Circulation Journal

Message From the Editor-in-Chief

Toyoaki Murohara

Released: July 25, 2017

[Advance Publication] Released: July 11, 2017

1063-1064

Bioresorbable Vascular Scaffolds　― Are We Facing a Time of Crisis or One of Breakthrough? ―

Jeehoon Kang, Jung-Kyu Han, Han-Mo Yang, Kyung Woo Park, Hyun-Jae Kang, Bon-Kwon Koo, Hyo-Soo Kim

Released: July 25, 2017

[Advance Publication] Released: July 06, 2017

1065-1074

Current 2nd-generation drug-eluting stents (DES) have dramatically improved clinical outcomes after percutaneous coronary intervention for coronary artery disease. However, DES implantation has major long-term limitations related to the permanent presence of foreign material in the coronary artery. Bioresorbable vascular scaffolds (BVS) were designed to overcome this limitation of permanent metal-based DES. However, because of immature manufacturing technology, BVS have several drawbacks, such as the thicker strut, poor deliverability, poor radio-opacity, poor radial strength, and cumbersome procedure to meet the principle of PSP (Preparation, Sizing, and Post-dilatation). Initial studies indicated that BVS outcomes were non-inferior to those of current DES and recent follow-up data of trials have revealed an additional critical drawback, higher rate of scaffold thrombosis, on the top of the existing limitations of BVS. Thus attention must be paid to the appropriate BVS-specific implantation protocols (i.e., PSP), as well as adequate intensity and duration of dual antiplatelet therapy. In any case, current BVS need further technical evolution to replace current metallic DES in routine clinical use.

Prognostic Value of Chronic Kidney Disease Measures in Patients With Cardiac Disease

Yejin Mok, Shoshana H. Ballew, Kunihiro Matsushita

Released: July 25, 2017

[Advance Publication] Released: July 06, 2017

1075-1084

Chronic kidney disease (CKD) is considered a global public health issue. The latest international clinical guideline emphasizes characterization of CKD with both glomerular filtration rate (GFR) and albuminuria. CKD is closely related to cardiac disease and increases the risk of adverse outcomes among patients with cardiovascular disease (CVD). Indeed, numerous studies have investigated the association of CKD measures with prognosis among patients with CVD, but most of them have focused on kidney function, with limited data on albuminuria. Consequently, although there are several risk prediction tools for patients with CVD incorporating kidney function, to our knowledge, none of them include albuminuria. Moreover, the selection of the kidney function measure (e.g., serum creatinine, creatinine-based estimated GFR, or blood urea nitrogen) in these tools is heterogeneous. In this review, we will summarize these aspects, as well as the burden of CKD in patients with CVD, in the current literature. We will also discuss potential mechanisms linking CKD to secondary events and consider future research directions. Given their clinical and public health importance, for CVD we will focus on 2 representative cardiac diseases: myocardial infarction and heart failure.

Noninvasive Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography　― Is This Just Another New Diagnostic Test or the Long-Awaited Game Changer? ―

Hiromasa Otake, Charles A. Taylor, Hitoshi Matsuo, Nobuhiro Tanaka, Takashi Akasaka

Released: July 25, 2017

[Advance Publication] Released: April 11, 2017

1085-1093

Despite the clinical importance of ischemia evaluation, obtaining fractional flow reserve (FFR) value has, heretofore, only been available during invasive cardiac catheterization. Although there is a clear linkage between morphology and physiology, a significant gap still exists. FFR derived from coronary computed tomography angiography (FFR_CT) is a novel method of quantifying the hemodynamic significance of coronary artery stenoses by translating morphological information into hemodynamic data. Improved diagnostic performance of FFR_CThas been repeatedly demonstrated in comparison with coronary computed tomography angiography alone with an invasive FFR reference standard. More recently, the potential benefit of this technology to safely defer non-indicated catheterizations and reduce healthcare costs has been established and indicates this technology may improve the management of patients with coronary artery disease. In this review, we summarize the scientific basis of FFR_CTand evidence from clinical trials, provide illustrative examples of clinical applications, discuss potential limitations, and outline avenues for future research.

QRS Score　― Possibilities and Limitations ―

Jun Kishihara, Junya Ako

Released: July 25, 2017

[Advance Publication] Released: July 04, 2017

1094-1095

Association Between Bathing and Sudden Death

Yoshio Tahara

Released: July 25, 2017

[Advance Publication] Released: July 11, 2017

1096-1097

Do We Expect Any Pleiotropic Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition for Reducing Cardiovascular Events Beyond Low-Density Lipoprotein Cholesterol Reduction?

Hayato Tada, Masa-aki Kawashiri, Masakazu Yamagishi

Released: July 25, 2017

[Advance Publication] Released: July 01, 2017

1098-1099

Yummy Food Is Made From Fat and Sugar

Shichiro Abe, Setsu Nishino, Tomoaki Kanaya, Teruo Inoue

Released: July 25, 2017

[Advance Publication] Released: July 04, 2017

1100-1101

Five-Year Outcomes of the First Pivotal Clinical Trial of Balloon-Expandable Transcatheter Aortic Valve Replacement in Japan (PREVAIL JAPAN)

Yoshiki Sawa, Morimasa Takayama, Tsuyoshi Goto, Shuichiro Takanashi, Tatsuhiko Komiya, Tetsuya Tobaru, Koichi Maeda, Toru Kuratani, Yasushi Sakata, on behalf of the PREVAIL JAPAN Investigators

Released: July 25, 2017

[Advance Publication] Released: March 17, 2017

1102-1107

Background:Transcatheter aortic valve replacement (TAVR) has been an alternative less invasive therapy for high-surgical risk/inoperable patients with aortic valve stenosis (AS) in Japan. We report 5-year outcomes of the first pivotal clinical trial of TAVR in Japan (PREVAIL JAPAN).

Methods and Results:A total of 64 patients with AS who were considered unsuitable candidates for surgery were enrolled at 3 centers in Japan (mean age: 84.3±6.1 years, female: 65.6%, STS score: 9.0±4.5%). Transfemoral approach (TF) and transapical approach (TA) was performed in 37 patients and 27 patients, respectively. At 5 years, freedom from all-cause death was 52.7% (TF: 51.3%, TA: 56.3%). Risk of all stroke at 5-year was 15.8% (TF: 8.9%, TA: 25.5%) and risk of major adverse cardiac and cerebrovascular events at 5 years was 58.0% (TF: 51.3%, TA: 69.2%). Mild or greater aortic regurgitation (AR) at 1 week was not associated with increased all-cause death at 5 years (69.1%) compared with none or trace AR (48.3%) (P=0.184). Patients with high STS score (>8) had higher mortality rate than those with low STS scores (≤8).

Conclusions:The 5-year data from PREVAIL JAPAN show the clinical benefit of TAVR and suggest that balloon-expandable TAVR is an effective treatment option for Japanese patients with severe AS who are not suitable for surgery. (Funded by Edwards Lifesciences Limited; ClinicalTrials.gov number, NCT01113983.)

Midterm Outcomes With a Self-Expandable Transcatheter Heart Valve in Japanese Patients With Symptomatic Severe Aortic Stenosis

Yoshiki Sawa, Kei Torikai, Junjiro Kobayashi, Hiroshi Niinami, Toru Kuratani, Koichi Maeda, Hideaki Kanzaki, Nobuyuki Komiyama, Yutaka Tanaka, Angie Zhang, Shigeru Saito

Released: July 25, 2017

[Advance Publication] Released: March 17, 2017

1108-1115

Background:Transcatheter aortic valve implantation (TAVI) is a viable alternative to surgical aortic valve replacement in high-risk or inoperable patients with aortic stenosis (AS). Here we report the midterm outcomes of high-risk Japanese patients with severe AS who underwent TAVI with a self-expandable TAV.

Methods and Results:The CoreValve Japan Trial was a prospective, multicenter trial of the CoreValve System. A group of 55 patients (mean age 82.5±5.5 years, 30.9% male, 100% NYHA class III/IV, STS 8.0±4.2%) were enrolled in the 26-mm/29-mm CoreValve study, and 20 patients (mean age 81.0±6.6 years, 5.0% male, 100% NYHA class III/IV, STS 7.0±3.3%) were enrolled in the 23-mm CoreValve study, which started 1 year later. For the 26-mm/29-mm cohort, the 3-year all-cause mortality rate was 32.6%; major stroke was 15.4%. Mean pressure gradient (MPG), effective orifice area (EOA), and NYHA class showed sustained improvement. Paravalvular regurgitation (PVR) at 3 years was 28.6% (none), 25.7% (trace), 40.0% (mild), 5.7% (moderate), and 0.0% (severe). For the 23-mm cohort, the 2-year all-cause mortality rate was 5.0%; major stroke was 5.0%. MPG, EOA, and NYHA class showed sustained improvement. PVR at 2 years was 16.7% (none), 33.3% (trace), 44.4% (mild), 5.6% (moderate), and 0.0% (severe).

Conclusions:TAVI with the CoreValve System was associated with sustained clinical and functional cardiac improvement in high surgical risk Japanese patients with severe AS. (Clinicaltrials.gov Identifiers: NCT01437098 and NCT01634269.)

AVJ-514 Trial　― Baseline Characteristics and 30-Day Outcomes Following MitraClip^® Treatment in a Japanese Cohort ―

Kentaro Hayashida, Satoshi Yasuda, Takashi Matsumoto, Makoto Amaki, Shingo Mizuno, Tetsuya Tobaru, Kentaro Jujo, Tatsushi Ootomo, Junichi Yamaguchi, Keiichi Fukuda, Shigeru Saito, Elyse Foster, Atif Qasim, Masafumi Kitakaze, Ryohei Yozu, Morimasa Takayama

Released: July 25, 2017

[Advance Publication] Released: March 17, 2017

1116-1122

Background:The MitraClip^®system is a transcatheter-based therapeutic option for patients with chronic mitral regurgitation (MR) who are at high risk for surgery. A prospective, multicenter, single-arm study was initiated to confirm the transferability of this system to Japan.

Methods and Results:Patients with symptomatic chronic moderate-to-severe (3+) or severe (4+) functional or degenerative MR with a Society of Thoracic Surgery (STS) score ≥8%, or the presence of 1 predefined risk factor were enrolled. Patients with left ventricular (LV) ejection fraction (EF) <30% were excluded. MR severity and LV function were assessed by an independent echocardiography core lab. Primary outcome included major adverse events (MAE) at 30 days and acute procedural success (APS). A total of 30 patients (age: 80±7 years; STS score: 10.3%±6.6%) were treated with the MitraClip^®. At baseline, all patients had MR 3+/4+ with 53%/47% patients with degenerative/functional etiology with mean LVEF of 50.2±12.8%, and 37% of patients were NYHA class III/IV. APS was achieved in 86.7% with no occurrence of MAE. At 30 days, 86.7% of patients had MR ≤2+ and 96.7% were NYHA class I/II.

Conclusions:The MitraClip^®procedure resulted in clinically meaningful improvements in MR severity, function and quality of life measures, and low MAE rates. These early results suggest the transferability of this therapy to appropriately selected Japanese patients. (Trial Registration: clinicaltrials.gov Identifier NCT02520310.)

Exercise Transcutaneous Oximetry of the Buttocks　― External Validation With Computed Tomography Angiography ―

Martin Audonnet, Isabelle Signolet, Christophe Colas-Ribas, Myriam Ammi, Pierre Abraham, Samir Henni

Released: July 25, 2017

[Advance Publication] Released: April 13, 2017

1123-1128

Background:Exercise transcutaneous oximetry (Ex-tcPO2) is a non-invasive test for exercise-induced buttock ischemia. Prior study defined Ex-tcPO2 normal/abnormal cut-offs against arteriography but no external validation was available. The aims of this study were therefore to (1) determine the diagnostic performance of Ex-tcPO2 against CTA; (2) determine the cut-off point for detection of stenosis >75% in arteries toward the hypogastric circulation; and (3) determine the effect of chest profile classification on the diagnostic performance of Ex-tcPO2.

Methods and Results:A total of 207 patients referred for Ex-tcPO2 were analyzed. DROP during Ex-tcPO2 was compared with the CTA results. Chest-tcPO2 changes were automatically classified into pre-defined profiles representing normal or abnormal responses. Using DROP <−15 mmHg as a cut-off, Ex-tcPO2 had 80.2% sensitivity, 72.3% specificity, 43.1% PPV, 93.3% NPV and 73.9% accuracy, to detect 1 stenosis >75% in arteries toward the hypogastric circulation. Optimal DROP to detect stenosis was: −15 mmHg. The overall diagnostic performance of Ex-tcPO2 was independent of chest profile classification.

Conclusions:Ex-tcPO2 has satisfactory diagnostic performance to detect arterial stenoses towards the hypogastric circulation. Abnormal chest-tcPO2 profile does not impair the overall diagnostic performance of the test.

QRS Score at Presentation Electrocardiogram Is Correlated With Infarct Size and Mortality in ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention

Hiroki Shiomi, Masami Kosuge, Takeshi Morimoto, Hiroki Watanabe, Tomohiko Taniguchi, Kenji Nakatsuma, Toshiaki Toyota, Erika Yamamoto, Satoshi Shizuta, Tomohisa Tada, Yutaka Furukawa, Yoshihisa Nakagawa, Kenji Ando, Kazushige Kadota, Kazuo Kimura, Takeshi Kimura, on behalf of the CREDO-Kyoto AMI Investigators

Released: July 25, 2017

[Advance Publication] Released: April 05, 2017

1129-1136

Background:In ST-segment elevation myocardial infarction (STEMI), QRS score at presentation ECG may reflect the progression of infarction and facilitate prediction of the degree of myocardial salvage achieved by reperfusion therapy.

Methods and Results:Admission electrocardiogram (ECG) was studied in 2,607 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) within 24 h of symptom onset. Patients were classified into 3 groups according to QRS score: low (0–3, n=1,227), intermediate (4–7, n=810), and high (≥8, n=570). An increase of infarct size estimated by median peak creatine phosphokinase was observed as QRS score increased (low score, 1,836 IU/L; inter-quartile range (IQR), 979–3,190 IU/L; intermediate score, 2,488 IU/L; IQR, 1,126–4,640 IU/L; high score, 3,454 IU/L; IQR, 1,759–5,639 IU/L; P<0.001). Higher QRS score was associated with higher long-term mortality (low, intermediate, and high score, 15.6%, 19.7%, and 23.7% at 5 years, respectively; log-rank P<0.001). The positive relationship of QRS score with mortality was consistently seen when stratified by infarct location. The association of high QRS score with increased mortality was most remarkably seen in patients with early (≤2 h) presentation (low, intermediate, and high score: 16.7%, 16.6%, and 28.1% at 5 years, respectively; log-rank P<0.001).

Conclusions:Higher QRS score at presentation ECG was associated with larger infarct size, and higher long-term mortality in patients with STEMI undergoing primary PCI. QRS score appears to be important in the early risk stratification for STEMI.

Efficacy of Precordial Percussion Pacing Assessed in a Cardiac Standstill Microminipig Model

Takeshi Wada, Hiroshi Ohara, Yuji Nakamura, Xin Cao, Hiroko Izumi-Nakaseko, Kentaro Ando, Mitsuru Honda, Katsunori Yoshihara, Yuji Nakazato, Keith G. Lurie, Atsushi Sugiyama

Released: July 25, 2017

[Advance Publication] Released: April 04, 2017

1137-1143

Background:Potential cardiovascular benefits of precordial percussion pacing (PPP) during cardiac standstill are unknown.

Methods and Results:A cardiac standstill model in amicrominipigwas created by inducing complete atrioventricular block with a catheter ablation technique (n=7). Next, the efficacy of cardiopulmonary resuscitation by standard chest compressions (S-CPR), PPP and ventricular electrical pacing in this model were analyzed in series (n=4). To assess the mechanism of PPP, a non-selective, stretch-activated channel blocker, amiloride, was administered during PPP (n=3). Peak systolic and diastolic arterial pressures during S-CPR, PPP and ventricular electrical pacing were statistically similar. However, the duration of developed arterial pressure with PPP was comparable to that with ventricular electrical pacing, and significantly greater than that with S-CPR. Amiloride decreased the induction rate of ventricular electrical activity by PPP in a dose-related manner. Each animal survived without any neurological deficit at 24, 48 h and 1 week, even with up to 2 h of continuous PPP.

Conclusions:In amicrominipigmodel of cardiac standstill, PPP can become a novel means to significantly improve physiological outcomes after cardiac standstill or symptomatic bradyarrhythmias in the absence of cardiac pacing. Activation of the non-selective stretch-activated channels may mediate some of the mechanophysiological effects of PPP. Further study of PPP by itself and together with S-CPR is warranted using cardiac arrest models of atrioventricular block and asystole.

Sudden Death Phenomenon While Bathing in Japan　― Mortality Data ―

Masaru Suzuki, Takuro Shimbo, Toshiharu Ikaga, Shingo Hori

Released: July 25, 2017

[Advance Publication] Released: April 08, 2017

1144-1149

Background:Bath-related sudden cardiac arrest frequently occurs in Japan, but the mortality data have not been sufficiently reported.

Methods and Results:This prospective cross-sectional observational study was conducted in the Tokyo Metropolis, Saga Prefecture and Yamagata Prefecture between October 2012 and March 2013 (i.e., in winter). We investigated the data for all occurrences in these areas for which the emergency medical system needed to be activated because of an accident or acute illness related to bathing. Emergency personnel enrolled the event when activation of the emergency medical system was related to bathing. Of the 4,599 registered bath-related events, 1,527 (33%) were identified as bath-related cardiac arrest events. Crude mortality (no. deaths per 100,000) during the observational period was 10.0 in Tokyo, 11.6 in Yamagata and 8.5 in Saga. According to the mortality data for age and sex, the estimated number of bath-related deaths nationwide was 13,369 in winter, for the 6 months from October (95% CI: 10,862–16,887). Most cardiac arrest events occurred in tubs filled with water with the face submerged in the water. This suggests that drowning plays a crucial role in the etiology of such phenomena.

Conclusions:The estimated nationwide number of deaths was 13,369 (95% CI: 10,862–16,887) in winter, for the 6 months from October. Crude mortality during the winter season was 10.0 in Tokyo, 11.6 in Yamagata and 8.5 in Saga.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　― Systematic Review and Meta-Analysis of Prospective Studies ―

Yunjun Xiao, Chaoqiong Peng, Wei Huang, Jinzhou Zhang, Yang Gao, Jean H. Kim, Eng-kiong Yeoh, Xuefen Su

Released: July 25, 2017

[Advance Publication] Released: April 11, 2017

1150-1157

Background:Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies.

Methods and Results:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models. On meta-analysis of 6 cohort and 1 nested case-control study, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events (overall RR, 1.12; 95% CI: 0.98–1.29; P=0.09), with significant heterogeneity (I²=55.1%, P_{heterogeneity}=0.038). The highest but not middle categories of circulating PCSK9 was significantly associated with the risk of cardiovascular events. On subgroup analysis of study design, mean age at baseline, sample size, follow-up time, and pre-existing disease, there was no significant association between PCSK9 and cardiovascular events. Sensitivity analysis with various exclusion and inclusion criteria did not materially change the results.

Conclusions:Circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events. More well-designed studies are needed to clarify the role of PCSK9 in cardiovascular risk.

Risk of Ischemic Stroke in Patients With Non-Valvular Atrial Fibrillation Not Receiving Oral Anticoagulants　― Korean Nationwide Population-Based Study ―

Si-Hyuck Kang, Eue-Keun Choi, Kyung-Do Han, So-Ryoung Lee, Woo-Hyun Lim, Myung-Jin Cha, Youngjin Cho, Il-Young Oh, Seil Oh

Released: July 25, 2017

[Advance Publication] Released: April 12, 2017

1158-1164

Background:Atrial fibrillation, the most common cardiac arrhythmia, is associated with an elevated thromboembolic risk, including ischemic stroke. Guidelines recommend the stratification of individual stroke risk and tailored antithrombotic therapy. This study investigated the demographics, comorbidities, and prognosis of non-valvular AF (NVAF) in Korean patients.

Methods and Results:We extracted data on 10,846 patients with newly diagnosed NVAF who were naïve to oral anticoagulants from the National Health Insurance Service-National Sample Cohort. CHADS₂and CHA₂DS₂-VASc scores were calculated for each subject using claims data. The study endpoints were ischemic stroke, thromboembolism, and mortality. Mean age was 63.7 years, and 46.8% of the patients were women. Women were older and had higher CHADS₂and CHA₂DS₂-VASc scores. During 30,138 person-years of follow-up, ischemic stroke occurred at a rate of 2.95/100 person-years. CHADS₂and CHA₂DS₂-VASc scores showed good performance in risk prediction. CHA₂DS₂-VASc score performed better at discriminating stroke risk in patients with low-risk profiles. The presence of female sex and vascular disease added little improvement in risk prediction.

Conclusions:Korean NVAF patients had high risk of stroke and mortality, and had multiple comorbidities. While both CHADS₂and CHA₂DS₂-VASc schema had good performance in risk prediction, CHA₂DS₂-VASc score was superior in identifying truly low-risk patients. Given that Asian ethnicity is associated with bleeding events, individualized accurate risk prediction is necessary to improve patient outcomes.

Coronary Atherosclerotic Plaque Characteristics and Cardiovascular Risk Factors　― Insights From an Optical Coherence Tomography Study ―

Roberta De Rosa, Mariuca Vasa-Nicotera, David M. Leistner, Sophia M. Reis, Claudia E. Thome, Jes-Niels Boeckel, Stephan Fichtlscherer, Andreas M. Zeiher

Released: July 25, 2017

[Advance Publication] Released: April 14, 2017

1165-1173

Background:The association between cardiovascular risk factors (CVRF) and the risk of coronary events is widely acknowledged. Whether individual risk factors may be associated with distinct plaque characteristics is currently unclear. We investigated the relationship between CVRF and coronary plaque burden and phenotype.

Methods and Results:We assessed coronary atherosclerotic plaque characteristics by optical coherence tomography in 67 patients with stable coronary artery disease undergoing coronary angiography. The plaque burden and the distinct plaque phenotypes were compared with regard to different CVRF. Overall plaque burden was significantly greater in patients with diabetes mellitus (P=0.010), prediabetes (P=0.035) and obesity (P=0.024), and correlated with the number of CVRF (R=0.358, P=0.003). Patients with diabetes had a greater extent of fibroatheroma (P=0.015), calcific fibroatheroma (P=0.031), thin-cap fibroatheroma (TCFA-P=0.011) and plaque erosion (P=0.002). Obese patients showed a greater extent of fibroatheroma (P=0.007), TCFA (P=0.015) and macrophage load (P=0.043). The number of CVRF correlated with fibroatheroma (R=0.425, P<0.001), calcific fibroatheroma (R=0.321, P=0.008), TCFA (R=0.347, P=0.004), macrophage load (R=0.314, P=0.010) and erosion (R=0.271, P=0.029). In the multivariate analysis, altered glycemic status and obesity were the only independent predictors of TCFA (P=0.026 and P=0.046, respectively), whereas altered glycemic status was the only independent predictor of plaque erosion (P=0.001).

Conclusions:Patients with diabetes, prediabetes and obesity show more extensive coronary atherosclerosis and more vulnerable plaque phenotypes.

Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction

Koichiro Fujisue, Koichi Sugamura, Hirofumi Kurokawa, Junichi Matsubara, Masanobu Ishii, Yasuhiro Izumiya, Koichi Kaikita, Seigo Sugiyama

Released: July 25, 2017

[Advance Publication] Released: April 18, 2017

1174-1182

Background:Several studies have reported that colchicine attenuated the infarct size and inflammation in acute myocardial infarction (MI). However, the sustained benefit of colchicine administration on survival and cardiac function after MI is unknown. It was hypothesized that the short-term treatment with colchicine could improve survival and cardiac function during the recovery phase of MI.

Methods and Results:MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then orally administered colchicine 0.1 mg/kg/day or vehicle from 1 h to day 7 after MI. Colchicine significantly improved survival rate (colchicine, n=48: 89.6% vs. vehicle, n=51: 70.6%, P<0.01), left ventricular end-diastolic diameter (5.0±0.2 vs. 5.6±0.2 mm, P<0.05) and ejection fraction (41.5±2.1 vs. 23.8±3.1%, P<0.001), as assessed by echocardiogram compared with vehicle at 4 weeks after MI. Heart failure development as pulmonary edema assessed by wet/dry lung weight ratio (5.0±0.1 vs. 5.5±0.2, P<0.01) and B-type natriuretic peptide expression in the heart was attenuated in the colchicine group at 4 weeks after MI. Histological and gene expression analysis revealed colchicine significantly inhibited the infiltration of neutrophils and macrophages, and attenuated the mRNA expression of pro-inflammatory cytokines and NLRP3 inflammasome components in the infarcted myocardium at 24 h after MI.

Conclusions:Short-term treatment with colchicine successfully attenuated pro-inflammatory cytokines and NLRP3 inflammasome, and improved cardiac function, heart failure, and survival after MI.

Chromium Exposure and Risk of Cardiovascular Disease in High Cardiovascular Risk Subjects　― Nested Case-Control Study in the Prevention With Mediterranean Diet (PREDIMED) Study ―

Mario Gutiérrez-Bedmar, Miguel Ángel Martínez-González, Carlos Muñoz-Bravo, Miguel Ruiz-Canela, Alberto Mariscal, Jordi Salas-Salvadó, Ramón Estruch, Dolores Corella, Fernando Arós, Monserrat Fito, José Lapetra, Lluís Serra-Majem, Xavier Pintó, Ángel Alonso-Gómez, Olga Portoles, Miquel Fiol, Mónica Bulló, Olga Castañer, Emilio Ros, Enrique Gómez-Gracia

Released: July 25, 2017

[Advance Publication] Released: April 08, 2017

1183-1190

Background:Epidemiological data on chromium (Cr) exposure and the risk of cardiovascular disease (CVD) are still limited. Toenail Cr level (TCL) provides a time-integrated measure reflecting long-term Cr exposure. We measured TCL to assess the hypothesis that long-term Cr exposure was inversely associated with incident CVD in a population at high risk for CVD.

Methods and Results:The associations between TCL and CVD were evaluated in a case-control study nested within the “PREvención con DIeta MEDiterránea” (PREDIMED) trial. We randomly selected 147 of the 288 patients diagnosed with CVD during follow-up and matched them on age and sex to 271 controls. Instrumental neutron activation analysis was used to assess TCL. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. The fully adjusted OR for the highest vs. lowest quartile of toenail Cr was 0.54 (95% CI: 0.26–1.14; P_trend=0.189) for the nested case-control study. On stratification for diabetes mellitus (DM), OR was 1.37 (95% CI: 0.54–3.46; P_trend=0.364) for the DM group, and 0.25 (95% CI: 0.08–0.80; P_trend=0.030) for the non-DM group (P for interaction=0.078).

Conclusions:The present findings, although not statistically significant, are consistent with previously reported inverse associations between TCL and CVD. These results, especially for non-DM patients, increase the limited epidemiological knowledge about the possible protective role of Cr against CVD. (Trial registration: www.controlled-trials.com; ISRCTN35739639.)

Association of Kidney Dysfunction With Asymptomatic Cerebrovascular Abnormalities in a Japanese Population With Health Checkups

Kaori Hayashi, Michiyo Takayama, Takeshi Kanda, Kazuhiro Kashiwagi, Akihito Hishikawa, Yasushi Iwao, Hiroshi Itoh

Released: July 25, 2017

[Advance Publication] Released: April 14, 2017

1191-1197

Background:Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.

Methods and Results:In total, 1,716 subjects aged 40–80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima–media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m²was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs.

Conclusions:Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.

Comparison of the Long-Term Outcomes of Mechanical and Bioprosthetic Aortic Valves　― A Propensity Score Analysis ―

Kenji Minakata, Shiro Tanaka, Nobushige Tamura, Shigeki Yanagi, Yohei Ohkawa, Shuichi Okonogi, Tatsuo Kaneko, Akihiko Usui, Tomonobu Abe, Mitsuomi Shimamoto, Yoshiharu Takahara, Kazuo Yamanaka, Hitoshi Yaku, Ryuzo Sakata

Released: July 25, 2017

[Advance Publication] Released: April 12, 2017

1198-1206

Background:The aim of this study was to assess the long-term outcomes of aortic valve replacement (AVR) with either mechanical or bioprosthetic valves according to age at operation.

Methods and Results:A total of 1,002 patients (527 mechanical valves and 475 bioprosthetic valves) undergoing first-time AVR were categorized according to age at operation: group Y, age <60 years; group M, age 60–69 years; and group O, age ≥70 years). Outcomes were compared on propensity score analysis (adjusted for 28 variables). Hazard ratio (HR) was calculated using the Cox regression model with adjustment for propensity score with bioprosthetic valve as a reference (HR=1). There were no significant differences in overall mortality between mechanical and bioprosthetic valves for all age groups. Valve-related mortality was significantly higher for mechanical valves in group O (HR, 2.53; P=0.02). Reoperation rate was significantly lower for mechanical valves in group Y (HR, 0.16; P<0.01) and group M (no events for mechanical valves). Although the rate of thromboembolic events was higher in mechanical valves in group Y (no events for tissue valves) and group M (HR, 9.05; P=0.03), there were no significant differences in bleeding events between all age groups.

Conclusions:The type of prosthetic valve used in AVR does not significantly influence overall mortality.

Rate of Stenotic Bicuspid Aortic Valve Aortic Dilatation After Aortic Valve Replacement, Calculated Using a 3-Dimensional Reconstruction Tool

Kaoru Hattori, Ikuo Fukuda, Kazuyuki Daitoku, Masahito Minakawa, Hiroyuki Itaya

Released: July 25, 2017

[Advance Publication] Released: March 31, 2017

1207-1212

Background:Progression of asymmetric dilated aorta associated with bicuspid aortic valve (BAV) is difficult to evaluate conventionally. The aim of the study was to calculate the rate of progression of the dilated BAV aorta after aortic valve replacement (AVR) using a 3-dimensional (3-D) reconstruction tool.

Methods and Results:Fourteen stenotic BAV and 14 stenotic tricuspid aortic valve (TAV) patients with mildly dilated ascending aorta were reviewed. A patient-specific 3-D aortic model was reconstructed from preoperative and postoperative computed tomography data (BAV, 2.5±1.9 years after AVR; TAV, 2.2±1.8 years after AVR). Aortic diameter, including the longest and shortest, was measured on the maximum perpendicular cross-section tangential to the 3-D centerline of the reconstructed model. The longest diameter was defined as that passing through the distal point of the greater curvature of the aorta. The shortest diameter was defined as perpendicular to the longest. The progression rates were compared between the BAV and TAV groups. The progression rate of ascending aortic diameter was greater for BAV (longest diameter, 1.02±1.03 vs. −0.075±0.78 mm/year, P<0.001; shortest diameter, 0.41±0.62 vs. −0.016±0.59 mm/year, P=0.003). The longest diameter of the proximal arch also grew more rapidly in the BAV group (P<0.001).

Conclusions:Ascending aortic dilatation with stenotic BAV progresses after AVR at a maximum rate of 1.02±1.03 mm/year. Expansion toward the greater curvature frequently progresses to the proximal arch.

Sex Differences in Severe Aortic Stenosis　― Clinical Presentation and Mortality ―

Mamoru Toyofuku, Tomohiko Taniguchi, Takeshi Morimoto, Kyohei Yamaji, Yutaka Furukawa, Kosuke Takahashi, Takashi Tamura, Hiroki Shiomi, Kenji Ando, Norio Kanamori, Koichiro Murata, Takeshi Kitai, Yuichi Kawase, Chisato Izumi, Makoto Miyake, Hirokazu Mitsuoka, Masashi Kato, Yutaka Hirano, Shintaro Matsuda, Tsukasa Inada, Tomoyuki Murakami, Yasuyo Takeuchi, Keiichiro Yamane, Mitsuru Ishii, Eri Minamino-Muta, Takao Kato, Moriaki Inoko, Tomoyuki Ikeda, Akihiro Komasa, Katsuhisa Ishii, Kozo Hotta, Nobuya Higashitani, Yoshihiro Kato, Yasutaka Inuzuka, Chiyo Maeda, Toshikazu Jinnai, Yuko Morikami, Naritatsu Saito, Kenji Minatoya, Takeshi Kimura, on behalf of the CURRENT AS Registry Investigators

Released: July 25, 2017

[Advance Publication] Released: April 08, 2017

1213-1221

Background:There is a paucity of data on the sex differences in the prevalence, clinical presentation, and prognosis of aortic stenosis (AS).

Methods and Results:A total of 3,815 consecutive patients with severe AS were enrolled in the multicenter CURRENT AS registry between January 2003 and December 2011. The registry included 1,443 men (38%) and 2,372 women (62%). Women were much older than men (79±10 vs. 75±10 years, P<0.0001), and the ratio of women to men increased with age. The cumulative 5-year incidence of all-cause death was significantly higher in men than in women (47% vs. 41%, P=0.003), although women were more symptomatic and much older. The 5-year mortality was similar between men and women at age <65 years (16% vs. 15%, P=0.99), whereas it was significantly higher in men than in women at age ≥65 years (65–74 years, 38% vs. 19%, P<0.0001; 75–84 years, 55% vs. 34%, P<0.0001; ≥85 years: 82% vs. 72%, P=0.03).

Conclusions:A large Japanese multicenter registry of consecutive patients with severe AS included a much higher proportion of women than men, with the female:male sex ratio increasing with age. The 5-year mortality rate of women was lower than that of men. Lower 5-year mortality rates in women were consistently seen across all age groups >65 years.

Enhancement of Nitric Oxide Production Is Responsible for Minimal Intimal Hyperplasia of Autogenous Rabbit Arterial Grafts

Koki Tabata, Kimihiro Komori, Ryo Otsuka, Junko Kajikuri, Takeo Itoh

Released: July 25, 2017

[Advance Publication] Released: April 05, 2017

1222-1230

Background:Vascular endothelium induces smooth muscle cell (SMC) relaxation mainly mediated by endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF). It has previously been reported that functions of these endothelium factors have been greatly impaired in vein grafts. The present study was undertaken to determine whether the functions of EDNO and EDHF might be altered in artery graft.

Methods and Results:In rabbits, the right carotid artery was excised and implanted in its original position as an autogenous graft (“artery graft”) and the non-operated left carotid artery served as the “control artery”. Histochemical changes, acetylcholine (ACh)-induced effects on the intracellular concentration of Ca²⁺([Ca²⁺]_i) in endothelial cells, endothelium-dependent SMC hyperpolarization and relaxation, and tissue cGMP content were examined on post-operative day 28. “Artery graft” displayed a minimal amount of intimal hyperplasia. When compared with the “control artery”, it exhibited greater ACh-induced, endothelium-dependent relaxation, but the reverse was true when EDNO production was blocked. In the “artery graft” (vs. the “control artery”), basal cGMP content was greater, whereas the [Ca²⁺]_iincrease in endothelial cells and the endothelium-dependent SMC-hyperpolarization induced by ACh were less.

Conclusions:It is suggested that the [Ca²⁺]_i-independent EDNO production covers the loss of function of endothelium-dependent SMC hyperpolarization and minimizes intimal hyperplasia caused by surgical operation in autogenous carotid artery graft.

Sequential Acute Coronary Syndrome 4 Days Apart: A Missed Opportunity?

Iwao Okai, Hiroshi Iwata, Eric A. Osborn, Kentaro Fukuda, Masayuki Shiozaki, Yuki Kimura, Yuichi Chikata, Kenji Inoue, Yasumasa Fujiwara, Farouc A. Jaffer, Hiroyuki Daida, Masataka Sumiyoshi

Released: July 25, 2017

[Advance Publication] Released: February 10, 2017

1231-1233