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Introduction: Arthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome., Methods: Patients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal., Results: In total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist., Conclusions: The detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.

Background & Aims: The existence of a direct pathogenic link between hepatitis C virus (HCV) infection and myocardial injury has not been confirmed. We investigated the association between myocardial conditions and HCV in patients with HCV-related chronic hepatitis using thallium-201 myocardial scintigraphy., Methods: In 217 consecutive cases of chronic HCV infection without overt heart disease, we performed electrocardiography (ECG), echocardiography, serum tests on myocardial injury and thallium-201 myocardial scintigraphy. Myocardial injury was confirmed by severity score (SS), which was calculated as the sum of thallium-201 perfusion defect scores. SS was followed prior to and after interferon (IFN) therapy in 200 patients with chronic hepatitis C., Results: An abnormal ECG was found in 9% of the patients with chronic hepatitis C. Abnormal SS was found in 87% of the chronic hepatitis C patients. Independent factors related to higher pretreatment SS were histology activity index score, serum HCV RNA titer, and indocyanine green disappearance rate. After IFN therapy, SS was improved in patients with sustained virologic response. Among relapsers, SS improved at the initial disappearance of HCV RNA, but it worsened with the reappearance of HCV RNA. SS in non-viral responders did not change with IFN therapy., Conclusions: Myocardial perfusion defects were found in 87% of the patients with chronic hepatitis C and improved with viral eradication with IFN therapy., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Activation of inducible nitric oxide synthase (iNOS) has been reported in congestive heart failure (CHF) conditions. However, it is unknown whether activation of iNOS affects prognosis of CHF patients. We prospectively studied the influence of activation of iNOS in the forearm on the outcome of CHF patients., Methods and Results: Forearm blood flow (FBF) responses to 3 doses of acetylcholine (ACh) and nitroglycerin (NTG), and 4 doses of a selective iNOS inhibitor (aminoguanidine: Amn) and a nonselective NOS inhibitor (L-NMMA) were examined using plethysmography in 68 patients with CHF from idiopathic dilated cardiomyopathy. Plasma brain natriuretic peptide (BNP) and tumor necrosis factor-alpha (TNF-alpha) were also measured in all patients. During the mean follow-up period of 3.8 years, 25 patients were hospitalized for worsening heart failure and 9 of these patients died. Patients with adverse events had a diminished vasodilator response to ACh (P < .001) compared to patients without adverse events. Amn significantly decreased FBF (P < .001) in patients with adverse events, but not in patients without adverse events. FBF responses to NTG and L-NMMA were not significantly different between the 2 groups. When grouped by maximum FBF responses to each drug above and below the median value, multivariate Cox proportional hazards model analyses for cardiac event showed a significance in the FBF response to Amn (adjusted hazard ratio 5.89, P < .001). FBF responses to maximum dose of Amn significantly correlated with BNP and TNF-alpha levels (both P < .001)., Conclusions: CHF patients with vascular iNOS activation, as demonstrated by a greater vasoconstrictor response to Amn, had poor outcomes. Activation of iNOS in peripheral vessels, associated with proinflammatory cytokines in accordance to the severity of heart failure, is a marker for, or contributes to, adverse events in patients with CHF.

Background: Although links have been found between microorganisms and cardiovascular diseases, the role of hepatitis C virus (HCV) infection in the pathogenesis of arteriosclerosis and cardiovascular events is unclear. The primary objective of this research was to examine whether HCV infection is associated with increased aortic stiffness and cardiovascular events in chronic hemodialysis patients., Subjects and Methods: A prospective cohort study was conducted in 94 dialysis outpatients from October 2002 to October 2004. Measurements included carotid-femoral pulse wave velocity (PWV), echocardiographic parameters, serum HCV-RNA (positive in 17 patients), and several items of biochemical data. Multiple logistic regression and the Cox proportional hazard model were used to assess independent determinants of high aortic PWV (> or =10.0 m/sec, mean) and cardiovascular events (including cerebral and peripheral vascular events), adjusting for several risk factors and duration of dialysis., Results: The HCV-positive group had higher aortic PWV and lower serum cholesterol levels. Multivariate analysis indicated mean blood pressure, hemoglobin A1c and HCV viremia to be independent determinants of high PWV. During the follow-up period, 13 patients suffered from cardiovascular events. Prevalence of the diseases at baseline, pulse pressure, left ventricular mass index, HCV viremia and aortic PWV were associated with cardiovascular events. The Kaplan-Meier analysis indicated a significant difference in event-free rates between HCV-positive and HCV-negative patients., Conclusion: HCV infection is closely associated with increased aortic stiffness and cardiovascular event in dialysis patients.

Long-term administration of nicorandil has been shown to improve outcomes through cardioprotective effects in patients with coronary artery disease. To identify the mechanisms responsible for these effects, this study examined the impact of long-term nicorandil administration on endothelial function, systemic inflammatory markers, and oxidative stress in patients with cardiovascular risk factors. Fifty-three patients were assigned to receive either nicorandil therapy (15 mg/day; n = 26) (nicorandil group) or usual care (n = 27) (nonnicorandil group). All study participants underwent flow-mediated vasodilatation (FMD) of the brachial artery 1 month before treatment, just before treatment, and at 3, 6, and 12 months following treatment. At identical time points, serum levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL) and high-sensitivity C-reactive protein (hs-CRP) were collected. Compared with the nonnicorandil group, the nicorandil group demonstrated significantly increased FMD at 12 months, a finding not replicated for endothelium-independent vasodilatation with nitroglycerine. Analysis of biochemical markers revealed significantly reduced MAD-LDL levels in the nicorandil group at 12 months, as compared to slightly increased MAD-LDL levels in the nonnicorandil group. Significant reductions in hs-CRP levels were also noted at 6 and 12 months in the nicorandil group, while no change was found in the nonnicorandil group. Results demonstrated that long-term nicorandil therapy is associated with gradual improvements in endothelial function. Our findings also suggest that nicorandil treatment may result in cardiovascular protection through pleiotropic effects including reductions in oxidative injury and systemic inflammation.

We report a case of a 66-year-old woman admitted to our hospital for examination and treatment of uterine and rectal prolapse, pleural and pericardial effusion, and ascites. On further examination, she was diagnosed with hypothyroidism. Test results showed markedly elevated concentrations of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125). We consequently performed multiple imaging studies, none of which detected a malignancy. Hormonal replacement therapy with levothyroxine was started, and the pleural and pericardial effusion and ascites gradually abated. Concentrations of serum CEA and CA125 also decreased gradually after therapy with levothyroxine. These findings indicate that in patients with hypothyroidism, elevated CEA and CA125 levels do not necessarily indicate malignancy. Conversely, in any patient with elevated serum CEA and/or CA125, hypothyroidism should be considered in the differential diagnosis.

There are few reports of cardiac involvement in patients with Kugelberg-Welander disease. We report a case of a 51-year-old man with Kugelberg-Welander disease who presented with syncope. His electrocardiogram showed complete right bundle branch block and transient complete atrioventricular block without escape rhythm. He was successfully treated with emergency temporary pacing followed by permanent pacemaker implantation. In this report, we review the relevant literature and argue that patients with Kugelberg-Welander disease should be evaluated regularly for cardiac disease.

1. Previous clinical studies with prostaglandin I(2) (PGI(2)) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2. Beraprost sodium (120 microg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium-dependent vasodilatation was assessed by plethysmography, and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) was measured at baseline, 4 weeks and 8 weeks. 3. Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8-iso-PGF(2alpha) remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8-iso-PGF(2alpha) decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8-iso-PGF(2alpha) (P < 0.001). 4. Beraprost sodium decreased oxidative stress and improved forearm endothelium-dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.

Background: Peripheral vascular endothelial dysfunction is an independent predictor of cardiovascular events, and can be assessed noninvasively by measuring reactive hyperemia, either by vascular ultrasound measurement of flow-mediated vasodilatation or, less commonly, by measurement of blood flow using plethysmography. In the present study reactive hyperemia was measured using plethysmography in healthy subjects with multiple cardiovascular risk factors., Methods and Results: Reactive hyperemia was measured following 5-min occlusion of the upper arm in 449 healthy subjects (302 men, 147 women, age range 20-70 years) with (n=352) and without (n=97) risk factors such as smoking, hypertension, diabetes mellitus, hypercholesterolemia, obesity, family history of cardiovascular disease, and menopause. Maximum blood flow and minimum vascular resistance in reactive hyperemia did not differ between subjects with and without risk factors regardless of gender. Duration of reactive hyperemia, however, was significantly shorter in subjects with risk factors. Age-adjusted mean value of duration of reactive hyperemia was significantly smaller in men with a smoking habit, diabetes mellitus, hypercholesterolemia or obesity, and in women with smoking habit, hypertension, diabetes mellitus or obesity. The number of risk factors significantly correlated with the duration of reactive hyperemia in both men (r=-0.56, p<0.001) and women (r=-0.62, p<0.001), suggesting that endothelial dysfunction increases with the number of risk conditions clustering in a single individual., Conclusions: Duration of reactive hyperemia reflects cardiovascular risk factors and decreases with the number of risk conditions. These findings suggest that the duration of reactive hyperemia measured with plethysmography is potentially useful for assessing endothelial dysfunction.

A 26-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) was admitted to our hospital for further cardiovascular examination. A muscle biopsy demonstrated strongly succinate dehydrogenase-reactive blood vessels. Pulse wave contour analysis revealed that both capacitive and oscillatory compliance were markedly reduced in this patient compared with 45 normal age-matched control subjects. Hepatocyte growth factor was remarkably elevated in this patient over that of 10 normal control subjects. These findings suggest that a MELAS patient has not only pathologic but also functional vascular involvement. If so, patients with MELAS need systemic vascular assessment.

Recent studies have demonstrated that proinflammatory cytokines induce large amounts of nitric oxide (NO) and that the amount increases in patients with congestive heart failure (CHF). There are, however, few reports regarding the relationships between NO production, cytokines and the severity of heart failure, so the plasma concentrations of nitrite and nitrate (NOx), tumor necrosis factor-alpha (TNF-alpha) and brain natriuretic peptide (BNP) were measured in 43 patients with CHF caused by dilated cardiomyopathy and 26 age- and sex-matched normal control subjects. Forearm blood flow (FBF) was measured using plethysmography during infusions of acetylcholine and nitroglycerin and after the administration of the NO synthesis inhibitor L-NMMA (N(G)-monomethyl-L-arginine). Plasma concentrations of both NOx and TNF-alpha were significantly higher in the patient group than in the control group (p<0.001) and correlated closely with BNP concentrations (p<0.001). There was a positive relationship between NOx and TNF-alpha concentrations (r=0.80, p<0.001). Administration of L-NMMA significantly reduced FBF in both groups, and the percent change in FBF from baseline correlated significantly with TNF-alpha concentrations (r=0.63, p<0.001). The FBF response to acetylcholine was depressed in the patient group and correlated inversely with TNF-alpha concentrations. The FBF response to nitroglycerin did not correlate with TNF-alpha concentrations. The findings indicate that the concentrations of NO and TNF-alpha in patients with CHF increase in proportion to the severity of heart failure, and that TNF-alpha plays a role in the enhanced systemic and local production of NO.

Objective: Liver cirrhosis is often accompanied by arterial hypoxemia in the absence of cardiopulmonary disease. The aim of this study was to investigate the relationship between various clinicopathological conditions and the hypoxemia seen in Japanese patients with liver cirrhosis., Methods: In 102 consecutive patients with alcoholic (N = 45) and nonalcoholic (N = 57) cirrhosis not associated with cardiopulmonary disease, we performed lung perfusion scintigraphy, contrast echocardiography, and arterial blood gas analysis and measured oxygen consumption., Results: No abnormality was seen in pulmonary blood flow in cirrhotic patients, but 38 (38%) of them had a decreased partial pressure of oxygen (PaO2). The hypoxemic patients did not show any pulmonary signs or symptoms. The hypoxemia was not associated with the Child-Pugh grade, and was observed in 32 (71%) of the 45 alcoholic patients but in only six (11%) of the 57 nonalcoholic patients (p < 0.001). Oxygen consumption was significantly higher in the alcoholic group than in the nonalcoholic group (p < 0.0001), and a high incidence of oxygen consumption was seen in all 45 (100%) of the alcoholic patients and in 34 (60%) of the nonalcoholic subjects, the difference being significant (p < 0.01). The relationship between oxygen consumption and PaO2 in the 102 cirrhotic patients showed an inverse correlation (r = -0.85, p < 0.0001). Among the alcoholic patients, the incidence of hypoxemia did not differ between the 33 smokers and the 12 nonsmokers. After 1 wk of abstinence from alcohol a significant increase (p < 0.0001) in the PaO2 was seen in 14 of 19 patients with alcoholic cirrhosis., Conclusions: We conclude that the hypoxemia in Japanese patients with liver cirrhosis occurs mainly in drinking alcoholic patients, presumably due to an increased oxygen consumption by alcohol.

1. Low doses of sublingual nifedipine are still used for the treatment of hypertensive crises, although recent studies have raised concerns that sublingual nifedipine may cause serious dose-dependent adverse effects. The present study was performed to test the safety of low-dose sublingual nifedipine administered to elderly hypertensive patients. 2. Systemic blood pressure measurements and electrocardiographic (ECG) examinations were performed before and 45-60 min after a 5 mg dose of sublingual nifedipine in 93 consecutive hypertensive patients, 65 years of age or older, who were without coronary artery disease. In 33 patients, the effects of nifedipine on myocardial lactate metabolism were studied during cardiac catheterization. 3. In all patients, following nifedipine administration, blood pressure (BP) decreased significantly, while heart rate (HR) increased, and symptoms associated with elevated BP disappeared. However, changes consistent with myocardial ischaemia appeared on the ECG in six of 55 patients with left ventricular hypertrophy (LVH) and in one of 38 patients without LVH, although only two of these seven patients experienced angina-like precordial tightness. Sublingual nifedipine decreased myocardial lactate extraction from 52 +/- 13 to 38 +/- 19% in 20 patients with LVH (P = 0.02), but myocardial lactate extraction remained stable in 13 patients without LVH (49 +/- 7 to 50 +/- 5%; NS). The change in lactate extraction was significantly correlated with the percentage change in diastolic arterial pressure (r = 0.77, P < 0.001). 4. These results suggest that sublingual nifedipine, even at the low dose of 5 mg, may cause myocardial ischaemia in some elderly patients with LVH that is associated with a marked reduction in coronary perfusion pressure.

Background and Hypothesis: Mechanisms of heart failure in elderly hypertensive patients with hypertrophy have not been studied sufficiently. We hypothesized that impaired increment of coronary blood flow in response to increases in heart rate could be responsible for the occurrence or aggravation of heart failure., Methods: To test this hypothesis, we measured coronary hemodynamics and lactate balance during basal conditions and atrial pacing in 21 elderly patients aged > or = 65 years (mean 74 +/- 6 years) without coronary arterial disease: 7 normotensive control patients (Group 1), 7 hypertensive hypertrophic patients without a history of congestive heart failure (Group 2), and 7 patients with such history (Group 3). Coronary sinus blood flow (CSBF) was measured in coronary sinus using a thermodilution catheter., Results: During basal conditions, heart rate did not differ among the three groups (67 +/- 3 in Group 1, 65 +/- 11 in Group 2, and 63 +/- 6 beats/ in Group 3). CSBF was significantly higher in the two hypertrophic groups than in the control group, but CSBF normalized by left ventricular mass was significantly lower in both hypertrophic groups. External mechanical efficiency (EME) obtained as left ventricular work divided by myocardial oxygen consumption did not differ among groups during basal conditions (36 +/- 9% in Group 1, 35 +/- 8% in Group 2, and 29 +/- 9% in Group 3, NS). During atrial pacing to increase heart rate by 25 +/- 5% (lower) and 54 +/- 6% (higher), the increases in CSBF were markedly limited in both hypertrophic groups, and the response in Group 3 was more depressed than that in Group 2. EME did not change in the control group or in Group 2, but did decrease to 21 +/- 5% in Group 3 during the higher pacing rate (p < 0.01 vs. basal conditions). In this group, the relationship between EME and heart rate showed a significant negative correlation (r = -0.56, p = 0.02). Lactate balance in coronary sinus blood showed a tendency to production in Group 3 during the higher pacing rate, suggesting myocardial ischemia., Conclusion: These findings suggest that in hypertensive hypertrophic patients with a history of heart failure, the coronary circulation system is vulnerable to increasing heart rate. In medical treatment of elderly hypertensive patients, control of heart rate in addition to blood pressure control should be considered to minimize the occurrence or aggravation of heart failure.

Objectives: This study attempted to evaluate the effects of supine and lateral recumbent positions on pulmonary venous flow by transesophageal Doppler echocardiography in healthy subjects., Background: Although transesophageal echocardiographic examination is usually performed with the patient lying in the left lateral decubitus or supine position, little attention has been paid to the effects of these positions on pulmonary venous flow., Methods: We performed pulsed Doppler transesophageal echocardiography of the left and right pulmonary veins in 16 normal subjects as they lay in the left and right lateral decubitus and supine positions., Results: Data are reported as mean value +/- SD. Adequate recordings were obtained in 12 subjects (75%). In the left pulmonary vein, peak systolic velocity and time-velocity integral of systolic flow increased significantly in the left compared with the right lateral decubitus position (56 +/- 12 vs. 44 +/- 13 cm/s, p < 0.05, and 15 +/- 4 vs. 9 +/- 4 cm, p < 0.05, respectively). In the right pulmonary vein, peak systolic velocity and time-velocity integral of systolic flow decreased significantly in the left compared with the right lateral decubitus position (38 +/- 10 vs. 48 +/- 9 cm/s, p < 0.05, and 9 +/- 2 vs. 12 +/- 2 cm, p < 0.05, respectively). There were no significant differences between positions in peak diastolic flow velocity, time-velocity integral of diastolic flow or peak velocity of flow reversal at atrial contraction., Conclusions: Pulmonary venous systolic peak velocities and time-velocity integrals of systolic flow increase when the pulmonary venous recording is from the recumbent subject's lower side. Therefore, the effects of position should be considered in evaluating left ventricular diastolic function by transesophageal Doppler echocardiography.

In previous studies, magnetic resonance imaging (MRI) using contrast agents was found to be useful in distinguishing reperfused infarcts from nonreperfused infarcts. However, there have been only a few detailed studies using consecutive MR images for the assessment of myocardial reperfusion during an acute myocardial infarction and also no studies have been performed using a percutaneous transluminal coronary occlusion model (closed chest model). We induced acute myocardial infarction in dogs by occluding and then reperfusing the coronary artery with a balloon catheter. ECG-gated MR images were taken using the spin-echo technique before and after Gd-DTPA injection during both coronary artery occlusion and after reperfusion. We defined the intensity ratio (IR) as the signal intensity at the ischemic area divided by that at the nonischemic area on MR images and compared each image by the IR. Without Gd-DTPA, there was no difference between infarcted and normally perfused myocardium. Infarcted myocardium had a low signal intensity (IR = 0.68 +/- 0.14) soon after Gd-DTPA injection. This difference diminished with time. After reperfusion the infarcted myocardium had a high signal intensity (IR:1.76 +/- 0.34). We conclude that Gd-DTPA- enhanced MRI can distinguish reperfused from nonreperfused infarcts soon after Gd-DTPA administration.