Growth differentiation factor-15 and metabolic features in chronic heart failure: Insights from the SUPPORT Trial -GDF15 across the BMI spectrum.

BACKGROUND: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. METHODS: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 ± 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m2; n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [≥25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. RESULTS: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1-2.9]). CONCLUSIONS: In underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.

Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome.

AIMS: More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. METHODS AND RESULTS: We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants-whether they cause HI or DN via altered functional domains-and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). CONCLUSION: Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.

Continuous and Early Progression of Carotid Intima-Media Thickness after Radiotherapy for Head and Neck Cancer: 5-Year Prospective Observational Study.

INTRODUCTION: Radiation-induced carotid artery stenosis (RI-CS) is known as one of long-term side effects of radiotherapy for head and neck cancer (HNC). However, the clinical time course after irradiation has been poorly understood. We aimed to investigate the natural history of radiation-induced carotid atherosclerosis, comparing the patients who received radiotherapy for HNC with the patients who were treated without radiotherapy. METHODS: The patients who received treatment of HNC at Department of Otolaryngology, Head and Neck Surgery of Kyoto University Hospital, from November 2012 to July 2015 were enrolled. The patients were assigned into the RT group and the control group, depending on whether radiotherapy was planned or not. Annual carotid ultrasound was performed from the enrollment to 5 years. The increase of mean intima-media thickness (IMT) at common carotid artery from the enrollment (Δmean IMT) was evaluated. RESULTS: Fifty-six patients in the RT group and 25 patients in the control group were enrolled. From 5-year follow-up data, the significant higher increase of Δmean IMT was consistently observed in the RT group than in the control group after 2 years. The RT group presented a 7.8-fold increase of mean IMT compared to the control group (0.060 mm per year in the RT group and 0.008 mm per year in the control group). Cumulative incidence curves obtained from the analysis of all vessels revealed that the RT group presented higher incidence of Δmean IMT ≥0.25 mm than the control group (p < 0.01). In the RT group, the patients with mean IMT ≥1.0 mm at enrollment exhibited significantly higher incidence of Δmean IMT ≥0.25 mm than the patients with mean IMT <1.0 mm (p < 0.01). DISCUSSION: Radiotherapy for HNC induces continuous carotid mean IMT progression. The irradiated carotid arteries with mean IMT ≥1.0 mm before radiotherapy presented earlier IMT progression than those with mean IMT <1.0 mm.

Sex Differences in Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD).Methods and Results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69-0.82, P<0.001, and HR: 0.92, 95% CI: 0.84-1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002). CONCLUSIONS: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.

Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis.

AIMS: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. METHODS AND RESULTS: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively). CONCLUSION: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS.

The effect of the Original MethOd at pharmacy To ENhAnce Support for Health Improvement in the limited Japanese proficiency patients visiting local community pharmacy: A randomized controlled trial.

OBJECTIVES: With an increase in globalization, the number of non-native-speaking citizens and tourists visiting local pharmacies is rapidly growing worldwide, creating linguistic and sociological problems. The aim of this study is to compare the effect of adding our original method, Original MethOd at pharmacy To ENhAnce Support for Health Improvement (OMOTENASHI), to the conventional medication counselling method (CMC) when counselling non-Japanese patients at the pharmacy. METHODS: The OMOTENASHI consists of tools written in multiple languages and illustrations to clarify the effects and side effects, and to confirm patients' understanding. 71 non-Japanese patients were recruited and randomly assigned to the OMOTENASHI or to the CMC in a 1:1 ratio. Comprehension and satisfaction level were evaluated. RESULTS: The overall comprehension level was significantly higher in the OMOTENASHI than in the CMC (75% vs 38%, p = 0.002), with a prominent difference in the recognition of the name, effects, side effects, precautions, and how to deal with side effects of the prescribed medication. CONCLUSION: The OMOTENASHI to be a helpful tool in providing essential information to non-native-speaking patients. PRACTICE IMPLICATION: The study highlighted the need to ensure every patient's safety and interests, and to avoid disadvantages caused by limited language proficiency in the globalization era.

Differences in mortality and causes of death between STEMI and NSTEMI in the early and late phases after acute myocardial infarction.

BACKGROUND: The detailed causes of death in non-ST-segment-elevation myocardial infarction (NSTEMI) have not been adequately evaluated compared to those in ST-segment elevation myocardial infarction (STEMI). METHODS: The study population was 6,228 AMI patients who underwent percutaneous coronary intervention (STEMI: 4,625 patients and NSTEMI: 1,603 patients). The primary outcome was all-cause death. RESULTS: Within 6 months after AMI, the adjusted mortality risk was not significantly different between NSTEMI patients and STEMI patients (HR: 0.83, 95%CI: 0.67-1.03, P = 0.09). Regarding the causes of death within 6 months after AMI, mechanical complications more frequently occurred in STEMI patients than in NSTEMI patients, while proportions of post resuscitation status on arrival and heart failure were higher in in NSTEMI patients than in STEMI patients. Beyond 6 months after AMI, the adjusted mortality risk of NSTEMI relative to STEMI was not significantly different. (HR: 1.04, 95%CI: 0.90-1.20, P = 0.59). Regarding causes of death beyond 6 months after AMI, almost half of deaths were cardiovascular causes in both groups, and breakdown of causes of death was similar between NSTEMI and STEMI. CONCLUSION: The mortality risk within and beyond 6 months after AMI were not significantly different between STEMI patients and NSTEMI patients after adjusting confounders. Deaths due to post resuscitation status and heart failure were more frequent in NSTEMI within 6 months after AMI.

Changes in demographics, clinical practices and long-term outcomes of patients with ST segment-elevation myocardial infarction who underwent coronary revascularisation in the past two decades: cohort study.

OBJECTIVE: To evaluate changes in demographics, clinical practices and long-term clinical outcomes of patients with ST segment-elevation myocardial infarction (STEMI) before and beyond 2010. DESIGN: Multicentre retrospective cohort study. SETTING: The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) AMI Registries Wave-1 (2005-2007, 26 centres) and Wave-2 (2011-2013, 22 centres). PARTICIPANTS: 9001 patients with STEMI who underwent coronary revascularisation (Wave-1: 4278 patients, Wave-2: 4723 patients). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was all-cause death at 3 years. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, target vessel revascularisation, ischaemia-driven target vessel revascularisation, any coronary revascularisation and any ischaemia-driven coronary revascularisation. RESULTS: Patients in Wave-2 were older, more often had comorbidities and more often presented with cardiogenic shock than those in Wave-1. Patients in Wave-2 had shorter onset-to-balloon time and door-to-balloon time, were more frequently implanted drug-eluting stents, and received guideline-directed medication than those in Wave-1. The cumulative 3-year incidence of all-cause death was not significantly different between Wave-1 and Wave-2 (15.5% and 15.7%, p=0.77). The adjusted risk of all-cause death in Wave-2 relative to Wave-1 was not significant at 3 years (HR 0.92, 95% CI 0.83 to 1.03, p=0.14), but lower beyond 30 days (HR 0.86, 95% CI 0.75 to 0.98, p=0.03). The adjusted risks of Wave-2 relative to Wave-1 were significantly lower for definite stent thrombosis (HR 0.59, 95% CI 0.43 to 0.81, p=0.001) and for any coronary revascularisation (HR 0.75, 95% CI 0.69 to 0.81, p<0.001), but higher for major bleeding (HR 1.34, 95% CI 1.20 to 1.51, p=0.005). CONCLUSIONS: We could not demonstrate improvement in 3-year mortality risk from Wave-1 to Wave-2, but we found reduction in mortality risk beyond 30 days. We also found risk reduction for definite stent thrombosis and any coronary revascularisation, but an increase in the risk of major bleeding from Wave-1 to Wave-2.

ECG Changes Through Immunosuppressive Therapy Indicate Cardiac Abnormality in Anti-MDA5 Antibody-Positive Clinically Amyopathic Dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a dermatomyositis (DM)-specific antibody, is strongly associated with interstitial lung disease (ILD). Patients with idiopathic inflammatory myopathy (IIM) who are anti-MDA5 antibody positive [anti-MDA5 (+)] often experience chest symptoms during the active disease phase. These symptoms are primarily explained by respiratory failure; nevertheless, cardiac involvement can also be symptomatic. Thus, the aim of this study was to investigate cardiac involvement in anti-MDA5 (+) DM. A total of 63 patients with IIM who underwent electrocardiography (ECG) and ultrasound cardiography (UCG) during the active disease phase from 2016 to 2021 [anti-MDA5 (+) group, n = 21; anti-MDA5-negative (-) group, n = 42] were enrolled in the study, and their clinical charts were retrospectively reviewed. The ECG and UCG findings were compared between the anti-MDA5 (+) and anti-MDA5 (-) groups. All anti-MDA5 (+) patients had DM with ILD. The anti-MDA5 (+) group showed more frequent skin ulcerations and lower levels of leukocytes, muscle enzymes, and electrolytes (Na, K, Cl, and Ca) than the anti-MDA5 (-) group. According to the ECG findings obtained during the active disease phase, the T wave amplitudes were significantly lower for the anti-MDA5 (+) group than for the anti-MDA5 (-) group (I, II, and V4-6 lead; p < 0.01; aVF and V3, p < 0.05). However, the lower amplitudes were restored during the remission phase. Except for the E wave, A wave and Sep e', the UCG results showed no significant differences between the groups. Four patients with anti-MDA5 (+) DM had many leads with lower T wave and cardiac abnormalities (heart failure, diastolic dysfunction, myocarditis) on and after admission. Though anti-MDA5 (+) patients clinically improved after immunosuppressive therapy, some of their ECG findings did not fully recover in remission phase. In conclusion, anti-MDA5 (+) DM appears to show cardiac involvement (electrical activity and function) during the active phase. Further studies are necessary to clarify the actual cardiac condition and mechanism of these findings in patients with anti-MDA5 (+) DM.

Antihyperglycemic therapies and cardiovascular outcomes in patients with type 2 diabetes mellitus: State of the art and future directions.

Type 2 diabetes mellitus is a progressive chronic disease and is an established risk factor for cardiovascular disease. Until recently, the cardiovascular safety and efficacy of antihyperglycemic drugs remained uncertain. However, after the changes in regulatory guidance in 2008, a wealth of data has been generated, expanding the focus of the treatment of diabetes from blood glucose control to the prevention of macro-and microvascular complications and improvement in mortality. This article will review cardiovascular outcome trials of antihyperglycemic agents and provide overview of ongoing trials.

Diabetes Mellitus and Long-Term Risk for Heart Failure After Coronary Revascularization.

BACKGROUND: The effect of diabetes mellitus (DM) status on the long-term risk for heart failure (HF) in patients undergoing coronary revascularization has not been adequately evaluated.Methods and Results:In this study, 15,231 patients who underwent coronary revascularization in the CREDO-Kyoto Registry Cohort-2 were divided into 2 groups according to DM status (DM group: n=5,999; Non-DM group: n=9,232). The DM group was further divided into 2 groups according to insulin treatment (insulin-treated DM [ITDM]: n=1,353; non-insulin-treated DM [NITDM]: n=4,646). The primary outcome measure was HF hospitalization. The cumulative 5-year incidence of HF hospitalization was significantly higher in the DM than non-DM group (11.0% vs. 6.6%, respectively; log-rank P<0.0001), and in the ITDM than NITDM group (14.6% vs. 10.0%, respectively; log-rank P<0.0001). After adjusting for confounders, the increased risk of HF hospitalization with DM relative to non-DM remained significant (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.30-1.67, P<0.0001), whereas the risk associated with ITDM relative to NITDM was not significant (HR 1.17, 95% CI 0.96-1.43, P=0.12). CONCLUSIONS: The adjusted long-term risk for HF hospitalization after coronary revascularization was significantly higher in DM than non-DM patients, regardless of revascularization strategy, but did not differ between ITDM and NITDM patients.

Sodium-glucose Co-transporters-2 Inhibitors and Heart Failure: State of the Art Review and Future Potentials.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are progressive chronic diseases that increase the risk of mortality and have worse outcomes when they coexist. There has been a paucity of data on effective therapeutic measures that reduce the risk of HF in patients with T2DM. However, the issuance of the Food and Drug Administration guidance in 2008 generated data on several antihyperglycemic agents that show cardiovascular (CV) benefits beyond glucose lowering. Among them, sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a class of drug with proven robust benefits in modulating HF and kidney diseases in patients with T2DM. In this article, we reviewed the epidemiology, pathophysiology, prognosis, lifestyle management, and therapeutic options, especially SGLT2 inhibitors, for HF and T2DM.

Direct comparison of optical coherence tomography and high-definition 60-MHz intravascular ultrasound imaging of intra-procedural stent thrombosis in a patient with acute coronary syndrome.

An 80-year-old man with ST-segment elevation myocardial infraction underwent coronary stenting using an everolimus-eluting stent, which resulted in a good coronary flow with no residual stenosis. However, 10 min after final coronary angiography, the patient complained of chest discomfort and the ECG again showed ST elevation. Repeat coronary angiography revealed multiple contrast filling defects in the stent. High-definition 60-MHz intravascular ultrasound (IVUS) examination showed multiple low echoic structures inside the stent, though its visualization was not clear. We also conducted optical coherence tomography (OCT) for further investigation, which clearly delineated the outline of the thrombus. An additional balloon dilatation was performed at the site of the stented lesion, and the patient's chest discomfort was relieved, and the ECG was normalized. The clinical implication of this case is that very early phase of intra-stent thrombus is low-density and coarse, and its visualization is better in OCT than in high-definition 60 MHz IVUS.

Overview of oral antithrombotic treatment in elderly patients with atrial fibrillation.

Atrial fibrillation (AF) is an age-related arrhythmia, particularly affecting elderly patients. The ultimate goals in the treatment of AF are to improve prognosis and quality of life. Anticoagulants are effective for stroke prevention in AF patients, however, managing anticoagulation in elderly patients is especially challenging; requiring a comprehensive assessment of the patient and deep understanding of available therapies and doses to maximize the net benefit. This review summarizes available evidence on the efficacy and safety of anticoagulation therapy, and provides contemporary updates on the management of elderly patients with AF.

Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

BACKGROUND: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex. METHODS AND RESULTS: In IMPROVE-IT, patients with acute coronary syndrome and low-density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in IMPROVE-IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low-density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79-0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90-1.01; P=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71-0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87-1.02; P=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men. CONCLUSIONS: IMPROVE-IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid-lowering therapy to optimize cardiovascular outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF-TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. METHODS AND RESULTS: Twenty-one thousand one-hundred and five patients enrolled in the ENGAGE AF-TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (Ptrend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66-1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70-0.99]). The absolute risk difference in major bleeding (-82 events/10 000 pt-yrs) and in intracranial hemorrhage (-73 events/10 000 pt-yrs) both favored edoxaban over warfarin in older patients. CONCLUSIONS: Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.