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Abstract Metabolic dysfunction–associated fatty liver disease (MAFLD) is a common liver disease associated with obesity and is caused by the accumulation of ectopic fat without alcohol consumption. Coxsackievirus and adenovirus receptor (CAR) are vital for cardiac myocyte-intercalated discs and endothelial cell-to-cell tight junctions. CAR has also been reported to be associated with obesity and high blood pressure. However, its function in the liver is still not well understood. The liver of obese mice exhibit elevated CAR mRNA and protein levels. Furthermore, in the liver of patients with non-alcoholic steatohepatitis, CAR is reduced in hepatocyte cell–cell junctions compared to normal levels. We generated liver-specific CAR knockout (KO) mice to investigate the role of CAR in the liver. Body and liver weights were not different between wild-type (WT) and KO mice fed a paired or high-fat diet (HFD). However, HFD induced significant liver damage and lipid accumulation in CAR KO mice compared with WT mice. Additionally, inflammatory cytokines transcription, hepatic permeability, and macrophage recruitment considerably increased in CAR KO mice. We identified a new interaction partner of CAR using a protein pull-down assay and mass spectrometry. Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3C) demonstrated a complex relationship with CAR, and hepatic CAR expression tightly regulated its level. Moreover, Apolipoprotein B (ApoB) and Low-density lipoprotein receptor (LDLR) levels correlated with APOBEC3C expression in the liver of CAR KO mice, suggesting that CAR may regulate lipid accumulation by controlling APOBEC3C activity. In this study, we showed that hepatic CAR deficiency increased cell-to-cell permeability. In addition, CAR deletion significantly increased hepatic lipid accumulation by inducing ApoB and LDLR expression. Although the underlying mechanism is unclear, CARs may be a target for the development of novel therapies for MAFLD.

Abstract A spiral‐artificial basilar membrane (S‐ABM) sensor is reported that mimics the basilar membrane (BM) of the human cochlea and can detect sound by separating it into 24 sensing channels based on the frequency band. For this, an analytical function is proposed to design the width of the BM so that the frequency bands are linearly located along the length of the BM. To fabricate the S‐ABM sensor, a spiral‐shaped polyimide film is used as a vibrating membrane, with maximum displacement at locations corresponding to specific frequency bands of sound, and attach piezoelectric sensor modules made of poly(vinylidene fluoride‐trifluoroethylene) film on top of the polyimide film to measure the vibration amplitude at each channel location. As the result, the S‐ABM sensor implements a characteristic frequency band of 96‐12,821 Hz and 24‐independent critical bands. Using real‐time signals from discriminate channels, it is demonstrated that the sensor can rapidly identify the operational noises from equipment processes as well as vehicle sounds from environmental noises on the road. The sensor can be used in a variety of applications, including speech recognition, dangerous situation recognition, hearing aids, and cochlear implants, and more.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45–62), and the median follow-up time was 3.9 years (IQR 2.0–5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09–0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19–0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.

AbstractLeft ventricular assist device (LVAD) has been highlighted as a new treatment option in the end-stage heart failure (HF). Kidney outcome after LVAD in severe cardiorenal syndrome (CRS) patients requiring kidney replacement therapy (KRT) is unclear. We investigated the impact of preoperative KRT on kidney function and survival in LVAD patients with severe CRS. A total of 50 patients followed up for at least 1 year after LVAD implantation was analyzed. The primary outcomes were estimated glomerular filtration rate and survival rate. Patients were divided into two groups depending on in-hospital KRT before LVAD implantation: the control group (n = 33) and the KRT group (n = 17). Postoperative KRT was performed for 76.5% of patients in the KRT group, and all of them discontinued KRT before discharge. There were no statistically significant differences in the degree of eGFR decline in survivors according to preoperative KRT. Although there were no statistically significant differences in the degree of eGFR decline in survivors regardless of preoperative KRT, old age (β −0.94, p

Abstract Background High glycemic variability (GV) is a poor prognostic marker in cardiovascular diseases. We aimed to investigate the association of GV with all-cause mortality in patients with acute heart failure (HF). Methods The Korean Acute Heart Failure registry enrolled patients hospitalized for acute HF from 2011 to 2014. Blood glucose levels were measured at the time of admission, during hospitalization, and at discharge. We included those who had 3 or more blood glucose measurements in this study. Patients were divided into two groups based on the coefficient of variation (CoV) as an indicator of GV. Among survivors of the index hospitalization, we investigated all-cause mortality at 1 year after discharge. Results The study analyzed 2,617 patients (median age, 72 years; median left-ventricular ejection fraction, 36%; 53% male). During the median follow-up period of 11 months, 583 patients died. Kaplan–Meier curve analysis revealed that high GV (CoV > 21%) was associated with lower cumulative survival (log-rank P

Abstract Background To assess the efficacy and safety of a combination therapy involving fimasartan, amlodipine, and rosuvastatin in patients with essential hypertension and dyslipidemia who fail to respond to fimasartan monotherapy. Methods This phase III, randomized, double-blind, multicenter study was conducted in adults aged 19–70 years. Patients who voluntarily consented were screened for eligibility to enroll in the study. Patients who failed to respond to 4 weeks of fimasartan monotherapy were randomized with a 1:1:1 ratio to the fimasartan 60 mg/amlodipine 10 mg + rosuvastatin 20 mg (FMS/ALD + RSV) as study group, fimasartan 60 mg/amlodipine 10 mg (FMS/ALD) as control 1 group, and fimasartan 60 mg + rosuvastatin 20 mg (FMS + RSV) as control 2 group. The primary efficacy endpoints were the change in the sitting systolic blood pressure and the rate of change in the low-density lipoprotein cholesterol (LDL-C) level from baseline to 8 weeks. The adverse events, adverse drug reactions, physical examination findings, laboratory test results, electrocardiograms, and vital signs were evaluated to assess safety in the study. Results Of 138 randomized patients, 131 were conducted efficacy analysis, and 125 completed the study. For the change in LDL-C and sitting SBP (SiSBP) as primary efficacy assessments, the change in LDL-C at week 8 was significantly reduce in the FMS/ALD + RSV group than in the control 1 group (P

Abstract Aims Increased blood pressure (BP) and decreased heart rate (HR) are signs of stabilization in patients admitted for acute HF. Changes in BP and HR during admission and their correlation with outcomes were assessed in hospitalized patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods A novel modified reverse shock index (mRSI), defined as the ratio between changes in systolic BP and HR during admission, was devised, and its prognostic value in the early outcomes of acute HF was assessed using the Korean Acute HF registry. Results Among 2697 patients with HFrEF (mean age 65.8 ± 14.9 years, 60.6% males), patients with mRSI ≥1.25 at discharge were significantly younger and were more likely to have de novo HF. An mRSI ≥1.25 was associated with a significantly lower incidence of 60‐day and 180‐day all‐cause mortality [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.31–0.77; HR 0.62, 95% CI 0.45–0.85, respectively], compared with 1 ≤ mRSI

Background Recently, diastolic stress testing and invasive hemodynamic measurements have been emphasized for diagnosis of heart failure with preserved ejection fraction (HFpEF) because when determined using noninvasive parameters it can fall into a nondiagnostic intermediate range. The current study evaluated the discriminative and prognostic roles of invasive measured left ventricular end‐diastolic pressure in the population with suspected HFpEF, particularly for patients with intermediate Heart Failure Association Pre‐test Assessment, Echocardiography & Natriuretic Peptide, Functional Testing, Final Etiology (HFA‐PEFF) score. Methods and Results A total of 404 patients with symptoms or signs of HF and preserved left ventricular systolic function were enrolled. All subjects underwent left heart catheterization with left ventricular end‐diastolic pressure measurement for confirmation of HFpEF (≥16 mm Hg). The primary outcome was all‐cause death or readmission due to HF within 10 years. Among the study population, 324 patients (80.2%) were diagnosed as invasively confirmed HFpEF, and 80 patients (19.8%) were as noncardiac dyspnea. The patients with HFpEF showed a significantly higher HFA‐PEFF score than the patients with noncardiac dyspnea (3.8±1.8 versus 2.6±1.5, P

Abstract Aims In 2021, vericiguat was approved by the US Food and Drug Administration (FDA) and the European Commission (EC) for reducing cardiovascular mortality and heart failure (HF) hospitalizations in patients with HF with reduced ejection fraction (HFrEF) based on the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial. However, there has been no report for characterizing the generalizability of vericiguat to real‐world clinical practice. Methods and results The Korean Acute Heart Failure (KorAHF) registry is a multicentre prospective cohort study. A total of 5625 patients who were admitted for HF decompensation were consecutively enrolled. We excluded the patients without left ventricular ejection fraction (LVEF) quantification, patients with LVEF > 45%, patients with in‐hospital death or urgent heart transplantation, and patients without natriuretic peptide measurement. Among a total of 3014 enrolled patients, there were 21.9% patients with lower systolic blood pressure (SBP) (

Background/Aims The continuous flow left ventricular assist device (cf-LVAD) has improved the survival of chronic end-stage heart failure (HF) patients. Here we describe our clinical experience of the initial 50 LVAD patients from a single center. Methods A total of 50 patients underwent LVAD implantation as bridge to transplantation (BTT; n = 28, 56%), bridge to candidacy (BTC; n = 2, 4%), or as destination therapy (DT; n = 20, 40%) from 2012 to 2019. Pre-implant characteristics and clinical outcomes were compared between BTT/BTC and DT. Results The median age of patients was 67 years (range, 59 to 73). Men were more likely to receive LVAD (76% vs. 24%) than women. DT patients were older, had smaller body surface area, and worse laboratory profiles than BTT/BTC patients. There was no in-hospital mortality. During an average of 14 months (range, 8 to 23), the all-cause mortality was 22%. The first-year survival was 86 and 90% in BTT/BTC and DT groups, respectively. Hemorrhagic stroke was the most common cause (27%) of death. In the BTT/BTC group, 22 patients successfully underwent heart transplantation during median duration of 10 months (range, 7 to 14). The most common post-LVAD complication during the first year of LVAD implantation was major bleeding (44%). A significant proportion (76%) of patients experienced rehospitalization with gastrointestinal bleeding as the most common cause. Conclusions We describe short-term clinical outcome of LVAD patients from a single center for the first time in Korea. With the newer generation LVAD and a dedicated team approach, improved clinical outcomes of LVAD for end-stage HF are expected.

Abstract Aims A waiting period of more than 3 months is recommended for patients before undergoing cardiac resynchronization therapy (CRT). However, due to an anticipated high mortality rate, early implementation of CRT might be beneficial for some patients. We aimed to evaluate the rate and the probability of left ventricular (LV) function improvement and their predictors in patients with heart failure (HF) with indications for CRT. Methods and results From March 2011 to February 2014, a total of 5625 hospitalized patients for acute HF were consecutively enrolled in 10 tertiary hospitals. Among them, we analysed 1792 patients (mean age 63.96 ± 15.42 years, female 63.1%) with left ventricular ejection fraction (LVEF) ≤ 35% at the baseline echocardiography and divided them into three groups: 144 with left bundle branch block (LBBB), 136 with wide QRS complexes without LBBB, and 1512 not having these findings (control). We compared and analysed these three groups for improvement of LV function at follow‐up echocardiography. In patients who met CRT indications (patients with LBBB or wide QRS complexes without LBBB), logistic regression was performed to identify risk factors for no improvement of LV. No improvement of LV was defined as LVEF ≤ 35% at follow‐up echocardiography or the composite adverse outcomes: death, heart transplantation, extracorporeal membrane oxygenation, or use of a ventricular assist device before follow‐up echocardiography. A classification tree was established using the binary recursive partitioning method to predict the outcome of patients who met CRT indications. In a median follow‐up of 11 months, LVEF improvement was observed in 24.3%, 15.4%, and 40.5% of patients with LBBB, wide QRS complexes without LBBB, and control, respectively. Patients meeting CRT indications had higher 3 month mortality rates than the control (24.6% vs. 17.7%, P = 0.002). Multivariable logistic regression analysis revealed that large LV end‐systolic dimension [odds ratio (OR) 1.10, 95% confidence interval (CI) 1.05–1.15, P

AimsThe goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs).MethodsWe examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234).ResultsMyocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02).ConclusionWe found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs.

Abstract Aims Cardiac involvement is crucial factor determining outcomes of light chain (AL) amyloidosis. This study evaluated whether capillary density (CD) quantified from endomyocardial biopsy is associated with structural and functional parameters of amyloid heart. Also, we investigated whether capillary density improves the prognostic value of the current staging system in AL amyloidosis patients with cardiac involvement. Methods and results A total of 67 patients with biopsy‐proven AL cardiac amyloidosis were prospectively enrolled in this study. All patients underwent transthoracic echocardiography and EBM at the time of diagnosis. Left ventricle global longitudinal strain was evaluated on two‐dimensional strain echocardiography. The primary endpoint was all‐cause mortality. Amyloid load and capillary density were calculated on endomyocardial biopsy stained immunohistochemically with antibody against amyloid P and CD31, respectively. Among the study population, 37 patients (55.2%) were classified as Stage IV, and the cumulative incidence of death at 1 year was 34% (23 patients). A total of 65 (97%) patients underwent chemotherapy. CD showed a significant correlation with left ventricle global longitudinal strain (r = 0.274, P = 0.025), log N‐terminal pro‐B type natriuretic peptide (r = −0.311, P = 0.005), and amyloid load (r = −0.438, P 220/mm2 (P = 0.026 by log‐rank test). A model based on the 2012 Mayo staging system and CD showed significantly better discrimination and reclassification ability than a model using the 2012 Mayo staging system alone (C‐index 0.582 vs.0.689, P for difference

BackgroundHigh C-reactive protein (CRP) levels are associated with poor outcomes of heart failure (HF), and statins are known to reduce CRP levels. We investigated the prognostic value of CRP and statin in patients with HF with reduced and preserved ejection fraction (EF).MethodsAltogether, 3,831 patients from the Korean Acute Heart Failure registry were included and stratified according to the tertiles of CRP levels (T1: CRP < 0.30 mg/dL, T2: 0.30–1.14 mg/dL, and T3: CRP > 1.14 mg/dL). HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF) were defined as left ventricular ejection fraction (LVEF) ≤ 40%, 41–49%, ≥50%, respectively. The primary endpoints were all-cause, in-hospital, and post-discharge mortality.ResultsNo significant correlation was observed between CRP levels and LVEF (r = 0.02, P = 0.131). The prevalence of risk factors increased gradually from T1 to T3 in both the types of HF. Overall, 139 (3.6%) and 1,269 (34.4%) patients died during the index admission and follow-up (median: 995 days), respectively. After adjustment, each increase in the CRP tertiles was independently associated with in-hospital mortality (HFrEF: OR 1.58 and 95% CI 1.09–2.30, HFmrEF: OR 1.51 and 95% CI 0.72–3.52, and HFpEF: OR 2.98, 95% CI 1.46–6.73) and post-discharge mortality (HFrEF: HR 1.20, 95% CI 1.08–1.33, HFmrEF: HR 1.38 and 95% CI 1.12–1.70, and HFpEF: HR 1.37, 95% CI 1.02–1.85). In only patients with LVEF > 40% with highest CRP tertile, statin-users showed better survival trend than those without statins.ConclusionCRP is an excellent prognostic marker for HFrEF, HFmrEF, and HFpEF, implying that the neurohumoral and inflammatory pathways might be independent pathways. Statins may be beneficial in HF patients with increased CRP levels.Clinical trial registration[https://clinicaltrials.gov/], identifier [NCT013 89843].

Abstract Background Patients with diabetes mellitus (DM) have a higher prevalence of heart failure (HF) than those without it. Approximately 40 % of HF patients have DM and they tend to have poorer outcomes than those without DM. This study evaluated the impact of insulin therapy on mortality among acute HF patients. Methods A total of 1740 patients from the Korean Acute Heart Failure registry with DM were included in this study. The risk of all-cause mortality according to insulin therapy was assessed using the Cox proportional hazard models with inverse probability of treatment weighting to balance the clinical characteristics (pretreatment covariates) between the groups. Results DM patients had been treated with either oral hypoglycemic agents (OHAs) alone (n = 620), insulin alone (n = 682), or insulin combined with OHAs (n = 438). The insulin alone group was associated with an increased mortality risk compared with the OHA alone group (HR = 1.41, 95 % CI 1.21–1.66]). Insulin therapy combined with OHAs also showed an increased mortality risk (HR = 1.29, 95 % CI 1.14–1.46) compared with the OHA alone group. Insulin therapy was consistently associated with increased mortality risk, regardless of the left ventricular ejection fraction (LVEF) or HF etiology. A significant increase in mortality was observed in patients with good glycemic control (HbA1c

Abstract Aims Tachycardia is a reversible event that may cause hemodynamic decompensation but may not necessarily cause direct damages to the myocardium. To evaluate the clinical outcomes of patients with heart failure (HF) and atrial fibrillation (AF), whose acute decompensation was tachycardia mediated. Methods and results The Korean Acute Heart Failure registry was a prospective registry that consecutively enrolled 5625 patients with acute HF. Patients were classified into three groups according to the rhythm and aggravating factor: (i) 3664 (65.1%) patients with sinus rhythm (SR), (ii) 1033 (18.4%) patients with AF whose decompensation was tachycardia‐mediated, AF‐TM (+), and (iii) N = 928 (16.5%) patients with AF whose decompensation was not tachycardia‐mediated, AF‐TM (−). The primary outcomes were in‐hospital and post‐discharge 1 year all‐cause mortality. At admission, the mean heart rate was 90.8 ± 23.4, 86.8 ± 26.8, and 106.3 ± 29.7 beats per minute for the SR, AF‐TM (−), and AF‐TM (+) groups, respectively. The AF‐TM (+) group had more favourable characteristics such as de novo onset HF, less diabetes, ischaemic heart disease, and higher blood pressure than the AF‐TM (−) group. In‐hospital mortality rates were 5.1%, 6.5%, and 1.7% for SR, AF‐TM (−), and AF‐TM (+) groups, respectively. In logistic regression analysis, the AF‐TM (+) group had lower in‐hospital mortality after adjusting the significant covariates (odds ratio, 0.49; 95% confidence interval, 0.26–0.93). The mortality rate did not differ between SR and AF‐TM (−) groups. During 1 year follow‐up, 990 (18.5%) patients died. In univariate and multivariate Cox proportional regression analyses, there was no difference in 1‐year all‐cause mortality between the three groups. Conclusions In patients with HF and AF, patients whose acute decompensation is tachycardia‐mediated have better in‐hospital, but similar post‐discharge outcomes compared with those with SR or those with AF whose decompensation is not tachycardia‐mediated. Clinical Trial Registration: ClinicalTrial.gov NCT01389843.

Abstract Renal dysfunction is considered as a relative contraindication for heart transplantation (HTx). However, in the real world setting, many patients with advanced heart failure (HF) experience worsening of renal function and some even require renal replacement therapy (RRT) by the time they undergo HTx. We aimed to investigate the prognosis and clinical outcomes of HTx patients who required RRT during the perioperative period. The Korean Organ Transplant Registry (KOTRY) is a nationwide organ transplant registry in Korea. A total of 501 HTx patients had been prospectively enrolled in the KOTRY registry during 2014–2018. Among the 501 patients, 13 underwent combined heart and kidney transplantation (HKTx). The 488 patients who underwent isolated HTx were grouped according to their pre- and postoperative RRT status. The primary outcome was progression to dialysis-dependent end-stage renal disease (ESRD) after HTx. The secondary outcome was all-cause mortality after HTx. The median follow-up was 22 months (9–39 months). Patients who needed preoperative RRT but were free from postoperative RRT showed comparable overall survival and renal outcome to patients who were free from both pre- and postoperative RRT. In multivariable analysis, preoperative RRT was not associated with progression to ESRD or all-cause mortality after HTx; however, postoperative RRT was a significant predictor for both progression to ESRD and all-cause mortality after HTx. Preoperative creatinine or estimated glomerular filtration rate (eGFR) were not predictive of progression to ESRD after HTx. The present analysis suggests that preoperative RRT requirement does not indicate irreversible renal dysfunction in patients waiting for HTx. However, postoperative RRT was associated with progression to ESRD and mortality after HTx.

BackgroundPost-transplant malignancy (PTM) causes long-term morbidity and mortality in heart transplant (HTx) recipients. However, the detailed characteristics or predictors of PTM are not well-known. We evaluated the incidence, characteristics, long-term outcomes, and predictors of de novo PTM using a single center large-volume database.MethodsWe retrospectively analyzed the types and characteristics of de novo PTM in 989 patients who underwent HTx. Univariate and multivariate logistic regression analyses were used for the PTM prediction model.ResultsTwo hundred and six patients (20.8%) had de novo PTMs (241 cancers) during a median follow-up of 11.5 years. PTM patients were older than non-PTM patients, received immunosuppressive therapy for a longer period, and were more likely to be male and white. Skin cancers were the most frequent types of malignancy (60.6%) followed by prostate (9.5%), lung (7.1%), and breast (4.1%) cancers. Although most cancers (88.8%) were surgically resected at initial presentation, about half (47.3%) recurred or progressed. Patients with skin cancer and non-skin cancer had significantly lower overall survival (P < 0.001) than patients without cancer. Older age (P < 0.001), white race (P = 0.001), and longer time receiving immunosuppressive therapy (P < 0.001) were independent predictors for PTM.ConclusionOlder age, white race, and longer administration of immunosuppressive therapies were independent risk factors for PTM, which was associated with increased mortality. Further research is necessary for the prevention and early detection of PTM in HTx recipients.

BackgroundMycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and a key immunosuppressant for improving graft survival in patients with heart transplantation (HTx). However, dose reduction or interruption is occasionally needed due to gastrointestinal (GI) side effects. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative form of MPA delivery to improve GI tolerability. In the present study, the efficacy of EC-MPS compared with MMF in HTx patients was investigated.MethodsIn this retrospective study, the Korean Organ Transplant Registry (KOTRY) data were used to analyze the efficacy and rejection rate of MMF and EC-MPS. A total of 611 patients was enrolled from 2014 to February of 2021. Patients were divided based on the use of MMF or EC-MPS at 6 months post-HTx. Patients who were not prescribed MMF or EC-MPS were excluded. Graft survival, all-cause mortality, and treated rejection were compared between the two groups. All statistical analyses were performed using SPSS; characteristics were compared using Pearson chi-square test and survival rate with Kaplan-Meier plot and log-rank test.ResultsA total of 510 HTx patients was analyzed (mean age: 51.74 ± 13.16 years, males: 68.2%). At 6 months after HTx, 78 patients were taking EC-MPA (12.8%) and 432 patients were taking MMF (70.7%). The median follow-up was 42.0 months (IQR: 21.7–61.0 months). Post-HTx outcomes including overall survival, all cause mortality, acute cell mediated rejection (ACR), acute antibody mediated rejection (AMR), treated rejection, and cardiac allograft vasculopathy (CAV) were comparable between the two groups during follow-up.ConclusionNotable differences were not observed in overall survival, all cause mortality, ACR, AMR, treated rejection, and CAV between MMF and EC-MPS groups. Efficacy of EC-MPS was similar to that of MMF in HTx patients during mid-term follow up after HTx.

BackgroundThe prognostic role of myocardial ischemia in patients with heart failure with preserved ejection fraction (HFpEF) has not been fully elucidated. Therefore, we investigated the change in echocardiographic parameters and clinical outcomes based on the presence of epicardial coronary artery disease (CAD) and positive stress tests in HFpEF patients.MethodsSymptomatic patients with left ventricular end diastolic pressure ≥15 mmHg who underwent coronary angiography were analyzed between January 2000 and August 2019 after exclusion of patients with acute coronary syndrome.ResultsA total of 555 HFpEF patients were invasively confirmed, 285 (51%) had angiographically-proven CAD. HFpEF patients with CAD displayed greater deterioration in left ventricular ejection fraction (p = 0.002) over time but this was not observed in those without CAD (p = 0.99) on follow-up echocardiography; however, the mitral annulus early diastolic velocity (e') was significantly decreased in both groups (p < 0.001 and p = 0.003, respectively). Among 274 patients that received stress tests, those with positive stress tests showed a decline in e' (p 0.001), but this was not found in subjects with negative stress tests (p = 0.44). There was no significant difference in all-cause mortality between patients with CAD and without CAD (p = 0.26) with a median follow-up of 10.6 years.ConclusionIn HFpEF patients, CAD was associated with greater deterioration in the left ventricular systolic function but not with mortality during the follow-up. In addition, myocardial ischemia with a positive stress test may contribute to greater deterioration of diastolic dysfunction.

AimCardiac involvement is the main prognostic determinant in AL amyloidosis. We sought to determine the prognostic significance of longitudinal change of left ventricular (LV) global longitudinal strain (GLS) in cardiac light chain (AL) amyloidosis patients undergoing chemotherapy.Methods and ResultWe retrospectively investigated 117 cardiac AL amyloidosis patients who underwent chemotherapy from 2005 to 2019. All patients underwent comprehensive 2D conventional transthoracic echocardiography at baseline and after completion of first-line chemotherapy. Speckle tracking analysis of images was performed offline. Absolute value of LV GLS was expressed as [LV GLS] and change of [LV GLS] after chemotherapy was expressed as Δ [LV GLS]. Clinical outcomes including cardiac response and all-cause mortality were analyzed.Baseline clinical and echocardiographic parameters were similar in patients with and without CR. Δ [LV GLS] significantly differed between the CR and non-CR groups (0.4 ± 2.8% in the CR group vs. −0.6 ± 2.5% in the non-CR group, P-value = 0.046). Δ [LV GLS] showed satisfactory predictive performance for all-cause mortality (cut-off value = 0.8%, AUC 0.643, 95% CI [0.537–0.748]). Adding Δ [LV GLS] to the Mayo stage + pre-chemotherapy [LV GLS] model showed incremental prognostic value (C-index: 0.637 vs. 0.708; Relative Integrated Discrimination Index 0.07, P-value = 0.003; Net Reclassification Improvement 0.54, P-value < 0.001). Δ [LV GLS] showed good correlation with cardiac response (AUC 0.820, 95% CI [0.737–0.904]).ConclusionIn cardiac amyloidosis patients who underwent chemotherapy, longitudinal change of [LV GLS] after chemotherapy showed significant association with overall survival as well as cardiac response.

The coxsackievirus and adenovirus receptor (CAR) is very well known as an epithelial tight junction and cardiac intercalated disc protein; it mediates attachment and infection via the coxsackievirus B3 (CVB3) and type 5 adenovirus. Macrophages play important roles in early immunity during viral infections. However, the role of CAR in macrophages is not well studied in relation to CVB3 infection. In this study, the function of CAR was observed in the Raw264.7 mouse macrophage cell line. CAR expression was stimulated by treatment with lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α). In thioglycollate-induced peritonitis, the peritoneal macrophage was activated and CAR expression was increased. The macrophage-specific CAR conditional knockout mice (KO) were generated from lysozyme Cre mice. The expression of inflammatory cytokine (IL-1β and TNF-α) was attenuated in the KO mice’s peritoneal macrophage after LPS treatment. In addition, the virus was not replicated in CAR-deleted macrophages. The organ virus replication was not significantly different in both wild-type (WT) and KO mice at days three and seven post-infection (p.i). However, the inflammatory M1 polarity genes (IL-1β, IL-6, TNF-α and MCP-1) were significantly increased, with increased rates of myocarditis in the heart of KO mice compared to those of WT mice. In contrast, type1 interferon (IFN-α and β) was significantly decreased in the heart of KO mice. Serum chemokine CXCL-11 was increased in the KO mice at day three p.i. compared to the WT mice. The attenuation of IFN-α and β in macrophage CAR deletion induced higher levels of CXCL-11 and more increased CD4 and CD8 T cells in KO mice hearts compared to those of WT mice at day seven p.i. These results demonstrate that macrophage-specific CAR deletion increased the macrophage M1 polarity and myocarditis in CVB3 infection. In addition, chemokine CXCL-11 expression was increased, and stimulated CD4 and CD8 T cell activity. Macrophage CAR may be important for the regulation of innate-immunity-induced local inflammation in CVB3 infection.

Background/Aims This study investigated the prognostic power of corrected QT (QTc) interval in patients with acute heart failure (AHF) according to sex. Methods We analyzed multicenter Korean Acute Heart Failure registry with patients with AHF admitted from 2011 to 2014. Among them, we analyzed 4,990 patients who were followed up to 5 years. Regarding QTc interval based on 12 lead electrocardiogram, patients were classified into quartiles according to sex. Results During follow-up with median 43.7 months, 2,243 (44.9%) patients died. The relationship between corrected QT interval and all-cause mortality followed a J-curve relationship. In Kaplan-Meier analysis, both sex had lowest mortality in the second QTc quartile. There were significant prognostic differences between the second and the fourth quartiles in male (log-rank p = 0.002), but not in female (log-rank p = 0.338). After adjusting covariates, the third (hazard ratio [HR], 1.185; 95% confidence interval [CI], 1.001 to 1.404; p = 0.049) and the fourth (HR, 1.404; 95% CI, 1.091 to 1.535; p = 0.003) quartiles demonstrated increased risk of mortality compared to the second quartile in male. In female, however, there was no significant difference across quartiles. QTc interval was associated with 5-year all-cause mortality in J-shape with nadir of 440 to 450 ms in male and 470 to 480 ms in female. Conclusions QTc interval was an independent predictor of overall death in male, but its significance decreased in female. The relationship between QTc interval and all-cause mortality was J-shaped in both sex.

Abstract Background Limited data are available on the impact of a specialized extracorporeal membrane oxygenation (ECMO) team on clinical outcomes in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). This study evaluated whether specialized ECMO team is associated with improved in-hospital mortality in AMI patients undergoing veno-arterial (VA) ECMO. Methods A total of 255 AMI patients who underwent VA-ECMO were included. In January 2014, a multidisciplinary ECMO team was founded at our institution. Eligible patients were classified into a pre-ECMO team group (n = 131) and a post-ECMO team group (n = 124). The primary outcome was in-hospital mortality. Results In-hospital mortality (pre-ECMO team vs. post-ECMO team, 54.2% vs. 33.9%; p = 0.002) and cardiac intensive care unit mortality (pre-ECMO team vs. post-ECMO team, 51.9% vs. 30.6%; p = 0.001) were significantly lower after the implementation of a multidisciplinary ECMO team. On multivariable logistic regression model, implementation of the multidisciplinary ECMO team was associated with reduction of in-hospital mortality [odds ratio: 0.37, 95% confidence interval (CI) 0.20–0.67; p = 0.001]. Incidence of all-cause mortality [58.3% vs. 35.2%; hazard ratio (HR): 0.49, 95% CI 0.34–0.72; p

Abstract Background Hypertrophic cardiomyopathy (HCM) is thought to be associated with microvascular dysfunction. Adenosine stress-perfusion cardiovascular magnetic resonance imaging (CMR) is a sensitive method for assessing microvascular perfusion abnormalities. We evaluated the prevalence and clinical characteristics of HCM patients with adenosine-induced perfusion defects on CMR. Methods Among 189 consecutive patients with HCM who underwent adenosine-stress perfusion CMR, 115 patients who had clinical, echocardiography, 24-h Holter monitoring and treadmill exercise test data were analyzed. We calculated myocardial perfusion ratio index from the intensity-over-time curve to quantify perfusion defects. The presence and extent of the stress-induced perfusion defect were compared with clinical characteristics, presence and extent of late gadolinium enhancement (LGE), left ventricular (LV) mass index and volume, presence of non-sustained ventricular tachycardia (NSVT) and results of treadmill exercise test. Results The mean age of enrolled patients was 51.8 ± 11.3 years. Most patients were asymptomatic except 25 subjects presented with New York Heart Association Class II dyspnea and 16 patients with atypical non-exertional chest discomfort. LGE was present in 103 (89.6%) subjects. Adenosine stress-induced perfusion defects were present in 48 (42%) subjects. None of the perfusion defects corresponded with a single or multiple coronary artery territories, showing a multiple patchy pattern in 24 (50.0%), a concentric subendocardial pattern in 20 subjects (41.7%), and as a single blot-like defect in the remaining 4 (8.3%). A perfusion defect was associated with NSVT, LV apical aneurysm, higher LV mass index, and higher LGE volume on univariate analysis. Multivariate analysis revealed female gender (P = 0.008), presence of apical aneurysm and NSVT (P = 0.036 and 0.047, respectively), and LV mass index (P = 0.022) to be independently associated with adenosine stress-induced perfusion defects. Conclusions In patients with HCM, adenosine-stress perfusion defects on CMR are present in more than 40% of subjects. This perfusion defect is associated with NSVT, higher LV mass index, and apical aneurysms. The prognostic value of this finding needs further elucidation.

Abstract Background Although more than one-third of the patients with acute heart failure (AHF) have diabetes mellitus (DM), it is unclear if DM has an adverse impact on clinical outcomes. This study compared the outcomes in patients hospitalized for AHF stratified by DM and left ventricular ejection fraction (LVEF). Methods The Korean Acute Heart Failure registry prospectively enrolled and followed 5625 patients from March 2011 to February 2019. The primary endpoints were in-hospital and overall all-cause mortality. We evaluated the impact of DM on these endpoints according to HF subtypes and glycemic control. Results During a median follow-up of 3.5 years, there were 235 (4.4%) in-hospital mortalities and 2500 (46.3%) overall mortalities. DM was significantly associated with increased overall mortality after adjusting for potential confounders (adjusted hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.03–1.22). In the subgroup analysis, DM was associated with higher a risk of overall mortality in heart failure with reduced ejection fraction (HFrEF) only (adjusted HR 1.14, 95% CI 1.02–1.27). Inadequate glycemic control (HbA1c ≥ 7.0% within 1 year after discharge) was significantly associated with a higher risk of overall mortality compared with adequate glycemic control (HbA1c

BackgroundRandomized clinical trials of spironolactone showed significant mortality reduction in patients with heart failure with reduced ejection fraction. However, its role in acute heart failure syndrome (AHFS) is largely unknown.AimTo investigate the prescription characteristics, efficacy and safety of spironolactone in real-world patients with AHFS.Methods5,136 AHFS patients who survived to hospital discharge using a nationwide prospective registry in Korea were analyzed. The primary efficacy outcome was 3-year all-cause mortality.ResultsSpironolactone was prescribed in 2,402 (46.8%) at discharge: 26%.ConclusionsAlthough spironolactone was frequently used at lower doses in real-world practice, use of spironolactone significantly reduced 3-year mortality in patients with severely reduced LVEF with acceptable safety profile. However, our findings remain prone to various biases and further prospective randomized controlled studies are needed to confirm these findings.

Background/Aims It is unknown whether different β-blockers (BBs) have variable effects on long-term survival of patients with heart failure with reduced ejection fraction (HFrEF). This study compares the effects of two BBs, carvedilol and bisoprolol, on survival in patients with HFrEF. Methods The Korean Acute Heart Failure (KorAHF) registry is a prospective multicenter cohort that includes 5,625 patients who were hospitalized for acute heart failure (AHF). We selected 3,016 patients with HFrEF and divided this study population into two groups: BB at discharge (n = 1,707) or no BB at discharge (n = 1,309). Among patients with BB at discharge, subgroups were formed based on carvedilol prescription (n = 831), or bisoprolol prescription (n = 553). Propensity score matching analysis was performed. Results Among patients who were prescribed a BB at discharge, 60.5% received carvedilol and 32.7% received bisoprolol. There was a significant reduction in allcause mortality in those patients with HFrEF prescribed a BB at discharge compared to those who were not (BB vs. no BB, 26.1% vs. 40.8%; hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.52 to 0.67; p < 0.001). However, there was no significant difference in the rate of all-cause mortality between those receiving different types of BB (carvedilol vs. bisoprolol, 27.5% vs. 23.5%; HR, 1.21; 95% CI, 0.99 to 1.47; p = 0.07). Similar results were observed after propensity score matching analysis (508 pairs, 26.2% vs. 23.8%; HR, 1.10; 95% CI, 0.86 to 1.40; p = 0.47). Conclusions In the treatment of AHF with reduced EF after hospitalization, mortality benefits of carvedilol and bisoprolol were comparable.

Abstract Background Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure–lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension. Methods This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome. Discussion Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients. Trial registration ClinicalTrials.gov Identifier: NCT03246555, registered on July 25, 2017.

Background The aim of this study was to investigate the clinical significance of Quilty lesions in endomyocardial biopsies (EMBs) of cardiac transplantation patients. Methods A total of 1190 EMBs from 117 cardiac transplantation patients were evaluated histologically for Quilty lesions, acute cellular rejection, and antibody-mediated rejection. Cardiac allograft vasculopathy was diagnosed by computed tomography coronary angiography. Clinical information, including the patients’ survival was retrieved by a review of medical records. Results Eighty-eight patients (75.2%) were diagnosed with Quilty lesions, which were significantly associated with acute cellular rejection, but not with acute cellular rejection ≥ 2R or antibody-mediated rejection. In patient sdiagnosed with both Quilty lesions and acute cellular rejection, the time-to-onset of Quilty lesions from transplantation was longer than that of acute cellular rejections. We found a significant association between Quilty lesions and cardiac allograft vasculopathy. No significant relationship was found between Quilty lesions and the patients’ survival. Conclusions Quilty lesion may be an indicator of previous acute cellular rejection rather than a predictor for future acute cellular rejection.

Background: The prognostic impact and predictors of NOAF in HF patients are not fully elucidated. This study aims to determine whether new-onset atrial fibrillation (NOAF) affects patient outcome and investigate predictors of atrial fibrillation (AF) in acute heart failure (HF) patients using real-world data. Methods: The factors associated with NOAF in 2894 patients with sinus rhythm (SR) enrolled in the Korean Acute Heart Failure (KorAHF) registry were investigated. Survival was analyzed using AF as a time-dependent covariate. Relevant predictors of NOAF were analyzed using multivariate proportional hazards models. Results: Over 27.4 months, 187 patients developed AF. The median overall survival time was over 48 and 9.9 months for the SR and NOAF groups, respectively. Cox regression analysis with NOAF as a time-dependent covariate showed a higher risk of death among patients with NOAF. Multivariate Cox modeling showed that age, worsening HF, valvular heart disease (VHD), loop diuretics, lower heart rate, larger left atrium (LA) diameter, and elevated creatinine levels were independently associated with NOAF. Risk score indicated the number of independent predictors. The incidence of NOAF was 2.9%, 9.4%, and 21.8% in the low-risk, moderate-risk, and high-risk groups, respectively (p < 0.001). Conditional inference tree analysis identified worsening HF, heart rate, age, LA diameter, and VHD as discriminators. Conclusions: NOAF was associated with decreased survival in acute HF patients with SR. Age, worsening HF, VHD, loop diuretics, lower heart rate, larger LA diameter, and elevated creatinine could independently predict NOAF. This may be useful to risk-stratify HF patients at risk for AF.

Background: Heart transplantation (HTx) is the final treatment option for patients with chronic heart failure. Several studies have reported that exercise therapy, which is a component of cardiac rehabilitation, improves exercise capacity and the quality of life (QOL) in patients with heart failure. Methods: Three patients, referred to an inpatient cardiac rehabilitation before HTx, participated in center-based cardiac rehabilitation (CBCR) during the hospitalization period. The CBCR, including aerobic exercises and resistance training, was conducted 3–4 days/week under cardiac rehabilitation team. Clinical outcomes included QOL using short form (SF)-36 questionnaire and the level of physical activity using international physical activity questionnaire (IPAQ) were evaluated before and after following the CBCR. Results: These patients showed an improved QOL in physical components with mean 32% and in mental components with mean 43%. The adherence to exercise confirmed by level of physical activity also increased as much as mean 1275 MET-minutes at 3 months after transplantation. Conclusions: The findings in case report show the safety and effectiveness of CBCR in patients waiting for HTx during hopitalization. This is the first case report showing the effect of CBCR in admission period in Korean patients undergoing HTx.

Protein kinase B2 (AKT2) is involved in various cardiomyocyte signaling processes, including those important for survival and metabolism. Coxsackievirus B3 (CVB3) is one of the most common pathogens that cause myocarditis in humans. The role of AKT2 in CVB3 infection is not yet well understood. We used a cardiac-specific AKT2 knockout (KO) mouse to determine the role of AKT2 in CVB3-mediated myocarditis. CVB3 was injected intraperitoneally into wild-type (WT) and KO mice. The mice’s survival rate was recorded: survival in KO mice was significantly decreased compared with WT mice (WT vs. KO: 73.3 vs. 27.1%). Myocardial damage and inflammation were significantly increased in the hearts of KO mice compared with those of WT mice. Moreover, from surface ECG, AKT2 KO mice showed a prolonged atria and ventricle conduction time (PR interval, WT vs. KO: 47.27 ± 1.17 vs. 64.79 ± 7.17 ms). AKT2 deletion induced severe myocarditis and cardiac dysfunction due to CVB3 infection. According to real-time PCR, the mRNA level of IL-1, IL-6, and TNF-α decreased significantly in KO mice compared with WT mice on Days 5 after infection. In addition, innate immune response antiviral effectors, Type I interferon (interferon-α and β), and p62, were dramatically suppressed in the heart of KO mice. In particular, the adult cardiac myocytes isolated from the heart showed high induction of TLR4 protein in KO mice in comparison with WT. AKT2 deletion suppressed the activation of Type I interferon and p62 transcription in CVB3 infection. In cardiac myocytes, AKT2 is a key signaling molecule for the heart from damage through the activation of innate immunity during acute myocarditis.

Abstract Background Limited data are available regarding prevention of limb ischemia in femorally cannulated patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). We investigated the association between strategy of distal perfusion catheter (DPC) insertion and vascular complications like limb ischemia in patients undergoing VA-ECMO. Methods We evaluated 230 patients from two tertiary hospitals who received VA-ECMO via femoral cannulation between August 2014 and July 2017. The patients were divided into two groups according to DPC insertion strategy: patients who underwent DPC insertion at the time of primary cannulation (DPC group, n = 96) and patients who were provisionally treated with DPC (No-DPC group, n = 134). The primary outcome was limb ischemia. Results Of the 96 patients in the DPC group, 61 (63.5%) underwent insertion under fluoroscopic guidance. The DPC group had a significantly lower incidence of limb ischemia (2.1% vs. 8.2%, p = 0.047) and a lower tendency of in-hospital mortality (38.5% vs. 50.7%, p = 0.067) than the No-DPC group. In the multivariable analysis, fluoroscopy-guided simultaneous insertion of the DPC (odds ratio 0.11; 95% confidence interval 0.01–0.98; p = 0.048) was a significant predictor of reduction of limb ischemia. Conclusions Simultaneous insertion of a DPC, particularly under fluoroscopy guidance, can be considered as a preventive strategy for limb ischemia in femorally cannulated patients on VA-ECMO.

Abstract Background It has been reported that left ventricular (LV) myocardial strain and late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging have prognostic value in patients with heart failure (HF). However, previous studies included patients with various systolic functions. This study aimed to investigate the prognostic value of LV myocardial strain and LGE on CMR imaging in patients with idiopathic dilated cardiomyopathy (DCM) with reduced ejection fraction (EF

Abstract Background Carvedilol is a non-selective, third-generation beta-blocker and is one of the cornerstones for treatment for patients with heart failure and reduced ejection fraction (HFrEF). However, due to its short half-life, immediate-release carvedilol (IR) needs to be prescribed twice a day. Recently, slow-release carvedilol (SR) has been developed. The aim of this study is to evaluate whether carvedilol-SR is non-inferior to standard carvedilol-IR in terms of its clinical efficacy in patients with HFrEF. Methods/design Patients with stable HFrEF will be randomly assigned in a 1:1 ratio to the carvedilol-SR group (160 patients) and the carvedilol-IR group (160 patients). Patients aged ≥ 20 years, with a left ventricular ejection fraction ≤ 40%, N-terminal pro B-natriuretic peptide (NT-proBNP) ≥ 125 pg/ml or BNP ≥ 35 pg/ml, who are clinically stable and have no evidence of congestion or volume retention, will be eligible. After randomization, patients will be followed up for 6 months. The primary endpoint is the change in NT-proBNP level from baseline to the study end. The secondary endpoints include the proportion of patients with NT-proBNP increment > 10% from baseline, composite of all-cause mortality and readmission, mortality rate, readmission rate, changes in blood pressure, quality of life, and drug compliance. Discussions The SLOW-HF trial is a prospective, randomized, open-label, phase-IV, multicenter study to evaluate the therapeutic efficacy of carvedilol-SR compared to carvedilol-IR in HFrEF patients. If carvedilol-SR proves to be non-inferior to carvedilol-IR, a once-daily prescription of carvedilol may be recommended for patients with HFrEF. Trial registration ClinicalTrials.gov, ID: NCT03209180. Registered on 6 July 2017.

Alterations in DNA methylation and gene expression have been implicated in the development of human dilated cardiomyopathy (DCM). Differentially methylated probes (DMPs) and differentially expressed genes (DEGs) were identified between the left ventricle (LV, a pathological locus for DCM) and the right ventricle (RV, a proxy for normal hearts). The data in this DiB are for supporting our report entitled “Methylome analysis reveals alterations in DNA methylation in the regulatory regions of left ventricle development genes in human dilated cardiomyopathy” (Bong-Seok Jo, In-Uk Koh, Jae-Bum Bae, Ho-Yeong Yu, Eun-Seok Jeon, Hae-Young Lee, Jae-Joong Kim, Murim Choi, Sun Shim Choi, 2016) [1].

Background Many patients with heart failure (HF) with reduced ejection fraction (HFrEF) experience improvement or recovery of left ventricular ejection fraction (LVEF). Data on clinical characteristics, outcomes, and medical therapy in patients with HF with improved ejection fraction (HFiEF) are scarce. Methods and Results Of 5625 consecutive patients hospitalized for acute HF in the KorAHF (Registry [Prospective Cohort] for Heart Failure in Korea) study, 5103 patients had baseline echocardiography and 2302 patients had follow‐up echocardiography at 12 months. HF phenotypes were defined as persistent HFrEF (LVEF ≤40% at baseline and at 1‐year follow‐up), HFiEF (LVEF ≤40% at baseline and improved up to 40% at 1‐year follow‐up), HF with midrange ejection fraction (LVEF between 40% and

Background Many hospitalized patients with heart failure and reduced ejection fraction (HFrEF) have a slow heart rate at discharge, and the effect of β‐blockers may be reduced in those patients. We sought to examine the variable effect of β‐blockers on clinical outcomes according to the discharge heart rate of hospitalized HFrEF patients. Methods and Results The KorAHF (Korean Acute Heart Failure) registry consecutively enrolled 5625 patients hospitalized for acute heart failure. In this analysis, we included patients with HFrEF (left ventricular ejection fraction ≤40%). Slow heart rate was defined as

AimsThis study aimed to develop and validate deep-learning-based artificial intelligence algorithm for predicting mortality of AHF (DAHF).Methods and results12,654 dataset from 2165 patients with AHF in two hospitals were used as train data for DAHF development, and 4759 dataset from 4759 patients with AHF in 10 hospitals enrolled to the Korean AHF registry were used as performance test data. The endpoints were in-hospital, 12-month, and 36-month mortality. We compared the DAHF performance with the Get with the Guidelines-Heart Failure (GWTG-HF) score, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score, and other machine-learning models by using the test data. Area under the receiver operating characteristic curve of the DAHF were 0.880 (95% confidence interval, 0.876-0.884) for predicting in-hospital mortality; these results significantly outperformed those of the GWTG-HF (0.728 [0.720-0.737]) and other machine-learning models. For predicting 12- and 36-month endpoints, DAHF (0.782 and 0.813) significantly outperformed MAGGIC score (0.718 and 0.729). During the 36-month follow-up, the high-risk group, defined by the DAHF, had a significantly higher mortality rate than the low-risk group(pConclusionDAHF predicted the in-hospital and long-term mortality of patients with AHF more accurately than the existing risk scores and other machine-learning models.

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s)ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men (P=8×10−6) and men with myocarditis (P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III‐IV heart failure (P=0.002), predominantly in men (P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old (r=0.231, P=0.0006), but not in women (r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis (P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone (P

Coxsackievirus and adenovirus receptor (CAR) is present in epithelial and vascular endothelial cell junctions. We have previously shown a hemorrhagic phenotype in germ-line CAR knock-out mouse embryos; we have also found that CAR interacts with ZO-1 and β-catenin. However, the role of CAR in vascular endothelial junction permeability has not been proven. To understand the roles of CAR in the vascular endothelial junctions, we generated endothelium-specific CAR knockout (CAR-eKO) mice. In the absence of CAR, the endothelial cell layer showed an increase in transmembrane electrical resistance (TER, Ω) and coxsackievirus permeability. Evans blue dye and 70 kDa dextran-FITC were delivered by tail vein injection. We observed increased vascular permeability in the hearts of adult CAR-eKO mice compare with wild-type (WT) mice. There was a marked increase in monocyte and macrophage penetration into the peritoneal cavity caused by thioglycolate-induced peritonitis. We found that CAR ablation in endothelial cells was not significantly increased coxsackievirus B3 (CVB3) induced myocarditis in murine model. However, tissue virus titers were significantly higher in CAR-eKO mice compared with WT. Moreover, CVB3 was detected in the brain of CAR-eKO mice. Endothelial CAR deletion affects the expression of major endothelial junction proteins, such as cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1) in the cultured endothelial cells as well as liver vessel. We suggest that CAR expression is required for normal vascular permeability and endothelial tight junction homeostasis. Furthermore, CVB3 organ penetration and myocarditis severities were dependent on the endothelial CAR level.

Aims: Coxsackievirus B3 (CVB3) is known to be an important cause of myocarditis and dilated cardiomyopathy. Enterovirus-2C (E2C) is a viral RNA helicase. It inhibits host protein synthesis. Based on these facts, we hypothesize that the inhibition of 2C may suppress virus replication and prevent enterovirus-mediated cardiomyopathy. Methods and Results: We generated a chemically modified enterovirus-2C inhibitor (E2CI). From the in vitro assay, E2CI was showed strong antiviral effects. For in vivo testing, mice were treated with E2CI intraperitoneally injected daily for three consecutive days at a dose of 8 mg/kg per day, after CVB3 post-infection (p.i) (CVB3 + E2CI, n = 33). For the infected controls (CVB3 only, n = 35), mice were injected with PBS (phosphate buffered saline) in a DBA/2 strain to establish chronic myocarditis. The four-week survival rate of E2CI-treated mice was significantly higher than that of controls (92% vs. 71%; p < 0.05). Virus titers and myocardial damage were significantly reduced in the E2CI treated group. In addition, echocardiography indicated that E2CI administration dramatically maintained mouse heart function compared to control at day 28 p.i chronic stage (LVIDD, 3.1 ± 0.08 vs. 3.9 ± 0.09, p < 0.01; LVDS, 2.0 ± 0.07 vs. 2.5 ± 0.07, p < 0.001; FS, 34.8 ± 1.6% vs. 28.5 ± 1.5%; EF, 67. 9 ± 2.9% vs. 54.7 ± 4.7%, p < 0.05; CVB3 + E2CI, n = 6 vs. CVB3, n = 4). Moreover, E2CI is effectively worked in human iPS (induced pluripotent stem cell) derived cardiomyocytes. Conclusion: Enterovirus-2C inhibitor (E2CI) was significantly reduced viral replication, chronic myocardium damage, and CVB3-induced mortality in DBA/2 mice. These results suggested that E2CI is a novel therapeutic agent for the treatment of enterovirus-mediated diseases.

Background Although current guidelines now define heart failure with midrange ejection fraction (HFmrEF) as HF with a left ventricular EF of 40% to 49%, there are limited data on response to guideline‐directed medical therapy in patients with HFmrEF. The current study aimed to evaluate the association between β‐blocker, renin‐angiotensin system blocker (RASB), or aldosterone antagonist (AA) treatment with clinical outcome in patients with HFmrEF. Methods and Results We performed a patient‐level pooled analysis on 1144 patients with HFmrEF who were hospitalized for acute HF from the KorHF (Korean Heart Failure) and KorAHF (Korean Acute Heart Failure) registries. The study population was divided between use of β‐blocker, RASB, or AA to evaluate the guideline‐directed medical therapy in patients with HFmrEF. Sensitivity analyses, including propensity score matching and inverse‐probability‐weighted methods, were performed. The use of β‐blocker in the discharge group showed significantly lower rates of all‐cause mortality compared with those who did not use a β‐blocker (β‐blocker versus no β‐blocker, 30.7% versus 38.2%; hazard ratio, 0.758; 95% confidence interval, 0.615–0.934; P=0.009). Similarly, the RASB use in the discharge group was associated with the lower risk of mortality compared with no use of RASB (RASB versus no RASB, 31.9% versus 38.1%; hazard ratio, 0.76; 95% confidence interval, 0.618–0.946; P=0.013). However, there was no significant difference in all‐cause mortality between AA and no AA in the discharge group (AA versus no AA, 34.2% versus 34.0%; hazard ratio, 1.063; 95% confidence interval, 0.858–1.317; P=0.578). Multiple sensitivity analyses showed similar trends. Conclusions For treatment of acute HFmrEF after hospitalization, β‐blocker and RASB therapies on discharge were associated with reduced risk of all‐cause mortality. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01389843.

BackgroundWorsening renal function (WRF) is associated with adverse outcomes in patients with heart failure. We investigated the predictors and prognostic value of WRF during admission, in patients with preserved ejection fraction (HFpEF) versus those with reduced ejection fraction (HFrEF). Methods and ResultsA total of 5625 patients were enrolled in the KorAHF (Korean Acute Heart Failure) registry. WRF was defined as an absolute increase in creatinine of ≥0.3 mg/dL. Transient WRF was defined as recovery of creatinine at discharge, whereas persistent WRF was indicated by a nonrecovered creatinine level. HFpEF and HFrEF were defined as a left ventricle ejection fraction ≥50% and ≤40%, respectively. Among the total population, WRF occurred in 3101 patients (55.1%). By heart failure subgroup, WRF occurred more frequently in HFrEF (57.0% versus 51.3%; P

BACKGROUND:We investigated the role of nutritional risk index (NRI) in predicting 1-year mortality in patients with acute decompensated heart failure (ADHF). METHODS:Among 5,625 cohort patients enrolled in Korean Acute Heart Failure (KorAHF) Registry, a total of 5,265 patients who were possible to calculate NRI [NRI = (1.519 x serum albumin [g/dl]) + (41.7 x weight [kg]/ideal body weight [kg])] were enrolled. The patients were divided into 4 groups according to the NRI quartile; Q1 100 (n = 1711, 65.6 ± 14.5 years, 779 males). Primary end-point was all-cause mortality at 1-year clinical follow-up. RESULTS:The 1-year mortality was significantly increased as the NRI quartile decreased, and the lowest NRI quartile was associated with the highest 1-year mortality (Q1: 27.5% vs. Q2: 20.9% vs. Q3: 12.9% vs. Q4: 8.7%, linear p