Regulation of GADD153 induced by mechanical stress in cardiomyocytes.

BACKGROUND: Growth arrest and DNA damage-inducible gene 153 (GADD153), an apoptosis regulated gene, increased during endoplasmic reticulum stress. However, the expression of GADD153 in cardiomyocytes under mechanical stress is little known. We aimed to investigate the regulation mechanism of GADD153 expression and apoptosis induced by mechanical stress in cardiomyocytes. MATERIALS AND METHODS: Aorta-caval shunt was performed in adult Sprague-Dawley rats to induce volume overload. Rat neonatal cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles min(-1). RESULTS: The increased ventricular dimension measured using echocardiography in the shunt group (n = 8) was reversed to normal by treatment with chaperon 4-phenylbutyric acid (PBA) (n = 8) at 500 mg kg(-1) day(-1) orally for 3 days. GADD153 protein and mRNA were up-regulated in the shunt group when compared with sham group (n = 8). Treatment with PBA reversed the protein of GADD153 to the baseline values. The TUNEL assay showed that PBA reduced the apoptosis induced by volume overload. Cyclic stretch significantly increased GADD153 protein and mRNA expression after 14 h of stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA and tumour necrosis factor-alpha (TNF-alpha) antibody 30 min before stretch, reduced the induction of GADD153 protein. Stretch increased, while GADD153-Mut plasmid, SP600125 and TNF-alpha antibody abolished the GADD153 promoter activity induced by stretch. GADD153 mediated apoptosis induced by stretch was reversed by GADD153 siRNA, GADD153-Mut plasmid and PBA. CONCLUSIONS: Mechanical stress enhanced apoptosis and GADD153 expression in cardiomyocytes. Treatment with PBA reversed both GADD153 expression and apoptosis induced by mechanical stress in cardiomyocytes.

Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that regulates expression of genes involved in O(2) homeostasis, including vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis. We sought to exploit this native adaptive response to hypoxia as a treatment for chronic ischemia. METHODS AND RESULTS: A hybrid protein consisting of DNA-binding and dimerization domains from the HIF-1alpha subunit and the transactivation domain from herpes simplex virus VP16 protein was constructed to create a strong, constitutive transcriptional activator. After transfection into HeLa, C6, and Hep3B cells, this chimeric transcription factor was shown to activate expression of the endogenous VEGF gene, as well as several other HIF-1 target genes in vitro. The bioactivity of HIF-1alpha/VP16 hybrid gene transfer in vivo was examined in a rabbit model of hindlimb ischemia. Administration of HIF-1alpha/VP16 was associated with significant improvements in calf blood pressure ratio, angiographic score, resting and maximal regional blood flow, and capillary density (all P:<0.01). CONCLUSIONS: The HIF-1alpha/VP16 hybrid transcription factor is able to promote significant improvement in perfusion of an ischemic limb. These results confirm the feasibility of a novel approach for therapeutic angiogenesis in which neovascularization may be achieved indirectly by use of a transcriptional regulatory strategy.

Recovery of atrial function after atrial compartment operation for chronic atrial fibrillation in mitral valve disease.

OBJECTIVES: We prospectively studied the recovery of atrial function after atrial compartment operation and mitral valve surgery in patients with chronic atrial fibrillation caused by mitral valve disease. BACKGROUND: Chronic atrial fibrillation is the most common arrhythmia in mitral valve disease. This arrhythmia is associated with excessive morbidity and mortality. Mitral valve surgery alone rarely eliminates it. METHODS: Twenty-two patients underwent mitral valve surgery and a new surgical method, atrial compartment operation. Doppler echocardiography was performed in all patients before operation and at 1 week and 2 and 6 months after operation in the successful cardioversion group. Peak early diastolic (E) and atrial (A) filling velocities, peak A/E velocity ratio and A/E integral ratio of the mitral and tricuspid valves were measured. RESULTS: Sinus rhythm was restored immediately after operation in 91% of patients and was maintained for > 1 week in 15 (68%) of 22 patients and > 6 months in 14 (64%) of 22. Eleven of 15 patients had left atrial paralysis (A/E integral ratio 0) at 1 week and 6 of 14 patients at 2 months. Nine of 15 patients had right atrial paralysis (A/E integral ratio 0) at 1 week and 1 of 14 patients at 2 months. Both left and right atrial contractile function (presence of an A wave on Doppler findings) was detected at 6 months in 14 patients. Mean (+/- SD) peak atrial filling velocity of the mitral valve was 15 +/- 26 cm/s at 1 week, 38 +/- 39 cm/s at 2 months and 93 +/- 32 cm/s at 6 months (p < 0.001). Mean peak atrial filling velocity of the tricuspid valve was 14 +/- 19 cm/s at 1 week, 33 +/- 19 cm/s at 2 months and 50 +/- 19 cm/s at 6 months (p < 0.001). Peak early diastolic and atrial filling velocities, peak A/E velocity ratio and A/E integral ratio of the mitral and tricuspid valves increased significantly from 1 week to 6 months. CONCLUSIONS: Chronic atrial fibrillation in mitral valve disease can often be eliminated by atrial compartment operation. No surgical mortality or significant complications were encountered. Both left and right atrial function, as manifested by Doppler findings, recover after compartment operation and improve over time. The mechanical function of the right atrium recovers earlier than that of the left.

Influence of additional partition on the recovery of atrial function after atrial compartment operation for atrial fibrillation.

Chronic atrial fibrillation can be eliminated by an atrial compartment operation, but additional partition on the right atrium impairs the recovery of right atrial mechanical function. Thus, it is important to appropriately divide the atria for both maintaining sinus rhythm and maximizing atrial mechanical function.

Morphologic characterization and quantitative assessment of mitral regurgitation with ruptured chordae tendineae by transesophageal echocardiography.

To compare the accuracy of transesophageal echocardiography (TEE) with that of transthoracic echocardiography (TTE) in the detection of morphologic characteristics and in the quantitative assessment of the severity of mitral regurgitation with ruptured chordae tendineae, 40 patients with ruptured chordae tendineae (group 1) and 20 patients with moderate or severe mitral regurgitation due to other causes (group 2) were studied. All echocardiograms were recorded before cardiac surgery. Cardiac catheterization was performed in 55 patients (92%). TEE showed greater sensitivity and negative predictive value than TTE (100 vs 65%, and 100 vs 56%, respectively; p < 0.005) in the diagnosis of ruptured chordae tendineae. Visualization of the ruptured chordae (termed snake-tongue sign) was highly sensitive and specific (93 and 95%, respectively) for establishing the diagnosis of ruptured chordae tendineae. The severity of mitral regurgitation in group 1 patients evaluated by TTE color flow mapping was underestimated by 2 grades in 1 patient and by 1 grade in 6 patients, and overestimated by 1 grade in 1 patient, compared with left ventriculography. In contrast, by TEE color flow mapping it was underestimated by 1 grade in 1 and overestimated by 1 grade in 1 patient. TEE color flow mapping showed better correlation with angiography than did TTE color flow mapping (r = 0.82 vs r = 0.49).

Usefulness of pulmonary venous flow pattern and maximal mosaic jet area detected by transesophageal echocardiography in assessing the severity of mitral regurgitation.

Pulmonary venous flow pattern detected by transesophageal echocardiography (TEE) has been reported to be a good marker of mitral regurgitation (MR) severity. In 89 patients with MR detected by TEE, both pulmonary venous flow pattern and maximal mosaic jet area were recorded for evaluating the severity of MR. Cardiac catheterization was performed in all patients for grading the severity of MR. Systolic reversed flow in pulmonary veins was a good marker for angiographic grade 3 or 4 MR with a sensitivity of 97% (33 of 34) and specificity of 95% (52 of 55). Maximal mosaic jet area had a good correlation with the grading of MR (r = 0.79). When a maximal mosaic jet area of > 6 cm2 was used to detect grade 3 or 4 MR, the sensitivity and specificity were lower than those of the systolic reversed flow (sensitivity 82 vs 97%, p = 0.073; specificity 80 vs 95%, p = 0.013). The accuracy of systolic reversed flow was not influenced by the cardiac rhythm or jet eccentricity. However, the sensitivity of maximal mosaic jet area was lower in patients with an eccentric jet than in patients with a central jet (67 vs 95%, p = 0.046). In conclusion, systolic reversed flow in pulmonary veins detected by TEE is better than the maximal mosaic jet area in detecting grade 3 or 4 MR, especially in patients with eccentric jet.

Low-serum, high-density lipoprotein cholesterol concentration is an important coronary risk factor in Chinese patients with low serum levels of total cholesterol and triglyceride.

The significance of low-serum high-density lipoprotein concentrations (<35 mg/dl) with respect to coronary atherogenesis in Chinese patients with low levels of total serum cholesterol (<200 mg/dl) and triglycerides (<250 mg/dl) was assessed. Persons with such a lipid profile pattern were still at high risk, and high-density lipoprotein. like smoking, appeared to be the most predictive independent coronary risk factor.

Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome.

To characterize the role of circulating intercellular adhesion molecules (ICAM-1) and E-selectin in patients with acute coronary syndrome, serum levels of ICAM-1 and E-selectin were measured by enzyme-linked immunosorbent assay (ELISA). Group 1 comprised 17 patients with acute myocardial infarction; group 2 included 17 patients with unstable angina; and group 3 included 19 control subjects. These 53 patients all had prolonged chest pain within 24 h and all underwent coronary angiography. Group 1 and 2 patients had significant coronary artery disease, while group 3 had normal coronary arteries. Blood samples were collected at the emergency department before antiplatelet agents were given. Serum levels of 1CAM-1 were higher in group 1 and 2 (383 +/- 27 and 337 +/- 11 ng/mL, respectively) as compared with group 3 (282 +/- 18 ng/mL) (group 1 vs 3, p<0.01; group 2 vs 3, p<0.05). The serum levels of ICAM-1 were not significantly different between group 1 and 2. Serum levels of E-selectin in group 1, 2, and 3 were 58 +/- 8, 51 +/- 4, and 58 +/- 5 ng/mL, respectively. The serum levels of E-selectin showed no significant difference among the three groups. In conclusion, serum levels of ICAM-1 were elevated in patients with acute coronary syndrome within 24 h, while the E-selectin levels did not change significantly. This finding suggests that adhesion molecule may play an important role in the postrolling process of leukocyte-endothelial cell interaction in acute coronary syndrome.

Spontaneous echo contrast in massive pericardial effusion with tamponade.

Spontaneous echo contrast is uncommon in pericardial effusion. We report the case of a patient with massive malignant pericardial effusion causing cardiac tamponade in which the intense spontaneous echo contrast was found in the effusion by echocardiography. It was suggested that both the heavy blood content and a large amount of pericardial effusion were needed to create the phenomenon of spontaneous echo contrast in the pericardial cavity.

Diagnostic accuracy of transesophageal echocardiography for detecting patent ductus arteriosus in adolescents and adults.

To compare the accuracy of transesophageal echocardiography (TEE) with that of transthoracic echocardiography (TTE) in the detection of patent ductus arteriosus (PDA) in the adolescent and the adult, 40 patients with PDA and 50 patients with other congenital heart diseases were studied. All echocardiograms were recorded before cardiac catheterization and surgery. The echocardiographic diagnosis of PDA was made by direct visualization of a shunt flow in the duct. A mosaic flow in the pulmonary artery without direct visualization of the duct was considered possible but not definitely diagnostic of PDA. TEE showed greater sensitivity and negative predictive value than TTE (97% vs 42%, and 98% vs 68%, respectively; p < 0.001) in confirming the diagnosis of PDA. The specificity and positive predictive value in establishing the diagnosis of PDA were the same for both techniques. In the subgroup of patients with Eisenmenger's syndrome, the sensitivity of TEE and TTE in confirming diagnosis of PDA was 100% and 12% (p < 0.01), respectively. The sensitivity of monoplane and biplane TEE in the diagnosis of PDA was comparable (95% and 100%, respectively; p = NS). In conclusion, TEE was highly sensitive and specific in detecting PDA in adolescents and adults. It was also highly valuable for detecting the cause of pulmonary hypertension in patients with Eisenmenger's syndrome.

Significant mitral regurgitation is protective against left atrial spontaneous echo contrast formation, but not against systemic embolism.

The prevalence of left atrial spontaneous echo contrast (SEC) and the occurrence of systemic embolism were prospectively studied in 176 consecutive patients. All had significant mitral regurgitation (MR) and underwent transesophageal echocardiographic (TEE) studies. Left ventriculography was performed in all patients to document the severity of MR. The underlying causes of MR included rheumatic heart disease in 84 patients, ruptured chordae tendineae in 37, mitral valve prolapse in 18, infective endocarditis in 20, coronary artery disease in 8, congenital heart disease in 5, and dilated cardiomyopathy in 4. No patient was found to have left atrial thrombus. Left atrial SEC was observed in three patients (1.7 percent), all of whom had atrial fibrillation, concomitant mitral stenosis, and huge left atria. Color flow mapping revealed that left atrial SEC was prominent in regions where the turbulent flow of MR was not present. Systemic embolism occurred in ten patients (5.7 percent). The underlying disease was infective endocarditis, rheumatic heart disease, and dilated cardiomyopathy in 6, 3, and 1 patient, respectively. The sites of embolization involved the central nervous system in eight patients and the spleen in the remaining two. Three patients with rheumatic heart disease and the one with dilated cardiomyopathy were in atrial fibrillation and had dilated left atria (diameter > 45 mm) when systemic embolism occurred. Only one patient with rheumatic heart disease was found to have left atrial SEC. The remaining six, with infective endocarditis, all had sinus rhythm. In conclusion, left atrial SEC or thrombus detected by TEE is uncommon in patients with significant MR. Clinical conditions may be of help to identify the subsets of patients at higher risk for systemic embolism.

Clinical implications of left atrial appendage flow patterns in nonrheumatic atrial fibrillation.

Left atrial appendage (LAA) function and flow patterns in 29 patients with chronic nonrheumatic atrial fibrillation were studied by transesophageal echocardiography. These 29 patients (16 men and 13 women; mean age, 63.8 years; range, 38 to 77 years) were classified into two groups according to different LAA flow patterns. Seventeen patients (group 1) had well-defined LAA emptying and filling Doppler flow signals, and the other 12 patients (group 2) had very low LAA flow signals. No significant differences were found in age, sex, mean duration of atrial fibrillation, left ventricular end diastolic dimension, and left ventricular ejection fraction between the two groups. However, group 2 patients had larger left atrial diameter (42.8 +/- 4.2 mm vs 36.6 +/- 8.8 mm; p < 0.05), lower LAA ejection fraction (26.4 +/- 15.2 percent vs 42.6 +/- 14.1 percent; p < 0.05), and lower LAA peak emptying velocity (0.13 +/- 0.03 m/s vs 0.36 +/- 0.16 m/s; p < 0.001). Higher incidence of LAA spontaneous echocardiographic contrast formation in group 2 patients (8/12 vs 1/17; p < 0.001) was noted. In conclusion, a subset of patients with nonrheumatic atrial fibrillation were found to have lower LAA blood flow and poorer LAA function. These patients had higher incidence of left atrial or LAA spontaneous echo contrast formation which had been proved previously to be a marker for future systemic thromboembolism.

Usefulness of transesophageal echocardiography in the treatment of critically ill patients.

To evaluate the usefulness of transesophageal echocardiography (TEE) in the treatment of critically ill patients, 80 patients (51 male and 29 female; mean age, 53 years) undergoing both transthoracic echocardiography (TTE) and TEE were studied in a 2-year period. Of these, 48 patients were studied in the ICU, while the other 32 patients were directly referred from the emergency departments. Indications for the study included suspected aortic dissection (34 patients), hemodynamic instability (22 patients), suspected cardiac source of embolism (11 patients), evaluation of the severity of mitral regurgitation (7 patients), and suspected infective endocarditis (6 patients). The probe was passed successfully in 78 of 80 attempts (98 percent). No significant complications were recorded during the transesophageal echocardiographic study. Transesophageal echocardiography provided critical information that was not obtained by TTE in 39 of 78 studies (50 percent, p < 0.005). Cardiac surgery was prompted by TEE findings in 14 patients (18 percent) and these findings were all confirmed at operation. Transesophageal echocardiography was a safe, well-tolerated, and valuable diagnostic approach for the rapid detection of specific cardiac abnormalities in patients with critical illness; TEE should be considered in the treatment of critically ill patients especially when TTE provided inadequate information.

Cardiac metastasis of hepatocellular carcinoma mimicking pericardial effusion on radionuclide angiocardiography.

A 51-year-old man presented with exertional dyspnea for two months. He had a history of hepatocellular carcinoma that was totally resected three years earlier. Radionuclide angiocardiography disclosed a large photopenic area separating the heart from the liver, and lung blood pools mimicking a large pericardial effusion. Echocardiography and magnetic resonance imaging of the heart, however, showed extensive tumor infiltration of the myocardium of both ventricles. Endomyocardial biopsy confirmed the diagnosis of metastatic hepatocellular carcinoma. There was no evidence of recurrent hepatoma in the liver.

Regression of left ventricular mass after mitral valve repair of pure mitral regurgitation.

To evaluate the effect of mitral valve repair on the regression of left ventricular mass, we studied 50 consecutive patients with severe, pure mitral regurgitation undergoing mitral valve repair. Two-dimensional echocardiograms were recorded a mean 2.5 +/- 2.0 weeks before and 6.5 +/- 2.5 months after valve operation. Postoperative significant mitral regurgitation was present in 3 patients. After mitral valve repair there were significant decreases in left ventricular end-diastolic volume index (133 +/- 39 mL/m2 to 79 +/- 35 mL/m2; p < 0.001), end-systolic volume index (44 +/- 26 mL/m2 to 30 +/- 26 mL/m2; p < 0.001), stroke volume index (89 +/- 29 mL/m2 to 49 +/- 19 mL/m2; p < 0.001), and mass index (211 +/- 82 g/m2 to 134 +/- 52 g/m2; p < 0.001). There also were significant decreases in left atrial dimension (47 +/- 9 mm to 38 +/- 9 mm; p < 0.001), left ventricular end-diastolic dimension (61 +/- 8 mm to 48 +/- 7 mm; p < 0.001), and end-systolic dimension (39 +/- 8 mm to 32 +/- 7 mm; p < 0.001). Left ventricular ejection fraction decreased slightly from 0.69 +/- 0.12 to 0.64 +/- 0.12; p < 0.01) after repair. Thus, correction of pure mitral regurgitation leads to reduction of the cardiac chamber size and left ventricular volumes as well as regression of the left ventricular mass.

Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke.

To investigate the role of circulating intercellular adhesion molecule-1 (ICAM-1) and E-selectin in ischaemic stroke, serum levels of ICAM-1 and E-selectin were measured by ELISA in 51 patients with acute ischaemic stroke within 24 h, and in 25 age-matched healthy controls and 10 young healthy volunteers. Carotid Doppler ultrasonography showed a significant stenosis (> 50%) of the carotid or vertebrobasilar artery in 11 of 51 stroke patients. Serum levels of ICAM-1 [mean (SE)] were higher (P < 0.01) in patients with ischaemic stroke [381 (30) ng/ ml] than in age-matched controls [271 (27) ng/ml] and young controls [246 (6) ng/ml]. There was no significant difference in serum E-selectin levels [mean (SE)] among stroke patients, age-matched and young controls [47 (6), 39 (3), and 41 (3) ng/ ml, respectively; P = NS]. The leucocyte count [mean (SD)] was higher (P < 0.01) in patients with ischaemic stroke [8310 (2800)] than in age-matched controls [6040 (930)]. Serum levels of ICAM-1 and E-selectin did not significantly differ between patients with or without abnormal carotid or vertebrobasilar artery disease. In conclusion, serum ICAM-1 level and leucocyte count were elevated in acute ischaemic stroke within 24 h, while the E-selectin level did not change significantly. This finding suggests that adhesion molecules may play an important role in the post-rolling process of leucocyte-endothelial cell interaction in acute ischaemic stroke.

Expanded indication: diagnosis of pulmonary embolism by transesophageal echocardiography.

Transesophageal echocardiography is a useful diagnostic tool not only in examination of the heart, but also in examination of the great arteries. Its role in the diagnosis of aortic aneurysm and dissection has been well-established. The pulmonary artery, especially the right pulmonary artery, also can be visualized clearly by this technique. In this report, we described a patient with massive pulmonary embolism which was diagnosed by transesophageal echocardiography, and was confirmed by pulmonary angiography.

Infundibular pulmonic stenosis with intact ventricular septum: a report of 15 surgically corrected patients.

Infundibular pulmonic stenosis with intact ventricular septum of primary origin is an uncommon condition. We report 15 such patients (nine males and six females, aged 7-36 years) who had undergone surgical correction for the anomaly during the period between 1975 and 1992. The occurrence of this clinical setting represents 0.19% (15/7826) of all cardiac operations and 0.46% (15/3222) of congenital heart diseases undergoing surgical correction during that period of time. The lesion was of discrete fibromuscular hypertrophy of the infundibulum in all 15 patients. The presenting symptoms of most patients were exertional dyspnea and syncope; however, five patients with severe obstruction were asymptomatic. The peak systolic pressure gradient across the infundibulum ranged from 71 to 230 mmHg. There was only one operative death; the remainder had remained well following the surgery over a mean follow-up period of 35 months. Surgical correction for infundibular pulmonic stenosis is rewarding in the absence of heart failure.

Clinical implications of left atrial appendage function: its influence on thrombus formation.

This study evaluated the relation between left atrial appendage (LAA) function and LAA spontaneous echo contrast (SEC) or thrombus formation. Seventy-five patients (45 men and 30 women, aged 14-79 years) referred for transesophageal echocardiography (TEE) were examined for LAA area (maximal and minimal), LAA ejection fraction ([LAA maximal area--LAA minimal area]/LAA maximal area), LAA peak emptying velocity, and these patients were classified into three groups by different LAA blood flow patterns: Group 1--25 patients with well-defined biphasic configuration of LAA flow; Group 2--28 patients with multiphasic configuration of LAA flow; Group 3--22 patients with very low LAA blood flow and, sometimes, barely detected Doppler signal. All the 25 patients in Group 1 had a sinus rhythm during TEE study, while the other 50 patients in Groups 2 and 3 were in atrial fibrillation. The patients in Group 3 had the lowest LAA ejection fraction and the lowest peak emptying velocity of these three groups. LAA SEC was present in five of 28 patients in Group 2 and 14 of 22 patients in Group 3, but in none of 25 patients in Group 1 (P < 0.001). LAA thrombus was present in one of 25 patients in Group 1, two of 28 patients in Group 2, and seven of 22 patients in Group 3 (P < 0.05). In conclusion, this study found that patients with poor LAA function, which was represented by lower LAA ejection fraction and lower peak emptying velocity, had higher incidence of LAA SEC or thrombus formation.