Circulation Journal

Message From the Editor-in-Chief

Toyoaki Murohara

Released: September 25, 2017

[Advance Publication] Released: September 13, 2017

1377-1378

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Yuichi Oike, Zhe Tian, Keishi Miyata, Jun Morinaga, Motoyoshi Endo, Tsuyoshi Kadomatsu

Released: September 25, 2017

[Advance Publication] Released: September 02, 2017

1379-1385

In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin-like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 autocrine/paracrine signaling in vascular tissue leads to chronic inflammation and pathologic tissue remodeling, accelerating CVD development. Excess ANGPTL2 autocrine/paracrine signaling induced in the pathologically stressed heart accelerates cardiac dysfunction by decreasing myocardial energy metabolism. Conversely, ANGPTL2 inactivation in vascular tissue and the heart delays development or progression of CVD and HF, respectively. Moreover, there is increased evidence for an association between elevated circulating ANGPTL2 levels and CVD and HF. Interestingly, ANGPTL2 expression is also associated with cellular senescence, which may promote premature aging and development of aging-associated diseases, including CVD and HF. Overall, ANGPTL2 autocrine/paracrine signaling is a new factor in accelerating heart disease development in the aging. Here, we focus on current topics relevant to ANGPTL2 function in heart disease.

Lipid-Lowering Therapy With Monoclonal Antibodies to Proprotein Convertase Subtilisin-Kexin Type 9　― Lessons From Recent Clinical Trials ―

Hideki Ishii, Toyoaki Murohara

Released: September 25, 2017

[Advance Publication] Released: June 03, 2017

1386-1387

Anatomic Feasibility of Next-Generation Stent Grafts for the Management of Type A Aortic Dissection in Japanese Patients

Naoki Fujimura, Shinji Kawaguchi, Hideaki Obara, Akihiro Yoshitake, Masanori Inoue, Satoshi Otsubo, Yuko Kitagawa, Hideyuki Shimizu

Released: September 25, 2017

[Advance Publication] Released: April 25, 2017

1388-1394

Background:The aims of the present study were to analyze the anatomical characteristics of type A aortic dissections (TAAD) in Japanese patients and evaluate the feasibility of 3 next-generation stent grafts dedicated to ascending/arch aortic lesions.

Methods and Results:We analyzed 172 consecutive patients surgically treated for TAAD at 2 institutions between 2007 and 2015. Computed tomography (CT) images and operative records were used to identify the location of entry tear (ET). The anatomical feasibility of the Zenith Ascend, Zenith A-branch, and TAG Thoracic Branch Endoprosthesis (TBE) was evaluated using the manufacturers’ instructions for use (IFU). In total, 131 patients were included in the final analysis. Dissection was present at the sinotubular junction (STJ) in 107 patients (81.7%), and the mean diameter of the STJ was 39.4±6.0 mm. The ET was at the STJ (n=33), ascending aorta (n=47), aortic arch (n=30), and descending aorta (n=21). The mean lengths from STJ to innominate artery and STJ to ET were 79.5±11.4 mm and 57.8±52.1 mm, respectively. When we applied the IFU to each anatomical measurement, we identified 0 patients as candidates for Zenith Ascend, 9 (6.9%) for Zenith A-branch, and 60 (45.8%) for TAG TBE.

Conclusions:Endovascular treatment for TAAD was not feasible for most of this study population, with risk of stent graft-induced new entry in 81.7% of patients, despite the use of next-generation stent grafts.

Predictors of Mortality, Rehospitalization for Syncope and Cardiovascular Events in Patients With Cardiovascular Syncope

Tatsuya Onuki, Makoto Shoji, Yuya Nakamura, Ko Ogawa, Akinori Ochi, Koichiro Inokuchi, Shiro Kawasaki, Yoshimi Onishi, Yoshimasa Onuma, Yumi Munetsugu, Miwa Kikuchi, Hiroyuki Ito, Yoshino Minoura, Norikazu Watanabe, Taro Adachi, Mitsuharu Kawamura, Taku Asano, Kaoru Tanno, Youichi Kobayashi

Released: September 25, 2017

[Advance Publication] Released: May 25, 2017

1395-1402

Background:Predictors of poor outcomes remain unknown for cardiovascular syncope patients after discharge.

Methods and Results:We reviewed the medical records of consecutive patients admitted to hospital with cardiovascular syncope. We then performed Cox stepwise logistic regression analysis to identify significant independent factors for death, rehospitalization for syncope, and cardiovascular events. The study group was 206 patients with cardiovascular syncope. Of them, bradycardia was diagnosed in 50%, tachycardia in 27%, and structural disease in 23%. During a 1-year follow-up period, 18 (8%) and 45 (23%) patients, respectively, were rehospitalized for syncope or a cardiovascular event, and 10 (4%) died. Independent predictors of cardiovascular events were systolic blood pressure <100 mmHg (odds ratio [OR] 3.25; 95%confidence interval [CI] 1.41–7.51, P=0.006) and implantation of a pacemaker (OR 0.19; 95% CI 0.05–0.51, P=0.0005) (inverse association). Drug-induced syncope (OR 4.57; 95% CI 1.54–12.8, P=0.007) was an independent risk factor for rehospitalization. Finally, a history of congestive heart failure (OR 11.0; 95% CI 2.78–54.7, P=0.0006) and systolic blood pressure <100 mmHg (OR 5.40; 95% CI 1.30–22.7, P=0.02) were identified as significant independent prognostic factors for death.

Conclusions:Drug-induced syncope, hypotension, no indication for a pacemaker, and a history of congestive heart failure are risk factors post-discharge for patients with cardiovascular syncope and careful follow-up of these patients for at least 1 year is recommended.

Sex-Related Differences in the Clinical Events of Patients With Atrial Fibrillation　― The Fushimi AF Registry ―

Hisashi Ogawa, Yasuhiro Hamatani, Kosuke Doi, Yuji Tezuka, Yoshimori An, Mitsuru Ishii, Moritake Iguchi, Nobutoyo Masunaga, Masahiro Esato, Yeong-Hwa Chun, Hikari Tsuji, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Gregory YH Lip, Masaharu Akao, on behalf of the Fushimi AF Registry Investigators

Released: September 25, 2017

[Advance Publication] Released: May 25, 2017

1403-1410

Background:Female sex is considered a risk factor for thromboembolism in patients with atrial fibrillation (AF), and is included in the risk stratification scheme, CHA₂DS₂-VASc score. The purpose of the present study was to investigate the clinical outcomes of female Japanese AF patients.

Methods and Results:The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto. Follow-up data were available for 3,878 patients. Female AF patients (n=1,551, 40.0%) were older (77.0 vs. 71.4 years; P<0.001) than male patients (n=2,327, 60.0%). Female patients were more likely to have heart failure (31.1% vs. 23.7%; P<0.001). Previous stroke incidence (19.2% vs. 21.4%; P=0.083) was comparable between male and female patients. During the median follow-up period of 1,102 days, Cox regression analysis demonstrated that female sex was not independently associated with a risk of stroke or systemic embolism (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.54–1.00, P=0.051). However, female sex showed an association with a lower risk of intracranial hemorrhage (adjusted HR 0.54; 95% CI: 0.30–0.95, P=0.032) and all-cause death (adjusted HR 0.56; 95% CI: 0.46–0.68, P<0.001).

Conclusions:We demonstrated that female sex is not independently associated with an increased risk of thromboembolism, but is associated with a decreased risk of intracranial hemorrhage and all-cause death in Japanese AF patients enrolled in the Fushimi AF Registry.

Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late I_Na-Mediated Focal Activity

Takashi Ogawa, Haruo Honjo, Masatoshi Yamazaki, Yasunori Kushiyama, Ichiro Sakuma, Itsuo Kodama, Kaichiro Kamiya

Released: September 25, 2017

[Advance Publication] Released: May 26, 2017

1411-1428

Background:Ventricular tachycardia/fibrillation (VT/VF) associated with acute myocardial ischemia is the most common cause of sudden cardiac death, but its underlying mechanisms are incompletely understood. It is hypothesized that late Na⁺current (I_Na) contributes to arrhythmogenic activity in ischemic myocardium.

Methods and Results:Langendorff-perfused rabbit hearts with regional ischemia in ventricles were optically mapped. Perfusion with ranolazine (10 μmol/L), a selective inhibitor of lateI_Na, significantly reduced excitation frequency and facilitated termination of VT/VF induced after occlusion of the left main coronary trunk. The activation pattern during ischemic VT/VF was characterized by breakthrough-type excitations (BEs) from multiple origins, predominantly in the ischemic border zone (BZ) and occasional short-lived rotors. Ranolazine perfusion significantly reduced the incidence of BEs in the BZ. Rotors tended to decrease with progression of ischemia and disappeared after ranolazine perfusion. During constant pacing, ranolazine attenuated ischemia-induced shortening of action potentials in the BZ without affecting conduction velocity, probably due toI_Krinhibition. In intact hearts without coronary occlusion, ranolazine (10 μmol/L) terminated aconitine-induced VT by inhibiting focal arrhythmogenic activity in the injection site.

Conclusions:LateI_Na-mediated focal arrhythmogenic activity plays important roles in the maintenance of ischemic VT/VF in isolated rabbit hearts. Suppression of lateI_Naby ranolazine may be a promising therapeutic strategy to reduce arrhythmic death during the acute phase of myocardial infarction.

Atrial Septostomy for Left Atrial Decompression During Extracorporeal Membrane Oxygenation by Inoue Balloon Catheter

Yen-Nien Lin, Yin-Huei Chen, Huang-Joe Wang, Jui-Sung Hung, Kuan-Cheng Chang, Ping-Han Lo

Released: September 25, 2017

[Advance Publication] Released: May 11, 2017

1419-1423

Background:Refractory pulmonary edema is an infrequent but serious complication in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) for myocardial failure. Left atrial (LA) decompression in this setting is important. Although a few methods have been reported, the experience is mostly limited to children. We aimed to evaluate the feasibility of Inoue balloon catheter in percutaneous trans-septal LA decompression in adult cardiogenic patients.

Methods and Results:We retrospectively analyzed 16 procedures of trans-septal LA decompression by Inoue balloon catheter in 15 VA-ECMO patients (aged 22–65 years, 6 men) with refractory pulmonary edema from May 2012 to December 2014. Mean left ventricular ejection fraction was 15%. The cause of cardiogenic shock included 7 cases of ischemic heart disease, 1 of dilated cardiomyopathy, 5 of myocarditis, and 2 of fatal ventricular arrhythmia.The procedures were performed 4.3 days after ECMO. Inoue balloon size was 24–27 mm. LA septostomy were successfully created in 14 patients. Procedure time on average was 36.8 min (range, 15–85 min). There were no procedure-related complications.Radiography on the next day showed rapid resolution of pulmonary edema.

Conclusions:Trans-septal LA decompression by Inoue balloon catheter is a feasible alternative method for adult patients with refractory pulmonary edema under ECMO.

Underuse of Cardiac Rehabilitation in Workers With Coronary Artery Disease　― Claims Database Survey in Japan ―

Natsuko Kanazawa, Kenji Ueshima, Shinjiro Tominari, Takeo Nakayama

Released: September 25, 2017

[Advance Publication] Released: May 11, 2017

1424-1431

Background:Workers with coronary artery disease (CAD) require evidence-based care in order to return to work safely. We assessed the use of cardiac rehabilitation (CR) among workers with CAD, and identified the factors associated with CR use.

Methods and Results:A retrospective cohort study based on data from a health insurance claims database was conducted. We identified workers aged ≥18 years who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) between 2006 and 2013, and reviewed the utilization of inpatient or outpatient CR. Logistic regression was used to identify the factors associated with CR use. A total of 1,699 patients were included. The frequency of inpatient and outpatient CR use was 23.7% (n=402) and 4.2% (n=72), respectively. Patients diagnosed with ST-elevated myocardial infarction were most likely to receive inpatient CR, and patients undergoing CABG were more likely to receive inpatient CR than those undergoing PCI. Moreover, inpatient CR use was associated with longer hospitalization duration, catecholamine use, and no history of chronic kidney disease. Furthermore, both unstable and stable angina were negatively correlated with outpatient CR use.

Conclusions:Most of the Japanese workers with CAD in this study did not undergo CR. The type of CAD was strongly associated with inpatient and outpatient CR use. Thus, a strong evidence-practice gap exists in secondary preventative care within this group of patients.

Long-Term Outcomes of Suture vs. Ring Tricuspid Annuloplasty for Functional Tricuspid Regurgitation

Hiroki Hata, Tomoyuki Fujita, Sayaka Miura, Yusuke Shimahara, Yuta Kume, Yorihiko Matsumoto, Kizuku Yamashita, Junjiro Kobayashi

Released: September 25, 2017

[Advance Publication] Released: April 29, 2017

1432-1438

Background:Whether there is a significant difference in the long-term surgical outcomes between suture annuloplasty and ring annuloplasty for the treatment of functional tricuspid regurgitation (TR) is still controversial. We compared the long-term outcomes of tricuspid annuloplasty (TAP) with and without an annuloplasty ring.

Methods and Results:From January 1996 to December 2015, we consecutively enrolled 684 patients (mean age, 65.5 years; 60% women) undergoing TAP for functional TR: 312 underwent conventional suture annuloplasty (Group S) and 372 underwent ring annuloplasty (Group R). Baseline characteristics were comparable between the 2 groups, except for age and the prevalence of prior cardiac surgery. The mean follow-up period was 7.3 years (range, 0.3–20.3 years).There was no significant difference in overall survival, freedom from major adverse cardiac and cerebrovascular events, and freedom from recurrent moderate to severe TR between Groups S and R, although postoperative mean TR grade and sPAP were significantly lower in Group R. Multivariate analysis revealed that age, prior cardiac surgery, and preoperative severe TR were independent predictors of recurrent moderate or greater TR.

Conclusions:There was no significant difference in the long-term surgical outcomes between ring and suture TAP, although postoperative mean TR grade was lower in the ring annuloplasty group.

Role of the Low-Density Lipoprotein-Cholesterol/High-Density Lipoprotein-Cholesterol Ratio in Predicting Serial Changes in the Lipid Component of Coronary Plaque

Ryo Kawakami, Ichiro Matsumoto, Motoi Shiomi, Mizuki Kurozumi, Yuichi Miyake, Makoto Ishizawa, Kaori Ishikawa, Kazushi Murakami, Takahisa Noma, Yuichiro Takagi, Naoki Nishimoto, Tetsuo Minamino

Released: September 25, 2017

[Advance Publication] Released: April 29, 2017

1439-1446

Background:The lipid component of coronary plaques is associated with their vulnerability. The aim of this study was to investigate which coronary risk factors were relevant in predicting serial changes in the lipid component of coronary plaques as evaluated by integrated backscatter intravascular ultrasound (IB-IVUS).

Methods and Results:We enrolled 104 patients who underwent IB-IVUS-guided percutaneous coronary intervention (PCI) and were followed up with repeat IB-IVUS 6 months later. We investigated the serial changes in the plasma lipoprotein levels and the percentage of the lipid component of coronary plaques on IB-IVUS. In the multivariate linear regression analysis, the low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol (L/H) ratio independently had a significant fixed effect with the percentage of the lipid component of coronary plaques at the time of PCI. In addition, the change in the L/H ratio at the 6-month follow-up was significantly associated with that in the lipid component of coronary plaques (regression coefficient, 9.645; 95% CI: 5.814–13.475; P<0.0001); furthermore, this change was also observed in patients with an LDL-C <100 mg/dL.

Conclusions:The L/H ratio was the most relevant parameter in predicting the lipid component of coronary plaques. Furthermore, strict management of the L/H ratio may reduce this lipid component, even in patients with an LDL-C <100 mg/dL.

Low Heart Rate Variability and Sympathetic Dominance Modifies the Association Between Insulin Resistance and Metabolic Syndrome　― The Toon Health Study ―

Isao Saito, Koutatsu Maruyama, Eri Eguchi, Tadahiro Kato, Ryoichi Kawamura, Yasunori Takata, Hiroshi Onuma, Haruhiko Osawa, Takeshi Tanigawa

Released: September 25, 2017

[Advance Publication] Released: May 30, 2017

1447-1453

Background:Insulin resistance is strongly associated with metabolic syndrome (MetS), but it is not known how this association is influenced by the autonomic nervous system, which controls insulin secretion.

Methods and Results:The subjects were 2,016 individuals aged 30–79 years enrolled between 2009 and 2012. MetS was determined using the harmonized MetS definition, which includes waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI) were calculated based on fasting and 2 h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. The 5-min heart rate variability (HRV) was evaluated using time-domain indices of standard deviations of NN intervals (SDNN) and root mean square of successive differences (RMSSD). Power spectral analysis yielded frequency-domain measures for HRV: high-frequency (HF) power, low-frequency (LF) power and LF/HF. Multivariable adjusted logistic models showed that the highest quartiles for SDNN, RMSSD, LF, and HF vs. the lowest quartiles had a significant association with MetS. RMSSD, HF, and LF/HF remained significantly associated with MetS after adjustment for HOMA-IR (or ISI). Additive interactions between the levels of high LF/HF and high HOMA-IR (or low ISI) were significantly positive.

Conclusions:Sympathovagal imbalance as evidenced by low HF and high LF/HF modified the association of insulin resistance or low insulin sensitivity with MetS.

Comparison of Prognostic Values of Daytime and Night-Time Systolic Blood Pressures on Renal Outcomes in Patients With Chronic Kidney Disease

Eisuke Katafuchi, Masaru Nakayama, Shigeru Tanaka, Teppei Sakoh, Ryota Yoshitomi, Akiko Fukui, Makiko Seki, Yusuke Nakamata, Mitsuhiro Tominaga, Kazuhiko Tsuruya, Takanari Kitazono

Released: September 25, 2017

[Advance Publication] Released: April 26, 2017

1454-1462

Background:Differences in the predictive value of daytime systolic blood pressure (SBP) and night-time SBP by ambulatory blood pressure monitoring on renal outcomes have not been fully investigated in chronic kidney disease (CKD) patients. This study compared the prognostic value between daytime and night-time SBP on renal outcomes in CKD.

Methods and Results:This prospective observational study included 421 patients. The composite renal endpoint was endstage renal disease (ESRD) or death. Cox models were used to determine associations of daytime and night-time SBP with renal outcomes. There were 150 renal events (ESRD, 130; death, 20). Multivariable Cox analyses demonstrated that hazard ratios (HRs) [95% confidence interval (CI)] for composite renal outcomes of every 10-mmHg increase in daytime and night-time SBP levels were 1.13 (1.02–1.26) (P=0.02) and 1.15 (1.05–1.27) (P<0.01), respectively. In addition, compared with the 1st daytime or night-time SBP quartile, HRs (95% CI) for outcomes in the 2nd, 3rd, and 4th quartiles were: daytime SBP, 1.25 (0.70–2.25), 1.09 (0.61–1.94), and 1.58 (0.88–2.85; P=0.13) (P for trend=0.16); night-time SBP, 1.09 (0.61–1.96), 1.31 (0.76–2.28), and 1.82 (1.00–3.30; P=0.049) (P for trend=0.03), respectively.

Conclusions:Night-time SBP appeared superior to daytime SBP for predicting renal outcomes in this population of patients.

Assessment of Left Ventricular Function and Mass on Free-Breathing Compressed Sensing Real-Time Cine Imaging

Tomoyuki Kido, Teruhito Kido, Masashi Nakamura, Kouki Watanabe, Michaela Schmidt, Christoph Forman, Teruhito Mochizuki

Released: September 25, 2017

[Advance Publication] Released: May 18, 2017

1463-1468

Background:Compressed sensing (CS) cine magnetic resonance imaging (MRI) has the advantage of being inherently insensitive to respiratory motion. This study compared the accuracy of free-breathing (FB) CS and breath-hold (BH) standard cine MRI for left ventricular (LV) volume assessment.

Methods and Results:Sixty-three patients underwent cine MRI with both techniques. Both types of images were acquired in stacks of 8 short-axis slices (temporal/spatial resolution, 41 ms/1.7×1.7×6 mm³) and compared for ejection fraction, end-diastolic and systolic volumes, stroke volume, and LV mass. Both BH standard and FB CS cine MRI provided acceptable image quality for LV volumetric analysis (score ≥3) in all patients (4.7±0.5 and 3.7±0.5, respectively; P<0.0001) and had good agreement on LV functional assessment. LV mass, however, was slightly underestimated on FB CS cine MRI (median, IQR: BH standard, 83.8 mL, 64.7–102.7 mL; FB CS, 79.0 mL, 66.0–101.0 mL; P=0.0006). The total acquisition times for BH standard and FB CS cine MRI were 113±7 s and 24±4 s, respectively (P<0.0001).

Conclusions:Despite underestimation of LV mass, FB CS cine MRI is a clinically useful alternative to BH standard cine MRI in patients with impaired BH capacity.

Antiplatelet Drug Regimen in Patients With Stent Thrombosis　― Insights From the PESTO French Optical Coherence Tomography Registry ―

Nicolas Amabile, Guillaume Cayla, Pascal Motreff, Charlotte Trouillet, Grégoire Range, Olivier Dubreuil, Estelle Vautrin, François Derimay, Lionel Mangin, Nicolas Meneveau, Christophe Caussin, Géraud Souteyrand

Released: September 25, 2017

[Advance Publication] Released: May 23, 2017

1469-1476

Background:Stent thrombosis (ST) may be triggered by different phenomena, including underlying device abnormalities and modification of the antiplatelet therapy (APT) regimen. This work investigated the characteristics of APT regimens and their relationships with ST mechanisms among a large cohort of patients evaluated by optical coherence tomography (OCT).

Methods and Results:A prospective multicenter registry was screened for patients with confirmed ST. OCT was performed after the initial intervention to the culprit lesion. ST was classified as acute (AST), subacute (SAST), late (LST) and very late (VLST). OCT records were analyzed in a central core laboratory. A total of 120 patients (median age 62 years, 89% male) were included in the study. VLST was the clinical presentation in 75%, LST in 6% and SAST+AST in 19% of the patients. Single APT (SAPT) was given in 61%, double APT (DAPT) in 27% and no APT in 12% of the cases at the time of the ST. A recent (≤15 days) APT modification was reported in 22% of the patients. An underlying mechanical abnormality was identified by OCT in 96.7% of the cases. Ruptured neoatherosclerotic lesions were significantly more frequent in patients without APT compared with the others.

Conclusions:ST mostly occurs in patients receiving DAPT or SAPT. Any underlying mechanical abnormality of ST can be involved, irrespective of the APT regimen.

Diagnostic Accuracy of Endocardial-to-Epicardial Myocardial Blood Flow Ratio for the Detection of Significant Coronary Artery Disease With Dynamic Myocardial Perfusion Dual-Source Computed Tomography

Yoshitaka Goto, Kakuya Kitagawa, Mio Uno, Shiro Nakamori, Tatsuro Ito, Naoki Nagasawa, Kaoru Dohi, Hajime Sakuma

Released: September 25, 2017

[Advance Publication] Released: April 25, 2017

1477-1483

Background:Previous dynamic stress computed tomography perfusion (CTP) studies used absolute myocardial blood flow (MBF in mL/100 g/min) as a threshold to discriminate flow-limiting coronary artery disease (CAD), but absolute MBF can be vary because of multiple factors. The aim of this study was to compare the diagnostic performance of absolute MBF and the transmural perfusion ratio (TPR) for the detection of flow-limiting CAD, and to clarify the influence of CT delayed enhancement (CTDE) on the diagnostic performance of CTP.

Methods and Results:We retrospectively enrolled 51 patients who underwent dual-source CTP and invasive coronary angiography (ICA). TPR was defined as the endocardial MBF of a specific segment divided by the mean of the epicardial MBF of all segments. Flow-limiting CAD was defined as luminal diameter stenosis >90% on ICA or a lesion with fractional flow reserve ≤0.8. Segmental presence and absence of myocardial scar was determined by CTDE. The area under the receiver-operating characteristics curve (AUC) of TPR was significantly greater than that of MBF for the detection of flow-limiting CAD (0.833 vs. 0.711, P=0.0273). Myocardial DE was present in 27 of the 51 patients and in 34 of 143 territories. When only territories containing DE were considered, the AUC of TPR decreased to 0.733.

Conclusions:TPR calculated from absolute MBF demonstrated higher diagnostic performance for the discrimination of flow-limiting CAD when compared with absolute MBF itself.

Epidemiology of Myocardial Infarction Caused by Presumed Paradoxical Embolism via a Patent Foramen Ovale

Franz X. Kleber, Telse Hauschild, Antonia Schulz, Anne Winkelmann, Leonhard Bruch

Released: September 25, 2017

[Advance Publication] Released: April 27, 2017

1484-1489

Background:Despite several negative prospective randomized trials on the efficacy of patent foramen ovale (PFO) occlusion, the discussion on indications is ongoing. Because the incidence of paradoxical coronary embolism through a PFO is unknown, we investigated the risk of paradoxical embolic myocardial infarction over a period of 13 years.

Methods and Results:We conducted a retrospective and a prospective study. In the former, we searched the hospital database of a tertiary referral center for cases of acute myocardial infarction (AMI) during the past 10 years and screened them for possible paradoxical MIs. On this basis we started a prospective evaluation over 39 months in another tertiary referral center. All patients with AMI and normal coronary arteries were screened for PFO and if no other reason for the AMI could be found, the case was judged as presumed paradoxical embolism. In the retrospective analysis we found 22 cases (0.45%) of presumed paradoxical coronary artery embolism under 4,848 AMI. In the prospective study there were 11 presumed paradoxical coronary artery embolisms among 1,654 patients with AMI, representing an incidence of 0.67%.

Conclusions:Our findings demonstrated that well below 1% of AMIs are caused by paradoxical embolism via an interatrial communication. Although this percentage appears low, it is not a negligible number of patients based on the huge number of MIs occurring in the industrialized world.

Effect of Reverse Vessel Remodeling on Regression of Coronary Atherosclerosis in Patients Treated With Aggressive Lipid- and Blood Pressure-Lowering Therapy　― Insight From MILLION Study ―

Tadatsugu Gamou, Kenji Sakata, Hayato Tada, Tetsuo Konno, Kenshi Hayashi, Hidekazu Ino, Masakazu Yamagishi, Masa-aki Kawashiri, on behalf of the MILLION Study Group

Released: September 25, 2017

[Advance Publication] Released: May 17, 2017

1490-1495

Background:The MILLION study, a prospective randomized multicenter study, revealed that lipid and blood pressure (BP)-lowering therapy resulted in regression of coronary plaque as determined by intravascular ultrasound (IVUS). In the present study we performed additional analysis to investigate the associated factors with regression of coronary plaque.

Methods and Results:We investigated serial 3D IVUS images from 68 patients in the MILLION study. Standard IVUS parameters were assessed at both baseline and follow-up (18–24 months). Volumetric data were standardized by length as normalized volume. In patients with plaque regression (n=52), plaque volume_normalizedsignificantly decreased from 64.8 to 55.8 mm³(P<0.0001) and vessel volume_normalizedsignificantly decreased from 135.0 to 127.5 mm³(P=0.0008). There was no difference in lumen volume_normalizedfrom 70.1 to 71.8 mm³(P=0.27). There were no correlations between % changes in vessel volume and cholesterol or BP. On the other hand, negative correlations between % change in vessel volume and vessel volume_normalizedat baseline (r=−0.352, P=0.009) or plaque volume_normalizedat baseline (r=−0.336, P=0.01) were observed.

Conclusions:The current data demonstrated that in patients with plaque regression treated by aggressive lipid and BP-lowering therapy, the plaque regression was derived from reverse vessel remodeling determined by vessel volume and plaque burden at baseline irrespective of decreases in lipids and BP.

Efficacy and Safety of Bococizumab (RN316/PF-04950615), a Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, in Hypercholesterolemic Japanese Subjects Receiving a Stable Dose of Atorvastatin or Treatment-Naive　― Results From a Randomized, Placebo-Controlled, Dose-Ranging Study ―

Koutaro Yokote, Shigeto Kanada, Osamu Matsuoka, Hisakuni Sekino, Keiji Imai, Junichi Tabira, Nobushige Matsuoka, Sandip Chaudhuri, Tamio Teramoto

Released: September 25, 2017

[Advance Publication] Released: May 23, 2017

1496-1505

Background:A Phase 2, dose-ranging study of bococizumab, a monoclonal anti-proprotein convertase subtilisin/kexin type 9 antibody, was conducted in Japanese subjects to assess its efficacy, safety, and tolerability in this population.

Methods and Results:Two different hypercholesterolemic study populations were enrolled concurrently: Japanese subjects with uncontrolled low-density lipoprotein cholesterol (LDL-C) despite atorvastatin treatment (LDL-C ≥100 mg/dL; n=121), and Japanese subjects naive to lipid-lowering agents and with LDL-C ≥130 mg/dL (n=97). Subjects within each study population were randomized to bococizumab 50, 100, or 150 mg, or placebo, q14D for 16 weeks; an open-label ezetimibe 10 mg daily arm was also included for the atorvastatin-treated population. Significant, dose-dependent reductions in fasting LDL-C levels were observed in all bococizumab arms of both study populations at Weeks 12 and 16 (adjusted mean percent changes from baseline: 54.1–76.7% for atorvastatin-treated subjects and 47.7–66.8% for treatment-naive subjects; P<0.001 vs. placebo for all). Bococizumab also caused dose-dependent changes in other lipid parameters in both study populations at Weeks 12 and 16. No serious adverse events (AEs) related to bococizumab treatment occurred and all treatment-emergent AEs were mild or moderate in severity. No dose-dependent relationship between bococizumab treatment and development of anti-drug antibodies was observed.

Conclusions:Bococizumab was well tolerated and significantly reduced fasting LDL-C in atorvastatin-treated and treatment-naive hypercholesterolemic Japanese subjects. (Clinicaltrials.gov identifier: NCT02055976.)

Prognostic Value of Combination of Plasma D-Dimer Concentration and Estimated Glomerular Filtration Rate in Predicting Long-Term Mortality of Patients With Stable Coronary Artery Disease

Hiroyuki Naruse, Junnichi Ishii, Hiroshi Takahashi, Fumihiko Kitagawa, Ryuunosuke Okuyama, Hideki Kawai, Takashi Muramatsu, Masahide Harada, Akira Yamada, Sadako Motoyama, Shigeru Matsui, Mutsuharu Hayashi, Masayoshi Sarai, Eiichi Watanabe, Hideo Izawa, Yukio Ozaki

Released: September 25, 2017

[Advance Publication] Released: May 25, 2017

1506-1513

Background:A modestly elevated circulating D-dimer level may be relevant to coronary artery disease (CAD), but its prognostic value, both independently and in combination with estimated glomerular filtration rate (eGFR), for long-term death has not been fully evaluated in stable CAD patients.

Methods and Results:Baseline plasma D-dimer levels and eGFR were measured in 1,341 outpatients (mean age: 65 years) with prior myocardial infarction (MI), coronary revascularization, and/or angiographic evidence of a significant stenosis (>50%) for at least one of the major coronary arteries. Among these patients, 43% had prior MI, 47% had prior coronary revascularization, 41% had multivessel CAD, 14% had paroxysmal or persistent atrial fibrillation, 32% had diabetes, and 32% had chronic kidney disease (eGFR <60 mL/min/1.73 m²). D-dimer levels weakly correlated with eGFR (r=−0.25; P<0.0001). During a mean follow-up period of 73 months, there were 124 deaths, including 61 cardiovascular deaths. Multivariate Cox regression analysis identified D-dimer levels (P=0.001) and eGFR (P=0.006) as independent predictors of all-cause death. Adding both D-dimer and eGFR to a baseline model with established risk factors improved the net reclassification (P<0.005) and integrated discrimination improvement (P<0.05) greater than that of any single biomarker or baseline model alone.

Conclusions:The combinatorial value of assessing D-dimer levels and eGFR may provide useful insight regarding stable CAD patients’ long-term risk stratification.

Stent Fracture and Peri-Stent Contrast Staining After Everolimus-Eluting Stent Implantation　― 5-Year Outcomes ―

Katsuya Miura, Takeshi Tada, Akinune Kuwayama, Takenobu Shimada, Masanobu Ohya, Hidewo Amano, Shunsuke Kubo, Yusuke Hyodo, Suguru Otsuru, Seiji Habara, Hiroyuki Tanaka, Yasushi Fuku, Tsuyoshi Goto, Kazushige Kadota

Released: September 25, 2017

[Advance Publication] Released: June 13, 2017

1514-1521

Background:Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent implantation are reported to be risk factors of adverse events. However, the effect of these after everolimus-eluting stent (EES) implantation on long-term outcomes remains unclear.

Methods and Results:The study sample comprised 636 patients (1,081 lesions) undergoing EES implantation in 2010 and follow-up angiography within 1 year. The 5-year cumulative rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE: a combination of all-cause death, myocardial infarction, and TLR) were compared between patients with and without SF or PSS. SF was observed in 2.7%, and PSS in 3.0%. The cumulative rates of MACE and TLR were significantly higher in the SF group than in the non-SF group (51.7% vs. 27.5% and 48.3% vs. 13.4%, respectively), but showed no significant differences between the PSS and non-PSS groups. In a landmark analysis, the rate of TLR within 1 year was significantly higher in the SF group than in the non-SF group (44.8% vs. 7.2%), but beyond 1 year showed no significant difference (6.3% vs 6.7%).

Conclusions:The 5-year clinical outcomes suggested that SF after EES implantation is related to increased risk of MACE and TLR, especially within 1 year after the procedure, but PSS after EES implantation is unrelated.

Acute Kidney Injury Following Cardiopulmonary Bypass in Children　― Risk Factors and Outcomes ―

Seon Hwa Lee, Soo-Jin Kim, Hyung Joong Kim, Jae Sung Son, Ran Lee, Tae Gyoon Yoon

Released: September 25, 2017

[Advance Publication] Released: May 17, 2017

1522-1527

Background:Acute kidney injury (AKI) is the most common and most serious complication following heart surgery. We aimed to determine the prevalence of, and risk factors for, AKI following pediatric cardiac surgery.

Methods and Results:We retrospectively analyzed 135 patients aged ≤18 years who underwent cardiac surgery for congenital heart defects; by RACHS-1 category, 58 patients (43%) had an operative risk score ≥3. AKI was defined and classified using the pediatric pRIFLE criteria (Pediatric Risk, Injury, Failure, Loss, and End-stage Kidney Disease); 19 patients (14.1%) developed AKI: 17 had AKI with a severity classified as risk (R) and 2 had AKI classified as injury (I). Body weight, height, body surface area, and preoperative mechanical ventilation were all independently associated with AKI development (P=0.038, 0.040, 0.033 and 0.008, respectively). Preoperative ventilation strongly correlated with AKI severity. Higher pRIFLE classification positively correlated with increased incidence of peritoneal dialysis, increased postoperative mechanical ventilation duration, and longer hospital stay (P=0.009, 0.039 and 0.042, respectively).

Conclusions:In this study, we found a low prevalence of postoperative AKI in pediatric patients undergoing severe cardiac surgery. AKI was associated with worse early postoperative outcomes. Early prediction and appropriate treatment of AKI during the postoperative period are emphasized.

Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice

Soo-Min Shon, Hee Jeong Jang, Dawid Schellingerhout, Jeong-Yeon Kim, Wi-Sun Ryu, Su-Kyoung Lee, Jiwon Kim, Jin-Yong Park, Ji Hye Oh, Jeong Wook Kang, Kang-Hoon Je, Jung E Park, Kwangmeyung Kim, Ick Chan Kwon, Juneyoung Lee, Matthias Nahrendorf, Jong-Ho Park, Dong-Eog Kim

Released: September 25, 2017

[Advance Publication] Released: September 05, 2017

1528-1536

Background:The aim of this study is to identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.

Methods and Results:Apolipoprotein-E knock-out (ApoE^−/−) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively correlated to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1.

Conclusions:Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.

Trend in the Prevalence of Atrial Fibrillation During the Past 15 Years in Iwate (Northeastern Area of Japan)

Kenji Tamaki, Makoto Koshiyama, Masaki Ohsawa

Released: September 25, 2017

[Advance Publication] Released: August 24, 2017

1537-1539

Background:The trend in age-specific prevalence of atrial fibrillation (AF) in Japan has not been reported.

Methods and Results:Age-specific prevalence (40–49, 50–59, 60–69, 70–79 and 80–89 years old) of AF in Iwate Prefecture was determined in 1997, 2002, 2007 and 2012 (n=818,577). A positive linear trend in the prevalence of AF across calender years was observed only in males in their 60 s and 70 s. The direct age-standardized rate in males increased from 1.55% to 1.85%, while the rate in females remained around 0.5%.

Conclusions:The age-specific prevalence of AF has increased only in elderly males.

Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension

Toshiaki Ohkuma, Hirofumi Tomiyama, Toshiharu Ninomiya, Kazuomi Kario, Satoshi Hoshide, Yoshikuni Kita, Toyoshi Inoguchi, Yasutaka Maeda, Katsuhiko Kohara, Yasuharu Tabara, Motoyuki Nakamura, Takayoshi Ohkubo, Hirotaka Watada, Masanori Munakata, Mitsuru Ohishi, Norihisa Ito, Michinari Nakamura, Tetsuo Shoji, Charalambos Vlachopoulos, Akira Yamashina, on behalf of the Collaborative Group for Japan Brachial-Ankle pulse wave VELocity individual participant data meta-analysis of prospective studies (J-BAVEL)

Released: September 25, 2017

[Advance Publication] Released: August 24, 2017

1540-1542

Background:The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.

Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD.

Conclusions:The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s.

Galectin-3 and the Mineralocorticoid Receptor Antagonist Canrenone in Mild Heart Failure

Francesco Clemenza, Serge Masson, Pier Giulio Conaldi, Daniele Di Carlo, Alessandro Boccanelli, Gian Francesco Mureddu, Lucio Gonzini, Donata Lucci, Aldo P. Maggioni, Andrea Di Lenarda, Enrico B. Nicolis, Massimo Vanasia, Roberto Latini, on behalf of the AREA IN-CHF Investigators

Released: September 25, 2017

[Advance Publication] Released: August 31, 2017

1543-1546

Background:Galectin-3 (Gal-3) is involved in collagen deposition and inflammation and is a prognostic biomarker in heart failure (HF).

Methods and Results:Gal-3 and other markers of fibrosis or cardiac stress were measured serially in 413 patients with mild HF randomized to the mineralocorticoid receptor antagonist canrenone or placebo to evaluate treatment effect and association with clinical outcome. Gal-3 increased slightly over 6 months in both arms of the study and was associated with clinical endpoints.

Conclusions:Although Gal-3 showed prognostic value, the effect of canrenone on clinical outcomes was unaffected by baseline concentrations of biomarkers of fibrosis or cardiac stress.

Adult Partial Anomalous Pulmonary Venous Connection With Drainage to Left Atrium and Inferior Vena Cava Clearly Visualized on a Combination of Multiple Imaging Techniques

Hajime Kasai, Toshihiko Sugiura, Takahiro Arano, Hiroki Shoji, Takayuki Jujo, Seiichiro Sakao, Nobuhiro Tanabe, Koichiro Tatsumi

Released: September 25, 2017

[Advance Publication] Released: March 31, 2017

1547-1549

Congenital Ostial Atresia of the Left Anterior Descending Artery

Yumi Ishii, Kunio Yufu, Tetsuji Shinohara, Hidekazu Kondo, Akira Fukui, Norihiro Okada, Hidefumi Akioka, Yasushi Teshima, Mikiko Nakagawa, Taiki Nishihara, Eisaku Okuyama, Keisuke Watanabe, Koichi Kikuta, Naohiko Takahashi

Released: September 25, 2017

[Advance Publication] Released: March 31, 2017

1550-1552

Intracardiac Echocardiography-Guided Biopsy of a Lipomatous Cardiac Tumor Arising From the Interatrial Septum

Akira Takashima, Tatsuro Ogata, Hirotsugu Yamada, Tetsuzo Wakatsuki, Masataka Sata

Released: September 25, 2017

[Advance Publication] Released: March 31, 2017

1553-1555

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Circulation Journal Vol. 81(2017) No. 10

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