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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Introduction: Functional tricuspid regurgitation (TR) caused by chronic atrial fibrillation with structurally normal tricuspid valve (TV) leaflets, normal right ventricular (RV) function, and dilated right atrium (RA), is considered as a new clinical entity, atrial functional TR (AF-TR). We sought to investigate TV geometry and right heart remodeling in AF-TR compared with ventricular functional TR with sinus rhythm (VF-TR). Methods: Transesophageal 3D echocardiography datasets of the TV and the RV were acquired in 51 symptomatic severe TR. 3D RV endocardial surfaces were reconstructed throughout the cardiac cycle and then postprocessed using semiautomated integration and segmentation software to calculate position of papillary muscle (PM) tips (Figure). Results: Compared with VF-TR, AF-TR had more dilated and posteriorly displaced annulus and less leaflet tethering angles with more prominent right atrium and smaller RV end-systolic volume. On the XY (annular) plane, the center of annulus was getting closer towards the anterior and posterior PM tips and was going away from the medial PM tip caused by prominent annular dilatation in AF-TR. On the Z axis, the position of each PM tip in AF-TR was not so much displaced apically as that in VF-TR. Multiple linear regression analyses revealed that right atrial volume and right atrial/RV end-systolic volume ratio were determinants of annular area and orientation in AF-TR, respectively (both P P Conclusion: Right heart remodeling and its association with TV geometry differ between AF-TR and VF-TR, which offers distinctive therapeutic implications.

Background Diagnostic criteria of flow‐mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin‐induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no‐risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow‐Mediated Dilation Japan study and the Flow‐Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver‐operator characteristic curve analysis of FMD to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no‐risk group was 7.1%. Receiver‐operator characteristic curve analysis of NID to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no‐risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of P P =0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.

Background: Recent publications suggested that epicardial adipose tissue (EAT) contributes to the pathogenesis of coronary atherosclerosis. Although some studies showed the association between EAT accumulation and left ventricular (LV) diastolic dysfunction, these associations are not fully understood. Methods: We evaluated 153 patients without coronary artery disease who underwent coronary computed tomography (CT) angiography and Doppler echocardiography. We evaluated 153 patients (mean age of 60 years and 54% men) with zero coronary artery calcium score in coronary CT. Visceral adipose tissue (VAT) area was simultaneously measured by abdominal scans, and EAT volume was also calculated. These measurements were corrected by body surface area; VAT area index (VATAI), and EAT volume index (EATVI). The early diastolic mitral annular velocity at the septal (septal E’) and lateral (lateral E’) were measured using tissue Doppler echocardiography. Results: The mean values of BMI, VATAI, EATVI, and LVMI were 23.7 ± 3.8 kg/m 2 , 52.6 ± 26.4 cm 2 /m 2 , 71.3 ± 29.8 cm 3 /m 2 , and 83.3 ± 17.7 g/m 2 , respectively. The mean septal E’ and lateral E’ velocities were 7.2 ± 2.2 cm/s and 9.8 ± 2.9 cm/s, respectively. Each E’ velocity was negatively correlated with EATVI (septal, R = 0.276, p < 0.001; lateral, R = 0.342, p < 0.001) and VATAI (septal, R = 0.241, p = 0.03; lateral, R = 0.255, p = 0.002; Figure). In contrast, each E’ velocity was not correlated with LVMI (septal, R = 0.161, p = 0.03; lateral, R = 0.118, p = 0.14) and BMI (septal, R = 0.182, p = 0.03; lateral, R = 0.152, p = 0.06). To determine each E’ velocity, we performed stepwise multiple regression analyses where all clinical parameters were entered. Diastolic blood pressure (p = 0.014), statin use (p = 0.011), LVMI (p = 0.003), and EATVI (p = 0.004) were independently correlated with septal E’ velocity, and statin use (p = 0.024), LVMI (p = 0.011), and EATVI (p < 0.001) were independently correlated with lateral E’ velocity. Conclusion: An increase in EATVI was associated with the decrease of early diastolic mitral annular velocity along each side of the left ventricle in patients with coronary calcium score of zero. These findings indicate that EAT accumulation may cause LV diastolic dysfunction in the early phase of coronary artery disease.

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation ( FMD ) and brachial–ankle pulse wave velocity (ba PWV ) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and ba PWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P =0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P =0.01) primary outcomes. ba PWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P =0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P =0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and ba PWV , stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and ba PWV were significant predictors of cardiovascular events. The combination of FMD and ba PWV provided further cardiovascular risk stratification. Clinical Trial Registration URL : www.umin.ac.jp . Unique identifier: UMIN 000012950.

Rho-associated kinases play an important role in a variety of cellular functions. Although Rho-associated kinase activity has been shown to be an independent predictor for future cardiovascular events in a general population, there is no information on Rho-associated kinase activity in patients with acute coronary syndrome. We evaluated leukocyte Rho-associated kinase activity by Western blot analysis in 73 patients with acute coronary syndrome and 73 age- and gender-matched control subjects. Rho-associated kinase activity within 2 hours of acute coronary syndrome onset was higher in patients with acute coronary syndrome than in the control subjects (0.95±0.55 versus 0.69±0.31; P P =0.03 and P =0.03, respectively) and then gradually decreased to 0.83±0.52 after 7 days, 0.78±0.42 after 14 days, and 0.72±0.30 after 6 months ( P =0.22, P =0.29, and P =0.12, respectively). During a median follow-up period of 50.8 months, 31 first major cardiovascular events (death from cardiovascular causes, myocardial infarction, ischemic stroke, and coronary revascularization) occurred. After adjustment for age, sex, cardiovascular risk factors, and concomitant treatment with statins, increased Rho-associated kinase activity was associated with increasing risk of first major cardiovascular events (hazard ratio, 4.56; 95% confidence interval, 1.98–11.34; P

The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure–matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P P r =−0.31; P r =−0.35; P r =−0.34; P r =−0.24; P =0.04), plasma aldosterone concentration ( r =0.33; P r =0.46; P

Objective— Cardiovascular diseases are associated with chronic activation of Rho-associated kinases (ROCKs) and endothelial dysfunction. Both increased ROCK activity and endothelial dysfunction are thought to be closely associated with conventional cardiovascular risk factors. The purpose of this study was to determine the relationships between ROCK activity, endothelial function, and cardiovascular risk factors. Methods and Results— We evaluated ROCK activity in peripheral leukocytes by Western blot analysis and flow-mediated vasodilation by ultrasonography in 242 men who had no cardiovascular or cerebrovascular diseases (mean age, 40±10 years; range, 20 to 73 years). ROCK activity was defined as the ratio of phospho myosin-binding subunit on myosin light chain phosphatase to total myosin-binding subunit. Univariate regression analysis revealed that leukocyte ROCK activity significantly correlated with body mass index ( r =0.29, P =0.003); systolic blood pressure ( r =0.25, P =0.01); low-density lipoprotein cholesterol level ( r =0.21, P =0.04); and Framingham risk factor score, a cumulative cardiovascular risk index for heart attack ( r =0.31, P r =−0.23, P =0.02), body mass index ( r =0.19, P =0.05), systolic blood pressure ( r =−0.22, P =0.03), total cholesterol level ( r =−0.21, P =0.04), low-density lipoprotein cholesterol level ( r =−0.22, P =0.04), glucose level ( r =−0.20, P =0.04), and Framingham risk factor score ( r =−0.37, P r =−0.41, P Conclusion— These findings suggest that cumulative cardiovascular risk may enhance ROCK activity and endothelial dysfunction, leading to progression of cardiovascular diseases and outcomes.

Rho-associated kinases (ROCKs) play an important role in Ca sensitization and vascular resistance. Activation of ROCKs is associated with hypertension. The purpose of this study was to evaluate the effect of the calcium channel blocker amlodipine on ROCKs activity in patients with hypertension.We evaluated ROCK activity in peripheral leukocytes by Western blot analysis in 651 patients with hypertension treated with antihypertensive agents, 28 untreated hypertensive patients and 28 healthy individuals, and the effects of treatment with amlodipine or losartan for 12 weeks on ROCK activity in 28 untreated hypertensive patients who were randomly divided into an amlodipine group (n = 14) and a losartan group (n = 14). ROCK activity was defined as the ratio of phospho myosin-binding subunit (MBS) on myosin light-chain phosphatase to total MBS.Leukocyte ROCK activity was greater in untreated patients with essential hypertension than in the healthy individuals (0.84 ± 0.24 vs. 0.61 ± 0.18, P = 0.03). In 651 patients with hypertension treated with antihypertensive agents, ROCK activity was significantly lower in the calcium channel blocker-treated group than in the groups treated with renin-angiotensin system inhibitors, diuretics, and β-blockers (0.70 ± 0.24 vs. 0.85 ± 0.29, 0.83 ± 0.24, and 0.86 ± 0.31, P0.05, respectively). ROCK activity after 4 and 12 weeks of treatment was significantly decreased in the amlodipine group (0 weeks: 0.85 ± 0.25, 4 weeks: 0.66 ± 0.16, 12 weeks: 0.64 ± 0.15, P0.05, respectively) but not in the losartan group, whereas the antihypertensive effects were similar in the two groups.These findings suggest that calcium channel blocker amlodipine inhibits ROCK activity in patients with hypertension.

Thromboangitis obliterans (TAO; Buerger's disease) and atherosclerosis obliterans (ASO) are associated with endothelial dysfunction. The purpose of this study was to evaluate the role of circulating progenitor cells (CPCs) in endothelial function in patients with TAO and ASO. We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation, and circulating CPCs in 30 patients with TAO and 30 age- and sex-matched healthy subjects and in 40 patients with ASO. FMD was smaller in both the TAO group and ASO group than in the control group (6.6±2.7%, 5.7±3.3% versus 9.5±3.1%, P P r =0.43 and r =0.40, P

The purpose of this study was to evaluate endothelial function in patients with periodontitis. We evaluated forearm blood flow responses to acetylcholine and sodium nitroprusside in patients with periodontitis who had no other cardiovascular risk factors (32 men; 25±3 years of age), in a normal control group (20 men; 26±3 years of age), and in hypertensive patients with periodontitis (28 men and 10 women; 56±12 years of age) and without periodontitis (control group; 18 men and 6 women; 54±13 years of age). Forearm blood flow was measured using strain-gauge plethysmography. Circulating levels of C-reactive protein and interleukin-6 were significantly higher in the periodontitis group than in the control group. Both in healthy and hypertensive subjects, forearm blood flow responses to acetylcholine were significantly smaller in the periodontitis group than in the control group. Sodium nitroprusside–stimulated vasodilation was similar in the 2 groups. Periodontal therapy reduced serum concentrations of C-reactive protein and interleukin-6 and augmented acetylcholine-induced vasodilation in periodontitis patients with and without hypertension. After administration of N G -monomethyl- l -arginine, an NO synthase inhibitor, forearm blood flow response to acetylcholine was similar before and after treatment. These findings suggest that periodontitis is associated with endothelial dysfunction in subjects without cardiovascular risk factors, as well as hypertensive patients, through a decrease in NO bioavailability and that systemic inflammation may be, at least in part, a cause of endothelial dysfunction, leading to cardiovascular diseases.

Introduction: Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE and vascular function. Methods: We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. Results: Univariate regression analysis revealed that FMD correlated with age (ρ=-0.38, P Conclusions: These findings suggest that sRAGE may have a counter-regulatory mechanism that is activated to counteract the vasotoxic effect of the AGEs-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

Introduction: Endothelial function is impaired in heavy or binge drinking. Heavy drinking should be a predictor of endothelial dysfunction. However, there is little information on the effects of dose-dependent alcohol consumption on endothelial function. Therefore, we evaluated the relationship between alcohol consumption and endothelial function in a large general population. Methods and Results: We measured flow-mediated vasodilation (FMD) in 2734 men who provided self-report about habitual alcohol intake. The subjects were divided into five groups by alcohol consumption: none (0 g/week), light (0 g/week< to ≤140 g/week), moderate (140 g/week< to ≤280 g/week), heavy (280 g/week< to ≤420 g/week), and excessive (420 g/week Conclusions: These findings suggest that even light alcohol consumption impair the endothelial function. Alcohol drinking may be harmful for vascular function.

Objective: In contrast to low-density lipoprotein cholesterol, and high density lipoprotein cholesterol, which are well-established independent risk factors for cardiovascular disease, the importance of triglycerides remains controversial. In this study, we evaluated the associations between triglycerides and endothelial function in the general population. Methods and Results: We enrolled 4,908 subjects (3842 men and 1066 women; mean age, 48±12 years) who were enrolled in FMD-Japan registry. And, we investigated cross-sectional associations between triglycerides and endothelial function by measurement of flow-mediated vasodilation (FMD). The triglycerides levels were negatively associated with FMD (r=-0.10, P Conclusions: These findings supported an independent association between triglycerides and cardiovascular disease.

Introduction: Flow-mediated vasodilation (FMD) as an index of endothelium-dependent vasodilation and nitroglycerine-induced vasodilation as an index of endothelium-independent vasodilation in the brachial artery using high-resolution ultrasound are useful for assessing vascular function. Some studies have shown that endothelial function assessed by FMD can serve as an independent predictor of cardiovascular events. Previously, we reported that nitroglycerine-induced vasodilationcan be used as a marker for identifying patients with advanced atherosclerosis. The purpose of this study was to determine the prognostic impact of cardiovascular events between FMD and FMD combined with nitroglycerine-induced vasodilation. Methods and Results: We measured FMD and nitroglycerine-induced vasodilation in 402 subjects (mean age, 58±17 years), including patients with cardiovascular diseases. We assessed the associations between FMD combined with nitroglycerine-induced vasodilation and cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, and revascularization). During a median period of 32.3 months (interquartile range, 17.1 to 49.1 months) of follow-up, 15 subjects died (5 from cardiovascular causes), 3 myocardial infarction, 7 stroke, and 26 revascularization. The receiver operating characteristic curve analysis revealed that FMD alone predicts cardiovascular events with an area under curve of 0.67. FMD combined with nitroglycerine-induced vasodilation predicts cardiovascular events with an area under curve of 0.70. FMD < median value of 3.9% and nitroglycerine-induced vasodilation < median value of 12.2% were associated with increased cardiovascular event. After adjustment for age, sex, body mass index, cardiovascular risk factors, below median FMD and nitroglycerine-induced vasodilation group remained a strong independent indicator of cardiovascular events (hazard ratio, 4.95; 95 percent confidence interval, 1.65 to 21.43; P=0.002). Conclusions: These findings suggest that the combination of FMD and nitroglycerine-induced vasodilation measurement could more accurately predict cardiovascular events than FMD alone.

Response: As the first step in the decision to perform amputation, the surgeon consults with the patient. In our hospital, the final decision for major amputation is made by mutual consent of cardiologists, surgeons, dermatologists, and anesthetists on the peripheral arterial disease committee. However, our study was not a randomized and placebo-control trial. It was difficult to compare the decisions for major amputation between the control group and the bone marrow mononuclear cell (BM-MNC) implantation group. We cannot deny the possibility of decision bias. In the atherosclerotic peripheral arterial disease control group, all patients with Rutherford category 4 or 5 who were …

Background: Buerger’s disease is associated with endothelial dysfunction. Several lines of evidence have shown that the circulating number and function of endothelial progenitor cells (EPCs) are surrogate biologic markers for cardiovascular diseases. Methods and Results: The purpose of this study was to evaluate the role of EPCs in endothelial function in Buerger’s disease. We measured flow-mediated vasodilation (FMD), nitroglycerine (NTG)-induced vasodilation, circulating levels of EPCs, cell migration response to vascular endothelial growth factor (VEGF), and serum levels of VEGF in 25 patients with Buerger’s disease and 25 age- and sex-matched healthy subjects, and 25 patients with atherosclerosis obliterans (ASO). Vascular reactivity of brachial artery was measured by using high-resolution ultrasound. Circulating EPCs were quantified by flow cytometry. Cell migration assay was performed by the Boyden chamber technique. FMD was lower in both the Buerger’s group and the ASO group than in the control group (Buerger; 6.6±3.1%, ASO; 5.5±5.4%, vs. control; 10.6±3.3%, p Conclusions: These findings suggest that FMD was impaired in patient with Burger’s disease as well as patients with ASO compared with normal control subjects and that the number and function of EPCs were not decreased in patients with Burger’s disease. EPCs may be mobilized to restore endothelial function in Buerger’s disease. In patients with ASO, both the mobilizations of EPCs and endothelial function were impaired.