Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

AIMS: Intravascular ultrasound (IVUS) imaging can visualize vulnerable plaque features including attenuation (AP) and echolucency (ELP). While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention, the relationship between these plaque features and clinical outcomes has not been established. This analysis aimed to evaluate the association of AP/ELP with cardiovascular events. METHODS AND RESULTS: Serial IVUS imaging was reviewed in 1497 patients, followed for 18-24 months, with coronary artery disease from two clinical trials. Attenuated plaque and ELP were identified to measure each characteristics (AP arc, ELP area, and lengths), which permitted calculation of an AP index (API) and ELP volume. Attenuated plaque/ELP progression was defined as patients with any increase of API or ELP volume on serial imaging. The major cardiovascular events (MACEs) were defined as death, myocardial infarction, stroke, and coronary revascularization. AP or ELP was identified in 282 patients (18.8%) at baseline and 160 (10.7%) patients demonstrated an increase in AP or ELP at follow-up. The incidence of MACE was higher in patients with baseline AP/ELP than those without (8.2% vs. 3.9%, P = 0.002). Patients with AP/ELP progression were more likely to be acute coronary syndrome (41.9 vs. 33.2%, P = 0.03) and have greater baseline percent atheroma volume (40.0% vs. 35.8%, P < 0.001) than those without. On multivariable analysis, AP/ELP progression was more strongly associated with MACE [baseline AP/ELP: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.05-2.97, AP/ELP progression: HR 2.19, 95% CI 1.24-3.86]. CONCLUSION: Attenuation/ELP progression was associated with a higher prevalence of cardiovascular events, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease.

Association between cholesterol efflux capacity and coronary restenosis after successful stent implantation.

The measurement of high-density lipoprotein (HDL) functionality could be useful for identifying patients who have an increased risk of coronary restenosis after stent implantation. In the present study, we elucidates whether HDL functionality can predict restenosis. The participants included 48 consecutive patients who had stable angina and were successfully implanted with a drug-eluting stent (DES) or bare-metal stent. Follow-up coronary angiography was performed after 6-8 months of stenting. Cholesterol efflux and the anti-inflammatory capacity of HDL were measured before stenting (at baseline) and at follow-up. The mean age was 64 ± 11 years and the body mass index was 24 ± 3 kg/m(2). While HDL cholesterol (HDL-C) significantly increased from baseline to follow-up, there was no significant association between HDL-C level at baseline and in-stent late loss. Cholesterol efflux capacity was significantly increased from baseline to follow-up. The efflux capacity at baseline was negatively correlated with in-stent late loss, whereas the anti-oxidative activity of HDL at baseline was not associated with in-stent late loss. We analyzed the predictors of in-stent late loss using independent variables (efflux capacity and anti-oxidative capacity at baseline in addition to age, gender, HDL-C and low-density lipoprotein cholesterol at baseline, hypertension, diabetes mellitus, smoking, lesion length and DES implantation, history of myocardial infarction and prior percutaneous coronary intervention) by a multiple regression analysis. The efflux capacity at baseline was only independently associated with in-stent late loss. In conclusion, cholesterol efflux capacity at baseline could predict coronary restenosis in patients with successful stent implantation.

CETP Inhibition in CVD Prevention: an Actual Appraisal.

By virtue of their effects on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cellular cholesterol efflux, there is considerable interest in the potential use of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) as a novel approach for cardiovascular disease prevention. This is supported by observations from genetic and animal studies suggesting that less CETP activity has favorable cardiovascular effects. Despite the adverse effects of the first CETP inhibitor to move forward in clinical development, torcetrapib, there remains considerable interest in developing alternative CETP inhibitors without the off-target effects of torcetrapib. The clinical development programs leading to a number of promising CETP inhibitors will be reviewed.

Impact of cigarette smoking cessation on high-density lipoprotein functionality.

BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.

Associations of High-Density Lipoprotein Functionality with Coronary Plaque Characteristics in Diabetic Patients with Coronary Artery Disease: Integrated Backscatter Intravascular Ultrasound Analysis.

High-density lipoprotein (HDL) functionality has been reported to be associated with coronary artery disease (CAD). However, little is known about the impact of HDL functionality on coronary atherosclerosis. Thirty-eight type 2 diabetic patients with CAD who underwent percutaneous coronary intervention were examined. Coronary atheroma burden and plaque composition of the culprit lesions were assessed using conventional gray-scale and integrated backscatter intravascular ultrasound. HDL-mediated cholesterol efflux capacity (HDL-CEC) and HDL antioxidant capacity, estimated as HDL inflammatory index (HII), were examined. The associations between HDL functionality and coronary plaques were analyzed using multivariate data analysis, including principal components analysis and orthogonal partial least squares (OPLS) models. Percent atheroma volume was correlated with HDL-CEC (r = 0.34, p = 0.04) but not with HII (p = 0.65). The OPLS model demonstrated that the percentage lipid volume was significantly associated with HDL functionality [coefficient (95% confidence interval); HDL-CEC: -0.26 (-0.49, -0.04); HII: 0.34 (0.08, 2.60), respectively]. HII exhibited the highest variable importance in projection score, indicating the greatest contribution. HDL functionality was associated with coronary plaque composition, a key component of plaque vulnerability. Our findings highlight the potential importance of HDL functionality for coronary plaque stabilization.

A Continuous Murmur as the Only Clinical Sign for Complex Coronary Artery Fistulas Diagnosis.

An asymptomatic patient presented at our hospital exhibiting a Brugada electrocardiography pattern with coronary artery fistulas. Coronary artery fistula is a congenital or acquired rare abnormal condition with increased symptoms and complications over time. In the absence of the therapeutic consensus, we discuss the association and management for this condition. (Level of Difficulty: Advanced.).

Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs.

Epidemiological studies and meta-analyses have consistently suggested the importance of lowering low-density lipoprotein cholesterol (LDL-C) to reduce cardiovascular (CV) events. However, these studies and mechanistic studies using intracoronary imaging modalities have reported patients who continue to experience CV events or disease progression despite optimal LDL-C levels on statins. These findings, including statin intolerance, have highlighted the importance of exploring additional potential therapeutic targets to reduce CV risk. Genomic insights have presented a number of additional novel targets in lipid metabolism. In particular, proprotein convertase subtilisin/kexin type 9 inhibitors have rapidly developed and recently demonstrated their beneficial impact on CV outcomes. Triglyceride (TG)-rich lipoproteins have been recently reported as a causal factor of atherosclerotic cardiovascular disease (ASCVD). Indeed, several promising TG-targeting therapies are being tested at various clinical stages. In this review, we present the evidence to support targeting atherogenic lipoproteins to target residual ASCVD risk in statin-treated patients.

The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial.

BACKGROUND: Apabetalone is a selective bromodomain and extra-terminal (BET) inhibitor which modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated coronary atherosclerotic plaque (AP), a measure of vulnerability, is unknown. METHODS: The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE; NCT01067820) study employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in 281 patients treated with apabetalone or placebo for 26 weeks. AP was measured at baseline and follow-up. Factors associated with changes in AP were investigated. RESULTS: AP was observed in 31 patients (11%) [27 (13.0%) in the apabetalone group and four (5.5%) in the placebo group]. The apabetalone group demonstrated reductions in AP length by - 1 mm [interquartile range (IQR) - 4, 1] (p = 0.03), AP arc by - 37.0° (IQR - 59.2, 8.2) (p = 0.003) and the AP index by - 34.6 mm° (IQR - 52.6, 10.1) (p = 0.003) from baseline. The change in AP index correlated with on-treatment concentration of high-density lipoprotein (HDL) particles (r = - 0.52, p = 0.006), but not HDL cholesterol (r = - 0.11, p = 0.60) or apolipoprotein A-1 (r = - 0.16, p = 0.43). Multivariable analysis revealed that on-treatment concentrations of HDL particles (p = 0.03) and very low-density lipoprotein particles (p = 0.01) were independently associated with changes in AP index. CONCLUSIONS: Apabetalone favorably modulated ultrasonic measures of plaque vulnerability in the population studied, which may relate to an increase in HDL particle concentrations. The clinical implications are currently being investigated in the phase 3 major adverse cardiac event outcomes trial BETonMACE.

Associations of ABCG1-mediated cholesterol efflux capacity with coronary artery lipid content assessed by near-infrared spectroscopy.

BACKGROUND: Although high-density lipoprotein (HDL) has atheroprotective properties, the association of HDL functionality with coronary plaques remains unclear. METHODS: We investigated the association between HDL-mediated cholesterol efflux capacity (CEC) and coronary lipid burden in 74 patients who underwent near-infrared spectroscopy (NIRS) imaging for acute coronary syndrome (ACS) or stable ischemic symptoms. We measured baseline HDL-mediated CEC, distinguishing the specific pathways, and stratified patients according to their median CEC values. Coronary lipid burden was assessed as lipid core burden index (LCBI) using NIRS at baseline (n=74) and on serial imaging (n=47). RESULTS: Patients with baseline ATP-binding cassette transporter G1 (ABCG1)-mediated CEC > median had a greater baseline LCBI {74 [20, 128] vs. 32 [5, 66]; P=0.04} or change in LCBI {-30 [-89, 0] vs. -3 [-16, 0]; P=0.048}. In addition to a negative association between baseline LCBI and change in LCBI (standardized ß=-0.31; P=0.02), multivariable analysis demonstrated a significant interaction effect between clinical presentation of coronary artery disease (CAD) and baseline ABCG1-mediated CEC on change in LCBI (P=0.003), indicating that baseline ABCG1-mediated CEC was inversely associated with change in LCBI in patients with ACS (standardized ß=-0.79, P=0.003), but not in those with stable ischemic symptoms (P=0.52). CONCLUSIONS: In this study, ABCG1-mediated CEC, but not ATP-binding cassette transporter A1 and scavenger receptor B type I, was associated with regression of coronary artery lipid content, especially in patients with high-risk phenotype. Further studies are required to determine the roles of ABCG1 pathway in the development coronary plaques.

High-Density Lipoprotein Infusions.

High-density lipoproteins (HDLs) have presented an attractive target for development of new therapies for cardiovascular prevention on the basis of epidemiology and preclinical studies demonstrating their protective properties. Development of HDL mimetics provides an opportunity to administer functional HDL. However, clinical trials have produced variable results, with no evidence to date that they reduce cardiovascular events. This article reviews development programs of HDL mimetics.

The relationship between segmental wall shear stress and lipid core plaque derived from near-infrared spectroscopy.

BACKGROUND AND AIMS: Wall shear stress (WSS) has an important role in the natural history of coronary atherosclerosis. The aim of this study is to investigate the relationship between WSS and the lipid content of atherosclerotic plaques as assessed by near-infrared spectroscopy (NIRS). METHODS: We performed serial NIRS and intravascular ultrasound (IVUS) upon Doppler coronary flow guidewire of coronary plaques at baseline and after 12-18 months in 28 patients with <30% angiographic stenosis, who presented with coronary artery disease. Segmental WSS, plaque burden and NIRS-derived lipid rich plaque (LRP) were evaluated at both time-points in 482 consecutive 2-mm coronary segments. RESULTS: Segments with LRP at baseline (n = 106) had a higher average WSS (1.4 ±â€¯0.6 N/m2), compared to those without LRP (n = 376) (1.2 ±â€¯0.6 N/m2, p<0.001). In segments without baseline LRP, WSS was higher in those who subsequently developed new LRP (n = 35) than those who did not (n = 341) (1.4 ±â€¯0.8 vs. 1.1 ±â€¯0.6 N/m2, p=0.002). Conversely, in segments with baseline LRP, WSS was lower in those who had regression of lipid content (n = 41) than those who did not (n = 65) (1.2 ±â€¯0.4 vs. 1.6 ±â€¯0.7 N/m2, p=0.007). Segments with the highest tertile of WSS displayed greater progression of LCBI irrespective of baseline lipid content (p<0.001). Multivariate analysis revealed that baseline WSS (p=0.017), PAV (p<0.001) and LCBI (p<0.001) were all independent predictors of change in LCBI over time. CONCLUSIONS: Coronary segments with high WSS associate with progression of lipid content over time, which may indicate transformation to a more vulnerable phenotype.

High-density lipoprotein cholesterol associated with change in coronary plaque lipid burden assessed by near infrared spectroscopy.

BACKGROUND AND AIMS: Little is known about the relation between serum lipid parameters and serial change in plaque composition using in vivo coronary imaging. The aim of this study was to examine the association between serum lipids and change in coronary plaque lipid burden assessed by near-infrared spectroscopy (NIRS). METHODS: We performed serial NIRS-intravascular ultrasound studies in 49 patients who underwent coronary angiography for an acute coronary syndrome (ACS) or stable ischemic symptoms. Univariable and multivariable linear regression analyses were applied to evaluate the relationship between serum lipid parameters and change in lipid core burden index at the 4-mm maximal segment (max LCBI4mm). RESULTS: Mean patient age was 61 ± 9 y, 29% were women, 35% had an ACS clinical presentation, 78% received statin therapy at baseline, and median low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglyceride levels were 101, 43, 174 and 133 mg/dL, respectively. During a median follow-up period of 13 months, max LCBI4mm significantly decreased from 277 to 194 (p = 0.001). On univariable analysis, the percent change in HDL-C negatively associated with the change in max LCBI4mm (ß = -3.19, p = 0.004). There were no significant associations between the other lipid parameters and change in max LCBI4mm. On multivariable analysis, percent change in HDL-C remained significantly associated with the change in max LCBI4mm (p = 0.002). CONCLUSIONS: Change in HDL-C, but not other lipids parameters, associated with changes in coronary plaque lipid burden assessed by NIRS. These findings highlight the potential therapeutic importance of high-density lipoprotein on serial change in plaque composition.

Stabilization of high-risk plaques.

The prevalence of atherosclerotic cardiovascular diseases (ASCVDs) is increasing globally and they have become the leading cause of death in most countries. Numerous experimental and clinical studies have been conducted to identify major risk factors and effective control strategies for ASCVDs. The development of imaging modalities with the ability to determine the plaque composition enables us to further identify high-risk plaque and evaluate the effectiveness of different treatment strategies. While intensive lipid-lowering by statins can stabilize or even regress plaque by various mechanisms, such as the reduction of lipid accumulation in a necrotic lipid core, the reduction of inflammation, and improvement of endothelial function, there are still considerable residual risks that need to be understood. We reviewed important findings regarding plaque vulnerability and some encouraging emerging approaches for plaque stabilization.

A novel inducible cholesterol efflux peptide, FAMP, protects against myocardial ischemia reperfusion injury through a nitric oxide pathway.

OBJECTIVE: We evaluated whether a novel inducible cholesterol efflux (iCE) peptide [Fukuoka University Apolipoprotein A-I Mimetic Peptide (FAMP)] protects against myocardial ischemia reperfusion injury (IRI) through a nitric oxide (NO) pathway by an improvement of high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: Male C57BL6/J mice were intraperitoneally injected with phosphate buffer as a control, low-dose (10 mg/kg) or high-dose (50 mg/kg) of FAMP before 18 h of IRI (n=6-12 in each group). After 30 min of ischemia followed by 6h of reperfusion, blood pressure, and infarct size were measured and cardiac function was evaluated by a Millar catheter. FAMP significantly improved stroke volume, cardiac output, left ventricular ejection fraction, and infarct size. FAMP significantly preserved cytochrome C in the mitochondrial fraction and inhibited its release into the cytosolic fraction in the heart, but did not significantly reduce mRNA levels of monocyte chemoattractant protein-1 or interluekin-6. In a TdT-mediated dUTP nick end labeling (TUNEL) assay, FAMP significantly suppressed the appearance of TUNEL-positive nuclear. We also performed same experiments with endothelial nitric oxide synthase-knockout (eNOS-KO) mice and FAMP-induced improvements of cardiac function were not observed in eNOS-KO mice. CONCLUSIONS: FAMP activated HDL-functionality and improved cardiac function in a model of myocardial IRI. It may have anti-apoptotic effects by protecting mitochondria through a NO pathway as a pleiotropic effect.

The ApoA-I mimetic peptide FAMP promotes recovery from hindlimb ischemia through a nitric oxide (NO)-related pathway.

BACKGROUND/OBJECTIVE: HDL has various atheroprotective functions and improves endothelial function. Apolipoprotein A-I (apoA-I) is a major protein of HDL and plays a crucial role in HDL functions. We developed a novel apoA-I mimetic peptide, FAMP (Fukuoka University ApoA-I Mimetic Peptide). It is unclear whether an apoA-I mimetic peptide can promote neovascularization in vivo. Here, we investigated the effect of FAMP on endothelial nitric oxide synthase (eNOS) activation and angiogenesis in a murine hindlimb ischemia model. METHODS AND RESULTS: Intramuscular administration of FAMP significantly enhanced blood flow recovery and increased capillary density in the ischemic limb of mice fed a high-cholesterol diet (HCD). In a gait analysis, FAMP ameliorated functional recovery compared with that in the control group. FAMP significantly activated Akt, ERK, and eNOS phosphorylation in endothelial cells, and improved the migratory functions of human aortic endothelial cells (HAECs). LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), significantly inhibited the activation of eNOS by FAMP. FAMP had no beneficial effects on blood flow recovery in eNOS(-/-) mice. CONCLUSIONS: FAMP promoted recovery from hindlimb ischemia through a nitric oxide (NO)-related pathway by activation of a PI3K/Akt pathway. FAMP may become a new therapeutic agent for the future clinical treatment of critical limb ischemia (CLI).

Newly developed apolipoprotein A-I mimetic peptide promotes macrophage reverse cholesterol transport in vivo.

BACKGROUND: We elucidated the effect of newly developed Fukuoka Apolipoprotein A-I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms. METHODS AND RESULTS: Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of (3)H-tracer. The amount of (3)H-tracer excreted into feces over 48h in the FAMP group was significantly higher than that in the control group. (3)H-cholesterol ester (CE)-HDL was injected intravenously and (3)H-cholesterol in blood was counted. In the FAMP group, plasma (3)H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate. CONCLUSIONS: The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential.

Safety and feasibility of high-dose administration of nicorandil before reperfusion therapy in acute myocardial infarction.

The efficacy and safety of high-dose nicorandil therapy in acute myocardial infarction (AMI) have not yet been clarified. This is a prospective study including 30 patients who received nicorandil at 0.06 mg/kg/h [standard dose nicorandil (SDN) group] and 32 patients who received a bolus injection of nicorandil 0.2 mg/kg followed by a continuous infusion at 0.2 mg/kg/h [high-dose nicorandil (HDN) group]. The benefits and adverse events were assessed during acute phase and 12-month follow-up period. There were no significant differences between the groups in blood pressure, heart rate or urine volume 2, 6 and 24 h after drug administration, although blood pressure decreased during acute phase. The percentages of patients who required dose reduction or discontinuation of nicorandil were 34.4 and 16.7 % in HDN and SDN groups, respectively (p = 0.11). In HDN group, subgroup analysis revealed that the TIMI frame count (TFC) was significantly lower in patients in whom the treatment was started within 12 h compared to those more than 12 h (17.0 vs. 21.0, p = 0.017) and in patients with baseline WBC elevation compared to those without it (16.5 vs. 22.0, p = 0.029). A TFC of >20 was significantly associated with being in HDN group [odds ratio (OR) 0.27; 95 % confidence interval, CI 0.07-0.89], onset-to-balloon time (OR 1.06; 95 % CI 1.01-1.16), and ∑creatine kinase (OR 7.27; 95 % CI 1.40-57.83). There were no significant differences in incidences of cardiovascular death, rehospitalization, and target lesion revascularization between the groups. HDN therapy may improve coronary microcirculation in patients with AMI.