Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis.

A 72-year-old woman with hypertrophic cardiomyopathy was admitted to the hospital after an appropriate implantable cardioverter-defibrillator shock for ventricular fibrillation. She was discharged after the addition of amiodarone. Eight months after discharge, she was admitted to the hospital with a sign of somnolence. She had low levels of serum sodium and plasma osmolality, as well as hepatic transaminitis. She underwent a computed tomography scan, which detected high liver density. Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis was diagnosed, and amiodarone was discontinued. After discharge, her hepatic transaminitis improved, and there was no recurrence of hyponatremia with a sign of somnolence. Amiodarone is an important drug used to treat ventricular arrhythmias. However, it has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered. Learning objective: Amiodarone is an important drug used to treat ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation. However, amiodarone has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered.

Recurrent Takotsubo Syndrome Presenting with Different Ballooning Patterns and Electrocardiographic Abnormalities.

A 73-year-old woman presented with takotsubo syndrome with apical ballooning patterns after quarreling with her husband. Two years later, she was admitted to the hospital with chest pain after experiencing the same emotional stress. Her electrocardiogram showed different abnormalities compared to the previous event, and her left ventriculogram demonstrated takotsubo syndrome with mid-ventricular ballooning patterns. Recurrence of takotsubo syndrome with different ballooning patterns is rare. We herein report our experience with a patient who developed recurrent takotsubo syndrome with various ballooning patterns and different electrocardiographic abnormalities along with a literature review.

Impact of activities of daily living on percutaneous coronary intervention and acute and long-term mortality in patients with acute myocardial infarction: Yamagata AMI registry.

BACKGROUND: A decrease in the activities of daily living (ADL) is an independent risk factor for cardiovascular disease. Although percutaneous coronary intervention (PCI) is known to prevent early mortality in patients with acute myocardial infarction (AMI), the relationship between ADL prior to myocardial infarction (MI), PCI implementation, and mortality in patients with AMI remains unknown. We investigated the impact of prehospital ADL on PCI implementation and on short- and long-term mortality in patients with AMI. METHODS: We investigated the prehospital ADL in 1479 patients with AMI using data from the Yamagata AMI registry (period: 2015-2017). The patients were divided into three groups (preserved ADL, mildly impaired ADL, and severely impaired ADL) and their clinical characteristics were compared. Multivariate regression analysis was performed to elucidate the association of ADL prior to MI with the PCI implementation and mortality in patients with AMI. RESULTS: Patients with impaired ADL were older, more likely to be female, less likely to have undergone PCI, and presented with higher acute mortality compared to those with preserved ADL. The proportion of patients with impaired ADL increased with age. Multivariate regression analysis showed that the lack of PCI implementation and prehospital ADL impairment were independent risk factors for acute death in patients with AMI after adjusting for confounding factors. Furthermore, univariate and multivariate analyses revealed that impaired ADL was associated with the PCI implementation. Cox proportional hazards analysis revealed that prehospital ADL impairment was an independent risk factor for long-term mortality in patients with AMI. CONCLUSIONS: Decreased levels of prehospital ADL were associated with lower PCI implementation and higher mortality in patients-especially older patients-with AMI.

Unmet needs for emergency care and prevention of prehospital death in acute myocardial infarction.

INTRODUCTION: Percutaneous coronary intervention (PCI) has successfully reduced the mortality of patients with acute myocardial infarction (AMI). However, patients with out-of-hospital cardiac arrest have high mortality, which is difficult to control by hospital staff. In this study, we investigated the prevalence of prehospital death (PHD) in patients with AMI. Furthermore, we investigated the risk factors associated with 30-day mortality in patients with AMI who survived PHD. METHODS: We investigated the prevalence of PHD using data from the Yamagata AMI registry and from death certification of the entire Yamagata Prefecture in Japan between 2010 and 2015. Furthermore, we investigated the risk factors for 30-day mortality in patients who survived PHD, using data from the Yamagata AMI registry from 1993 to 2015. AMI was identified by the International Classification of Diseases, 10th revision code I21. RESULTS: Out of the 6984 patients with AMI, 3771 patients had PHD. Patients with PHD were older and more likely to be women than those without PHD. More PHD occurred in winter and spring than in summer or autumn. Multivariate regression analysis showed that age, female sex, and winter onset were independently associated with PHD. We also investigated the risk factors associated with 30-day mortality in 9675 patients who survived PHD. The rate of PCI was remarkably lower in patients with acute death than in those without acute death. Multivariate regression analysis showed that age, anterior infarction, estimated glomerular filtration rate, Killip class, and PCI were independently associated with 30-day mortality after adjusting for confounding factors. CONCLUSION: Approximately half of the patients with AMI died before they could reach the destination hospital. Although emergency PCI is the most important factor in reducing 30-day mortality in patients with AMI, attempts to reduce patient delay and system delay are possibly needed to further reduce PHD.

The association between microRNA-21 and hypertension-induced cardiac remodeling.

Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-ß1 (TGF-ß1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-ß1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-ß1 signaling pathway.

Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling.

AIMS: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS. METHODS AND RESULTS: We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3' untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions. CONCLUSION: miR-34a plays an important role in the development of CAVS via Notch1-Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.

Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response.

High-mobility group box 1 (HMGB1) is a deoxyribonucleic acid (DNA)-binding protein associated with DNA repair. Decreased nuclear HMGB1 expression and increased DNA damage response (DDR) were observed in human failing hearts. DNA damage and DDR as well as cardiac remodeling were suppressed in cardiac-specific HMGB1 overexpression transgenic mice after angiotensin II stimulation as compared with wild-type mice. In vitro, inhibition of HMGB1 increased phosphorylation of extracellular signal-related kinase 1/2 and nuclear factor kappa B, which was rescued by DDR inhibitor treatment. DDR inhibitor treatment provided a cardioprotective effect on angiotensin II-induced cardiac remodeling in mice.

Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm.

Increased reactive oxygen species (ROS) contributes to the development of endothelial dysfunction, which is involved in coronary artery spasm (CAS). Xanthine oxidoreductase (XOR) plays a pivotal role in producing both uric acid and ROS. However, the association between plasma XOR activity and CAS has not been elucidated. The aim of this study was to investigate whether plasma XOR activity is associated with CAS. We measured XOR activity in 104 patients suspected for CAS, who presented without significant coronary artery stenosis and underwent intracoronary acetylcholine provocation tests. CAS was provoked in 44 patients and they had significantly higher XOR activity as compared with those without CAS. The patients were divided into three groups based on the XOR activity. The prevalence rate of CAS was increased with increasing XOR activity. A multivariate logistic regression analysis showed that the 3rd tertile group exhibited a higher incidence of CAS as compared with the 1st tertile group [odds ratio (OR) 6.9, P = 0.001) and the 2nd tertile group (OR 3.2, P = 0.033) after adjustment for conventional CAS risk factors, respectively. The C index was significantly improved by the addition of XOR activity to the baseline model based on CAS risk factors. Furthermore, the 3rd tertile group had the highest incidence of severe spasm defined as total obstruction, flow-limiting stenosis, diffuse spasm, multivessel spasm, and/or lethal arrhythmia. This is a first report to elucidate the association of plasma XOR activity with CAS. Increased plasma XOR activity is significantly associated with CAS.

Decreased Psoas Muscle Computed Tomography Value Predicts Poor Outcome in Peripheral Artery Disease.

BACKGROUND: The prognosis of peripheral artery disease (PAD) and comorbid sarcopenia is poor. Some reports indicate that the computed tomography (CT) value of skeletal muscle, which reflects intramuscular fat deposition as well as skeletal muscle mass, is considered a marker of sarcopenia. However, it remains unclear if skeletal muscle area and CT value are associated with poor outcomes in patients with PAD. Methods and Results: Psoas muscle area and CT value were measured by manual trace at the level of the third lumbar vertebral body in 327 consecutive patients with PAD undergoing endovascular therapy (EVT). The endpoint was major adverse cardiovascular and limb events (MACLE). There were 60 MACLE during the follow-up period. Patients with MACLE had lower mean psoas muscle CT value than those without. However, there was no significant difference in total psoas muscle area between patients with and without MACLE. Kaplan-Meier analysis demonstrated that the lowest tertile of psoas muscle CT value was associated with the highest risk of MACLE. Multivariate Cox hazard analysis revealed that psoas muscle CT value was associated with MACLE after adjustment for Fontaine class, previous ischemic heart disease, prevalence of diabetes mellitus, brain natriuretic peptide, and serum albumin. CONCLUSIONS: Psoas muscle CT value is a feasible predictor of MACLE in patients with PAD.

Ventricular wall stress and silent myocardial damage are associated with pulse pressure in the general population.

Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart-type fatty acid-binding protein (H-FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community-based annual health check. Serum levels of BNP and H-FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H-FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H-FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H-FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H-FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure.

The impact of non-alcoholic fatty liver disease fibrosis score on cardiac prognosis in patients with chronic heart failure.

Liver abnormalities have a strong impact on clinical outcomes in patients with heart failure (HF), and are known as cardio-hepatic syndrome. The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has been developed to identify liver fibrosis in patients with NAFLD. It remains to be determined whether NFS is associated with cardiovascular prognosis in patients with chronic heart failure (CHF). We calculated NFS in 516 patients with CHF admitted to our hospital. The clinical endpoints were deaths due to progressive HF, myocardial infarction, stroke, and sudden cardiac death, and rehospitalization for worsening HF. There were 173 cardiovascular events noted during a median follow-up of 464 days. Patients with cardiovascular events showed a higher NFS as compared with those without. We divided the patients into four groups according to quartiles of NFS. The proportion of New York Heart Association functional class III/IV and serum brain natriuretic peptide levels were increased with increasing NFS. Kaplan-Meier analysis revealed that cardiovascular event rate was increased with increasing NFS in patients with CHF. In multivariate Cox proportional hazards analysis, NFS was independently associated with cardiovascular events after adjustment for confounding factors. Elevated NFS was associated with unfavorable outcomes in patients with CHF. Liver fibrosis assessed by NFS may provide valuable prognostic information in patients with CHF.

Impact of Objective Malnutrition Status on the Clinical Outcomes in Patients With Peripheral Artery Disease Following Endovascular Therapy.

BACKGROUND: Peripheral artery disease (PAD) is an athero-occlusive disease and a known risk factor for cardiovascular events. The controlling nutritional status (CONUT) score and geriatric nutritional risk index (GNRI) are objective tools for evaluating malnutrition and are reportedly associated with poor clinical outcomes in patients with fatal diseases. However, the effect of malnutrition on the clinical outcomes in patients with PAD remains unclear.Methods and Results:We enrolled 357 patients with PAD who underwent endovascular therapy. Malnutrition was diagnosed by CONUT score and GNRI as in previous reports. During a median follow-up period of 1,071 days, there were 67 major adverse cardiovascular and leg events (MACLEs). The CONUT score- and GNRI-based malnutrition statuses were identified in 56% and 46% of the patients, respectively. Proportion of malnutrition increased with advancing Fontaine class. The multivariate Cox proportional hazard regression analysis demonstrated that both the CONUT score- and GNRI-based malnutrition status was an independent predictor of MACLEs. The Kaplan-Meier analysis demonstrated that the MACLE ratio increased with deteriorating malnutrition. Finally, the addition of the CONUT score or GNRI to the known risk factors significantly improved the net reclassification index and integrated discrimination index. CONCLUSIONS: Malnutrition was common and closely associated with the clinical outcomes in patients with PAD, indicating that it is a novel therapeutic target in the management of these patients.

Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure.

BACKGROUND: Oxidative stress due to purine degradation is associated with the development of chronic heart failure (CHF). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine degradation that plays a key role in uric acid (UA) production with a resultant increase in reactive oxygen species. However, the relationship between plasma XOR activity and CHF severity and clinical outcome remains unclear. METHODS AND RESULTS: We measured XOR activity in 440 patients with CHF and 44 control subjects. Abnormally high and low XOR activities were identified based on the results for 95% of the control subjects (high and low XOR activities ≥120 and <33pmol/100µL/h, respectively). The prevalence rates of high and low XOR activities increased with advancing New York Heart Association functional class. There were 158 cardiac events during a median follow-up period of 1034days. Multivariate Cox proportional hazard regression analysis showed that both high and low XOR activities were significantly associated with cardiac events in patients with CHF after adjustment for confounding risk factors including serum UA and loop diuretic use. Kaplan-Meier analysis revealed that the cardiac event rate was significantly higher in patients with either high or low XOR activity. The net reclassification index was significantly improved by adding XOR activity to the basic risk factors. CONCLUSIONS: We provide the first evidence of an association of plasma XOR activity with CHF severity and clinical outcome. Plasma XOR activity could be used to identify high-risk CHF patients and could be a therapeutic target for XOR inhibitors.

The role of macrophage transcription factor MafB in atherosclerotic plaque stability.

BACKGROUND AND AIMS: Macrophage differentiation is associated with the development of atherosclerosis and plaque vulnerability and is regulated by transcription factor MafB. We previously reported that MafB attenuates macrophage apoptosis, which is associated with atherosclerotic plaque instability. The aim of this study was to elucidate the role of MafB in the progression of atherosclerotic plaque. METHODS: We generated macrophage-specific dominant-negative (DN) MafB transgenic mice and intercrossed DN-MafB mice with apolipoprotein E (ApoE) knockout (KO) mice. RESULTS: There was no significant difference in advanced atherosclerotic lesion area between DN-MafB/ApoE KO mice and littermate control ApoE KO mice 9 weeks after high-cholesterol diet. However, DN-MafB/ApoE KO mice showed significantly larger necrotic cores and lower collagen content in atherosclerotic plaques than ApoE KO mice. Although there was no difference in intraplaque macrophage infiltration and efferocytosis, DN-MafB/ApoE KO mice showed significantly more apoptotic macrophages at the plaque edges than did ApoE KO mice. Real-time PCR analysis revealed that peritoneal macrophages of DN-MafB/ApoE KO mice had a greater increase in matrix metalloproteinase-9 and mRNA expression of inflammatory/M1 macrophage markers (tissue necrosis factor-α, interleukin-6, CD11c, and p47phox) after lipopolysaccharide stimulation than those of ApoE KO mice. CONCLUSION: Macrophage-specific inhibition of MafB may destabilize atherosclerotic plaques in advanced lesions.