MicroRNAs (miRNAs) are small non-protein-coding RNAs that negatively regulate gene expression. They bind to the 3’-untranslated region of specific mRNAs and inhibit translation or promote mRNA degradation. Dyslipidemia/hyperlipidemia is a well-accepted risk factor for the development of atherosclerosis. The pathogenesis factors involved in lipid abnormalities are being examined extensively, and there is emerging evidence linking miRNAs to lipid metabolism. Among them, recent studies, including ours, have demonstrated that miRNAs control the expression of genes associated with high-density lipoprotein (HDL) cholesterol (HDL-C) metabolism, including ABCA1, ABCG1, and scavenger receptor class B, type I. Moreover, HDL-C itself was proved to carry miRNAs and deliver them to several different types of cells. In this review, we describe the current understanding of the functions of miRNAs in HDL metabolism and their potential in therapy for treating cardiometabolic diseases.
Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon-like peptide-1 (GLP-1), which play an important role in blood glucose control, mediate cardioprotection. There are many lines of basic research evidence indicating that GLP-1 improves the pathophysiology of HF: In murine and canine HF models, either GLP-1 analogues or DPP-IV inhibitors improved cardiac functions. The first question that arises is how either GLP-1 analogues or DPP-IV inhibitors mediate cardioprotection. Cardiovascular diseases are tightly linked to impaired glucose tolerance (IGT): IGT is not only one of the causes of cardiovascular events but also the result of HF. Indeed, the treatment of IGT improved HF, showing that one of the mechanisms attributable to DPP-IV inhibitors is related to the improvement of IGT. Intriguingly, either DPP-IV inhibitors or GLP-1 analogues mediate cardioprotection even without IGT, suggesting two possible explanations: One is that GLP-1 analogues directly activate the prosurvival kinases, such as Akt and Erk1/2, and another is that DPP-IV inhibition increases cardioprotective peptides such as BNP and SDF-1α. The next question is whether cardioprotection is translated to clinical medicine. Small scale clinical trials proved their cardioprotective effects; however, several large scale clinical trials have not proved the beneficial effects of DPP-IV inhibitors. Taken together, GLP-1 analogues or DPP-IV inhibitors can mediate cardioprotection, however, what needs to be clarified is who mainly receives their benefits among the patients with cardiovascular diseases and/or DM.
High sensitive C-reactive protein (hs-CRP) levels are associated with short- and long-term mortality in patients with acute coronary syndrome (ACS). We investigated whether baseline hs-CRP levels are associated with burden of coronary atherosclerosis assessed by SYNTAX score (SXScore). We enrolled 321 patients with ACS who underwent coronary angiography. The patients were divided into tertiles according to the SXScore: low SXScore (≤ 22), and intermediate-high SXScore (≥ 23). Subjects in the intermediate-high SXScore tertile had higher serum hs-CRP levels compare to low SXScore tertile patients (7.7 ± 3.4 mg/L versus 4.9 ± 2.5 mg/L, P < 0.001). The mean age of patients and prevalance of diabetes in the intermediate-high SXScore tertile were significantly higher than in the low SXScore tertile (63 ± 13 versus 58 ± 12 years P = 0.001 for age, P = 0.007 for diabetes). Multivariate logistic regression analysis showed that the strongest predictors of high SXScore were increased serum hs-CRP levels (OR: 1.14) together with multivessel disease (OR: 0.23), left ventricular ejection fraction (LVEF) (OR: 0.90), and troponin levels (OR: 1.12). Serum hs-CRP levels on admission in patients with ACS could predict the severity and complexity of coronary atherosclerosis together with multivessel disease, LVEF, and troponin levels. Thus, increased serum levels of hs-CRP were one of the strong predictors of high SXScore in ACS patients.
Microvascular dysfunction after primary percutaneous coronary intervention (PCI) augments myocardial damage and prognosis in acute myocardial infarction. However, the relationship between baseline anemia and coronary microcirculation in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed primary PCI in 337 consecutive patients with STEMI. Anemia was defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women. Admission anemia was present in 17.5% of the patients enrolled. Data on epicardial coronary flow, STsegment resolution (STR) on electrocardiography, myocardial injury, and the incidence of adverse cardiac events defined as cardiac death or hospitalization for congestive heart failure were analyzed. The median follow-up period was 54.8 months. Despite comparable epicardial coronary flow, the rate of STR ≥ 50% was lower in anemic patients compared with non-anemic patients (55.9% versus 71.2%, P = 0.02). On multivariate logistic regression analysis, baseline anemia was an independent negative predictor of STR ≥ 50% (odds ratio, 0.53; 95% confidence interval: 0.31-0.92, P = 0.03). Moreover, anemic patients had higher maximum creatine kinase levels normalized for body surface area (2,215 ± 1,318 IU/L/m2 versus 1,797 ± 1,199 IU/L/m2, P = 0.047). Anemia remained an independent significant predictor of adverse events on multivariate Cox proportional hazard analysis (hazard ratio, 2.34; 95% confidence interval: 1.01-5.64, P = 0.048). In conclusion, admission anemia was related to microcirculatory dysfunction and poor prognosis in patients with STEMI. The decreased oxygen delivery might exacerbate microvascular function.
The early phase arterial reaction after implantation of second-generation drug-eluting stents (2nd DES) and baremetal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. The MECHANISM pilot study is a multi-center prospective registry that enrolled 24 STEMI patients (from 11 centers) who had undergone implantation of everolimus-eluting (n = 6), biolimus A9-eluting (n = 6) or zotarolimus-eluting stents (n = 6), or BMS (n = 6). Scheduled optical coherence tomography (OCT) was performed 2 weeks after implantation, and images were independently analyzed at a core laboratory in a blinded fashion. Intra-stent thrombus was quantitatively analyzed in terms of the maximal area and the percentage of cross-sections with thrombus (the numbers of cross-section with thrombus × 100 divided by total number of cross-sections within the stented segment). More than 90% of struts were already covered 2 weeks after the index procedure, regardless of the stent type. There were no differences in stent diameter, minimal lumen diameter, minimal lumen area, neointimal thickness, or the frequencies of malapposed and uncovered struts among the 4 groups. The quantity of intra-stent thrombus also did not differ among the 4 groups. The results of this pilot study suggest that the 2-week vascular responses seem to be similar among 2nd DES and BMS in STEMI patients. Considering the possible advantage of 2nd DES in the prevention of restenosis, 2nd DES are a feasible option for the treatment of patients with STEMI.
Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for the prevention of ischemic strokes in patients with nonvalvular atrial fibrillation (AF). At present, NOACs have been evaluated for the treatment of deep vein thrombosis (DVT). We examined the efficacy of dabigatran, the first NOAC for anticoagulation of AF in Japan, in outpatients who suffered from DVTs under a deteriorated general condition. Thirty-six consecutive outpatients diagnosed with DVT at our institute were enrolled. Not all patients could be hospitalized due to other clinical problems; 15 (42%) had malignant tumors, 9 (25%) psychological disorders, and 6 (17%) postoperative orthopedic disease. Dabigatran was administered at a dose of 110-150 mg once or twice daily, depending on the renal function and age. The mean dosage of dabigatran was 211.7 ± 36.6 mg per day. In 18 (50%) patients, the DVTs were completely dissolved and disappeared over a treatment term of 4.3 ± 4.3 months. In 9 patients (25%), the DVTs partly dissolved, but in the remaining 9 (25%) patients, dabigatran was totally ineffective. During a follow-up of 30.5 ± 5.3 months, DVTs did not recur with dabigatran in 18 patients with an effective efficacy. In a multivariate analysis, patients with small sized thromboses and those without malignant tumors were significantly associated with the DVTs dissolving (P = 0.003 and P = 0.006, respectively). Dabigatran was effective for dissolving DVTs in outpatients with a poor condition, particularly when the size of the DVT was small and malignant tumors were absent.
We analyzed the long-term results of two surgical techniques (beating versus non-beating) for isolated tricuspid valve (TV) surgery. The long-term results of 92 consecutive patients who underwent isolated TV surgery were analyzed. We compared patients with beating heart (BH) surgery (n = 48) with patients undergoing arrested heart (AH) surgery (n = 44). BH surgery was more frequently chosen in urgent/emergent operations (P = 0.029) and in redo-operations (P < 0.001). Preoperatively, the rates of renal insufficiency (P = 0.002) and EuroSCORE (P = 0.019) were higher in the BH group than in the AH group. There were no differences in perioperative outcomes and 30-day mortality between the groups. However, freedom from reoperation was significantly lower in the BH group compared to the AH group (P = 0.039). We observed a trend towards lower survival rates at 1, 5, and 10 years in the BH group (77%, 54%, and 41%) compared to those of the AH group (86%, 75%, and 72%, P = 0.062). Multivariate Cox hazard model analysis revealed preoperative heart rhythm (P = 0.014, odds ratio [OR] = 2.296) and EuroSCORE (P = 0.022, OR = 1.049) as independent risk factors for mortality after isolated TV surgery. The superiority of BH surgery over AG surgery was not proven. Surgical intervention should be considered early, since patients with elevated EuroSCORES and arrhythmia have significantly higher mortality rates.
To quantitatively assess the geometric changes in mitral valve apparatus in mitral regurgitation (MR) by dualsource computed tomography (DSCT) and to analyze its impact on MR. The study subjects consisted of 20 controls, 20 patients with mild MR, and 30 patients with moderate to severe MR, all of whom underwent DSCT. The geometric parameters of the mitral valve were measured by CT and compared among the 3 groups. The correlations between DSCT measurements and MR severity were also analyzed. As regurgitation worsened, our results showed progressive enlargements of the mitral annular area, anteroposterior diameter, and mitral valve tenting area at the central level. Moreover, a higher mitral valve sphericity index and longer distance between the heads of the papillary muscles reflected a more outward displacement of the papillary muscles. The mitral annular area and tenting area at the central level had strong correlations with regurgitation severity. DSCT is available to quantitatively assess mitral valve morphology and provide additional information regarding its geometry. The mitral annular area and tenting area at the central level were the strongest determinants of MR severity.
Hypertrophic cardiomyopathy (HCM) has various morphological and clinical features. A decade has passed since the previous survey of the epidemiological and clinical characteristics of Japanese HCM patients. The Aichi Hypertrophic Cardiomyopathy (AHC) Registry is based on a prospective multicenter observational study of HCM patients. The clinical characteristics of 42 ambulant HCM patients followed up for up to 5 years were investigated. The primary endpoint was major adverse cardiac events (MACE), defined as death, non-fatal stroke, admission due to congestive heart failure (CHF), or episodes of sustained ventricular tachycardia/fibrillation. The MACE-free survival during the 5-year follow-up period was 76% according to Kaplan–Meier analysis. HCM-related death occurred in 3 (7%) patients and SCD occurred in 2 (5%) patients. Additionally, 3 (7%) patients were admitted to the hospital due to CHF. Meanwhile, sustained VT was detected in one (2%) of the patients who received ICD implantation and subsequently terminated with antitachycardia pacing using an ICD. The patients with HCM exhibiting left ventricular outflow obstruction (HOCM) had a slightly lower MACE-free survival rate than those with neither HOCM nor dilated-HCM (dHCM) (71% versus 81%, log-rank P = 0.581). Furthermore, the patients with dHCM demonstrated a significantly lower MACE-free survival rate than those with neither HOCM nor dHCM (33% versus 81%, log-rank P = 0.029). In the AHC Registry targeting current Japanese HCM patients, we demonstrated that many HCM patients continue to suffer from MACE despite the development of various treatments for HCM.
Arrhythmias are associated with reduced quality of life and poor prognosis in patients with hypertrophic cardiomyopathy (HCM). Recent genome-wide association studies revealed that a nonsynonymous single nucleotide polymorphism, rs6795970, in the SCN10A gene was associated with the PR interval. We examined whether the PR prolonging allele (A allele) in the SCN10A gene may be associated with cardiac conduction abnormalities in HCM patients. We genotyped the polymorphism in 149 HCM patients. Conduction abnormalities were defined as first-degree heart block, bundle-branch block, and bifascicular heart block. Patients were divided into two groups: group A consisted of 122 patients (82%) without a conduction abnormality; and group B consisted of 27 patients (18%) with one or more cardiac conduction abnormalities. The frequency distribution of the SCN10A genotypes (G/G, G/A, and A/A) among the patients with HCM was 71%, 26%, and 3%, respectively. A cardiac conduction abnormality was documented in 9% with G/G and 40% with G/A or A/A. There was a significant difference in the genotype distribution between the two groups (P = 0.0002). In the dominant A allele model, there was a significant difference in genotypes between the two groups (P < 0.0001). In addition, the A allele remained significant after adjusting for other covariates in a multivariate model (odds ratio = 6.30 [95% confidence interval: 2.24 to 19.09], P = 0.0005). The rs6795970 in the SCN10A gene, which is reported to carry a high risk of heart block, might be associated with cardiac conduction abnormalities in HCM patients.
The aim of this study was to identify the factors that influence atrial septal occluder dislodgement in adults and children. From June 2003 to June 2013, a total of 213 patients (115 adults and 98 children) diagnosed with secundum atrial septal defects (ASD) underwent transcatheter closure of their defects with an atrial septal occluder (ASO) in our hospital. The ASO was implanted under transesophageal echocardiography (TEE) guidance. Ten patients suffered from ASO dislodgement, and the other 203 patients comprised the successful group. We compared the preprocedural data related to general demographics, defects, margins, and minor post-implantation complications between the two groups with the goal of identifying the factors that affected ASO dislodgement. Univariate logistic regression analyses identified a high Qp/Qs value, the Qp/Qs ratio > 3.13, ASO size, ASO size greater than 32 mm, ASO size/BSA ratio > 15.13 and IAS erosion, floppiness or aneurysm formation as factors with significant predictive value. Multivariate analysis revealed that a Qp/Qs ratio > 3.13, and interatrial septum (IAS) erosion, floppiness and aneurysm formation post-implantation were independent predictors of ASO dislodgement (P = 0.001 and P = 0.006, respectively) in both adults and children. Percutaneous device closure of ASDs is safe and effective in the current era. The Qp/Qs ratio > 3.13 and IAS erosion, floppiness or aneurysm formation post-implantation might be predictors of ASO dislodgement in adults and children.
Some heart failure (HF) patients develop ventilatory oscillation which is composed of exercise periodic breathing (EPB) and sleep apnea. The ventilatory oscillation is associated with exercise intolerance. This study employed an integrated monitoring system to elucidate the way of central and peripheral hemodynamic adaption responding to exercise. This study recruited 157 HF patients to perform exercise testing using a bicycle ergometer. A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy (NIRS) was used to assess perfusion and O2 extraction in the frontal cerebral lobe (FC) and vastus lateralis muscle (VL) during exercise respectively. Furthermore, quality of life (QoL) was measured with the Short Form-36 (SF-36) and the Minnesota Living with Heart Failure questionnaires (MLHFQ). The patients were divided into an EPB group (n = 65) and a non-EPB group (n = 92) according to their ventilation patterns during testing. Compared to their non-EPB counterparts, the patients with EPB exhibited 1) impaired aerobic capacity with a smaller peak oxygen consumption (VO2peak) and oxygen uptake efficiency slopes; 2) impaired circulatory and ventilatory efficiency with relatively high cardiac output and ventilation per unit workload; 3) impaired ventilatory/hemodynamic adaptation in response to exercise with elevated deoxyhemoglobin levels in the FC region; and 4) impaired QoL with lower physical component scores on the SF-36 and higher scores on the MLHFQ. In conclusion, EPB may reduce circulatory-ventilatory-hemodynamic efficiency during exercise, thereby impairing functional capacity in patients with HF.
Sodium hydroxide pinpoint pressing permeation (SHPPP) was investigated in order to build a rat model of sick sinus syndrome (SSS), which is easy to operate and control the degree of damage, with fewer complications and applicable for large and small animals. Thirty healthy Wistar rats (15 males and 15 females, weighing 250-350 g) were randomly divided into 3 groups, namely a formaldehyde thoracotomy wet compressing group (FTWC), formaldehyde pinpoint pressing permeation group (FPPP) group, and SHPPP group. The number of surviving rats, heart rate (HR), sinoatrial node recovery time (SNRT), corrected SNRT (CSNRT), and sinoatrial conduction time (SACT) were recorded 3 days, one week, and two weeks after modeling. The achievement ratio of modeling was 10% in the FTWC group, 40% in the FPPP group, and 70% in the SHPPP group, and the differences were statistically significant (χ2 = 7.250, P = 0.007). Meanwhile, the HR was reduced by about 37% in these 3 groups 3 days after modeling, while the reduction was maintained only in SHPPP (P > 0.05) and the HR was re-elevated in the FTWC and FPPP groups 2 weeks after modeling (P < 0.05). Additionally, the SNRT, cS-NRT, and SACT were significantly prolonged compared with pre-modeling in all 3 groups (P < 0.01). SHPPP was the best method with which to build an SSS model with stable and lasting low HR and high success rate of modeling, which might be helpful for further studies on the SSS mechanisms and drugs.
Our study aimed to investigate the gene expression at different myocardial infarction (MI) phases and to understand the development mechanisms of congestive heart failure (CHF) after MI. Dataset GSE1957 including 24 samples of rat left ventricles at 1-day post MI or sham operation and 7-day post MI or sham operation was downloaded from Gene Expression Ominibus. The data were normalized with an affyPLM package and differentially expressed genes (DEGs) were identified with a Linear Models for Microarray Data package. Heat maps of the DEGs were constructed using Cluster 3.0. GO (Gene Ontology) enrichment analysis of the DEGs was performed in Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed by Biomolecular Interaction Network Database and visualized by Cytoscape, and a subnetwork was analyzed using plugin ClusterONE in Cytoscape. A total of 5 DEGs at 1-day post-MI, 5 DEGs at 7-day post-MI, and 7 DEGs between the MI and sham groups at 1-day and 7-day post-MI were identified. For the GO category analysis, DEGs at 1-day post-MI were enriched in response to cytokine stimulus. DEGs at 7-day post-MI were enriched in response to inorganic substance and chemical homeostasis. DEGs between 1-day and 7-day post-MI including CDK2 and CDC20 were significantly enriched in mitosis. CDK2, ANXA1, CDC20, and AQP2 were included in the PPI network, and CDK2 was the only DEG included in the subnetwork. In conclusion, the induction of DEGs at 7-day post-MI might participate in the response to a hormone and endogenous stimulus to regulate the development of CHF after MI.
Long QT syndrome (LQTS) is a genetic cardiac disease. Gene mutation affects the structure or function of ion channels that are associated with a high risk of sudden death. The goal of this study was to determine the frequency of KCNQ1, KCNH2, and SCN5A mutations in LQTS in a Taiwanese population. Genomic DNA was extracted from peripheral blood samples obtained from 5 patients with LQTS and the family members of 3 LQTS patients. High resolution melting (HRM) analysis and direct DNA sequencing were used to characterize the KCNQ1, KCNH2, and SCN5A genetic variations. HRM analysis was successfully optimized for 14 of the 16 exons of the KCNQ1, 5 of the 15 exons of the KCNH2, and 23 of the 27 exons of the SCN5A. HRM and direct DNA sequencing was applied to the cohort of 5 cases and some of their family. The genetic testing revealed two pathogenic mutations (p.T309I in KCNQ1 and p.R744fs in KCNH2) and all of the mutational frequencies in KCNQ1 and KCNH2 were 20%. In the two patients who carry the pathogenic mutation presenting with recurrent syncope due to ventricular fibrillation, an implantable cardioverter defibrillator was implanted. We also discovered 11 polymorphisms in KCNQ1, 3 in KCNH2, and 5 in SCN5A. Two-fifths of cases (40%) presented with one of the three major LQTS-causing gene mutations.
Pathological cardiac hypertrophy inevitably leads to the unfavorable outcomes of heart failure (HF) or even sudden death. microRNAs are key regulation factors participating in many pathophysiological processes. Recently, we observed upregulation of microRNA-340-5p (miR-340) in failing human hearts because of dilated cardiomyopathy, but the functional consequence of miR-340 remains to be clarified. We transfected neonatal cardiomyocytes with miR-340 and found fetal gene expression including Nppa, Nppb and Myh7. We also observed eccentric hypertrophy development upon treatment which was analogous to the phenotype after cardiotrophin-1 (CT-1) stimulation. As a potent inducer of cardiac eccentric hypertrophy, treatment by IL-6 family members CT-1 and leukemia inhibitory factor (LIF) led to the elevation of miR-340. Knockdown of miR-340 using antagomir attenuated fetal gene expression and hypertrophy formation, which means miR-340 could convey the hypertrophic signal of CT-1. To demonstrate the initial factor of miR-340 activation, we constructed a volume overloaded abdominal aorta–inferior vena cava fistula rat HF model. miR-340 and CT-1 were found to be up-regulated in the left ventricle. Dystrophin (DMD), a putative target gene of miR-340 which is eccentric hypertrophy-susceptible, was decreased in this HF model upon Western blotting and immunohistochemistry tests. Luciferase assay constructed in two seed sequence of DMD gene 3’UTR showed decreased luciferase activities, and miR-340 transfected cells resulted in the degradation of DMD. miR-340 is a pro-eccentric hypertrophy miRNA, and its expression is dependent on volume overload and cytokine CT-1 activation. Cardiomyocyte structure protein DMD is a target of miR-340.
A 67-year-old man who had cardiopulmonary arrest (CPA) at home was admitted to our institution. His spontaneous circulation was restored by bystander cardiopulmonary resuscitation (CPR) performed by his wife and an automated external defibrillator (AED). J waves were observed in the inferior leads of an electrocardiogram. We performed an implantable cardioverter defibrillator (ICD) implantation. After the ICD implantation, appropriate shocks due to ventricular fibrillation (VF) were observed on interrogation of the ICD at a frequency of twice a month. Most VF events occurred in the early morning between 1:00 to 6:00, and ventricular premature contractions (VPCs) were detected just before the occurrence of VF. Since the VF events always occurred in the early morning, we started long-acting disopyramide (150 mg/day, before bedtime), which has a muscarinic receptor blocking action. As a result, he has not received any appropriate ICD shocks for more than two years.
Although both beta-blocker treatment and cardiac resynchronization therapy (CRT) have been established as the standard therapeutic strategy to achieve left ventricular reverse remodeling (LVRR) and improve prognosis in heart failure (HF) patients with systolic LV dysfunction, some patients do not respond to such treatments. We here report a HF patient with left bundle branch block due to nonischemic cardiomyopathy who did not respond to 20 mg/day of carvedilol in terms of LVRR. Subsequent CRT only achieved insufficient LVRR, and we further titrated carvedilol up to 40 mg/day. Marked LVRR was accomplished at a fixed 70 bpm heart rate under CRT, and therefore it was considered as heart rate-independent. Up-titration of beta-blocker after CRT may be necessary to induce optimal LVRR in some populations.
Anthracycline-containing chemotherapy can cause irreversible and progressive left ventricular dysfunction. Epirubicin, which is widely used for breast cancer chemotherapy, is an anthracycline that has less cardiac toxicity than doxorubicin. The present report describes the case of a 70-year-old woman with breast cancer who developed severe congestive heart failure and severe cardiac dysfunction at 6 weeks from epirubicin final administration. Left ventricular function gradually improved after intensive treatment for heart failure and recovered completely within 2 months. To the best of our knowledge, this is the first report to describe epirubicin-induced subacute reversible cardiotoxicity.
A special deformity associated with the use of left atrial disc hubless atrial septal occluders has been described in 3 children. This chalice-shaped deformity that occurred during the use of Occlutech and Lifetech septal occluders was given the name “Holy Grail Configuration”. Despite being easily reversible, reduction of the metal load on the left atrium has been suggested to have some negative effects.
Although endothelin receptor antagonists (ERAs) including bosentan and ambrisentan are essential tools for the treatment of pulmonary arterial hypertension (PAH), each agent has a specific adverse effect with non-negligible frequency, ie, liver dysfunction for bosentan and peripheral edema for ambrisentan. These adverse effects often hinder the titration of the doses of ERAs up to the therapeutic levels. Portopulmonary hypertension, which is complicated with liver cirrhosis and successive portal hypertension, is one of the PAHs refractory to general anti-PAH agents because of the underlying progressed liver dysfunction and poor systemic condition. We here present a patient with portopulmonary hypertension, which was treated safely by combination therapy that included low-dose bosentan and ambrisentan, minimizing the adverse effects of each ERA. Combination therapy including different types of ERAs at each optimal dose may become a breakthrough to overcome portopulmonary hypertension in the future.
An error appeared in the article titled “Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders” by Ippei Shimizu, Yohko Yoshida, and Tohru Minamino (Vol. 56, No. 3, 255-259, 2015). The figure on page 257 should be replaced by the following figure.