Inhibition of norepinephrine-induced cardiac hypertrophy in s100beta transgenic mice.

We have recently reported that the Ca2+-binding protein S100beta was induced in rat heart after infarction and forced expression of S100beta in neonatal rat cardiac myocyte cultures inhibited alpha1-adrenergic induction of beta myosin heavy chain (MHC) and skeletal alpha-actin (skACT). We now extend this work by showing that S100beta is induced in hearts of human subjects after myocardial infarction. Furthermore, to determine whether overexpression of S100beta was sufficient to inhibit in vivo hypertrophy, transgenic mice containing multiple copies of the human gene under the control of its own promoter, and CD1 control mice were treated with norepinephrine (NE) (1.5 mg/kg) or vehicle, intraperitoneally twice daily for 15 d. In CD1, NE produced an increase in left ventricular/body weight ratio, ventricular wall thickness, induction of skACT, atrial natriuretic factor, betaMHC, and downregulation of alphaMHC. In transgenic mice, NE induced S100beta transgene mRNA and protein, but provoked neither hypertrophy nor regulated cardiac-specific gene expression. NE induced hypertrophy in cultured CD1 but not S100beta transgenic myocytes, confirming that the effects of S100beta on cardiac mass reflected myocyte-specific responses. These transgenic studies complement in vitro data and support the hypothesis that S100beta acts as an intrinsic negative regulator of the myocardial hypertrophic response.

Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression.

Continued adverse remodeling of myocardium after infarction may lead to progressive ventricular dilation and heart failure. We tested the hypothesis that exercise training in a healed myocardial infarction-dysfunction rat model can favorably modify the adverse effects of ventricular remodeling including attenuation of abnormal myosin gene expression. Sprague-Dawley rats were subjected to either proximal LAD ligation or sham operation. At 5 wk after the operation, animals were randomly assigned to sedentary conditions or 6 wk of graduated swim training, creating four experimental groups: infarct sedentary (IS), infarct exercise (IE), sham sedentary (SS), and sham exercise (SE). At 11 wk all rats were sacrificed and analyzed. Compared to sedentary infarct controls, exercise training attenuated left ventricular (LV) dilation and allowed more hypertrophy of the non infarct wall. The exercise-trained hearts also showed a reduction in the estimated peak wall tension. Northern blot analysis showed an increase in beta-myosin heavy chain expression in the hearts of the sedentary infarction group soon after infarction when compared to sham controls. However, with exercise training, there was a significant attenuation of the beta-myosin heavy chain expression in the myocardium. Exercise training in a model of left ventricular dysfunction after healed myocardial infarction can improve the adverse remodeling process by attenuating ventricular dilation and reducing wall tension. The abnormal beta-myosin expression was also attenuated in the exercise trained group. This is evidence that abnormal gene expression following severe myocardial infarction dysfunction can be favorably modified by an intervention.

Early degradation of collagen after acute myocardial infarction in the rat.

After acute myocardial infarction (MI), proteolysis of necrotic myocardium is mediated by infiltrating inflammatory cells at the infarct margins. Collagen forms a structural fibroskeleton in healthy myocardium, and after MI this collagen may continue to provide significant tensile strength to the necrotic muscle wall. To determine whether collagen is also degraded (which might decrease infarct wall strength) and, if so, whether inflammatory cell proteases are implicated, hydroxyproline was measured from infarct zone and normal zone tissue from 24-hour infarcts produced in control rats and in rats made leukopenic (white blood cell count less than 300/mm3) by prior whole-body irradiation. Hydroxyproline was measured after precipitation of tissue homogenates with trichloroacetic acid to separate partially degraded collagen from larger collagen molecules that might retain structural importance. At 24 hours, there was significant (25%) collagen degradation in the infarct zone (p less than 0.01) in control rats but not in leukopenic rats. Tissue cell counts revealed a paucity of inflammatory cells in the infarct margins in leukopenic rats. Electron microscopic studies revealed greater preservation of collagen in the 24-hour-old infarcts of irradiated leukopenic rats compared with those of control rats. These results suggest that at 24 hours after experimental MI in the rat, there is significant collagen degradation mediated by inflammatory cell proteases.

Histological and morphometric analyses of early and late aortocoronary vein grafts and distal anastomoses.

BACKGROUND: Aortocoronary vein grafts develop fibromuscular intimal hyperplasia within the first year of implantation. Tissue remodeling may promote development of graft atherosclerosis and thrombosis. Angiographic studies show that human aortocoronary vein grafts in situ for one or more years become stenosed, preferentially at the distal anastomosis versus the body or trunk of the graft or at the proximal anastomosis. Previous studies have not reported morphological data on the nature and distribution of intimal lesions around the distal graft/artery anastomoses. OBJECTIVE: To examine and quantify histological and morphometric changes within the intima of 27 aortocoronary vein grafts and their distal anastomoses. METHODS: Seventy-two hearts obtained at autopsy and one at heart transplantation were examined, photographed and fixed in 10% buffered formaldehyde solution. Three to seven 3 mm long segments of grafts and their distal anastomoses were sectioned, stained and examined by light microscopy. RESULTS: Eleven early grafts were implanted for six weeks or less, and they showed significant cellular hyperplasia mainly at the suture line. In 16 late grafts in situ 1.5 to 15 years, the degree of fibromuscular intimal thickening was greatest on the hood and at the suture line, whereas on the floor of the native artery and in the graft body the degree of thickening was approximately one-third and two-thirds, respectively, that seen on the hood. CONCLUSIONS: Stenosis of aortocoronary vein grafts at their distal anastomosis is likely related to the preferential development of intimal thickening on the hood of the graft and at the suture line. Because fibromuscular intimal hyperplasia has been reported to play a role in the development of atherosclerosis and thrombosis in the body of vein grafts, this focal hyperplasia at the distal anastomosis may also play a role in vein graft failure.

Giant cell myocarditis and myositis associated with thymoma and leprosy.

Myocarditis is an inflammatory form of heart disease which is usually preceded by a viral infection. Giant cell myocarditis is an uncommon and nonspecific form of this disease. Sporadic reports have linked giant cell myocarditis with thymoma and concomitant myositis. The authors report a patient with leprosy who, six months after initiation of treatment, developed sudden onset of congestive heart failure and cardiac arrhythmias unresponsive to aggressive medical therapy. In addition to confirming leprosy, autopsy showed a mixed cell type thymoma, severe giant cell myocarditis and extensive myositis.

Right heart pulmonary embolism in transit: a review of therapeutic considerations.

Two patients with pulmonary emboli and right heart masses detected on echocardiography are described. One patient underwent successful surgical embolectomy and the other was successfully treated with intravenous thrombolysis. Both were alive and well at six months' follow-up. The presence of a right heart clot in the setting of pulmonary emboli carries a very high mortality rate and warrants urgent therapy, which may include anticoagulation, thrombolysis or surgical embolectomy. Because limited information is available, therapy must be individualized based on patient characteristics, clot location and local expertise. The pertinent literature is reviewed and relevant issues in decision making are discussed.

Intracardiac extension of intravenous leiomyomatosis in a pregnant woman: A case report and review of the literature.

Intravenous leiomyomatosis is an uncommon clinical entity characterized by the growth of a benign, smooth muscle tumour within the venous system. Intracardiac extension of this tumour is rare, and approximately 35 cases have been reported in the literature. The second case of massive intracardiac extension of intravenous leiomyomatosis is reported in a pregnant patient diagnosed after the unusual presentation of seizure activity. Tumours were successfully removed from the right internal iliac vein, inferior vena cava, and right atrium and ventricle in a single-stage operation using cardiopulmonary bypass and circulatory arrest. Concomitant total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Nine months after diagnosis, the patient was evaluated for recurrent disease. A review of the literature from 1994 to 1998 is presented.

Myectomy for hypertrophic obstructive cardiomyopathy after failed alcohol septal ablation: clinicopathological correlations.

Hypertrophic cardiomyopathy - a genetically transmitted cardiac disorder - has diverse clinical, pathological and molecular manifestations. Echocardiography is the most reliable tool for clinical diagnosis of hypertrophic cardiomyopathy. Reduction of the intraventricular pressure gradient and improvement of symptoms are major objectives of all therapeutic strategies. The recently introduced concept of catheter-based interventional treatment involves selective coronary perforator branch injection of 96% ethanol to reduce septal thickness, left ventricular outflow obstruction, left ventricular filling pressure and symptoms. The long term morphological features after medical ablation are presented for the first time and compared with both the echocardiographic findings and the findings reported in the English-language literature. The findings show that injection of ethanol into the perforator branch is associated with a fairly localized area of myocardial scarring.

Clofazimine induced cardiotoxicity--a case report.

A 66-year-old Indian male who had been treated for recurrent erythema nodosum leprosum with 300 mg of clofazimine per day for 11 months presented to hospital with a 4 week history of severe gastrointestinal upset. Soon after admission he developed several short runs of ventricular tachycardia with a morphology suggestive of torsade de pointe. The patient had a slightly low magnesium level which was corrected within 2 days; however, his rhythm disturbance persisted for 5 days despite management with intravenous lidocaine. His gastrointestinal symptoms abated 2 weeks after clofazimine was discontinued. Subsequent investigations showed that the patient had a keratopathy and myelin-type figures in his polymorphonuclear white cells similar to that seen with the cardiotoxic drugs chloroquine and amiodarone. It is postulated that clofazimine alone or in conjunction with electrolyte disturbance was responsible for the patient's cardiac arrythmia.

Aortic valve replacement with stentless porcine bioprostheses.

Aortic valve replacement with stentless porcine valve should provide superior hemodynamic results to stented porcine valve because the obstruction caused by the stent and the sewing ring is eliminated. In addition, the coronary sinuses of the recipient may allow for better dissipation of the mechanical stress to which the leaflets are subjected during diastole, thus enhancing durability of the heterograft. Aortic valve replacement with stentless glutaraldehyde-fixed aortic porcine bioprosthesis was carried out successfully in six young sheep. These animals were hemodynamically evaluated at 3 to 6 months after operation and found to have no resting gradients or any degree of aortic regurgitation. Explantation of the aortic heterograft revealed that it was well healed in the aortic root and had no evidence of any calcification. A clinical trial has been initiated and the results in the first five humans who underwent aortic valve replacement with a stentless porcine aortic bioprosthesis have been satisfactory.

Trypanosoma cruzi: ultrastructural changes produced by an anti-trypanosomal factor from Pseudomonas fluorescens.

Trypomastigotes and amastigotes of Trypanosoma cruzi exhibited distinct ultrastructural alterations when treated with an extracellular lytic substance (anti-trypanosomal factor) produced by Pseudomonas fluorescens. Marked swelling of the parasites and detachment of the plasma membrane from the subjacent cytoplasm were observed after 15 min of treatment. After 3 hr, the nucleus was extensively damaged, the kinetoplast was indistinguishable, the mitochondrion was markedly swollen, the cytoplasm was disrupted, and the plasma membrane showed extensive blebbing and focal loss of subpellicular microtubules. These changes were progressive, as shown by the occurrence of parasite ghosts after 10 hr. Amastigotes exhibited an extremely swollen mitochondrion with disrupted internal structure, widening of the perinuclear space, and blebbing of the external nuclear membrane. The kinetoplast, however, remained clearly discernible. The drugs used today in controlling Chagas' disease are toxic. Therefore, there is a need for new anti-trypanosomal agents such as the Pseudomonas fluorescens antibiotics. The observations described in this study indicate the potential chemotherapeutic usefulness of these compounds for this disease.

Minimally invasive cardiac surgery for removal of the greater saphenous vein.

OBJECTIVE: To determine if saphenous vein required for coronary bypass could be quickly, easily and safely removed with a minimally invasive technique. DESIGN: A consecutive series. SETTING: A university centre. MATERIAL AND METHODS: In cadavers, a standard mediastinoscope was used to remove segments of the greater saphenous vein. Thigh segments, superior leg segments and ankle segments were removed. Fifteen minutes were allowed for removal of a segment. RESULTS: Segments of vein 15 to 17 cm long could be removed. One segment could not be removed within 15 minutes. Thigh segments were easy to remove, calf segments were the most difficult. There were no avulsed side branches. All incisions were less than 5 cm long. CONCLUSIONS: Saphenous vein can be harvested quickly and safely by a minimally invasive method. Lower extremity complications may be reduced and long-term patency improved with this in-situ technique of vein removal.

Prospective assessment of cardiac function in patients with Kaposi's sarcoma and the acquired immune deficiency syndrome.

Prospective evaluation of cardiac function was undertaken in 21 patients with Kaposi's sarcoma (KS) and the acquired immune deficiency syndrome (AIDS) as part of a phase II clinical trial of 4'epirubicin. All patients were homosexual or bisexual males of median age 34 years (range 23-65). All patients had disseminated cutaneous involvement by KS and seven had systemic organ involvement. No patient had a history of cardiac symptoms, and physical examination of the cardiovascular system was within normal limits for all patients. The baseline ECG was normal in only nine patients (45%). Five had non-specific S-T segment and T-wave changes. Two had poor R-wave progression, and one patient each had incomplete right bundle branch block, left axis deviation, and voltage criteria suggestive of left ventricular hypertrophy. Radionuclide angiography was performed on all patients and compared to 12 age-matched, low-likelihood male controls. The mean ejection fraction (EF) at rest was 61.0 +/- 8.4%, and was not significantly different from the normal control value of 62.4 +/- 7.0%. Similarly the EF during exercise was 66.7 +/- 5.0%, again not significantly different from the control value of 67.8 +/- 5.8%. A drop in EF during exercise was seen in five of 15 KS patients compared to three of 12 controls. Chamber size was normal for both ventricles in only 14 patients (67%) with right ventricular dilatation seen in seven patients (33%). Wall motion abnormalities were also seen in nine patients (42.9%), with the right ventricle affected in eight patients (38.1%), chiefly involving the apex. No chamber size or wall motion abnormalities were seen in the control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone pulmonary toxicity: functional and ultrastructural evaluation.

Pulmonary function, chest radiographic appearances, and the cellular composition of bronchoalveolar lavage fluid were assessed in 13 patients who were receiving amiodarone treatment. Eight of the patients had developed clinical and radiological evidence of lung disease and five were symptom free. The proportions of lymphocytes (mean 8.6 (SD 6.9)) and neutrophils (mean 3.4 (3.3)) obtained by bronchoalveolar lavage were similar in patients with and without lung complications. Electron microscopic examination of alveolar macrophages showed intralysosomal inclusion bodies in all subjects, regardless of clinical state. There was no significant difference in the mean number of inclusion bodies per macrophage transection between those with and those without lung disease. The differential cell count in bronchoalveolar lavage fluid and the presence of macrophage inclusion bodies were therefore not useful as markers of disease activity. Among those who developed clinical and radiological evidence of lung disease, the cumulative drug dose per kilogram of body weight and the duration of treatment (mean 16.5 (SD 9.0) months) were significantly correlated with the degree of lung restriction as measured by total lung capacity and forced vital capacity. It is concluded that, while the severity of the restrictive pulmonary defect that is induced by amiodarone is largely dose related, the development of lung toxicity is to some extent idiosyncratic.

Persistence of viral genome into late stages of murine myocarditis detected by polymerase chain reaction.

BACKGROUND: Enteroviruses have been considered as the most common etiologic agents in clinical myocarditis and dilated cardiomyopathy; however, their pathogenetic role remains unknown. Hence, the relation of viral replication and development of cardiomyopathy has been determined in a murine model of myocarditis by evaluating the persistence of viral genome during acute and chronic stages of myocarditis by means of Northern blot hybridization and polymerase chain reaction (PCR). METHODS AND RESULTS: DBA/2 mice (n = 146) were injected peritoneally with 10 plaque-forming units of encephalomyocarditis (EMC) virus, and the control mice (n = 33) were injected with normal saline. Animals were randomly killed at 4, 7, 10, 14, 21, 28, 35, and 42 days after infection. Histology revealed acute myocardial necrosis with massive inflammatory cell infiltrate peaking on day 14 followed by increasing fibrosis and declining chronic inflammation features compatible with dilated cardiomyopathy between days 21 and 42. Northern blot analysis of control and infected hearts showed detectable viral RNA in the infected hearts initially at day 4, peaking by day 7, diminishing between day 7 and day 14, and absent at day 21 and day 28. However, potential viral remnants present in low quantities and undetectable by Northern blot were further detected by PCR followed by confirmation with an internal oligonucleotide probe after day 14 up to day 42. CONCLUSIONS: Viral RNA signals on Northern blot showed a strong correlation with massive myocyte necrosis on day 14, but the viral RNA fragment was consistently detectable into late stages of cardiomyopathy on days 21, 28, 35, and 42 by PCR. This indicated that the mature virions are fully developed early in infection and are capable of persisting in the myocardium after virus-mediated myocytolysis stage. Therefore, PCR is an extremely sensitive method for detecting residual viral genome and viral persistence in the myocardium and may offer insights into the pathogenesis of chronic myocarditis leading to dilated cardiomyopathy.

S100beta inhibits alpha1-adrenergic induction of the hypertrophic phenotype in cardiac myocytes.

In an experimental rat model of myocardial infarction, surviving cardiac myocytes undergo hypertrophy in response to trophic effectors. This response involves gene reprogramming manifested by the re-expression of fetal genes, such as the previously reported isoform switch from adult alpha- to embryonic beta-myosin heavy chain. We now report the transient re-expression of a second fetal gene, skeletal alpha-actin in rat myocardium at 7 days post-infarction, and its subsequent down-regulation coincident with the delayed induction of S100beta, a protein normally expressed in brain. In cultured neonatal rat cardiac myocytes, co-transfection with an S100beta-expression vector inhibits a pathway associated with hypertrophy, namely, alpha1-adrenergic induction of beta-myosin heavy chain and skeletal alpha-actin promoters mediated by beta-protein kinase C. The induction of beta-myosin heavy chain by hypoxia was similarly blocked by forced expression of S100beta. Our results suggest that S100beta may be an intrinsic negative regulator of the hypertrophic response of surviving cardiac myocytes post-infarction. Such negative regulators may be important in limiting the adverse consequences of unchecked hypertrophy leading to ventricular remodeling and dysfunction.

Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction.

Recent molecular studies have suggested that viral myocarditis frequently underlies human congestive cardiomyopathy; however, only moderately sensitive and specific techniques were used. Polymerase chain reaction (PCR) gene amplification is a sensitive, specific technique ideally suited for the diagnosis of viral disease in small tissue samples where low copy numbers of the viral genome may be present. Using PCR and high stringency condition, we screened biopsies taken from 48 patients with clinically suspected myocarditis or dilated cardiomyopathy. Five patients demonstrated positive enteroviral signals by PCR; two of them had myocarditis by pathology, whereas the other three had changes consistent with cardiomyopathy. Four other patients had myocarditis diagnosed by pathology from 3 months to 1 year earlier but were now negative by both PCR and pathology. Both pathology and PCR were negative for active myocarditis in all other patients. Ventricular samples taken from left ventricular myectomy in four additional patients with hypertrophic cardiomyopathy, normal human ventricle samples, and uninfected monkey kidney cells were also negative by PCR. This study supports a link between viral infection and dilated cardiomyopathy in some patients. PCR gene amplification provides a new diagnostic approach to patients with suspected myocarditis.