Dissertations / Theses on the topic 'Subclinical atherosclerosi'

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.

Background: Cardiovascular health disparities across subpopulations and geographies have been well-documented in urban areas. Evidence suggests that racial minorities and low-socioeconomic groups have high risks of developing cardiovascular diseases (CVD). Residents of the Appalachia also exhibit high rates of CVD, but little is known about the relationships between cardiovascular risk factors, spatial disadvantage, and cardiovascular health outcomes in this region. Thus, this study aimed to examine the independent association between neighborhood factors and subclinical atherosclerosis in an asymptomatic population from central Appalachia. Methods: Community-dwelling asymptomatic individuals (n=210) were screened for Coronary Artery Calcium (CAC), a subclinical marker for coronary atherosclerosis, from January 2010 to January 2014. Based on the standard Agatston Scale, participants were grouped into 4 CAC scores: zero (CAC = 0), mild (CAC = 1-99), moderate (CAC = 100-399) and severe (CAC ≥ 400) to determine the severity of coronary artery disease (CAD). Demographic information (e.g., age, gender, race, and marital status), cardiovascular risk factors (e.g., hypertension, hypercholesterolemia, obesity, smoking, and family history of CAD), and neighborhood level characteristics (racial and socioeconomic characteristics of the population) were used in ordinal logistic regression analyses performed in Stata 14.1. Results: Of the 210 participants, over three-fourths (79%) had a CAC score greater than 1. While 67% of the participants were hypertensive, 80% had hypercholesterolemia, 75% were overweight or obese, 52% had a history of smoking, and 55% had a family history of CAD. There were significant differences in the socioeconomic environment of these residents. Specifically, zip-code median household income was higher for individuals with zero CAC score. Additionally, the zip-code household poverty percentage was higher for those with CAC scores ≥ 1. Although all the neighborhood factors increased the odds of having higher CAC score, none of them were statistically significant. Conclusion: The positive, albeit statistically non-significant, association of adverse neighborhood factors with higher CAC scores suggests the need for larger studies for further understanding of this association. Finally, achieving the Healthy People 2020 goal of reducing or eliminating disparities requires risk factor screening and control in high prevalent areas such as central Appalachia, and understanding the neighborhood level dynamics for CVD.

La malaltia cardiovascular és la primera causa de morbiditat i mortalitat mundial. Els individus amb diabetis i malaltia renal crònica (MRC) presenten un major risc d’esdeveniments cardiovasculars (ECV) respecte a la població general. En la diabetis, l’increment de el risc cardiovascular és heterogeni i s’ha relacionat amb el grau d’afectació renal. D’altra banda, els algoritmes tradicionals per calcular el risc cardiovascular no traslladen amb suficient precisió el risc futur de ECV. L’avaluació de l’aterosclerosi subclínica (AS) mitjançant ecografia multiterritorial representa una eina vàlida per refinar el risc cardiovascular. El propòsit d’aquesta tesi va ser analitzar mitjançant ecografia multiterritorial la prevalença, distribució i progressió de AS, així com factors de risc associats, en una àmplia cohort de pacients, sense malaltia cardiovascular, amb MRC i amb i sense diabetis. Posteriorment, es va avaluar el valor pronòstic de l’AS per determinar la incidència d’ECV en aquesta població d’alt risc. Inicialment, es van analitzar les dades dels subjectes amb MRC, amb diabetis i sense diabetis, de la cohort de l’estudi NEFRONA reclutats a l’inici de l’estudi i que van assistir a la visita de control als 24 mesos. Després de realitzar un estudi ultrasonogràfic carotidi i femoral tant en la visita inicial com en la de seguiment, es va avaluar la correlació de factors de risc associats amb prevalença i progressió de placa mitjançant anàlisi multivariables. Així mateix, es va realitzar una altra anàlisi amb tots els subjectes de l’estudi, amb i sense diabetis, reclutats inicialment i als quals se’ls va seguir durant 48 mesos. Durant el període de seguiment es van registrar els ECV incidents. Es van utilitzar anàlisis bivariades i anàlisi de model de riscos competitius de Fine-Grey per a l’estudi estadístic. L’índex C es va estimar per als models de risc resultants amb més potència. Com a resultats, es va observar que la proporció d’individus amb placa basal va ser més gran entre els subjectes amb diabetis. Els subjectes amb diabetis també van presentar amb més freqüència l’afectació amb placa de més de dos territoris vasculars. També es va observar més progressió de placa entre els individus amb diabetis. Després de realitzar l’anàlisi multivariable, es va demostrar que la presència de placa basal s’associava amb l’edat, el gènere masculí, l’hàbit tabàquic i la diàlisi en els subjectes sense diabetis mentre que, en els subjectes amb diabetis, la presència de placa basal es associar tan sols a l’edat i al gènere masculí. La progressió de placa es va associar a l’edat, a el nombre de territoris amb placa basal, a l’hàbit tabàquic i a la diàlisi en els dos grups. Es van registrar un total de 107 ECV entre els subjectes sense diabetis (19.58 per 1000 anys-persona) i 96 entre els subjectes amb diabetis (44.44 per 1000 anys-persona). El model que millor va predir futurs ECV en individus sense diabetis contenia les variables: edat, 25-OH vitamina D i nombre de territoris amb placa basal. Entre els participants amb diabetis el model més robust en predir ECV incidents contenia tan sols la variable nombre de territoris amb placa basal. Per a tots dos models, l’índex estadístic C, estimat als 24 i als 48 mesos, va ser superior a 0.70. La AS és més prevalent, comporta major càrrega i és més progressiva en individus amb MRC i diabetis. En aquests subjectes, la diabetis supera altres factors de risc descrits. Així mateix, la càrrega d’AS és el predictor més potent de futurs ECV en individus amb diabetis i MRC. La detecció precoç de càrrega AS mitjançant ultrasonografia multiterritorial podria millorar la predicció de ECV en aquesta població.
La enfermedad cardiovascular es la primera causa de morbilidad y mortalidad mundial. Los individuos con diabetes y enfermedad renal crónica (ERC) presentan un mayor riesgo de eventos cardiovasculares (ECV) con respecto a la población general. En la diabetes, el incremento del riesgo cardiovascular es heterogéneo y se ha relacionado con el grado de afectación renal. Por otra parte, los algoritmos tradicionales para calcular el riesgo cardiovascular no trasladan con suficiente precisión el riesgo futuro de ECV. La evaluación de la aterosclerosis subclínica (AS) mediante ecografía multiterritorial representa una herramienta válida para refinar el riesgo cardiovascular. El propósito de esta tesis fue analizar mediante ecografía multiterritorial la prevalencia, distribución y progresión de AS, así como factores de riesgo asociados, en una amplia cohorte de pacientes, sin enfermedad cardiovascular, con ERC y con y sin diabetes. Posteriormente, se evaluó el valor pronóstico de la AS para determinar la incidencia de ECV en esta población de alto riesgo. Inicialmente, se analizaron los datos de los sujetos con ERC, con diabetes y sin diabetes, de la cohorte del estudio NEFRONA reclutados al inicio del estudio y que asistieron a la visita de control a los 24 meses. Tras realizar un estudio ultrasonográfico carotídeo y femoral tanto en la visita inicial como en la de seguimiento, se evaluó la correlación de factores de riesgo asociados con prevalencia y progresión de placa mediante análisis multivariables. Asimismo, se realizó otro análisis con todos los sujetos del NEFRONA, con y sin diabetes, reclutados inicialmente y a los que se les siguió durante 48 meses. Durante el periodo de seguimiento se registraron los ECV incidentes. Se utilizaron análisis bivariados y análisis de modelo de riesgos competitivos de Fine-Grey para el estudio estadístico. El índice C se estimó para los modelos de riesgo resultantes con mayor potencia. Como resultados, se observó que la proporción de individuos con placa basal fue mayor entre los sujetos con diabetes. Los sujetos con diabetes presentaron con mayor frecuencia la afectación con placa de más de dos territorios vasculares. También se observó una mayor progresión de placa en los individuos con diabetes. Tras realizar el análisis multivariable, se demostró que la presencia de placa basal se asociaba con la edad, el género masculino, el hábito tabáquico y la diálisis en los sujetos sin diabetes mientras que, en los sujetos con diabetes, la presencia de placa basal se asoció tan sólo a la edad y al género masculino. La progresión de placa se asoció a la edad, al número de territorios con placa basal, al hábito tabáquico y a la diálisis en ambos grupos. Se registraron 107 ECV entre los sujetos sin diabetes (19.58 por 1000 años-persona) y 96 entre los sujetos con diabetes (44.44 por 1000 años-persona). El modelo que mejor predijo futuros ECV en individuos sin diabetes contenía las variables: edad, 25-OH vitamina D y número de territorios con placa basal. Entre los participantes con diabetes el modelo más robusto en predecir ECV incidentes contenía tan sólo la variable ‘número de territorios con placa basal’. Para ambos modelos, el índice estadístico C, estimado a los 24 y a los 48 meses, fue superior a 0.70. La AS es más prevalente, conlleva mayor carga y es más progresiva en individuos con ERC y diabetes. En estos sujetos, la diabetes supera otros factores de riesgo descritos. Así mismo, la carga de AS es el predictor más potente de futuros ECV en individuos con diabetes y ERC. La detección precoz de carga AS mediante ultrasonografía multiterritorial podría mejorar la predicción de ECV en esta población.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Individuals with diabetes and chronic kidney disease (CKD) have remarkably high rates of CVD risk. Moreover, incremental cardiovascular risk in diabetes is heterogeneous and has been often related to concomitant CKD. Typically used risk equations based on traditional cardiovascular risk factors fail to accurately predict cardiovascular risk not only in the general population but also in these subsets of the population. Multi-territorial ultrasonography to assess subclinical atherosclerosis (SA) has emerged as a valid tool to refine cardiovascular risk assessment beyond traditional risk factors. The purpose of this thesis was to analyse the prevalence, distribution, and progression of SA, as well as the associated cardiovascular risk factors in a large cohort of CKD subjects with and without diabetes, free from CVD, using multi-territorial ultrasonography. Subsequently, we further evaluated the prognostic value of SA in determining the incidence of first cardiovascular events (CVE) in this high-risk population. First, we included the data from CKD subjects with and without diabetes and free from previous CVE from the NEFRONA cohort, that were recruited at baseline, and that attended a follow-up visit 24 months later. Participants underwent carotid and femoral ultrasound examinations at baseline and at 24-month follow-up. Risk factors associated with the prevalence and progression of SA were evaluated using multivariate model analyses. In the second hand, we also conducted another analysis including data from the NEFRONA cohort subjects with and without diabetes that were recruited initially and were followed-up for 48 months. During the follow-up period, all CVE were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. Concordance Index (C-statistics) was estimated for the strongest resulting risk models. We found that at baseline, the proportion of subjects with plaque at any of the examined territories was higher among diabetic individuals. Diabetic subjects more frequently had more than two vascular territories with plaque. During a 24-month follow-up period, plaque progression occurred in 72.2% individuals with diabetes whereas, among individuals without diabetes, plaque progression occurred in 55.8%. Multivariable analysis indicated that plaque at baseline was significantly associated with age, male gender, smoking, and dialysis in the non-diabetic subjects, while only age and male gender were associated with plaque presence in diabetic subjects. Plaque progression was significantly associated with age, the number of territories with basal plaque, smoking, and renal replacement therapy in both groups. Additionally, during a mean follow-up time of 48 months, CVE rate among participants without diabetes was 19.58 per 1000 person-years and 44.44 per 1000 person-years among participants with diabetes. After competing risk analyses and model selection, those variables that better predicted CVE in individuals without diabetes were the number of territories with plaque, age and serum concentrations of 25-OH vitamin D. Among participants with diabetes, the strongest model predicting incident CVE had only one variable: the number of territories with basal plaque. For both models, the concordance (C) index score was greater than 0.7 at both 24 and 48 months. We concluded that SA is more prevalent, carries a higher plaque burden, and is more progressive in CKD subjects with diabetes than in CKD subjects without diabetes. In these individuals, diabetes outweighs other risk factors associated with the presence of SA. SA is the strongest predictor of future CVE in diabetic individuals with CKD. Early detection of the SA burden by multi-territorial vascular ultrasound could improve CVE prediction in this population.

Background: Type 2 diabetes is a common disease with increased mortality and morbidity due to cardiovascular disease (CVD). This thesis is based on three studies that evaluated traditionally used and emerging risk markers to identify individuals with high-risk of developing CVD in middle-aged men and women with type 2 diabetes. One study was conducted to compare the equivalence between two different ultrasound techniques to measure intima-media thickness since IMT was used to evaluate subclinical atherosclerosis as a surrogate endpoint. Methods: Data from the cohort study, cardiovascular risk in type 2 diabetes – a prospective study in primary care (CARDIPP) was used in paper I, III and IV. In paper I, baseline data from the first 247 subjects was analysed. Associations between traditionally measured lipids, apolipoproteins, glycaemic control and low-grade inflammation and IMT were analysed. In paper III, the full baseline cohort, with data from 761 subjects from the CARDIPP study was cross-sectionally analysed regarding correlations between abdominal obesity measured as waist circumference (WC) and sagittal abdominal diameter (SAD), inflammatory markers and IMT and pulse wave velocity (PWV). In paper IV, the associations reported in paper I and III were prospectively investigated with data from the first year of follow-up four years after the baseline investigations in CARDIPP-revisited. In paper II a study was performed on 24 young healthy subjects, both men and women. IMT was measured in the common carotid artery (CCA) and in the abdominal aorta (AA), by two skilled ultrasonographers, with 2 different ultrasound techniques in a randomised order. Results: ApoB/apoA-I ratio (r=0.207, p=0.001), apoB (r=0.166, p=0.009) and non HDLcholesterol (nHDL-c) (0.129, p=0.046) correlated with IMT. In CCA IMT was equivalent using B-mode- and M-mode respectively. However in AA, IMT was 11.5% thicker using B-mode. Abdominal obesity were significantly correlated with; IL-6 and CRP (both p<0.001, WC and SAD respectively), IMT (WC p=0.012, SAD p=0.003) and PWV (p<0.001 WC and SAD respectively). Adjusting for age, sex, treatment with statins, systolic blood pressure (SBP), Body Mass Index (BMI), CRP and HbA1c, SAD (p=0.047) but not WC, remained associated with IMT. There were significant correlations between apoB (r=0.144, p=0.03) and CRP (r=0.172, p=0.009) measured at baseline and IMT measured at follow-up. After adjustment for sex, age, treatment with statins and Hba1c, the associations remained statistically significant. HbA1c, total cholesterol or LDL-cholesterol did not correlate to IMT at follow-up. Baseline body mass index (BMI) (r=0.130, p=0.049), WC (r=0.147, p=0.027) and SAD (r=0.184, p=0.007) correlated to PWV at follow-up. Challenged with sex, SBP and HbA1c, the association between SAD, not WC nor BMI, and PWV remained statistically significant (p=0.036). Conclusions: There was a significant association between apoB/apoA-I ratio and IMT. The association was independent of conventional lipids, CRP, glycaemic control and use of statins. Both SAD and WC were associated with inflammation, atherosclerosis and arterial stiffness. However, SAD was slightly more robustly associated to subclinical organ damage, compared with WC. Prospectively; apoB and CRP, but not LDL-cholesterol predicted increased subclinical atherosclerosis. Furthermore, SAD was more independent in predicting arterial stiffness over time, compared with WC, in middle-aged men and women with type 2 diabetes. The two different ultrasound techniques, B-mode and M-mode, measured different IMT thickness in the aorta, emphasizing the importance of using similar technique when comparing the impact of absolute values of IMT on cardiovascular disease.

Objective: To examine the association between subclinical atherosclerosis (ascertained as coronary artery calcium; CAC) in asymptomatic individuals in the Central Appalachian region of the United States and individual- and geographic-level factors. Methods: Data were obtained from participants in CAC screening during 2012 and 2016. CAC score was assessed as CAC=0 (no plaque), 1≤CAC≤99 (mild plaque), 100≤CAC≤399 (moderate plaque), and CAC≥400 (severe plaque). Additionally, data on demographics (age, sex, and race), medical conditions, lifestyle factors, and family history of coronary artery disease (CAD) were obtained. Further, zip codes of place of residence for participants were used to generate geographic-level data. Descriptive statistics were used to estimate the prevalence of CAC, and multinomial logistic regression models were used to delineate significant factors. Results: Of 1512 participants, 57.6% had CAC>0. The prevalence of mild, moderate, and severe plaques was 31.6%, 16.3%, and 9.7%, respectively. Demographic, medical conditions, lifestyle factors, and family history of CAD were associated with increased risk for subclinical atherosclerosis. Further, the proportion of minority residents significantly increased the risk for severe plaque [RRR=1.06; p-value=0.04] and the proportion of residents on government assistance significantly decreased the risk for mild plaque [RRR=0.93; p-value=0.03]. Conclusion: The results imply that the proportion of minority residents in a geographic area is associated with increased relative risk for subclinical atherosclerosis, while the proportion of residents on government assistance decreased such risk. However, future geographic or neighborhood-level studies with larger sample size are needed to delineate further the consistency of these results in the Central Appalachian population.

Subclinical atherosclerosis is an important area of research to evaluate stroke risk and predict localization of plaque. The current methods for detecting atherosclerosis risk are insufficient because it is based on The Framingham Risk Score and carotid intima media thickness, therefore an engineering detection model based on quantifiable data is needed. Laminar and turbulent flow, dictated by Reynolds number and relative roughness, was modeled through the carotid artery bifurcation to compare shear stress and shear rate. Computer-aided design and fluid flow software were used to model hemodynamics through the carotid artery. Data from the model was derived from governing equations programmed in COMSOL for both laminar and turbulent flow. A carotid artery model is accurate enough to describe how relative roughness, flow profiles, and shear rate can be a good prediction of subclinical atherosclerosis.

Introduction: Patients with inflammatory polyarthritis (IP) have an excess risk of cardiovascular (CVD) mortality due to accelerated atherosclerosis. Markers identifying individuals with subclinical atherosclerosis as measured by carotid intima-medial thickness (cIMT) and plaque may allow for attenuation of CVD risk. The objective of this study was to identify associated risk markers for atheromatous plaque and cIMT in an incident cohort of patients with early IP and to assess the risk markers associated with progression of cIMT and plaque after 2 years of follow-up.Methods: From 2004 to 2008 consecutive patients with early IP (≥2 joints swollen for ≥4 weeks) aged 18-65 years, who were within 24 months of symptom onset (±6 months) were recruited as part of a primary-care-based inception cohort. Apparently healthy controls were recruited on a frequency matched 'buddy' pair system. Patients underwent joint and blood pressure examination. Patients and controls underwent BMI measurement and their medication was recorded. Patients' blood was taken for measurement of rheumatoid factor, anti-citrullinated protein antibody, C reactive protein, glucose, lipids (LDL, HDL, triglycerides, paroxonase 1, apolipoprotein A1 and B) and markers of vascular damage (E-selectin, VCAM) and adipocytokines (leptin and adiponectin). Patients and controls underwent B mode Doppler ultrasound examination of the carotid arteries to assess for cIMT and the presence of plaque. In univariate analyses we identified factors that were associated with cIMT and plaque presence after age and gender adjustment. An additive stepwise multivariable logistic regression model was created to investigate the independence of any associations.Results: The 329 IP subjects had a median (IQR) age of 51 (42-58) years and 96 (29%) were male. IP subjects were more likely to be smokers, have a family history of CVD, have diabetes, higher BP and be overweight than their apparently healthy counterparts. IP subjects with plaque at baseline often did not have prior CVD. Subjects with IP had a 2.87 fold higher plaque frequency at the baseline but a similar median cIMT relative to the controls. Traditional CVD risk markers such as age, systolic BP and LDL were associated with cIMT and plaque at baseline. Adiponectin levels were negatively associated with cIMT and positively associated with plaque. IP subjects had a significant increase in their cIMT in the first 2 years of follow-up. The rate of progression of cIMT was 1.5-2.2 fold greater in IP than reported in the general population. Novel risk factors added to the model above and beyond traditional risk factors in predicting atherosclerosis. Steroid exposure at 2 years was associated with atherosclerosis progression.Conclusion: Markers known to be associated with atherosclerosis in the general population are associated with cIMT and plaque presence in early IP prior to established inflammatory disease and therapy. While cIMT in subjects and controls was the same at baseline there was an accelerated rate of progression of cIMT in IP subjects relative to that reported in the general population.

Aim: To examine the association of cardiovascular disease risk factors with and their cumulative effect on coronary artery calcium in hard-to-reach asymptomatic patients with diabetes. Methods: : A total of 2563 community-dwelling asymptomatic subjects from Central Appalachia participated in coronary artery calcium screening at a heart centre. Binary variable was used to indicate that coronary artery calcium was either present or absent. Independent variables consisted of demographic and modifiable risk factors and medical conditions. Descriptive statistics and multinomial logistic regression analyses were conducted. Results: : In total, 55.8% and 13.7% of study participants had subclinical atherosclerosis (coronary artery calcium ⩾1) and diabetes, respectively. The presence of coronary artery calcium was higher in subjects with diabetes (68.5%) than those without (53.8%). Compared to subjects without diabetes with coronary artery calcium = 0, obesity, hypertension, hypercholesterolaemia and smoking increased the odds of the presence of coronary artery calcium (coronary artery calcium score ⩾1) regardless of diabetes status; however, with larger odds ratios in subjects with diabetes. Compared to subjects without diabetes with coronary artery calcium score = 0, having 3, 4 and ⩾5 risk factors increased the odds of presence of coronary artery calcium in subjects with diabetes by 14.06 (confidence interval = 3.26–62.69), 32.30 (confidence interval = 7.41–140.82) and 47.12 (confidence interval = 10.35–214.66) times, respectively. Conclusion: : There is a need for awareness about subclinical atherosclerosis in patients with diabetes and more research about coronary artery calcium in subpopulations of patients.

Background: The prevalence of diabetes is disproportionately distributed in Central Appalachia compared with other regions in the U.S. Previous research reveals that nearly 65% and 17% of patients with diabetes reported having history of cardiovascular heart disease (CHD) and coronary artery disease (CAD) respectively. This study examined the prevalence of factors associated with subclinical atherosclerosis (measured as coronary artery calcium) in patients with diabetes in geographic locations of rural Central Appalachia. Methods: The study population consisted of 2479 asymptomatic individuals from the rural Central Appalachian region of Kentucky, North Carolina, Tennessee, and Virginia between August 2012 and November 2016. Descriptive analysis was completed for the total sample size with sub analysis of individuals with diabetes. T-test was used for comparison of categorical (example: hypertension and physical inactivity) and continuous variables (example: age and BMI), respectively. In addition, multinomial logistic regression was conducted to assess the association between multiple risk factors including CAC scores, and geographic locations of patients with diabetes in rural Central Appalachia. Results: There was no significant difference between ages for diabetic and non-diabetic patients. Individual factors which are associated with diabetes include current CAC score (p<0.001, CI: 45.90 – 189.98), BMI (p<0.001, CI: 3.01 – 5.64), sedentary lifestyle (p<0.005, CI: 0.039 – 0.215), history of CAD (p<0.001, CI: 0.08 - 0.19), hypercholesterolemia (p<0.001, CI: 0.64 – 0.23), and hypertension (p<0.001, CI: 0.18 – 0.34). There was no significant correlation between geographic locations and diabetes. Among male and female genders, hypertension, hypercholesterolemia, history of CAD, sedentary lifestyle, current CAC score, and BMI have a significant positive correlation with diabetes except for self-reported obesity which only has a significant positive correlation with the female gender. Conclusion: Individual factors remain associated with diabetes across the male and female genders regardless of the geographic locations of the diabetic patients in rural Appalachia. There is strong evidence that cardiovascular related factors could be associated with diabetes across both genders in rural Central Appalachia. We suggest the implementation of evidence-based public health strategies to address the modifiable behaviors that can improve the health of people in rural Central Appalachia.

This study examined racial/ethnic differences in pre-clinical disease, social support, and tested whether social support was a moderator of racial/ethnic differences in subclinical atherosclerosis. Participants were NHWs, NHBs, and Latinos (n = 283) from the baseline and cross-sectional sample of the North Texas Heart Study. Results from unadjusted models showed no significant racial/ethnic differences for common or bifurcation intima-media thickness (cIMT). However, unadjusted models for cIMT showed a main effect for race/ethnicity F(2, 229) = 3.12, p = .046, partial η2 = .027, with Latinos demonstrating significantly greater internal cIMT compared to NHB but not NHWs. In minimally adjusted models, there was a main effect for race/ethnicity, F(2, 227) = 3.10, p = .047, partial η2 = .027, with significantly greater internal cIMT in Latinos compared to NHBs but not NHWs. In fully adjusted models, racial/ethnic differences in cIMT were attenuated. Contrary to study hypotheses, no racial/ethnic differences in social support were found and social support was not a moderator of racial/ethnic differences in subclinical disease. In the North Texas Heart Study, few racial/ethnic differences emerged, with fully adjusted risk factor models accounting for these differences.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.
Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Public Health, Department of Epidemiology." Discipline: Epidemiology; Department/School: Public Health.

Orientador: Maria Elena Guariento
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Fundamento: O hipotireoidismo subclínico é mais prevalente em mulheres idosas e existe uma correlação direta entre esta condição e as dislipidemias, com um conseqüente potencial aterosclerótico para a ocorrência de doenças cardiovasculares. Objetivo: Verificar em mulheres idosas com hipotireoidismo subclínico a ocorrência de variações em seus perfis lipídicos e o consequente risco cardiovascular. Métodos: Foram estudadas 121 mulheres com idade ? 65 anos, 76 delas com hipotireoidismo subclínico (grupo 1), comparadas a um grupo controle de 45 mulheres eutireoideas (grupo 2). Foi estudada a relação entre hipotireoidismo subclínico e valores de colesterol total, suas frações e triglicérides. Os índices de Castelli I e II foram utilizados para avaliar o risco cardiovascular. Foram excluídas outras condições que causem dislipidemia. Resultados: Pacientes com hipotireoidismo subclínico apresentaram valores mais elevados de colesterol total, suas frações (exceto HDL-c) e triglicérides; e os índices de Castelli I e II, quando comparadas ao grupo controle (p < 0,01). No grupo 1 foram identificados dois subgrupos de pacientes, o primeiro com menores valores na elevação TSH e nos Índices Castelli I e II; o segundo com maiores valores na elevação de TSH, e nos Índices de Castelli I e II. Conclusão: O estudo demonstrou uma forte correlação entre dislipidemia e hipotireoidismo subclínico e que quanto mais elevado o TSH, mais alterado o perfil lipídico, e mais elevados os índices de Castelli I e II, com conseqüente aumento do risco cardiovascular
Abstract: Background: Subclinical hypothyroidism is more prevalent in elderly women. There is a direct correlation between this condition and dyslipidemia, with consequent arteriosclerotic potential for the occurrence of cardiovascular diseases. Objective: The objective of this study was to verify in elderly women with subclinical hypothyroidism lipid profile variation, with consequent modification in cardiovascular risk. Methods: There were included 121 female patients with age ? 65 years old, 76 with subclinical hypothyroidism (group 1). They were compared with a 45 group control of euthyroid patients (group 2). Other conditions that lead to dyslipidemia were excluded. The relation between subclinical hypothyroidism and the levels of total cholesterol and its fractions, and triglycerides were studied. Also, indexes of Castelli I and II were used to evaluate cardiovascular risk. Results: Patients with subclinical hypothyroidism presented higher levels of all the fractions of cholesterol (except HDL-c), triglycerides and indexes of Castelli I and II, when compared to control group (p<0.01). In group 1, there were identified two subgroups of patients, being the first one with less elevated levels of TSH e lower levels of Castelli I and II, and the second one with higher levels of TSH and with a higher variation of the indexes of Castelli I and II. Conclusions: This study demonstrated a strong correlation between dyslipidemia and subclinical hypothyroidism in elderly women; in addition, it showed that the higher the TSH, the worse the lipid profile, and the higher indexes of Castelli I and II
Doutorado
Clinica Medica
Doutor em Clínica Médica

Background: Atherosclerosis is an important cause of stroke. Ultrasound offers the convenience of real-time and detailed assessment of carotid plaque features as well as arterial wall thickening and composition. Evaluation of these features is important for determining patients’ risk of suffering vascular events and also contributes to selecting the best treatment strategy. Methods: Using ultrasound data analysis we have determined plaque features in the bifurcation and internal carotid artery (ICA), including: surface plaque irregularities, calcification, echogenicity (grey scale median-GSM) and other textural plaque features (Juxtaluminal black area, entropy, coarseness). In addition, intima media thickens (IMT) and its grey scale median (IM-GSM) was measured in common carotid artery (CCA). Using Cone Beam CT (CBCT) we have quantified calcification volume of the carotid plaques extracted after carotid endarterectomy procedure. For the meta-analysis we have used comprehensive meta-analysis software version 3. Study I: We have included 39 patients and we compared carotid plaque features of the contralateral arteries with those located ipsilateral to symptomatic side and arteries of asymptomatic patients. Study II: The accuracy of US to detect atherosclerosis calcification was assessed against CBCT in 88 patients. Study III: Based on the previous vascular events in coronary, carotid and lower extremity arterial system, 87 patients were divided into three groups: asymptomatic, symptoms in one vascular system and symptoms in more that one vascular system. IMT, IM-GSM and plaque features were compared between groups. Study IV: We have meta-analyzed ten cohort prospective studies evaluating carotid plaque echogenicity for cerebrovascular symptoms prediction. Results: Study I. Plaques of the contralateral to symptomatic arteries had similar features to those in symptomatic and more vulnerable than asymptomatic arteries. Study II. Carotid ultrasound was accurate in detecting calcification volumes of ≥8mm3 with very high sensitivity but it was less accurate in detecting lower calcification volumes (<8mm3). Carotid calcification was not different between symptomatic and asymptomatic patients. Study III. Echogenicity of the intima-media complex (IM-GSM), but not its thickness (IMT), was significantly decreased with increasing number of arterial systems affected by atherosclerosis. IM-GSM was lower in patients with prior myocardial infarction and stroke. Study IV. Carotid plaque echogenicity evaluated by US could predict future cerebrovascular events in patients with asymptomatic, relative risk RR 2.72 (95% CI, 1.86 to 3.96), and recurrent symptoms in symptomatic patients, RR 2.97 (95% CI, 1.85-4.78). Conclusion: Plaques located in the contralateral to symptomatic arteries have similar features as symptomatic side and more vulnerable than asymptomatic arteries. Carotid ultrasound could accurately detect larger but not smaller carotid plaque calcification volumes (<8 mm3). Low IM- GSM could identify patients with multi-system atherosclerosis disease, suggesting a better marker for determining systemic atherosclerosis disease burden compared to conventional IMT. Finally, carotid plaque echogenicity predicts future cerebrovascular events in patients with symptomatic and asymptomatic carotid stenosis.

Thesis (Ph.D. in Epidemiology) -- University of Colorado Denver, 2007.
Typescript. Includes bibliographical references (leaves 100-117). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

INTRODUCTION: The risk factors for cardiovascular disease (CVD) are associated with coronary atherosclerosis and having multiple risk factors potentiates atherosclerosis. This study examined the prevalence of multiple biological and lifestyle/behavioral risk factors and their association with coronary artery calcium (CAC), a marker for subclinical coronary atherosclerosis. METHODS: This is a cross-sectional study of 1607 community-dwelling asymptomatic individuals from central Appalachia who participated in CAC screening between January 2011 and December 2012. Data on demographics (sex and age) and 7 traditional risk factors for coronary artery disease (CAD) were collected and categorized into 5 groups (0-1, 2, 3, 4, and ≥5). Prevalence of these risk factors and CAC scores (0, 1-99, 100-399, ≥400) were assessed, and the impact of the number of risk factors on CAC scores were delineated using multiple logistic regression. RESULTS: Over 98% of participants had ≥1 risk factor. While obesity, diabetes, hypertension, and family history of CAD significantly increased the odds of having CAC, CAC scores significantly increased with number of risk factors. After adjusting for demographic factors, having 3, 4, and ≥5 risk factors was significantly associated with increased odds of having higher CAC scores when compared to zero CAC score by more than one and half times [OR=1.65, CI (1.20-2.25)], two times [OR=2.32, CI (1.67-3.23)] and three times [OR=3.45, CI (2.42-4.92)], respectively. CONCLUSION: The high prevalence of multiple risk factors in the study population suggests the need for aggressive multiple risk factors interventions for primary prevention of CAD, which could address CVD health disparities.

Orientadores: Andrei Carvalho Sposito, Eliana Cotta de Faria
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Doenças cardiovasculares constituem a principal causa de mortalidade no Brasil e no mundo. Baixas concentrações de HDL - colesterol são consideradas um fator de risco cardiovascular independente. Esta relação inversa tem sido atribuída às diferentes propriedades protetoras da HDL, dentre as quais podemos destacar seu papel no transporte reverso de colesterol, por meio do efluxo de colesterol, sua habilidade de inibir a agregação plaquetária, e suas atividades antioxidantes e anti-inflamatórias. No entanto, estudos recentes indicam que baixas concentrações de HDL - colesterol constituem um preditor significante de doença aterosclerótica somente em indivíduos assintomáticos e que a capacidade de efluxo de colesterol é um melhor preditor de carga aterosclerótica do que HDL - colesterol. Em conjunto, estes achados sugerem que a função da HDL poderia ser um fator chave na relação entre concentrações de HDL - colesterol e o desenvolvimento de doença aterosclerótica. Se o for, alterações das funções da HDL podem discernir melhor, entre os indivíduos com hipoalfalipoproteinemia, aqueles com maior propensão a desenvolver doença aterosclerótica. Assim, investigamos, em indivíduos sem doença cardiovascular previamente manifesta, se funções da HDL estão associadas a concentrações de HDL - colesterol e carga aterosclerótica. Participantes foram classificados em HDL - colesterol baixo (LH; HDL-C? 32 mg/dL; n=33), intermediário (IH; HDL-C= 40-67 mg/dL; n=33), ou alto (HH; HDL-C?78mg/dL; n=35). Nós avaliamos composição química da HDL, tamanho da partícula, capacidade de efluxo de colesterol, atividade antioxidante, susceptibilidade à oxidação, atividade anti-inflamatória, e habilidade de inibir agregação plaquetária. O grupo LH foi associado à espessura intimo-medial de carótidas (IMT) aumentada (p?0,001), maior conteúdo de triglicérides (4±2% vs. 4±2% em IH e 3±1% em HH, p?0,001), menor conteúdo de fosfolípides (12±4% vs. 14±5% em IH e 13±3% em HH, p=0,035), menor tamanho de partículas (7,33±0,33nm vs. 7,72±0,45nm em IH e 8,49±0,42nm em HH, p?0,001) e menor capacidade de efluxo de colesterol celular (9±3 % vs. 12±3 % em IH e 11±4 % em HH, p?0,001). Indivíduos HH apresentaram menor atividade antioxidante (37(53)% vs. 48(35)% em IH e 55(41)% em LH, p=0,003), maior suscetibilidade à oxidação (57±22% vs. 45±20% em IH e 46±25% em LH, p=0,017) e maior habilidade de inibir agregação plaquetária (45±25% vs. 31±18% em IH e 37±24 % em LH, p=0,0026). Indivíduos com IMT acima de 1 mm apresentaram partículas com menor tamanho (7,55±0,49 nm vs. 7,89±0,64 nm, p?0,001), atividade antioxidante (37(23)% vs. 49(42)%, p=0,018) e capacidade de efluxo de colesterol (31±14% vs. 40±14%, p=0,02). Nenhuma diferença foi encontrada para as outras características ou propriedades funcionais da HDL. Nós concluímos que, em um contexto de prevenção primária, o menor tamanho da partícula, o conteúdo reduzido de fosfolípides, e capacidade de efluxo de colesterol diminuída são relacionados com ambos LH e magnitude da doença aterosclerótica subclínica. Nestes indivíduos, estas características podem explicar a associação entre HDL - colesterol e o desenvolvimento da doença aterosclerótica.
Abstract: Cardiovascular diseases are the main cause of death in Brazil and worldwide. Low HDL-C levels are considered an independent cardiovascular risk factor. This inverse relationship has been attributed to different protective properties described for HDL, such as its role in the reverse cholesterol transport, through cholesterol efflux, its ability to inhibit platelet aggregation, and its antioxidant and anti-inflammatory effects. However, recent studies indicate that low HDL-cholesterol is a significant predictor of atherosclerotic disease in healthy individuals and that cholesterol efflux capacity is a better predictor of carotid atherosclerotic burden as compared to HDL-cholesterol. Altogether these findings have suggested that HDL function would be the key factor for the link between HDL-cholesterol concentration and the subclinical disease in a primary prevention setting. If so, changes in HDL function could help to discriminate, among individuals with hypoalphalipoproteinemia, those who are prone to develop atherosclerotic disease. Hence, in a primary prevention setting, we investigated whether HDL dysfunction is associated with HDL-cholesterol concentration and atherosclerotic burden. Participants were classified as low (LH; HDL-C? 32 mg/dL; n=33), intermediate (IH; HDL-C= 40-67 mg/dL; n=33), or high HDL-cholesterol (HH; HDL-C?78mg/dL; n=35). We measured HDL chemical composition, particle size, cholesterol efflux capacity, antioxidant activity, susceptibility to oxidation, anti-inflammatory activity, and ability to inhibit platelet aggregation. LH was associated to enhanced carotid intima-media thickness (IMT;p?0.001), high HDL triglyceride (4±2% vs. 4±2% in IH and 3±1% in HH, p?0.001), low HDL-phospholipids (12±4% vs. 14±5% in IH and 13±3% in HH, p=0.035), decreased particle size (7.33±0.33nm vs. 7.72±0.45nm in IH and 8.49±0.42nm in HH, p?0.001) and reduced cholesterol efflux capacity (9±3 % vs. 12±3 % in IH and 11±4 % in HH, p?0.001). The HH group presented reduced antioxidant activity (37(53)% vs. 48(35)% in IH and 55(41)% in LH, p=0.003), and increased susceptibility to oxidation (57±22% vs. 45±20% in IH and 46±25% in LH, p=0.017) and ability to inhibit platelet aggregation (45±25% vs. 31±18% in IH and 37±24 % in LH, p=0.0026). Carotid IMT>1mm was associated with reduced HDL size (7.55±0.49 nm vs. 7.89±0.64 nm, p?0.001), antioxidant activity (37(23)% vs. 49(42)%, p=0.018), and cholesterol efflux capacity (31±14% vs. 40±14%, p=0.02). No differences were found for the other HDL characteristics or functional properties. We conclude that in a primary prevention setting, small particle size, reduced HDL-phospholipids content, and diminished cholesterol efflux capacity are related to both LH and carotid IMT. In these individuals, these characteristics may underlie the association between HDL-cholesterol and atherosclerotic burden
Doutorado
Ciencias Biomedicas
Doutora em Ciências Médicas

Motivation: Ischemic heart disease is the eighth leading cause of death in an African population. Silent ischemia can be defined as an ischemic episode without associated pain. The clinical significance of silent ischemia is growing and can now be considered as a risk factor in the development of coronary disease. Hypertension and associated risk factors, hypercholesterolemia and diabetes are associated with silent ischemia. Other factors such as higher pulse pressure, double product, heart rate and higher carotid intima-media thickness are also associated with silent ischemia. Urbanisation is rising in South-Africa. This new lifestyle is associated with several risk factors including: poor diets, lower physical activity levels, hypertension and increased smoking and alcohol abuse. The prevalence of stroke is high among Africans, which can be due to a higher prevalence of hypertension, diabetes and obesity. Purpose: The purpose of this study was to determine the associations between silent ischemia and cardiovascular function in African men. The focus fell on hypertension and associated risk factors, higher total cholesterol levels, and increased pulse pressure, heart rate and sub-clinical atherosclerosis. vi Methodology: This study constituted a population study in the North-West province carried out on urbanized African male teachers aged between 20-60 years. The SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) sub-study consisted of a total of 80 African male volunteers. The Cardiotens apparatus was placed on each participant on the first morning. This apparatus took ambulatory blood pressure measurements as well as Electrocardiogram measurements. Hereafter, participants continued with their normal work day until 1700. After an overnight stay at the Metabolic unit of the North-West University Potchefstroom campus, the apparatus was removed at 0600. During statistical analyses, the African males were divided into groups of participants with silent ischemia (SI) and those without silent ischemia (nSI), as determined by the ambulatory electrocardiogram. Statistical analyses were performed by means of the Statistica version 10 software program. Results: In comparison with the nSI men, the SI showed the following: above normal high sensitivity C-reactive protein and glucose, higher ambulatory blood pressure, heart rate, pulse pressure, resting ST-segment depression and carotid intima-media thickness. Multiple regression analyses indicated that ambulatory silent ischemia is associated with sub-clinical atherosclerosis, possibly increasing their stroke risk.
Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2012.

Dissertação (mestrado) - Pontifícia Universidade Católica do Paraná, Curitiba, 2008
Inclui bibliografia
Aterosclerose acelerada está presente em algumas doenças auto-imunes, principalmente em lúpus eritematoso sistêmico e artrite reumatóide. Apesar do uso de corticosteróides ser um fator de confusão por seus efeitos negativos em diversos fatores de risco ca
Accelerated atherosclerosis has been described in some autoimmune iseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. Although the high prevalence of corticosteroids use may be a confounding factor due to their detrimental effects on

As doenças cardiovasculares e o diabete melito fazem parte das DCNT prioritárias da OMS, devido às altas taxas de morbimortalidade e incapacidade que geram a cada ano. Estima-se que no mundo existam 387 milhões de diabéticos e outros 316 milhões de pessoas com características de risco, como pré-diabete. Cerca de 60% dos pacientes com DM2 desenvolvem doença cardiovascular, a qual inicia de forma concomitante aos distúrbios do metabolismo da glicose, podendo existir mecanismos fisiopatológicos comuns entre as doenças. Metade dos eventos coronarianos, inclusive a morte súbita, ocorrem em indivíduos assintomáticos, evidenciando a necessidade de novos marcadores precoces, já que em muitos deles a morte é a primeira manifestação. Recentemente, tem sido sugerido que os miRNAs envolvidos na regulação da expressão gênica podem ser caracterizados como biomarcadores em diversas doenças. Nosso objetivo é identificar alterações no perfil de miRNAs circulantes em indivíduos euglicêmicos e pré-diabéticos com e sem aterosclerose subclínica, utilizando a tecnologia de qPCR Arrays, com a finalidade de identificar candidatos a biomarcadores moleculares dessa condição. Encontrou-se que a aterosclerose subclínica esteve associada com o envelhecimento, a menopausa, etnia branca, dislipidemia, resistência à insulina, o aumento da adiposidade, leptina e do TNF-α. O aumento do miR98-5p e a diminuição dos miRNAs miR-212-3p, miR-145-5p, miR-93-5p, miR15a-5p, miR-19a-3p, miR32-5p levaram a ativação da via de sinalização da aterosclerose. Os resultados sugerem que a inflamação foi o principal mecanismo associado com o desenvolvimento de aterosclerose subclínica neste estudo.
Cardiovascular Disease and Diabetes Mellitus are relevant NCDs for the WHO. It´s estimated that, worldwide, there are 387 millions of diabetics and 316 millions of people with risk characteristics like prediabetes. About 60% of patients with T2DM develops cardiovascular disease, which starts at the same time as disorders of glucose metabolism, there may be common pathophysiological mechanisms among diseases. Half of coronary events, including sudden death, occurs in asymptomatic individuals. This fact, highlights the need for new early markers of the disease, especially in asymptomatic patients, since in many of them, death is the first manifestation. It has been recently suggested that miRNAs involved in pos-transcriptional regulation of gene expression, could be characterized as biomarkers of diseases. Our goal is to identify changes in the profile of circulating microRNAs in euglycemic and prediabetic patients with or without subclinical atherosclerosis, by quantitative Polymerase Chain Reaction array (qPCR Array) in order to find molecular biomarkers of this condition. We found that subclinical atherosclerosis was associated with aging, menopause, white ethnicity, dyslipidemia, insulin resistance, increased adiposity, leptin and TNF-α. The up-regulation of miR98-5p and the down-regulation miR-212-3p, miR-145-5p, miR-93-5p, miR15a-5p, miR-19a-3p, miR32-5p led to activation of the signaling pathway of atherosclerosis. The results suggest that inflammation was the main mechanism associated with the development of subclinical atherosclerosis in this study.

Introducción: La enfermedad cardiovascular se presenta de forma muy precoz en los pacientes con enfermedad renal crónica (ERC) y trasplantados renales, siendo la principal causa de mortalidad en estas poblaciones. Los factores de riesgo clásicos de enfermedad cardiovascular como la hipertensión y la diabetes son muy prevalentes en la enfermedad renal crónica pero esto no explica el enorme incremento del riesgo cardiovascular. Los factores de riesgo no clásicos como la disfunción endotelial, inflamación subclínica, las alteraciones de la Mannose binding lectin (MBL) que es un componente de la inmunidad innata, son un hecho importante en la ERC y trasplante. La presencia y progresión de aterosclerosis subclínica evaluada mediante ecografía carotidea, permite la mejor estratificación del riesgo cardiovascular. Dicho esto, el objetivo de esta tesis es evaluar si el trasplante modifica de forma independiente del grado de insuficiencia renal la presencia y progresión aterosclerosis subclínica. Material y métodos: En dos cohortes de pacientes con enfermedad renal crónica y trasplantados renales con filtrado glomerular estimado (FG-e) <60 ml/min/1.73 m2 no en diálisis, se determinaron en la visita basal, niveles de ADMA, VEGF, ICAM-1, IL-6, TNFR2, MCP-1 y MBL, se cuantificaron el número de células progenitoras endoteliales y células circulantes endoteliales. Se realizó monitorización ambulatoria de presión arterial de 24 horas (MAPA), índice tobillo brazo, velocidad de onda de pulso (VOP) y ecografía carotidea con la cuantificación del grosor de intima media y número de placas carotideas. Se realizó seguimiento de los pacientes a los 18 meses con realización de VOP y ecografía carotidea y a los 36 meses, se realizaron MAPA 24 horas, ITB, VOP y ecografía carotidea, y se registraron los eventos renales y cardiovasculares. Resultados: la presión arterial en la consulta fue similar en ambos grupos. La presión arterial por MAPA de 24h (133.9±14.3 vs. 126.2±16.1, P=0.014), PAS diurna (135.6±15.2 vs. 128.7±16.2, P=0.042), y PAS nocturna (131.2±16.2 vs. 120.2±17.9, P=0.0014) fue más elevada en los trasplantados renales. Además, presentaban una mayor proporción de pacientes con hipertensión arterial nocturna y non dipper (68.5% vs. 47.4%,P=0.03). Para estudiar la contribución del trasplante a esta diferencia, se incluyó en el modelo multivariado el hecho de ser trasplantado como una variable independiente, resultando que para la PAS 24h, diurna y nocturna, el trasplante era un predictor independiente para un incremento de PAS. Se observó que los trasplantados renales presentaban unos niveles de IL-6 más elevados así como una mayor proporción de pacientes con placas carotideas (55.4% vs 30%, P=.016) con respecto a los pacientes con ERC. Las variables que se asociaban a la PAS 24 horas fueron la proteinuria y los monocitos circulantes (P=.001), mientras que IL-6, creatinina sérica y el número total de placas se asociaban de forma independiente a la ausencia de caída de la presión arterial nocturna (P=.0001). Conclusiones: La MAPA de 24 horas está más elevada en los trasplantados, a expensas de la hipertensión nocturna y presentan una mayor proporción de pacientes con hipertensión arterial nocturna y patrón "non dipper", lo que sugiere un peor perfil de riesgo cardiovascular. Existe un mayor grado de inflamación subclínica en el paciente trasplantado renal evaluado mediante el número de monocitos circulantes y los niveles de IL-6. Los pacientes trasplantados tienen más aterosclerosis subclínica que los pacientes con ERC a igualdad de función renal y proteinuria. La ausencia de caída de presión arterial o patrón "non dipper" en el trasplante se asocia a la inflamación sistémica medida mediante la IL-6 y a la carga aterosclerótica.
Introduction: Cardiovascular disease is prevalent in patients with chronic kidney disease (CKD) and kidney transplants and constitutes a main cause of death in these patients. The classical cardiovascular risk factors (i.e. hypertension and diabetes) are very prevalent but they do not explain the increase of cardiovascular risk and mortality. Moreover, non-traditional cardiovascular risk factors such as endothelial dysfunction, subclinical inflammation, mannose binding lectin alterations, are important in CKD and kidney transplants recipients. The presence and progression of subclinical atherosclerosis evaluated by carotid ultrasound, allows a better stratification of cardiovascular risk in general populations and populations at risk. Thus, the aim of this doctoral thesis is evaluate if kidney transplants modify the presence and progression of subclinical atherosclerosis independently of renal function. Material and methods: Two cohorts of patients with CKD and kidney transplants recipients with glomerular filtration rate (GFR-e) < 60 ml/min/1.73 m2 not on dialysis were included. In basal visit levels of ADMA, VEGF, ICAM-1, IL-6, TNFR2, MCP-1 and MBL were determined, number of endothelial progenitor cells and circulating endothelial cells were quantified. Ambulatory blood pressure monitoring (ABPM), ankle-brachial index, pulse wave velocity (PWV) and carotid ultrasound were performed at basal visit and 36 months of follow-up. At 18 months of follow up, a PWV and carotid ultrasound were recorded. In each visit, cardiovascular and renal events were registered. Results: Office BP was not different between transplants and CKD patients (139.5±14.3 vs. 135.2±19.3, P=1.00, respectively). ABPM 24-hr systolic blood pressure (SBP) (133.9±14.3 vs. 126.2±16.1, P=0.014), awake SBP (135.6±15.2 vs. 128.7±16.2, P=0.042), and sleep SBP (131.2±16.2 vs. 120.2±17.9, P=0.0014) were higher in renal transplants. When patients were classified according to BP patterns associated with highest cardiovascular risk, the proportion of patients with both nocturnal hypertension and non-dipper pattern was higher in transplants (68.5% vs. 47.4%,P=0.03). In the multivariate regression analysis, transplantation was an independent predictor of 24-hr, awake, and sleep SBP. Log IL-6 (P=.011), and total number of carotid plaques (P=.013) were higher, while the percentage decline of SBP from day to night was lower in kidney transplant recipients (P=.003). Independent predictors of 24-hour SBP were urinary protein/creatinine ratio and circulating monocytes (P=.001), while Log IL-6, serum creatinine, and total number of carotid plaques (P=.0001) were independent predictors of percentage decline of SBP from day to night. Conclusions: Office BP is similar in kidney transplants and CKD patients with similar renal function. On the contrary, hypertension is more severe in kidney transplants when evaluated with ABPM mainly as a result of increased sleep systolic BP. Thus, precise evaluation of hypertension in kidney transplants requires ABPM. Kidney transplants presents a higher levels of IL-6 and more subclinical atherosclerosis, and subclinical atherosclerosis and systemic inflammation are associated with hypertension after transplantation.

A aterosclerose e suas complicações são a principal causa de morbidade e mortalidade no mundo ocidental. O aumento da espessura da camada médio-intimal da carótida está associado com risco para doenças cardiovasculares, pois representa um marcador de aterosclerose subclínica, podendo ser detectada precocemente em indivíduos assintomáticos. O objetivo desse estudo foi identificar variáveis clínicas e nutricionais associadas com a aterosclerose subclínica em mulheres hipertensas. Estudo transversal envolvendo uma amostra de conveniência composta por 116 mulheres hipertensas entre 40 e 65 anos. Dados clínicos, como pressão arterial (PA) sistólica e diastólica, história de tabagismo, atividade física, uso de medicamentos foram coletados; foi feita a análise do perfil lipídico, glicemia e proteína C reativa (PCR); a avaliação dietética obtida pelo Recordatório de 24 horas e pelo Registro de três dias. A espessura médio-intimal (EMI) de carótidas foi realizada pelo aparelho de ultrassonografia. As pacientes foram divididas em dois grupos, de acordo com os valores da espessura médio-intimal de carótidas: EMI 0,9mm ou EMI > 0,9mm. Houve diferença significativa entre os grupos em relação à idade (50,846,62 vs 53,547,13; p=0,044), PA sistólica (134,5216,54 vs 142,9821,47; p=0,020), pressão de pulso (PP) (49,3611,03 vs 60,15 17,77; p<0,001), HDL (48,988,54 vs 44,057,45; p=0,004) e PCR (2,311,21 vs 3,051,34; p=0,016). Não houve diferença significativa em relação aos parâmetros antropométricos, exceto em relação à reactância (65,199,69 vs 61,447,88; p=0,036), avaliada pela bioimpedância elétrica (BIA). Quanto ao padrão de consumo alimentar, somente o consumo de gordura monoinsaturada foi diferente entre os grupos, sendo o maior consumo no grupo com menor valor de EMI (7,882,09 vs 7,022,06; p=0,031). Não houve diferença em relação à frequência de tabagismo e atividade física. Quando foi feita a análise de correlação da amostra, foi encontrada uma correlação entre a EMI de carótidas e idade (r=0,25; p=0,0067), PAS (r=0,19; p=0,0086); PP (r=0,30; p=0,0009), LDL (r=0,19; p=0,0434), assim como com gordura monoinsaturada (r= -0,25; p=0,0087), PCR (r=0,31; p=0,007) e HDL (r=-0,33; p=0,0004), porém apenas as variáveis HDL, PCRus e pressão de pulso mostraram ser preditoras independentes da EMI de carótida após feita uma análise de regressão linear multivariada. A proteína C reativa, HDL colesterol e pressão de pulso são importantes preditores independentes de aterosclerose subclínica.
Atherosclerosis and its complications are the main cause of morbidity and mortality in the Western world. Increased carotid intima-media thickness is associated with cardiovascular risk,and it represents a marker of subclinical atherosclerosis, which can be detected early in asymptomatic individuals. The aim of this study was to identify clinical and nutritional variables associated with subclinical atherosclerosis in hypertensive women. Cross-sectional study involving a convenience sample composed by 116 hypertensive women aged between 40 and 65. Clinical data such systolic and diastolic blood pressure (BP), smoking history, physical activity, medication use were collected, a lipid profile, blood glucose and C-reactive protein (CRP)analysis was performed, the dietary assessment was obtained by dietary recall 24 hours and three days food record. Carotid intima-media thickness was performed by the high resolution ultrasound. Patients were divided into two groups according to the values of carotid IMT: IMT 0.9 mm or IMT > 0.9 mm. There was significant difference between the groups regarding age (50.846.62 vs 53.547.13; p=0.044), systolic BP(134.5216.54 vs 142.9821.47; p=0.020), pulse pressure (PP) (49.3611.03 vs 60.15 17.77; p<0.001), HDL-cholesterol (49.3611.03 vs 60.1517.77; p<0.001)and CRP(2.311.21 vs 3.051.34; p=0.016). There was no significant difference regarding to anthropometric parameters, except for the reactance (65.199.69 vs 61.447.88; p=0.036), measured by bioelectrical impedance analysis (BIA). Regarding the dietary pattern, only the monounsaturated fat intake was different between the groups 65.199.69 vs 61.447.88; p=0.036),. There was no difference in smoking and physical activity. In the correlation analysis, we have found a correlation between carotid IMT and age (r = 0.25, p = 0.0067), SBP (r= 0.19, p = 0.0086); PP (r = 0.30, p = 0.0009), LDL (r = 0.19, p = 0.0434), and monounsaturated fat (r = -0.25, p = 0.0087), CRP (r = 0.31, p = 0.007) and HDL (r =- 0.33, p = 0.0004), but only HDL-cholesterol, hsCRP and pulse pressure were shown to be independent predictors of carotid IMT after made a multivariate analysis. Conclude that C reactive protein, HDL-cholesterol and pulse pressure are important predictors for subclinical atherosclerosis.

La incidencia de la enfermedad cardiovascular (ECV) se ha incrementado en los pacientes infectados por el VIH. La replicación del VIH y la terapia antirretroviral pueden contribuir de forma independiente al aumento del riesgo de ECV. Sin embargo, la causa de este aumento del riesgo es multifactorial. Métodos: Esta tesis se centra en el estudio de los trastornos metabólicos y cardiovasculares en una cohorte de pacientes infectados por el VIH. Para ello, se llevaron a cabo tres estudios: Un primer estudio, diseñado con el propósito de determinar si un análisis combinado de variantes genéticas en algunos de los genes responsables de las anomalías lipídicas ayudarían a discriminar los pacientes infectados por el VIH con niveles altos de triglicéridos y bajos niveles de HDL-colesterol (pacientes con perfil aterogénico), considerado un marcador claro de riesgo cardiovascular. Para ello, se realizó la caracterización genética y metabólica de 321 pacientes infectados por el VIH en tratamiento antirretroviral, a través de la determinación del perfil lipídico, la determinación de partículas remanentes de colesterol y la determinación de los genes implicados en la formación y en la eliminación de partículas remanentes de la circulación. Se identificaron varios genes responsables de la modulación de los parámetros lipídicos en esta población. Sin embargo, el diseño transversal del estudio y el pequeño tamaño de la muestra no permitió conclusiones definitivas acerca de la asociación entre polimorfismos en los genes asociados con el metabolismo de los lípidos y los trastornos de lípidos en pacientes infectados por el VIH. El segundo estudio, se centró en la detección precoz de la aterosclerosis subclínica. Para ello, se evaluó la elasticidad arterial a través de la determinación de la velocidad de la onda de pulso (VOP) en pacientes infectados por el VIH, en comparación con sujetos no infectados. Se identificaron factores de riesgo asociados con la alteración de la elasticidad arterial. Pacientes infectados por el VIH con supresión virológica mostraron elasticidad arterial similar a sujetos no infectados. Condiciones relacionadas con el VIH no se asociaron con la rigidez arterial. Sin embargo, la presión arterial diastólica y triglicéridos altos en el momento de la VOP fueron factores de riesgo asociados. Por último, se realizó un tercer estudio descriptivo, observacional, retrospectivo para determinar la prevalencia de la enfermedad coronaria en una cohorte Mediterránea de pacientes infectados por el VIH, identificándose los factores de riesgo modificables más importantes y el manejo de los mismos en la práctica clínica. Se observó una baja prevalencia de eventos coronarios en esta población, los factores de riesgo cardiovascular fueron mal controlados, un bajo porcentaje de pacientes alcanzaron niveles óptimos en los parámetros lipídicos y se observó un mal control de los factores de riesgo no lipídicos después del evento coronario. El diseño retrospectivo de este estudio no permitió determinar la tasa real de algunos factores de riesgo y por lo tanto evaluar los cambios de los factores de riesgo en el tiempo. Conclusión: Algunas variantes genéticas son predoctoras de cambios en los parámetros lipídicos, la información genética podría ayudar a los médicos a individualizar el tratamiento del paciente para reducir el riesgo cardiovascular. Tenemos que ser más proactivos en el diagnóstico, el manejo y el seguimiento de estos factores de riesgo en la población infectada por el VIH y los planes de salud cardiovasculares deben ser una prioridad para garantizar el control adecuado del riesgo cardiovascular en esta población.
The incidence of cardiovascular disease (CVD) has increased among HIV-infected patients. Both HIV replication and antiretroviral therapy may contribute independently to increase the risk of CVD. However, the cause of this increased risk is multifactorial. Methods: This thesis focuses on the study of metabolic and cardiovascular disorders in a cohort of HIV-infected patients. Three studies were conducted: A first study was designed with the purpose of ascertaining whether a combined analysis of several genetic variants in some of the genes responsible of lipid abnormalities helped discriminate HIV-infected patients with high triglycerides and low levels of HDL-cholesterol (patients with atherogenic profile), clear marker of cardiovascular risk. It was carried out metabolic and genetic characterization of 321 HIV-infected patients receiving antiretroviral therapy, through the determination of the lipid profile, determination of remnant cholesterol particles and determination of genes involved in the formation, as in removing remaining particles from circulation. Several genes responsible for modulation of lipid parameters in this population were identified. However, the cross-sectional design of the study and the small sample size does not allow definitive conclusions about the association between polymorphisms in genes associated with lipid metabolism and lipid disorders in HIV-infected patients. The second study focused on the early detection of subclinical atherosclerosis. For this, arterial elasticity was evaluated through the determination of the pulse wave velocity (PWV) in HIV-infected patients, compared to non-infected subjects. Risk factors associated with impaired arterial compliance were identified. HIV-infected patients with virologic suppression showed similar arterial elasticity than non-infected subjects. HIV-related conditions were not associated with arterial stiffness. However, high diastolic pressure at the time of the PWV and high triglycerides were risk factors. Finally, we conducted a descriptive, observational, retrospective study (third study) to determine the prevalence of coronary disease in a Mediterranean cohort of HIV-infected patients, also identified the most important modifiable risk factors and the management of these in the clinical practice. We observed a low prevalence of coronary events in this population, the cardiovascular risk factors were poorly controlled, low percentage of patients reached optimal levels in lipid parameters after coronary event and poor control of non-lipid risk factors was performed. The retrospective design of this study did not allow to determinate the actual rate of some risk factors and therefore assess changes over time. However, it gives us a clear picture of actual clinical practice and has given us to know the weaknesses in this context. Conclusions: Some genetic variants are predictive of changes in lipid parameters; genetic information could help physicians individualize patient management to reduce cardiovascular risk. We must be more proactive in the diagnosis, management and monitoring of these risk factors in the population infected by HIV and cardiovascular health plans are a priority to implement and control of cardiovascular risk factors in these subjects.

La disfunció endotelial, el gruix íntima-mitja (GIM) i la rigidesa arterial es consideren avui dia marcadors d’arteriosclerosis precoç. La obesitat i l’excés de pes s’han associat a disfunció endotelial, major gruix íntima-mitja i pitjor rigidesa arterial, però no existeixen dades concretes sobre l’efecte de la obesitat mòrbida en aquests paràmetres. Els nostres objectius van ser estudiar marcadors d’arteriosclerosis subclínica com el GIMc, la funció endotelial i la rigidesa arterial en una població de pacients amb sobrepès, obesitat i obesitat mòrbida i avaluar els determinants d’aquests en la població estudiada. També vam valorar l’efecte que una dieta Very Low Calorie Diet tenia sobre la funció endotelial. Els resultats dels estudis permeten concloure que els individus amb sobrepès, obesitat i obesitat mòrbida, presenten una alta prevalença de GIM augmentat; tot i que la obesitat mòrbida no s’associa a un major grau d’arteriosclerosis subclínica. Si bé els paràmetres lipídics i la pressió arterial són els principals determinants de l’alteració vascular en els pacients amb sobrepès/obesitat; la disglicèmia i, molt probablement, els mediadors inflamatoris juguen un paper més important en els obesos mòrbids. La pèrdua de pes corporal aconseguida després d’una Very Low Calorie Diet millora la funció endotelial en pacients amb obesitat severa.
La disfunción endotelial, el grosor íntima-media (GIM) y la rigidez arterial se consideran hoy día marcadores de arteriosclerosis precoz. La obesidad y el exceso de peso se han asociado a disfunción endotelial, mayor grosor íntima media y peor rigidez arterial, pero no existen datos concretos sobre el efecto de la obesidad mórbida en estos parámetros. Nuestros objetivos fueron estudiar marcadores de arteriosclerosis subclínica como el GIMc, la función endotelial y la rigidez arterial en una población de pacientes con sobrepeso, obesidad y obesidad mórbida y evaluar los determinantes de éstos en la población estudiada. También valoramos el efecto que una dieta Very Low Calorie Diet tenía sobre la función endotelial. Los resultados de los estudios permiten concluir que los individuos con sobrepeso, obesidad y obesidad mórbida, presentan una alta prevalencia de GIM aumentado; aunque la obesidad mórbida no se asocia con un mayor grado de ateriosclerosis subclínica. Si bien los parámetros lipídicos y la presión arterial son los principales determinantes de la alteración vascular en los pacientes con sobrepeso/obesidad; la disglicemia y, muy probablemente, los mediadores inflamatorios juegan un papel más importante en los obesos mórbidos. La pérdida de peso corporal conseguida tras Very Low Calorie Diet mejora la función endotelial en pacientes con obesidad severa.
Endothelial dysfunction, intima-media thickness (IMT) and arterial wall stiffness are considered markers of early atherosclerosis today. Obesity and overweight have been associated with endothelial dysfunction, increased intima-media thickness and worse arterial wall stiffness, but there are no specific data on the effect of morbid obesity on these parameters. Our objectives were to study markers of subclinical atherosclerosis as GIMc, endothelial function and arterial wall stiffness in a population of patients with overweight, obesity and morbid obesity and to assess the determinants of those parameters in the study population. We also assessed the effect of a Very Low Calorie Diet on endothelial function. Study results allow us to conclude that individuals with overweight, obesity and morbid obesity have a high prevalence of increased GIM; although morbid obesity is not associated with a greater degree of subclinical atherosclerosis. While lipid parameters and blood pressure are major determinants of vascular impairment in patients with overweight / obesity; the dysglycemia and probably inflammatory mediators play an important role in morbidly obese. The weight loss achieved after a Very Low Calorie Diet improves endothelial function in patients with severe obesity.

碩士
國立陽明大學
臨床醫學研究所
99
Abstract Objective: To determine the risk factors associated with subclinical coronary atherosclerosis (CA) assessed by coronary computed tomographic angiography (CTA) in subjects with or without metabolic syndrome (MetS). Research Design and Methods: Case-controlled, cross-sectional study in single medical center. From July 2004 to December 2008, 550 consecutive subjects without clinical evidences of coronary artery disease received contrast-enhanced coronary CTA. Recognition of MetSyn was based on the ethnicity-modified National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP-III) criteria. Any presence of coronary artery calcification (CAC) or, absence of CAC with noncalcified plaques among the proximal third major coronary artery segment(s) was defined as subclinical CA. Results: In total 550 subjects, 290 (38%) subjects were defined with MetS. MetS as a whole was independently associated with subclinical CA in multivariate analysis (OR=3.40, 95% CI=2.34 to 4.96, P&lt;0.001). Multivariate regression analysis revealed that fasting blood glucose?d110mg/dL or the diagnosis of diabetes mellitus was the independent indicator of subclinical CA in non-MetS subjects (OR=1.40, 95% CI=1.08 to 1.82, P&lt;0.05) while total cholesterol (TC) / high density lipoprotein-cholesterol (HDL-C) ?d4.2% was the independent indicator of subclinical CA in MetS subjects (OR=4.44, 95% CI=1.93 to 10.20, P&lt;0.001). Conclusions: Risk factors of subclinical CA in coronary CTA are different between subjects with and without MetS. Fasting blood glucose?d110mg/dL / diagnosis of diabetes mellitus and TC/HDL-C?d4.2% are independent indicators for subclinical CA defined by coronary CTA study in non-MetS and MetS subjects respectively. Key words: Metabolic syndrome, Cholesterol ratio, and Coronary atherosclerosis

The foundations for cardiovascular disease (CVD) in adults are laid in childhood and accelerated by the presence of comorbid conditions. Early detection of manifestations of cardiovascular pathology is an important clinical objective to identify those at risk for subsequent cardiovascular morbidity and events, and to initiate behavioral and medical interventions to reduce risk. Children were once considered to be at low risk, but with the growing health concerns related to lifestyle, cardiovascular screening may be needed earlier. Several noninvasive procedures are available to assess the cumulative effect of these exposures. These include carotid ultrasound, flow-mediated dilation, pulse wave velocity and measures left ventricular mass. This dissertation analyzes the comorbid conditions that increase cardiovascular risk in youth, namely obesity and low physical fitness, using carotid intima-media thickness to objectively detect early manifestations of cardiovascular pathology. Until recently researchers have not used surrogate markers of subclinical atherosclerosis to examine the role of a single bout of exercise. Utilizing the acute exercise model can be advantageous as it allows for an efficient manipulation of exercise variables and permits greater experimental control of confounding variables. It is possible that the effects of a bout of exercise can predict the effects of chronic exercise. We analyze the physiological factors pertinent to arterial stiffness using arterial distensibility and pulse wave velocity in the context of acute exercise in children and adults. In some instances, those who amend their trajectory by not maintaining risk factors into adulthood experience reductions in subclinical markers to levels associated with never having had the risk factor. Though avoidance of risk factors in youth is ideal, there is still a window for intervention where long-lasting cardiovascular effects might be avoided. In this dissertation we present preliminary findings linking modifiable youth risk factors to subclinical markers of CVD in adulthood.
As bases da doença cardiovascular (DCV) em adultos são estabelecidas na infância e aceleradas pela presença de comorbidades. A deteção precoce de manifestações da patologia cardiovascular é um objetivo clínico importante na identificação daqueles com risco de subsequente morbidade e eventos cardiovasculares, e no estabelecimento de intervenções comportamentais e médicas para reduzir o risco. As crianças já foram considerados de baixo risco, mas com as crescentes preocupações de saúde associadas ao estilo de vida, o rastreio cardiovascular é cada vez mais precoce. Vários procedimentos não invasivos estão disponíveis para avaliar o efeito cumulativo dessas exposições. Estes incluem ultrassom da artéria carótida, a dilatação fluxo-mediada, velocidade de onda de pulso e medidas da massa ventricular esquerda. Esta dissertação analisa comorbidades conhecidas que aumentam o risco cardiovascular em crianças e adolescentes, como a obesidade, pressão arterial elevada e baixa aptidão física, usando a espessura da parede intima-media da carótida para detetar objetivamente as manifestações precoces de patologia cardiovascular. Até recentemente, estes marcadores subclínicos de aterosclerose foram pouco utilizados para examinar os efeitos de uma única sessão de exercício físico. No entanto, a utilização do modelo de exercício agudo pode ser vantajoso, pois permite uma manipulação eficiente das variáveis do exercício e permite maior controle experimental de variáveis de enviezamento. É possível que os efeitos de uma sessão de exercício possam prever os efeitos do exercício crónico. Nesta dissertação analisamos os fatores fisiológicos associados à rigidez arterial usando a distensibilidade arterial e velocidade da onda de pulso no contexto de exercício agudo em crianças e adultos. Em alguns casos, aqueles que melhoram o seu perfil de risco de risco para as DCV até à idade adulta experienciam reduções em marcadores subclínicos de aterosclerose para níveis saudáveis. Embora a prevenção de fatores de risco na juventude seja o ideal, existe ainda uma janela para a intervenção em que os efeitos cardiovasculares de longa duração pode ser evitada. Nesta dissertação apresentamos resultados preliminares que ligam fatores de risco modificáveis na juventude com marcadores subclínicos de DCV na idade adulta.

Indiana University-Purdue University Indianapolis (IUPUI)
Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.

Aims: While the association between periodontitis and systemic diseases is well known, little evidence is available on the potential impact of peri-implant diseases on systemic conditions. The aim of this dissertation was to investigate, either cross-sectionally and prospectively, the association between subclinical atherosclerosis, evaluated using the surrogate marker carotid intima media thickness (IMT), and periodontal and peri-implant diseases in a sample of patients suffering from primary hypertension. Material and Methods: In a first cross-sectional study, patients with primary hypertension and at least one dental implant with >5 years of functional loading were screened to evaluate their metabolic, periodontal and peri-implant status. A 24-hours ambulatory blood pressure monitoring and ultrasound assessment of carotid arteries were recorded for all patients, while anthropometric measurements and venous blood samples were obtained in the early morning after an overnight fast. Furthermore, every patient received a periodontal examination, collecting the Periodontal Screening and Recording (PSR) index in each of the sextants. After periodontal examination, patients were instructed to seek treatment of periodontal and peri-implant conditions diagnosed at their referring dental professionals. Only oral hygiene instructions were provided, and no further treatment was implemented. The diagnostic criteria of the ESC/ESH were adopted: arterial hypertension was defined as systolic BP (SBP) values ≥140 mmHg and/or diastolic BP (DBP) values ≥90 mmHg. Metabolic syndrome diagnosis was established in accordance with the NCEP ATP III criteria, while case definitions of the 2017 World Workshop were adopted for peri-implant and periodontal diseases. For each implant, probing pocket depths, mucosal redness, bleeding on probing, suppuration, plaque index and marginal bone loss were recorded. Using variables obtained at the baseline evaluation, a binomial logistic regression was performed to investigate the potential association between each parameter collected and the dependent variables (IMT > 0.9mm or IMT ≤ 0.9mm with the presence of carotid atherosclerotic plaque versus IMT ≤ 0.9mm and absence of atherosclerotic plaques (Model 1); IMT > 0.9mm versus IMT ≤ 0.9mm (Model 2); presence of carotid atherosclerotic plaque versus absence of carotid atherosclerotic plaque (Model 3). Correlation analyses between mean IMT values and cumulative PSR were further investigated using Spearman's rank-order testing. Then, a prospective cohort study was designed, contacting all patients evaluated two years before in the cross-sectional analysis, with an established diagnosis of periodontitis and peri-implant diseases. Among patients successfully recalled, a complete follow-up medical visit was conducted, collecting new biomarkers and performing a novel vascular assessment. The comparison between medical parameters collected at baseline and follow-up was assessed by Mann-Whitney U test for continuous variables and by Chi-square test of homogeneity and Fisher's exact test for categorical variables. Then, a multiple regression (backward stepwise) was performed to ascertain the effects of independent variables on average IMT as continuous outcome. Statistical significance was set at p≤0.05. Results: A total of 151 patients had complete available data on their hypertensive state at the baseline evaluation. In the cross-sectional analysis, three different statistical models were used to determine which independent predictors were associated with increased values of IMT. Periodontitis (OR ranging from 3.43 to 8.97) and cumulative PSR values (OR range: 1.19-1.32) were statistically significant in all models adopted, while peri-implant mucositis was found to be significant in Model 1 (OR= 3.34) and Model 2 (OR= 3.05) and peri-implantitis was not statistically significant in any model. In the linear regression model, a positive significant association with increased IMT was found out for cumulative PSR values (β=0.011, SE 0.002, p<0.001), presence of periodontitis (β=0.114, SE 0.020, p<0.001) and presence of peri-implant diseases (when considering mucositis and peri-implantitis aggregated) (β=0.011, SE 0.002, p<0.001). In this scenario, gingival inflammation was strongly related with systemic inflammation, as outlined by the Spearman's rank-order correlation (rs = .354; p < 0.001). In the prospective analysis, 71 patients were successfully recalled. Among parameters investigated, only IMT values were statistically significant higher (p= 0.015) at follow-up when compared with baseline (mean IMT values of 0.76 ±0.13 mm, 0.88 ± 0.19 mm, respectively). The linear regression model revealed a positive significant association with increased IMT and cumulative PSR values, CRP, Triglycerides and Creatinine, with an R2 = 0.863. Conclusions: Based on the results of the cross-sectional analysis, gingival inflammation, expressed as cumulative PSR, was strongly associated with higher IMT values and plaque presence, reporting for the first time an association with peri-implant diseases. Based on the results of the prospective analysis, we can cautiously conclude that gingival inflammation is related with the progression of subclinical atherosclerosis. Among a cohort of patients untreated for periodontitis and peri-implant diseases, with no differences for hypertensive and lipidic profiles and medications taken, there was a mean progression rate of 0.06 mm/year during the two years observation period, consistently higher compared to values reported in large epidemiological studies. When taking into account all cofounding variables, the linear regression model revealed a positive significant association with increased IMT and cumulative PSR values, CRP, Triglycerides and Creatinine.

Thesis (Ph.D.)--State University of New York at Buffalo, 2007.
Title from PDF title page (viewed on Mar. 07, 2008) Available through UMI ProQuest Digital Dissertations. Thesis adviser: Crespo, Carlos C. Includes bibliographical references.

Background and objective. Ultrasonic evaluation of carotid intima media thickness (IMT) has been widely used as a surrogate of atherosclerosis. Few studies have specifically examined risk factors related to subclinical atherosclerosis (SA) among early postmenopausal women, in particular in the Chinese population. There is also little information on the distribution of IMT in Asian midlife women. We described the prevalence of SA, as determined by IMT and carotid plaque, and the associated risk factors in early postmenopausal Chinese women in Hong Kong.
Conclusions. Our findings showed that age, SBP, HDL-C, and LDL-C were independent predictors of IMT, while age, LDL-C, and abdominal obesity were independent predictors of the presence of plaque. The optimal IMT cutoff of 0.783 mm was defined and that a prevalence of SA (IMT ≥ 0.783 mm) of 38.6% was found among 'healthy' early postmenopausal Chinese women in Hong Kong.
Methods. 518 women aged 50 to 64 years, and within 10 years since menopause were recruited from random telephone dialing. Women with surgical menopause, established cardiovascular diseases (CVD), and severe disease conditions such as cancer and renal failure were excluded. Sociodemographic, anthropometric and lifestyle factors were obtained based on standardized questionnaires. Fasting blood sample was also obtained. B-mode ultrasound was used for measuring IMT at 12 sites of the carotid arteries and plague index, which is the sum of the grades (ranged from 0 to 3) at the 6 segments. The relations between traditional risk factors, and other potential risk factors such as inflammatory markers, as well as lifestyle factors including physical activity, dietary intake, and psychological factors with SA were also assessed.
Results. The mean IMT +/- SD was 0.76 +/- 0.12 mm, with a range from 0.53 to 1.00 mm. IMT was higher on the far wall than on the near wall (P<0.01), and differ among segments (greatest at the bulb and least at the ICA) (P<0.01). One-fifth of women had at least 1 plaque in the carotid artery with most of the plaque occurred in the bulb area. IMT increased with age, and was positively associated with carotid plaque. With the use of receiver operating characteristic curve (ROC) analysis, the optimal cutoff IMT for diagnostic plaque was 0.783 mm, at which sensitivity and specificity was 80.5% and 75.1%, respectively. The prevalence of SA was 38.6%. Among the traditional risk factors, systolic blood pressure (SBP), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were associated with high IMT. Abdominal obesity assessed by waist circumference (WC) and waist hip ratio (WHR) was also found to be positively associated with IMT. Stepwise multiple regression showed that age, SBP, HDL-C, and LDL-C were independent predictors of IMT. Multiple logistic regression showed that women with LDL-C ≥ 130 mg/dL were associated with a 2.4-fold (95% CI 1.5-3.7) higher risk of having plaque compared to those with LDL-C < 130 mg/dL. In addition, women with abdominal obesity (WHR ≥ 0.85) had a 1.7-fold (95% CI 1.08-2.67) higher risk of having plaque than women with WHR < 0.85 after adjustment for age, and potential confounders including physical activity, dietary intakes etc. Significant inverse associations were observed between physical activity and indices of obesity, as well as fasting blood glucose, while psychological perceived stress and trait anxiety were independent risk factors for both total cholesterol and LDL-C.
Yu Ho-yan.
"February 2006."
Adviser: Suzanne C. Ho.
Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6350.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (p. 220-256).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.