Academic literature on the topic 'Clinical atherosclerosi'

AbstractProprotein convertase subtilisin/kexin Type 9 (PCSK9) is now identified as an important and major player in hypercholesterolaemia and atherosclerosis pathophysiology. PCSK9, through promoting lysosomal degradation of hepatic low-density lipoprotein (LDL) receptor, can decrease the clearance of plasma LDLs, leading to hypercholesterolaemia and consequent atherosclerotic plaque formation. Hypercholesterolaemia has been found to promote systemic and vascular inflammation, which can cause atherosclerotic lesion formation and progression and subsequent incidence of cardiovascular disease. Recent studies have shown the involvement of PCSK9 in the inflammatory pathway of atherosclerosis. Although trials with PCSK9 inhibitors have not shown any alteration in plasma C-reactive protein levels, there is accumulating evidence showing lessened inflammatory response in the arterial wall that could attenuate atherosclerotic plaque development beyond the established LDL-lowering effect of PCSK9 inhibition. In this review, we represent mounting evidence indicating that PCSK9 can locally increase vascular inflammation and contribute to atherosclerotic plaque progression in patients with hypercholesterolaemia.

Atherosclerosis, the main cause of heart attack and stroke, is the leading cause of death in most modern countries. Preventing clinical events depends on a better understanding of the mechanism of atherosclerotic plaque destabilization. Our knowledge on the characteristics of vulnerable plaques in humans has grown past decades. Histological studies have provided a precise definition of high-risk lesions and novel imaging methods for human atherosclerotic plaque characterization have made significant progress. However the pathological mechanisms leading from stable lesions to the formation of vulnerable plaques remain uncertain and the related clinical events are unpredictable. An animal model mimicking human plaque destablization is required as well as an in vivo imaging method to assess and monitor atherosclerosis progression. Magnetic resonance imaging (MRI) is increasingly used for in vivo assessment of atherosclerotic plaques in the human carotids. MRI provides well-characterized morphological and functional features of human atherosclerotic plaque which can be also assessed in animal models. This review summarizes the most common species used as animal models for experimental atherosclerosis, the techniques to induce atherosclerosis and to obtain vulnerable plaques, together with the role of MRI for monitoring atherosclerotic plaques in animals.

Aim. To examine the differences in clinical parameters in patients with coronary atherosclerosis based on fatty acid profile.Methods.60 men with angiographically verified atherosclerosis of the coronary arteries underwent the analysis of fatty acids followed by coronary endarterectomy. Patients were divided into two groups after histological analysis of the intimamedia fragments. Men without unstable plaques in the coronary arteries were included in Group 1, whereas patients with unstable atherosclerotic plaques were included in Group 2. Blood serum levels of fatty acids were measured by highefficiency gas-liquid chromatography.Results.The predicted probability value and the predicted group membership in men with coronary atherosclerosis were calculated using the logistic regression. The following clinical patterns in men with unstable atherosclerotic plaques included increased prevalence of myocardial infarction with the event over 10 years ago, severe angina pectoris (III and IV functional class) and chronic heart failure, in comparison with CAD patients without unstable plaques.Conclusion. Fatty acid profile was associated with altered individual history of coronary atherosclerosis.

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.

Abstract Coronary atherosclerosis is a chronic inflammatory disease that can lead to varying degrees of blood flow obstruction and a common pathophysiological basis of cardiovascular disease. Inflammatory factors run through the whole process of atherosclerotic lesions. Macrophages, T cells, and neutrophils play important roles in the process of atherosclerotic inflammation. Considering the evolutionary characteristics, atherosclerosis can be divided into different stages as early atherosclerotic plaque, plaque formation stage, and plaque rupture stage. In this paper, the changes in inflammatory cells at different stages of lesions and their related mechanisms are discussed, which can provide new insights from a clinical to bench perspective for atherosclerosis me chanism.

OBJECTIVE: TO review the current literature on the effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors in secondary prevention and regression of atherosclerosis. DATA SOURCES A MEDLINE and journal search of recent studies evaluating the effects of lipid lowering with HMG-CoA reductase inhibitors on serum cholesterol as well as progression and regression of atherosclerotic coronary or carotid disease in patients with established atherosclerotic disease was conducted. Articles addressing the pathophysiology of atherosclerotic disease were identified by using the same sources. STUDY SELECTION: All available studies evaluating the use of HMG-CoA reductase inhibitors in the progression and regression of coronary and carotid atherosclerosis were reviewed. DATA SYNTHESIS: Lowering of total serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, as well as increasing high-density lipoprotein cholesterol can be achieved with HMG-CoA reductase inhibitors. Aggressive lipid lowering has been demonstrated to alter progression of established atherosclerotic disease and, in some patients, actually induce regression of the atheroma. An unexpected finding of several trials was the early and significant reduction in clinical cardiac events. Other mechanisms by which clinical event reduction may be explained include plaque stabilization and restoration of endothelium vasodilation. CONCLUSIONS: Aggressive lipid-lowering therapy using HMG-CoA reductase inhibitors appears to alter the natural progression and promote regression of atherosclerosis in selected patients with established coronary or carotid atherosclerosis. However, it is unlikely that regression of atherosclerosis alone is responsible for the marked reduction in clinical cardiac events seen in these trials.

Abstract. The estimation of risk for atherosclerotic and cardiovascular events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical disease in individual subjects: blood markers of atherosclerosis and preclinical deterioration of the arterial wall. Elevated levels of several inflammatory mediators have been found in subjects with atherosclerosis. Increased basal levels of cytokines, the cell adhesion molecules, selectins and acute-phase reactants such as high sensitive C-reactive protein (hsCRP), fibrinogen, and serum amyloid A are related to an increased risk of cardiovascular events. For clinical purposes, the most promising inflammatory biomarker appears to be hsCRP. In the last decade, markers of plaque stability and unstable coronary artery disease have been sought. Further, markers of endothelial dysfunction, like circulating molecules as well as indicators of functional deterioration of the arterial wall were identified. It was shown that endothelial dysfunction is closely related to different risk factors of atherosclerosis, and to their intensity and duration. Intima-media thickness measurement has emerged as one of the methods of choice for determining the anatomic extent of preclinical atherosclerosis and for assessing cardiovascular risk.Determination of markers of preclinical atherosclerosis improve individual risk determination and could influence the decision of a clinician to intervene with medication and to use more aggressive treatment of risk factors in high risk subjects and in patients with atherosclerotic disease.

It has been suggested that circulating immune complexes containing low density lipoproteins (LDL-CIC) play a role in atherogenesis and are involved in the formation of early atherosclerotic lesions. The complexes, as well as anti-LDL antibody were found in the blood of patients with atherosclerotic process in various cardiovascular diseases, well as in the blood of animals with experimentally modulated atherosclerosis. One can assume that the presence anti-LDL antibodies in blood is a result of an immune response that is induced by modification of lipoproteins. LDL-CIC differ from native LDL in many aspects. They have much lower levels of sialic acid, a smaller diameter and a higher density electronegativity than native LDL. The fraction of the LDL-CIC in serum is an important manifestation of the atherosclerotic process. LDL-CIC, unlike the native LDL is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol in cell cultures obtained from healthy human aortic intima and macrophages in culture. After removal of the LDL-CIC, the serum of CHD-patients loses its atherogenic properties. The titer of the LDL-CIC in the blood serum significantly correlate with the progression of atherosclerosis and in vivo has the highest diagnostic yield of measured among other lipid parameters. Increasing CIC- cholesterol could also increase the risk of coronary artery atherosclerosis.

Atherosclerosis, a systemic chronic inflammatory disease, can lead to thrombosis and vascular occlusion, thereby inducing a series of serious vascular diseases. Currently, distinguishing unstable plaques early and achieving more effective treatment are the two main clinical concerns in atherosclerosis. Organic nanoparticles have great potential in atherosclerotic imaging and treatment, showing superior biocompatibility, drug-loading capacity, and synthesis. This article illustrates the process of atherosclerosis onset and the key targeted cells, then systematically summarizes recent progress made in organic nanoparticle-based imaging of different types of targeted cells and therapeutic methods for atherosclerosis, including optical and acoustic-induced therapy, drug delivery, gene therapy, and immunotherapy. Finally, we discuss the major impediments that need to be addressed in future clinical practice. We believe this article will help readers to develop a comprehensive and in-depth understanding of organic nanoparticle-based atherosclerotic imaging and treatment, thus advancing further development of anti-atherosclerosis therapies.

Abstract Atherosclerosis continues to be a major cause of death in patients with cardiovascular diseases. The cooperative role of immunity has been recently considered in atherosclerotic plaque inflammation, especially adaptive immune response by T cells. In this review, we examine the possible role of T cells in atherosclerosis-mediated inflammation and conceivable therapeutic strategies that can ameliorate complications of atherosclerosis. The cytokines secreted by T-lymphocyte subsets, different pathophysiological profiles of microRNAs (miRs), and the growth factor/receptor axis have diverse effects on the inflammatory cycle of atherosclerosis. Manipulation of miRNA expression and prominent growth factor receptors involved in inflammatory cytokine secretion in atherosclerosis can be considered diagnostic biomarkers in the induction of anergy and blockade of atherosclerotic development. This manuscript reviews immunomodulation of T cells responses in atherosclerosis anergy.

Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), together with LDLR and APOB genes, had been identified as the third gene associated with Familial Hypercholesterolemia (FH). Secreted PCSK9 in fact, targets the hepatic LDL receptor (LDLR) for degradation thus preventing its recycling on the cell surface. The decreased expression of LDLR determines an increase in the circulating LDL particles, leading to increased cholesterol levels. Secreted PCSK9 is mainly derived from the liver, but it is also expressed in other tissues such as the brain, the kidney, the pancreas as well as the cells that composed the arterial wall. It is therefore possible that it could exert multiple paracrine effects. Our research group found that PCSK9 is expressed and secreted by smooth muscles cells (SMCs) which constitute the atherosclerotic plaque. The aim of my project was to determine the paracrine role of PCSK9 on the neointima formation through preclinical and clinical approaches. The immunohistochemical analysis of Pcsk9-/- and Pcsk9+/+ mice revealed that, after vascular manipulation, the PCSK9-null mice were protected from the formation of neointima with lower intima area (28100 ± 4901 µm2 and 14350 ± 2990 µm2 for Pcsk9+/+ and Pcsk9-/- mice respectively, p<0.05), associated with decreased intima/media ratio of 1.48 ± 0.34 and 0.60 ± 0.18 for Pcsk9+/+ and Pcsk9-/- mice respectively, (p<0.05). The in vitro studies on isolated SMCs from Pcsk9-/- and Pcsk9+/+ mice showed that the absence of PCSK9 induced a more contractile phenotype, associated with a reduced proliferation rate (doubling time were 57.3 ± 2.1h and 106.3 ± 4.5h, respectively [p<0.001]). The response to the chemotactic agent PDGF-BB (Platelet-derived growth factor), measured with Boyden’s chamber assay, was also impaired in the absence of PCSK9. These were rescued after the reconstitution of PCSK9 in the Pcsk9-/- cell line, which led to a more synthetic phenotype associated with a doubling time of 32.2± 3.1h and 41.2 ± 1.9h [p< 0.001], for Pcsk9-/- and Pcsk9-/-REC SMCs, respectively. The difference in proliferation between Pcsk9-/- and Pcsk9-/-REC SMCs was maintained also after the incubation with 40µM of simvastatin, suggesting that PCSK9 could improve SMCs proliferation through mechanism independently from cholesterol levels. The cell cycle analyses of the Pcsk9-/- and Pcsk9-/-REC SMCs showed a decreased activation of p21 and p27, associated with an increased expression of cyclin E and cyclin D1; presumably due to a different activation of the PDGF receptor pathway mediated by LRP1. Finally, the observational study, carried out in collaboration with the Brisighella Heart Study research group, demonstrated that serum levels of PCSK9, together with aging, is positively correlated to the pulse wave velocity. This is an indirect parameter used to evaluate the arterial stiffness and hence the presence of atherosclerotic plaques. Taken together, these results demonstrated that aside from its function on in regulating cholesterol homeostasis, PCSK9 plays a direct pro-atherogenic role in the arterial wall by sustaining SMC synthetic phenotype, proliferation, and migration.

Contesto e scopo: La proproteina convertasi subtilisina/kexina di tipo 9 (PCSK9), uno dei principali regolatori del metabolismo del recettore delle LDL, è stata associata allo sviluppo di aterosclerosi. Diversi studi hanno confermato tale associazione attraverso vie lipidiche e non lipidiche. Tuttavia, le relazioni dirette tra PCSK9 circolante e marcatori di aterosclerosi subclinica e clinica sono ancora da chiarire. Pertanto, abbiamo valutato le relazioni tra i livelli plasmatici di PCSK9 ed alcuni indici di aterosclerosi subclinica (marcatori di imaging) e clinica (eventi vascolari; EV). Un altro obiettivo è stato l'identificazione dei determinanti indipendenti di PCSK9, con particolare attenzione ai lipidi e ai biomarcatori infiammatori. Infine, abbiamo anche valutato la relazione tra alcuni marcatori di imaging e quattro SNPs del gene PCSK9, noti per essere associati alla presenza di bassi livelli di colesterolo LDL. Per validare i risultati ottenuti in quest’ultima parte, le analisi genetiche sono state replicate in una coorte indipendente reclutata nel Regno Unito (UK). Metodi: Lo studio è stato realizzato sfruttando le banche dati, biobanche e la banca di immagini dello studio IMPROVE. 3,703 soggetti europei (54-79 anni; 48% uomini), privi di EV al basale e definiti ad alto rischio per la presenza di almeno tre fattori di rischio vascolare, sono stati reclutati e seguiti per 36 mesi. PCSK9 è stata misurata tramite ELISA e trasformata in logaritmo prima delle analisi. I marcatori di imaging convenzionali [spessore medio-intimale carotideo (cIMT, dall’inglese intima-media thickness) e dimensione della placca carotidea] ed emergenti [cambiamento di cIMT nel tempo, ecolucenza dello spessore del complesso medio intimale della carotide comune misurato in zone libere da placca (PF CC-IMTmean), ecolucenza della placca più grande rilevata in tutto l'albero carotideo e punteggio di calcio carotideo (cCS, dall’inglese carotid calcium score)] sono stati misurati su scansioni ultrasonografiche conservate nella banca di immagini. In particolare, l'ecolucenza è stata misurata in termini di mediana della scala dei grigi (GSM, dall’inglese grey scale median) della distribuzione dei pixel di una specifica regione d’interesse, mentre il cCS è stato calcolato come somma delle lunghezze dei coni d’ombra acustici generati dal calcio all'interno delle placche carotidee. I lipidi sono stati misurati con metodi enzimatici (ad eccezione del colesterolo LDL che è stato calcolato con la formula di Friedewald). Tra i marcatori infiammatori, la proteina C reattiva ad alta sensibilità (hs-PCR) è stata misurata con la turbidimetria, mentre il conteggio dei globuli bianchi (WBC, dall’inglese white blood cells) e la formula leucocitaria sono stati misurati localmente. Tutti i soggetti dello studio IMPROVE e della coorte UK (n=22,179; 48 % uomini) sono stati genotipizzati. Risultati: Nell'analisi univariata, PCSK9 correlava positivamente con colesterolo totale, LDL e HDL e con trigliceridi e basofili (tutte le p <0.0001), mentre correlava negativamente con neutrofili ed eosinofili (entrambe le p=0.04). Le correlazioni positive osservate con hs-PCR e con il conteggio dei WBC erano solo vicine alla significatività statistica (p=0.060 e 0.064, rispettivamente). Le terapie con fibrati o statine (positivamente; entrambe le p <0.0001), così come sesso maschile e storia familiare di diabete (negativamente; entrambe le p <0.05) erano i predittori indipendenti più forti dei livelli plasmatici di PCSK9. Nell'analisi non aggiustata, si osservava una correlazione negativa tra PCSK9 e variabili basali di cIMT (IMTmean, IMTmax, IMTmean-max, e PF CC-IMTmean), una correlazione negativa tra PCSK9 e la variazione di cIMT nel tempo (Fastest-IMTmax-progr) e cCS (tutte le p ≤0.01), mentre si osservava un trend positivo tra PCSK9 e GSM sia del PF CC-IMTmean che della placca carotidea (entrambe le p ≤0.0001). Il cCS (positivamente) e il GSM del PF CC-IMTmean (positivamente) erano associati significativamente (o vicini alla significatività) a PCSK9 in diversi modelli multivariati (tutte le p ≤0.064). Tutte le correlazioni osservate all’analisi univariata tra PCSK9 e le variabili basali di cIMT, Fastest-IMTmax-progr e GSM della placca carotidea perdevano la significatività statistica dopo aggiustamento delle stesse per età, sesso, latitudine ed altri potenziali confondenti. Durante il follow-up [mediana (intervallo interquartile): 3.01 (2.98; 3.12) anni], sono stati registrati 215 EV: 125 coronarici, 73 cerebrali e 17 EV periferici. Tra questi, 37 erano eventi hard (infarto miocardico, morte improvvisa ed ictus). Nell'analisi non aggiustata, PCSK9 era associata positivamente ad eventi combinati e coronarici (entrambe le p <0.01), ma non ad eventi cerebrovascolari. Anche in questo caso, tuttavia, tutte le associazioni osservate perdevano la significatività statistica dopo aggiustamento delle analisi per età, sesso e stratificazione per latitudine. La mancanza di associazione con EV era confermata anche nel modello aggiustato per tutti i fattori confondenti considerati e nelle analisi focalizzate sugli eventi hard. Per quanto riguarda il ruolo delle varianti genetiche, nessuno dei quattro SNPs considerati correlava con cIMT (IMTmean, IMTmax, IMTmean-max) quando l'analisi era effettuata nei soggetti reclutati nello studio IMPROVE. La variante rs11591147, invece, correlava negativamente con l’IMTmax misurato nella popolazione UK (p=0.002). Combinando le quattro varianti genetiche in uno score, la relazione con cIMT era non significativa nello studio IMPROVE, mentre era negativa e significativa nella popolazione UK (tutte le p <0.01). Conclusioni: I livelli plasmatici di PCSK9 non sono associati a EV. Per quanto riguarda i marcatori dell'aterosclerosi subclinica, i livelli plasmatici di PCSK9 non sono associati né alla dimensione della lesione, né all'ecolucenza della placca carotidea, ma sono associati all'ecolucenza dello spessore della parete carotidea e al carotid calcium score. Ulteriori studi sono pertanto necessari per comprendere meglio il ruolo di tale proproteina nell'ecolucenza dello spessore della parete carotidea e nel carotid calcium score. La terapia con fibrati o statine, così come il sesso maschile e la storia familiare di diabete sono i predittori indipendenti più forti di PCSK9 circolante. È stata inoltre confermata l'associazione, precedentemente osservata, tra PCSK9 circolante e alcuni marcatori lipidici ed infiammatori. La relazione tra i livelli plasmatici di PCSK9 ed altri marcatori infiammatori (neutrofili, basofili ed eosinofili) merita ulteriori indagini, così come merita ulteriori indagini l’associazione tra le quattro varianti genetiche di PCSK9 selezionate e il cIMT nella coorte britannica, in quanto lascia intravvedere un possibile ruolo di SNPs o polimorfismi genici di PCSK9 nell’aterosclerosi e nelle strategie della sua prevenzione.
Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of LDL receptor metabolism, has been associated with atherosclerosis development. Several studies have confirmed such association through both lipid and non-lipid pathways. However, the direct relationships between circulating PCSK9 and markers of subclinical and clinical atherosclerosis are still matter of debate. Therefore, we investigated the relationships between plasma PCSK9 levels and some indexes of subclinical (imaging markers) and clinical (vascular events; VEs) atherosclerosis. Another objective was the identification of the independent determinants of PCSK9, with particular attention to lipids and inflammatory biomarkers. Finally, we also assessed the relationship between some imaging markers and four SNPs of the PCSK9 gene, known to be associated with the presence of low levels of LDL-cholesterol. In order to validate the results obtained in this last part, the genetic analyses were replicated in an independent cohort recruited in the United Kingdom (UK). Methods: The study was carried out taking advantage of databases, biobanks and imaging-bank of the IMPROVE study. 3,703 European subjects (54-79 years; 48% men), free of VEs at baseline and defined at high risk for the presence of at least three vascular risk factors, were recruited and followed-up for 36 months. PCSK9 was measured by ELISA and log-transformed prior to analyses. Conventional imaging markers [carotid intima-media thickness (cIMT) and carotid plaque-size], and emerging imaging markers [cIMT change over time, echolucency of the intima-media thickess of common carotid measured in plaque free areas (PF CC-IMTmean), echolucency of the biggest plaque detected in the whole carotid tree, and carotid calcium score (cCS)] were measured on ultrasonographic scans stored in the imaging-bank. In particular, echolucency was measured in terms of grey scale median (GSM) of pixels distribution of a specific region of interest, whereas cCS was calculated as sum of lengths of acoustic shadow cones generated by calcium within carotid plaques. Lipids were measured with enzymatic methods (except for LDL-cholesterol, which was calculated by Friedewald's formula). Among inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) was measured by turbidimetry, whereas white blood cells (WBC) count and the leukocyte formula had already been measured locally. All the IMPROVE study and UK (n=22,179; 48% men) subjects have been genotyped. Results: In the univariate analysis, PCSK9 was positively correlated with total, LDL-, and HDL-cholesterol, and with triglycerides and basophils (all p <0.0001), whereas was negatively correlated with neutrophils and eosinophils (both p=0.04). The positive correlations observed with hs-CRP and WBC count were just close to the statistical significance (p=0.060 and 0.064, respectively). Fibrates or statins therapies (positively; both p <0.0001), as well as male sex and family history of diabetes (negatively; both p <0.05) were the strongest independent predictors of plasma PCSK9 levels. In the unadjusted analysis, a negative correlation was observed between PCSK9 levels and basal cIMT variables (i.e. carotid IMTmean, IMTmax, IMTmean-max, and PF CC-IMTmean), a negative correlation between PCSK9 and cIMT change over time (Fastest-IMTmax-progr) and cCS (all p ≤0.01), whereas a positive trend was observed between PCSK9 and GSM of both PF CC-IMTmean and carotid plaque (both p ≤0.0001). The cCS (positively) and the GSM of PF CC-IMTmean (positively) were significantly (or almost significantly) associated with PCSK9 in several multivariate models (all p ≤0.064). All correlations observed in the univariate analysis between PCSK9 and basal cIMT variables, Fastest-IMTmax-progr and GSM of carotid plaque lost the statistical significance after adjustment for age, sex, latitude, and other potential confounders. During the follow-up [median (interquartile range): 3.01 (2.98; 3.12) years], 215 VEs were recorded: 125 coronary, 73 cerebral and 17 peripheral VEs. Among these, 37 were hard events (i.e. myocardial infarction, sudden death and stroke). In the unadjusted analysis, PCSK9 was positively associated with combined and coronary events (both p <0.01), but not with cerebrovascular events. Also in this case, however, all the associations observed lost the statistical significance after adjustment of the analyses for age, sex, and stratification for latitude. The lack of association with VEs was confirmed also in the model adjusted for all confounding factors considered, and in the analyses focused on hard events. With regard to the role of genetic variants, none of the four SNPs considered was correlated with cIMT (i.e. IMTmean, IMTmax, IMTmean-max) when the analysis was performed in the subjects recruited in the IMPROVE study. The rs11591147 variant, by contrast, was negatively correlated with IMTmax measured in the UK population (p=0.002). By combining the four genetic variants in a score, the relationship with cIMT was not significant in the IMPROVE study, whereas was negative and significant in the UK population (all p <0.01). Conclusions: Plasma PCSK9 levels are not associated with VEs. Regarding markers of subclinical atherosclerosis, PCSK9 levels are associated neither with lesion size, nor with carotid plaque echolucency, but are associated with echolucency of carotid wall thickness and with carotid calcium score. Therefore, further studies are needed to better understand the role of such circulating proprotein in carotid wall thickness echolucency and in carotid calcium score. Fibrates or statins therapies, as well as male sex and family history of diabetes are the strongest independent predictors of PCSK9 levels. The associations, previously observed, between circulating PCSK9 and some lipid and inflammatory markers have been confirmed. The relationship between plasma levels of PCSK9 and other inflammatory markers (neutrophils, basophils and eosinophils) deserves further investigation, as does the association between the four selected PCSK9 variants and cIMT in the UK cohort, as it suggests a possible role of PCSK9 SNPs or gene polymorphisms in atherosclerosis and in its preventive strategies.

Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.

Background: South Asians demonstrate high coronary heart disease mortality, largely unexplained by conventional risk factors and unidentified by risk stratification tools. Developments in technology allow us to visualize coronary atherosclerosis non-invasively, thus providing the potential to identify presence of coronary atherosclerosis before it manifests clinically. Coronary artery calcification is closely correlated with total plaque burden and provides an assessment of coronary plaque burden. Myocardial perfusion scintigraphy provides an estimate of myocardial blood flow and thus, severity of coronary artery disease. Increased coronary artery calcification and silent myocardial ischemia predict future risk of coronary heart disease mortality, independent of conventional factors. Inflammation is a key factor in initiation and progression of atherosclerosis. High sensitivity C-reactive protein (CRP) is an important marker of active inflammation and is considered an independent predictor of future cardiovascular events. Thus, markers of subclinical atherosclerosis and inflammation could provide us with a tool for early identification of South Asians at risk of coronary events, unidentified by traditional means. However, majority of the data for such markers is from North American and European populations, with no data evaluating the role of coronary artery calcification, myocardial perfusion scintigraphy and CRP in assessing the coronary heart disease risk in South Asians. Methods and Results: I carried out assessments including coronary artery calcium, myocardial perfusion imaging and assessment of high sensitivity C-reactive protein for a cohort of asymptomatic South Asians and Europeans men and women, aged 35 to 75 years, who were part of the London Life Sciences Population (LOLIPOP) study. I found that: 1) Coronary artery calcification scores were closely associated with age, male gender, cigarette smoking, hypertension, systolic blood pressure, diabetes and total cholesterol. 2) There were no differences in either coronary artery calcification prevalence or mean levels of coronary artery calcification between South Asians and Europeans, after adjustment for the measured cardiovascular risk factors. 3) Presence of diabetes and increasing coronary artery calcification were independent predictors for silent myocardial ischemia. 4) South Asian ethnicity did not influence the prevalence or the extent of silent myocardial ischemia, after adjustment for conventional risk factors. 5) C-reactive protein levels did not correlate with measures of plaque burden. 5) South Asian ethnicity was an independent predictor of inflammation as seen by levels of high sensitivity C-reactive protein. This effect was independent of, and remained significant after adjusting for conventional cardiovascular risk factors and novel factors linked to inflammation such as diabetes and indices of abdominal obesity. Conclusions: While traditional risk factor correlate well with markers of atherosclerosis, the higher coronary heart disease risk and mortality observed in South Asians is not identified by markers of atherosclerotic burden such as coronary artery calcification and myocardial perfusion scintigraphy. South Asians have elevated levels of inflammation as seen by high sensitivity C-reactive protein levels. C-reactive protein levels are not correlated with coronary artery calcium or myocardial ischemia measured by myocardial perfusion scintigraphy. These findings suggest a role of factors such as systemic and plaque inflammation, unrelated to and unmeasured by plaque burden assessment in the higher coronary heart disease mortality observed among South Asians. The study therefore suggests a role of potential risk stratification tools reflecting the multisystem nature of CHD. These could be a combination of clinical risk factors contributing towards CHD, imaging of atherosclerotic plaque and assessment of plaque or systemic inflammation.

A large number of studies have established that raised cholesterol levels increase the probability of the development of atherosclerotic vascular disease, and that reducing serum cholesterol will result in fewer cardiac events in the treated population, both in those with and without evidence of pre-existing coronary disease. More direct evidence that this is due to alteration of the progression of the atheromatous plaques has resulted from angiographic studies demonstrating the halting of progression or even regression of the stenotic lesions. Some workers have found a relationship between the extent of lowering of the serum lipoproteins and the likelihood of regression, although it has not been clear whether this continues to hold true at the lower extremes, nor whether there may be a threshold level which requires to be achieved before regression may take place. The principal purpose of these studies was to investigate the effects of applying very intensive lipid-lowering therapy, including LDL-apheresis, in a group of patients with coronary artery disease and moderately severe hypercholesterolaemia to achieve subnormal lipoprotein levels, and comparing the effects of such treatment with those achieved in another group of subjects treated with drug therapy to the currently recommended therapeutic targets for such patients. The studies involved the measurement of lipids and lipoproteins before and after apheresis and at regular intervals throughout the two-year study period. ApoB metabolism was assessed at baseline and following completion of the treatment period, and the data analysed using a multicompartmental mathematical model. The patients were assessed non-invasively by exercise electrocardiography at regular intervals, and by thallium scintigraphy at baseline and at annual intervals. The principal end-point was the proportion of arterial segments undergoing regression or progression in each group assessed by computer-assisted analysis of coronary angiograms performed at baseline and on completion of the intervention. The results from these studies demonstrated radical differences in lipoprotein concentration and composition during treatment. There was increased catabolism of LDL precursors with diminished flux of apoB which may reflect up-regulation of the LDL-receptor, but a rapid return to pre-treatment lipid levels indicated the effects on lipoprotein metabolism were transient. There was a reduction in the progression of coronary disease in the majority of lesions, with a small number in each group undergoing definite regression. There were significant differences in the changes in exercise tolerance with treatment, and the likely mechanisms for this are discussed. The thallium scans demonstrated no difference between the groups in the number of segments with improved perfusion, but were shown to have some value in the non-invasive assessment of predicting angiographic changes in the proximal segments, particularly in the right coronary artery. The findings are put into the context of the recent publications on cholesterol reduction in coronary disease; implications for clinical management are drawn, and areas of potential future research are highlighted.

Atherosclerotic renovascular disease (ARVD) is a significant cause of chronic kidney disease (CKD) and is associated with an increased risk for cardiovascular morbidity and mortality. Randomised controlled trials, representing over 2100 patients, have failed to demonstrate any prognostic benefit of percutaneous renal revascularisation when utilised in addition to standard medical therapy. This negative finding has been interpreted in three ways. Firstly, that ARVD may be an association of CKD and not a specific disease process. Secondly, that published studies have recruited low-risk patients who are least likely to benefit from revascularisation. Thirdly, that the focus of treatment for patients with ARVD should be optimal medical therapy, not renal revascularisation. This research project had a series of linked aims. These were investigated in two large patient cohorts that had been accumulated at this centre over the last decade. These cohorts comprised > 900 patients with ARVD, the Salford Renovascular Database (SRVD), and > 2500 patients with all-cause CKD, the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). The first aim was to consider whether ARVD should be considered as a specific cause of CKD. Here risks for death and progression to renal replacement therapy were compared between patients having ARVD as their primary cause of renal failure and patients with other coded causes of CKD. In this analysis, patients with ARVD had a greater risk for death and a lesser risk for RRT than patients with other forms of CKD.The second aim of this thesis was to consider if specific patient sub-groups of ARVD could be identified. Patients in the SRVD with currently accepted high- risk clinical presentations were selected and outcomes compared to patients without a high-risk presentation. In this analysis, presentation with flash pulmonary oedema (but with not refractory hypertension or rapidly declining renal function) was associated with an increased risk for death and cardiovascular event. When the effects of revascularisation were considered in patients with high-risk presentations, a mortality benefit was observed in patients with flash pulmonary oedema and in patients presenting with rapidly declining renal function and refractory hypertension in combination. A separate analysis was performed in the SRVD to consider if a high-risk sub-group of ARVD patients could be identified using laboratory measurements. Here, a classification tree methodology was employed to identify ARVD patients with the greatest risk for progression to end stage kidney disease. The results of this analysis were converted into a practically applicable clinical scoring system incorporating renal function, proteinuria, medications, smoking history and renal artery occlusion. The final aim of this thesis was to describe how the majority of ARVD patients should be treated. In this analysis of the SRVD effects of treatment with anti- platelet and beta-blocker therapy were considered, and shown to be associated with reduced risks for cardiovascular events and death.

Stroke is the third leading cause of death and the most common cause of disability in the world. To relieve the heavy burden of stroke, we need to understand the mechanisms that will form the basis of improved prevention and treatment. Epidemiological studies have found evidence for a genetic influence on the common form of stroke. However the genetic of stroke is still in its infancy. Subclinical intracranial atherosclerosis is sometime a predisposing factor for ischemic stroke (IS). This study was carried out to elucidate genetic factors influencing the complex phenotype of IS and subclinical intracranial atherosclerosis.

In the Belgium Stroke Study (BSS), we collected 237 middle-aged (45-60 yrs) patients with small vessel occlusion (SVO) or large vessel atherosclerosis (LVA) IS, according to the Acute Stroke Treatment (TOAST) criteria, 326 ethnicity and gender matched subjects were used as controls. We tested variants in cholesterol-related candidate genes (sterol regulatory element binding protein, SREBP, SREBP-cleavage activating protein, SCAP, Apolipoprotein E, APOE, and Proprotein convertase subtilisin/kexin type 9, PCSKA) for association with IS. Significant gene-IS associations were further tested in a Finnish autopsy collection of 1004 cases with a quantitative assessment of atherosclerosis in the circle of Willis.

While we could not detect any significant association between polymorphisms in the SREBP and SCAP genes and IS, we found evidence for association at the APOE and PCSK9 loci. The APOE &949;4+ genotype was related to a more severe intracranial atherosclerosis score in men, and within the most common APOE &949;3/&949;3 genotype group a higher risk of IS was associated with the G-allele at the -219G/T promoter polymorphisms. At PCSK9, the minor allele (G) of the tagging E670G polymorphism appeared as a significant predictor of LVA (OR = 3.52, 95% CI 1.25-9.85; p = 0.017). Accordingly, in the Finnish autopsy series, G-allele carriers tended to have more severe allele copy number-dependent (p=0.095) atherosclerosis in the circle of Willis and in its branches.

Our findings in this unique combination of clinical and autopsy data suggest a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE &949;4+ genotype did not predict the risk of IS, but was associated with severity of subclinical intracranial atherosclerosis in men. In contrast, the promoter variants affecting apoE expression were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS independently of subclinical intracranial atherosclerosis. Furthermore, we demonstrated that PCSK9 associates with the risk of LVA stroke subtype, and suggest that the risk is related to the severity of the underlying intracranial atherosclerosis.

Atherogenesis is considered as an active, inflammatory process, interleukin (IL)-18 a proinflammatory cytokine, is thought to play a central role in the development of atherosclerosis and more specifically in plaque rupture. We genotyped four haplotype tagging polymorphisms at the IL18 gene in the BSS and the Finnish autopsy series. The minor alleles of the IL18 -607 and +127 polymorphisms, as well as the haplotype carrying both minor alleles, associated with IS after adjustment for all cardiovascular risk factors. No association was seen with the development of subclinical intracranial atherosclerosis. Our findings suggest that variation in the IL18 gene influences the acute atherosclerotic IS event, but not the previous development of subclinical intracranial atherosclerosis, suggesting a causal role of IL18 in the vulnerability of cerebral arterial atherosclerotic plaques to acute rupture and subsequent thrombosis.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Public Health Epidemiology." Discipline: Epidemiology; Department/School: Public Health.

It is generally accepted that early atherosclerosis develops in low shear-stress (SS) regions such as the outer wall of arterial bifurcations and the inner bend of curved vessels (1). However, in clinical practice, it is common to observe atherosclerotic plaques at the flow-divider, or carina, of coronary bifurcations (2). Plaques at the carina are more frequently found in symptomatic patients, and may represent a more advanced stage of atherosclerosis. The carina is located in a region which is exposed to high SS. We hypothesize that if plaques are located in atheroprotective high SS regions, they have grown circumferentially from the atherogenic low SS regions.

Atherosclerosis is a degenerative disease that affects coronary, carotid and other peripheral arteries in the body. Arterial occlusions ensuing from aggressive atherosclerotic plaque progression can often culminate in an ischemic attack, such as an apoplectic attack or a myocardial infarction [1–3]. Several interventional procedures are available to the clinician but in recent years drug eluting stents (DES) have become the preferred choice and by the beginning of 2006 more than 8 out of 10 coronary stents were DES [4] at a cost of between $4 and $5 billion annually [5].

Coronary artery atherosclerosis is a leading cause of morbidity and mortality in western societies. Atherosclerosis is a progressive fibroinflammatory disease identified by intimal thickening, the focal accumulation of lipids, fibrous elements, and cellular elements within the walls of large arteries. These lesions preferentially develop at arterial branches, the outer walls of bifurcations, and the inner walls of curved sections; the cause of this focal vasculopathy is not fully understood. It is, however, understood from epidemiological and clinical studies that individual susceptibility to the development and progression of atherosclerotic lesions is influenced by “traditional” systemic risk factors, including smoking, diabetes mellitus, obesity, hypertension, and high cholesterol. However, these risk factors cannot account for half of the variability in occurrence of this disease; this indicates additional risk factors have not been identified. One prevalent explanation of the focal nature of the disease is that the local fluid mechanical stresses at the walls of coronary arteries, as well as mechanical stresses within the vessel wall, may mediate the phenotype of endothelial cells thereby producing atherosusceptible sites. Therefore, it has been speculated [1] that certain aspects of arterial geometry and motion, which vary substantially among individuals, may increase an individual’s susceptibility to developing atherosclerosis — “geometric risk factors”.

Mechanical forces play an important role in the complicated process of atherosclerotic plaque rupture which often leads to serious clinical events such as stroke and heart attack [4]. Factors causing the vulnerable plaque cap to fracture are important clinically [2–7]. It is known that coronary plaques are more likely to rupture compared to carotid plaques under comparable conditions (such as stenosis severity at about 50% by diameter). One possible reason is that coronary arteries are under cyclic bending caused by heart motions and compressions. We hypothesize that cyclic bending of coronary atherosclerotic plaques may be a major contributor to critical stress variations in the plaque leading to increased plaque rupture risk. We have developed MRI-based 3D multi-component models with fluid-structure interactions (FSI) in order to perform flow and stress/strain analysis for atherosclerotic plaques and identify possible mechanical and morphological indices for accurate plaque vulnerability assessment [6–7].

Abstract During the latter half of this century biomechanics has made an enormous impact on medicine and biology. This started with the recognition that many tissues within the human body reside in a mechanical environment, i.e. they are subjected to mechanical stresses. Initially the intent was to apply existing knowledge of mechanics to problems arising from medicine and biology. As with all of bioengineering, what has evolved, however, is a true integration of the biology with the mechanics. With this biomechanics has emerged as an important field of endeavor in our attempt to understand basic biological mechanisms, the physiology of the human body, and disease processes. It also has contributed to the development of new clinical treatment strategies and to improved medical devices and implants.

Purpose of the study. To rate prognostic properties of changes in mitochondrial DNA concentration in the blood plasma of patients with chronic cerebral ischemia and ischemic heart disease in relation to the disease and the effectiveness of the therapy. Materials and methods. The study involved patients suffering from coronary heart disease (CHD) and chronic cerebral ischemia (CCI) with stable and unstable atherosclerotic plaques, who have signed informed consent to the data processing within the framework of scientific research. The patients were admitted to the hospital for examination and treatment of CHD and CCI in Cardiology and Neurology Unit of the Hospital of ISC SB RAS. The subjects underwent laboratory and instrumental examination and analysis of the level of free circulating serum mitochondrial DNA by real-time PCR (copies/ml). The examination results considered as satisfactory were compared with the mtDNA levels before and after the treatment. Results. The average value of the mtDNA levels before and after the treatment in patients of neurological and cardiological profile were significantly different: 1 093 686 copies/ml vs 418 046 copies/ml, respectively (p = 0.02). Unlike women, men mtDNA levels statistically significantly (p = 0.03) decreased after the treatment. We revealed statistically significant differences in mtDNA level indicators before and after the treatment, depending on the definition of the series (p = 0.0010) for rank test Kruskal – Wallis test. The results of the proposed research will help to identify prognostic factors of destabilization of cell damage and plaques in endothelial dysfunction, atherosclerosis and its complications, to conduct clinical test of the method for predicting and diagnostics of cellular damage in chronic ischemia on a background of atherosclerosis.

Non-invasive diagnosis of cardiovascular diseases is a valuable tool to reduce patient’s risk and discomfort. The main aim of this work is to investigate the possibilities of using computational fluid dynamics as a tool to investigate the biomechanical characteristics of the aorta under different medical conditions. These conditions include an aorta with healthy conditions, atherosclerosis and aneurysm. A three dimensional pulsatile flow model for an elastic aorta is developed and constructed in ANSYS® CFX 12. Abnormalities are simulated as diameter changes at the root of the ascending aorta. The computational model shows the reflection of these diseases on the blood flow and the artery wall at other locations downstream along the aorta. This 3D model has several advantages over previously published 1D and 2D models by giving more realistic results as compared with clinical trials.

Twelve million people worldwide die of diseases associated with atherosclerosis. It is estimated that atherosclerosis costs the US economy 100 billion dollars each year. From clinical studies, it is well known that atherosclerosis has preferred locations in the vascular system, primarily sited in the carotid arteries, coronary arteries, and in vessels supplying the lower extremities in the arterial system [1]. In the vicinity of a bifurcating, arterial flow tends to separate forming recirculation regions. In addition, due to the pulsatile character of blood flow during the deceleration part of the cycle, the flow becomes unstable and transition to turbulence may occur. The combination of the above-described phenomena generates abnormal shear stress levels and high shear stress gradients, especially at the reattachment point of the separated region.

The near wall motion and residence time of cells that participate in atherosclerosis is an important factor in the development and progression of atherosclerotic lesions. Attachment of leukocytes and monocytes depends upon a complex biological milieu, including expression of adhesion molecules and receptors at cell surfaces, but biomechanical forces also come into play in the local microenvironment. Cell attachment to the endothelium begins with rolling at the surface and can consummate in firm adhesion. These phenomena are influenced by flow-induced forces and moments acting on the cell in proximity to the endothelium. The initial rolling condition and capture process are related to the local shear flow, and there have been extensive investigations — both theoretical and experimental — of these phenomena for various cell types [1–3]. In most studies, steady flow and analytical methods based on Stokes equations were widely used, since the Reynolds numbers are extremely low. In our study, we focus on relating simulated cell motion to conditions in the region of an atherosclerotic plaque in an effort to assist in the interpretation of concurrent investigations of plaque development and progression in human coronary arteries. Thus, our studies are not designed to address fundamental questions of the biology of cell attachment but rather are aimed at elucidation of clinical observations. An inherent challenge is the fact that the length scales of interest vary from sub-micron to millimeters, a range ∼ 104–105 that presents a significant computational task if tackled directly. Hence, various schemes have been employed to address this multi-scale computational problem. Our approach here is intended to decouple the macro (∼ sub-mm) and micro (∼ sub-μm) flows in an effort to achieve computational simplicity, yet preserve accuracy, and thus to concentrate on relevance to flow in the human coronary arteries.