A Propensity Score Matched Analysis of Statin Effects on Major Adverse Cardiac Events after Percutaneous Coronary Intervention in Patients Over 75 Years Old.

Objective In an extremely aging society, it is beneficial to reconsider the value of medical treatment for extremely elderly patients. We therefore focused on the efficacy of statin therapy in extremely elderly patients. This study investigated the efficacy of statins for secondary prevention in patients over 75 years old. Methods This prospective multicenter registry included 1,676 consecutive extremely elderly patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). The patients were followed up clinically for up to three years or until the occurrence of major adverse cardiac events (MACEs), defined as a composite of all-cause death and non-fatal myocardial infarction. Using propensity score methodology to eliminate selection bias, in a 1:1 matching ratio, we selected 466 pairs of patients for the analysis. Results During the median follow-up period of 25 months, MACEs occurred in 176 patients. The Kaplan-Meier analysis showed that statin treatment correlated with a lower probability of initial MACE occurrences within 30 days compared with no statin treatment (log-rank test, p<0.001). According to a landmark analysis at day 30, statin treatment still showed consistent effectiveness for reducing MACE occurrence during the follow up period (p=0.04). A multivariable Cox hazard analysis showed that statin therapy significantly reduced MACE occurrence (hazard ratio 0.55 [0.40-0.75], p<0.001). In the stratification analysis, statin therapy was especially beneficial in patients without symptomatic heart failure. Conclusion Statins were effective in preventing MACEs in extremely elderly patients after PCI.

Group V Secretory Phospholipase A2 Regulates Endocytosis of Acetylated LDL by Transcriptional Activation of PGK1 in RAW264.7 Macrophage Cell Line.

AIMS: It was suggested that group V secretory phospholipase A2 (sPLA2-V) existed in the nucleus. This study examined whether nuclear sPLA2-V plays a role in endocytosis of acetylated low-density lipoprotein (AcLDL) in monocyte/macrophage-like cell line RAW264.7 cells. METHODS: RAW264.7 cells were transfected with shRNA vector targeting sPLA2-V (sPLA2-V-knockdown [KD] cells) or empty vector (sPLA2-V-wild-type [WT] cells). AcLDL endocytosis was assessed by incubation with 125I-AcLDL or AcLDL conjugated with pHrodo. Actin polymerization was assessed by flow cytometry using Alexa Fluor 546-phalloidin. RESULTS: In immunofluorescence microscopic studies, sPLA2-V was detected in the nucleus. ChIP-Seq and ChIP-qPCR analyses showed binding of sPLA2-V to the promoter region of the phosphoglycerate kinase 1 (Pgk1) gene. In the promoter assay, sPLA2-V-KD cells had lower promoter activity of the Pgk1 gene than sPLA2-V-WT cells, and this decrease could be reversed by transfection with a vector encoding sPLA2-V-H48Q that lacks enzymatic activity. Compared with sPLA2-V-WT cells, sPLA2-V-KD cells had decreased PGK1 protein expression, beclin 1 (Beclin1) phosphorylation at S30, and class III PI3-kinase activity that could also be restored by transfection with sPLA2-V-H48Q. sPLA2-V-KD cells had impaired actin polymerization and endocytosis, which was reversed by introduction of sPLA2-V-H48Q or PGK1 overexpression. In sPLA2-V-WT cells, siRNA-mediated depletion of PGK1 suppressed Beclin1 phosphorylation and impaired actin polymerization and intracellular trafficking of pHrodo-conjugated AcLDL. CONCLUSIONS: Nuclear sPLA2-V binds to the Pgk1 gene promoter region and increases its transcriptional activity. sPLA2-V regulates AcLDL endocytosis through PGK1-Beclin1 in a manner that is independent of its enzymatic activity in RAW264.7 cells.

Stratification Analysis of Statin Effect on Major Adverse Cardiac Events After Percutaneous Coronary Intervention in Patients on Hemodialysis.

ABSTRACT: The statin use in patients on hemodialysis remains controversial, and no beneficial effects of statin on the reduction of adverse cardiovascular events have been reported in these patients. This study used stratification analysis to examine the clinical factors in patients on hemodialysis who could benefit from statin for secondary prevention. This prospective multicenter study included 234 consecutive patients on hemodialysis with coronary artery disease who underwent successful reperfusion therapy with percutaneous coronary intervention. The patients were followed up for up to 3 years or until the occurrence of major adverse cardiac events (MACEs; defined as a composite of all-cause death and nonfatal myocardial infarction). Inverse probability of treatment weighting adjustment was used to remove the selection bias. During the median follow-up period of 30 months, MACEs occurred in 55 patients. Patients with MACEs had significantly lower statin therapy (P < 0.001). Multivariable Cox proportional hazards analysis showed that the patients on statins had a significantly reduced rate of MACE occurrence [adjusted hazard ratio 0.30 (0.11-0.81), P = 0.02]. The stratification analysis of outcomes according to the presence of clinical factors showed that beneficial effects of statin were associated with man, elderly, lower body mass index, lower abdominal circumference, hypertension, diabetes, higher C-reactive protein, symptomatic heart failure, lower left ventricular function, nonacute coronary syndrome, and shorter stent length. Statin was effective for the prevention of MACEs in patients on hemodialysis who underwent percutaneous coronary intervention. We identified specific clinical factors affecting statin effectiveness for secondary prevention.

Glutaredoxin-1 levels in plasma can predict future events in patients with cardiovascular diseases.

Reactive oxygen species that increase during cardiovascular disease (CVD) react with protein cysteine residues to form a glutathione adduct by S-glutathionylation, which is selectively removed by glutaredoxin-1 (Glrx). We previously showed that S-glutathionylation and Glrx play important roles in mouse models of CVD, such as heart failure and peripheral artery disease models. However, there are few clinical studies on Glrx in CVD. Although Glrx is a cytosolic protein expressed in various organs, it is detectable in human plasma. Studies have reported that Glrx in plasma is a potential disease maker, such as CVD and chronic kidney disease and diabetes, however, it remains unclear whether Glrx is related to the prognosis of patients with CVD. The purpose of this study was to elucidate whether Glrx levels in plasma are associated with future events in patients with CVD. Plasma levels of Glrx were measured in 555 patients with CVD who underwent cardiac catheterization using enzyme-linked immunosorbent assay. All patients were followed prospectively for ≤36 months or until occurrence of adverse events, including all-cause death, non-fatal myocardial infarction, and worsening heart failure. During a mean follow-up period of 33 months, 54 adverse events occurred. Kaplan-Meier analysis showed that higher levels of Glrx (>0.622 ng/mL, determined by receiver-operating characteristic curve) resulted in a higher probability for adverse events compared with lower levels of Glrx (≤0.622 ng/mL) (P < 0.01, log-rank test). Multivariate Cox proportional hazards analysis showed that Glrx was a significant predictor of adverse events after adjustment for known risk factors. In conclusion, levels of plasma Glrx >0.662 ng/mL can predict future events in patients with CVD.

Dramatic response to alectinib in an ALK-positive LCNEC patient with a poor performance status: A case report.

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene, a driver mutation in lung carcinoma, is fairly common in lung adenocarcinoma but rare in large cell neuroendocrine carcinoma (LCNEC). Here we report a case of stage IV LCNEC positive for this fusion gene in a patient with a poor performance status (PS) who was effectively treated with alectinib. The patient was a 72-year-old non-smoking man diagnosed as LCNEC with multiple metastases. Because of his poor PS, cytotoxic chemotherapy was not indicated, but he was later found to be positive for the ALK fusion gene and treated with alectinib as first-line therapy. One month later, the tumour had shrunk remarkably, and the therapeutic effect was rated as a partial response. The PS also improved from 4 to 1. Investigating actionable driver mutations seems worth doing for advanced LCNEC, especially if the patient's PS is poor.

Evaluation of renal tubulointerstitial damage as a residual renal risk factor for adverse cardiac events in patients with myocardial infarction.

BACKGROUND: Renal dysfunction, defined as a lower estimated glomerular filtration rate (eGFR), has been shown to be related to cardiovascular events in patients with myocardial infarction (MI). However, the contribution of renal tubulointerstitial damage to the predictive value for cardiovascular events has not been established. The aim of this study was to elucidate whether renal tubulointerstitial damage is associated with the occurrence of cardiac death and recurrence of MI in patients who have had MI. METHODS AND RESULTS: Urinary ß2-microglobulin (ß2MG) was measured in 681 consecutive patients with MI in our hospital. All patients were followed up for <12 years or until the occurrence of cardiac death and MI. During a median follow-up period of 6 years, the cumulative cardiac death rate was 5.4%, and the MI rate was 3.1%. When outcomes were divided into two groups according to the ß2MG levels, cardiac death and MI rates were lower in patients with lower levels of ß2MG (<0.319 mg/gCre: determined by receiver operating characteristic analyses) than in those with ß2MG ≥0.319 mg/gCre (5.9% versus 17.1%, p<0.01). When outcomes were stratified according to the ß2MG levels in combination with eGFR levels, Kaplan-Meier analyses showed that cardiac death and MI rates increased depending on an increase in the ß2MG levels (p<0.05). Moreover, multivariate Cox analyses revealed that high levels of ß2MG were a significant independent predictor of adverse events (hazard ratio: 1.956; 95% confidence interval: 1.014-3.774; p = 0.045). The addition of high levels of ß2MG to conventional risk factors, including eGFR and urinary albumin, improved the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.5447, p = 0.0002; IDI 0.0126, p = 0.0454). CONCLUSION: Renal tubulointerstitial damage, as assessed by urinary ß2MG, is associated with the occurrence of cardiac death and recurrence of MI independent of renal glomerular function in patients with MI.

Echolucency of carotid plaque is useful for selecting high-risk patients with chronic coronary artery disease who benefit from intensive lipid-lowering therapy.

BACKGROUND: Ultrasound assessment of the carotid artery provides prognostic information on coronary events. This study examined whether ultrasound assessments of plaque echolucency of the carotid artery are useful for identifying patients with coronary artery disease (CAD) who are at high risk but could benefit from lipid-lowering therapy for secondary prevention. METHODS: Ultrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis was performed in 393 chronic CAD patients with low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL on statin therapy. All patients were prospectively followed up for a maximum of 96 months or until the occurrence of one of the following coronary events: cardiac death, nonfatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization. RESULTS: During the follow-up period, 45 coronary events occurred. Patients were stratified by IBS (≤-16.3 or >-16.3 dB, median value) and LDL-C level (<70 or 70-99 mg/dL). Multivariate Cox proportional hazards analysis showed that patients with lower IBS and LDL-C 70-99 mg/dL had significantly higher probabilities of coronary events compared with those with higher IBS and LDL-C <70 mg/dL, after adjustment for a baseline model of risk factors (hazard ratio 5.15; 95% confidence interval 1.21-22.0, p = 0.03). In contrast, patients with lower IBS and LDL-C <70 mg/dL had an improved prognosis comparable with those with higher IBS. Addition of LDL-C levels to the baseline model of risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) in patients with lower IBS (NRI, 0.44, p = 0.04; and IDI, 0.035, p < 0.01), but not in those with higher IBS. CONCLUSIONS: Evaluation of echolucency of the carotid artery was useful for selecting CAD patients at high risk of secondary coronary events but who could benefit from lipid-lowering therapy.

Structural Thickening of Medial Layer in Coronary Artery With Spasm in Patients With Myocardial Infarction.

Background The underlying pathophysiology of coronary artery spasm (CAS) remains unclear. We aim to determine whether coronary artery medial layer thickness is associated with CAS using optical coherence tomography. Methods and Results A total of 50 patients with previous myocardial infarction underwent optical coherence tomography of the left anterior descending artery: 20 with CAS and 30 without CAS. Intimal and medial layer areas were measured by planimetric analysis of optical coherence tomography images. The medial area/external elastic membrane (EEM) area was significantly greater in patients with than without CAS (0.13±0.01 versus 0.09±0.01, respectively, P<0.01), whereas the intimal area/EEM area was similar in the 2 groups. In patients without CAS, the relationship of intimal area/EEM area with medial area/EEM area and coronary diameter response to intracoronary injection of acetylcholine was characterized by an inverted U-shaped curve (y=-1.85x2+0.81x+0.01, R2=0.43, P<0.001) and a U-shaped curve (y=2993.2x2-1359.6x+117.1, R2=0.53, P<0.001), respectively. Thus, the medial layer became thin and the contractile response became weak in coronary arteries with greater intimal area in the non-CAS patients. In contrast, in patients with CAS, the intimal area/EEM area had no significant relationship with the medial area/EEM area in either linear correlation analysis or quadratic regression analysis. Thus, even when the intimal layer thickened, the medial layer did not thin in patients with CAS. Conclusions The structural thickness of the coronary medial layer was increased in patients with CAS, which may provide mechanistic insight into the pathogenesis of CAS. Registration URL: https://www.upload.umin.ac.jp; Unique identifier: UMIN000018432.

Impact of persistent endothelial dysfunction in an infarct-related coronary artery on future major adverse cardiovascular event occurrence in STEMI survivors.

Although coronary endothelial vasomotor dysfunction predicts future coronary events, few human studies have shown the relationship between persistent endothelial vasomotor dysfunction and major adverse cardiovascular events (MACE) using serial assessments in the same coronary artery. This study examined whether persistent endothelial vasomotor dysfunction is related to MACE occurrence in the infarct-related coronary artery (IRA) of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessments of the coronary vasomotor response to acetylcholine (ACh). This study included 169 consecutive patients with a first acute STEMI due to left anterior descending coronary artery (LAD) occlusion and successful reperfusion therapy with percutaneous coronary intervention. Vasomotor response to ACh in the LAD was measured within 2 weeks of acute myocardial infarction (AMI) (first test) and repeated 6 months (second test) after AMI under optimal anti-atherosclerotic therapy. MACE was defined as the composite of all-cause death, non-fatal MI, angina recurrence requiring percutaneous intervention or surgical bypass, and hospitalization for heart failure. We followed up 126 patients for a period of ≤ 60 months until MACE occurrence after second test. Nineteen MACEs occurred during the follow-up. The log-rank test, Kaplan-Meier curves and univariate Cox proportional hazards regression analysis showed that MACE occurrence was significantly associated with the persistent impairment of epicardial coronary artery dilation and coronary blood flow increases in response to ACh (log-rank test, p < 0.001 and p < 0.001, respectively) (Hazard ratio, p = 0.001 and p = 0.002, respectively). Persistent impairment of endothelial vasomotor function in the infarct-related conduit arterial segment and resistance arteriole were the significant predictor of future MACE occurrence in STEMI survivors.

Improvement in Brachial Endothelial Vasomotor Function and Brachial-Ankle Pulse Wave Velocity Reduces the Residual Risk for Cardiovascular Events after Optimal Medical Treatment in Patients with Coronary Artery Disease.

AIM: To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD). METHODS: We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (＜5.5%) and increased baPWV (＞1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for ＜60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs. RESULTS: During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). CONCLUSIONS: The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

Group V secreted phospholipase A2 plays a protective role against aortic dissection.

Aortic dissection is a life-threatening aortopathy involving separation of the aortic wall, whose underlying mechanisms are still incompletely understood. Epidemiological evidence suggests that unsaturated fatty acids improve cardiovascular health. Here, using quantitative RT-PCR, histological analyses, magnetic cell sorting and flow cytometry assays, and MS-based lipidomics, we show that the activity of a lipid-metabolizing enzyme, secreted phospholipase A2 group V (sPLA2-V), protects against aortic dissection by endogenously mobilizing vasoprotective lipids. Global and endothelial cell-specific sPLA2-V-deficient mice frequently developed aortic dissection shortly after infusion of angiotensin II (AT-II). We observed that in the AT-II-treated aorta, endothelial sPLA2-V mobilized oleic and linoleic acids, which attenuated endoplasmic reticulum stress, increased the expression of lysyl oxidase, and thereby stabilized the extracellular matrix in the aorta. Of note, dietary supplementation with oleic or linoleic acid reversed the increased susceptibility of sPLA2-V-deficient mice to aortic dissection. These findings reveal an unexplored functional link between sPLA2-driven phospholipid metabolism and aortic stability, possibly contributing to the development of improved diagnostic and/or therapeutic strategies for preventing aortic dissection.

Persistent Myocardial Production of Follistatin-like 1 Is Associated With Left Ventricular Adverse Remodeling in Patients With Myocardial Infarction: Myocardial production of FSTL1 in AMI patients.

BACKGROUND: Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction. METHODS AND RESULTS: FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and -0.43, respectively, all P < .001). CONCLUSIONS: The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.

Protein S-glutathionylation stimulate adipogenesis by stabilizing C/EBPß in 3T3L1 cells.

Reactive oxygen species (ROS) increase during adipogenesis and in obesity. Oxidants react with cysteine residues of proteins to form glutathione (GSH) adducts, S-glutathionylation, that are selectively removed by glutaredoxin-1 (Glrx). We have previously reported that Glrx knockout mice had increased protein S-glutathionylation and developed obesity by an unknown mechanism. In this study, we demonstrated that 3T3L1 adipocytes differentiation increased ROS and protein S-glutathionylation. Glrx ablation elevated protein S-glutathionylation and lipid content in 3T3L1 cells. Glrx replenishment decreased the lipid content of Glrx KO 3T3L1 cells. Glrx KO also increased protein expression and protein S-glutathionylation of the adipogenic transcription factor CCAAT enhancer-binding protein (C/EBP) ß. Protein S-glutathionylation decreased the interaction of C/EBPß and protein inhibitor of activated STAT (PIAS) 1, a small ubiquitin-related modifier E3 ligase that facilitates C/EBPß degradation. Experiments with truncated mutant C/EBPß demonstrated that PIAS1 interacted with the liver-enriched inhibitory protein (LIP) region of C/EBPß. Furthermore, mass spectrometry analysis identified protein S-glutathionylation of Cys201 and Cys296 in the LIP region of C/EBPß. The C201S, C296S double-mutant C/EBPß prevented protein S-glutathionylation and preserved the interaction with PIAS1. In summary, Glrx ablation stimulated 3T3L1 cell differentiation and adipogenesis via increased protein S-glutathionylation of C/EBPß, stabilizing and increasing C/EBPß protein levels.

Deficiency of Phospholipase A2 Receptor Exacerbates Autoimmune Myocarditis in Mice.

Secretory phospholipase A2 (sPLA2) plays a critical role in the pathogenesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA2 receptor 1 (PLA2R) acts as a clearance receptor for sPLA2s. This study examined whether PLA2R plays a role in the pathogenesis of experimental autoimmune myocarditis using PLA2R-deficient (PLA2R KO) mice on a BALB/c background. Autoimmune myocarditis was induced by immunization with murine α-myosin heavy chain. In the immunostaining of PLA2R wild-type (WT) myocardium, PLA2R and sPLA2s were expressed in α-SMA+ cells and neutrophils, respectively. In immunoblot analyses, tissue from PLA2R KO myocardium after immunization had five to tenfold increases in the protein level of sPLA2-IB and sPLA2-IIA compared with PLA2R WT myocardium. However, the mRNA expression levels of these sPLA2s were similar in PLA2R KO and WT myocardium. Compared with PLA2R WT myocardium, PLA2R KO myocardium after immunization showed 40% increase in areas affected by infiltration of inflammatory cells, eight to tenfold increase in levels of PGE2 and TXB2, and a threefold increase in number of Th17 cells in heart infiltrates assessed by flow cytometric analysis. Finally, PGE2 promoted IL-23-induced expansion of Th17 cells in vitro. In conclusion, PLA2R-deficiency increased sPLA2-IB and sPLA2-IIA levels in the myocardium after immunization probably through impaired clearance, leading to increased levels of PGE2 in the myocardium. Elevated PGE2 induced Th17 cell expansion, exacerbating myocarditis in PLA2R KO mice. Thus, PLA2R plays an important role in pathogenesis of experimental autoimmune myocarditis.

Sustained endothelial dysfunction in the infarct-related coronary artery is associated with left ventricular adverse remodeling in survivors of ST-segment elevation myocardial infarction.

BACKGROUND: Ischemia-reperfusion causes endothelial injury and dysfunction in the infarct-related coronary artery (IRA). Using serial assessment of coronary endothelial vasomotor function and left ventriculography (LVG), this study prospectively investigated the clinical impact of endothelial vasomotor dysfunction in the patent IRA on left ventricular (LV) remodeling in survivors of ST-elevation myocardial infarction (STEMI). METHODS: This study included 78 patients with STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention. All of them had LV ejection fraction (LVEF) <55%. LVG and the vasomotor responses to acetylcholine (ACh) in the LAD were examined within 2 weeks (1st test) and 6 months (2nd test) after MI. Cut-off values for coronary vasomotor dysfunction in response to ACh were based on the lower 10% of the distribution of coronary vasomotor responses to ACh in 20 control subjects. RESULTS: LV adverse remodeling, defined as a >10% increase in either LV end-diastolic volume index (LVEDVI) and/or end-systolic volume index (LVESVI) from the 1st to the 2nd test, occurred in 21 (70%) of 30 patients with sustained impairment of the coronary flow response to ACh at both the 1st and 2nd tests and 14 (29%) of 48 in the other coronary flow response group (p < 0.01). In multivariate logistic regression analysis, a >10% increase in LVEDVI and LVESVI was respectively associated with sustained impairment of the coronary diameter and flow responses to ACh (OR 4.9 and 3.5, 95% CI 1.7-14.1 and 1.1-10.9, p < 0.01 and p = 0.03, respectively), that was independent of hypertension, peak creatine phosphokinase, and the baseline coronary flow response to ACh at the 1st test. CONCLUSIONS: Sustained endothelial vasomotor dysfunction in the IRA was associated with LV adverse remodeling in STEMI survivors with successful reperfusion therapy.

Relationship of a thinned medial layer to the attenuated contractile response in atherosclerotic coronary arteries.

Coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis. This study aimed to clarify the relationship between thickness of the medial layer and the contractile response to acetylcholine (ACh) in coronary artery using optical coherence tomography (OCT). The OCT and the vasomotor response to ACh in the left anterior descending coronary artery were assessed in 32 patients with previous myocardial infarction. The intimal and medial layer areas were measured by planimetric analysis of the OCT images. The coronary contractile response to ACh had a positive linear relationship with medial area (r = 0.61, P < 0.001). In contrast, the relationship between the coronary contractile response to ACh and intimal area was described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.35, P = 0.002, y-axis, contraction; x-axis, intimal area). The contractile response increased as the intimal layer thickened up to the inflection point; thereafter, the contractile response declined. The relationship between medial area and intimal area was also described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.41, P < 0.01, y-axis, medial area; x-axis, intimal area). The medial area increased as the intimal area thickened up to the inflection point; thereafter, the medial area thinned. In conclusion, the thinned medial layer was associated with the attenuated contractile response in a coronary artery with greater atherosclerosis.NEW & NOTEWORTHY This is the first clinical study to show the relationship between the contractile response and the thickness of medial smooth muscle layer in coronary artery of patients with previous myocardial infarction using OCT. The contractile response to acetylcholine was attenuated, and medial layer area was thinned in coronary artery with greater atherosclerosis compared with those in coronary artery with mild or moderate atherosclerosis. The coronary contractile response was positively correlated with thickness of the medial layer in coronary arteries with either mild or greater atherosclerosis. Thus, coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis, which could be related to the thinned medial layer.

Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.

BACKGROUND: Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS: A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS: Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p =  0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION: Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

Failure of drug-coated balloon angioplasty to treat bare metal in-stent restenosis accompanied by late stent thrombosis but successful treatment of binary in-stent restenosis.

Drug-coated balloons (DCB) are effective in treating in-stent restenosis (ISR) with neointimal proliferation after bare-metal stent (BMS) implantation, but it is unclear whether DCB are effective in treating BMS-ISR accompanied by thrombosis. An 84-year-old man with previous inferior myocardial infarction and atrial fibrillation developed acute myocardial infarction (AMI) during hospitalization for intracerebral hemorrhage. Emergent coronary angiography (CAG) revealed severe stenosis of the distal left circumflex coronary artery. We implanted a BMS to avoid long-term triple antithrombotic therapy. He received aspirin, clopidogrel, and rivaroxaban for 1 month and then received clopidogrel and rivaroxaban. Seventy days after BMS implantation, he developed AMI, and emergent CAG revealed occlusion of the BMS due to late stent thrombosis. After thrombus aspiration, intravascular ultrasound showed incomplete neointimal healing in the proximal portion of the stent and excessive neointimal proliferation in the distal portion of the stent. DCB angioplasty of the entire BMS was performed after scoring balloon pre-dilation. Seven months after BMS implantation, follow-up CAG revealed binary ISR. DCB angioplasty of the entire BMS was performed again after scoring balloon pre-dilation. Thirteen months after BMS implantation, follow-up CAG did not reveal recurrence of ISR. .

Remnant Lipoproteins Are Residual Risk Factor for Future Cardiovascular Events in Patients With Stable Coronary Artery Disease and On-Statin Low-Density Lipoprotein Cholesterol Levels <70 mg/dL.

BACKGROUND: This study examined the predictive value of remnant lipoprotein levels for cardiovascular events (CVEs) in patients with stable coronary artery disease (CAD) and low-density lipoprotein cholesterol (LDL-C) levels <70 mg/dL on statin treatment.Methods and Results:Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol: RLP-C) were measured by an immunoseparation method in 247 consecutive patients with CAD who had on-statin LDL-C levels <70 mg/dL. All the patients were followed prospectively for a period of ≤60 months or until the occurrence of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, worsening heart failure, peripheral artery disease, aortic event, and ischemic stroke. During a mean follow-up period of 38 months, 33 CVEs occurred. Kaplan-Meier analysis demonstrated that higher RLP-C levels (≥3.9 mg/dL, determined by ROC curve) resulted in a significantly higher probability for the primary endpoint than did lower RLP-C levels (<3.9 mg/dL) (P<0.01 by log-rank test). Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of the primary endpoint after adjustment for known risk factors and lipid variables including triglycerides, and total apolipoprotein B (hazard ratio 1.62, 95% confidence interval 1.26-2.07, P<0.01). CONCLUSIONS: RLP-C levels are a residual risk factor for future CVEs in patients with CAD and on-statin LDL-C <70 mg/dL.