John J. Fenoglio

Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing.

Structural and electrophysiological properties of the epicardial muscle which survives on the surface of transmural infarcts of the canine heart (epicardial border zone) were studied at different times after occlusion of the left anterior coronary artery (LAD). Isolated preparations were superfused in vitro, transmembrane potentials recorded, and impulse propagation mapped. In preparations from subacute infarcts (1 and 5 days), resting potential, action potential amplitude, upstroke velocity, and duration were all significantly reduced. Well-defined directional differences in propagation occurred. Propagation was more rapid in the direction perpendicular to the left anterior coronary artery than in the direction perpendicular to the base of the heart, because of the uniform anisotropic structure of the surviving muscle fibers which were arranged in tightly packed bundles oriented perpendicular to the left anterior coronary artery. The only ultrastructural abnormalities found in these muscle fibers was an accumulation of large amounts of lipid droplets. As the infarcts healed, resting potential, action potential amplitude, and upstroke velocity returned to normal by 2 weeks, although action potential duration decreased further. Lipid droplets had disappeared, and connective tissue had invaded the epicardial border zone, separating the muscle bundles. By 2 months, action potentials were normal, but the muscle fibers were widely separated and disoriented by the connective tissue (parallel bundles no longer were found). In these regions with a nonuniform anisotropic structure, the well-defined directional differences in impulse propagation were lost. However, activation was very slow, perhaps because of diminished connections between cells. The persistence of slow conduction in healed infarcts may contribute to the occurrence of chronic arrhythmias.

Diagnosis and Classification of Myocarditis by Endomyocardial Biopsy

Myocarditis was diagnosed by endomyocardial biopsy in 34 patients with otherwise unexplained heart failure. On the basis of both clinical and histologic findings these patients were divided into three groups. Seven patients had acute myocarditis (mean age, 20 years; mean ejection fraction, 22 per cent) characterized by an interstitial inflammatory infiltrate and extensive, acute cell damage. Five of these patients died after a mean duration of illness of eight weeks. Eighteen patients had rapidly progressive myocarditis (mean age, 35 years; mean ejection fraction, 19 per cent) characterized by patchy acute and healing cell damage and fibrosis; 17 of them died after a mean duration of illness of 23 months. Nine patients had chronic myocarditis (mean age, 31 years; mean ejection fraction, 31 per cent) characterized by focal inflammation and cell damage. All nine were alive after a mean follow-up period of 39 months. In four of these nine, clinical and hemodynamic improvement occurred after one month of immunosuppressive therapy. Our study suggests that a clinically useful classification of myocarditis can be accomplished by endomyocardial biopsy.

Survival of Subendocardial Purkinje Fibers after Extensive Myocardial Infarction in Dogs

Alterations in cardiac electrophysiology that accompany myocardial infarction were studied in dogs subjected to a two-stage ligation of the anterior descending coronary artery. A multipolar transmural needle electrode was used to record electrical activity from the in situ infarcted heart 24 hours after coronary occlusion. Bipolar electrograms recorded from subendocardial regions of infarcted myocardium demonstrated the persistence of early, rapid deflections suggesting Purkinje fiber activity; evidence of ventricular muscle activity in the infarct was absent in both subendocardial and intramural electrograms. The infarcted myocardium and the adjacent non-infarcted tissue were then excised and studied with intracellular microelectrodes in vitro. Transmembrane action potentials could be recorded from one or two cell layers of subendocardial Purkinje fibers at all sites within the infarcted region, but no ventricular muscle action potentials were found. Subendocardial Purkinje fibers which survived in the infarct had reduced maximum diastolic potentials, action potential amplitudes, and maximum depolarization velocities compared with normal subendocardial Purkinje fibers; also, action potential durations in these surviving fibers were extraordinarily prolonged. Spontaneous diastolic depolarization was evident in some surviving fibers. Since subendocardial Purkinje fibers that generate abnormal action potentials survive in an infarct, these fibers may participate in the genesis of ventricular arrhythmias that accompany infarction.

Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses: Experimental approach and initial results demonstrating reentrant excitation☆

Epicardial activation patterns were determined during repetitive responses and nonsustained and sustained ventricular tachycardias induced by premature impulses in infarcted canine hearts. A multiplexing system enabled recordings to be obtained from up to 192 electrodes simultaneously either from the entire epicardial surface with a sock electrode array or only from the sheet of epicardial muscle that survives over the infarcts, with a plaque electrode array. In hearts with an infarct caused by permanent occlusion of the left anterior descending coronary artery, the earliest epicardial excitation during nonsustained tachycardias occurred on the anterior left ventricle at the border of the infarcted region and in epicardial muscle surviving over the infarcted region. Circuitous conduction patterns leading to reentry occurred in the epicardial muscle over the infarct and probably caused the arrhythmias. During sustained tachycardia in hearts with an infarct caused either by permanent or temporary occlusion of the left anterior descending coronary artery, the earliest epicardial excitation also occurred at the border of the infarcted region, but there was no evidence of reentry in the surviving epicardial muscle.

Congenital bicuspid aortic valve after age 20.

The bicuspid aortic valve is recognized as a frequent cause of aortic stenosis in adults. Aortic stenosis has been reported to occur in as many as 72 percent of adults with a congenital bicuspid aortic valve, with peak incidence occurring in the 5th and 6th decades of life. Review of the clinical records of 152 patients aged 20 years and older found to have a bicuspid aortic valve at autopsy revealed aortic stenosis in only 28 percent. The incidence of aortic stenosis increased progressively with age; 46 percent of patients over age 50 years and 73 percent over age 70 years had some degree of stenosis. The stenotic valves were obstructed by nodular, calcareous masses but commissural fusion was present in only eight cases. The largest group of patients in the series (40 percent) died of infective endocarditis; 77 percent of these were under age 50 years. Primary aortic regurgitation without infective endocarditis was uncommon. Thirty-two percent of the patients in this series had an apparently normally functioning aortic valve, and this rate remained relatively constant with increasing age; 37 percent of patients over age 50 years and 27 percent over age 70 years had an apparently normal valve. The bicuspid aortic valve in patients over age 20 does not invariably become stenotic or insufficient.

Protracted ventricular tachcardia induced by premature stimulation of the canine heart after coronary artery occlusion and reperfusion.

The effects of premature ventricular stimuli were studied in two groups of dogs with infarcts, one group subjected to permanent occlusion of the left anterior descending coronary artery and the other to temporary occlusion for 2 hours. In dogs with permanent occlusion, spontaneous ventricular arrhythmias occurred after 3-6 hours. In 13 dogs with temporary occlusion, ventricular arrhythmias occurred immediately after reperfusion and then persisted. In five dogs with temporary occlusion, ventricular arrhythmias did not occur spontaneously until 13-15 hours after occlusion. On days 2-9 after surgery, after sinus rhythm had returned, the ventricles of each awake dog were stimulated. After permanent occlusion, premature stimuli occurring on the T wave usually induced from one to 10 repetitive responses on days 2-4. Protracted ventricular tachycardia (lasting greater than 10 seconds) was induced in only two of 10 dogs. The response to premature stimuli was similar after temporary occlusion when ventricular arrhythmias did not occur spontaneously until 13-15 hours after occlusion. Protracted tachycardia was not induced. In the dogs with temporary occlusion, which initially had continuous arrhythmias, premature stimuli occurring on the T wave on days 3-5 after surgery induced both repetitive responses and protracted ventricular tachycardia. Stimuli applied to the ventricles during tachycardia terminated it. Histological studies on all infarcts showed that, after permanent occlusion, necrosis was uniform; after temporary occlusion, viable myocardium survived in the necrotic region. These salvaged myocardial fibers may provide reentrant pathways, causing long-lasting tachycardia.

Time course for reversal of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs.

The electrophysiological properties of subendocardial Purkinje fibers surviving in myocardial infarcts were studied with intracellular microelectrodes in isolated superfused preparations and correlated with subsequent light and electron microscopic studies. Transmembrane action potentials could always be recorded from one or two cell layers of subendocardial Purkinje fibers in infarcted regions 3 days to 7 weeks after coronary artery occlusion; ventricular muscle action potentials were rarely found. Microscopic studies also demonstrated several layers of intact subendocardial Purkinje fibers; the subjacent ventricular muscle cells were irreversibly injured and replaced by scar. At all time intervals, surviving Purkinje fibers had significantly reduced maximum diastolic potentials, action potential amplitudes, and depolarization velocities as well as prolonged action potential durations. These parameters normalized between 24 hours and 7 weeks after coronary artery occlusion. Surviving Purkinje fibers with electrophysiological abnormalities at 24 hours and 3 days contained vast lipid deposits. Lipid was less prevalent at 10 days when action potential characteristics had improved. By 7 weeks, action potentials were nearly normal and lipid was absent. Subendocardial Purkinje fibers surviving in infarcts are subject to conditions which cause electrophysiological and ultrastructural abnormalities. Persistent abnormalities in the electrophysiological properties of these surviving Purkinje fibers may cause persistent altered electrophysiological properties of the infarcted heart.

Pericardial cysts. A radiologic-pathologic correlation and review

Pericardial cysts are generally described as round radiodensities typically found at the right cardiophrenic angle in asymptomatic individuals. A review of all cases of pericardial cysts from the files of this Institute reveals that approximately one third of the cysts are found in other locations and that approximately one third of patients have symptoms of chest pain, dyspnea, or persistent cough. The radiographs of 41 patients show that in all but 6 of the cases the cyst is visualized as a round radiodensity touching both the hemidiaphragm and the anterior chest wall. Surprisingly, 15 of the 41 occurred on the left border of the heart. The six cysts significantly above the diaphragm were difficult to diagnosis radiologically and were usually mistaken for thymomas or pulmonary masses; two such cysts caused bronchial obstruction. In general, the possibility that a mass in either anterior cardiophrenic angle is a pericardial cyst should be strongly considered, even if the mass is on the left side and even if the patient is symptomatic.

Drug related vasculitis: Clinicopathologic correlations in 30 patients*

Drug related vasculitis has variously been described as necrotizing hypersensitivity or allergic angiitis or microscopic panarteritis nodosa. We reviewed tissue sections from 30 patients with validated drug hypersensitivity and vasculitis in order to precisely define this entity. No evidence of necrotizing vascular lesions or of fibrinoid associated with necrosis was found. The vascular lesions in all 30 patients involved small arteries, arterioles, capillaries, and venules. The inflammatory infiltrate consisted primarily of mononuclear cells and prominent numbers of eosinophils and was present in all three layers of the involved vessel walls. Clinically the patients developed either localized or systemic vasculitis, which could not be predicted on the basis of the associated drug. The findings of a skin rash, fever, or eosinophilia and the development of symptoms consistent with a hypersensitivity reaction while medication was being taken were all suggestive of the diagnosis of drug related vasculitis.

Electrophysiological properties of cardiac muscle in the anterior mitral valve leaflet and the adjacent atrium in the dog. Possible implications for the genesis of atrial dysrhythmias.

Transmembrane action potentials were recorded from multiple sites in isolated canine anteromedial left atrial wall preparations with the anterior mitral valve leaflet attached. The preparations were superfused with Tyrodes solution. When the left atrial wall was electrically stimulated, activity propagated into the mitral valve leaflet. Typical atrial action potentials occurred in atrial wall fibers. However, maximum diastolic potential, total action potential amplitude, and rate of depolarization decreased markedly in the atrium overlying the fibrous annulus (junctional region), and repolarization characteristics were altered in this region. Mitral valve muscle fibers demonstrated still lower maximum diastolic potential, action potential amplitude, and rate of depolarization. Electrical excitation of single discrete regions in the mitral valve leaflet did not result in conduction to the atrium; conduction block occurred in the junctional region. However, simultaneous excitation of several mitral valve sites did cause an impulse to propagate to the atrium, but transmembrane action potentials of junctional fibers were characteristically different from those recorded from the same junctional fibers during activation from the atrium. Muscle fibers in the mitral valve leaflet were capable of developing spontaneous diastolic depolarization, which resulted in automatic impulse initiation, when they were exposed to epinephrine or norepinephrine (1 × 10−7 to 1 × 10−5M) or when they were stretched. Spontaneous diastolic depolarization and automaticity also occurred occasionally without pharmacological or other experimental interventions; moreover, spontaneous activity originating in the mitral valve leaflet could propagate into and activate the atrial wall. Acetylcholine abolished spontaneous activity. These data suggest that the mitral valve could act as a site of ectopic impulse initiation in the left atrium.