Faculty Bibliography

INTRODUCTION/BACKGROUND:Radiofrequency (RF) catheter ablation for ventricular tachycardia (VT) in healed infarction is modestly successful. More extensive, anatomically based procedures and irrigated RF delivery may improve outcome. However, limited data exist regarding the characteristics of irrigated RF lesions in infarcted myocardium. This study addresses this shortcoming. METHODS AND RESULTS/RESULTS:Linear lesions were created at the medial border of a healed anterior infarct in eight pigs using irrigated RF energy guided by sinus rhythm electroanatomic voltage mapping and intracardiac echocardiography (ICE). Lesion morphology and effects on ventricular function were assessed with ICE imaging and pathologic analysis (n = 5). The response to programmed stimulation also was determined before and after linear lesions (n = 6). A mean of 9.4 +/- 1.3 RF applications created linear lesions 37.0 +/- 10.6 mm long, 5 to 12 mm wide, and 4 to 8 mm deep. Thrombus formation was not observed. Lesion delivery resulted acutely in increased local wall thickness at the RF site (26.9% +/- 27.5%; P < 0.0001) and transient systolic dysfunction in adjacent normal myocardium (fractional shortening -38% +/- 34%; P < 0.01). Uniform sustained VT (cycle length 232 +/- 41 msec) was induced in 4 of 6 pigs before ablation, but sustained VT could not be induced afterward. CONCLUSION/CONCLUSIONS:Irrigated RF energy produced relatively large lesions in infarcted myocardium without thrombus formation. Changes in tissue thickness and echo density observed with ICE verify irrigated RF lesion delivery. Temporary left ventricular dysfunction is consistently observed in the normal myocardium adjacent to the linear lesion.

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.

BACKGROUND:In this study we tested the hypothesis that delayed reperfusion of ischemic myocardium-too late to save myocytes-attenuates infarct expansion and improves collagen synthesis. METHODS:The hypothesis was tested in a sheep model of anteroapical infarction that has no collateral blood flow to the area at risk. After coronary ligation or arterial occlusion for 1 or 6 hours, sheep had serial hemodynamic and quantitative echocardiographic studies before and after infarction and 2, 5, 8, and 12 weeks later. Hearts were examined by light and electron microscopy at 2 and 12 weeks; hydroxyproline and ratios of type I/III collagen were measured at 12 weeks. RESULTS:After coronary occlusion, left ventricular (LV) function progressively decreased and size increased to form an anteroapical aneurysm. After 1 hour of ischemia, neither resting LV size nor function changed; the infarct contained a midmyocardial scar between epicardial and endocardial muscle. After 6 hours of ischemia, LV function was significantly better than that in nonperfused sheep. Two weeks after 6 hours of ischemia, no viable myocytes were visible by light microscopy, but electron micrographs showed rare intact nucleated myocytes with scarce cytoplasmic myofibrils. At the 12th week epicardial and endocardial myocytes reappeared in the infarct. Infarct collagen type I/III ratios were 1.2 in reperfused groups and 0.7 in nonperfused sheep. CONCLUSIONS:Delayed reperfusion causes loss and subsequent reappearance of ovine epicardial myocytes, improves collagen type I/III ratios, and attenuates LV dilatation and loss of function. One hypothesis to explain the reappearance of myocytes is that reperfusion partially reverses an incomplete apoptotic process.

A 33-year-old man had cardiomegaly on a routine x-ray examination. He was asymptomatic with no history of infarction, syncope, or palpitations. There was no family history of congenital heart disease or sudden death. Two-dimensional transthoracic echocardiography demonstrated marked enlargement of the right atrium and ventricle with severely depressed right and left ventricular function that was consistent with right ventricular dysplasia. The patient was treated with an angiotensin-converting enzyme inhibitor and did well for 6 months, but then developed symptomatic left-sided congestive heart failure. Short-term improvement was obtained with intravenous inotropic therapy, but he continued to have progressive symptoms of heart failure. Approximately 7 months after his initial presentation, the patient underwent orthotopic heart transplantation for intractable congestive heart failure. Pathologic examination of the explanted heart established the diagnosis of right ventricular dysplasia with left ventricular involvement. This is an uncommon presentation of right ventricular dysplasia with biventricular involvement and no known family history.