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Background: The optimal medication therapy for patients with angiographically intermediate coronary artery stenosis in whom revascularization was deferred by fractional flow reserve (FFR) remains to be fully established. The aim of this study was to investigate the long-term outcomes of continuous statin therapy in those patients. Methods: This sub-analysis of the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) included 1113 patients who have completed 2-year follow-up and were divided into 2 groups according to continuation of statin treatment. Landmark analyses were performed that compared treatments during the follow-up period between 2 years and 5 years to assess the composite endpoints, including target vessel failure and non-cardiac death in the Cox proportional hazard regression with mixed effects account for institutional variety and inverse probability of treatment weighting (IPTW) analyses. Target vessel failure was defined as cardiac death, target-vessel related myocardial infarction, and clinically driven target vessel revascularization. Results: By the start of the landmark at 2-year, 681 (61.2%) patients had continued the statin, whereas 432 (38.8%) had not continued. Composite endpoint was observed in 68 (10.0%) patients with continuous statin and 54 (12.5%) in those with discontinuous statin. The multivariate mixed effects Cox regression model and IPTW adjusted for baseline characteristics, comorbidity, FFR value, culprit vessel, and medication revealed that the continuous statin was not associated with a low risk of composite endpoint (HR: 0.81, 95% CI: 0.54 to 1.21, HR: 0.81, 95% CI: 0.62 to 1.05, respectively). Subgroup analysis showed significant interaction between sex, prior myocardial infarction (pMI) and the continuous statin, indicating that the continuous statin therapy was associated with a low risk of composite endpoint in male (HR: 0.62, 95% CI: 0.41, 0.93) and patients with pMI (HR: 0.42, 95% CI 0.22, 0.82). Conclusions: The present study showed that continuous statin therapy was not associated with better long-term outcomes in patients with deferral of coronary intervention based on FFR.

Background Stent thrombosis (ST) after drug‐eluting stent (DES) implantation remains a life‐threatening complication. Recurrent ST (RST) is not a rare phenomenon, potentially contributing to high mortality after the index ST events. However, little evidence is available about the incidence, risk factors, and clinical outcomes of definite RST after DES thrombosis. Methods and Results From REAL‐ST (Retrospective Multicenter Registry of ST After First‐ and Second‐ Generation DES Implantation), this study evaluated 595 patients with definite ST (first‐generation DES thrombosis, n=314; second‐generation DES thrombosis, n=281). During a median follow‐up of 31 months, we identified 32 patients with definite RST after first‐generation DES thrombosis (n=18) and second‐generation DES thrombosis (n=15). Cumulative incidence of RST was 4.5% and 6.0% at 1 and 5 years, respectively, which did not significantly differ between first‐generation DES thrombosis and second‐generation DES thrombosis. Independent predictors of definite RST were early ST (hazard ratio [HR], 2.38; 95% CI, 1.06–5.35 [ P =0.035]) and multivessel ST (HR, 3.47; 95% CI, 1.03–11.7 [ P =0.044]). Definite RST was associated with a 2.8‐fold increased risk of mortality (adjusted HR, 2.78; 95% CI, 1.35–5.73 [ P =0.006]). Conclusions Cumulative incidence of definite RST did not significantly differ between first‐generation DES thrombosis and second‐generation DES thrombosis. Early ST and multivessel ST were risk factors of definite RST. Definite RST significantly increased mortality after DES thrombosis, highlighting the clinical importance of preventing RST to improve outcomes of patients with ST. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: UMIN000025181.

Background: Ultrasonic flow ratio (UFR) is a novel method for fast computation of fractional flow reserve (FFR) from intravascular ultrasound images. The objective of this study is to evaluate the diagnostic performance of UFR using wire-based FFR as the reference. Methods: Post hoc computation of UFR was performed in consecutive patients with both intravascular ultrasound and FFR measurement in a core lab while the analysts were blinded to FFR. Results: A total of 167 paired comparisons between UFR and FFR from 94 patients were obtained. Median FFR was 0.80 (interquartile range, 0.68–0.89) and 50.3% had a FFR≤0.80. Median UFR was 0.81 (interquartile range, 0.69–0.91), and UFR showed strong correlation with FFR ( r =0.87; P P P =0.48), prior myocardial infarction ( P =0.29), and imaging catheters ( P =0.22). Intraobserver and interobserver variability of UFR analysis was 0.00±0.03 and 0.01±0.03, respectively. Median UFR analysis time was 102 (interquartile range, 87–122) seconds. Conclusions: UFR had a strong correlation and good agreement with FFR. The fast computational time and excellent analysis reproducibility of UFR bears the potential of a wider adoption of integration of coronary imaging and physiology in the catheterization laboratory.

Background: The safety of fractional flow reserve (FFR)-based deferral of revascularization remains to be fully established in real-world practice. We sought to assess clinical outcomes after deferral of revascularization based on FFR. Methods: The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR at 28 Japanese centers. The primary study end point was the cumulative 2-year incidence of target vessel failure, including cardiac death, target-vessel related myocardial infarction, and clinically driven target vessel revascularization. Results: The mean FFR was 0.86±0.06. At 2 years, the target vessel failure rate was 5.5% in deferred lesions, mainly driven by a high rate of clinically driven target vessel revascularization (5.2%), and significantly increased with decreasing FFR, especially in the proximal location. Cardiac death and target-vessel related myocardial infarction rarely occurred during the 2-year follow-up (0.41% and 0.41%, respectively). Independent predictors of 2-year target vessel failure were FFR value (per 0.01 decrease; hazard ratio [HR] 1.07 [95% CI, 1.04–1.11], P P P =0.003), hemodialysis (HR, 2.90 [95% CI, 1.11–7.58]; P =0.03), and right coronary artery lesion (HR, 1.78 [95% CI, 1.02–3.11], P =0.042). Conclusions: The J-CONFIRM registry demonstrated the 2-year target vessel failure rate was 5.5% in deferred lesions, highlighting the safety of FFR-based deferral of revascularization in daily practice. Clinical Trial Registration: URL: http://www.umin.ac.jp . Unique identifier: UMIN000014473.

Background Total atherosclerosis disease burden is associated with clinical outcomes in patients with coronary artery disease. However, the influence of sex on the relationship between total anatomical and physiologic disease burdens and their prognostic implications have not been well defined. Methods and Results A total of 1136 patients who underwent fractional flow reserve (FFR) measurement in all 3 major coronary arteries were included in this study. Anatomical and physiologic total disease burden was assessed by SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score, residual SYNTAX score, a total sum of FFR in 3 vessels (3‐vessel FFR), and functional SYNTAX score. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and ischemia‐driven revascularization at 2 years. There were no differences in angiographic diameter stenosis, SYNTAX score, or residual SYNTAX score between women and men. However, both per‐vessel FFR (0.89±0.10 versus 0.87±0.11, P P< 0.001) were higher in women. Multivariable Cox regression analyses showed that total anatomical and physiologic disease burdens were significantly associated with 2‐year major adverse cardiac events, and there was no significant interaction between sex and total disease burden for clinical outcomes. Conclusions Despite similar angiographic disease severity, both per‐vessel and per‐patient physiologic disease severity was less in women than in men. There was no influence of sex on prognostic implications of total anatomical and physiologic disease burdens in patients with coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01621438.

Background: The basis of discordance between invasive coronary angiographic (ICA) anatomic stenosis and fractional flow reserve (FFR) is not fully understood. We analyzed coronary computed tomography angiography (CTA) characteristics of ICA-verified nonobstructive lesions in the proximal or midleft anterior descending artery with FFR ≤0.8, that is, anatomy-physiology mismatch. Methods and Results: CTA and ICA were performed in 108 patients. FFR was measured during intravenous ATP (180 μg/[kg·min]) infusion. CTA-verified plaque characteristics between 53 consecutive ICA-FFR mismatch (ICA–quantitative coronary angiography 0.8) vessels were compared. CTA-verified vessel area (20.7±6.7 versus 16.9±4.8 mm 2 ; P =0.0007), positive area remodeling index (ARI; 1.38±0.23 versus 1.06±0.11; P P P = 0.006), and the prevalence of low attenuation plaque (45.3% versus 9.1%; P 1.13 for predicting ICA-FFR mismatch were 88.7% and 78.2%, respectively. Conclusions: In the absence of anatomically significant stenosis, abnormal FFR is more frequently encountered in patients with CTA-derived positive remodeling, larger plaque burden, and low attenuation plaque. These findings contribute to a better understanding of how FFR-based decision-making might translate into demonstrated superior clinical outcomes.

OBJECTIVES The purpose of this study was to assess the prevalence and to quantify the thin-cap fibroatheroma (TCFA) and ruptured plaques in patients with coronary artery disease using optical coherence tomography (OCT). BACKGROUND TCFA lesions are the most prevalent precursors of plaque rupture, and are responsible for acute coronary syndromes (ACS). There are limited data regarding the frequency and distribution of TCFA in diseased coronary arteries. METHODS Coronary artery OCT was performed in 78 vessels in 47 patients, with stable angina (SA) or ACS. OCT plaque characteristics were derived using criteria that had been validated earlier. TCFA was defined as rich in lipid (two or more quadrants) with thin fibrous cap (

Background— Retrograde approach through collaterals has been introduced for percutaneous recanalization of chronic total occlusion (CTO) of the coronary arteries. We investigated the safety and efficacy of retrograde approaches used for percutaneous recanalization of CTO in a consecutive series of patients. Methods and Results— We studied 157 consecutive patients who underwent retrograde CTO recanalization between 2003 and 2008 at a single center. A total of 118 (75.2%) of these patients have had previously failed antegrade attempts. Septal, epicardial, and saphenous vein graft collaterals were used in 67.5%, 24.8%, and 7.6% of cases, respectively. Collateral channel was crossed by guide wire successfully in 115 (73.2%) cases, and the procedure was successful by retrograde approach in 103 (65.6%) cases. Collateral channels (CCs) were graded as follows: CC0, no continuous connection; CC1, continuous thread-like connection; and CC2, continuous, small sidebranch-like connection. CC1, collateral tortuosity P P =0.01), CC0, corkscrew channel ( P 90� ( P =0.0007), and nonvisibility of connection with recipient vessel were found to be significant predictors of procedural failure. The CC dissection was observed in 6 patients, with 1 needing coil embolization and others who were managed conservatively. The major adverse cardiac events were low, with 1 coronary artery bypass graft, 1 Q-wave myocardial infarction, 5 non–Q-wave myocardial infarctions, and no deaths in this group of patients. Conclusions— The retrograde approach in CTO percutaneous coronary intervention is effective in recanalizing CTO. The success rate by retrograde approach was 65.6%, and final success was 85% in this group with acceptable overall adverse events. We have identified predictors of failure related to collateral morphology.

Introduction: Coronary angiographic anatomical stenosis has not been well correlated with physiological fractional flow reserve (FFR), however, the mechanism of the discordance remains poorly understood. We focused on the patients who had no anatomical significant stenosis by coronary angiogram (CAG) but physiological significant stenosis by FFR (reverse mismatch) in the proximal or mid left anterior descending artery (LAD). We explored what coronary CT angiography (CCTA) findings of the target lesion of the LAD predict abnormal FFR. Methods: ECG-gated CCTA was performed using SOMATOM Definition AS+ (128 slice Siemens) and CAG underwent within 4 weeks. FFR was measured using a pressure guide wire (verrata, Volcano) during ATP infusion. Forty consecutive reverse mismatch (with no anatomical stenosis and FFR≦0.8) pts and 40 no mismatch (with no anatomical stenosis and FFR>0.8) pts were selected. Results: There were no significant differences in mean age (72±10y vs 74±8y), gender (M/F 21/19 vs 28/12), coronary risk factors (DM (9 vs 17), HT(32 vs 30), dyslipidemia (23 vs 18), Smoking (5 vs 4)), angle of LAD and LCX (70±21vs71±20 deg.), proximal reference lumen area (0.14±0.14 vs 0.14±0.11 mm2) and vessel area (0.15±0.04 vs 0.15±0.06mm2), distal reference lumen area (0.11±0.12 vs 0.10±0.04mm2) and vessel area (0.14±0.13 vs 0.12±0.04mm2), grade of plaque calcification, and presence of low density plaque (8 vs 7 pts) between no mismatch and reverse mismatch groups. However, vessel area (0.21±0.07mm2, P=0.0004) and positive remodeling area index (1.40±0.26, P Conclusions: Even if anatomical significant stenosis is not observed, FFR was depressed in patients with large vessel area and positive remodeling area index derived from CCTA at MLA. Large plaque at MLA may be one of the mechanisms of reverse mismatch.

Objective— We performed an association study to identify gene polymorphisms for assessing the genetic risk of ischemic or hemorrhagic stroke. Methods and Results— The study population comprised 3151 unrelated Japanese individuals: 1141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2010 controls. The genotypes for 202 polymorphisms of 152 genes were determined by suspension array technology. Multivariable logistic regression analysis with adjustment for conventional risk factors revealed that the –572G→C polymorphism of the interleukin-6 (IL-6) gene ( IL6 ) was significantly ( P UCP3 ), the –863C→A polymorphism of the tumor necrosis factor (TNF) gene ( TNF ), and the G→A (Gly243Asp) polymorphism of the polycystic kidney disease 1–like gene ( PKD1-like ) were significantly associated with subarachnoid hemorrhage. Conclusions— IL6 genotype may be useful in assessing the genetic risk for atherothrombotic cerebral infarction and intracerebral hemorrhage, and genotypes for UCP3 , TNF , and PKD1-like may be similarly beneficial in assessment of the risk for subarachnoid hemorrhage. Validation of our findings will require additional studies with independent subject panels.

Abstract We investigated the relationships between hyperinsulinemia (a major indicator of the insulin resistance syndrome), blood pressure, dyslipidemia, and coagulation factors in 2606 community-dwelling Japanese individuals as part of the Jichi Medical School Cohort Study. An age-related decrease of the fasting insulin level was found in men but not in women. Body mass index, systolic and diastolic blood pressure, triglyceride and fasting glucose levels, and factor VII activity all increased in both sexes as the insulin level became higher, while the HDL cholesterol level decreased. In addition, total cholesterol and LDL cholesterol levels increased as the insulin level became higher and lipoprotein(a) levels decreased in the men. Fibrinogen levels were not related to the insulin level in either sex. Multiple logistic regression analysis revealed that fasting insulin levels were positively correlated with body mass index and fasting glucose and factor VII activity levels, whereas they were negatively correlated with HDL cholesterol in both sexes. In addition, fasting insulin levels were positively correlated with LDL cholesterol levels in men and with triglyceride levels in women. Our results indicate that hyperinsulinemia is associated with high factor VII activity in a general Japanese population as well as with high blood pressure and dyslipidemia. The accumulation of these cardiovascular risk factors in hyperinsulinemic subjects appears to contribute to cardiovascular events in the Japanese as well as in westerners.

Background: The aim of this study is to asses the effect of 12 month treatment with Fluvastatin (60 mg daily) on progression of fibroatheroma in a non-culprit vessel. Methods: This prospective study was performed at 2 centers and designed to enroll 80 patients. Patients were randomized to receive lipid-lowering therapy by Fluvastatin or a lipid lowering diet. All patients with high low-density lipoprotein-cholesterol level (> 140 mg/dl) were included in the Fluvastatin group. Non-culprit vessels were imaged with a 20 MHz phased-array intravascular ultrasound (IVUS) catheter with motorized pull-back system at 0.5 mm/s. Virtual Histology-derived fibroatheroma (VHD-FA) was defined as 1) percent necrotic core area >20%; 2) percent plaque plus media cross-sectional area >40%. For each image, the area of vessel and each plaque component were calculated. At 12-month followup repeat IVUS measurements were performed. Results: A total of 44 VHD-FAs in the Fluvastatin group and 47 VHD-FAs in the control group were detected at baseline. In the Fluvastatin group, fibrous and fibro-fatty areas are significantly decreased, necrotic core did not increase, and there was a significant reduction in atherogenic lipoproteins. In the control group, fibrous, necrotic core and dense calcium areas significantly increased (table ). Conclusion: Lipid-lowering therapy with Fluvastatin prevented progression of coronary fibroatheroma. Laboratory data and IVUS measurements

Introduction. Hypertriglyceridemia is an important risk factor for coronary heart disease. The purpose of the present study was to identify gene polymorphisms associated with hypertriglyceridemia (serum triglyceride concentration, ≥1.65 mmol/L) for assessment of the genetic risk for this condition. Methods. A total of 5206 individuals from two independent populations was examined: Subject panel A comprised 3787 individuals who either visited outpatient clinics of or were admitted to the participating hospitals because of various symptoms or for a health checkup; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Given the multiple comparisons of genotypes with hypertriglyceridemia, we adopted the criterion of a false discovery rate (FDR) of Results. Evaluation of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that seven polymorphisms [−1131T→ C, −3A→G, and 553G→T (Gly185Cys) of APOA5 ; 1100C→T of APOC3 ; 85T→C of APOA1 ; 41A→G (Glu14Gly) of ACAT2 ; C→G (Ser47Stop) of LPL ] were significantly (FDR < 0.05) associated with hypertriglyceridemia in subject panel A. To validate these associations, we examined the same polymorphisms in subject panel B. The six polymorphisms of APOA5 , APOC3 , APOA1 , and LPL , but not that of ACAT2 , were again significantly associated with hypertriglyceridemia. Serum triglyceride concentrations differed significantly ( P< 0.05, ANOVA) among genotypes of each of these six polymorphisms in both subject panels. The three polymorphisms of APOA5 were in linkage disequilibrium. Conclusions. Polymorphisms of APOA5 , APOC3 , APOA1 , and LPL are determinants of hypertriglyceridemia. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for hypertriglyceridemia and may contribute to the personalized prevention of this condition.

Introduction. A low serum concentration of HDL-cholesterol and a high serum concentration of LDL-cholesterol are risk factors for atherosclerosis. Our goal was to identify genetic variants that confer susceptibility to a low serum concentration of HDL-cholesterol ( Methods. A total of 5213 individuals from two independent populations was examined: Subject panel A comprised 3794 individuals who either visited outpatient clinics of or were admitted to the participating hospitals because of various symptoms or for a health checkup; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined. Given the multiple comparisons of genotypes with these conditions, we adopted the criterion of a false discovery rate (FDR) of Results. Examination of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that six [−1131T→C, −3A→G, and 553G→T (Gly185Cys) of APOA5 ; −250G→A and −515C→T of LIPC ; 13989A→G (Ile119Val) of CYP3A4 ] and three [4070C→T (Arg158Cys) and 3932T→C (Cys112Arg) of APOE ; 190G→A (Val64Ile) of CCR2 ] polymorphisms were significantly (FDR < 0.05) associated with low HDL-cholesterol and high LDL-cholesterol, respectively, in subject panel A. To validate these associations, we examined the same polymorphisms in subject panel B. The three polymorphisms of APOA5 and two polymorphisms of APOE were significantly associated with low HDL-cholesterol and high LDL-cholesterol, respectively. The serum concentrations of HDL-cholesterol and LDL-cholesterol differed significantly ( P < 0.01, ANOVA) among genotypes of the corresponding polymorphisms in both subject panels. The polymorphisms of APOA5 and APOE were each in linkage disequilibrium. Conclusions. Polymorphisms of APOA5 and APOE are determinants of low HDL-cholesterol and high LDL-cholesterol, respectively. Genotyping of these polymorphisms may prove informative for prediction of the genetic risk for these conditions.

Introduction: Aneurysms and dissections at the thoracic aorta (TAA) are the leading causes of mortality and morbidity in the United States and Japan. Although hypertension is a major risk for TAA, several studies have indicated that genetic factors also influence the structural formation of TAA. The purpose of the present study was to identify gene polymorphisms associated with TAA among hypertensive patients for assessment of the genetic risk for this condition. Methods: This case-control study comprised 1351 hypertensive individuals, including 88 subjects with TAA and 1263 without any cardiovascular complications. The genotypes for 142 polymorphisms of 121 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Results: Evaluation of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, body mass index, and prevalence of smoking, diabetes mellitus, hypercholesterolemia, and metabolic syndrome revealed that the T→G (3′ UTR) polymorphism of the thrombospondin 2 gene ( THBS2 ; odds ratio, 4.7) is significantly (P < 0.05) associated with TAA in hypertensive subjects, with the variant G allele representing a risk factor for this condition. Furthermore, the -110A→C polymorphism of heat-shock 70-kD protein 8 gene ( HSPA8 ; odd ratio, 0.3), the C→T (Pro198Leu) polymorphism of the glutathione peroxidase gene ( GPX1 ; odds ratio, 0.3), the -6G→A polymorphism of angiotensin 1 gene ( AGT ; odds ratio, 0.3), and the -850C→T polymorphism of tumor necrosis factor gene ( TNF ; odds ratio, 0.5) were significantly associated with this condition, with the variant allele of each polymorphism being protective against this condition. A stepwise forward selection procedure revealed that polymorphisms of THBS2 , HSPA8 , GPX1 , AGT , and TNF significantly affected the prevalence of TAA. Conclusions: Genetic variant of THBS2 may be a risk factor for TAA in hypertensive patients, whereas variants of HSPA8 , GPX1 , AGT , and TNF may be protective against this condition. Determination of genotypes for these polymorphisms may prove informative for assessment of the genetic risk for TAA.