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Background Hypereosinophilic syndrome (HES) is characterized by moderate to severe eosinophilia, exclusion of neoplastic or secondary origins of eosinophilia, and systemic involvement with end-organ damage. Coronary arteries can be affected to cause vasospastic angina (VSA); however, the association of the two diseases is not well recognized. Case summary A 55-year-old woman who had a history of multiple allergic disease such as bronchial asthma and chronic sinusitis with nasal polyps was hospitalized due to attacks of chest pain at rest. During a spontaneous attack of chest pain, ECG revealed ST-segment elevation in the inferior leads and emergency coronary angiography showed focal spasms of the right and left anterior descending coronary arteries, both of which were relieved after intracoronary administration of nitroglycerine. She was diagnosed with VSA according to the Japanese Circulation Society guidelines. Despite conventional vasodilator therapies, her resting angina remained refractory. Laboratory findings were notable for moderate eosinophilia. A comprehensive evaluation to uncover the underlying cause of refractory VSA led to the diagnosis of HES, concomitant with eosinophilic pneumonia and eosinophilic chronic rhinosinusitis. Pericoronary inflammation by fat attenuation index (FAI) was increased in the proximal segment of the right coronary artery. Treatment was initiated with oral prednisolone at a starting dose of 30 mg/day. The response to treatment was rapid, with her symptoms disappearing and a regression of eosinophilia observed the following day. Discussion Hypereosinophilic syndrome manifests with refractory VSA, and eosinophil-suppressing corticosteroid therapy proves effective in improving both conditions along with reduction of the pericoronary inflammation by FAI. [ABSTRACT FROM AUTHOR]

A 17-year-old male was diagnosed with acute myocarditis based on the presence of CD3-positive T-lymphocytes in myocardial biopsy, normal coronary angiography, and focal increase in late gadolinium enhancement, T2 intensity and native T1 value. On day 2, the patient suffered from recurrence of chest pain with new ST segment elevations on electrocardiogram. A transient metabolic alteration (inversed lactate level of the coronary sinus relative to that of the coronary artery) accompanied by chest pain and electrocardiographic changes without epicardial coronary spasm in acetylcholine provocation test led to the diagnosis of microvascular angina, which is characterized by a transient myocardial ischemia secondary to a dysfunction of the resistance coronary vessels (<500 μm) that, because of their small size, are not visualized at coronary angiography. Benidipine, a dihydropyridine calcium channel antagonist, was started for chest pain due to microvascular angina. On 6 months after admission, when the findings of cardiac magnetic resonance were recovered, intracoronary infusion of acetylcholine did not induce chest pain, electrocardiographic changes, epicardial coronary spasm, and adverse changes of lactate levels of the coronary artery and sinus. The patient had no chest symptoms 2 years after discontinuation of benidipine. The present case of microvascular angina, which was complicated with acute myocarditis on acute phase and recovered in chronic phase, indicates an association of myocardial inflammation with reversible coronary microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: Delirium is an important prognostic factor in postoperative patients undergoing cardiovascular surgery and intervention, including transcatheter aortic valve implantation (TAVI). However, delirium after transcatheter aortic valve implantation (DAT) is difficult to predict and its pathophysiology is still unclear. We aimed to investigate whether preoperative cerebral blood flow (CBF) is associated with DAT and, if so, whether CBF measurement is useful for predicting DAT. Methods: We evaluated CBF in 50 consecutive patients before TAVI (84.7±4.5 yrs., 36 females) using 99mTc ethyl cysteinate dimer single-photon emission computed tomography. Preoperative CBF of the DAT group (N = 12) was compared with that of the non-DAT group (N = 38) using whole brain voxel-wise analysis with SPM12 and region of interest-based analysis with the easy-Z score imaging system. Multivariable logistic regression analysis with the presence of DAT was used to create its prediction model. Results: The whole brain analysis showed that preoperative CBF in the insula was lower in the DAT than in the non-DAT group (P<0.05, family-wise error correction). Decrease extent ratio in the insula of the DAT group (17.6±11.5%) was also greater relative to that of the non-DAT group (7.0±11.3%) in the region of interest-based analysis (P = 0.007). A model that included preoperative CBF in the insula and conventional indicators (frailty index, short physical performance battery and mini-mental state examination) showed the best predictive power for DAT (AUC 0.882). Conclusions: These results suggest that preoperative CBF in the insula is associated with DAT and may be useful for its prediction. [ABSTRACT FROM AUTHOR]

Background  Cardiac sarcoidosis is a chronic, inflammatory disease that can affect the heart and often results in heart failure and lethal arrhythmias. A multimodality imaging approach without endomyocardial biopsy allows for the diagnosis of isolated cardiac sarcoidosis. Coronary vasomotion abnormalities are highly prevalent in various cardiovascular and inflammatory diseases. It remains unknown whether active myocardial inflammation due to cardiac sarcoidosis is associated with coronary vasomotion abnormalities. Case summary  A 68-year-old man without a past medical history experienced an out-of-hospital cardiac arrest due to ventricular fibrillation and was successfully resuscitated without neurologic sequelae. Coronary angiography showed normal coronary arteries; however, intracoronary acetylcholine provocation testing demonstrated both epicardial coronary and coronary microvascular spasm. He was diagnosed with isolated cardiac sarcoidosis by fulfilling the diagnostic criteria proposed by the Japanese Circulation Society 2016 diagnostic guidelines, including fatal ventricular arrhythmia, focal left ventricular wall asynergy, increased myocardial fluorodeoxyglucose uptake by positron emission tomography, and late gadolinium enhancement by cardiac magnetic resonance in the heart. He was treated with calcium-channel blocker for coronary artery spasm and prednisolone for cardiac sarcoidosis and underwent implantation of an implantable cardioverter-defibrillator for secondary prevention. Following the treatment, the severity of coronary artery spasm was reduced along with regression of the myocardial inflammation. Discussion  Epicardial coronary artery and coronary microvascular spasm can be accompanied by active myocardial inflammation of isolated cardiac sarcoidosis, and the treatment with corticosteroid and calcium-channel blocker may be effective for relieving the severity of coronary artery spasm in association with regression of myocardial inflammation of the disease. [ABSTRACT FROM AUTHOR]

The endothelium plays crucial roles in modulating vascular tone by synthesizing and releasing endothelium‐derived relaxing factors (EDRFs), including vasodilator prostaglandins, nitric oxide (NO) and endothelium‐dependent hyperpolarization (EDH) factors. Thus, endothelial dysfunction is the hallmark of atherosclerotic cardiovascular diseases. Importantly, the contribution of EDRFs to endothelium‐dependent vasodilatation varies in a distinct vessel size‐dependent manner; NO mainly mediates vasodilatation of relatively large, conduit vessels (eg epicardial coronary arteries), while EDH factors in small resistance vessels (eg coronary microvessels). Endothelium‐derived hydrogen peroxide (H2O2) is a physiological signalling molecule serving as one of the major EDH factors especially in microcirculations and has gained increasing attention in view of its emerging relevance for cardiovascular diseases. In the clinical settings, therapeutic approaches targeting NO (eg NO donors) or non‐specific elimination of reactive oxygen species (eg antioxidant supplements) are disappointingly ineffective for the treatment of various cardiovascular diseases, in which endothelial dysfunction and coronary microvascular dysfunction are substantially involved. These lines of evidence indicate the potential importance of the physiological balance between NO and H2O2/EDH factor. Further characterization and better understanding of endothelium‐dependent vasodilatations are important to develop novel therapeutic strategies in cardiovascular medicine. In this MiniReview, we will briefly summarize the current knowledge on the emerging regulatory roles of endothelium‐dependent vasodilatations in the cardiovascular system, with a special reference to the two major EDRFs, NO and H2O2/EDH factor, in health and disease. [ABSTRACT FROM AUTHOR]

Diffuse and focal epicardial coronary disease and coronary microvascular abnormalities may exist side-by-side. Identifying the contributions of each of these three players in the coronary circulation is a difficult task. Yet identifying coronary microvascular dysfunction (CMD) as an additional player in patients with coronary artery disease (CAD) may provide explanations of why symptoms may persist frequently following and why global coronary flow reserve may be more prognostically important than fractional flow reserve measured in a single vessel before percutaneous coronary intervention. This review focuses on the challenges of identifying the presence of CMD in the context of diffuse non-obstructive CAD and obstructive CAD. Furthermore, it is going to discuss the pathophysiology in this complex situation, examine the clinical context in which the interaction of the three components of disease takes place and finally look at non-invasive diagnostic methods relevant for addressing this question. [ABSTRACT FROM AUTHOR]

Background: Metabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD)-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK), a key molecule of metabolic conditions. Methods and Results: Mice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1), with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C. Conclusions: These results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that Rho-kinase is also a novel therapeutic target of metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: Larger epicardial plaque burden (PB) and coronary microvascular endothelial dysfunction (CMED) have both been associated with major adverse cardiovascular events (MACE). However, the relationship between PB and CMED remains unknown. Methods: 148 patients with chest pain, referred for evaluation of coronary vasomotion and found to have angiographically normal coronary arteries or mild coronary artery disease (CAD) [<40% stenosis], underwent acetylcholine (Ach) assessment of CMED (defined as coronary blood flow [CBF] change <50% post ACh) and gray-scale intravascular ultrasound (IVUS) imaging of the left anterior descending artery for evaluation of vessel-averaged epicardial plaque area (PA) and PB (PB: PA/vessel area x 100). Results: Baseline clinical characteristics were not significantly different between patients with (n=87, 58.8%) vs. those without CMED (n=61, 41.2%). We observed a significant inverse linear relationship between both IVUS segment-level PA and PB with CBF (Figure). Patients with CMED had significantly higher averaged epicardial PA and PB (Figure). Hypertension (β=0.179, p=0.027 for PA and β=0.166, p=0.036 for PB), hyperlipidemia (β=0.26, p=0.001 for PA and β=0.311, p<0.001 for PB), and CMED (β=0.189, p=0.017 for PA and β=0.20, p=0.01 for PB) were independent predictors of larger PA and higher PB after adjusting for age, sex, hypertension, hyperlipidemia, diabetes mellitus, smoking and CMED. Conclusion: Coronary microvascular endothelial dysfunction is an independent predictor of larger epicardial PA and higher PB in patients with non-obstructive CAD. [ABSTRACT FROM AUTHOR]

Background: Epicardial coronary endothelial dysfunction is associated with development and progression of local coronary atherosclerotic lesion. However, the role of coronary microvascular endothelial function in the development of coronary atherosclerosis is largely unknown. The aim of the present study was to test the hypothesis that coronary microvascular endothelial dysfunction (CMED) is associated with epicardial atherosclerotic coronary artery disease (CAD). Methods and Results: 148 patients with chest pain, referred for the evaluation of coronary vasomotion and found to have angiographically normal coronary arteries or mild CAD (<40% stenosis), underwent invasive coronary endothelial function testing and virtual-histology intravascular ultrasound (VH-IVUS) of the left anterior descending coronary artery. Endothelium-dependent coronary vascular reactivity was evaluated by graded administration of intracoronary acetylcholine. CMED was defined as percent increase in coronary blood flow of ≤50% in response to a maximum dose of acetylcholine. Patients with CMED (n=87), as compared to those with normal microvascular endothelial function (n=61), had higher averaged epicardial plaque necrotic core area [0.07 (0.01-0.34) vs. 0.03 (0.00-0.17) mm2, p=0.016] and higher frequency of imaged arteries containing at least one VH-IVUS-derived thin-cap fibroatheroma (TCFA) [n=22 (25.3%) vs. 5 (8.2%), p=0.008] (Figure). After adjusting for age, gender and CAD risk factors, CMED was an independent predictor of VH-IVUS-derived larger averaged necrotic core area (β=0.176, p=0.033) and TCFA frequency (β=0.180, p=0.028). Conclusions: CMED is an independent predictor of larger necrotic core plaque area and higher TCFA frequency, both of which are characteristics of rupture-prone plaques. [ABSTRACT FROM AUTHOR]

Professor Maseri pioneered the research and treatment of coronary vasomotion abnormalities represented by coronary vasospasm and coronary microvascular dysfunction (CMD). These mechanisms can cause myocardial ischaemia even in the absence of obstructive coronary artery disease, and have been appreciated as an important aetiology and therapeutic target with major clinical implications in patients with ischaemia with non-obstructive coronary artery disease (INOCA). Coronary microvascular spasm is one of the key mechanisms responsible for myocardial ischaemia in patients with INOCA. Comprehensive assessment of coronary vasomotor reactivity by invasive functional coronary angiography or interventional diagnostic procedure is recommended to identify the underlying mechanisms of myocardial ischaemia and to tailor the best treatment and management based on the endotype of INOCA. This review highlights the pioneering works of Professor Maseri and contemporary research on coronary vasospasm and CMD with reference to endothelial dysfunction, Rho-kinase activation and inflammation., Competing Interests: Disclosure: HS is on the editorial board of European Cardiology Review; this did not influence peer review. All other authors have no conflicts of interest to declare. Funding: This work was supported, in part, by the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (21K16044)., (Copyright © 2023, Radcliffe Cardiology.)

Due to the coronavirus disease 2019 (COVID-19) pandemic, the first state of emergency had been declared from April 7 to May 25, 2020, in Japan. This pandemic might affect the management for patients with acute myocardial infarction (AMI). Method and Results: To evaluate the critical care and outcomes of AMI patients during the COVID-19 outbreak, we examined the patients with AMI hospitalized in 2020 (n = 1186) and those in 2017-2019 (n = 4877) using a database of the Miyagi AMI Registry Study. The door-to-device time under the emergency declaration became longer as compared with that of the same period in 2017-2019 [83(65-111) vs 74(54-108) min, p = 0.04]. Importantly, the time delay was noted in only patients with Killip class I on arrival, but not in those with Killip class II-IV. Meanwhile, there were no significant changes in the duration from the symptom onset to hospital arrival, the use rate of ambulance and the performance rate of primary percutaneous coronary intervention before and after the COVID-19 outbreak. Eventually, in-hospital mortality had not deteriorated under the state of emergency (6.7 vs 7.8 %, P = 0.69). Conclusion: The emergence of the COVID-19 outbreak seemed to affect AMI management and highlight understanding the barriers to cardiovascular critical care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary atherosclerotic stenosis. This clinical condition has recently been described as ischaemia with non-obstructive coronary arteries (INOCA). Coronary functional abnormalities are central to the pathogenesis of INOCA, including epicardial coronary spasm and coronary microvascular dysfunction composed of a variable combination of increased vasoconstrictive reactivity and/or reduced vasodilator function. During the last decade - in INOCA patients in particular - evidence for the prognostic impact of coronary functional abnormalities has accumulated and various non-invasive and invasive diagnostic techniques have enabled the evaluation of coronary vasomotor function in a comprehensive manner. In this review, the authors briefly summarise the recent advances in the understanding of pathophysiology and diagnosis of epicardial coronary artery spasm and coronary microvascular dysfunction., Competing Interests: Disclosure: HS is an international advisor on the European Cardiology Review editorial board; this did not affect peer review. All other authors have no conflicts of interest to declare. Support: This work was supported in part by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (16K09413, 17K15983) and the Agency for Medical Research and Development (21gk0210030h0001)., (Copyright © 2021, Radcliffe Cardiology.)

There is accumulating evidence highlighting a close relationship between inflammation and coronary microvascular dysfunction (CMD) in various experimental and clinical settings, with major clinical implications. Chronic low-grade vascular inflammation plays important roles in the underlying mechanisms behind CMD, especially in patients with coronary artery disease, obesity, heart failure with preserved ejection fraction and chronic inflammatory rheumatoid diseases. The central mechanisms of coronary vasomotion abnormalities comprise enhanced coronary vasoconstrictor reactivity, reduced endothelium-dependent and -independent coronary vasodilator capacity and increased coronary microvascular resistance, where inflammatory mediators and responses are substantially involved. How to modulate CMD to improve clinical outcomes of patients with the disorder and whether CMD management by targeting inflammatory responses can benefit patients remain challenging questions in need of further research. This review provides a concise overview of the current knowledge of the involvement of inflammation in the pathophysiology and molecular mechanisms of CMD from bench to bedside., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2021, Radcliffe Cardiology.)

Aims: The aim of this study was to test the hypothesis that coronary microvascular endothelial dysfunction (CMED) is associated with epicardial coronary atherosclerosis., Methods and Results: We performed a cross-sectional analysis of a comprehensive invasive assessment of coronary physiology with a focus on endothelium-dependent coronary microvascular function and virtual-histology intravascular ultrasound (VH-IVUS) in a total of 148 consecutive patients with chest pain and angiographically normal coronary arteries or non-obstructive coronary artery disease (CAD). Endothelium-dependent coronary vascular reactivity was evaluated by graded doses of intracoronary acetylcholine (ACh). CMED was defined as a percent increase in coronary blood flow of ≤50% in response to ACh. Patients with CMED (n=87) showed more vulnerable plaque characteristics as compared to those without (n=61); they showed higher plaque burden in association with larger necrotic core volume and higher frequency of imaged arteries containing at least one VH-IVUS-derived thin-capped fibroatheroma (TCFA) (n=22 [25.3%] vs 5 [8.2%], p=0.008). Multivariate logistic regression analysis revealed that CMED was an independent predictor of VH-IVUS-derived TCFA (adjusted odds ratio 2.28 [95% confidence interval: 1.30-4.02], p=0.004)., Conclusions: Independently of conventional coronary risk factors, CMED was associated with vulnerable plaque characteristics in patients with non-obstructive CAD.

Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. We have previously demonstrated that endothelium-derived H 2 O 2 is an endothelium-dependent hyperpolarization (EDH) factor and that loss of endothelial caveolin-1 reduces EDH/H 2 O 2 in the microcirculation. Caveolin-1 (Cav-1) is a scaffolding/regulatory protein that interacts with diverse signaling pathways, including angiogenesis. However, it remains unclear whether endothelial Cav-1 plays a role in ischemic angiogenesis by modulating EDH/H 2 O 2 . In the present study, we thus addressed this issue in a mouse model of hindlimb ischemia using male endothelium-specific Cav-1 (eCav-1) knockout (KO) mice. In isometric tension experiments with femoral arteries from eCav-1-KO mice, reduced EDH-mediated relaxations to acetylcholine and desensitization of sodium nitroprusside-mediated endothelium-independent relaxations were noted ( n = 4~6). An ex vivo aortic ring assay also showed that the extent of microvessel sprouting was significantly reduced in eCav-1-KO mice compared with wild-type (WT) littermates ( n = 12 each). Blood flow recovery at 4 wk assessed with a laser speckle flowmeter after femoral artery ligation was significantly impaired in eCav-1-KO mice compared with WT littermates ( n = 10 each) and was associated with reduced capillary density and muscle fibrosis in the legs ( n = 6 each). Importantly, posttranslational protein modifications by reactive nitrogen species and ROS, as evaluated by thiol glutathione adducts and nitrotyrosine, respectively, were both increased in eCav-1-KO mice ( n = 6~7 each). These results indicate that endothelial Cav-1 plays an important role in EDH-mediated vasodilatation and ischemic angiogenesis through posttranslational protein modifications by nitrooxidative stress in mice in vivo. NEW & NOTEWORTHY Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. The present study provides a line of novel evidence that endothelial caveolin-1 plays important roles in endothelium-dependent hyperpolarization and ischemic angiogenesis in hindlimb ischemia in mice through posttranslational protein modifications by reactive nitrogen species and ROS in mice in vivo.

Axitinib has emerged as a promising antineoplastic agent for the treatment of advanced renal cell carcinoma. Although the administration of axitinib was well-tolerated in clinical trials, the real-world safety and tolerability remain unverified. We herein report a patient with metastatic renal cell carcinoma who suddenly developed life-threatening hyperkalemia following the initiation of axitinib treatment. Although hyperkalemia has been reported with an incidence of <10%, acute severe hyperkalemia may be a considerably critical adverse event of axitinib therapy, especially in patients with risk factors for hyperkalemia. An abundance of caution for unusual and unpredictable toxicities is warranted when using axitinib.

Endothelium-dependent hyperpolarization (EDH) plays important roles in the systemic circulation, whereas its role in the pulmonary circulation remains largely unknown. Furthermore, the underlying mechanisms of pulmonary hypertension (PH) also remain to be elucidated. We thus aimed to elucidate the role of EDH in pulmonary circulation in general and in PH in particular. In isolated perfused lung and using male wild-type mice, endothelium-dependent relaxation to bradykinin (BK) was significantly reduced in the presence of N ω -nitro-l-arginine by ~50% compared with those in the presence of indomethacin, and the combination of apamin plus charybdotoxin abolished the residual relaxation, showing the comparable contributions of nitric oxide (NO) and EDH in the pulmonary microcirculation under physiological conditions. Catalase markedly inhibited EDH-mediated relaxation, indicating the predominant contribution of endothelium-derived H 2 O 2 . BK-mediated relaxation was significantly reduced at day 1 of hypoxia, whereas it thereafter remained unchanged until day 28. EDH-mediated relaxation was diminished at day 2 of hypoxia, indicating a transition from EDH to NO in BK-mediated relaxation before the development of hypoxia-induced PH. Mechanistically, chronic hypoxia enhanced endothelial NO synthase expression and activity associated with downregulation of caveolin-1. Nitrotyrosine levels were significantly higher in vascular smooth muscle of pulmonary microvessels under chronic hypoxia than under normoxia. A similar transition of the mediators in BK-mediated relaxation was also noted in the Sugen hypoxia mouse model. These results indicate that EDH plays important roles in the pulmonary microcirculation in addition to NO under normoxic conditions and that impaired EDH-mediated relaxation and subsequent nitrosative stress may be potential triggers of the onset of PH. NEW & NOTEWORTHY This study provides novel evidence that both endothelium-dependent hyperpolarization and nitric oxide play important roles in endothelium-dependent relaxation in the pulmonary microcirculation under physiological conditions in mice and that hypoxia first impairs endothelium-dependent hyperpolarization-mediated relaxation, with compensatory upregulation of nitric oxide, before the development of hypoxia-induced pulmonary hypertension.

Thyroid storm is a life-threatening disorder that remains a therapeutic challenge. Although β-blockers are the mainstay for treatment, their use can be challenging in cases complicated by rapid atrial fibrillation and decompensated heart failure. We present a case of thyroid storm-associated atrial fibrillation and decompensated heart failure complicated by gastrointestinal dysfunction secondary to diffuse peritonitis that was successfully managed by a switching therapy, in which the continuous intravenous administration of landiolol was changed to bisoprolol via transdermal patch, in the acute phase treatment. This switching therapy may offer a promising therapeutic option for this potentially lethal disorder.

Paroxysmal sympathetic hyperactivity (PSH) is a distinct syndrome of episodic sympathetic hyperactivities following severe acquired brain injury, characterized by paroxysmal transient fever, tachycardia, hypertension, tachypnea, excessive diaphoresis and specific posturing. PSH remains to be an under-recognized condition with a diagnostic pitfall especially in the intensive care unit (ICU) settings due to the high prevalence of concomitant diseases that mimic PSH. A consensus set of diagnostic criteria named PSH-Assessment Measure (PSH-AM) has been developed recently, which is consisted of two components: a diagnosis likelihood tool derived from clinical characteristics of PSH, and a clinical feature scale assigned to the severity of each sympathetic hyperactivity. We herein present a case series of patients with PSH who were diagnosed and followed by using PSH-AM in our tertiary institutional medical and surgical ICU between April 2015 and March 2017 in order to evaluate the clinical efficacy of PSH-AM. Among 394 survivors of 521 patients admitted with acquired brain injury defined as acute brain injury at all levels of severity regardless of the presence of altered consciousness, including traumatic brain injury, stroke, infectious disease, and encephalopathy, 6 patients (1.5%) were diagnosed as PSH by using PSH-AM. PSH-AM served as a useful scoring system for early objective diagnosis, assessment of severity, and serial evaluation of treatment efficacy in the management of PSH in the ICU settings. In conclusion, critical care clinicians should consider the possibility of PSH and can use PSH-AM as a useful diagnostic and guiding tool in the management of PSH.

Biguanides are a drug of choice for the treatment of type 2 diabetes mellitus. Although they can cause lactic acidosis in susceptible patients with predisposing risk factors, the incidence of lactic acidosis is reported to be very low when they are used properly. We herein present a case of biguanide-associated severe lactic acidosis complicated with thiamine deficiency that was provoked without predisposing factors for thiamine deficiency. Diabetic patients taking biguanide may be predisposed to thiamine deficiency, even when there is no evidence of risk factors, and the high-dose administration of thiamine may be essential in the treatment of this otherwise under-recognized disorder.

The specific roles of nitric oxide (NO) synthases (NOSs) in bladder smooth muscle remain to be elucidated. We examined the roles of NOSs in β-adrenoceptor (AR)-mediated bladder relaxation. Male mice (C57BL6) deficient of neuronal NOS [nNOS-knockout (KO)], endothelial NOS (eNOS-KO), neuronal/endothelial NOS (n/eNOS-KO), neuronal/endothelial/inducible NOS (n/e/iNOS-KO), and their controls [wild-type (WT)] were used. Immunohistochemical analysis was performed in the bladder. Then the responses to relaxing agents and the effects of several inhibitors on the relaxing responses were examined in bladder strips precontracted with carbachol. Immunofluorescence staining showed expressions of nNOS and eNOS in the urothelium and smooth muscle of the bladder. Isoproterenol-induced relaxations were significantly reduced in nNOS-KO mice and were further reduced in n/eNOS-KO and n/e/iNOS-KO mice compared with WT mice. The relaxation in n/e/iNOS-KO mice was almost the same as in n/eNOS-KO mice. Inhibition of Ca 2+ -activated K + (K Ca ) channel with charybdotoxin and apamin abolished isoproterenol-induced bladder relaxation in WT mice. Moreover, direct activation of K Ca channel with NS1619 caused comparable extent of relaxations among WT, nNOS-KO, and n/eNOS-KO mice. In contrast, NONOate (a NO donor) or hydrogen peroxide (H 2 O 2 ) (another possible relaxing factor from eNOS) caused minimal relaxations, and catalase (H 2 O 2 scavenger) had no inhibitory effects on isoproterenol-induced relaxations. These results indicate that both nNOS and eNOS are substantially involved in β-AR-mediated bladder relaxations in a NO- or H 2 O 2 -independent manner through activation of K Ca channels., (Copyright © 2017 the American Physiological Society.)

Endothelium-dependent relaxations are predominantly regulated by nitric oxide (NO) in large conduit arteries and by endothelium-dependent hyperpolarization (EDH) in small resistance vessels. Although the nature of EDH factors varies depending on species and vascular beds, we have previously demonstrated that endothelial NO synthases (eNOS)-derived hydrogen peroxide (H2O2) is an EDH factor in animals and humans. This vessel size-dependent contribution of NO and EDH is, at least in part, attributable to the diverse roles of endothelial NOSs system; in large conduit arteries, eNOS mainly serves as a NO-generating system to elicit soluble guanylate cyclase-cyclic guanosine monophosphate-mediated relaxations, whereas in small resistance vessels, it serves as a superoxide-generating system to cause EDH/H2O2-mediated relaxations. Endothelial caveolin-1 may play an important role for the diverse roles of NOSs. Although reactive oxygen species are generally regarded harmful, the physiological roles of H2O2 have attracted much attention as accumulating evidence has shown that endothelium-derived H2O2 contributes to cardiovascular homeostasis. The diverse functions of endothelial NOSs system with NO and EDH/H2O2 could account for a compensatory mechanism in the setting of endothelial dysfunction. In this review, we will briefly summarize the current knowledge on the diverse functions of endothelial NOSs system: NO and EDH/H2O2.