Nuclear imaging, predominantly with single-photon emission tomography, has established and demonstrated value for the assessment of cardiovascular disease (CVD). Formerly, the clinical application of positron emission tomography (PET) was precluded by methodological complexity, high operating costs and lack of widespread availability. However, as PET and radiotracer development technologies have improved and continue to do so, PET is expected to become a mainstay diagnostic cardiovascular imaging modality. Not only is PET imaging of great importance for routine clinical decision-making and diagnosing CVD, it is also gaining prominence in fundamental and translational research models. The scope of this review is to summarize the state-of-the-art advances in PET imaging methodology, clinical utility and potential future application.  (Circ J 2013; 77: 836–848)

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Although seemingly diverse, the tissue injury at sites of diabetic complications, whether in the heart, kidneys or eyes, shares the common histopathological feature of endothelial cell loss, a consequence of both increased cell death and deficient regeneration. In medium-sized and larger arteries the loss of the protective lining contributes to the atherosclerotic process, while at sites of microvascular disease endothelial cell loss leads to capillary rarefaction and ischemia. The pathophysiology of these changes and their consequences on organ structure and function in diabetes are reviewed, and the potential for endothelial regenerative strategies to enhance repair and ameliorate the long-term complications of diabetes is explored.  (Circ J 2013; 77: 849–856)

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Systemic hypertension represents a significant global concern, because it contributes to vascular and renal morbidity, cardiovascular mortality, and economic burden, hence the impact of hypertension is a major issue in public health worldwide. Improving high blood pressure management is therefore fundamental to influencing clinical outcomes. Despite adherence to multiple available medical therapies, a significant proportion of patients has persistent blood pressure elevation, a condition termed “resistant hypertension”. Renal sympathetic innervations contribute to lack of response of anti-hypertensive drugs through an imbalance of regulatory mechanisms. Renal afferent nerve fibers are responsible for sympathetic activation and contribute to blood pressure homeostasis while afferent signals from the kidneys are integrated at the central nervous system and enhance sympathetic nerve discharge. In this regard, a novel strategy that selectively removes these hypertensive contributors represents a new therapeutic opportunity. Recently, a catheter-based method to induce renal sympathetic denervation has been introduced into daily practice. Clinical evaluation of selective renal sympathetic denervation demonstrated a decrease of renal norepinephrine spillover and renin activity, an increase of renal plasma flow, and has confirmed clinically significant, sustained reductions in blood pressure in patients with resistant hypertension. This review summarizes the available data on the role of sympathetic activation in the pathophysiology of hypertension and the current concepts in transcatheter renal artery ablation with radiofrequency delivery for systemic hypertension. Suggestions regarding targets for future systemic hypertension management are also described.  (Circ J 2013; 77: 857–863)

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Atrial fibrillation (AF) is becoming an epidemiologically important syndrome among the developed countries. Although racial differences exist with regard to AF prevalence, it remains unclear whether the AF mortality and morbidity rates exhibit racial differences. Medical treatment and management of AF is aimed at improving the clinical course of AF patients who reside in a particular region; therefore, the AF mortality and morbidity rates should be assessed from both global and local viewpoints. AF is a progressive disease that might be first detected as paroxysmal, persistent, or permanent. The associations between AF progression and AF-related cardiovascular morbidities and those between the cardiovascular morbidity and mortality rates of AF are important matters of discussion, as they reflect the rationale of AF therapy. At present, AF patients have a wide variety of backgrounds, and these analyses would require stratification by risks, which would not be free from racial differences. In this review, the mortality and morbidity rates of Japanese AF patients are reviewed and discussed.  (Circ J 2013; 77: 864–868)

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Coronary artery disease remains a major cause of morbidity and mortality in many developed countries, despite the multidisciplinary approach to its prevention and treatment. Over the past 2 decades, several catheter-based imaging modalities have been developed for precisely visualizing the morphology of coronary plaques that are susceptible to causing subsequent cardiovascular events. This review article summarizes the pathology of vulnerable plaque as a target for invasive imaging technology, and discusses the current role of invasive coronary imaging technologies in identifying high-risk coronary atherosclerotic lesions and supporting clinical decision-making.  (Circ J 2013; 77: 869–875)

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For the past 10 years in the post-genomic era, emerging technologies in human genomic research have provided us with a plethora of genetic variations implicated in the pathogenesis of cardiovascular diseases. Discovering the key target genes in genomic research has contributed to biomedical research on the mechanical pathways of the diseases. In an era with dramatic development of brand new strategies, the conventional evaluation of family aggregation, environmental exposure and clinical phenotype remains of great importance to promote genomic research. Notwithstanding the promising progress in genomic research, we still have an enormous number of issues to overcome before approaching the ultimate goal of human genomics: the successful application of genomic data to personalized medicine.  (Circ J 2013; 77: 876–885)

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The high prevalence of patients with heart failure (HF) with preserved ejection fraction (HFpEF) has highlighted the pivotal role of diastolic function in the development of HF. Abnormalities of diastolic function induce elevated left ventricular (LV) end-diastolic pressure, which leads to pulmonary edema and the symptoms of HF because the LV, left atrium and the pulmonary veins form 1 chamber while the mitral valve is opening. Thus, LV diastolic dysfunction results in the development of HF, in particular, HFpEF. LV stiffness mainly contributes to the transition to HFpEF, but noninvasive assessment and the therapeutic strategy for LV stiffness have not been fully established. This review will focus on the contribution of LV passive stiffness to the development of HFpEF and on the evaluation and treatment of LV stiffening based on insights gained from a hypertensive HFpEF animal model we have developed.  (Circ J 2013; 77: 886–892)

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Background: A rapid heart rate (HR) during atrial fibrillation (AF) and atrial flutter (AFL) in left ventricular (LV) dysfunction often impairs cardiac performance. The J-Land study was conducted to compare the efficacy and safety of landiolol, an ultra-short-acting β-blocker, with those of digoxin for swift control of tachycardia in AF/AFL in patients with LV dysfunction. Methods and Results: The 200 patients with AF/AFL, HR ≥120beats/min, and LV ejection fraction 25–50% were randomized to receive either landiolol (n=93) or digoxin (n=107). Successful HR control was defined as ≥20% reduction in HR together with HR <110beats/min at 2h after starting intravenous administration of landiolol or digoxin. The dose of landiolol was adjusted in the range of 1–10μg·kg^–1·min^–1 according to the patient’s condition. The mean HR at baseline was 138.2±15.7 and 138.0±15.0beats/min in the landiolol and digoxin groups, respectively. Successful HR control was achieved in 48.0% of patients treated with landiolol and in 13.9% of patients treated with digoxin (P<0.0001). Serious adverse events were reported in 2 and 3 patients in each group, respectively. Conclusions: Landiolol was more effective for controlling rapid HR than digoxin in AF/AFL patients with LV dysfunction, and could be considered as a therapeutic option in this clinical setting.  (Circ J 2013; 77: 908–916)

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Background: Recent clinical trials using rosuvastatin, a hydrophilic statin, did not show beneficial effects on cardiovascular events in patients with heart failure. We examined the cardioprotective effects of pitavastatin, a lipophilic statin, on Japanese patients with chronic heart failure (CHF). Methods and Results: A total of 574 Japanese patients with CHF were randomly assigned to the pitavastatin group (n=288) or the control group (n=286). There was no significant difference between the 2 groups for the primary outcome, which was a composite of cardiac death and hospitalization for worsening HF (adjusted hazard ratio (aHR): 0.922, 95% confidence interval (CI): 0.632–1.345, P=0.672). A strongly significant statistical interaction between the effect of pitavastatin and left ventricular ejection fraction (LVEF) was found (P=0.004). In patients with LVEF ≥30%, a significant reduction in the primary outcome (aHR: 0.525, 95% CI: 0.308–0.896, P=0.018) was observed in the pitavastatin group. Pitavastatin did not show any effects on the primary outcome (aHR: 1.582, 95% CI: 0.890–2.813, P=0.118) in the subgroup of patients with LVEF <30%. Conclusions: Pitavastatin did not reduce cardiac death or hospitalization for worsening HF in Japanese patients with CHF. (UMIN-ID: UMINC000000428).  (Circ J 2013; 77: 917–925)

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Background: A disease management program can reduce mortality and rehospitalization of patients with heart failure (HF), but little is known about whether it can improve psychological status. The purpose of this study was to determine the effects of home-based disease management on the psychological status of patients with HF. Methods and Results: We randomly assigned patients hospitalized for HF to undergo either home-based disease management (n=79) or usual care (n=82). The mean age of the study patients was 76 years, 30% were female, and 93% were in NYHA class I or II. Home-based disease management was delivered by nurses via home visit and telephone follow-up to monitor symptoms and body weight and to educate patients. The primary endpoint was psychological status, including depression and anxiety assessed by the Hospital Anxiety and Depression Scale during follow-up of 1 year. Secondary endpoints included quality of life, all-cause death and hospitalization for HF. The intervention group had significantly lower depression (P=0.043) and anxiety (P=0.029) scores than the usual-care group. There were no significant differences in all-cause death [hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.37–2.61, P=0.967]. However, hospitalization for HF was significantly lower in the intervention group than in the usual-care group (HR 0.52, 95% CI 0.27–0.96, P=0.037). Conclusions: Home-based disease management improved psychological status and also reduced rehospitalization for HF in patients with HF.  (Circ J 2013; 77: 926–933)

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Background: Japanese patients have been at low risk for cardiovascular events compared with Western countries, but the data regarding current treatment status and rate of subsequent atherothrombotic events after acute coronary syndrome (ACS) are limited in Japanese patients. The objective of this study was to clarify the treatment status and long-term outcomes in Japanese ACS patients. Methods and Results: The Prevention of AtherothrombotiC Incidents Following Ischemic Coronary attack (PACIFIC) registry is a multicenter, prospective observational study of Japanese ACS patients. Consecutive patients aged ≥20 years hospitalized for ACS were enrolled from 96 hospitals and followed up for 2 years (n=3,597). ST-segment elevation myocardial infarction (STEMI) was the most frequent type of ACS (59.4%). The vast majority (93.5%) of patients underwent percutaneous coronary intervention (PCI), with a success rate of 93.9%. Frequent use of guideline-recommended pharmacological treatments was also indicated. Cumulative incidence of major adverse cardiac and cerebrovascular events (MACCE) was 6.4% (7.5% for STEMI and 4.8% for non-STEMI or unstable angina), and all-cause mortality was 6.3%. Conclusions: The PACIFIC registry has identified an incidence of MACCE of 6.4% and that of mortality at 6.3% in Japanese ACS patients at 2-year follow-up. A high proportion of patients underwent PCI, and the PCI success rate was high. Proactively performed successful PCI was considered to have contributed to favorable outcomes in these patients.  (Circ J 2013; 77: 934–943)

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Background: Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF. Methods and Results: The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality. Conclusions: The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.  (Circ J 2013; 77: 944–951)

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Background: Our goal was to investigate the correlation between the dysregulation of transforming growth factor-β₁ (TGF-β₁) and cystic medial degeneration in the aortic aneurysmal tissues of in Marfan syndrome (MFS) patients. Although aortic aneurysm in animal models of MFS is related to the dysregulation of TGF-β, it has yet to be determined whether TGF-β dysregulation correlates with pathogenic aneurysmal characteristics in MFS patients. Methods and Results: Compared with aortic tissue from normal individuals, the medial layers of aortic tissue from MFS patients exhibited profound cystic medial degeneration and cellular apoptosis. These histopathologic changes positively correlated with the extent of TGF-β₁ signaling activation (Smad2 phosphorylation) in aneurysmal aortic tissue. In addition, the level of TGF-β₁ expression in peripheral blood and aneurysmal aortic tissues was significantly elevated in MFS patients. A significant positive correlation was observed between the plasma level of active TGF-β₁ in MFS patients and the severity of cystic medial degeneration and Smad2 phosphorylation in aneurysmal aortic medial layers. Conclusions: We found a strong association between the dysregulation of TGF-β₁ and aortic pathogenesis in human MFS patients. This suggests that the plasma concentration of TGF-β₁ in MFS patients might be a useful biomarker of the progression of aortic aneurysms.  (Circ J 2013; 77: 952–958)

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Background: Brugada syndrome (BrS) is characterized by specific alterations on ECG in the right precordial leads and associated with ventricular arrhythmia that may manifest as syncope or sudden cardiac death. The major causes of BrS are mutations in SCN5A for a large subunit of the sodium channel, Nav1.5, but a mutation in SCN3B for a small subunit of sodium channel, Navβ3, has been recently reported in an American patient. Methods and Results: A total of 181 unrelated BrS patients, 178 Japanese and 3 Koreans, who had no mutations in SCN5A, were examined for mutations in SCN3B by direct sequencing of all exons and adjacent introns. A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls. The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells. Whole-cell patch clamp recordings of the transfected cells revealed that the sodium currents were significantly reduced by the SCN3B mutation. Conclusions: The Val110Ile mutation of SCN3B is a relatively common cause of SCN5A-negative BrS in Japan, which has a reduced sodium current because of the loss of cell surface expression of Nav1.5.  (Circ J 2013; 77: 959–967)

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Background: Idiopathic ventricular fibrillation (VF) or polymorphic ventricular tachycardia (PVT) arising from the right ventricular outflow tract (RVOT) is occasionally observed. The difference in the initial ventricular premature contraction (VPC) between VF/PVT and monomorphic VT (MVT) from the RVOT, however, has not yet been fully investigated. Methods and Results: The electrocardiogram findings and the clinical characteristics were compared between 14 patients with PVT and 77 with MVT. The episodes of syncope were more frequent in the VF and/or PVT group (57%) than in the MVT group (10%). An initial VPC with a positive QRS complex in lead I was observed in 10 (71%) of 14 patients with VF/PVT, and in 27 (35%) of 77 patients with MVT (P<0.05). Although radiofrequency (RF) catheter ablation targeting the trigger VPC often produced a morphological change, VF/PVT was eliminated in 13 (93%) of 14 patients after additional RF applications. Conclusions: Malignant arrhythmias from the RVOT, although rare, should be considered when the patient has a syncopal episode and VPC with a positive QRS complex in lead I.  (Circ J 2013; 77: 968–974)

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Background: Pericardial effusion (PE) may complicate permanent heart rhythm device (HRD: pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy) placement. Incidence of and risk factors for this complication have never been prospectively evaluated. Methods and Results: The subjects of this prospective observational study were 968 consecutive patients undergoing HRD implantation or upgrade, and underwent echocardiographic evaluation before and 24h after the operation. PE was documented in 98 patients (10%), 14 (1.5%) of whom progressed to cardiac tamponade requiring pericardiocentesis (n=12; 86%) or surgical treatment (n=2; 14%). In 70% (10/14) of those patients a bloody effusion suggested cardiac perforation of an implanted lead; acute pericarditis was observed in the remaining 30% (4/14). At multivariate analysis, female gender (hazard ratio [HR], 2.7; 95% confidence interval [CI]: 1.4–3.5, P=0.01) was predictive in the case of any post-procedural PE, whereas intake of antiplatelet medication (HR, 3.1; 95% CI: 2.1–3.8, P=0.01) was predictive for cardiac tamponade. Previous cardiac surgery (HR, 0.70; 95% CI: 0.50–0.92, P=0.02) was a protective factor in any PE and cardiac tamponade. None of the 84 patients with small or moderate PE required pericardial drainage. After 3.1±0.5 months, a PE was no longer observed at echocardiography in 71% of those patients. Conclusions: PE is frequently seen after HRD implantation, but rarely requires any therapy. Female gender and antiplatelet therapy are risk factors, whereas previous cardiac surgery was a protective factor.  (Circ J 2013; 77: 975–981)

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Background: We assessed radiographic kidney enhancement following an emergency coronary procedure as a predictor of contrast-induced nephropathy (CIN) and poor long-term outcome. Methods and Results: We enrolled 126 consecutive patients who underwent an emergency coronary procedure and abdominal X-ray within 24h. We defined kidney enhancement as positive when the density of the kidneys was equal to or higher than that of the lumbar vertebrae. Of the 126 patients, 11 showed kidney enhancement and 115 did not. There were no significant differences in the baseline characteristics of patients with and without kidney enhancement. The incidence of CIN was significantly higher in patients with than in those without kidney enhancement (91% vs. 6%, P<0.01). During a mean follow-up of 21±16 months, 5 of 11 patients with kidney enhancement had poor outcomes, such as renal replacement therapy or death, whereas poor outcomes were observed in only 12 of 115 patients without kidney enhancement. Kaplan-Meier analysis revealed a significant difference in the probability of a poor outcome between patients with and those without kidney enhancement (46% vs. 10%, P<0.01). Conclusions: Radiographic kidney enhancement following a percutaneous coronary procedure predicts the occurrence of CIN and poor clinical outcome.  (Circ J 2013; 77: 982–987)

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Background: In long-term follow-up after drug-eluting stents (DES) implantation, late target lesion revascularization (TLR) is occasionally required. However, the incidence and predictors for late TLR with DES have not been fully investigated. Methods and Results: Between August 2004 and March 2005, 249 consecutive patients underwent percutaneous coronary intervention with sirolimus-eluting stents (SES) at our institution. Angiographic follow-up data were obtained in 228 patients (91.6%) with 274 lesions (91.6%) at 8 months. TLR incidence was evaluated up to 5 years. The 5-year clinical follow-up data were obtained in 222 patients (97.4%) with 264 lesions (96.4%). The incidence of early TLR before 1 year was 16.7%, and that of late TLR (1–5 years) was 8.3% (2.1% per year). Multivariate analysis indicated that significant predictors for late TLR were insulin-treated diabetes mellitus (DM) (odds ratio (OR) 10.88, P=0.001), stent fracture (OR 27.24, P=0.012), and age (OR 0.94, P=0.026). No association was observed between late TLR and lesion characteristics, including parameters measured by quantitative coronary angiography other than stent fracture, at baseline, post procedure, and follow-up. Conclusions: Late TLR after SES implantation occurred in approximately 2.1% of lesions per year after the first year without attenuation up to 5 years. Significant predictors for late TLR were insulin-treated DM, stent fracture and younger age. Careful long-term follow-up after SES implantation might be recommended.  (Circ J 2013; 77: 988–994)

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Background: A novel control system for the EVAHEART left ventricular assist device (LVAD), known as the Native Heart Load Control System (NHLCS), can change the device’s rotational speed (RS) in synchrony with the heartbeat. The system enhanced coronary flow (CoF) with the counter-pulse mode in normal goats’ hearts, so we examined the change in CoF in goats with acute ischemic heart failure (HF). Methods and Results: We studied 14 goats (56.1±6.9kg) with acute ischemic HF induced by coronary microsphere embolization. We installed EVAHEART and ran the device in 4 modes [continuous support, circuit-clamp, counter-pulse (raise RS in diastole), and co-pulse (raise RS in systole)] with 50% or 100% bypass in each mode. In comparison with the circuit-clamp mode, CoF was 121.0±14.1% in the counter-pulse mode and 102.9±7.9% in the co-pulse mode, whereas it was 113.5±10.6% in the continuous mode, with 100% bypass (P<0.05). The same difference was confirmed with 50% bypass. The results indicated that a LVAD in an acute ischemic heart enhanced CoF, and that CoF was greater in the counter-pulse mode and smaller in the co-pulse mode relative to the continuous mode. Conclusions: By using NHLCS to change CoF, recovery of native heart function with a LVAD has a better prognosis.  (Circ J 2013; 77: 995–1000)

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Background: The aim of this study was to examine trends of clinical outcome and to clarify surrogate markers when titrating β-blocker in heart failure patients with reduced left ventricular ejection fraction (HFrEF, LVEF <50%). Methods and Results: Consecutive HFrEF patients starting on β-blocker were divided into 2 groups according to time of dose fixation attainment: before 31 December 2005 (group 1, n=108) or after 1 January 2006 (group 2, n=119). There were no significant differences in patient characteristics between the 2 groups at baseline. Beta-blocker fixed dose was higher with lower resting heart rate in group 2 (6.2±5.7mg/day vs. 9.5±9.1mg/day in carvedilol equivalent dose, P=0.001; 74.2±11.1beats/min vs. 70.2±9.7beats/min, P=0.004). The rate of HF hospitalization and/or all-cause death after 36 months was lower in group 2 than in group 1 (22% vs. 38%, P=0.011; hazard ratio, 0.90; P=0.012). Cox regression analysis showed that β-blocker ≥10mg/day and achieved heart rate ≤71beats/min predicted a better outcome (both P<0.05). Conclusions: Recent improvement of clinical outcome among HFrEF patients may be attributable to the up-titration policy accompanying lowered heart rate. Resting heart rate ≤71beats/min and β-blocker ≥10mg/day (ie, 50% of the target dose for Japanese patients) could be surrogate markers when titrating β-blocker.  (Circ J 2013; 77: 1001–1008)

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Background: Cadmium-zinc-telluride (CZT) solid-state detectors have been recently introduced into the field of myocardial perfusion imaging. The aim of this study was to prospectively compare the diagnostic performance of the CZT high-speed gamma camera (Discovery NM 530c) with that of the standard 3-head gamma camera in the same group of patients. Methods and Results: The study group consisted of 150 consecutive patients who underwent a 1-day stress-rest ^99mTc-sestamibi or tetrofosmin imaging protocol. Image acquisition was performed first on a standard gamma camera with a 15-min scan time each for stress and for rest. All scans were immediately repeated on a CZT camera with a 5-min scan time for stress and a 3-min scan time for rest, using list mode. The correlations between the CZT camera and the standard camera for perfusion and function analyses were strong within narrow Bland-Altman limits of agreement. Using list mode analysis, image quality for stress was rated as good or excellent in 97% of the 3-min scans, and in 100% of the ≥4-min scans. For CZT scans at rest, similarly, image quality was rated as good or excellent in 94% of the 1-min scans, and in 100% of the ≥2-min scans. Conclusions: The novel CZT camera provides excellent image quality, which is equivalent to standard myocardial single-photon emission computed tomography, despite a short scan time of less than half of the standard time.  (Circ J 2013; 77: 1009–1017)

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Background: Endothelial dysfunction and autonomic nervous system imbalance are both risk markers of atherosclerotic vascular damage. The relationship between these 2 factors, however, has not been clarified concisely. Methods and Results: Flow-mediated dilation (FMD) was measured in 47 patients with ischemic heart disease (IHD; mean age, 68.1±7.1 years) using an ultrasound semi-automatic measuring system (UNEXEF18G), and autonomic nervous system activity was evaluated by simultaneous measurements of heart rate variability. FMD was significantly correlated with standard deviation of normal-to-normal beats (r=0.33, P=0.022) and the power ratio of low-frequency power to high-frequency power (LF/HF; r=–0.38, P=0.0087). Furthermore, multiple regression analysis indicated that LF/HF was the most important predictor of the magnitude of FMD. This interaction was severely blunted by β-blockers and the presence of diabetes. Moreover, standardized FMD according to autonomic nervous system activity was a better predictor of future cardiovascular events than FMD. Subjects with cardiovascular events had a significantly smaller corrected FMD (event (+), 3.62±0.41; event (–), 5.10±2.35; P=0.001), and the higher corrected FMD was associated with longer event-free survival. Conclusions: Autonomic nervous system activity is an important regulatory factor of FMD in subjects with IHD. Assessment of this interaction can help provide more accurate risk stratification of subjects with IHD.  (Circ J 2013; 77: 1018–1025)

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Background: Little is known about the prognostic significance of elevated serum heart-type fatty acid-binding protein (H-FABP) in post-acute myocardial infarction (post-AMI) patients. Methods and Results: A total of 1,283 post-AMI patients with available serum samples collected in the convalescent stage were studied. During a median follow-up period of 1,785 days, 176 patients (14%) had adverse events (all-cause mortality, n=81; non-fatal MI, n=44; readmission for heart failure [HF], n=51). Patients were divided into 2 groups according to a serum H-FABP level of 6.08ng/ml, which was determined to be the optimal cut-off for discriminating all-cause mortality based on the maximum value of the area under the receiver operating characteristic curve. Patients with elevated H-FABP (>6.08ng/ml, n=224) had a significantly higher incidence of death (18.3% vs. 3.8%, P<0.001) and readmission for HF (10.3% vs. 2.6%, P<0.001), but not of non-fatal MI (4.5% vs. 3.2%, P=0.187), compared to those with H-FABP <6.08ng/ml. Multivariate Cox regression analysis indicated that elevated serum H-FABP was associated with an increased risk of mortality (hazard ratio [HR], 1.91; 95% confidence interval [CI]: 1.03–3.51, P=0.039) and readmission for HF (HR, 2.49; 95% CI: 1.15–5.39, P=0.020). Conclusions: Elevated serum H-FABP during the convalescent stage of AMI predicted long-term mortality and readmission for HF after survival discharge in the post-AMI patients.  (Circ J 2013; 77: 1026–1032)

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Background: The clinical significance and prevalence of exercise-induced ST elevation (ESTE) in non-ischemic dilated cardiomyopathy (NIDCM) patients are unknown. Methods and Results: We retrospectively examined 12-lead ECGs during cardiopulmonary exercise testing in 360 consecutive NIDCM patients (left ventricular ejection fraction (LVEF) <45%) with narrow QRS. ESTE was defined as ≥1.0mm ST (J-point) elevation compared with baseline. During long-term follow-up for major cardiac events (death, transplantation, or LV assist device implantation), ESTE was recognized in 50 patients (14%). They had much lower LVEF than patients without ESTE (20±7% vs. 27±7%, respectively, P<0.001), whereas the differences in peak VO₂ (P=0.01) and VE/VCO₂ slope (P=0.04) were relatively small. Major cardiac events occurred more frequently in patients with ESTE than in those without ESTE (39% vs. 12% at 48 months). Increased event rates were associated with low peak VO₂ (<14ml·min^–1·kg^–1) in patients without ESTE (39% vs. 23%, P<0.05), but not in those with ESTE (50% vs. 62%, NS). Cox multivariate analysis revealed ESTE as the strongest independent prognosticator among exercise parameters (hazard ratio: 2.41 [95% confidence interval 1.03–5.63], P<0.05). Conclusions: A substantial number of NIDCM patients exhibit ESTE, which indicates a poor prognosis. Low peak VO₂ and ESTE may reflect different aspects of the pathophysiological processes that deteriorate heart failure.  (Circ J 2013; 77: 1033–1039)

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Background: The interventricular septum in hypertrophic cardiomyopathy (HC) has a unique shape, which is characterized by the convex curvature toward the left ventricle (LV). The aim of this study was to examine the relationship between curvature of the LV wall and regional myocardial strain. Methods and Results: Fifty-six patients with HC (mean age, 55±12 years) and 20 age- and sex-matched control subjects (mean age, 56±8 years) were enrolled. The curvature index (1/radius) was measured by drawing along the endocardial surface from the apical 4-chamber and short axis views. Peak systolic strain was calculated in the septal and lateral walls using 2-D speckle tracking echocardiography. The septal curvature index and septal longitudinal strain were significantly lower in the HC group than in the control group. A multivariate model using the HC patient data showed that the septal curvature index and septal thickness were the independent determinants of septal longitudinal strain (septal curvature index: β=–0.421, P<0.001; septal thickness: β=0.401, P=0.002). In addition, global longitudinal strain and E/e’ were worse in the lower septal curvature index group compared with the higher group. Conclusions: Septal longitudinal strain is associated with the degree of septal curvature. This indicates a possible link between LV wall configuration and regional myocardial function.  (Circ J 2013; 77: 1040–1045)

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Background: A limited number of studies have assessed the benefit and risk among the different antiplatelet and antithrombotic therapies in patient with stroke and peripheral artery disease (PAD). We compared the efficacy and safety of clopidogrel, cilostazol, warfarin, and aspirin. Methods and Results: A retrospective cohort study analyzing the Taiwan National Health Insurance Research Dataset identified patients with stroke and PAD from 2002 to 2008. Patients were stratified according to their use of aspirin, clopidogrel, cilostazol, warfarin or combination therapy. A total of 1,686 patients were enrolled: aspirin (n=862), clopidogrel (n=92), warfarin (n=136), cilostazol only (n=515), and cilostazol-based combination therapy (n=81). Compared with aspirin, cilostazol could reduce the risk of ischemic stroke [hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.63–0.98, P=0.0349) and no increase in hemorrhagic events (HR 0.98, 95% CI 0.74–1.32, P=0.9122). Clopidogrel decreased the risk of ischemic stroke (HR 0.47, 95% CI 0.29–0.78, P=0.0033) and hemorrhagic events (HR 0.64, 95% CI 0.31–0.96, P=0.034) more than aspirin. There was no statistical difference regarding the risk of stroke and hemorrhagic events among warfarin, cilostazol-based combination therapy and aspirin. Conclusions: Cilostazol and clopidogrel were more effective in preventing recurrent ischemic stroke without increased hemorrhagic events than aspirin in patients with PAD.  (Circ J 2013; 77: 1046–1052)

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Background: Prostacyclin (PGI₂) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI₂ in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI₂ in EPC-mediated angiogenesis using BM-specific IP deletion mice. Methods and Results: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP^–/–). Recovery of blood flow (RBF) in WT/BM(IP^–/–) was impaired for 28 days after HLI, whereas RBF in IP^–/–/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP^–/–) was completely recovered by intramuscular injection of WT EPCs but not IP^–/– EPCs. The impaired effects of IP^–/– EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP^–/–EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin β1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects. Conclusions: PGI₂ may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects.  (Circ J 2013; 77: 1053–1062)

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Background: The implantation of skeletal myoblast (SMB) cell-sheets over the damaged area of a myocardial infarction (MI) has been shown to improve global left ventricular (LV) function through a paracrine effect. However, the regeneration process has not been fully evaluated. We hypothesized that the use of tissue Doppler strain M-mode imaging to assess myocardial layer-specific strain might enable detailed visual evaluation of the regenerative ability of SMBs. Methods and Results: SMBs were cultured on temperature-responsive culture dishes to generate cell-sheets. At 4 weeks after inducing anterior MI, the animals were divided into 2 groups: SMB cell-sheet implantation and sham operation (n=6 in each). A total of 30 cell-sheets (1.5×10⁷ cells/sheet) were placed on the epicardium, covering the infarct and border regions. Subendocardial and subepicardial strain values were measured in the infarct, border, and remote regions by tissue Doppler strain analysis. SMB cell-sheet implantation produced the following major effects: progression of LV remodeling was prevented and global LV ejection fraction increased; the subendocardial strain was significantly greater than the subepicardial strain in the treated border region; vascular density in the subendocardium was significantly higher than in the subepicardium in the treated region; the expression of vascular endothelial growth factor was significantly increased. Conclusions: Tissue Doppler strain analysis allows precise evaluation of the effect of cell-sheet implantation on layer-specific myocardial function.  (Circ J 2013; 77: 1063–1072)

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Background: The purpose of this study was to evaluate the effect of anatomical variation of the brachial artery on flow-mediated vasodilation (FMD) in healthy subjects and patients with cardiovascular disease (CVD). Methods and Results: There was no significant difference in the prevalence of double brachial artery between healthy subjects (6.1%) and patients with CVD (6.5%). In healthy subjects, FMD was larger in a single brachial artery than in large and small vessels of a double brachial artery (7.2±3.4% vs. 4.7±3.3% and 4.5±2.5%, P<0.01, respectively). In patients with CVD, there were no significant differences in FMD among a single brachial artery, large vessel of a double brachial artery and small vessel of a double brachial artery (3.3±1.4%, 3.1±2.3% and 3.6±2.1%). FMD in a single brachial artery was smaller in patients with CVD than in healthy subjects. There were no significant differences in FMD in the large vessel of a double brachial artery between the 2 groups or in the small vessel of a double brachial artery between the 2 groups. Nitroglycerine-induced vasodilation was similar in all arteries in healthy subjects and patients with CVD. Conclusions: When measuring FMD, the existence of a double brachial artery should be checked. FMD measured in a double brachial artery may be underestimated in healthy subjects.  (Circ J 2013; 77: 1073–1080)

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