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.

Temporal Trends in Antithrombotic Therapy for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention From 2014 to 2022 in Japan.

Background: Recent revisions of clinical guidelines by the Japanese Circulation Society, American Heart Association/American College of Cardiology, and European Society of Cardiology updated the management of antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, the extent to which these guidelines have been implemented in real-world daily clinical practice is unclear. Methods and Results: We conducted surveys on the status of antithrombotic therapy for patients with AF undergoing PCI every 2 years from 2014 to 2022 in 14 cardiovascular centers in Japan. The primary use of drug-eluting stents increased from 10% in 2014 to 95-100% in 2018, and the use of direct oral anticoagulants increased from 15% in 2014 to 100% in 2018, in accordance with the revised practice guidelines. In patients with acute coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2018, and increased to >70% from 2020. In patients with chronic coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2016, and >75% from 2018. Since 2020, the most common timing of discontinuation of dual antiplatelet therapy to transition to anticoagulation monotherapy during the chronic phase of PCI has been 1 year after PCI. Conclusions: Japanese interventional cardiologists have updated their treatment strategies for patients with AF undergoing PCI according to revisions of clinical practice guidelines.

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.

The Functional Severity Assessment of Coronary Stenosis Using Coronary Computed Tomography Angiography-Based Myocardial Mass at Risk and Minimal Lumen Diameter.

BACKGROUND: We investigated whether or not the addition of myocardial mass at risk (MMAR) to quantitative coronary angiography was useful for diagnosing functionally significant coronary stenosis in the daily practice. METHODS: We retrospectively enrolled 111 consecutive patients with 149 lesions who underwent clinically indicated coronary computed tomography angiography and subsequent elective coronary angiography with fractional flow reserve (FFR) measurement. MMAR was calculated using a workstation-based software program with ordinary thin slice images acquired for the computed tomography, and the minimal lumen diameter (MLD) and the diameter stenosis were measured with quantitative coronary angiography. RESULTS: The MLD and MMAR were significantly correlated with the FFR, and the MMAR-to-MLD ratio (MMAR/MLD) showed a good correlation. The area under the receiver operating characteristic curve (AUC) of MMAR/MLD for FFR ≤ 0.8 was 0.746, and the sensitivity, specificity, positive predictive value, and negative predictive value were 60%, 83%, 68%, and 77%, respectively, at a cut-off value of 29.5 ml/mm. The addition of MMAR/MLD to diameter stenosis thus made it possible to further discriminate lesions with FFR ≤ 0.8 (AUC = 0.750). For the proximal left coronary artery lesions, in particular, MMAR/MLD showed a better correlation with the FFR, and the AUC of MMAR/MLD for FFR ≤ 0.8 was 0.919 at a cut-off value of 31.7 ml/mm. CONCLUSIONS: The index of MMAR/MLD correlated well with the physiological severity of coronary stenosis and showed good accuracy for detecting functional significance. The MMAR/MLD might be a useful parameter to consider when deciding the indication for revascularization.

Clinical benefits of deep sedation with a supraglottic airway while monitoring the bispectral index during catheter ablation of atrial fibrillation.

BACKGROUND: Pulmonary vein antrum isolation (PVAI) under sedation has proven to be a useful strategy for catheter ablation of atrial fibrillation (AF). METHODS: To evaluate the clinical benefits of respiratory management using supraglottic airways (SGAs) under deep sedation while monitoring the bispectral (BIS) index during the PVAI and the durations from admission to the catheterization room to starting the radiofrequency energy delivery (Time α), and from starting the radiofrequency energy delivery to completion of the PVAI (Time ß), X-ray time, frequency of dislocations of the three-dimensional maps (D3DM), procedure-related complications, and proportion of an AF-free rate 15 months after the PVAI (PAFFR) in patients who received deep sedation without SGAs (Group A: n=48) and those with SGAs (Group B: n=51) were evaluated. RESULTS: There were no significant differences in patient characteristics, Time α (77±3 versus 78±2 min; p=0.816), complications of cardiac tamponade (2% versus 2%; p=0.966), or PAFFR (81% versus 88%; p=0.313) between the two groups. However, the Time ß (84±4 versus 67±3; p=0.001), X-ray time (53±2 versus 34±2; p<0.001), and minor complications of nasal bleeding (25% versus 0%; p=0.001) were significantly shorter and lower in Group B than in Group A, in accordance with a reduction in the hypoxia (15% versus 0%; p=0.007) and D3DM (31% versus 8%; p=0.003). CONCLUSIONS: These results may demonstrate the clinical benefits of deep sedation with SGAs while monitoring the BIS index without any hypoxia during PVAI in patients with AF.

Long-term treatment with eicosapentaenoic acid improves exercise-induced vasodilation in patients with coronary artery disease.

We have previously shown that long-term treatment with eicosapentaenoic acid (EPA) improves endothelium-dependent vasodilation of the atherosclerotic arteries in both animals and humans. The aim of the present study was to examine whether EPA treatment also improves metabolic vasodilation evoked by exercise in patients with coronary artery disease (CAD). Forearm blood flow (FBF) was measured by strain gauge plethysmography in 10 patients with stable CAD, before and 3 months after oral treatment with EPA (1,800 mg/kg). FBF was measured at rest and during intra-arterial infusion of acetylcholine or sodium nitroprusside, before and after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, an inhibitor of nitric oxide (NO) synthesis). A rhythmic handgrip exercise was also performed for 3 min before and after L-NMMA, and FBF was measured for 3 min just after the handgrip exercise. These protocols were repeated after the long-term treatment with EPA for 3 months. The long-term treatment with EPA significantly improved the FBF responses to acetylcholine (p < 0.01), which was significantly reduced by acute administration of L-NMMA (p < 0.01). By contrast, the EPA treatment did not affect the endothelium-independent responses to sodium nitroprusside. Metabolic increases in FBF caused by the handgrip exercise were not significantly decreased by L-NMMA before the EPA treatment. The EPA treatment significantly augmented the exercise-induced increases in FBF (p < 0.05) and L-NMMA acutely abolished this augmentation (p < 0.01). These results indicate that long-term treatment with EPA improves both endothelium-dependent and exercise-induced forearm vasodilations in patients with CAD and that NO is substantially involved in the EPA-induced improvement of the FBF responses in patients with CAD.

Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients.

BACKGROUND: Coronary risk factors for the onset of acute coronary syndrome (ACS), including polyunsaturated fatty acids (PUFAs), in younger adult patients may be different from those in older patients. METHODS AND RESULTS: We enrolled 578 patients who underwent coronary angiography at Fukuoka Saiseikai Hospital, and divided them into a younger adult group (YG) (<50 years, n=47) and a middle-aged older group (OG) (≥50 years, n=531). In a multivariate analysis, lower levels of high-density lipoprotein cholesterol and the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) (EPA/AA), and less aspirin, oral hypoglycemic agent, and calcium channel blocker (CCB) use were independent risk factors for ACS in all patients. In YG, lower levels of EPA/AA and less angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were the independent risk factors. In OG, smoking, lower levels of EPA/AA, less aspirin and CCB use were the risk factors. While lower levels of EPA/AA was the only risk factor for ACS that was common to all patients, YG and OG, docosahexaenoic acid/AA was not associated with ACS in YG and OG. CONCLUSIONS: Lower level of EPA/AA is a common critical risk factor for ACS in middle-aged older patients as well as younger adult patients. Some of the risk factors for the onset of ACS in younger patients were different from those in older patients.

Left ventricular false-pseudo and pseudo aneurysm: serial observations by cardiac magnetic resonance imaging.

A case of extensive inferior myocardial infarction complicated by a large ventricular aneurysm is presented. Magnetic resonance (MR) imaging 4 days after the onset showed a small protrusion from the necrotic inferior myocardium, which expanded 10 days after onset with a marked pericardial effusion. The follow-up examination by MR and CT imaging 6 months after the onset revealed a large ventricular aneurysm from the inferior cardiac wall. After the aneurysmectomy, the histological study revealed that the aneurysm wall was made up of 2 different types of walls; the peripheral part was a false-pseudo aneurysm and the central part was a pseudo aneurysm. From the serial MR imaging, it is considered that such an aneurysm is primarily formed from a small discontinuation of the LV wall followed by oozing type rupture. Finally, the ruptured central part of the LV wall, which was covered by the pericardium, formed a pseudo aneurysm and the stretched peripheral area, which contains myocardium, formed a false-pseudo aneurysm afterward and then they extended together. Thus, MR imaging provided the important information for the understanding of the formation process of the pseudo and false pseudo LV aneurysm.