Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy.

Myotonic dystrophy (DM) is caused by expansions of C(C)TG repeats in the non-coding regions of the DMPK and CNBP genes, and DM patients often suffer from sudden cardiac death due to lethal conduction block or arrhythmia. Specific molecular changes that underlie DM cardiac pathology have been linked to repeat-associated depletion of Muscleblind-like (MBNL) 1 and 2 proteins and upregulation of CUGBP, Elav-like family member 1 (CELF1). Hypothesis solely targeting MBNL1 or CELF1 pathways that could address all the consequences of repeat expansion in heart remained inconclusive, particularly when the direct cause of mortality and results of transcriptome analyses remained undetermined in Mbnl compound knockout (KO) mice with cardiac phenotypes. Here, we develop Myh6-Cre double KO (DKO) (Mbnl1-/-; Mbnl2cond/cond; Myh6-Cre+/-) mice to eliminate Mbnl1/2 in cardiomyocytes and observe spontaneous lethal cardiac events under no anesthesia. RNA sequencing recapitulates DM heart spliceopathy and shows gene expression changes that were previously undescribed in DM heart studies. Notably, immunoblotting reveals a nearly 6-fold increase of Calsequestrin 1 and 50% reduction of epidermal growth factor proteins. Our findings demonstrate that complete ablation of MBNL1/2 in cardiomyocytes is essential for generating sudden death due to lethal cardiac rhythms and reveal potential mechanisms for DM heart pathogenesis.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

Comparison of two titration programmes for adding insulin detemir to oral antidiabetic drugs in patients with poorly controlled type 2 diabetes mellitus.

AIM: To explore the effect of active insulin titration versus usual titration on glycaemic control in patients with type 2 diabetes mellitus uncontrolled with oral antidiabetic drugs (OADs). METHODS: In a 24-week, prospective and randomized study, 172 patients with uncontrolled type 2 diabetes were randomly assigned to either active titration or usual titration. Efficacy and safety outcomes included changes in glycated haemoglobin (HbA1c) and fasting plasma glucose, percentage of individuals achieving HbA1c<53 mmol/mol, and hypoglycaemic events. RESULTS: At Week 24, change in HbA1c was -1.08% ± 1.60% in the active titration group and -0.95% ± 1.34% in the usual titration group (P = 0.569). The percentages of individuals achieving HbA1c<53 mmol/mol were 29.4% and 16.1% in the active and usual titration groups, respectively (P = 0.037). There was no significant difference in the incidence of hypoglycaemia between the two groups. Multivariate logistic regression indicated that, with active titration, baseline HbA1c levels and postprandial glucose excursion were significantly associated with achieving HbA1c<53 mmol/mol. CONCLUSION: Addition of basal insulin using active titration for 24 weeks provided a higher rate of HbA1c target achievement without significant hypoglycaemia compared to usual titration in individuals with uncontrolled type 2 diabetes.

Progression to myocardial infarction short-term death based on interval sequential pattern mining.

BACKGROUND: Myocardial infarction (MI) is one of the significant cardiovascular diseases (CVDs). According to Taiwanese health record analysis, the hazard rate reaches a peak in the initial year after diagnosis of MI, drops to a relatively low value, and maintains stable for the following years. Therefore, identifying suspicious comorbidity patterns of short-term death before the diagnosis may help achieve prolonged survival for MI patients. METHODS: Interval sequential pattern mining was applied with odds ratio to the hospitalization records from the Taiwan National Health Insurance Research Database to evaluate the disease progression and identify potential subjects at the earliest possible stage. RESULTS: Our analysis resulted in five disease pathways, including "diabetes mellitus," "other disorders of the urethra and urinary tract," "essential hypertension," "hypertensive heart disease," and "other forms of chronic ischemic heart disease" that led to short-term death after MI diagnosis, and these pathways covered half of the cohort. CONCLUSION: We explored the possibility of establishing trajectory patterns to identify the high-risk population of early mortality after MI.

Development and Validation of a Novel Risk Score for All-Cause Mortality Risk Stratification Prior to Permanent Pacemaker Implantation in Octogenarians or Older.

Background and Objectives: The demand for permanent pacemaker (PPM) implantation for extremely old patients is increasing. Prior to implanting PPMs, life expectancy evaluation is essential but difficult. We aimed to develop and validate a scoring system for all-cause mortality risk stratification prior to PPM implantation in patients aged ≥80. Materials and Methods: A total of 210 patients aged ≥80 who received PPM implantation were included. Multivariable analysis was performed to assess the effects of different variables on all-cause mortality in a derivation cohort (n = 100). We developed the MELODY score for stratifying all-cause mortality prior to PPM implantation and tested the scoring system in a validation cohort (n = 102). Results: After 4.0 ± 2.7 years of follow-up, 54 patients (54%) had died. The 0.5-, 1- and 2-year all-cause mortality rates were 7%, 10% and 24%, respectively. The MELODY score based on body mass index <21 kg/m2 (HR: 2.21, 95% CI: 1.06-4.61), estimated glomerular filtration rate <30 mL/min/1.73 m2 (3.35, 1.77-6.35), length of hospitalization before PPM implantation >7 days (1.87, 1.02-3.43) and dyspnea as the major presenting symptom (1.90, 1.03-3.50) successfully distinguished patients at high risk of mortality. Patients with MELODY scores ≥3 had a higher risk of mortality compared to those with MELODY scores <3 (8.49, 4.24-17.00). The areas under the receiver operating characteristic curves in predicting 0.5, 1 and 2 years mortality rates were 0.86, 0.81 and 0.74, respectively. The predictive value of the model was confirmed in a validation cohort. Conclusions: The novel scoring system is a simple and effective tool for all-cause mortality risk stratification prior to PPM implantation in patients aged ≥80.

Stress Hyperphenylalaninemia Is Associated With Mortality in Cardiac ICU: Clinical Factors, Genetic Variants, and Pteridines.

OBJECTIVES: Hyperphenylalaninemia predicts poor outcomes in patients with cardiovascular disease. However, the prognostic value and factors associated with stress hyperphenylalaninemia (SHP) were unknown in critical patients in the cardiac ICU. DESIGN: Prospective observational study. SETTING: Single-center, cardiac ICU in Taiwan. PATIENTS: Patients over 20 years old with Acute Physiology And Chronic Health Evaluation II scores greater than or equal to 15 and/or ventilatory support in the cardiac ICU. INTERVENTIONS: We measured plasma phenylalanine levels serially during patients' stays in the ICU to investigate their prognostic value for 90-day mortality. Gene array was performed to identify genetic polymorphisms associated with SHP (phenylalanine level ≥ 11.2 µmol/dL) and to develop a Genetic Risk Score (GRS). We analyzed the associations between SHP and clinical factors and genetic variants and identified the correlation between pteridines and genetic variants. MEASUREMENTS AND MAIN RESULTS: The study enrolled 497 patients. Increased phenylalanine concentration was independently associated with increased mortality risk. Patients with SHP had a higher mortality risk compared with those without SHP (log rank = 41.13; p < 0.001). SHP was associated with hepatic and renal dysfunction and with genetic polymorphisms on the pathway of tetrahydrobiopterin (BH4) synthesis (CBR1 and AKR1C3) and recycling (PCBD2). Higher GRSs were associated with lower BH4 bioavailability in response to stress ( p < 0.05). In patients without SHP at baseline, those with GRSs gretaer than or equal to 2 had a higher frequency of developing SHP during the ICU stay (31.5% vs 16.1%; p = 0.001) and a higher mortality risk ( p = 0.004) compared with those with GRSs less than 2. In patients with SHP at baseline, genetic variants did not provide additional prognostic value. CONCLUSIONS: SHP in patients admitted to the ICU was associated with a worse prognosis. In patients without SHP, genetic polymorphisms associated with SHP measured using a GRS of greater than or equal to 2 was associated with the subsequent SHP and higher mortality risk.

Factors associated with elevated plasma phenylalanine in patients with heart failure.

Elevated phenylalanine has been observed in patients with advanced heart failure (HF) and in community cohorts at risk of HF, and has been shown to have prognostic value. This study aimed to explore the factors associated with elevated phenylalanine in HF patients. Mass spectrometry was performed on blood from 669 participants, including 75 normal controls and 594 HF patients (stages A, B, and C). We measured phenylalanine and associated degradation products on the catecholamine pathway, C-reactive protein, valerylcarnitine, methionine sulfoxide, estimated glomerular filtration rate (eGFR), and B-type natriuretic peptide. Longitudinal analysis was conducted on 61 stage C HF patients who had recovered systolic function after 1 year. Phenylalanine and tyrosine levels increased from normal through stages A, B and C. Cross-sectional analysis in patients at stage C showed that phenylalanine levels were related to total bilirubin, eGFR, valerylcarnitine, methionine sulfoxide, C-reactive protein, and male gender. Longitudinal analysis in the patients at stage C with recovered systolic function after 1 year revealed that phenylalanine, tyrosine, methionine sulfoxide, total bilirubin, and C-reactive protein levels significantly decreased from baseline to 12 months. Based on a generalized estimating equations analysis model with time interaction considered, the only significant factor associated with changes in phenylalanine was changes in C-reactive protein concentrations from baseline to 12 months [B (coefficient) = 0.81, P < 0.001] after adjusting for methionine sulfoxide and total bilirubin levels. In conclusion, phenylalanine levels respond sensitively to HF improvement. Our findings suggest that inflammation plays a pivotal role in the elevation of phenylalanine levels in patients with HF.

Relationship of symptom stress, care needs, social support, and meaning in life to quality of life in patients with heart failure from the acute to chronic stages: a longitudinal study.

BACKGROUND: Patients with heart failure (HF) experience continuous changes in symptom distress, care needs, social support, and meaning in life from acute decompensation to chronic phases. The longitudinal relationship between these four factors and quality of life (QOL) was not fully explored. AIMS: To simultaneously investigate the relationship between all factors and QOL from hospitalization to 6 months after discharge, and the impact of the changes in these factors on QOL at different time points. METHODS: A longitudinal design with panel research (4 time points) was used. From January 2017 to December 2019, patients hospitalized due to acute decompensated HF were consecutively enrolled and followed up for 6 months. Patients were interviewed with questionnaires assessing symptom distress, care needs, social support, meaning in life and QOL at hospitalization and 1, 3 and 6 months after discharge. RESULTS: A total of 184 patients completed 6 months of follow-up. From baseline to 6 months, QOL continuously improved along with decreases in symptoms and care needs, but increases in social support and meaning in life. Better QOL was associated with younger age, higher education level, economic independence, less symptom distress and care needs, and stronger meaning in life (p < 0.05). Compared with hospitalization, decreases in care needs and increases in meaning in life at 1, 3 and 6 months were associated with an increase in physical QOL (p < 0.01). The decrease in care needs and increase in meaning in life at 3 months were associated with an increase in mental QOL (p < 0.05). The increase in social support at 6 months was associated with increases in both physical and mental QOL (p < 0.01). Changes in symptom distress were not correlated with changes in QOL from baseline to all time points. In the multivariable analysis, these findings were independent of age, educational level and economic status. CONCLUSIONS: Although symptom distress is associated with QOL after acute decompensated HF, QOL cannot be improved only by improvement in symptoms. With differential duration of improvement in each factor, the integration of alleviation in care needs and strengthening in social support and meaning in life might provide additional benefits in QOL.

Therapeutic potential of cPLA2 inhibitor to counteract dilated-cardiomyopathy in cholesterol-treated H9C2 cardiomyocyte and MUNO rat.

BACKGROUND AND PURPOSE: The pathogenesis of cardiomyopathy in metabolically unhealthy obesity (MUO) has been well studied. However, the pathogenesis of cardiomyopathy typically associated with high cholesterol levels in metabolically unhealthy nonobesity (MUNO) remains unclear. We investigated whether cholesterol-generated LysoPCs contribute to cardiomyopathy and the role of cytosolic phospholipase A2 (cPLA2) inhibitor in cholesterol-induced MUNO. EXPERIMENTAL APPROACH: Cholesterol diet was performed in Sprague-Dawley rats that were fed either regular chow (C), or high cholesterol chow (HC), or HC diet with 10 % fructose in drinking water (HCF) for 12 weeks. LysoPCs levels were subsequently measured in rats and in MUNO human patients. The effects of cholesterol-mediated LysoPCs on cardiac injury, and the action of cPLA2 inhibitor, AACOCF3, were further assessed in H9C2 cardiomyocytes. KEY RESULTS: HC and HCF rats fed cholesterol diets demonstrated a MUNO-phenotype and cholesterol-induced dilated cardiomyopathy (DCM). Upregulated levels of LysoPCs were found in rat myocardium and the plasma in MUNO human patients. Further testing in H9C2 cardiomyocytes revealed that cholesterol-induced atrophy and death of cardiomyocytes was due to mitochondrial dysfunction and conditions favoring DCM (i.e. reduced mRNA expression of ANF, BNP, DSP, and atrogin-1), and that AACOCF3 counteracted the cholesterol-induced DCM phenotype. CONCLUSION AND IMPLICATIONS: Cholesterol-induced MUNO-DCM phenotype was counteracted by cPLA2 inhibitor, which is potentially useful for the treatment of LysoPCs-associated DCM in MUNO.

Decreases in Circulating Concentrations of Short-Chain Acylcarnitines are Associated with Systolic Function Improvement After Decompensated Heart Failure.

Impaired fatty acid metabolism is associated with heart failure (HF) prognosis. However, specific changes in acylcarnitine profiles and their potential clinical value have not been well explored in patients recovering from acute decompensation.This study recruited 79 HF patients hospitalized because of acute decompensation with a left ventricular ejection fraction (LVEF) of < 40% and 51 normal controls. Patients were dichotomized into two groups, namely, the "improved (IMP) " and the "non-improved (NIMP) " groups, as defined by the changes in LVEF from baseline to 12 months after discharge. Mass spectrometry was used to quantify the acylcarnitine concentrations at baseline and 6 and 12 months after discharge. The IMP and NIMP groups contained 42 and 37 patients, respectively. At baseline, HF patients had higher plasma concentrations of specific long-, medium-, and short-chain acylcarnitines compared to normal controls. From baseline to 12 months post-discharge, the IMP group showed significant decreases in long- and short-chain acylcarnitine concentrations, but significant increases in medium-chain acylcarnitines. In the NIMP group, none of the acylcarnitines significantly decreased, and significant increases were noted in long-, medium-, and short-chain acylcarnitines. Generalized estimating equations demonstrated that nine acylcarnitines could discriminate the IMP group from the NIMP group, including three long-chain (C18:1, C16, and C16:1) and six short-chain acylcarnitines (C5, C5-OH, C4, C4:1-DC, C3, and C2). After adjusting for age, the six short-chain acylcarnitines remained significant. Changes in short-chain acylcarnitine profiles are independently associated with the improvement in cardiac systolic function after acute decompensation.

Predictors of long-term survival prior to permanent pacemaker implantation in octogenarians or older.

BACKGROUND: There is an increased need for permanent pacemaker (PPM) implantation for older patients with multiple comorbidities. The current guidelines recommend that, before implanting PPM, clinicians should discuss life expectancy with patients and their families as part of the decision-making process. However, estimating individual life expectancy is always a challenge. AIMS: We investigated predictors of long-term survival prior to PPM implantation in patients aged 80 or older. METHODS AND RESULTS: From September 2004 to September 2015, 100 patients aged ≥ 80 years who received PPM implantation were included for retrospective survival analysis. The end point was all-cause mortality. Follow-up duration was 4.0 ± 2.7 years. By the end of the study, 54 patients (54%) had died. Of the 54 who died, 40 patients (74.1%) died of non-cardiac causes. Their survival rates at 1, 2, 3, 5, and 7 years were 90%, 76%, 54%, 32%, and 16%, respectively. Patients with a longer length of hospital stay before PPM implantation (LOS-B) [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.02-1.05, p < 0.001], estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 (HR 4.07, 95% CI 1.95-8.52, p < 0.001), body mass index (BMI) < 21 kg/m2 (HR 2.50, 95% CI 1.16-5.39, p = 0.02), and dyspnea as the major presenting symptom (HR 2.88, 95% CI 1.27-6.55, p = 0.01) were associated with lower cumulative survival. CONCLUSIONS: Longer LOS-B, lower eGFR and BMI, and dyspnea as the major presenting symptom are pre-PPM implantation predictors of long-term survival in patients aged 80 or older.

2019 Focused Update of the Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure.

Heart failure is a growing epidemic, especially in Taiwan because of the aging population. The 2016 Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry showed that the guideline-recommended therapies were prescribed suboptimally both at the time of hospital discharge and during follow-up. We, therefore, conducted this 2019 focused update of the guidelines of the Taiwan Society of Cardiology for the diagnosis and treatment of heart failure to reinforce the importance of new diagnostic and therapeutic modalities of heart failure. The 2019 focused update discusses new diagnostic criteria, pharmacotherapy, non-pharmacological management, and certain co-morbidities of heart failure. Angiotensin receptor neprilysin inhibitor and If channel inhibitor is introduced as new and recommended medical therapies. Latest criteria of cardiac resynchronization therapy, implantable cardioverter-defibrillator, heart transplantation, and ventricular assist device therapy are reviewed in the non-pharmacological management chapter. Co-morbidities in heart failure are discussed including chronic kidney disease, diabetes, chronic obstructive pulmonary disease, and sleep-disordered breathing. We also explain the adequate use of oxygen therapy and non-invasive ventilation in heart failure management. A particular chapter for chemotherapy-induced cardiac toxicity is incorporated in the focused update to emphasize the importance of its recognition and management. Lastly, implications from the TSOC-HFrEF registry and post-acute care of heart failure are discussed to highlight the importance of guideline-directed medical therapy and the benefits of multidisciplinary disease management programs. With guideline recommendations, we hope that the management of heart failure can be improved in our society.

Simplified plasma essential amino acid-based profiling provides metabolic information and prognostic value additive to traditional risk factors in heart failure.

In heart failure (HF), metabolic disturbances represent functional perturbations in peripheral tissues and also predict patient outcomes. This study developed a simplified essential amino acid-based profile and tested whether it could improve prognostication. Plasma essential amino acids and lipidomics were measured on 1084 participants. The initial cohort included 94 normal controls and 599 patients hospitalized due to acute/decompensated HF. The validation cohort included 391 HF patients. Patients were followed for composite events (death/HF related re-hospitalization) and were categorized into three groups: high risk type 1 (leucine ≥145 µM and phenylalanine ≥ 88.9 µM), high risk type 2 (leucine < 81.2 µM), and low risk (other). Types 1 and 2 were associated with higher event rates [hazard ratio (95% confidence intervals) = 1.88 (1.27-2.79) and 7.71 (4.97-11.9), respectively, p < 0.001]. Compared to the low-risk group, both types of high-risk patients were older and had lower blood pressure and estimated glomerular filtration rates, but higher B-type natriuretic peptides (BNP). In addition, type 1 was associated with more incompletely metabolized lipids in the blood; type 2 patients had lower body mass indexes, rates of using guideline-based medications, and levels of cholesterol, hemoglobin, and albumin. The prognostic value of types 1 and 2 remained significant after adjusting for age, BNP and other risk factors. The value of using high-risk types for prognosis was confirmed in the validation cohort. In conclusion, simplified essential amino acid-based profiling identified two high-risk populations and provided metabolic information and prognostic value additive to traditional risk factors.

Understanding the Epidemiology of Heart Failure to Improve Management Practices: An Asia-Pacific Perspective.

Heart failure (HF) is a major global healthcare problem with an estimated prevalence of approximately 26 million. In Asia-Pacific regions, HF is associated with a significant socioeconomic burden and high rates of hospital admission. Epidemiological data that could help to improve management approaches to address this burden in Asia-Pacific regions are limited, but suggest patients with HF in the Asia-Pacific are younger and have more severe signs and symptoms of HF than those of Western countries. However, local guidelines are based largely on the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines, which draw their evidence from studies where Western patients form the major demographic and patients from the Asia-Pacific region are underrepresented. Furthermore, regional differences in treatment practices likely affect patient outcomes. In the following review, we examine epidemiological data from existing regional registries, which indicate that these patients represent a distinct subpopulation of patients with HF. In addition, we highlight that patients with HF are under-treated in the region despite the existence of local guidelines. Finally, we provide suggestions on how data can be enriched throughout the region, which may positively affect local guidelines and improve management practices.

Indoxyl sulfate suppresses endothelial progenitor cell-mediated neovascularization.

Patients with chronic kidney disease have an increased prevalence of peripheral arterial disease. Endothelial progenitor cells (EPC) are pivotal in neovascularization, but their role in mediating peripheral arterial disease in chronic kidney disease is not fully known. Here we studied the impact of indoxyl sulfate, a protein-bound uremic toxin, on EPC function in response to tissue ischemia or cell hypoxia in mice that underwent subtotal nephrectomy or sham operation. At 16 weeks, unilateral hindlimb ischemia was induced in all. Four weeks later, subtotal nephrectomy mice had significantly increased plasma levels of indoxyl sulfate, reduced reperfusion, decreased EPC mobilization, and impaired neovascularization in ischemic hindlimbs compared with control mice. Treatment with AST-120, an oral adsorbent of uremic toxins, reversed these changes. Ischemia-induced protein expression including phospho-eNOS, phospho-STAT3, interleukin-10, and VEGF were significantly decreased in ischemic hindlimbs of subtotal nephrectomy mice versus control mice; all effects were reversed by AST-120. Subtotal nephrectomy mice fed a diet with indole for 12 weeks resulted in impaired neovascularization in ischemic hindlimbs; also reversed by AST-120. In cultured human EPCs, VEGF expression was increased in hypoxia through HIF-1α and interleukin-10/STAT3 signaling; effects suppressed by pretreatment with indoxyl sulfate. Moreover, indoxyl sulfate markedly attenuated hypoxia-induced EPC migration and tube formation. Thus, indoxyl sulfate may be a therapeutic target for EPC-rescue of impaired neovascularization in patients with chronic kidney disease and peripheral arterial disease.

Myocardial triglyceride content at 3 T cardiovascular magnetic resonance and left ventricular systolic function: a cross-sectional study in patients hospitalized with acute heart failure.

BACKGROUND: Increased myocardial triglyceride (TG) content has been recognized as a risk factor for cardiovascular disease. However, its relation with cardiac function in patients on recovery from acute heart failure (HF) remains unclear. In this cross-sectional study, we sought to investigate the association between myocardial TG content measured on magnetic resonance spectroscopy ((1)H-MRS) and left ventricular (LV) function assessed on cardiovascular magnetic resonance (CMR) in patients who were hospitalized with HF. METHODS: A total of 50 patients who were discharged after hospitalization for acute HF and 21 age- and sex-matched controls were included in the study. Myocardial TG content and LV parameters (function and mass) were measured on a 3.0 T MR scanner. Fatty acid (FA) and unsaturated fatty acid (UFA) content was normalized against water (W) using the LC-Model algorithm. The patient population was dichotomized according to the left ventricular ejection fraction (LVEF, <50% or ≥ 50%). RESULTS: H-MRS data were available for 48 patients and 21 controls. Of the 48 patients, 25 had a LVEF <50% (mean, 31.2%), whereas the remaining 23 had a normal LVEF (mean, 60.2%). Myocardial UFA/W ratio was found to differ significantly in patients with low LVEF, normal LVEF, and controls (0.79% vs. 0.21% vs. 0.14%, respectively, p = 0.02). The myocardial UFA/TG ratio was associated with LV mass (r = 0.39, p < 0.001) and modestly related to LV end-diastolic volume (LVEDV; r = 0.24, p = 0.039). We also identified negative correlations of the myocardial FA/TG ratio with both LV mass (r = -0.39, p < 0.001) and LVEDV (r = -0.24, p = 0.039). CONCLUSIONS: As compared with controls, patients who were discharged after hospitalization for acute HF had increased myocardial UFA content; furthermore, UFA was inversely related with LVEF, LV mass and, to a lesser extent, LVEDV. Our study may stimulate further research on the measure of myocardial UFA content by (1)H-MRS for outcome prediction. TRIAL REGISTRATION: ClinicalTrial.gov: NCT02378402 . Registered 27/02/2015.