Search

Purpose of Review: The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression., Recent Findings: Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target., (© 2024. The Author(s).)

Diabetes mellitus (DM) is strongly associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) was recently identified as an important regulator of circulating low-density lipoprotein-cholesterol (LDL-C) levels via degradation of the LDL receptor, proving to be a valid target to improve lipoprotein profiles and cardiovascular outcomes in patients with ASCVD. Beyond LDL receptor processing and cholesterol homeostasis, the PCSK9 protein has recently been verified to be associated with glucose metabolism. Importantly, clinical trials suggest that treatment with PCSK9 inhibitors for patients with DM is more effective. Hence, in this review, we summarize the current findings derived from experimental, preclinical, and clinical studies regarding the association between PCSK9 and glucose metabolism, including the relationship of PCSK9 genetic mutations to glucose metabolism and diabetes, the link between plasma PCSK9 concentrations and glucose metabolic parameters, the effects of glucose-lowering drugs on plasma PCSK9 levels and the impacts of PCSK9 inhibitors on cardiovascular outcomes of patients with DM. Clinically, exploring this field may improve our understanding regarding the roles of PCSK9 in glucose metabolism and may offer an in-depth interpretation of how PCSK9 inhibitors exert effects on the treatment of patients with DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms., Methods: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence., Results: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1β and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway., Conclusions: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia., (© 2022. The Author(s).)

Background and Aims: Heterogeneity exists among patients with atherosclerotic cardiovascular disease (ASCVD) with regard to the risk of recurrent events. Current guidelines have definitely refined the disease and we aimed to examine the practicability in Chinese population., Methods: A cohort of 9944 patients with ASCVD was recruited. Recurrent events occurred during an average of 38.5 months' follow-up were collected. The respective and combinative roles of major ASCVD (mASCVD) events and high-risk conditions, being defined by 2018 AHA/ACC guideline, in coronary severity and outcome were studied., Results: The number of high-risk conditions was increased with increasing number of mASCVD events (1.95 ± 1.08 vs. 2.16 ± 1.10 vs. 2.42 ± 1.22). Trends toward the higher to the highest frequency of multi-vessel coronary lesions were found in patients with 1- (71.1%) or ≥2 mASCVD events (82.8%) when compared to those without (67.9%) and in patients with 2- (70.5%) or ≥3 high-risk conditions (77.4%) when compared to those with 0-1 high-risk condition (61.9%). The survival rate was decreased by 6.2% between none- and ≥2 mASCVD events or by 3.5% between 0-1 and ≥3 high-risk conditions. Interestingly, diabetes was independently associated with outcome in patients with 1- [1.54(1.06-2.24)] and ≥2 mASCVD events [1.71(1.03-2.84)]. The positive predictive values were increased among groups with number of mASCVD event increasing (1.10 vs. 1.54 vs. 1.71)., Conclusion: Propitious refinement of ASCVD might be reasonable to improve the survival. Concomitant diabetes was differently associated with the incremental risk among different ASCVD categories, suggesting the need of an appropriate estimate rather than a 'blanket' approach in risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Guo, Zhu, Wu, Xu, Dong, Qian, Dou and Li.)

Aims: Familial hypercholesterolemia patients are characterized by early onset of coronary artery calcification and atherosclerosis, and high incidence of cardiovascular events. Plasma proprotein convertase subtilisin/kexin type 9 was reported to be a predictor for cardiovascular risk in the general population. However, its prognostic value for predicting recurrent cardiovascular events in familial hypercholesterolemia patients remains undetermined., Methods: A total of 249 patients with molecularly and/or clinically (Dutch Lipid Clinic Network score > 6) defined familial hypercholesterolemia who had experienced a first cardiovascular event were consecutively included and plasma proprotein convertase subtilisin/kexin type 9 concentrations were measured by enzyme-linked immunosorbent assay. Coronary artery calcification was measured using Agatston method and coronary severity was assessed by Gensini score, respectively. All patients received standard lipid-lowering therapy and were followed-up for recurrent cardiovascular events. Univariate and multivariate regression and Cox analyses was used to calculate hazard ratios with 95% confidence interval., Results: Circulating proprotein convertase subtilisin/kexin type 9 concentrations were positively associated with coronary artery calcification scores and Gensini score by both univariate and multivariate analyses. During a mean follow-up of 43 ± 19 months, 29 (11.51%) recurrent cardiovascular events occurred. Kaplan-Meier analysis showed that patients with the highest proprotein convertase subtilisin/kexin type 9 levels had the lowest event-free survival time. Multivariable Cox regression analysis revealed that proprotein convertase subtilisin/kexin type 9 was independently associated with recurrent cardiovascular events (hazard ratio: 1.45, 95% confidence interval: 1.11-1.88). The combination of proprotein convertase subtilisin/kexin type 9 to Cox prediction model led to an enhanced predictive value for recurrent cardiovascular events., Conclusions: Increased level of proprotein convertase subtilisin/kexin type 9 was a significant risk factor of atherosclerosis and independently predicted future recurrent cardiovascular events in familial hypercholesterolemia patients receiving standard lipid-lowering treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Although non-invasive liver fibrosis scores (LFSs) have already been considered as effective tools for estimating cardiovascular risk, their roles in predicting disease severity and cardiovascular event (CVEs) in patients with stable coronary artery disease (CAD) are not comprehensively evaluated. The aim of the present study was to investigate whether non-alcoholic fatty liver disease fibrosis score (NAFLD-FS) and fibrosis-4 (FIB-4) are associated with CVEs in a large cohort with long-term follow-up., Methods: A cohort of 5143 patients with angiography-proven stable CAD were consecutively enrolled and followed up for CVEs. The degree of coronary severity was assessed using the number of diseased vessels, Gensini, Syntax, and Jeopardy scores. The predictive values of NAFLD-FS and FIB-4 scores to coronary severity, coronary calcification (CAC), and CVEs were assessed, respectively., Results: During a median follow-up of 7 years, 435 CVEs were recorded. Both NAFLD-FS and FIB-4 were predictors for the presence of CAC. The degree of coronary stenosis was significantly higher in high NAFLD-FS categories while FIB-4 was only positively associated with the number of diseased vessels and Gensini score. In Kaplan-Meier analysis, the patients with intermediate and high NAFLD-FS and FIB-4 had higher risk of CVEs and cardiovascular mortality. In multivariate Cox regression analysis, NAFLD-FS and FIB-4 were independently associated with CVEs [hazard ratio (95% confidence interval): 1.150 (1.063-1.244), p < 0.001 and 1.128 (1.026-1.240), p = 0.012]., Conclusion: The current data first indicated that both NAFLD-FS and FIB-4 scores were not only significantly related to coronary severity but also associated with CAC and CVEs., Clinical Trials Registration: None.

It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein (LDL) cholesterol (LDL-C), but its impact on lipoprotein subfractions and oxidized low-density lipoprotein (oxLDL) has not been determined. The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein (HDL) as well as oxLDL in untreated patients with coronary atherosclerosis (AS). Thirty-six subjects were enrolled in this study. Of them, 18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls. The plasma lipid profile, lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively. The results showed that pitavastatin treatment indeed not only decreased LDL-C, total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB) levels, and increased HDL cholesterol (HDL-C), but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions. Meanwhile, pitavastatin could decrease plasma oxLDL levels. Furthermore, a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment. We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.

Background: Conflicting results have been yielded as to whether low-density lipoprotein (LDL) cholesterol (LDL-C) or non-high-density lipoprotein (HDL) cholesterol (non-HDL-C) is a better marker of coronary artery disease (CAD) risk. Recently, plasma LDL and HDL subfractions have been suggested to be more accurately reflecting the lipoproteins' atherogenicity., Objective: We sought to compare the relationship between LDL-C or non-HDL-C and lipoprotein subfractions., Methods: We conducted a cross-sectional study in 351 consecutive stable CAD patients without lipid-lowering therapy. The LDL and HDL separations were performed using the Lipoprint System. The LDL-C levels were measured directly, and the non-HDL-C levels were calculated., Results: The cholesterol concentrations of LDL (large, medium, and small) and HDL (small) particles were increased (all P < .001) by non-HDL-C or LDL-C quartiles, whereas the mean LDL particle size and cholesterol concentrations of HDL (large) were decreased (both P < .001) by non-HDL-C quartiles. In age- and gender-adjusted analysis, the cholesterol in small LDL was much strongly related to non-HDL-C than to LDL-C (r = 0.539 vs 0.397, both P < .001). Meanwhile, the mean LDL particle size was more closely associated with non-HDL-C than LDL-C (r = -0.336 vs r = -0.136, both P < .05). Significantly, the cholesterol in large HDL was negatively correlated with non-HDL-C (r = -0223, P < .001) but not with LDL-C. These correlations were further confirmed by the fully adjusted multivariable linear regression analysis., Conclusions: Non-HDL-C, in comparison to LDL-C, was more relevant to atherogenic lipoprotein subfractions in patients with stable CAD, supporting that it may be better in assessing cardiovascular risk., (Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Coronary artery disease (CAD) due to obstructive atherosclerosis is a leading cause of death and has been recognized as a worldwide health threat. Measures to decrease low-density lipoprotein cholesterol (LDL-C) levels are the cornerstone in the management of patients with atherosclerotic cardiovascular disease, particularly those with CAD, for over two decades. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays a key role in cholesterol homeostasis by enhancing degradation of hepatic LDL receptor (LDLR). Interestingly, PCSK9 is also involved in the inflammatory process. Plasma PCSK9 and lipid or nonlipid cardiovascular risk factors are correlated, and the associations between PCSK9 with cardiovascular health and disease make this protein worthy of attention for the treatment of hyperlipidemia and atherosclerosis. Here, we provide an overview of the physiological role of PCSK9, which contributes to atherosclerosis, and provide data on PCSK9 as a novel pharmacological target. Clinical evidence shows that PCSK9 inhibition is as promising as statins as a target to treat CAD. The efficacy of these drugs may potentially enable effective CAD prophylaxis for more patients.

We investigated the effect of atorvastatin on the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) and nitric oxide (NO) in a rabbit model, and the relationship between these effects and peroxisome proliferator-activated receptor γ (PPAR-γ). In our experiments, 24 male Japanese rabbits were divided into 3 groups: the high-cholesterol diet group (the high-C group), the high-cholesterol diet plus atorvastatin group (the atorvastatin group), and the normal diet group (the control group). All rabbits were killed after a 16-week feeding. The expression of PPAR-γ and the plasma concentrations of NO and PAI-1 were evaluated by an immunohistochemical assay while the level of the plasma lipid profile was measured using a commercially available kit. The atorvastatin not only reduces the plasma levels of the total cholesterol (TC) and the low-density lipoprotein cholesterol (LDL-C), but also increases the expression of PPAR-γ and the concentration of NO in comparison to the control group [16.11 ± 2.35% vs 7.68 ± 1.04%; 249.30 ± 27.90 vs 179.12 ± 28.51 (μml/L), p<0.05 respectively]. In addition, the concentration of PAI-1 in the atorvastatin group is lower than that in the control group (0.11 ± 0.01A vs 0.14 ± 0.02A, p<0.05). The changes of PAI-1 and NO in the atorvastatin group are in good accordance to that of PPAR-γ. Results show that atorvastatin significantly up-regulates the expression of nuclear transcription factor, namely PPAR-γ, and induces the changes of the other two factors, which might provide mechanisms for the antiatherosclerotic and antithrombotic effects of atorvastatin., (Copyright © 2008. Published by Elsevier Ireland Ltd.)

Unlabelled: Short-term administration of losartan reduced the aortic surface lesion area and mean intimal thickness. The mechanisms for reducing atherosclerotic progression by losartan may be related to decreased macrophage proliferation and accumulation in the arterial wall, decreased activation of nuclear factor-kappa B and expression of its target gene ICAM-I., Objective: Recent studies suggest that angiotensin II (Ang II) may contribute to the vascular inflammatory response and atherosclerosis. Losartan is a specific AT1 receptor antagonist which can effectively inhibit the effects of Ang II. However, the effects of losartan on atherogenesis have been rarely demonstrated. We designed this study to investigate the effects of short-term administration of losartan on atherosclerotic lesions in the aorta from rabbits fed a cholesterol-enriched diet and the possible mechanisms of its anti-atherogenic effects., Methods and Results: The rabbits were randomly divided into three groups: (a) cholesterol group; (b) losartan-treated group; (c) normal control group. We observed that mean serum lipid levels in the cholesterol group were significantly higher than those in normal control rabbits, while blood pressure between two groups did not change significantly. Treatment with losartan did not affect serum lipid levels or systolic blood pressure but did reduce the aortic surface lesion area and mean intimal thickness. The number of macrophages markedly decreased after administration of losartan. Losartan also attenuated the activation of nuclear factor-kappa B and the expression of its target gene ICAM-I., Conclusions: In summary, losartan inhibited atherosclerotic progression by decreasing macrophage proliferation and accumulation in the arterial wall. The mechanisms for reducing atherosclerotic progression by losartan may be related to decreased activation of nuclear factor-kappa B.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered to have multiple roles in the development of atherosclerosis, which is recently reported to participate in the thrombotic process. We aimed to examine the relationship between PCSK9 concentration, coagulation indexes and cardiovascular events. Methods: A total of 2293 consecutive patients with angina-like chest pain and without lipid-lowering drugs treatment were enrolled and followed up for major adverse cardiovascular events (MACEs). Circulating PCSK9 concentration was determined by ELISA. The routine coagulation tests including activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time were performed. The associations between PCSK9 concentration, routine coagulation indicators and MACEs were analyzed. Results: Patients with high PCSK9 levels had lower PT and APTT levels (all p < 0.05). However, PCSK9 concentration was only independently and negatively correlated with PT (β = − 0.115, p < 0.001). During a mean of 38.3 months, 186 (8.1%) MACEs were occurred. Multiple Cox regression analysis indicated high PCSK9 or low PT levels as risk factors related to MACEs. When the prognosis was analyzed by the combination of PCSK9 and PT levels, patients with high PCSK9 and low PT had higher incidence of MACEs compared to those with low PCSK9 and high PT. Conclusions: Our study firstly suggested that PCSK9 concentration was negatively correlated with plasma levels of PT. Furthermore, high PCSK9 and low PT were associated with MACEs and the combination of PCSK9 with PT had an addictive effect on predicting cardiovascular outcomes in patients with chest pain, which was useful for further subdivision of cardiovascular risks. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a growing burden across the world. In Asia and the Middle East, in particular, CVD is among the most prevalent and debilitating diseases. Dyslipidemia is an important factor in the development of atherosclerosis and associated cardiovascular events, and so effective management strategies are critical to reducing overall cardiovascular risk. Multiple dyslipidemia guidelines have been developed by international bodies such as the European Society of Cardiology/European Atherosclerosis Society and the American College of Cardiology/American Heart Association, which all have similarities in practice recommendations for the optimal management of dyslipidemia. However, they differ in certain aspects including pharmacological treatment, lifestyle modification and the target levels used for low-density lipoprotein cholesterol. The evidence behind these guidelines is generally based on data from Western populations, and their applicability to people in Asia and the Middle East is largely untested. As a result, practitioners within Asia and the Middle East continue to rely on international evidence despite population differences in lipid phenotypes and CVD risk factors. An expert panel was convened to review the international guidelines commonly used in Asia and the Middle East and determine their applicability to clinical practice in the region, with specific recommendations, or considerations, provided where current guideline recommendations differ from local practice. Herein, we describe the heterogeneous approaches and application of current guidelines used to manage dyslipidemia in Asia and the Middle East. We provide consensus management recommendations to cover different patient scenarios, including primary prevention, elderly, chronic kidney disease, type 2 diabetes, documented CVD, acute coronary syndromes and family history of ischemic heart disease. Moreover, we advocate for countries within the Asian and Middle East regions to continue to develop guidelines that are appropriate for the local population. [ABSTRACT FROM AUTHOR]

Background Recent data have suggested an important role of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) in the development of atherosclerotic cardiovascular disease (ASCVD) in both general population and family hypercholesterolemia (FH), while the relation of Lp(a) to PCSK9 has not been examined. Objective The aim of the present study was to investigate the association between plasma PCSK9 and Lp(a)in patients with heterozygous FH (HeFH). Methods Two hundred and fifty-five molecularly confirmed patients with HeFH were compared to 255 age- and gender-matched non-FH controls. Plasma PCSK9 and Lp(a) concentrations were measured using ELISA and immunoturbidimetric method respectively, and finally their association was assessed. Results Both plasma PCSK9 and Lp(a) levels were significantly higher in patients with HeFH compared to control group (p < 0.001). Besides, the Lp(a) concentration and percentage of Lp(a) ≥ 300 mg/L were increased by PCSK9 tertiles in HeFH group (both p < 0.05) while not in control group. In partial correlation analysis, Lp(a) was associated with PCSK9 (r = 0.254, p < 0.001) in HeFH group but not in control, which were further confirmed by multivariable linear regression analysis. Furthermore, significant associations between Lp(a) and PCSK9 were also found in subgroups of HeFH group irrespective of definite or probable FH, with and without coronary artery disease (CAD), and with statin or not. Conclusions Plasma Lp(a) level was associated with PCSK9 in patients with HeFH alone, suggesting that much about the interaction of PCSK9 with Lp(a) in FH need further explorations. [ABSTRACT FROM AUTHOR]

Background: Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size. Methods and Results: We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082–1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889–1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383–2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833–1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155–2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L. Conclusions: Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population. [ABSTRACT FROM AUTHOR]

Statins can significantly reduce low-density lipoprotein-cholesterol ( LDL-C) and modestly raise or not alter high-density lipoprotein-cholesterol ( HDL-C). However, their impact on high-density lipoprotein ( HDL) and low-density lipoprotein ( LDL) subfractions has been less examined. The aim of the present study was to investigate the short-term impact of low-dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty-seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day ( n = 17) or 20 mg/day ( n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL-C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL-C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size. [ABSTRACT FROM AUTHOR]

Abstract: Background: Coronary artery ectasia (CAE) is well-recognized, angiographic finding of abnormal coronary dilatation. The role of inflammation in atherosclerosis is increasingly well known. However, the association between inflammation and CAE has been controversial. Method: Fifty-five patients with CAE and non-obstructive coronary artery disease (CAD), 38 with obstructive CAD, and 33 angiographically normal coronary controls were enrolled in the study. The peripheral blood was taken, and white blood cell count (WBCC) as well as other leukocyte subtypes including neutrophils, lymphocytes, and monocyte cell count (MCC) were measured. The plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6) were determined by ELISA. Results: The higher number of WBCC, neutrophil and MCC were found in patients with CAE compared with obstructive CAD patients as well as normal controls (p <0.01, respectively). Moreover, levels of plasma CRP and IL-6 were also significantly higher in patients with CAE than that in patients with obstructive CAD, and subjects without coronary artery disease (p <0.001, respectively). Univariate analysis showed that the sex, current smoking, numbers of WBCC, neutrophil, MCC, levels of CRP and IL-6 were related with CAE, while MCC was independently linked with a diagnosis of CAE. CRP was the independent variable most strongly associated with CAE by multivariate analysis. Conclusions: Taken together, this study confirmed and expanded previous limited findings that a more significant chronic inflammation might be linked with the pathogenesis of CAE that was associated with not only inflammatory markers but also inflammatory cells in patients with CAE. [Copyright &y& Elsevier]

Abstract: Vascular calcification is an age-dependent, common finding in human coronary arteries and begins as early as the second decade of life, just after fatty streak formation. Previous studies have showed that the severity of coronary calcification is closely related to atherosclerotic plaque burden and cardiac event rate. In the past few decades, coronary calcification has been considered passive and degenerative. With recent clinical and basic research, however, there is increasing recognition that coronary calcification is an active, regulated process. Current diagnostic methods for coronary artery calcification (CAC) are usually traditional coronary angiography, intravascular ultrasound (IVUS), electron beam computed tomography (EBCT) and multi-slice computed tomography (MSCT) while treatment for patients with calcified coronary arteries is troublesome. Several lines of evidence suggest that inflammation plays a major role in the development of atherosclerosis as well as its clinical manifestations. Recent study showed that inflammatory process might be also involved in coronary calcification. Accordingly, measurements of inflammatory markers such as C-reactive protein (CRP) may in part reflect indices of atherosclerosis, such as coronary calcification, and are likely to provide distinct information regarding cardiovascular risk. In this article, we review the current evidence of relationship between coronary calcification and inflammation for purpose of drawing the more attention on the inflammatory mechanism of coronary calcification, which may change our research as well as therapeutic strategies for coronary calcification in the future. [Copyright &y& Elsevier]

Summary: Peripheral arterial disease (PAD) includes a wide range of manifestations in the lower limb, from asymptomatic to symptomatic disease ranging from intermittent claudication to critical limb ischemia, with ulcers, rest pain, or gangrene. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in these patients. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Recently, it has become clear that inflammation is fundamental to the process of atherosclerosis. Although the relation between inflammation and PAD is not well characterized, the emerging data demonstrated that PAD is a common manifestation of atherosclerosis that is associated with a systemic inflammation. The most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors. Serum levels of inflammatory markers, especially after exercise, have been found to be higher in patients with PAD than in controls, and associated with prognosis as well as restenosis in patients with PAD after revascularization. In the general United States adult population, inflammation is independently associated with PAD in a cross-sectional, nationally large representative sample. All of those evidences indicate that PAD is one aspect of atherosclerosis, a disease rationally connects with inflammation, which may further change our preventive and therapeutic strategies. [Copyright &y& Elsevier]

Summary: Coronary artery ectasia (CAE) is well-recognized, angiographic finding of abnormal coronary dilatation, and detected in 0.3–5.3% of angiographic studies. The gold standard for diagnosis this type of aneurysm is coronary angiography, which provides information about the size, sample, location and number of aneurysms. Despite growing prevalence in recent years, controversy still exists as to the pathogenetic mechanisms that underlie this entity. An increased incidence of CAE has been reported in several disorders. Examples include atherosclerotic vascular disease, heterozygous familial hypercholesterolemia, usage of substances including herbicide spray, acetylcholinesterase inhibitors and nitrates, previous arterial balloon angioplasty, polyarteritis nodosa and Kawasaki syndrome. In addition, possible factors contributing to CAE are imbalance between matrix metalloproteinase and tissue inhibitor of metalloproteinase, angiotensin converting enzyme genotype, elevated homocysteine levels, cocaine user, smoking, vascular trauma, nitrate use and diabetes. Emerging investigations have pinpointed inflammation as a central process in all stages of atherosclerosis. This inflammatory process culminates in acute thrombotic complications and clinical events, which is involved in different clinical settings of atherosclerotic diseases. Recent data have also showed that CAE is associated with inflammatory response presented as elevated inflammatory cytokines and C-reactive protein. Accordingly, more complete understanding of the pro- and anti-inflammatory circuits that operate during CAE in particular may foster the development of novel therapeutic approaches. [Copyright &y& Elsevier]

Summary: Inflammation has been recognized as having an important role in the development and progression of atherosclerosis. Statins reduce cardiovascular events mainly by cholesterol lowering. A large number of investigations have demonstrated that administration of statin could modify inflammatory response with a concurrent fall in cardiovascular events. Despite the known benefit of statin therapy, many cardiac patients abruptly discontinue therapy because of financial constraints, forgetfulness, or side effects. More recently, several studies have shown that abrupt cessation of statin therapy during treatment could increase the incidence of cardiac events in patients with atherosclerotic heart disease. However, the mechanisms of the increased incidence of cardiovascular events after abruptly stopping statin therapy are still unknown. A few data suggest that abrupt withdrawal of statin therapy deteriorates endothelial function, result in expression of pro-inflammatory gene involved in the development and progression of atherosclerosis. We hypothesis that rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Our very recent data showed that abrupt termination of statin therapy resulted in a rapid increased C-reactive protein (CRP) and interleukin-6 (IL-6) levels in patients with hypercholesterolemia. This finding may be of important interest in the connection between inflammatory response and abrupt withdrawal of statin therapy in patients with coronary artery disease. [Copyright &y& Elsevier]

Summary: Cardiologists are familiar with the phenomenon of slow progression of angiographic contrast in the coronary arteries in the absence of stenosis in the epicardial vessels in some patients presenting with chest pain. This phenomenon is called as coronary slow flow phenomenon, and firstly described in 1972, while it remains scantily studied. The pathophysiological mechanisms of coronary slow flow phenomenon remain uncertain. Several hypotheses however, have been suggested for slow coronary flow phenomenon, including a form of early phase of atherosclerosis, small vessel dysfunction, Hagen–Poiseuille’s equation model, imbalance between vasoconstrictor and vasodilatory factors, and platelet function disorder. More recently, there has been mounting evidence that inflammation plays an important role in the initiation, development as well as evolution of atherosclerosis, suggesting that atherosclerosis is an inflammation disease. New evidence has also indicated that inflammation may be involved in the development of slow coronary flow phenomenon. Coronary slow flow phenomenon is an important clinical entity because it may be the cause of angina at rest or during exercise, acute myocardial infarction, and hypertension. Despite the good prognosis of this kind of patients, the chronic, frequent nature of the persistent uncomfortable chest can significantly impair the quality of life. Whether this is really a new kind of coronary disease involving in inflammation, however, is still unknown and deserves further investigation. [Copyright &y& Elsevier]

Summary: Pathogenesis of the atherosclerotic process is deemed as multi-factorial, and characterized by chronic inflammatory response. Although hypertension is known to be one of the most important risk factors for atherosclerosis in causasians, its relative contribution to early atherosclerosis are still unknown. Increased evidence has indicated that hypertension, through the vasoactive peptides, such as angiotensin and endothelin-1, promotes and accelerates the atherosclerotic process via inflammatory mechanisms. In animal and human studies pro-inflammatory properties of angiotensin II has been demonstrated in large conduit and small arteries, in the kidney as well as in the heart. Activation of oxidative stress by angiotensin II is a key component of this process. Angiotensin II stimulates nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide oxidase in endothelium, smooth muscle cells, and the adventitia of blood vessel to generate reactive oxygen species, leading to endothelial dysfunction, growth, and inflammation, upregulation of endothelin-1, adhesion molecules, nuclear factor-kappa B, and other inflammatory mediators, as well as increased breakdown of nitric oxide and uncoupling of nitric oxide synthase, contribute to the progression of vascular disease and atherogenesis. In addition, recent advances concerning role of endothelin-1 as another important mediator of chronic inflammation in the vascular wall has been documented, and relationship between endothelin-1 and angiotensin II on vascular inflammation demonstrated. Inflammatory mechanisms, therefore, are important participants in the pathophysiology of hypertension-related cardiovascular disease, including atherosclerosis. In experimental models as well as human studies of atherosclerosis, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers have demonstrated the ability to prevent or reverse the progression of atherosclerosis, which was in part associated with decreased expression of inflammatory mediators and improve endothelial functions. Based on those increasing evidence, we hypothesize that inflammation may be a bridge connecting hypertension and atherosclerosis. [Copyright &y& Elsevier]

Abstract: Background: Inflammation plays a critic role in atherosclerosis and C-reactive protein (CRP) may directly facilitate the development of a proinflammatory and proatheroscleroitc phenotype. The nuclear factor-+A7o-B (NF-+A7o-B) signal transduction is known to play a key role in the expression of these proatherogenic entities including tumor necrosis factor-+A7E (TNF-+A7E). Much data suggest that statin possess a potential anti-inflammatory effect. However, the effects of statin on the expression of TNF-+A7E and activation of NF-+A7o-B in endothelial cells stimulated by CRP are less studied. We determined the effects of CRP in inducing inflammatory response and the effect of fluvastatin on CRP-dependent inflammatory activation in human cultured endothelial cells. Methods: Human vascular endothelial cells were cultured and stimulated by concentrations of CRP (5+IBMAkw-100 +A7w-g/ml) for 0, 2, 4, 8, 16, 24, and 48 h. Also 10 +A7w-mol/l of fluvastatin was pre-incubated for 2 h with cells in the presence of CRP. The activity of transcription factor NF-+A7o-B was evaluated by electrophoretic mobility shift assay (EMSA). Measurements of TNF-+A7E were performed from supernatants of cultured medium in duplicate, using commercial assay kits. Results: CRP increased the release of TNF-+A7E rapidly as a dose-and time-dependent manner. Induction of TNF-+A7E was detected at 5 +A7w-g/ml and reached a maximum at 100 +A7w-g/ml of CRP. The CRP also significantly induces the activation of NF-+A7o-B in endothelial cells, and those effects were apparently inhibited by 10 +A7w-mol/l of fluvastatin, but not complete. Conclusions: CRP stimulation result in induction of TNF-+A7E and activation of NF-+A7o-B, and this effect could be significantly inhibited by fluvastatin, suggesting that CRP may play a direct role in atherogenesis by activating endothelial cells, and statins inhibit this response, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of statins. [Copyright &y& Elsevier]

Inflammatory response has been demonstrated in patients with coronary artery disease after percutaneous coronary intervention (PCI). Such response following renal artery stenting has not yet been established, however, in patients with atherosclerotic renal artery stenosis.A total of 44 patients were enrolled in this study. Of them, 22 patients with atherosclerotic renal artery stenosis received renal angioplasty with stent (group A, mean age 51±8 years), and 22 patients with age- and gender-matched underwent renal angiography for diagnostic purpose as a control group (group B, age 50±8 years). The peripheral blood samples were taken immediately before the procedure, 1, 6 and 24 h after the procedure in both groups. The concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured using ELISA.The result showed that there was no difference in clinical characteristics and baseline levels of CRP and IL-6 between the groups. The IL-6 increased in the first hour (before: 5.8±3 pg/ml; 1 h: 8.6±5 pg/ml, p<0.01), lasted at 6 h (12.2±8 pg/ml), returned to baseline at 24 h (5.4±3 pg/ml) in group A. The CRP did not changed at the first hour after stenting, but mean CRP increased from 0.30±0.09 to 0.37±0.15 mg/dl at 6 h (p<0.05), and peaked at 24 h (0.43±0.18 mg/dl, p<0.001 compared with baseline and control) after stenting in group A, while no such changes were observed in group B (p>0.05 at different time points compared with baseline and group B, respectively).The data indicated that renal artery stenting could trigger inflammatory response by evidence of increased plasma levels of CRP and IL-6. IL-6, however, was an early initiator of inflammatory cytokine, and CRP was a later marker of systemic inflammatory response to renal artery stenting. [Copyright &y& Elsevier]

Apoprotein C-III (apoC-III), originating from the apoA-I/C-III/A-IV gene cluster affected by multiple regulating factors, has been demonstrated to have a validated link with hypertriglyceridemia in humans. Following genome studies establishing the impact of apoC-III on both plasma triglyceride (TG) level and cardiovascular disease (CVD), apoC-III offers us a novel explanation attempting to resolve the long-existing confusion with regard to the atherogenic effect of TG. Notably, apoC-III exerts its atherogenic effect by means of not only intervening in the function and metabolism of various lipid molecules, but also accelerating pro-inflammatory effects between monocytes and endothelial cells. Data have suggested that diabetes, a common endocrine disease, also correlates closely with apoC-III in its apoptosis process of islet βcells. In fact, apoC-III genes, with various mutations among individuals, are also found to have relevance to other diseases, including fatty liver disease. Fortunately, besides present day therapeutic strategies, such as lifestyle changes and lipid-lowering drug treatments, a promising new antisense drug specifically targeting on apoC-III gene expression opens up new avenues. This article mainly summarizes the clinical implication of apoC-III and its future directions of treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Resistin is a novel cysteine-rich protein that plays a role in the development of insulin resistance and atherosclerosis in rodents, while its role in humans is unclear. C-reactive protein (CRP) is an important risk predictor for coronary heart disease, and it can also modify the expression of genes involved in atherogenesis. Statins have been demonstrated to possess lipid lowering effects as well as pleiotropic properties. We hypothesize that CRP may result in overexpression of resistin, and statin may decrease CRP-induced resistin expression in cultured human peripheral blood monocytes (PBMC). Purpose: The aim of the present study, therefore, was to assess the effects of both CRP on resistin expression and simvastatin on CRP-induced of resistin expression in cultured human PBMC. Methods: Human PBMC were isolated from the whole blood of healthy volunteers by density gradient centrifugation. First, cells were incubated with varying concentrations of CRP (0, 5, 10, 25 and 50μg/ml) for 24h for assessing the dose-dependent effects on resistin expression. Second, 25μg/ml of CRP was used to time-dependent evaluation on resistin expression (0, 3, 6, 12 and 24h). Moreover, cells were pretreated with simvastatin at concentrations from 0.1 to 1μM for 2h, and then co-incubated with 25μg/ml CRP for 24h for evaluating effect of statin on resistin production subjected to CRP. Finally, in additional experiments, monocytes were incubated with 1μM simvastatin in the absence or presence of 100μM mevalonate or 10μM geranylgeranyl-pyrophosphate (GGPP) or 10μM farnesylpyrophosphate (FPP) for 2h, then co-incubated with CRP for 24h for examining whether effects of statin on CRP-induced resistin expression was independent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Results: The results showed that CRP induced both mRNA expression and protein secretion of resistin in a dose- and time-dependent manner. Co-incubation with simvastatin significantly inhibited CRP-induced up-regulation of mRNA and protein expression of resistin. Treatment with mevalonate, GGPP, but not FPP, reversed the inhibition of resistin expression caused by simvastatin, suggesting that simvastatin regulated resistin expression in culture human PBMC through the mevalonate–GGPP signal pathway. Conclusions: In the present study, the data showed that CRP could significantly increase resistin expression in cultured human PBMC, and this effect was inhibited by simvastatin, suggesting that CRP and resistin might be involved in the pathogenesis of atherosclerosis, and statin therapy might be beneficial for atherosclerotic disease by modifying CRP-induced resistin overexpression in PBMC. [Copyright &y& Elsevier]

Abstract Background and aims The relation of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) has been well established in the general population, while little is known about the association between Lp(a) or PCSK9 and atherosclerotic lesions of different artery sites in patients with familial hypercholesterolemia (FH). Methods One hundred and fifty-one patients with verified genotyped heterozygous FH (HeFH) were enrolled. There were available data regarding coronary angiography and carotid ultrasonography in 151 patients and femoral ultrasonography in 55 patients. Coronary and carotid severity was evaluated by Gensini score and Crouse score. PCSK9 and Lp(a) concentrations were determined by ELISA and immunoturbidimetry, respectively. Finally, the correlation of PCSK9 and Lp(a) with the presence and severity of CAD and peripheral artery disease (PAD) was assessed. Results The distributions of PCSK9 and Lp(a) were skewed and a close correlation between them in HeFH patients was found. PCSK9 levels were significantly higher in patients with coronary and carotid atherosclerotic lesions compared to their non-atherosclerotic groups, while no difference was found in femoral atherosclerotic lesions groups. Lp(a) levels only differed between patients with or without coronary atherosclerotic lesions. Patients with highest PCSK9 and Lp(a) concentrations had the highest prevalence and severity of atherosclerotic lesions. Multivariate regression analysis showed that PCSK9 was independently associated with CAD and PAD, while Lp(a) was only associated with CAD. Conclusions Circulating PCSK9 concentrations were associated with an increased risk of CAD and PAD, while Lp(a) was only a marker for CAD in HeFH patients. Highlights • Circulating PCSK9 levels were significantly elevated in HeFH patients with atherosclerosis. • Elevated PCSK9 was a good marker for predicting the presence and severity of CAD and PAD in HeFH patients. • Lp(a) levels were only associated with CAD but not with PAD in HeFH patients. [ABSTRACT FROM AUTHOR]

Objective : Although the study on the relationship between ABO blood groups and coronary atherosclerosis has a long history, few data is available regarding ABO to severity of coronary atherosclerosis in a large cohort study. Therefore, the present study aimed to investigate the relation of the ABO blood groups to the severity of coronary atherosclerosis assessed by Gensini score (GS) in a large Chinese cohort undergoing coronary angiography. Methods : A total of 2919 consecutive patients undergoing coronary angiography were enrolled, and their baseline characteristics and ABO blood groups were collected. The GS was calculated as 1st tertile (0–10), 2nd tertile (11–36), 3rd tertile (>36) according to angiographic results. The relation of the ABO blood groups to GS was investigated. Results : The frequency of blood group A was significantly higher in the upper GS tertiles (24.4% vs. 28.2% vs. 29.5%, p = 0.032). Multivariable linear regression analysis revealed that blood group A was independently associated with GS ( β = 0.043, p = 0.017). Likewise, multivariable logistic regression analysis showed that group A remained significantly associated with mid-high GS (OR = 1.44, 95% CI 1.16–1.80, p = 0.001), and the group O was showed as a protective factor (OR = 0.77, 95% CI = 0.65–0.92, p = 0.004). Conclusion : In this large Chinese cohort study, the data indicated that there was an association between ABO blood groups and the severity of coronary atherosclerosis. Moreover, the blood group A was an independent risk factor for serious coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent studies have suggested that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with atherosclerosis and plays a potential role in inflammation. However, the correlation between PCSK9 and white blood cell count (WBCC) has not yet been assessed. The objective of the present study was to examine the association of the WBCC and its subset counts with plasma PCSK9 levels in patients with stable coronary artery disease (CAD). Methods: In this cross-sectional study, a total of 251 consecutive, stable CAD patients who were not treated with lipid-lowering drugs were enrolled at our center between October 2012 and October 2013. The baseline clinical characteristics were collected, and the plasma PCSK9 levels were determined using ELISA. The associations of plasma PCSK9 levels with the WBCC and its subsets were investigated. Results: In the overall population, plasma PCSK9 levels were positively associated with the WBCC (r = 0.167, p = 0.008). Multivariable regression analysis revealed that the plasma PCSK9 levels were significantly and independently associated with the WBCC (β = 0.217, p < 0.001) and its subsets (neutrophil β = 0.152, p < 0.05; lymphocyte β = 0.241, p < 0.001). However, the relationships between PCSK9 and WBCC and its subsets remained significant in men (WBCC r = 0.234, p = 0.001; neutrophil r = 0.181, p = 0.014; lymphocyte r = 0.226, p = 0.002) but were not significant in women when the analysis was performed based on gender. Conclusions: These data demonstrate that the plasma PCSK9 levels are independently associated with the WBCC and its subsets, suggesting a potential interaction between PCSK9 and chronic inflammation in patients with CAD. [Copyright &y& Elsevier]