Association of Serum Oxysterols with Cholesterol Metabolism Markers and Clinical Factors in Patients with Coronary Artery Disease: A Covariance Structure Analysis.

Oxysterols have been implicated in the pathogenesis of cardiovascular diseases. Serum levels of oxysterols could be positively correlated with cholesterol absorption and synthesis. However, physiological regulation of various serum oxysterols is largely unknown. The aim of this study was to investigate the relationship between clinical factors and cholesterol metabolism markers, and identify oxysterols associated with cholesterol absorption and synthesis in patients with coronary artery disease. Subjects (n = 207) who underwent coronary stenting between 2011 and 2013 were studied cross-sectionally. We measured lipid profiles including serum oxysterols. As for the serum biomarkers of cholesterol synthesis and absorption, oxysterol levels were positively correlated with campesterol and lathosterol. Covariance structure analysis revealed that dyslipidemia and statin usage had a positive correlation with "cholesterol absorption". Statin usage also had a positive correlation with "cholesterol synthesis". Several oxysterols associated with cholesterol absorption and/or synthesis. In conclusion, we elucidated the potential clinical factors that may affect cholesterol metabolism, and the associations between various oxysterols with cholesterol absorption and/or synthesis in patients with coronary artery disease.

Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial.

AIM: Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial. METHODS: The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up. RESULTS: After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (ß-epoxycholesterol, 4ß-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression. CONCLUSIONS: Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.

Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

BACKGROUND: Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis. RESULTS: A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36). CONCLUSIONS: In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan　- Insights From GARFIELD-AF.

BACKGROUND: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. CONCLUSIONS: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Impact of the extent of low-voltage zone on outcomes after voltage-based catheter ablation for persistent atrial fibrillation.

BACKGROUND: Low-voltage zones (LVZs), as measured by electroanatomic mapping, are thought to be associated with fibrosis. We reported the efficacy of atrial fibrillation (AF) ablation aiming to homogenize left atrial (LA) LVZ. The purpose of this study was to evaluate the impact of LVZ extension outcomes after LVZ homogenization in patients with nonparoxysmal AF. METHODS: This prospective observational cohort study included 172 patients with nonparoxysmal AF undergoing their initial ablation. LVZ was defined as an area with bipolar electrograms <0.5mV during sinus rhythm. LVZ extent was calculated as the percentage of LA surface area, and subsequently, LVZ was categorized into stages I (<5%), II (≥5% to <20%), III (≥20% to <30%), and IV (≥30%). Patients with LVZs underwent LVZ ablation aimed at homogenization of ≥80% of LVZs following pulmonary vein isolation. The primary endpoint was atrial tachyarrhythmia recurrence-free survival after a single procedure at 18 months off antiarrhythmic drugs. The association of %LVZ with recurrence-free survival was examined using Cox proportional hazard models. RESULTS: The survival rates were 76%, 74%, 57%, and 28% in patients with stages I, II, III, and IV LVZ, respectively. The difference was significant between stages I and IV (log-rank, p<0.001), while not significant between stages I vs. II and I vs. III (p=0.843, p=0.073, respectively). Cox proportional hazard model revealed that %LVZ was an independent predictor of recurrence-free survival (hazard ratio, 1.025 per 1% increase, p<0.001; unadjusted model). The results were similar after demographic and clinical covariate adjustments and after excluding 12 patients who did not achieve homogenization of ≥80% of LVZ. CONCLUSIONS: The extent of LVZ is an independent predictor for recurrence even after LVZ homogenization.

Feasibility of total intravenous anesthesia by cardiologists with the support of anesthesiologists during catheter ablation of atrial fibrillation.

BACKGROUND: The optimal methodology for sedation and anesthesia during atrial fibrillation (AF) ablation has not been well established. We assessed the feasibility of total intravenous anesthesia (TIVA) by cardiologists with support from anesthesiologists during AF ablation and quality of pulmonary vein isolation (PVI) and single procedure success rate at 12 months. METHODS: TIVA was performed by cardiologists using IV propofol and fentanyl under controlled ventilation via i-gel™ without neuromuscular blocking drugs in 160 consecutive patients (80 nonparoxysmal) with no anticipated difficult airway or other severe diseases. Anesthesiologists were requested to be on standby during the procedure. The incidence of anesthesia-associated complications and ablation-associated complications were assessed. To evaluate the quality of PVI, the prevalence of acute adenosine triphosphate (ATP)-provoked PV reconnections and late PV reconnections among those requiring a redo procedure was analyzed. RESULTS: TIVA was successfully completed in 152 patients (95%). In five (3%), we requested help from anesthesiologists, and in three (2%), TIVA was abandoned. No major anesthesia-associated complications were observed. Ablation-associated complications were observed in seven patients (4%). ATP provocation test was performed in 141 patients, and no acute PV reconnections were observed in 134 (95%). Success rates at 12 months were 85% of patients off antiarrhythmic drugs. Twenty-one of 24 patients with recurrence underwent a redo session, and 18 (86%) had no PV reconnections. CONCLUSIONS: TIVA by cardiologists with support from anesthesiologists during AF ablation may be feasible. The success rate at 12 months was high, and prevalence of acute and late PV reconnection was very low.

Significance of troponin I level as a marker of disease activity in the management of acute necrotizing eosinophilic myocarditis with normal peripheral eosinophil count: a case report.

BACKGROUND: Eosinophilic myocarditis is characterized by myocardial eosinophilic infiltration and is largely associated with hypereosinophilia. However, eosinophilic myocarditis with a normal peripheral eosinophilic count has been previously reported. Since the absence of eosinophilia poses a challenge for therapeutic management, we evaluated whether troponin I (TnI) levels can be used in the management of eosinophilic myocarditis where peripheral eosinophilia is absent. CASE SUMMARY: We report the case of a 77-year-old woman who developed cardiogenic shock due to acute necrotizing eosinophilic myocarditis, which required mechanical circulatory support. She did not have hypereosinophilia, but endomyocardial biopsy confirmed massive infiltration of eosinophils into the myocardium. We administered high-dose corticosteroids for 3 days and she dramatically improved. Along with this, the TnI level, which was elevated at the time of patient presentation, also decreased after steroid therapy. Troponin I level did not increase again without taking any oral prednisolone, and the follow-up biopsy after 6 months showed complete recovery of eosinophilic myocarditis. DISCUSSION: Troponin I-guided treatment is a useful tool in the management of eosinophilic myocarditis because it helps with therapeutic decisions, especially in the absence of eosinophilia.

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial.

OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. CONCLUSIONS: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels.

Efficacy of Left Atrial Voltage-Based Catheter Ablation of Persistent Atrial Fibrillation.

BACKGROUND: Low-voltage zones (LVZs) represent fibrotic tissue and are substrates for atrial fibrillation (AF). We hypothesized that LVZ-based substrate modification along with pulmonary vein isolation (PVI) would improve outcomes in persistent AF (PeAF) patients with LVZs, whereas PVI alone would work in patients without LVZs. METHODS AND RESULTS: Voltage mapping of the left atrium (LA) was performed during sinus rhythm in 101 PeAF patients in whom LVZ was defined as an area with bipolar electrograms <0.5 mV. Thirty-nine patients had LVZs and underwent ablation of the entire LVZ area after PVI (LVZabl group). In the remaining 62 patients without LVZs, PVI alone was performed with no further substrate modifications (PVI group). An additional group of 16 consecutive PeAF patients with LVZ did not undergo any substrate modification after PVI and were used as a comparison group (LVZnon-abl group) despite having similar size of LVZs to that in the LVZabl group. After a single session, 28 (72%) patients in the LVZabl group had no recurrence, whereas 49 (79%) patients in the PVI group had no recurrence during 18 ± 7 months of follow-up (log-rank, P = 0.400). In the LVZnon-abl group, only 6 patients (38%) had no recurrence during 32 ± 7 months of follow-up, even after a mean number of sessions of 1.8 (log-rank, P < 0.001, compared with the LVZabl group). CONCLUSIONS: Additional LVZ-based substrate modification after PVI improved the outcome in PeAF patients with LVZs, whereas PVI alone worked in patients without LVZs, even in those with PeAF.

Coronary aneurysm associated with coronary perforation after sirolimus-eluting stents implantation: close follow-up exceeding 2 years by coronary 3-dimensional computed tomography.

Both coronary perforation and aneurysms associated with sirolimus-eluting stent (SES) implantations are uncommon complications. We describe an unusual case of a coronary aneurysm associated with a coronary perforation after SES implantation. Although their pathogenesis has not yet been completely elucidated, some technical factors including the use of excessive pressure during the stent deployment, and sirolimus-induced vascular inflammatory reactions and poor healing response at the perforation site may be related to the shape of the aneurismal formation. Fortunately and interestingly, the size of the coronary aneurysm gradually decreased, and finally by 26 months a nearly complete resolution of the aneurysm had taken place. Furthermore, close follow-up by coronary 3-dimensional computed tomography (3DCT) could clearly demonstrate the natural course of this aneurysm. To the best of our knowledge, there have been no reports on the natural course of coronary aneurysm associated with a coronary perforation after SES(s) implantation for more than 2 years using coronary 3DCT as in this present case. The phenomenon of the spontaneous resolution of the coronary aneurysm after SES implantation may have clinical therapeutic implications.

Intracardiac echocardiography-guided cardiac tumor biopsy.

A 63-year-old woman was admitted to hospital with the chief complaint of new onset chest discomfort and pretibial pitting edema. Transthoracic echocardiography revealed a large invasive tumor on the heart protruding into the right atrium and right ventricle, which obstructed the outflow tract. She underwent transvenous 9Fr, 9-MHz ultra intracardiac echocardiography (ICE) (EP Technologies, Boston Scientific Corporation, San Jose, CA, USA) guided biopsy, and a diagnosis of malignant lymphoma was established from the specimen obtained. ICE-guided cardiac tumor biopsy may be one of the most useful strategies for diagnosis of cardiac tumors.

Vitamin C improves attenuated angiotensin II-induced endothelium-dependent vasodilation in human forearm vessels.

Endothelial dysfunction might be related to an increase in superoxide anion production in patients with hypertension, hypercholesterolemia, diabetes mellitus, and heart failure. Studies in animal models indicate that angiotensin II increases superoxide anion production by vascular tissues. We examined whether angiotensin II attenuates endothelium-dependent vasodilation via an increase in superoxide anion production in human forearm vessels in vivo. Forearm blood flow was measured in 23 healthy young men. We examined forearm vasodilator responses to an intra-arterial infusion of acetylcholine (4, 8, and 16 microg/min) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min) before and during an intra-arterial infusion of anglotensin II (n=8), angiotensin II plus vitamin C (n=8), and vitamin C alone (n=4). Angiotensin II attenuated the forearm vasodilatory response to acetylcholine (p<0.05), and this attenuated response was abolished by vitamin C. Angiotensin II did not alter the forearm vasodilatory response to sodium nitroprusside, and vitamin C infusion did not affect the forearm vasodilatory response to either acetylcholine or sodium nitroprusside. The forearm vasodilator response to acetylcholine did not change during infusion of norepinephrine (n=3), which reduced forearm blood flow to a degree similar to that by angiotensin II infusion. These results suggest that angiotensin II attenuates endothelium-dependent forearm vasodilation, and vitamin C improves this impairment. Thus, angiotensin II likely attenuates endothelium-dependent vasodilation via an increase of superoxide anion production in the human forearm in vivo.

Tetrahydrobiopterin improves impaired endothelium-dependent forearm vasodilation in patients with heart failure.

Endothelium-dependent vasodilation is impaired in patients with chronic heart failure (CHF). However, the mechanisms responsible for this effect are not fully understood. The vasodilator response to acetylcholine (ACh) has been used to examine the endothelium-dependent vasodilation in humans and is known to be mediated by nitric oxide (NO). The impaired production of NO or an increase in its degradation is thought to be responsible for the endothelial dysfunction in CHF. The aim of this study was to determine whether the decrease in availability of tetrahydrobiopterin (BH(4)), an essential cofactor of NO synthase, contributes to the impairment of endothelium-dependent vasodilation in patients with CHF. Fourteen patients with CHF (New York Heart Association functional class II-IV, age: 59 +/- 4 years, ejection fraction: 28 +/- 3%) and seven age-matched control subjects were examined. Forearm blood flow (FBF) was measured by plethysmography during an intra-arterial infusion of a graded dose of ACh (4, 8, and 16 microg/min) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 microg/min). These procedures were repeated during a co-infusion of BH(4) (400 microg/min). The forearm vasodilator response to ACh was significantly enhanced during co-infusion of BH(4) in patients with CHF, whereas no effect was observed in healthy subjects. In contrast, the response to SNP was not affected by BH(4) in either group. The administration of BH(4) did not alter the baseline FBF in either group. These results suggest that an acute administration of BH(4 ) improves endothelium-dependent forearm vasodilation in patients with CHF.