Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells.

Plasma concentrations of a pleiotropic cytokine, interleukin (IL)-6, are increased in patients with cardiac myxoma. We investigated the regulation of IL-6 in cardiac myxoma. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) revealed that IL-6 and its receptors, IL-6 receptor (IL-6R) and gp130, co-existed in the myxoma cells. Myxoma cells were cultured, and an antibody array assay showed that a conditioned medium derived from the cultured myxoma cells contained increased amounts of IL-6. Signal transducer and activator of transcription (STAT) 3 and Akt were constitutively phosphorylated in the myxoma cells. An enzyme-linked immunosorbent assay (ELISA) showed that the myxoma cells spontaneously secreted IL-6 into the culture medium. Real-time PCR revealed that stimulation with IL-6 + soluble IL-6R (sIL6R) significantly increased IL-6 mRNA in the myxoma cells. Pharmacological inhibitors of STAT3 and Akt inhibited the IL-6 + sIL-6R-induced gene expression of IL-6 and the spontaneous secretion of IL-6. In addition, IL-6 + sIL-6R-induced translocation of phosphorylated STAT3 to the nucleus was also blocked by STAT3 inhibitors. This study has demonstrated that IL-6 increases its own production via STAT3 and Akt pathways in cardiac myxoma cells. Autocrine regulation of IL-6 may play an important role in the pathophysiology of patients with cardiac myxoma.

Successful Treatment of a Life-Threatening Pulmonary Embolism Following Retroperitoneal Tumor Surgery.

We encountered a case of life-threatening pulmonary embolism (PE) after an extensive retroperitoneal tumor (RT) surgery. The patient complained of abdominal distension. Preoperatively, an ovarian tumor and colon adenoma were suspected. Upon laparotomy, tumor resection and partial rectal resection were performed; the tumor had originated from the retroperitoneum. On postoperative day 11, the patient suddenly went into fatal shock complicated by strong back pain and dyspnea after the continuous pressure drain was removed. Thrombolysis, anticoagulation, and percutaneous catheter-directed treatment were attempted for the massive PE; however, these induced copious intra-abdominal bleeding. A substantial blood transfusion was required, which increased her body mass by 40 kg. On day 22, an intra-abdominal embolism was resected, and hemodynamics stabilized. RTs have a potential risk of perioperative thromboembolism; therefore, we suggest that surgery should take place in an academic hospital with an experienced circulatory team. To preserve life after PE, early diagnosis and multidisciplinary treatment are indispensable.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Prediagnostic electrocardiographic and echocardiographic findings of biopsy-proven hypertrophic cardiomyopathy.

We present two cases of biopsy-proven hypertrophic cardiomyopathy (HCM). Both cases showed abnormal electrocardiographic (ECG) findings more than 8 years before diagnosis. A 16-year-old healthy male experienced a rescued cardiac arrest. Another male adolescent showed abnormal Q wave and thickened ventricular wall at 15 years old. Retrospective analyses of ECGs performed at 6 years old indicated abnormal ECG findings. However, the diagnosis was normal because no ventricular wall thickening was present in echocardiography. For early diagnosis of HCM to prevent sudden cardiac arrest or death, it is essential to establish ECG and echocardiographic criteria to screen HCM in the young.

Relationship between vascular endothelial growth factor and left ventricular dimension in patients with acute myocardial infarction.

BACKGROUND: Although vascular endothelial growth factor (VEGF) is elevated in patients with acute myocardial infarction (AMI), the clinical significance of its elevation remains unclear. The present study was designed to determine the relationship between VEGF and left ventricular dimension in patients with AMI. METHODS AND RESULTS: Plasma VEGF levels were examined by enzyme-linked immunosorbent assay daily for one week and then weekly for four weeks in 38 patients with AMI (65.4 ± 1.7 years). Left ventriculography was performed at 14 days, 6 months, and 2 years after the onset of AMI. Plasma VEGF levels were significantly elevated and reached a peak on day 6. Peak plasma VEGF levels positively correlated with both end-diastolic and end-systolic volume indices at 14 days after the onset of AMI. When patients with AMI were divided into two groups according to plasma VEGF levels on admission, left ventricular volume indices were higher in the high VEGF group than in the low VEGF group at the subacute phase of AMI (14 days). These differences were no longer present in the chronic phase of AMI. CONCLUSION: Plasma VEGF levels were increased in patients with AMI, and peak levels were associated with left ventricular volume indices in the subacute phase, suggesting an important role of endogenous VEGF in the left ventricular dimension in patients with AMI.

Primary leiomyosarcoma of the pulmonary artery: a case of a 20-month survivor after incomplete surgical resection.

We report a 53-year-old man who presented with dyspnea and low-grade fever. Cardiac ultrasound showed pulmonary hypertension and an ill-defined echogenic mass within the pulmonary trunk. Computed tomography scan revealed an inhomogeneous mass which filled the main pulmonary trunk with near-total occlusion, and extended into both pulmonary arteries. Anticoagulant therapy was administered based on a presumptive diagnosis of pulmonary thromboembolism. Positron-emission tomography scan was useful for differentiating the mass, which was determined as a pulmonary artery sarcoma by surgical resection. Although complete resection was impossible, the patient survived for 20 months with adjuvant chemotherapy and medical treatment.

Multidetector-row computed tomography-based clinical assessment of fondaparinux for treatment of acute pulmonary embolism and acute deep vein thrombosis in Japanese patients.

BACKGROUND: Unfractionated heparin (UFH) is the standard drug for the initial treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) in Japan, whereas fondaparinux is the standard drug in Europe and the United States. Here, we examine the efficacy and safety of fondaparinux in Japanese patients. METHODS AND RESULTS: In 2 randomized, open-label, multicenter studies, 80 Japanese patients with acute PE or DVT received either subcutaneous fondaparinux or intravenous UFH as a non-comparative reference, in a 3:1 ratio, for 5-10 days. Concomitant warfarin therapy was continued until Day 90. Multidetector-row computed tomography-based assessment showed that 57.9% and 45.9% of the patients with acute PE and acute proximal DVT had proximal DVT and PE as a complication, respectively. There was no recurrence of symptomatic venous thromboembolism. In the fondaparinux group, the respective improvement rates at the end of the initial treatment and follow-up periods were 71.4% and 86.8% for 42 patients with PE, and 57.8% and 83.3% for 46 patients with DVT; similar results were noted in the UFH group. One patient in the fondaparinux group experienced major bleeding during the initial treatment, but no such episode in the UFH group. CONCLUSIONS: Once-daily, subcutaneous fondaparinux is as effective and safe without monitoring as adjusted-dose intravenous UFH for the initial treatment of acute PE and DVT in Japanese patients.

Irrelevant B-type natriuretic peptide levels in patients with mechanical prostheses in the mitral position presenting with congestive heart failure.

BACKGROUND: Plasma B-type natriuretic peptide (BNP) level is reported to be a strong marker of congestive heart failure (CHF). Heterogeneity of the BNP levels among individuals with CHF, however, can cause confusion in interpreting the results. The influence of mitral mechanical prostheses on BNP levels in patients presenting with CHF is not well known. METHODS AND RESULTS: In the present study 214 consecutive patients with CHF diagnosed using the Framingham criteria were enrolled and divided into 2 groups with and without mitral mechanical prostheses (prosthesis group, n=31; native group, n=183). The plasma BNP levels were measured, and clinical examinations including echocardiography were performed at the same time to assess cardiac performance. There was no difference in the left ventricular ejection fractions between the 2 groups. Despite having a lower body mass index, larger prevalence ratio of atrial fibrillation and larger size of the left atrium, the prosthesis group had a significantly lower logBNP level than the native group (prosthesis group vs native group: 5.12+/-1.01 vs 6.21+/-0.92, P<0.001; BNP level: 167+/-324 pg/ml vs 498+/-380 pg/ml). On multivariate analysis the presence of a mitral mechanical prosthesis was extracted as an independent predictor for decreased BNP level in patients with CHF. CONCLUSIONS: Plasma BNP level cannot correctly reflect the severity of CHF in patients with mechanical prostheses in the mitral position.

Rapid progression of aortic regurgitation with thoracic aortic aneurysm due to Takayasu arteritis associated with ulcerative colitis.

A 25-year-old woman with ulcerative colitis developed heart failure due to severe aortic regurgitation. Although chest X-ray 18 months previously showed a normal cardiac shadow, thoracic aortic aneurysm progressed due to Takayasu arteritis. Aortic valve and ascending aorta replacement were performed successfully, but re-valve replacement for severe aortic regurgitation due to prosthetic valve detachment and aortic root replacement for valsalva sinus rupture were required. Human leukocyte antigen analysis showed B35 and B52, the typical haplotype in cases with coexistence of both diseases and associated sustained inflammation. Close observation and early aortic root replacement were needed in this case.

Mid-term mortality of very elderly patients with acute myocardial infarction with or without coronary intervention.

BACKGROUND: The risk benefit of percutaneous coronary intervention (PCI) in very elderly patients with acute myocardial infarction (AMI) is currently unclear. Here, we aim to identify the characteristics of these patients and clarify their mid-term mortality rate with or without PCI. METHODS AND RESULTS: 77 patients (> or =80 years) were chosen from 506 patients with AMI, and treated with (n=32) or without (n=45) PCI. The mean age and time from onset to admission increased in patients having undergone no PCI. The reasons for PCI refusal were patient/family preference (40%), renal dysfunction (17.8%), or cognitive impairment (13.3%). Patients treated with PCI had lower mid-term mortality than those without PCI (34.4% vs 62.2%; p=0.02), while patients taking beta-blockers displayed a significantly lower mortality rate than those without (18.2% vs 63.6%; p=0.0003). Cognitively impaired patients had a higher mortality rate compared with cognitively normal patients (80.0% vs 46.3%; p=0.005). Multivariate analysis indicated that systolic blood pressure on admission, PCI, and beta-blocker therapy independently decreased mid-term mortality in these patients. CONCLUSIONS: PCI and beta-blocker therapy displayed significantly beneficial effects on mid-term mortality in very elderly AMI patients. Elderly-specific trials concerning coexisting disorders are needed to further examine the treatment-related benefits.

Successful treatment of spontaneous coronary bypass rupture using a polytetrafluoroethylene-covered stent.

A 57-year-old man with coronary bypass surgery experienced spontaneous rupture of a vein graft 16 months following his operation. Multislice computed tomography revealed a perforation of the saphenous vein graft to the obtuse marginal branch. 3D imaging was useful for diagnosis and in planning treatment. Hesitation to perform surgical treatment occurred due to inflammation in the patient, therefore we successfully implanted a polytetrafluoroethylene-covered stent to occlude the site of perforation. The use of a covered stent for a patient showing clear leakage of dye during angiography should be considered as an alternative to surgical intervention for a ruptured vein.

Comparison of blood glucose values on admission for acute myocardial infarction in patients with versus without diabetes mellitus.

Previous studies have reported that acute hyperglycemia is associated with high mortality after acute myocardial infarction (AMI). However, optimal plasma glucose level may be different between diabetic and nondiabetic patients. The purpose of this study was to assess the relation between admission glucose and in-hospital mortality after AMI in patients with and without diabetes. This study consisted of 3,750 patients who were admitted to the 35 hospitals participating to the Japanese Acute Coronary Syndrome Study (JACSS) group within 48 hours after the onset of AMI. Plasma glucose was measured at the time of hospital admission. In patients without a history of diabetes, there was a linear relation between admission glucose and in-hospital mortality. Nondiabetic patients with a glucose level <6 mmol/L had the lowest mortality (2.5%). As admission glucose increased by 1 mmol/L, mortality increased by 17% (13% to 21%, p <0.001). In patients with a history of diabetes, however, there was a U-shape relation between glucose and mortality. Diabetic patients with glucose 9 to 10 mmol/L had the lowest mortality (1.9%); not only severe hyperglycemia (glucose > or =11 mmol/L, 9.1%, p <0.001) but also euglycemia (glucose <7 mmol/L, 9.4%, p = 0.009) were associated with higher mortality compared to moderate hyperglycemia (glucose 9 to 11 mmol/L, 3.2%). Diabetic patients with admission glucose 9 to 10 mmol/L had the lowest mortality, whereas lower glucose was better in nondiabetic patients. In conclusion, optimal glucose level on admission may be different between diabetic and nondiabetic patients with AMI.

A novel clinical course of free-floating left atrial ball thrombus without mitral stenosis treated by anticoagulants.

Free-floating left atrial ball thrombus is rare. We describe a case of a 48-year-old man who had free-floating left atrial ball thrombus that was not accompanied by mitral stenosis and that was treated aggressively with anticoagulants. Echocardiography revealed dramatic disappearance of the thrombus.

Case of transient mid-ventricular ballooning syndrome with a rapid and uncommon recovery.

A 60-year-old woman presented with acute pulmonary edema followed by cardiopulmonary arrest due to idiopathic ventricular fibrillation. Owing to immediate cardioversion, her electrocardiogram showed sinus rhythm and echocardiography did not show any wall motion abnormalities. The next day, echocardiographic re-examination was characterized by akinesis of both apical and mid segments of the left ventricle. One hour later, subsequently performed coronary angiography revealed non-occlusive coronary artery disease, but left ventriculography demonstrated only akinesis of mid-ventricular segment with hypercontractile other segments. Further echocardiographic investigation on the following day showed total resolution of left ventricular wall motion abnormalities. The diagnosis of mid-ventricular ballooning syndrome was made according to the findings of left ventriculography. In this case, the time course changes of both patient's pathophysiological condition and echocardiographic wall motion from the onset to recovery are rapid and uncommon.

Impact of decreased renal function on coagulation and fibrinolysis in patients with non-valvular atrial fibrillation.

BACKGROUND: The prothrombotic state in non-valvular atrial fibrillation (NVAF) increases the risk of thromboembolic events. It is also well known that a prothrombotic state exists in renal failure. Hemostatic disorders play a role in thromboembolic mortality in both NVAF and renal failure. However, little is known about the influence of renal function on hemostasis in patients with NVAF. METHODS AND RESULTS: A total of 190 consecutive outpatients with NVAF who were not receiving anticoagulant therapy were enrolled in the present study. Patients were stratified in groups based on estimated glomerular filtration rate (eGFR). Plasma concentrations of thrombin-antithrombin complex (TAT) and D-dimer were measured and the influence of renal function on coagulation and fibrinolysis was assessed. A relatively weak and inverse relationship of eGFR to TAT and D-dimer was observed (r=0.28, P=0.0001; r=0.30, P<0.0001). Both mean TAT and D-dimer concentrations in groups gradually and significantly increased as eGFR decreased (P<0.0001). On multivariate regression analysis, decreased eGFR concentration was a significant predictor for elevation of TAT (P<0.05) and D-dimer (P<0.01) in patients with NVAF. CONCLUSIONS: The enhanced coagulation activation appeared to be related to a reduction in residual renal function in patients with NVAF. This suggests that decreased renal function might be a candidate predictor of thromboembolic events in patients with NVAF.

Combined prognostic utility of white blood cell count, plasma glucose, and glomerular filtration rate in patients undergoing primary stent placement for acute myocardial infarction.

Although high white blood cell (WBC) count and plasma glucose (PG) and low glomerular filtration rate (GFR) on admission have been associated with poor outcomes after acute myocardial infarction (AMI), the combined prognostic utility of these 3 variables was unclear. The association of WBC count, PG, and GFR on admission to in-hospital outcomes was examined in 2,633 patients who underwent primary stent placement for ST-segment elevation AMI within 48 hours after symptom onset. In-hospital mortality progressively increased as the number of the variables of high WBC count (> or =11,120/microl; upper tertile), high PG (> or =10.4 mmol/L; upper tertile), and low GFR (< or =60 ml/min/1.73 m(2); lower tertile) increased. Patients with all 3 variables had a strikingly higher in-hospital mortality rate (25.9%). After adjusting for baseline characteristics, multivariate analysis showed that compared with patients who had none of these variables, odds ratios for in-hospital mortality were 1.63 (95% confidence interval [CI] 0.88 to 3.03, p = 0.12) in patients with only 1 variable, 2.33 (95% CI 1.28 to 3.96, p = 0.047) in those with 2 variables, and 6.16 (95% CI 2.98 to 12.6, p <0.001) in those with all 3 variables. In conclusion, combined evaluation of WBC count, PG, and GFR on admission was a simple and useful method for the early prediction of risk of in-hospital death in patients undergoing primary stent placement for ST-segment elevation AMI.