Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice.

BACKGROUND: To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. METHODS AND RESULTS: After 16 weeks of "Western-type" diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. CONCLUSIONS: eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.

Left ventricular hamartoma associated with ventricular tachycardia.

Cardiac hamartomas are a rare type of benign tumor affecting the heart. We describe a 33-year-old patient who presented with a wide complex tachycardia. Diagnostic imaging revealed a mass in the patient's left ventricular wall, near the apex of the heart. The mass was surgically resected and appeared benign. Its pathology was that of a hamartoma of mature cardiac myocytes. Postoperative electrophysiology evaluation showed no inducible focus and the patient remains alive and asymptomatic after 2 years of follow-up.

Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction.

We sought to evaluate the underlying coronary pathology of fatal postoperative myocardial infarction (MI). It has been hypothesized that most MIs following noncardiac surgery occur in the setting of increased oxygen demand that exceeds coronary blood supply. However, most MIs not associated with surgery are caused by plaque rupture and intracoronary thrombosis. In a retrospective cohort study, we reviewed 1841 consecutive autopsy records from 1981 to 1995 at two institutions and identified 26 cases of postoperative MI with coronary arteries available. Plaque rupture was present in 12 cases (46%, 95% confidence interval [CI] 27%-67%). Of the 9 (35%) patients with intracoronary thrombus, 5 (56%; 19% of entire group) had total occlusion. Thrombus occurred on a >50% stenosis (by cross-sectional area) in a total of 33% (95% CI 16%-55%) of patients. The only statistically significant difference in clinical variables between patients with and without plaque rupture was longer interval from surgery to death in patients with plaque rupture (7.8+/-4.4 days versus 4.4+/-4.8 days; p = 0.047). In this autopsy series, coronary plaque rupture was associated with almost half of fatal postoperative MI cases. Strategies aimed at reducing triggers of plaque rupture with coronary occlusion might reduce postoperative MI fatality.

Segmental mediolytic arteriopathy of the splenic and hepatic arteries mimicking systemic necrotizing vasculitis.

Segmental mediolytic arteriopathy, a rare, noninflammatory arterial disease, is fundamentally a variant of fibromuscular dysplasia. The characteristic angiographic findings of segmental mediolytic arteriopathy include the "string of beads" and microaneurysms which are indistinguishable from those of vasculitis, and the correct diagnosis can be made only after histopathologic evaluation of the arterial lesions. Thrombosis, arterial wall hemorrhage, and dissection are among the complications of segmental mediolytic arteriopathy. We describe herein a patient with segmental mediolytic arteriopathy who presented with hemoperitoneum. The patient underwent urgent surgical repair of a ruptured hepatic artery aneurysm. The postoperative visceral arteriography findings led to a clinical diagnosis of polyarteritis nodosa, and immunosuppressive therapy was initiated. This treatment was stopped as soon as the correct biopsy diagnosis of segmental mediolytic arteriopathy was obtained through outside consultation. The patient recovered without drug treatment and was spared the potentially life-threatening complications of immunosuppression.

Local delivery of c-myb antisense oligonucleotides during balloon angioplasty.

Intraluminal delivery of antisense oligonucleotides to c-myb was assessed following balloon angioplasty in swine peripheral arteries. Successful delivery and intramural persistence of oligonucleotide for over 24 h were demonstrated following angioplasty with hydrogel balloons coated with 32P-labeled antisense. Delivery of fluorescein-labeled antisense demonstrated further localization within the arterial media and intracellularly. Preliminary in vitro studies demonstrated the feasibility of inhibition of porcine lymphocyte proliferation using the murine antisense to c-myb. Twelve iliac or carotid arteries underwent angioplasty with antisense-coated balloons, while the contralateral vessels underwent angioplasty with the same-sized balloons coated with the complementary sense strand. Six to seven days later, dilated arterial segments were surgically isolated. In 10 of 12 vessel pairs, antisense-treated vessels demonstrated less cellular proliferation than did contralateral sense-treated vessels, as assessed by quantitative immunohistochemical staining of proliferating cell nuclear antigen, and smooth muscle cell proliferation was reduced 18% in antisense-treated vessels compared to the contralateral sense-treated vessels (PCNA-positive nuclear area: 7.7 +/- 4.9% vs. 9.3 +/- 5.2%, P < 0.04)-intraluminal delivery of antisense oligonucleotides to c-myb is feasible with a catheter-based system and may reduce smooth muscle cell proliferation following arterial injury.

Multicenter validation study of real-time ultrasonography, arteriography, and pathology: pathologic evaluation of carotid endarterectomy specimens.

The morphologic description and measurements of endarterectomy specimens are usually believed to be accurate and are used as the gold standard against which the findings of diagnostic procedures are judged. Pathology data on 289 endarterectomy specimens from five participating centers and the corresponding angiography and B-mode ultrasonography data provided a basis for scrutinizing the validity of using the morphologic measurements as a standard. Discrepancies of greater than 1 mm between pathology and angiography measurements of minimum residual lumen occurred in 35% of the cases and between pathology and B-mode ultrasonography measurements in 64% of the cases. Discrepancies of greater than 1 mm between pathology- and angiography-measured lesion width occurred in 81% of the cases and between pathology and B-mode ultrasonography measurements in 64% of the cases. The cases representing mismatches of greater than 1 mm at one participating center were subjected to a rigorous review, with remeasurement of all morphologic features, in an attempt to explain the discrepancies. Various types of artifactual distortion of the specimens, the presence of slit-like and occluded lumens that were likely related to loss of perfusion pressure, and an inability to match planes of interrogation used in angiography and B-mode ultrasonography with pathology planes contributed significantly to the existence of mismatches. On the other hand, fixation and decalcification produced minimal and insignificant distortional changes. We conclude that the acquisition of quantitative data from endarterectomy specimens and the acceptance of morphologic data as a standard are limited by a number of problems that can be defined but have been difficult to resolve.

Enhanced myocardial protection during ischemic arrest. Oxygenation of a crystalloid cardioplegic solution.

To determine if, during elective cardiac arrest, the myocardial protection afforded by a cold (4 degrees C) crystalloid potassium cardioplegic solution could be improved by oxygenation of the solution, we placed 16 dogs on cardiopulmonary bypass and subjected their hearts to 4 hours of cold cardioplegic arrest. Group 1 hearts (n = 8) received aerated crystalloid solution perfused through the aortic root every 20 minutes. Group 2 hearts (n = 8) were treated identically except that the crystalloid cardioplegic solution was fully oxygenated. Left ventricular function curves (ejecting heart) were generated before arrest (control) and after 45 minutes of reperfusion. A cardiac output of 1,000 ml/min could be attained in only two hearts of Group 1 after reperfusion, whereas all but one heart of Group 2 had excellent functional preservation. Mean postreperfusion adenosine triphosphate (ATP) levels in Group 1 and Group 2 hearts were 62% and 89% of control, respectively (p less than 0.01). Myocardial water content had increased significantly (p less than 0.002) after reperfusion in Group 1, but not in Group 2. During cardioplegic solution infusion, myocardial oxygen consumption (MVO2) was 1.42 +/- 0.15 ml O2/min/100 gm LV for Group 1 and 6.91 +/- 1.27 ml O2/min/100 gm LV for Group 2 (p less than 0.001). Oxygen consumed per minute of arrest was 0.027 +/- 0.003 ml O2/min/100 gm LV for Group 1 and 0.128 +/- 0.015 ml O2/min/100 gm LV for Group 2 (p less than 0.001). Postreperfusion ultrastructural evaluation of two of the Group 1 hearts revealed severe ischemic damage in contrast to the normal ultrastructural appearance of two of the Group 2 hearts. With careful attention given to maintenance of myocardial hypothermia and cardioplegic delivery methods, the myocardial protection afforded by an oxygenated crystalloid cardioplegic solution exceeds that provided by the aerated control and compares favorably with other methods of myocardial protection during ischemic arrest.

Comparison of myocardial preservation with hypothermic potassium and nifedipine arrest.

Preservation of regional myocardial function, high-energy phosphate stores and ultrastructure were assessed in 28 canine hearts subjected to 2 hours of global ischemia at either 12 degrees C or 21 degrees C. The preservation achieved with a potassium arrest solution was simultaneously compared in the same heart with either a nifedipine arrest solution or a potassium plus nifedipine arrest solution. There were no statistically significant differences in regional function recovery between the three arrest solutions at either temperature. At 12 degrees C, slightly better functional preservation was noted for each solution. End-systolic chord length was significantly less elongated after preservation at the lower temperature (p = 0.03). The concentration of ATP and myocardial water content were not significantly better preserved with any solution at either temperature. Myocardial ultrastructure was well preserved regardless of the solution or temperature used. The degree of hypothermia appears to be more important to functional preservation than differences between the three solutions tested. We conclude that with respect to preservation of myocardial function, high-energy phosphate stores, water content and ultrastructure, nifedipine arrest offers no advantages over potassium arrest.

Cutaneous malignant mixed tumor.

Two cases of cutaneous malignant mixed tumor occurred in a 70-year-old man and a 69-year-old man. Nine previously described patients with cutaneous malignant mixed tumor resembled the two patients in this report, both clinically and histologically. All cases with adequate long-term follow-up evaluations were characterized by recurrence or metastasis. In contrast to benign mixed tumors, these tumors tend to occur on the extremities, are of larger size, and may exhibit rapid growth. Histologically, cellular atypism, increased cellularity, increased mitotic rate, invasion of surrounding tissue, and necrosis may be identified.