Background: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. Methods: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). Results: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). Conclusion There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications.

Background: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. Methods: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation–Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. Results: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence inter val [CI], 0.55– 0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% 0.56–0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79–1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65–2.17; P = 0.582). Conclusion In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.

BACKGROUND AND OBJECTIVES: We aim to explore the additional discriminative accuracy of a deep learning (DL) algorithm using repeated-measures data for identifying people at high risk for cardiovascular disease (CVD), compared to Cox hazard regression.METHODS: Two CVD prediction models were developed from National Health Insurance Service-Health Screening Cohort (NHIS-HEALS): a Cox regression model and a DL model. Performance of each model was assessed in the internal and 2 external validation cohorts in Koreans (National Health Insurance Service-National Sample Cohort; NHIS-NSC) and in Europeans (Rotterdam Study). A total of 412,030 adults in the NHIS-HEALS; 178,875 adults in the NHIS-NSC; and the 4,296 adults in Rotterdam Study were included.RESULTS: Mean ages was 52 years (46% women) and there were 25,777 events (6.3%) in NHIS-HEALS during the follow-up. In internal validation, the DL approach demonstrated a C-statistic of 0.896 (95% confidence interval, 0.886–0.907) in men and 0.921 (0.908–0.934) in women and improved reclassification compared with Cox regression (net reclassification index [NRI], 24.8% in men, 29.0% in women). In external validation with NHIS-NSC, DL demonstrated a C-statistic of 0.868 (0.860–0.876) in men and 0.889 (0.876–0.898) in women, and improved reclassification compared with Cox regression (NRI, 24.9% in men, 26.2% in women). In external validation applied to the Rotterdam Study, DL demonstrated a C-statistic of 0.860 (0.824–0.897) in men and 0.867 (0.830–0.903) in women, and improved reclassification compared with Cox regression (NRI, 36.9% in men, 31.8% in women).CONCLUSIONS: A DL algorithm exhibited greater discriminative accuracy than Cox model approaches.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02931500
Adult ; Artificial Intelligence ; Cardiovascular Diseases ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Insurance, Health ; Learning ; Male ; Mass Screening ; National Health Programs

BACKGROUND AND OBJECTIVES: We aim to explore the additional discriminative accuracy of a deep learning (DL) algorithm using repeated-measures data for identifying people at high risk for cardiovascular disease (CVD), compared to Cox hazard regression. METHODS: Two CVD prediction models were developed from National Health Insurance Service-Health Screening Cohort (NHIS-HEALS): a Cox regression model and a DL model. Performance of each model was assessed in the internal and 2 external validation cohorts in Koreans (National Health Insurance Service-National Sample Cohort; NHIS-NSC) and in Europeans (Rotterdam Study). A total of 412,030 adults in the NHIS-HEALS; 178,875 adults in the NHIS-NSC; and the 4,296 adults in Rotterdam Study were included. RESULTS: Mean ages was 52 years (46% women) and there were 25,777 events (6.3%) in NHIS-HEALS during the follow-up. In internal validation, the DL approach demonstrated a C-statistic of 0.896 (95% confidence interval, 0.886–0.907) in men and 0.921 (0.908–0.934) in women and improved reclassification compared with Cox regression (net reclassification index [NRI], 24.8% in men, 29.0% in women). In external validation with NHIS-NSC, DL demonstrated a C-statistic of 0.868 (0.860–0.876) in men and 0.889 (0.876–0.898) in women, and improved reclassification compared with Cox regression (NRI, 24.9% in men, 26.2% in women). In external validation applied to the Rotterdam Study, DL demonstrated a C-statistic of 0.860 (0.824–0.897) in men and 0.867 (0.830–0.903) in women, and improved reclassification compared with Cox regression (NRI, 36.9% in men, 31.8% in women). CONCLUSIONS A DL algorithm exhibited greater discriminative accuracy than Cox model approaches.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02931500

Cereblon (CRBN), a negative modulator of AMP-activated protein kinase (AMPK), is highly expressed in the retina. We confirmed the expression of CRBN in ARPE-19 human retinal cells by Western blotting. We also demonstrated that CRBN knock-down (KD) could effectively downregulate IL-6 and MCP-1 protein and gene expression in LPS-stimulated ARPE-19 cells. Additionally, CRBN KD increased the phosphorylation of AMPK/acetyl-coenzyme A carboxylase (ACC) and the expression of heme oxygenase-1 (HO-1) in ARPE-19 cells. Furthermore, CRBN KD significantly reduced LPS-induced nuclear translocation of NF-κB p65 and activation of NF-κB promoter activity. However, these processes could be inactivated by compound C (inhibitor of AMPK) and zinc protoporphyrin-1 (ZnPP-1; inhibitor of HO-1). In conclusion, compound C and ZnPP-1 can rescue LPS-induced levels of proinflammatory cytokines (IL-6 and MCP-1) in CRBN KD ARPE-19 cells. Our data demonstrate that CRBN deficiency negatively regulates proinflammatory cytokines via the activation of AMPK/HO-1 in the retina.

Background: β-blockers (BBs) are considered primary therapy in stable heart failure (HF) with reduced ejection fraction (HFrEF) without atrial fibrillation (AF); evidence-based benefits of BB on outcome have been documented. However, BBs have not been shown to improve mortality or reduce hospital admissions in HF patients with AF. This study assessed the relationship between BBs at discharge and relevant clinical outcomes in acute heart failure (AHF) patients with AF. Methods: From the Korean Acute Heart Failure Registry, 936 HFrEF and 639 HF patients with preserved ejection fraction (HFpEF) and AF were selected. Propensity score (PS) matching accounted for BB selection bias when assessing associations. Results: BB-untreated patients in the overall cohort of HFrEF and HFpEF had greater deteriorated clinical and laboratory characteristics. In the 670 PS-matched cohort of HFrEF patients, incidences of all clinical events at 60 days and 1 year were not different according to use of BBs. In the 470 PS-matched cohort of HFpEF, rehospitalization and composite outcome at 6 months and 1 year more frequently occurred in non-users of BBs. After adjusting for covariates in the multivariable Cox model of matched cohorts, BB was not associated with clinical outcomes at 60 days and 1 year in HFrEF with AF patients. In HFpEF patients with AF, BB use was associated with reduced 6-month (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.74) and 1-year rehospitalization (HR, 0.53; 95% CI, 0.34–0.82). Conclusion In the HFrEF with AF PS-matched cohort, the use of BBs at discharge was not associated with clinical outcome. However, in HFpEF with AF, the use of BB was associated with reduced rehospitalization during the 6-month and 1-year follow up.

Background: There are sparse data on the utilization rate of implantable cardioverterdefibrillator (ICD) and its beneficial effects in Korean patients with heart failure with reduced left ventricular ejection fraction (LVEF). Methods: Among 5,625 acute heart failure (AHF) patients from 10 tertiary university hospitals across Korea, 485 patients with reassessed LVEF ≤ 35% at least 3 months after the index admission were enrolled in this study. The ICD implantation during the follow-up was evaluated. Mortality was compared between patients with ICDs and age-, sex-, and follow-up duration matched control patients. Results: Among 485 patients potentially indicated for an ICD for primary prevention, only 56 patients (11.5%) underwent ICD implantation during the follow-up. Patients with ICD showed a significantly lower all-cause mortality compared with their matched control population: adjusted hazard ratio (HR) (95% confidence interval [CI]) = 0.39 (0.16–0.92), P = 0.032. The mortality rate was still lower in the ICD group after excluding patients with cardiac resynchronization therapy (adjusted HR [95% CI] = 0.09 [0.01–0.63], P = 0.015).According to the subgroup analysis for ischemic heart failure, there was a significantly lower all-cause mortality in the ICD group than in the no-ICD group (HR [95% CI] = 0.20 [0.06– 0.72], P = 0.013), with a borderline statistical significance (interaction P = 0.069). Conclusion Follow-up data of this large, multicenter registry suggests a significant underutilization of ICD in Korean heart failure patients with reduced LVEF. Survival analysis implies that previously proven survival benefit of ICD in clinical trials could be extrapolated to Korean patients.

BACKGROUND AND OBJECTIVES: Beta-blockers are indicated in patients with heart failure (HF) with reduced ejection fraction. However, their efficacy in patients with HF with preserved ejection fraction (HFpEF) is uncertain. We investigated the hypothesis that beta-blockers are associated with reduced adverse events in patients with HFpEF. METHODS: The Korea Acute Heart Failure (KorAHF) is a prospective observational multicentre cohort study. The 5,625 patients hospitalized for acute HF syndrome in 10 tertiary university hospitals across the country have been consecutively enrolled between March 2011 and February 2014. Of these patients, 2,152 patients with HFpEF (ejection fraction ≥40%) were investigated. The primary outcome was all-cause mortality according to beta-blocker use. RESULTS: During a median follow-up duration of 807 days, 702 patients died. In Cox proportional hazards model beta-blocker use was associated with a 14% reduced all-cause death (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), but not with reduce rehospitalization (HR, 1.03; 95% CI, 0.85–1.27). In the propensity-score matched population, beta-blockers were also associated with reduced all-cause death (HR, 0.80; 95% CI, 0.69–0.94) but not with reduced rehospitalization (HR, 1.08; 95% CI, 0.87–1.33). CONCLUSIONS: In Korean patients with HFpEF, use of beta-blockers is associated with reduced all-cause death but not with reduced rehospitalization.
Cohort Studies ; Diastole ; Follow-Up Studies ; Heart Failure ; Heart ; Hospitals, University ; Humans ; Korea ; Mortality ; Proportional Hazards Models ; Prospective Studies

BACKGROUND AND OBJECTIVES: Conflicting data exist regarding the prognostic implication of ventricular conduction disturbance pattern in patients with heart failure (HF). This study investigated the prognostic impact of ventricular conduction pattern in hospitalized patients with acute HF. METHODS: Data from the Korean Acute Heart Failure registry were used. Patients were categorized into four groups: narrow QRS (<120 ms), right bundle branch block (RBBB), left bundle branch block (LBBB), and nonspecific intraventricular conduction delay (NICD). The NICD was defined as prolonged QRS (≥120 ms) without typical features of LBBB or RBBB. The primary endpoint was the composite of all-cause mortality or rehospitalization for HF aggravation within 1 year after discharge. RESULTS: This study included 5,157 patients. The primary endpoint occurred in 39.7% of study population. The LBBB group showed the highest incidence of primary endpoint followed by NICD, RBBB, and narrow QRS groups (52.5% vs. 49.7% vs. 44.4% vs. 37.5%, p<0.001). In a multivariable Cox-proportional hazards regression analysis, LBBB and NICD were associated with 39% and 28% increased risk for primary endpoint (LBBB hazard ratio [HR], 1.392; 95% confidence interval [CI], 1.152–1.681; NICD HR, 1.278; 95% CI, 1.074–1.520) compared with narrow QRS group. The HR of RBBB for the primary endpoint was 1.103 (95% CI, 0.915–1.329). CONCLUSIONS: LBBB and NICD were independently associated with an increased risk of 1-year adverse event in hospitalized patients with HF, whereas the prognostic impacts of RBBB were limited. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843
Bundle-Branch Block ; Heart Failure ; Heart ; Humans ; Incidence ; Mortality ; Prognosis

BACKGROUND AND OBJECTIVES: Conflicting data exist regarding the prognostic implication of ventricular conduction disturbance pattern in patients with heart failure (HF). This study investigated the prognostic impact of ventricular conduction pattern in hospitalized patients with acute HF. METHODS: Data from the Korean Acute Heart Failure registry were used. Patients were categorized into four groups: narrow QRS (<120 ms), right bundle branch block (RBBB), left bundle branch block (LBBB), and nonspecific intraventricular conduction delay (NICD). The NICD was defined as prolonged QRS (≥120 ms) without typical features of LBBB or RBBB. The primary endpoint was the composite of all-cause mortality or rehospitalization for HF aggravation within 1 year after discharge. RESULTS: This study included 5,157 patients. The primary endpoint occurred in 39.7% of study population. The LBBB group showed the highest incidence of primary endpoint followed by NICD, RBBB, and narrow QRS groups (52.5% vs. 49.7% vs. 44.4% vs. 37.5%, p<0.001). In a multivariable Cox-proportional hazards regression analysis, LBBB and NICD were associated with 39% and 28% increased risk for primary endpoint (LBBB hazard ratio [HR], 1.392; 95% confidence interval [CI], 1.152–1.681; NICD HR, 1.278; 95% CI, 1.074–1.520) compared with narrow QRS group. The HR of RBBB for the primary endpoint was 1.103 (95% CI, 0.915–1.329). CONCLUSIONS LBBB and NICD were independently associated with an increased risk of 1-year adverse event in hospitalized patients with HF, whereas the prognostic impacts of RBBB were limited.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843