Faculty Bibliography

This study tests the hypothesis that hypocontractile, borderzone myocardium adjacent to an expanding infarct becomes progressively larger and more hypocontractile as remodeling continues. Early infarct expansion following anteroapical myocardial infarction (MI) is associated with progressive ventricular dilation and heart failure. The contribution of perfused, hypocontractile, borderzone myocardium to this process is unknown. Using a sheep model of anteroapical infarction, sonomicrometry array localization and serial microsphere injections were used to track changes in regional myocardial contractility, geometry, and perfusion. Eight sheep were studied before and after infarction and two, five, and eight weeks later. Thirty intertransducer chord lengths were analyzed to measure regional contractility and serial changes in regional geometry at end systole. Beginning as a narrow band of fully perfused hypocontractile myocardium adjacent to the infarction, borderzone myocardium extends to involve additional contiguous myocardium that progressively loses contractile function as the heart remodels. Three distinct myocardial zones develop as a result of transmural MI: infarct, borderzone (perfused but hypocontractile), and remote (perfused and normally functioning).This study demonstrates that hypocontractile, fully perfused borderzone myocardium extends to involve contiguous normal myocardium during postinfarction remodeling. This borderzone myocardium is a unique type of perfused, hypocontractile myocardium, which is distinct from hibernating or stunned myocardium. Preventing extension of borderzone myocardium by medical or surgical means offers the prospect of preventing late-onset heart failure following transmural expanding MIs.

BACKGROUND:Coronary arterial disease is the major cause of congestive heart failure, but suitable animal models of postinfarction, dilated cardiomyopathy do not exist. This article describes an ovine model that develops after an anterobasal infarction. METHODS:The distribution of ovine myocardium supplied by the first two diagonal branches of the left homonymous artery were determined in 20 slaughterhouse hearts and eight live sheep using methylene blue and tetrazolium injections, respectively. Seven additional animals had the infarction and underwent serial hemodynamic, microsphere and echocardiographic studies more than 8 weeks and histologic studies at the eighth week. Infarcts represented 24.6% +/- 4.7% and 23.9% +/- 2.2% of the left ventricular mass in slaughterhouse and live hearts, respectively. RESULTS:During remodeling, left ventricular end-systolic and end-diastolic volumes increased 115% and 73%, respectively, ejection fraction decreased from 41.2% +/- 6.7% to 29.1% +/- 5.7%, systolic wall thickening remote from the infarct decreased by 68%, sphericity index increased from 0.465 +/- 0.088 to 0.524 +/- 0.038, and left ventricular end-diastolic pressure increased from 1.7 +/- 1.0 to 8.2 +/- 3.5 mm Hg. Serial microsphere measurements documented normal blood flow (1.34 mL/g per minute) to all uninfarcted myocardium and 22% of normal to the infarct. Viable myocardium showed mild interstitial fibrosis. CONCLUSIONS:This ovine model meets all criteria for postinfarction, dilated cardiomyopathy and has the advantages of controlling for variations in coronary arterial anatomy, collateral vascularity, and differences in the numbers, location, and severity of atherosclerotic lesions that confound human studies of the pathogenesis of this disease. This simple model contains only infarcted and fully perfused, hypocontractile myocardium produced by a moderate-sized, regional infarction.

BACKGROUND:There is increasing evidence to support a role for stem cells in the regeneration and repair of the human cardiovascular system. However, significant controversy still remains about the extent of chimerism present in blood vessels and myocytes of transplanted human hearts. METHODS AND RESULTS/RESULTS:We investigated the contribution of infiltrating host cells to human cardiac allografts by evaluating the origin of vascular smooth muscle cells and cardiac myocytes in hearts after orthotopic cardiac transplantation. Smooth muscle cells were identified in pathological human coronary artery specimens with antibodies against smooth muscle alpha-actin. DNA in situ hybridization for the human Y chromosome was then performed on the same samples to identify cells of male origin. Both myocytes and vascular smooth muscle cells were examined for the presence of the Y chromosome in sex-mismatched specimens. In positive control samples, 34.7% of nuclei contained a detectable Y chromosome; in sex-mismatched samples, 2.6% of the smooth muscle cells examined were of host origin. The Y chromosome in myocyte nuclei in male positive controls was detected; however, despite examination of >6000 myocyte nuclei in sex-mismatched specimens, we were unable to detect any nuclei with the clear presence of the Y chromosome. CONCLUSIONS:Vascular smooth muscle cells of infiltrating host cell origin can be found in human cardiac allografts. However, unlike prior reports, we found no evidence that chimerism is present in cardiac myocytes.

INTRODUCTION/BACKGROUND:Limitations in lesion volume and particularly lesion depth may negatively effect the efficacy of catheter ablation procedures using radiofrequency energy. This study evaluated the safety and efficacy of myocardial ablation using direct intramural injection of ethanol with a novel injection catheter system. METHODS:Left ventricular lesions were performed in 9 male swine (80-85 pounds); two animals were studied 6 weeks following anterior infarction produced by agarose gel embolization. An 8 Fr deflectable catheter equipped with a 27 gauge adjustable depth, retractable needle was directed to the LV using a retrograde aortic approach. Lesion deployment was guided by fluoroscopy and intracardiac echocardiography (ICE). Lesion characteristics were assessed with ICE imaging and pathologic analysis. RESULTS:Ethanol lesions were confined to the tissue directly adjacent to the injection port. Lesions were intramural with no evidence of overlying thrombus. Lesions delivered with a single port injection needle in normal myocardium (n = 24) averaged 1910 +/- 1066 mm(3) with a depth of 8.9 +/- 3.3 mm. Lesions directed to infarct border zones (n = 4) averaged 929 +/- 882 mm(3) with a depth of 4.3 +/- 2.8 mm. Lesions were immediately evident on ICE imaging, and were visualized by increased echo density and tissue swelling. Pathological analysis revealed homogenous lesions with intramural hemorrhage and contraction band necrosis. CONCLUSIONS:Myocardial catheter ablation using direct ethanol injection is feasible, and relatively large and deep intramural lesions can be delivered, even in the infarct border zone. This technique may prove useful in ablation of arrhythmia substrates that are deep to the endocardial surface.

The contractile force of the cardiomyocyte is transmitted through the adherens junction, a component of the intercalated disc, enabling the myocardium to function as a syncytium. The cadherin family of cell adhesion receptors, located in the adherens junction, interact homophilically to mediate strong cell-cell adhesion. Ectopic expression of cadherins is associated with changes in tumor cell behavior and pathology. To examine the effect of cadherin specificity on cardiac structure and function, we expressed either the epithelial cadherin, E-cadherin, or N-cadherin in the heart of transgenic mice. E-cadherin was localized to the intercalated disc structure in these animals similar to endogenous N-cadherin. Both N- and E-cadherin transgenic animals developed dilated cardiomyopathy. However, misexpression of E-cadherin led to earlier onset and increased mortality compared with N-cadherin mice. A dramatic decrease in connexin 43 was associated with the hypertrophic response in E-cadherin transgenic mice. Myofibril organization appeared normal although, vinculin, which normally localizes to the intercalated disc, was redistributed to the cytoplasm in the E-cadherin transgenic mice. Furthermore, E-cadherin induced cyclin D1, nuclear reduplication, and karyokinesis in the absence of cytokinesis, resulting in myocytes with two closely opposed nuclei. By contrast, N-cadherin overexpressing transgenic mice did not exhibit an increase in cyclin D1, suggesting that E-cadherin may provide a specific growth signal to the myocyte. This study demonstrates that modulation of cadherin-mediated adhesion can lead to dilated cardiomyopathy and that E-cadherin can stimulate DNA replication in myocytes normally withdrawn from the cell cycle.

Cardiac myxomas are the most frequent cardiac tumors and cause for significant morbidity and mortality. Recent evidence indicates that cardiac myxomas are, in fact, neoplasms rather than organized thrombi. Cardiac myxomas may present as solitary lesions or in association with the Carney complex. Carney complex has been linked to chromosome 2p16 and the PRKAR1A gene at 17q22-24. In this study, we analyzed sporadic cardiac myxomas to evaluate whether the genetic alterations seen in Carney complex are present in non Carney complex associated cardiac myxomas as well. We analyzed microdissected material from 13 patients with cardiac myxomas for the markers PRKAR1 9CA, D2S2153, D2S2251 and D2S123. None of the cases demonstrated loss of heterozygosity or definite band changes suggestive of microsatellite instability for any of the markers used. We conclude that sporadic cardiac myxomas are genetically not related to Carney complex and most likely do not represent an incomplete form of Carney complex.