresponds to the TQ segment in the ECG. Because the injured cells have a less negative resting potential, they will have a more negative (less positive) extracellular charge relative to normal myocardium. This difference in potential between normal and injured myocardium will create an electrical gradient during diastole that is directed away from the injured cells, toward the more positive normal myocardium. This causes the ECG baseline (TQ segment) to shift downward, away from the surface electrode overlying the area of injury (Fig. 24.22). During systole, all myocardial cells are discharged, erasing the potential difference between injured cells and normal cells. This will cause the ECG to compensate and return the ST segment to its previous baseline before the injury, resulting in apparent ST elevation. The opposite will occur if the injury is subendocardial.

Figure 24.24: Q Waves. Diagrammatic representation of a transmural infarct. The necrotic area (black) involves the whole thickness of the myocardium and consists of cells that cannot be depolarized. Thus, an electrode overlying the necrotic area will normally record the electrical activity on the opposite side of the myocardium (red arrow), resulting in q waves.

·   Apparent ST segment depression from diastolic current of injury: The mechanism of ST segment depression from subendocardial injury is shown in Figure 24.23. When there is subendocardial injury, phase 4 or resting potential of the injured subendocardial myocardial cells is less negative when compared with normal myocardial cells. This difference in potential between normal and injured myocardium will create an electrical gradient during diastole. Because the injured cells are in a state of partial depolarization, a diastolic current of injury is directed away from the injured subendocardium toward the normal subepicardium causing the TQ segment to shift upward toward the surface electrode overlying the ischemic area. During systole, all myocardial cells are discharged simultaneously, erasing the diastolic gradient between injured cells and normal cells. This will cause the ECG to compensate and return the ST segment to its previous baseline before the injury, resulting in apparent ST segment depression (Fig. 24.23).

·   In summary, the direction of systolic current of injury is always toward the injured myocardium, whereas diastolic current of injury, equivalent to the TQ segment, is always directedaway from the injured myocardium.

Q Waves

·   Pathologic Q waves: Pathologic Q waves can be prevented if the ischemic process is relieved within a timely fashion. However, if myocardial injury progresses, myocardial necrosis will occur resulting in pathologic Q waves. Electrocardiographically, Q waves indicate transmural myocardial necrosis, which signify permanent myocardial damage and are usually not reversible. However, some Q waves may reverse because of contraction of the scar tissue during the healing process. Additionally, the injured myocardium may be temporarily stunned during the acute episode and may be unable to conduct an electrical impulse locally, which may be transient and reversible. Pathologic Q waves is the usual sequelae of ST elevation MI, although it may also occur in approximately 25% of patients with non-ST elevation MI. Abnormal Q waves have been previously discussed in Chapter 23, Acute Coronary Syndrome: ST Elevation Myocardial Infarction.

·   Summary of the evolution of the ECG in acute coronary syndrome:

o    T-wave abnormalities: Alterations confined to the T waves indicate myocardial ischemia. These T-wave abnormalities are reversible. However, if the ischemic process continues unabated, alterations in the ST segment will follow.

o    ST segment abnormalities: Changes involving the ST segment suggest a more advance stage of myocardial ischemia and indicate myocardial injury. Alterations involving the ST segment and T wave may be reversible. However, if the ischemic process continues unrelieved, changes in the QRS complex will follow.

o    Q waves: Q waves indicate the presence of myocardial necrosis and are usually not reversible.

Non-ST Elevation MI and Unstable Angina

ECG of Non-ST Elevation MI and Unstable Angina

·   J point and ST segment depression of ≥1 mm below baseline.

·   Symmetrically inverted T waves measuring ≥2 mm.

·   The ST and T wave abnormalities may be less specific.

Mechanism

·   Normal ventricular myocardium: Unlike the single muscle cell where depolarization and repolarization occur in the same direction, depolarization and repolarization of the normal ventricular myocardium occur in opposite directions. Thus, depolarization of the myocardium is endocardial to epicardial because the impulse originates from the Purkinje fibers, which are located subendocardially. An electrode overlying the myocardium will record a tall QRS complex. Although the epicardium is the last to be depolarized, it is the earliest to recover because it has shorter action potential duration compared to other cells in the myocardium. Thus, the repolarization wave travels from epicardium to endocardium, away from the recording electrode resulting in upright T wave in the ECG. In addition to the shorter action potential duration of epicardial cells, there are other reasons why the epicardium recovers earlier than the endocardium, even if the epicardium is the last to be depolarized.

o    The subendocardium has a higher rate of metabolism, thus requiring more oxygen when compared with the epicardium.

o    The subendocardium is the deepest portion of the myocardium and is farthest from the coronary circulation.

o    The subendocardium is immediately adjacent to the ventricular cavities. Because the ventricles generate the highest pressure in the cardiovascular system, the subendocardium is subject to a higher tension than the epicardium.

o    Repolarization (the ST segment and T wave) occurs during systole when the myocardium is mechanically contracting. There is no significant myocardial perfusion during systole especially in the subendocardium at the time of repolarization.

·   Myocardial ischemia: Myocardial ischemia is a pathologic condition resulting from an imbalance between oxygen supply and demand. Depending on the severity of myocardial ischemia, the ECG changes may involve the T wave, the ST segment, or the QRS complex. Changes confined to the T waves are traditionally called myocardial ischemia. Alterations in the ST segment are described as myocardial injury and when the QRS complex is altered with development of pathologic Q waves or decreased amplitude of the R wave, the abnormality is myocardial necrosis.

o    Changes involving the T waves: Changes affecting only the T waves indicate myocardial ischemia, which may be subendocardial resulting in tall T waves or transmural resulting in deeply inverted T waves. An abnormal T wave associated with troponin elevation is consistent with non-ST elevation MI or more specifically, a T-wave infarct.

§  Subendocardial ischemia: The endocardial cells immediately adjacent to the ventricular cavities are able to extract nutrients directly from blood within the ventricles. Thus, it is the deeper subendocardial cells and not the endocardium itself that are at risk for myocardial ischemia. When there is subendocardial ischemia, the repolarization wave is not significantly altered and normally starts from epicardium to endocardium resulting in upright T waves. The repolarization wave, however, is delayed after it reaches the ischemic area, causing the T wave to be symmetrical and taller than normal in leads overlying the area of ischemia.

§  Transmural or subepicardial ischemia: If the ischemia is transmural involving the whole thickness of the myocardium, the direction of the repolarization wave is reversed, starting from endocardium to epicardium, causing the T wave to become deeply inverted instead of upright. Because the duration of the action potential of ischemic cells becomes longer than normal, the repolarization wave travels slowly causing the T wave to be symmetrical with slightly prolonged QT.

o    Changes involving the ST segment: Changes in the ST segment indicate myocardial injury, which is a more advanced form of myocardial ischemia. Myocardial injury may be transmural resulting in ST segment elevation or it may be subendocardial, resulting in ST segment depression.

§  Transmural or subepicardial injury: Transmural or subepicardial injury causes the ST segment to become elevated. ST elevation is a more severe form of myocardial injury, which is almost always associated with troponin elevation consistent with ST elevation MI. Elevation of the ST segment may be due to systolic or diastolic current of injury.

§  Systolic current of injury: Systolic current of injury occurs during phases 1 through 3 of the action potential corresponding to the ST segment and T wave in the ECG. Systolic current of injury always points to the direction of the injured myocardium. This causes the ST segment to become elevated in leads overlying the area of injury.

§  Diastolic current of injury: Diastolic current of injury occurs during phase 4 of the action potential corresponding to the T-Q segment in the ECG. Diastolic current of injury is always directed away from the area of injury. Thus, the baseline or T-Q segment of the ECG is shifted downward, away from the recording surface electrode overlying the area of injury. During electrical systole corresponding to the QT interval in the ECG, all cells are depolarized, eliminating all the electrical charges of both injured cells and normal cells. This will cause the ECG to compensate and return the ST segment back to its previous baseline before the injury, resulting in apparent ST elevation. In pericarditis, only the epicardial cells are injured. The endocardial cells remain preserved. A diastolic current of injury will flow from epicardium to endocardium, away from the injured area and away from the recording surface electrodes. This will similarly cause the baseline T-Q segment to shift downward. During electrical systole, apparent ST segment elevation will occur as the ECG returns to its previous baseline.

§  Subendocardial injury: Subendocardial injury depresses the ST segment and represents a less severe form of myocardial injury involving the subendocardium. ST depression with troponin elevation is non-ST elevation MI. More specifically, it is an ST depression MI. Depression of the ST segment may be due to systolic or diastolic current of injury.

§  Systolic current of injury: Systolic current of injury always flows toward the area of injury. Thus, a current of injury flows from normal myocardium (subepicardium) toward the subendocardium, away from the recording surface electrode, resulting in depression of the ST segment.

§  Diastolic current of injury: Diastolic current of injury flows in the opposite direction, which is away from the injured myocardium. Thus, during electrical diastole, the current of injury will flow away from subendocardium toward normal myocardium (subepicardium) in the direction of the recording electrode, shifting the T-Q segment upward. During electrical systole, all cells are discharged, eliminating the potential difference between injured cells and normal cells. This will cause the ECG to compensate and return the ST segment downward to its previous baseline before the injury, resulting in apparent ST depression.

o    Changes involving the QRS complex: If myocardial ischemia is not relieved and collateral flow is not adequate, myocardial injury will progress irreversibly to myocardial necrosis resulting in alteration of the QRS complex. Thus, changes in the QRS complex resulting in pathologic Q waves or diminished amplitude of the R wave represent transmural myocardial necrosis. These changes are usually permanent. Cells that are necrotic or infarcted do not depolarize or conduct electrical activity. If an electrode is positioned over a necrotic myocardium, Q waves or QS complexes will be recorded, which represent activation of normal myocardium away and opposite the infarcted area, causing a negative deflection in the ECG.

Clinical Implications

·   Myocardial ischemia with elevation of the ST segment is due to complete occlusion of the vessel lumen. When blood supply is completely interrupted for a duration of more than 20 minutes, myocardial necrosis always occurs and troponin elevation is always expected.

·   Myocardial ischemia with depression of the ST segment or inversion of the T wave may be due to either diminished coronary flow or increased myocardial oxygen demand or a combination of both. It may also be due to a completely occluded artery, but has collateral flow. These ST and T wave abnormalities may or may not be associated with troponin elevation, depending on the severity of myocardial ischemia. When cardiac troponins are elevated in the circulation, non-ST elevation MI is present. If the troponins are not elevated, the clinical picture is one of unstable angina. These patients with non-ST elevation MI or unstable angina may not show any abnormalities in the ECG.

·   Unlike ST segment elevation and pathologic Q waves, T-wave inversion is not specific for myocardial ischemia. Although deep and symmetrical T-wave inversions measuring ≥2 mm are typical for myocardial ischemia, ischemiclooking T waves may be seen in patients without ischemic heart disease.

·   ST depression from myocardial injury usually measures ≥1 mm. The ST depression may be horizontal, downsloping, or slow upsloping in configuration. The J point (junction between the QRS complex and ST segment) should be depressed by ≥1 mm if the ST depression is from myocardial ischemia. ST depression is less specific if the J point is not depressed or if the J point is depressed by <0.5 mm. ST depression is not only the result of myocardial ischemia, but could also be due to the effect of drugs such as digitalis, antiarrhythmic agents, Ritalin, and tricyclic antidepressants. ST depression can also occur in patients with cardiac diseases not due to ischemia such as left ventricular hypertrophy, electrolyte abnormalities, mitral valve prolapse, and other noncardiac abnormalities, including anemia.

·   The severity of ST depression and T wave inversion provide important diagnostic and prognostic information. For example, patients with ST depression ≥0.5 mm have higher morbidity and mortality compared to patients with T wave inversion or those without ECG findings.

·   Although ST elevation MI is synonymous with a Q wave MI, not all patients with ST elevation will develop Q waves. Additionally, approximately 25% of patients with non-ST elevation MI will also develop Q waves. The rest (75%) will have a non-Q wave MI. Thus, ST elevation MI and non-ST elevation MI are preferred over Q wave and non-Q wave MI. Similarly, Hurst emphasizes that non-ST elevation MI, which is the terminology used in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines, does not specify the abnormality present in the ECG. Thus, when a non-ST elevation MI occurs, he prefers to identify the infarct either as a T-wave MI or ST depression MI rather than a non-ST elevation MI.

·   The infarct related artery can be predicted using the 12-lead ECG when there is ST elevation MI, T-wave MI, or Q-wave MI. Identifying the culprit vessel is more difficult when the MI is associated with ST segment depression. Very often, myocardial ischemia with ST segment depression is due to multivessel coronary disease, including the possibility of a significant left main coronary artery lesion.

Treatment

·   Unlike ST elevation MI, which indicates that the coronary artery is completely occluded and there is urgency in immediately establishing coronary flow with a thrombolytic agent or primary PCI, non-ST elevation MI and unstable angina indicate that the coronary artery is partially occluded, resulting in imbalance between oxygen supply and demand. Thus, the patient can be initially risk stratified so that patients who are high risk for reinfarction or death should undergo an early invasive strategy, whereas patients who are not identified as being high risk can undergo an early conservative approach.

o    Early conservative: The early conservative approach includes mainly medical therapy. Cardiac catheterization is reserved only when there is evidence of continuing ischemia either spontaneously occurring or exercise induced in spite of intensive medical therapy.

o    Early invasive: The early aggressive approach includes medical therapy and an early invasive strategy with cardiac catheterization and revascularization of the occluded vessel performed within 4 to 24 hours after the patient is hospitalized regardless of the presence or absence of continuing ischemia.

·   High-risk patients: According to the ACC/AHA 2007 guidelines for the management of patients with unstable angina and non-ST elevation MI, high-risk patients include any of the following findings:

o    Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy

o    Elevated cardiac biomarkers

o    New or presumably new ST depression

o    Signs or symptoms of heart failure or new or worsening mitral regurgitation

o    High-risk findings from noninvasive testing

o    Hemodynamically unstable patient

o    Sustained ventricular tachycardia

o    Left ventricular dysfunction with ejection fraction of <40%

o    Previous PCI within 6 months

o    Prior coronary artery bypass surgery

o    High risk score using risk stratification models

·   Antiplatelet and anticoagulant therapy: Antithrombotic agents are the mainstay in the therapy of patients with non-ST elevation MI and unstable angina, whether or not an early conservative or a more aggressive strategy is used.

 

 TABLE 24.1 Summary of the Initial and Maintenance Doses of Aspirin and Clopidogrel according to the American  College of Cardiology/American Hospital Association 2007 Guidelines on Non-ST Elevation Myocardial Infarction  and Unstable Angina

 

Medically Treated
(No Stent)

Percutaneous Coronary Intervention

 
 

Bare Metal Stent

Sirolimus Stent

Paclitaxel Stent

 

 Aspirin (initial dose)

162-325 mg

162-325 mg

162-325 mg

162-325 mg

 

 Minimum duration

 

162-325 mg for ≥1 month

162-325 mg for ≥3 months

162-325 mg for ≥6 months

 

 Maintenance dose

75-162 mg daily indefinitely

75-162 mg daily indefinitely

75-162 mg daily indefinitely

75-162 mg daily indefinitely

 

 Clopidogrel (initial  dose)

300-600 mg loading dose

300-600 mg loading dose

300-600 mg loading dose

300-600 mg loading dose

 

 Minimum duration

75 mg daily for ≥1 month

75 mg daily for ≥1 month

75 mg daily for ≥12 months

75 mg daily for ≥12 months

 

 Maintenance dose

Ideally up to 12 months

Ideally up to 12 months

Ideally up to 12 months

Ideally up to 12 months

 
             

 

·  Aspirin: Aspirin should be given as soon as possible, often in the prehospital setting when diagnosis of acute coronary syndrome is suspected. The initial dose of aspirin is 162 to 325 mg of plain (nonenteric coated) aspirin given orally.

·   Medically treated patients: Among patients who are treated medically and are not stented, aspirin is continued at a dose of 75 to 162 mg daily indefinitely.

·   Stented patients: In patients undergoing PCI with stent placement, the dose of enteric-coated aspirin depends on the type of stent used.

·   Bare metal stent: Aspirin is given at a dose of 162 to 325 mg daily given for at least 1 month if a bare metal stent was deployed. This is followed by 75 to 162 mg daily indefinitely.

·   Drug-eluting stent: The dose of aspirin is 162 to 325 mg daily for at least 3 months if a sirolimus-coated stent was deployed and for at least 6 months for paclitaxelcoated stent. This is followed by a maintenance dose of 75 to 162 mg daily indefinitely.

·  Clopidogrel: The loading dose of clopidogrel is usually 300 mg given orally. A higher loading dose of 600 to 900 mg inhibits platelets more rapidly, although its safety and clinical efficacy needs to be established.

·   Medically treated patients: Among medically treated patients who are not stented, 75 mg of clopidogrel is given daily for at least 1 month and ideally up to 1 year. Clopidogrel should not be given or should be discontinued for 5 to 7 days in patients undergoing coronary bypass surgery.

·   Bare metal stent: Clopidogrel is given at a maintenance dose of 75 mg/day for at least 1 month and ideally up to 1 year for patients who have bare metal stents.

·   Drug-eluting stent: The maintenance dose is 75 mg daily for at least 1 year.

·  Table 24.1 summarizes the initial dose, minimum duration, and maintenance dose of aspirin and clopidogrel according to the ACC/AHA 2007 guidelines on non-ST elevation MI and unstable angina.

·  Unfractionated heparin or low-molecular-weight heparin

·   Patients undergoing PCI: Intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin in addition to aspirin and clopidogrel is a Class I recommendation in patients undergoing PCI. Enoxaparin, a low-molecular-weight heparin, is preferred to unfractionated heparin except when there is renal failure or when bypass surgery is planned within 24 hours. The use of bivalirudin or fondaparinux also receives a Class I recommendation.

·   Patients not undergoing PCI: The use of unfractionated heparin, enoxaparin, and fondaparinux among patients who are treated conservatively also receives a Class I recommendation. Fondaparinux is the preferred agent when there is increased risk of bleeding. Enoxaparin and fondaparinux is preferred over unfractionated heparin unless bypass surgery is being planned within 24 hours.

·  IIb/IIIa antagonists:

·   Patients undergoing PCI: The use of IIb/IIIa platelet antagonists such as abciximab (ReoPro), eptifibatide (Integrilin), or tirofiban (Aggrastat) is a Class I indication for patients with acute coronary syndrome undergoing PCI.

§  Patients not undergoing PCI: For patients not undergoing PCI, IIb/IIIa antagonists can also be given as medical therapy to high-risk patients in addition to aspirin and clopidogrel. Patients appear to benefit with tirofiban or eptifibatide (Class IIb recommendation), but not with abciximab. The use of abciximab, therefore, as medical treatment of acute coronary syndrome in patients who are not undergoing PCI is not recommended (Class III).

o    Thrombolytic agents: Thrombolytic agents such as alteplase, streptokinase, reteplase, or tenecteplase are contraindicated in non-ST elevation MI and unstable angina.

·   In addition to the use of antiplatelet agents, the general medical therapy of non-ST elevation MI and unstable angina is similar to that of ST elevation MI because both entities have the same pathophysiologic substrate: plaque rupture with thrombotic occlusion of the vessel lumen. General medical therapy for patients with non-ST elevation MI and unstable angina are similar and include:

o    Oxygen: Oxygen is initially given to patients with hypoxemia or arterial oxygen saturation of <90% or those of questionable respiratory status.

o    Nitroglycerin: Nitroglycerin 0.4 mg sublingual tablets or spray 5 minutes apart for 3 doses followed IV if there are symptoms of ischemia. The IV infusion is started at 10 mcg/minute and increased by 10 mcg/minute every 3 to 5 minutes until symptoms are improved or systolic blood pressure drops. No definite maximum dose is recommended although the top dose is usually 200 mcg/minute.

o    Morphine: Morphine sulfate 1 to 5 mg IV may be given if chest pain is not relieved after three sublingual nitroglycerin tablets or chest pain recurs in spite of anti-ischemic therapy. This may be repeated every 5 to 30 minutes if necessary. Although morphine sulfate continues to be a Class I indication for patients with ST elevation MI, the more recent ACC/AHA 2007 guidelines on non-ST elevation MI has downgraded the use of morphine for ischemic pain associated with non-ST elevation MI and unstable angina from Class I to Class IIa.

o    Beta blockers: The latest 2007 AHA/ACC guidelines recommend that beta blockers should be given orally within the first 24 hours when there are no contraindications. Contraindications to beta blocker therapy include PR interval >0.24 seconds, second degree atrioventricular block or higher, severe left ventricular dysfunction, or history of asthma. The agent should be gradually titrated in patients with moderate left ventricular dysfunction. Intravenous beta blockers should be used cautiously and avoided when there is heart failure, hypotension, or hemodynamic instability.

o    Renin-angiotensin antagonists: Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and aldosterone antagonists should be given when there is associated left ventricular dysfunction in the absence of contraindications.

o    Statins: Statins to lower the low-density lipoprotein to a target goal of <70 mg/dL.

·   Patients who continue to have ischemia, the following agents or procedures can be given:

o    A combination of nitrates and beta blockers are the drugs of choice for myocardial ischemia.

o    Calcium blockers are second- or third-line agents:

§  Calcium channel blockers may be given if ischemia is not relieved by nitrates and beta blockers.

§  Nondihydropyridine calcium antagonists such as verapamil and diltiazem are given when beta blockers are contraindicated.

§  Calcium channel blockers should not be given when there is evidence of left ventricular dysfunction.

§  Intra-aortic balloon pump may be used for severe ischemia not responsive to medical therapy.

§  Oxygen and morphine sulfate is usually given as part of general medical therapy

Prognosis

·   Non-ST elevation MI and unstable angina have a lower inhospital mortality of approximately 1% to 3% when compared with ST elevation MI. Myocardial involvement is less extensive and left ventricular systolic function is usually preserved.

·   Non-ST elevation MI is associated with a higher recurrence of cardiovascular events after hospital discharge compared with ST elevation MI and exacts a higher post-hospital mortality. Although ST elevation MI has a higher initial mortality, overall mortality of ST and non-ST elevation MI will be similar after a 2- to 3-year follow-up. Patients with non-ST elevation MI and unstable angina who are high risk for cardiovascular events should be identified so that they can be revascularized.

Suggested Readings

Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50:e1-e157.

Birnbaum Y, Solodky A, Hertz I, et al. Implications of inferior ST-segment depression in anterior acute myocardial infarction: electrocardiographic and angiographic correlation. Am Heart J. 1994;127:1467-1473.

Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol. 2000;36:970-1062.

Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: Summary article: a report of the ACC/AHA Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina. Circulation. 2002;106:1893-1900.

Channer K, Morris F. ABC of clinical electrocardiography. Myocardial ischaemia. BMJ. 2002;324:1023-1026.

Dunn MI, Lipman BS. Myocardial Infarction, injury and ischemia. In: Clinical Electrocardiography. 8th ed. Chicago: Year Book Medical Publishers, Inc; 1989:160-209.

Edhouse J, Brady WJ, Morris F. ABC of clinical electrocardiography. Acute myocardial infarction-Part II. BMJ. 2002;324:963-966.

Goldberger A, Goldberger E. Myocardial ischemia and infarction I and II. Clinical Electrocardiography. 5th ed. St. Louis: Mosby-Year Book, Inc. 1994:87-122.

Grines CL, Bonow RO, Casey DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;49:734-739.

Hurst JW. Abnormalities of the S-T segment—part I. Clin Cardiol. 1997;20:511-520.

Hurst JW. Abnormalities of the S-T segment—part II. Clin Cardiol. 1997;20:595-600.

Hurst JW. Thoughts about the ventricular gradient and its current clinical use (part I of II). Clin Cardiol. 2005;28:175-180.

Hurst JW. Thoughts about the ventricular gradient and its current clinical use (part II of II). Clin Cardiol. 2005;28:219-224.

Hurst JW. Thoughts about the abnormalities in the electrocardiogram of patients with acute myocardial infarction with emphasis on a more accurate method of interpreting ST segment displacement: part I. Clin Cardiol. 2007;30:381-390.

Hurst JW. Thoughts about the abnormalities in the electrocardiogram of patients with acute myocardial infarction with emphasis on a more accurate method of interpreting ST segment displacement: part II. Clin Cardiol. 2007;30:443-449.

The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-969.

Mirvis DM, Goldberger AL. Electrocardiography. In: Zipes DP, Libby P, Bonow RO, et al, eds. Braunwald's Heart Disease, A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: Elsevier/Saunders; 2005:107-148.

Morris F, Brady WJ. ABC of clinical electrocardiography. Acute myocardial infarction—part I. BMJ. 2002;324:831-834.

Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint International Society and Federation of Cardiology/World Health Organization task force on standardization of clinical nomenclature. Circulation. 1979;59:607-609.

Sgarbossa EB, Wagner GS. Electrocardiography. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1329-1363.

Wagner GS. Ischemia and injury due to insufficient blood supply. In: Marriott's Practical Electrocardiography. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2001: 163-178.

Yan G-X, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation. 1998;98:1928-1936.

Yan G-X, Lankipalli RS, Burke JF, et al. Ventricular repolarization components on the electrocardiogram. Cellular basis and clinical significance. J Am Coll Cardiol. 2003;42:401-409.