Plaque stabilization by intensive LDL-cholesterol lowering therapy with atorvastatin is delayed in type 2 diabetic patients with coronary artery disease—Serial angioscopic and intravascular ultrasound analysis

BackgroundDiabetes mellitus (DM) is a major risk factor for cardiovascular events. The study purpose was to compare DM and non-DM (nDM) patients in terms of statin-induced change of plaque characteristics using intravascular ultrasound (IVUS) and coronary angioscopy.MethodsPatients with coronary artery disease and hypercholesterolemia who were enrolled to the TWINS were selected and classified into two groups: DM group and nDM group. Eleven DM patients and 28 nDM patients were studied.ResultsLow-density lipoprotein cholesterol levels decreased significantly to a similar extent at weeks 28 and 80 from baseline in DM and nDM (p < 0.001). The mean angioscopic color grades of yellow plaques in DM and nDM were similar at baseline and significantly decreased at week 80 from baseline in both groups, however, the mean change of angioscopic color grade from baseline in DM were not significantly decreased and the mean angioscopic color was significantly higher than that in nDM (1.34 vs. 1.00, p < 0.05) at week 28. IVUS showed plaque volume reduction in both groups (p < 0.01) except at week 80 in DM group, which was not statistically significant different compared to the baseline.ConclusionIn DM patients, plaque volume regression by atorvastatin was shown to be attenuated, and its color improvement was significantly delayed. However, the yellowness became comparable between DM and nDM groups at week 80. These results indicate that patients with DM should be treated by intensive lipid-lowering therapy with atorvastatin for at least 80 weeks to stabilize vulnerable plaque.     

Multi-modality intra-coronary plaque characterization: a pilot study

BackgroundThe risk of rupture and subsequent thrombosis of the atherosclerotic coronary plaques is related to the presence of necrotic core with high lipid content.We conducted an exploratory pilot trial to compare the capability for lipid tissue detection using four intra-coronary diagnostic techniques: greyscale intravascular ultrasound (GS IVUS), IVUS radiofrequency data (IVUS RFD) analysis, optical coherence tomography (OCT) and intravascular magnetic resonance spectroscopy (IVMR).MethodsTwenty-four matched target plaques were analyzed with the 4 techniques in non-culprit lesions in five patients with stable angina. Following IVUS pullback, OCT and IVMR was performed. Plaque composition was assessed using established criteria of each technology.ResultsAtherosclerotic plaques classified as soft by GS IVUS were mainly composed by fibro-fatty (80%) or necrotic core (20%) by IVUS RFD. These soft plaques were classified as “lipid-rich” by OCT in the majority of cases (80%). IVMR confirmed the presence of lipid with a lipid fraction index ranging between 36 and 79 in these soft plaques. Besides this good agreement for soft plaques, GS IVUS, IVUS RFD and OCT had 100% agreement in the identification of calcified plaques.ConclusionThe present study explored multi-modality imaging of atherosclerotic plaque in-vivo. Assessing specifically lipid-rich plaques, there was generally good agreement for plaque components identified as soft by traditional GS IVUS with RFD and OCT whereas IVMR showed a varying amount of lipid in these regions. Nevertheless there continues to remain inherent variation, namely as a result of the different imaging resolutions and the lack of common nomenclature and classification.     

Recombinant apolipoprotein A-IMilano for the treatment of cardiovascular diseases

Apolipoprotein A-I_Milano (apoA-I_M) is a natural variant of apoA-I characterized by a cysteine for arginine substitution at position 173 of the primary sequence. ApoA-I_M carriers have much less atherosclerosis than expected from their very low plasma high-density lipoprotein (HDL) cholesterol levels, suggesting that the variant might be protective. Synthetic HDL (sHDL) made with a recombinant form of the dimeric A-I_M (A-I_M/A-I_M) and phospholipids given in single or multiple injections is effective in inducing the regression of atherosclerotic plaques, preventing arterial restenosis, and limiting cardiac dysfunction after ischemia/reperfusion injury. In a phase II trial in patients with acute coronary syndromes, a short-term treatment with A-I_M/A-I_M sHDL caused a remarkable reduction of atheroma burden. Although at early stages of drug development, A-I_M/A-I_M sHDL holds vast promise for the treatment of a variety of cardiovascular diseases in humans.     

El tratamiento antiviral no mejora la ateromatosis subclínica en pacientes con hepatitis crónica por virus de la hepatitis C

IntroductionChronic infection with hepatitis C virus is a risk factor for developing atheromatous plaques, although the possible effect of virus clearance is unknown. Our aim was to determine whether or not subclinical atheromatosis improved and there was any modification in the composition of the plaques 12 months after eradication of hepatitis C virus by direct-acting antiviral agents.Materials and methodsProspective study that included 85 patients with chronic hepatitis C virus infection in different stages of fibrosis who were on direct-acting antiviral agents. Patients with a cardiovascular history, diabetes and kidney disease were excluded. An arterial ultrasound (carotid and femoral) was performed to diagnose atheromatous plaques (defined as intima-media thickness ≥ 1.5 mm) and the composition (percentage of lipids, fibrosis and calcium with HEMODYN4 software) was analysed at the beginning of the study and 12 months after stopping the therapy.ResultsAfter follow-up no changes were detected in the intima-media thickness (0.65 mm vs. 0.63 mm, P = .240) or in the presence of plaques (65.9% vs 71.8%, P = .063). There was also no significant change in their composition or affected vascular territory, with an increase in blood lipid profile (P < .001) after 12 months of treatment. These results were confirmed in subgroups by severity of liver disease.DiscussionThe eradication of hepatitis C virus by direct-acting antiviral agents does not improve the atheroma plaques and nor does it vary their composition, regardless of liver fibrosis. More prospective studies are needed to evaluate residual cardiovascular risk after virus eradication.     

Pathological mechanisms and dose dependency of erythrocyte-induced vulnerability of atherosclerotic plaques

To test our hypothesis that erythrocytes may induce plaque vulnerability and investigate the mechanism involved, we established a novel model of intraplaque hemorrhage in 56 New Zealand white rabbits with established plaques. Three distinct abdominal aortic plaques with similar thickness were identified in each rabbit with use of intravascular ultrasound (IVUS) imaging. Rabbits were equally divided into 4 groups depending on dosage of treatment; with the guidance of IVUS, one of the three plaques from each rabbit was injected from adventitia with autologous erythrocytes (RBC) or cholesterol (CH) for the following groups: RBC, 50 microL or 100 microL, and CH, 50 microL or 100 microL. One of the other two plaques in each rabbit received an equal volume of normal saline (NS) and one received no injection. Plaques in the 100 microL RBC group had a higher plaque rupture rate than its respective NS or blank controls plaques (57.1% vs. 14.3% or 14.3%, P<0.05). Plaques from the RBC or cholesterol groups showed, dose-dependently, more macrophage infiltration, more superoxide and lipid content, thinner plaque fibrous cap, higher mRNA level of MCP-1, IL-1 or IFN-gamma and higher vulnerability index than controls, especially in the RBC group. Thus, erythrocyte treatment can dose-dependently induce the vulnerability of plaques. Accumulation of lipid content and augmentation of oxidative stress and inflammation in the plaques are the probable pathological mechanisms involved.     

Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis

ObjectivesPsoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis.Methods and resultsWe prospectively enrolled a consecutive sample of patients with psoriasis (n = 122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n = 134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n = 100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dl (36–58) vs 50 (42–62), p < 0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002–1498) vs 1115 (935–1291), p = 0.02] with decrease in LDL size [20.6 (20.3–21.1) vs 21.3 (20.6–21.1), p < 0.001] beyond CV risk factors and HOMA-IR (p = 0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta ?0.14, p = 0.001).ConclusionsThese data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.     

Sex‐specific risk factors of carotid atherosclerosis progression in a high‐risk population of cardiovascular disease

BackgroundThe progression of carotid intima‐media thickness (cIMT) and plaques are associated with cardiovascular health, especially for high‐risk population of cardiovascular disease (CVD).HypothesisRisk factors for atherosclerosis may vary by sex. This study aimed to investigate the sex‐specific risk factors of cIMT and plaque progression.MethodsWe selected subjects who were identified as high‐risk population of CVD, and collected their carotid ultrasound data and baseline characteristics. Linear regression and logistic regression analyses were used to identify risk factors for cIMT and plaque progression. Sex‐specific risk factors were identified respectively.ResultsA total of 7908 participants were included. The mean age was 57.75 ± 9.45 years and 61.51% were female. During mean follow‐up of 1.92 ± 0.89 years, the median annual cIMT change rate was −7.25 μm/year. Seven hundred and fifteen subjects free from plaques at baseline developed plaque. Age, smoking, hypertension, and diabetes were common risk factors for carotid atherosclerosis progression in all participants. Smoking and alcohol drinking were significantly associated with increased cIMT change in women, while hypertension and antihypertensive medication were significant in men. Increased total cholesterol and diabetes were significantly associated with new plaque presence in women, while smoking, increased triglyceride, and dyslipidemia were significant in men (p ˂ .05 for all cases). The association of baseline cIMT and smoking with annual cIMT change rate and increased total cholesterol with new plaque presence were significantly differentiated between both sexes (p for interaction ˂ .05).ConclusionsThe risk factors for cIMT and plaque progression differed by sex.     

Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits

This study analyzed the antiatherogenic effects of newly developed apolipoprotein A-I (ApoA-I) mimetic peptide/phospholipid complexes (ETC-642) against the aortic plaque burden in vivo. We used human macrophage cells to analyze cholesterol efflux by ETC-642. Watanabe-heritable hyperlipidemic (WHHL) rabbits were divided into 3 groups: low- (15 mg/kg) and high-dose ETC-642 (50 mg/kg), and placebo. The test material was injected twice/week for 12 weeks. The aortic plaque burden was assessed by intravascular ultrasound (IVUS) at 0 and 12 weeks. Plasma lipid profiles were analyzed by capillary isotachophoresis every 4 weeks. ETC-642 had an effect on cholesterol efflux comparable to that of conventional rHDL. In WHHL rabbits, high-dose ETC-642 inhibited the progression of aortic atherosclerosis compared to placebo. There was no change in the percentage of plaque volume (%PV) in the high-dose group between before (30.9%) and after infusion (28.6%), whereas there was a significant increase in the control group from 27.8% to 37.9%. ETC-642 significantly reduced charge-modified low-density lipoprotein (LDL) by converting more negative-charged modified LDL to less negative-charged LDL, and reduced small dense (sd) LDL by converting it into large, buoyant (lb) LDL. Changes in the %PV were positively correlated with changes in negative-charged modified LDL (r = 0.61, p < 0.01) and sdLDL (r = 0.59, p < 0.01), and negatively correlated with changes in less negative-charged LDL (r = −0.43, p < 0.01) and lbLDL (r = −0.57, p < 0.01). In conclusion, the ETC-642-induced remodeling of sdLDL to large and lbLDL and the enhancement of cholesterol efflux may prevent progression of the aortic plaque burden. HDL-based therapy may be useful for preventing the progression of plaque volume.     

Metabolic syndrome (MetS) predicts cardio and cerebrovascular events in a twenty years follow-up. A prospective study

ObjectivesTo investigate the extent of subclinical atherosclerosis in asymptomatic familial hypercholesterolemia (FH) patients using non-invasive images techniques.Patients, methods and resultsThe atherosclerotic burden of 36 molecularly defined FH patients (18 males, 45.7 ± 10.9 years) without evidence of cardiovascular disease receiving lipid-lowering treatment and 19 (47.8 ± 11.3 years) controls was investigated. Descending thoracic aorta magnetic resonance imaging (MRI) was performed in a 1.5 T equipment with T1 and T2 sequences to characterize atherosclerotic plaques and to measure aortic wall volumen. Carotid intima-media thickness (cIMT) and presence of plaques were measured using B-mode carotid ultrasound.Mean aortic wall volumen, cIMT and atherosclerotic plaques in aorta were significantly higher in FH cases (P < 0.001). A significant correlation between aortic wall volume and cIMT was observed (P < 0.01). Aortic MRI detected plaques in 94% and carotid ultrasound in 14% of cases. Lipid-rich plaques were observed only in FH cases (33%) and were associated with family history of premature coronary artery disease (P < 0.05).ConclusionsAsymptomatic middle-aged FH patients have significantly higher atherosclerotic burden than controls. cIMT has shown a significant correlation with aortic wall volume and MRI allowed the detection of lipid-rich plaques in FH subjects that were associated with family history of premature coronary artery disease.     

Association between impaired glucose tolerance and carotid atherosclerosis: A study in 64-year-old women and a meta-analysis

Background and aimsImpaired glucose tolerance (IGT) is regarded as a transient metabolic state leading to type-2 diabetes, and is known to predict future risk of cardiovascular disease. This study was designed to investigate if IGT is associated with subclinical atherosclerosis.Methods and resultsIn a population-based cohort of 64-year-old women, a group with IGT determined by repeated oral glucose tolerance tests (n = 205) was compared with healthy women with normal glucose tolerance (NGT, n = 188). Intima-media thickness (IMT) and plaques in the common carotid arteries (CCA) and bulbs were measured by ultrasound. The 95% confidence interval (CI) of the difference between the IGT and NGT groups was −0.03 to 0.03 mm. There was no difference in carotid bulb IMT or in the occurrence, size, and characteristics of plaques between the IGT and NGT groups. A meta-analysis was used to calculate summary measures of 12 reviewed studies showing a difference of 0.030 (95% CI 0.012–0.048) mm in carotid IMT between IGT and NGT groups. Heterogeneity in IMT differences between studies was shown.ConclusionsIn our population-based cohort of 64-year-old women, IGT was not associated with increased occurrence of subclinical atherosclerosis. However, a meta-analysis of 12 studies, including our current study, showed that IGT was associated with a small increase in the CCA IMT.     

Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit

Objectives. This study was designed to test the hypothesis that long-term oral supplementation of dietary l-arginine (to provide a sustained elevation of nitric oxide activity) would inhibit atherogenesis in hypercholesterolemic rabbits, as assessed by histomorphometric measurements.Background. Endothelium-derived nitric oxide inhibits a number of processes that are critical in atherogenesis. Hypercholesterolemia reduces endothelial nitric oxide activity, and we postulate that this may promote atherogenesis. This reduction in nitric oxide activity can be reversed acutely by intravenous infusion of l-arginine, the precursor of nitric oxide. We show that dietary supplementation of l-arginine abrogates the development of coronary atheroma in hypercholesterolemic rabbits.Methods. Male New Zealand White rabbits were fed normal rabbit chow, 1% cholesterol chow or 1% cholesterol chow with dietary arginine or methionine supplementation to increase their intake of these amino acids sixfold. After 1 or 10 weeks of dietary intervention, the left main and left anterior descending coronary arteries were harvested for histologic study. Plasma cholesterol measurements were elevated to the same degree in all groups of rabbits receiving the 1% cholesterol diet, whereas plasma arginine levels were doubled in the arginine-treated group. High density lipoprotein (HDL) cholesterol values were not affected by arginine treatment.Results. In rabbits receiving the 1% cholesterol diet, with or without methionine supplementation, light and electron microscopy revealed a marked increase from 1 to 10 weeks in the intimal accumulation of macrophages, associated with an increase in the intimal area of the left main coronary artery. By contrast, in arginine-treated hypercholesterolemic rabbits, there was a near absence of adherent monocytes and tissue macrophages and no progression of intimal thickness from 1 to 10 weeks.Conclusions. Dietary supplements of l-arginine prevent intimal thickening in the coronary arteries of hypercholesterolemic rabbits. This antiatherogenic effect is not due to an alteration in plasma total cholesterol, HDL cholesterol or caloric or nitrogen balance. The data are consistent with the hypothesis that nitric oxide has antiatherogenic properties.     

Determinants of coronary compliance in patients with coronary artery disease: An intravascular ultrasound study

Objectives. The aim of this study was to elucidate determinants of coronary compliance in patients with coronary artery disease.Background. Intravascular ultrasound potentially enables in vivo evaluation of coronary artery compliance.Methods. Twenty-seven patients (mean age [±SD] 57 ± 11 years, three women) undergoing coronary angioplasty were studied with intravascular ultrasound imaging. A mechanical intravascular ultrasound system (4.8F, 20 MHz) was used. A total of 58 dilferent coronary segments (proximal to the target angiographic lesion) were studied. Of these, 35 were located in the left anterior descending, 9 in the left main, 8 in the left circumflex and 6 in the right coronary arteries. During intravascular ultrasound imaging, 22 segments (38%) appeared normal, but 36 (62%) had plaque (24 fibrotic, 3 lipidic and 9 calcified). Systolic-diastolic changes in area (ΔA) and pressure (ΔP) with respect to vessel area (A) were used to study normalized compliance (Normalized compliance = [ΔA/AJ/ΔP [mm Hg⁻¹×x 10³]).Results. Lumen area and plaque area were 12.6 ± 5.7 and 3 ± 3 mm², respectively. Plaque was concentric (more than two quadrants) at 10 sites, but the remaining 26 plaques were eccentric. Compliance was inversely related to age (r = −0.34, p < 0.05) but was not related to other clinical variables. Compliance was greater in the left main coronary artery (3.9 ± 2.1 vs. 1.8 ± 1.2 mm Hg⁻¹, p < 0.05) and in coronary segments with normal findings on ultrasound imaging (2.9 ± 1.9 vs. 1.6 ± 1.1 mm Hg⁻¹, p < 0.01). Moreover, at diseased coronary segments compliance was lower in calcified plaques than in other types of plaques (1.2 ± 9.7 vs. 2.3 ± 1.6 mm Hg⁻¹, p < 0.01) but was similar in concentric and eccentric plaques (1.6 ± 1.5 vs. 1.6 ± 0.9 mm Hg⁻¹). Plaque area (r = − 0.38, p < 0.01) was inversely correlated with compliance. On multivariate analysis, only age and plaque area were independently related to compliance.Conclusions. Intravascular ultrasound may be used to evaluate compliance in patients with coronary artery disease. Compliance is reduced with increasing age and is mainly determined by the arterial site and by the presence, size and characteristics of plaque on intravascular ultrasound imaging.     

PCSK9 Inhibitors in Heart Transplant Patients: Safety,Efficacy, and Angiographic Correlates

BackgroundStatins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation.Methods and ResultsWe identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8–9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8–3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102–148 mg/dL) to 55 mg/dL (IQR, 35–74 mg/dL) after starting PCSK9i (P < .001), with 72% of patients achieving a low-density lipoprotein cholesterol of <70 mg/dL after treatment. There were also significant reductions of total cholesterol, non–high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area.ConclusionsAmong heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.     

普伐他汀对兔腹主动脉易损斑块内细胞凋亡影响的研究

目的 探讨普伐他汀对兔动脉粥样硬化易损斑块内细胞凋亡的影响.方法 新西兰大白兔30只,随机分为三组,均通过动脉内膜损伤术加高脂饮食形成动脉粥样硬化斑块.术后一组给予高脂饮食（对照组）,另一组给予高脂饮食加普伐他汀（普伐他汀1组,P1组）,第三组术后2个月内给予高脂饮食,第3个月起加普伐他汀（普伐他汀2组,P2组）,三组均通过超声检测斑块形成情况,测量内中膜厚度（IMT）.饲养4个月后处死兔子,取易损斑块,通过TUNEL法检测斑块细胞凋亡情况.结果 兔腹主动脉IMT逐渐增厚,术后1个月后普伐他汀组明显小于高脂饮食组（P＜0.01）;细胞凋亡在高脂饮食组中的表达,集中在脂核区和纤维帽区,明显高于其他两区（P＜0.01,P＜0.01）;普伐他汀组凋亡细胞主要在脂核区,明显大于其他三区（P＜0.01）;两组比较细胞凋亡在纤维帽区,普伐他汀2组明显小于高脂饮食组（P＜0.01）.结论 IMT与动脉粥样硬化程度高度相关,普伐他汀能通过减少纤维帽区的细胞凋亡而稳定斑块.     

Impact of Intravascular Ultrasound on Long-Term Clinical Outcomes in Patients With Acute Myocardial Infarction

ObjectivesThe aim of this study was to examine the impact of intravascular ultrasound (IVUS)–guided percutaneous coronary intervention (PCI) on long-term clinical outcomes in patients with acute myocardial infarction (AMI).BackgroundIVUS-guided PCI has been associated with improved cardiovascular outcomes. However, the beneficial effect of IVUS-guided PCI in patients with AMI in the drug-eluting stent era remains unclear.MethodsPatients who underwent PCI with drug-eluting stents were selected from 10,719 patients enrolled in a multicenter AMI registry. The included patients were classified into 2 groups according to the use or nonuse of IVUS. The primary outcome was a composite of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and target lesion revascularization, during long-term follow-up.ResultsA total of 9,846 patients were treated with IVUS-guided PCI (n = 2,032) or angiography-guided PCI (n = 7,814). IVUS-guided PCI was associated with reduced MACE (HR: 0.779; 95% CI: 0.689-0.880; P < 0.001). The results were consistent after multivariable regression and propensity score matching. One-year landmark analysis showed a lower risk for MACE within 1 year (HR: 0.766; 95% CI: 0650-0.903; P = 0.002) and beyond 1 year (HR: 0.796; 95% CI: 0663-0.956; P = 0.014) after index PCI.ConclusionsThe use of IVUS was associated with better long-term cardiovascular outcomes. The clinical benefit of IVUS was maintained both within and beyond 1 year after index PCI. The use of IVUS in PCI should be considered for patients with AMI.     

Pancreatic β-cell function relates positively to HDL functionality in well-controlled type 2 diabetes mellitus

BackgroundHigh density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic β-cell function relates to HDL functionality, as determined by HDL anti-oxidative capacity and cellular cholesterol efflux to plasma.Subjects and methodsHDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0 ± 1.0%). Homeostasis model assessment was used to estimate pancreatic β-cell function (HOMA-β) and insulin resistance (HOMAir).ResultsHOMA-β was lowest, whereas HOMAir was highest in T2DM (P < 0.01 and P < 0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P < 0.05) and cellular cholesterol efflux (P < 0.01) were positively correlated with HOMA-β in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P = 0.001) and cellular cholesterol efflux (P = 0.042) on HOMA-β. HbA1c interacted similarly with HDL functionality measures on HOMA-β.ConclusionsPancreatic β-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of β-cell function in subjects with well-controlled T2DM.     

Relationship between tissue characterization with 40 MHz intravascular ultrasound imaging and 64-slice computed tomography

BackgroundIdentification of coronary plaque composition is important for selecting the treatment strategy, and 64-slice computed tomography (CT) is a noninvasive method of characterizing atherosclerotic plaques. However, the correlation between plaque characteristics detected by CT and intravascular ultrasound (IVUS) is not clear. A 40 MHz IVUS imaging system (iMap-IVUS) has recently been developed to evaluate plaque composition. The aim of this study was to compare iMap-IVUS with 64-slice CT angiography for the characterization of non-calcified coronary plaques.Methods and resultsBoth 64-slice CT angiography and iMap-IVUS were performed in 19 patients (38 plaques). CT values were measured as Hounsfield units (HU) in circular regions of interest (ROI) drawn on the plaques. The iMap-IVUS system analyzed coronary plaques as fibrotic, lipidic, necrotic, or calcified tissue based on the radiofrequency spectrum.A positive correlation was found between CT values and the percentage of fibrotic plaque (r = 0.34, p = 0.036) or calcified plaque (r = 0.40, p = 0.011). Conversely, a negative correlation was found between CT values and the percentage of lipidic plaque (r = ?0.41, p = 0.01), or necrotic plaque (r = ?0.41, p = 0.01).ConclusionsGood correlations were observed between the characteristics of non-calcified plaque determined by iMap-IVUS and the CT values of plaque detected by 64-slice CT scanning.     

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation

BackgroundEnhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit.Methods and ResultsCAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16).ConclusionsEarly ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events.     

Serum albumin modified by carbamoylation impairs macrophage cholesterol efflux in diabetic kidney disease

Background and aimsAbnormalities in lipid metabolism, accumulation of uremic toxins and advanced glycation end products may contribute to worsening atherosclerosis. This study characterized the glycation and carbamoylation profile of serum albumin isolated from individuals with diabetic kidney disease and its influence on cholesterol efflux.Material and methods49 patients with type 2 diabetes (T2DM) and different eGFR evaluated glycation and carbamoylation profile by measurement of carboxymethyl lysine (CML) and carbamoylated proteins (CBL) in plasma by ELISA, homocitrulline (HCit) in plasma by colorimetry. In the isolated albumins, we quantified CBL (ELISA) and total AGE and pentosidine by fluorescence. Macrophages were treated with albumin isolated, and ¹⁴C-Cholesterol efflux mediated by HDL₂ or HDL₃ was measured. Kruskal-Wallis test, Jonckheere-Terpstra test and Brunner's posttest were used for comparisons among groups.ResultsDetermination of CML, HCit, CBL in plasma, as total AGE and pentosidine in albumins, did not differ between groups; however, CBL in the isolated albumins was higher in the more advanced stages of CKD (p = 0.0414). There was reduction in the ¹⁴C-cholesterol efflux after treatment for 18 h with albumin isolated from patients with eGFR<60 mL/min/1.73m² compared with control group mediated by HDL₂ (p = 0.0288) and HDL₃ (p < 0.0001), as well as when compared with eGFR ≥60 mL/min/1.73m² per HDL₂ (p = 0.0001) and HDL₃ (p < 0.0001). Treatment for 48 h showed that eGFR<15 mL/min/1.73m² had a lower percentage of ¹⁴C-cholesterol efflux mediated by HDL₂ compared to control and other CKD groups (p = 0.0274).ConclusionsAlbumins isolated from individuals with T2DM and eGFR<60 mL/min/1.73m² suffer greater carbamoylation, and they impair the cholesterol efflux mediated by HDL₂ and HDL₃. In turn, this could promote lipids accumulation in macrophages and disorders in reverse cholesterol transport.     

Ritonavir protects against the development of atherosclerosis in APOE*3-Leiden mice

ObjectiveThe use of the HIV-protease inhibitor ritonavir (RTV) is associated with induction of hypertriglyceridemia, which is a cardiovascular risk factor. Therefore, we investigated the effect of RTV on atherosclerosis development in APOE*3-Leiden transgenic mice, a model for human-like lipoprotein metabolism and atherosclerosis.Methods and resultsAPOE*3-Leiden mice were fed a Western-type diet without or with RTV (35 mg/kg/day) for 19 weeks. RTV increased plasma TG levels throughout the study (～2-fold; P < 0.05). Despite these increased TG levels, RTV decreased the atherosclerotic lesion area in the aortic root (?57%; P < 0.05), concomitant with reduced macrophage area (?72%; P < 0.01) and decreased lesion severity. This could not be explained by reduced inflammatory markers in plasma (i.e. serum amyloid A, E-selectin and fibrinogen), nor by decreased lipid accumulation in macrophages or increased cholesterol efflux from macrophages, as assessed using peritoneal macrophages in vitro. Rather, whereas RTV did not affect plasma total cholesterol levels, RTV decreased (V)LDL-cholesterol and increased cholesterol in apoE-rich large HDL.ConclusionDespite inducing hypertriglyceridemia, RTV decreases atherosclerotic lesion area and severity, associated with decreased (V)LDL-cholesterol and increased atheroprotective apoE-rich large HDL.