Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels.

Nardilysin (NRDC) has been shown to be involved in post-translational histone modifications, in addition to enhancement in ectodomain shedding of membrane-anchored protein, which play significant roles in various pathophysiology, including glucose homeostasis, inflammatory diseases and cancer. The present study sought to determine roles of NRDC in the liver on lipid and lipoprotein metabolism. We established liver-specific NRDC deficient mice by use of NRD1 floxed mice and albumin promoter-Cre recombinase (Cre) transgenic mice, and found that their serum low-density lipoprotein (LDL) cholesterol levels were significantly lower than those in control littermate mice. In the liver, LDL receptor (LDLR) mRNA expression was significantly upregulated, while inducible degrader of LDLR (IDOL) and microsomal triglyceride transfer protein (MTP) mRNA expression was significantly downregulated, in liver-specific NRDC deficient mice. Hepatic cell-surface LDLR expression levels were significantly elevated and serum pro-protein convertase subtilisin-kexin type 9 (PCSK9) levels were significantly reduced in mice with hepatic NRDC deficiency. In cultured hepatocytes, NRDC deficiency significantly reduced secreted PCSK9 and increased cell-surface LDLR expression. On the other hand, NRDC overexpression in cultured hepatocytes significantly increased secreted PCSK9 and lowered cell-surface LDLR expression. Thus, NRDC in murine hepatocytes appears to play key roles in cholesterol homeostasis, although the precise molecular mechanisms remain to be determined.

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

Genome-wide profiling of nardilysin target genes reveals its role in epigenetic regulation and cell cycle progression.

Post-translational histone modifications, such as acetylation and methylation, are prerequisites for transcriptional regulation. The metalloendopeptidase nardilysin (Nrdc) is a H3K4me2-binding protein that controls thermoregulation and ß-cell functions through its transcriptional coregulator function. We herein combined high-throughput ChIP-seq and RNA-seq to achieve the first genome-wide identification of Nrdc target genes. A ChIP-seq analysis of immortalized mouse embryo fibroblasts (iMEF) identified 4053 Nrdc-binding sites, most of which were located in proximal promoter sites (2587 Nrdc-binding genes). Global H3K4me2 levels at Nrdc-binding promoters slightly increased, while H3K9ac levels decreased in the absence of Nrdc. Among Nrdc-binding genes, a comparative RNA-seq analysis identified 448 candidates for Nrdc target genes, among which cell cycle-related genes were significantly enriched. We confirmed decreased mRNA and H3K9ac levels at the promoters of individual genes in Nrdc-deficient iMEF, which were restored by the ectopic introduction of Nrdc. Reduced mRNA levels, but not H3K9ac levels were fully restored by the reintroduction of the peptidase-dead mutant of Nrdc. Furthermore, Nrdc promoted cell cycle progression at multiple stages, which enhanced cell proliferation in vivo. Collectively, our integrative studies emphasize the importance of Nrdc for maintaining a proper epigenetic status and cell growth.

Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis.

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis.

Rationale and Design of the PROSPECTIVE Trial: Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease.

BACKGROUND: Reduction of serum LDL-cholesterol by statins was shown to improve clinical outcomes in patients with coronary heart disease (CHD). Although intensive statin therapy significantly reduced cardiovascular risks, atherosclerotic cardiovascular events have not been completely prevented. Therefore, effective pharmacologic therapy is necessary to improve "residual risks" in combination with statins. Probucol has a potent antioxidative effect, inhibits the oxidation of LDL, and reduces xanthomas. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease (PROSPECTIVE) is a multicenter, randomized, prospective study designed to test the hypothesis that the addition of probucol to other lipid-lowering drugs will prevent cerebro- and cardiovascular events in patients with prior coronary events and high LDL cholesterol levels. STUDY DESIGN: The study will recruit approximately 860 patients with a prior CHD and dyslipidemia with LDL-C level ≥140 mg/dl without any medication and those treated with any lipid-lowering drugs with LDL-C level ≥100 mg/dl. Lipid-lowering agents are continuously administered during the study period in control group, and probucol (500 mg/day, 250 mg twice daily) is added to lipid-lowering therapy in the test group. The efficacy and safety of probucol with regard to the prevention of cerebro- and cardiovascular events and the intima-media thickness of carotid arteries as a surrogate marker will be evaluated. SUMMARY: PROSPECTIVE will determine whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes in patients with prior coronary heart disease. Furthermore, the safety of a long-term treatment with probucol will be clarified.

EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.

Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4-associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis.

Incidence and outcome of surgical procedures after coronary artery bypass grafting compared with those after percutaneous coronary intervention: a report from the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2.

BACKGROUND: Noncardiac surgery after percutaneous coronary intervention (PCI) has been reported to be carrying high risk for both ischemic and bleeding complications. However, there has been no report comparing the incidence and outcomes of surgical procedures after coronary artery bypass grafting (CABG) with those after PCI. METHODS AND RESULTS: Among 14 383 patients undergoing first coronary revascularization (PCI, n=12 207; CABG, n=2176) enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2, surgical procedures were performed more frequently after CABG (n=560) than after PCI (n=2398; cumulative 3-year incidence: 27% versus 22%; unadjusted P<0.0001), particularly <6 months of coronary revascularization. The risk for the primary ischemic outcome measure (death/myocardial infarction) at 30-day postsurgical procedures was not significantly different between the CABG and PCI groups (cumulative incidence: 3.1% versus 3.2%; unadjusted P=0.9; adjusted hazard ratio, 0.97; 95% confidence interval, 0.47-1.89; P=0.9). The risk for the primary bleeding outcome measure (moderate or severe bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification) was lower in the CABG groups than in the PCI group (cumulative incidence: 1.3% versus 2.6%; unadjusted P=0.07; adjusted hazard ratio, 0.36; 95% confidence interval, 0.12-0.87; P=0.02). There were no interactions between the timing of surgery and the types of coronary revascularization (CABG/PCI) for both ischemic and bleeding outcomes. CONCLUSIONS: Surgical procedures were performed significantly more frequently after CABG than after PCI, particularly <6 months after coronary revascularization. Surgical procedures after CABG as compared with those after PCI were associated with similar risk for ischemic events and lower risk for bleeding events, regardless of the timing after coronary revascularization.

MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.

Relation of contrast-induced nephropathy to long-term mortality after percutaneous coronary intervention.

There is little information on the effect of contrast-induced nephropathy (CIN) on long-term mortality after percutaneous coronary intervention in patients with or without chronic kidney disease (CKD). Of 4,371 patients who had paired serum creatinine (SCr) measurements before and after percutaneous coronary intervention and were discharged alive in the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry, the incidence of CIN (an increase in SCr of ≥0.5 mg/dl from the baseline) was 5% in our study cohort. The rate of CIN in patients with CKD was 11%, although it was 2% without CKD (p <0.0001). During a median follow-up of 42.3 months after discharge, 374 patients (8.6%) died. After adjustment for prespecified confounders, CIN was significantly correlated with long-term mortality in the entire cohort (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.62 to 2.29, p <0.0001) and in patients with CKD (HR 2.62, 95% CI 1.91 to 3.57, p <0.0001) but not in patients without CKD (HR 1.23, 95% CI 0.47 to 2.62, p = 0.6). Sensitivity analyses confirmed these results using the criteria defined as elevations of the SCr by ≥25% and 0.3 mg/dl from the baseline, respectively. In conclusion, CIN was significantly correlated with long-term mortality in patients with CKD but not in those without CKD.

Timing of valve repair for severe degenerative mitral regurgitation and long-term left ventricular function.

OBJECTIVES: Current guidelines recommended surgery for patients with severe degenerative mitral regurgitation (MR) when specific left ventricular (LV) dimensions or ejection fraction (EF) are reached, based on previous postoperative survival studies. The aim of this study was to evaluate the incidence and predictors of long-term postoperative LV dysfunction, and investigate the preoperative parameters necessary to maintain or recover long-term LV function in the era of mitral valve (MV) repair. METHODS: We retrospectively reviewed 473 consecutive patients undergoing MV repair for severe degenerative MR for whom both preoperative and 3-year postoperative echocardiographic data were available in our institution. Preoperative and 3-year postoperative echocardiographic data and clinical outcomes were evaluated. RESULTS: Receiver operating characteristic analysis identified preoperative LVEF 63% or less (area under curve [AUC], 0.725; P<.001) and LV end-systolic dimension (ESD) 39 mm or greater (AUC, 0.724; P<.001) as cut-off values for predicting LVEF less than 50% 3 years after surgery. On multivariate analysis, both preoperative LVEF and LVESD were not significant predictors of 3-year postoperative LV dysfunction among patients with preoperative LVEF greater than 63% and LVESD less 39 mm, whereas preoperative LVESD (odds ratio [OR], 2.22; P=.004), higher age (OR, 1.03; P=.04), and atrial fibrillation (OR, 2.68; P=.01) were independent predictors among patients with preoperative LVEF 63% or less or LVESD 39 mm or greater. CONCLUSIONS: Early MV repair with LVEF greater than 63% and LVESD less than 39 mm preserved long-term postoperative LV function well, and smaller preoperative LVESD was associated with long-term LV function recovery, even in patients with preoperative LV dysfunction.

Impact of occult renal impairment on early and late outcomes following coronary artery bypass grafting.

OBJECTIVES: High serum creatinine is considered an independent risk factor for poor outcomes following coronary artery bypass grafting (CABG). However, the impact of occult renal impairment (ORI), defined as an impaired glomerular filtration rate (GFR) with a normal serum creatinine (SCr) level, remains unclear. Thus, we sought to investigate the impact of ORI on outcomes after CABG. METHODS: Among patients undergoing their first percutaneous coronary intervention (PCI) or CABG enrolled in the CREDO-Kyoto Registry (a registry of first-time PCI and CABG patients in Japan), 1842 patients with normal SCr levels undergoing CABG were enrolled in the study. Patients were divided into two groups based on preoperative estimated GFR calculated by the Cockcroft-Gault equation: 1339 patients with estimated GFR of ≥ 60 ml/min/1.73 m(2) (normal group) and 503 with estimated GFR of <60 ml/min/1.73 m(2) (ORI group). RESULTS: Preoperative estimated GFR differed between the groups (51.3 ± 6.6 vs 85.8 ± 23.0 ml/min/1.73 m(2), P < 0.01). ORI was associated with high in-hospital mortality (3.2 vs 1.0%, P < 0.01) and need for dialysis (2.0 vs 0.2%, P < 0.01). In terms of long-term outcomes, ORI was associated with high mortality compared with the normal (hazard ratio [95% confidence interval]: 1.72 [1.16-2.54], P < 0.01) and high incidence of composite cardiovascular events (death, stroke or myocardial infarction: 1.53 [1.16-2.02], P < 0.01). CONCLUSIONS: ORI was an independent risk factor for early and late death as well as cardiovascular events in patients undergoing CABG with normal SCr levels. A more accurate evaluation of renal function through a combination of SCr and estimated GFR is needed in patients with normal SCr levels.

Influence of initial acute myocardial infarction presentation on the outcome of surgical procedures after coronary stent implantation: a report from the CREDO-Kyoto PCI/CABG Registry Cohort-2.

Several previous publications have consistently reported that surgical procedures performed early after coronary stenting were associated with significantly higher risk for ischemic events than those performed late. In the current post hoc analysis of the Coronary REvascularization Demonstrating Outcome Study in Kyoto PCI/coronary artery bypass grafting Registry Cohort-2, we compared the outcomes of early (within 42 days) versus late surgery (beyond 42 days) after coronary stenting stratified by the initial clinical presentations [acute myocardial infarction (AMI) [early N = 153, and late N = 586] and non-AMI (early N = 202, and late N = 1457)]. Cumulative incidence of death/myocardial infarction/stent thrombosis at 30 days after surgery was significantly higher in the early group than in the late group in the AMI stratum [18.4 vs. 2.6 %, P < 0.0001, and adjusted HR 5.65 (95 % CI 2.42-13.5), P < 0.0001], but not in the non-AMI stratum [3.0 vs. 1.8 %, P = 0.3, and adjusted HR 1.52 (95 % CI 0.47-4.17), P = 0.5]. There was a significant interaction for the risk of ischemic events between the clinical presentation and the timing of surgery (P interaction = 0.03). Deaths in patients with early surgery in the AMI stratum were mostly related to preoperative complications of AMI (76 %), but not related to perioperative stent-related complications (4.0 %). In conclusion, significantly higher risk of early versus late surgery for perioperative ischemic events was seen only in patients with initial AMI presentation, but not in patients with non-AMI presentation. Previous observations suggesting higher risk in early surgery might not be related to the timing after stent implantation per se, but related to more morbid preoperative conditions in patients who underwent early surgery.

Benefits of off-pump coronary artery bypass grafting in high-risk patients.

BACKGROUND: The benefits of off-pump coronary artery bypass graft (OPCAB) compared with conventional on-pump coronary artery bypass graft (CCAB) remain controversial. Thus, it is important to investigate which patient subgroups may benefit the most from OPCAB rather than CCAB. METHODS AND RESULTS: Among the patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto Registry (a registry of first-time percutaneous coronary intervention and coronary artery bypass graft patients in Japan), 2468 patients undergoing coronary artery bypass graft were entered into the study (mean age, 67 ± 9 years). Predicted risk of operative mortality (PROM) of each patient was calculated by logistic EuroSCORE. Patients were divided into tertile based on their PROM. Mortality rates and the incidences of cardiovascular events were compared between CCAB and OPCAB within each PROM tertile using propensity score analysis. A total of 1377 patients received CCAB whereas 1091 received OPCAB. Adjusted 30-day mortality was not significantly different between CCAB and OPCAB patients regardless of their PROM range. However, the odds ratio of 30-day stroke in CCAB compared with OPCAB in the high-risk tertile was 8.30 (95% confidence interval, 2.25-30.7; P<0.01). Regarding long-term outcomes, hazard ratio of stroke in CCAB compared with OPCAB in the high-risk tertile was 1.80 (95% confidence interval, 1.07-3.02; P=0.03). Nevertheless, hazard ratio of overall mortality in the high-risk tertile was 1.44 (95% confidence interval, 0.98-2.11; P=0.06), indicating no statistically significant difference between the 2 procedures. CONCLUSIONS: OPCAB as opposed to CCAB is associated with short-term and long-term benefits in stroke prevention in patients at higher risk as estimated by EuroSCORE. No survival benefit of OPCAB was shown regardless of preoperative risk level.

Comparison of frequency of postoperative stroke in off-pump coronary artery bypass grafting versus on-pump coronary artery bypass grafting versus percutaneous coronary intervention.

The stroke rate after coronary artery bypass grafting (CABG) compared to percutaneous coronary intervention (PCI) is generally considered high because cardiopulmonary bypass and aortic manipulations are often associated with cerebrovascular complications. However, an increasing number of CABGs performed without cardiopulmonary bypass (OPCAB) may improve those outcomes. Of 6,323 patients with multivessel and/or left main coronary artery disease, 3,877 patients underwent PCI, 1,381 conventional on-pump CABG, and 1,065 OPCAB. Median follow-up was 3.4 years. Stroke types were classified as early (onset of stroke within 24 hours after revascularization), delayed (within 30 days), and late (after 30 days). Propensity score analysis showed that the incidences of early, delayed, and late stroke did not differ between PCI and OPCAB (0.65, 95% confidence interval 0.08 to 5.45, p = 1.00; 0.36, 0.10 to 1.29, p = 0.23; 0.81, 0.52 to 1.27, p = 0.72, respectively). In contrast, incidence of early stroke after on-pump CABG was higher than after OPCAB (7.22, 1.67 to 31.3, p = 0.01), but incidences of delayed and late stroke were not different (1.66, 0.70 to 3.91, p = 0.50; 1.18, 0.83 to 1.69, p = 0.73). In conclusion, occurrence of stroke was not found to differ in patients after PCI versus OPCAB regardless of onset of stroke. Occurrence of early stroke after OPCAB was lower than that after on-pump CABG, yet occurrences of delayed and late strokes were similar for the 3 revascularization strategies.

Impact of aortic regurgitation on the prognosisof severe aortic stenosis.

OBJECTIVE: Many patients with aortic stenosis (AS) have coexisting aortic regurgitation (AR). However, few data exist regarding its clinical significance and prognostic value. The aim of this study was to examine the effect of concomitant significant AR on clinical outcomes in patients with non-surgically treated severe AS. DESIGN: A single centre, retrospective cohort study. PATIENTS AND METHODS: We retrospectively reviewed 306 consecutive patients (age, 72±11 years) with severe AS in whom non-surgical management was primarily planned at our institution between January 1999 and December 2011. There were 74 patients with moderate or severe AR (ASR) and 232 patients without significant AR (isolated AS). Clinical outcomes were compared between the two groups. MAIN OUTCOME MEASURES: All-cause mortality and valve-related events, were defined by a composite of cardiac death and hospitalisation because of heart failure. RESULTS: The mean follow-up period was 4.5±3.3 years. Although the overall survival was comparable between the groups (p=0.07), the event-free survival, defined as survival without cardiac death or hospitalisation because of heart failure, was significantly worse in ASR than in isolated AS (p=0.02). Concomitant AR was an independent predictor of adverse events in patients with severe AS (HR, 2.10; p=0.003). Among patients who did not eventually undergo aortic valve replacement, ASR was associated with significantly worse survival and event-free survival than isolated AS (p=0.002 and p=0.03, respectively). CONCLUSIONS: Concomitant AR might worsen the prognosis of severe AS. Greater consideration of surgery might be beneficial in patients with ASR.

Comparison of long-term outcome after percutaneous coronary intervention versus coronary artery bypass grafting in patients with unprotected left main coronary artery disease (from the CREDO-Kyoto PCI/CABG Registry Cohort-2).

The long-term outcome of percutaneous coronary intervention (PCI) compared to coronary artery bypass grafting (CABG) for unprotected left main coronary artery disease (ULMCAD) remains to be investigated. We identified 1,005 patients with ULMCAD of 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG Registry Cohort-2. Cumulative 3-year incidence of a composite of death/myocardial infarction (MI)/stroke was significantly higher in the PCI group than in the CABG group (22.7% vs 14.8%, p = 0.0006, log-rank test). However, the adjusted outcome was not different between the PCI and CABG groups (hazard ratio [HR] 1.30, 95% confidence interval [CI] 0.79 to 2.15, p = 0.30). Stratified analysis using the SYNTAX score demonstrated that risk for a composite of death/MI/stroke was not different between the 2 treatment groups in patients with low (<23) and intermediate (23 to 33) SYNTAX scores (adjusted HR 1.70, 95% CI 0.77 to 3.76, p = 0.19; adjusted HR 0.86, 95% CI 0.37 to 1.99, p = 0.72, respectively), whereas in patients with a high SYNTAX score (≥33), it was significantly higher after PCI than after CABG (adjusted HR 2.61, 95% CI 1.32 to 5.16, p = 0.006). In conclusion, risk of PCI for serious adverse events seemed to be comparable to that after CABG in patients with ULMCAD with a low or intermediate SYNTAX score, whereas PCI compared with CABG was associated with a higher risk for serious adverse events in patients with a high SYNTAX score.

Early surgery for asymptomatic mitral regurgitation: importance of atrial fibrillation.

BACKGROUND AND AIM OF THE STUDY: It remains controversial whether early mitral valve (MV) repair should be performed for severe degenerative mitral regurgitation (MR) without symptoms, left ventricular (LV) dilatation or dysfunction, atrial fibrillation (AF) or pulmonary artery hypertension (PH), even at experienced surgical centers. The study aim was to reconsider the optimal timing of intervention for asymptomatic patients with severe degenerative MR at experienced surgical centers. METHODS: Clinical outcomes were reviewed retrospectively for 298 consecutive asymptomatic patients (mean age 57 +/- 12 years) who underwent MV surgery for degenerative MR. The patients were allocated to two groups based on the following comorbid conditions: LVEF < or = 60%, LV end-systolic dimension 40 mm, AF, and PH. Group A comprised 122 patients with none of these conditions, while group B comprised 176 patients with any one of the conditions. The clinical outcomes were compared between the two groups at a mean of 7.0 +/- 4.5 years after surgery. RESULTS: MV repair had been attempted in all patients, with a success rate of 100%. At 10 years, survival among group B patients was poorer than in group A (93% and 81%, respectively; p = 0.02), and there was a lower freedom from valve-related events (89% and 71%, respectively; p < 0.01). The independent predictors of valve-related events were preoperative AF (hazard ratio 3.34; p < 0.001) and age > 60 years (hazard ratio 2.50; p < 0.01). CONCLUSION: Early MV repair is a reasonable option in asymptomatic patients, while preoperative AF may be a more appropriate predictor of an adverse outcome than LV function, as is currently recommended.

Intensity of statin therapy, achieved low-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after coronary revascularization. Perspectives from the CREDO-Kyoto registry cohort-2.

BACKGROUND: Association of the type of statin and the achieved level of low-density lipoprotein cholesterol (LDL-C) with cardiovascular outcome has not been fully elucidated. METHODS AND RESULTS: The study included 14,866 patients who underwent a first coronary revascularization in 2005-2007. We identified 7,299 patients with statin therapy at discharge (so-called strong statins [atorvastatin, rosuvastatin, and pitavastatin]: 4,742 patients; standard statins [pravastatin, simvastatin, and fluvastatin]: 2,557 patients). Unadjusted 3-year incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) was significantly lower (7.5% vs. 9.6%, P=0.0008) in the strong statin group, and there was a trend in adjusted risk of MACE favoring strong statins (hazard ratio [HR] 0.87, [95% confidence interval (CI) 0.73-1.04], P=0.13). Among 4,846 patients with follow-up LDL-C data available, outcomes were evaluated according to achieved LDL-C level (<80, 80-99 [reference], 100-119, ≥120 mg/dl). Compared with the reference group, the risk for MACE was significantly higher in the ≥120 mg/dl group (adjusted HR 1.74 [95%CI 1.11-2.71], P=0.01), although it was comparable in the 100-119 mg/dl group (adjusted HR 1.23 [95%CI 0.78-1.94], P=0.38) and in the <80 mg/dl group (adjusted HR 1.15 [95%CI 0.75-1.75], P=0.52). CONCLUSIONS: Strong statin therapy was associated with a trend toward lower cardiovascular risk compared with standard statin therapy. When LDL-C <120 mg/dl was achieved, risks for cardiovascular events were comparable irrespective of achieved LDL-C level.

Mitral valve repair for double-orifice mitral valve with flail leaflet: the usefulness of real-time three-dimensional transesophageal echocardiography.

We describe a 66-year-old man who required an operation for severe mitral regurgitation associated with a double-orifice mitral valve. Real-time 3-dimensional transesophageal echocardiography clearly demonstrated a double-orifice mitral valve with a central fibrous bridge. A flail posterior leaflet was observed on the anterolateral mitral valve orifice. Mitral valve repair using P1 triangular resection, anterolateral commissure plication, and ring annuloplasty with Duran band (Medtronic, Minneapolis, MN) was successfully performed. Postoperative real-time 3-dimensional transesophageal echocardiography demonstrated a double-orifice mitral valve without regurgitation or stenosis.

Incidence and outcome of surgical procedures after coronary bare-metal and drug-eluting stent implantation: a report from the CREDO-Kyoto PCI/CABG registry cohort-2.

BACKGROUND: There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. METHODS AND RESULTS: During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P=0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P=0.4 and 3.2% versus 2.1%, P=0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P=0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P=0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P=0.053). CONCLUSIONS: Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.