The TIMI Study Group's Contributions to the Advancement of Cardiology --With Focus on Atherosclerotic Cardiovascular Disease--

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality across the world, warranting continuous research in this field. The elucidation of the atherogenesis mechanism is considered one of the most relevant scientific accomplishments of the last century. This has led to the clinical development of various novel therapeutic interventions for patients with or at risk of ASCVD, in which randomized clinical trials played a crucial role.The Thrombolysis in Myocardial Infarction (TIMI) Study Group was initially established to conduct a clinical trial studying thrombolysis for treatment of myocardial infarction. owever, over the years, the TIMI Study Group has expanded their research interests to include antithrombotic therapy, lipid lowering, anti-diabetes, anti-obesity, and even heart failure. By leading large-scale, international, randomized, controlled trials of novel therapeutics, the TIMI Study Group has helped shape the very practice of cardiovascular medicine for over a quarter of a century, and decades of research continue to provide future promise for further advancement. Through a mutual goal to improve the care of ASCVD patients, the Japanese scientific community has become one of the important contributors to the TIMI Study Group’s clinical research.In this review article, the authors aim to summarize major research lead by the TIMI Study Group in the ASCVD field

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

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 (P trend<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

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 ( 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

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

Controlling Factors of Volatile Organic Compounds in Cloud Water at the Summit of Mt. Fuji in the Free Troposphere during the Summer

2010年から2018年までの7月と8月に富士山頂（標高3,776 m）で大気および雲水を採取して、27種類の人為起源揮発性有機化合物 (AVOCs) （塩素化炭化水素16種、単環芳香族炭化水素8種、二環芳香族炭化水素3種）と6種類の生物起源揮発性有機化合物を分析した。雲水中VOCs （体積加重平均VOCs濃度：2.07 nM、n=159）の約9割はAVOCsであり、主成分はトルエンであった。これは富士山頂における大気中トルエン濃度が高いことを反映していた。雲水中AVOCs濃度は空気塊が大陸南部から輸送されたときに高く、最低濃度を示した海洋由来時の約1.5倍であった。雲水中トルエン濃度は総無機イオンの低下とともに指数関数的に減少した。雲水中クロロホルム、o-キシレン、リモネン濃度は大気中濃度とヘンリー定数から求めた計算値に比べて実測値は数倍高く、ヘンリー則からの予測値以上に濃縮されていた。疎水性が高いVOCsほど雲水に高濃縮されており、自由対流圏における雲水でもHULIS （フミン様物質）のような界面活性物質がVOCsの高濃縮に関与していることが示唆された。At the summit of Mt. Fuji in July and August from 2012 to 2018, 27 kinds of anthropogenic volatile organic compounds (AVOCs) and 6 types of biogenic volatile organic compounds (BVOCs) in the air and in cloud water were determined. AVOCs occupied about 90% of the VOCs in the cloud water (volume-weighted mean VOCs concentration: 2.07 nM, n=159) and the main component was toluene, reflecting its high concentration in the ambient air. The concentration of the AVOCs in the cloud water was high when the airmass was transported from the southern continent and was about 1.5 times higher than that when it came from the ocean. The concentration of toluene in the cloud water decreased exponentially with the increase in the total ion concentration. The concentrations of some VOCs such as chloroform, o-xylene, and limonen in the cloud water were several times higher than their Henry’s law predicted values. Among the chlorinated hydrocarbons, highly hydrophobic chloroform was more concentrated than dichloromethane in the cloud water. Atmospheric surfactants such as HULIS (Humic-like Substances) could affect the enrichment of the VOCs in the cloud water even in the free troposphere

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 ( 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

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&lt;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