Ensaio clínico randomizado duplo-cego do perfil inflamatório e do nível de estresse oxidativo em indivíduos com diagnóstico polissonográfico de SAOS antes e após o uso de CPAP

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Association of arterial events with the coexistence of metabolic syndrome and primary antiphospholipid syndrome

Objective Metabolic syndrome (MetS) is highly prevalent in rheumatic diseases and is recognized as a new independent cardiovascular risk factor. This study was undertaken to determine the clinical significance of MetS in patients with primary antiphospholipid syndrome (APS). Methods Seventy-one primary APS patients and 73 age- and sex-matched healthy controls were included. Serum samples were tested for lipid profile, Lp(a), glucose, insulin, thyroid-stimulating hormone, free T4, erythrocyte sedimentation rate, C-reactive protein level, and uric acid. MetS was defined by the International Diabetes Federation criteria, and insulin resistance was established using the homeostasis model assessment index. Results The prevalence of MetS was 33.8%, and further comparison between primary APS patients with and without MetS revealed that the former had a higher frequency of arterial events (79.2% versus 42.6%; P = 0.003), angina (29.2% versus 2.1%; P = 0.002), and positive lupus anticoagulant antibody (95.8% versus 76.6%; P = 0.049). In addition, primary APS patients with MetS, as expected, had a higher prevalence of cardiovascular risk factors. On multivariate analysis, only MetS was independently associated with arterial events in primary APS. Conclusion Coexistence of primary APS and MetS seems to identify a subgroup of patients with higher risk of arterial events, suggesting that MetS may aggravate existing endothelial abnormalities of primary APS.

The perception of sleep quality in kidney transplant patients during the first year of transplantation

OBJECTIVE: Poor sleep quality is one of the factors that adversely affects patient quality of life after kidney transplantation, and sleep disorders represent a significant cardiovascular risk factor. The objective of this study was to investigate the prevalence of changes in sleep quality and their outcomes in kidney transplant recipients and analyze the variables affecting sleep quality in the first years after renal transplantation. METHODS: Kidney transplant recipients were evaluated at two time points after a successful transplantation: between three and six months (Phase 1) and between 12 and 15 months (Phase 2). The following tools were used for assessment: the Pittsburgh Sleep Quality Index; the quality of life questionnaire Short-Form-36; the Hospital Anxiety and Depression scale; the Karnofsky scale; and assessments of social and demographic data. The prevalence of poor sleep was 36.7% in Phase 1 and 38.3% in Phase 2 of the study. RESULTS: There were no significant differences between patients with and without changes in sleep quality between the two phases. We found no changes in sleep patterns throughout the study. Both the physical and mental health scores worsened from Phase 1 to Phase 2. CONCLUSION: Sleep quality in kidney transplant recipients did not change during the first year after a successful renal transplantation.

Asymmetrisches Dimethylarginin als kardiovaskulärer Risikofaktor : Transportmechanismen und Auswirkungen einer Akkumulation

Die vorliegende Dissertation beschäftigt sich mit dem Membrantransporter-vermittelten Export von asymmetrischem Dimethyl-L-Arginin (ADMA) aus der Endothelzelle. Da ADMA-Plasmakonzentrationen mit Erkrankungen wie koronaren Herzkrankheiten, Atherosklerose, Bluthochdruck und Endotheldysfunktion in Verbindung gebracht werden, ist ein effektiver ADMA-Export aus der Zelle heraus unabdingbar. Um den Mechanismus hierfür aufzuklären, wurden die immortalisierte Endothelzelllinie EA.hy926 und weitere primäre Endothelzellen (humane Umbilikalvenenendothelzellen und Endothelzellen der großen und kleinen Herzgefäße) auf die Expression basischer Aminosäuretransporter mittels einer qRT-PCR hin untersucht. Dabei zeigte sich, dass alle getesteten Endothelzellen die Aminosäuretransporter hCAT-1, y+LAT1 und y+LAT2 exprimierten. Basierend auf ADMA-Exportdaten, die mit entsprechenden Transporter-überexprimierenden Xenopus laevis-Oozyten gewonnen wurden, wurde festgestellt, dass alle drei Membrantransporter ADMA exportieren konnten. Der physiologisch wichtige Exportweg für intrazellulär anfallendes ADMA scheint dabei der via y+L zu sein, da es sich hierbei um einen aktiven Exportmechanismus handelt, der im Gegentransport von im humanen Plasma reichlich vorhandenen neutralen Aminosäuren und Natriumionen den nach innen gerichteten Natriumgradienten ausnutzt. Die Wichtigkeit des Membrantransportes für die Kontrolle intrazellulärer ADMA-Konzentrationen wurde in vitro durch Entzug von extrazellulären Austauschsubstraten und einer daraus resultierenden Blockade der Transportfunktion gezeigt. Hierbei wurde innerhalb von zwei Stunden ein 2,5-facher Anstieg der intrazellulären ADMA-Konzentration festgestellt, die bei Präsenz von Austauschsubstrat für die Transporter nicht auftrat. Die Relevanz der y+LATs für den ADMA-Export wurde durch Herunterregulation dieser Proteine mittels siRNA sichtbar: Unter diesen Bedingungen konnte ADMA auch in Anwesenheit von Austauschsubstrat für das System y+L weniger effektiv exportiert werden. Eine wichtige Aufgabe des humanen Endothels ist die Bildung bioaktiven Stickstoffmonoxids, das unter anderem eine Vasodilatation der Gefäße bewirkt. Für diese NO-Synthese wird L-Arginin als Substrat von der endothelialen NO-Synthase benötigt. ADMA stellt einen kompetitiven Inhibitor dar, dessen erhöhtes intrazelluläres Vorkommen möglicherweise hemmend auf die NO-Synthase wirken könnte. Es konnten hier allerdings keine Auswirkungen eines um das 4-fache gestiegenen, intrazellulären ADMA-Spiegels auf die Tätigkeit der endothelialen NO-Synthase festgestellt werden. Möglicherweise bedarf es eines noch weiter zu Gunsten des ADMAs verschobenen, intrazellulären L-Arginin:ADMA-Verhältnisses, um eine Hemmung der NO-Synthase festzustellen. Dies könnte bei einem pathologischen Transporterausfall eintreten, der intrazellulär permanent höhere ADMA-Konzentrationen zur Folge hätte. Des Weiteren hätte ein Anstieg der Arginasetätigkeit und damit einhergehend ein Substratdefizit für die NO-Synthase den gleichen Effekt. Der translationale Ansatz mit humanen peripheren mononukleären Blutzellen von Patienten aus der 2. Medizinischen Klinik zeigte die Tendenz einer Korrelation zwischen dem ADMA-Exportvermögen und der Endothelfunktion und brachte zudem die Erkenntnis eines individuell äußerst variablen ADMA-Exportvermögens zutage.

Progression of coronary artery disease during long-term follow-up of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II)

Background: This study evaluates cardiovascular risk factors associated with progression of coronary artery disease (CAD) in patientswith silent ischemia followingmyocardial infarction. Hypothesis: Coronary artery disease only progresses slowly with comprehensive risk factor intervention. Methods: A total of 104 of 201 patients (51.7%) of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) with baseline and follow-up coronary angiography were included. All patients received comprehensive cardiovascular risk factor intervention according to study protocol. Logistic regression was used to evaluate associationsbetween baseline cardiovascular risk factors and CAD progression. Results: The mean duration of follow-upwas 10.3 ± 2.4 years. At baseline, 77.9% of patients were smokers, 45.2% had hypertension, 73.1% had dyslipidemia, 7.7% had diabetes, and 48.1% had a family history of CAD. At last follow-up, only 27 patients of the initial 81 smokers still smoked, only 2.1% of the patients had uncontrolled hypertension, 10.6%of the patientshad uncontrolled dyslipidemia, and 2.1%of the patientshad uncontrolled diabetes. Coronary artery disease progression was found in up to 81 (77.9%) patients. Baseline diabetes and younger age were associatedwith increased odds of CAD progression.The time intervalbetween baseline and follow-up angiography was also associatedwith CAD progression. Conclusion: Coronary artery disease progressionwas highly prevalent in these patients despite comprehensive risk factor intervention. Further research is needed to optimize treatment of known risk factors and to identify other unknown and potentiallymodifiable risk factors.

Cause or effect of arteriogenesis: compositional alterations of microparticles from CAD patients undergoing external counterpulsation therapy

Recently, a clinical study on patients with stable coronary artery disease (CAD) showed that external counterpulsation therapy (ECP) at high (300 mmHg) but not at low inflation pressure (80 mmHg) promoted coronary collateral growth, most likely due to shear stress-induced arteriogenesis. The exact molecular mechanisms behind shear stress-induced arteriogenesis are still obscure. We therefore characterized plasma levels of circulating microparticles (MPs) from these CAD patients because of their ambivalent nature as a known cardiovascular risk factor and as a promoter of neovascularization in the case of platelet-derived MPs. MPs positive for Annexin V and CD31CD41 were increased, albeit statistically significant (P<0.05, vs. baseline) only in patients receiving high inflation pressure ECP as determined by flow cytometry. MPs positive for CD62E, CD146, and CD14 were unaffected. In high, but not in low, inflation pressure treatment, change of CD31CD41 was inversely correlated to the change in collateral flow index (CFI), a measure for collateral growth. MPs from the high inflation pressure group had a more sustained pro-angiogenic effect than the ones from the low inflation pressure group, with the exception of one patient showing also an increased CFI after treatment. A total of 1005 proteins were identified by a label-free proteomics approach from MPs of three patients of each group applying stringent acceptance criteria. Based on semi-quantitative protein abundance measurements, MPs after ECP therapy contained more cellular proteins and increased CD31, corroborating the increase in MPs. Furthermore, we show that MP-associated factors of the innate immune system were decreased, many membrane-associated signaling proteins, and the known arteriogenesis stimulating protein transforming growth factor beta-1 were increased after ECP therapy. In conclusion, our data show that ECP therapy increases platelet-derived MPs in patients with CAD and that the change in protein cargo of MPs is likely in favor of a pro angiogenic/arteriogenic property.

Essential hypertension - which genes can be held responsible for it?

Hypertension is a common heritable cardiovascular risk factor. Some rare monogenic forms of hypertension have been described, but the majority of patients suffer from essential hypertension, for whom the underlying genetic mechanisms are not clear. Essential hypertension is a complex trait, involving multiple genes and environmental factors. Recently, progress in the identification of common genetic variants associated with essential hypertension has been made due to large-scale international collaborative projects. In this article we review the new research methods used as well as selected recent findings in this field.

Treatment of hypercholesterolemia in patients with primary biliary cirrhosis might be more beneficial than indicated

Cholesterol circulating levels are elevated in most of the patients with primary biliary cirrhosis. This review questions whether hypercholesterolaemia represents a cardiovascular risk in primary biliary cirrhosis and whether it should be treated. The published evidence indicates that hypercholesterolaemia in patients with primary biliary cirrhosis should be considered a cardiovascular risk factor only when other factors are present. Ursodeoxycholic acid the standard treatment of primary biliary cirrhosis improves the cholestasis and hereby lowers circulating levels of cholesterol. Primary biliary cirrhosis is not a contraindication to prescribe statins or fibrates to these patients. Interestingly, these two classes of drugs have been shown to improve not only the lipid profile but also the liver tests. In particular fibrates have been found to normalize liver tests in patients responding incompletely to ursodeoxycholic acid. Statins as well as fibrates possess specific anti-inflammatory properties which may be beneficial in primary biliary cirrhosis. In conclusion, hypercholesterolaemia in the absence of other cardiovascular risk factors does not require specific therapeutic intervention in patients with primary biliary cirrhosis. However, statins as well as fibrates seem to have beneficial effects on the primary biliary cirrhosis itself and deserve formal testing within clinical trials.

Anatomical eligibility of the renal vasculature for catheter-based renal denervation in hypertensive patients.

OBJECTIVES This study sought to determine the vascular anatomical eligibility for catheter-based renal artery denervation (RDN) in hypertensive patients. BACKGROUND Arterial hypertension is the leading cardiovascular risk factor for stroke and mortality globally. Despite substantial advances in drug-based treatment, many patients do not achieve target blood pressure levels. To improve the number of controlled patients, novel procedure- and device-based strategies have been developed. RDN is among the most promising novel techniques. However, there are few data on the vascular anatomical eligibility. METHODS We retrospectively analyzed 941 consecutive hypertensive patients undergoing coronary angiography and selective renal artery angiography between January 1, 2010, and May 31, 2012. Additional renal arteries were divided into 2 groups: hilar (accessory) and polar (aberrant) arteries. Anatomical eligibility for RDN was defined according to the current guidelines: absence of renal artery stenosis, renal artery diameter ≥4 mm, renal artery length ≥20 mm, and only 1 principal renal artery. RESULTS A total of 934 hypertensive patients were evaluable. The prevalence of renal artery stenosis was 10% (n = 90). Of the remaining 844 patients without renal artery stenosis, 727 (86%) had nonresistant hypertension and 117 (14%) had resistant hypertension; 62 (53%) of the resistant hypertensive and 381 (52%) of the nonresistant hypertensive patients were anatomically eligible for sympathetic RDN. CONCLUSIONS The vascular anatomical eligibility criteria of the current guidelines are a major limiting factor for the utilization of RDN as a therapeutic option. Development of new devices and/or techniques may significantly increase the number of candidates for these promising therapeutic options.

The effect of life events on blood pressure and body mass index in children

In Conroe, Texas, 492 students ages 5 to 15 participated in a screening examination for cardiovascular risk factor study. Among 492 students, 141 elementary and junior high students participated in the present sub-study to investigate the effect of the number of recent life events on blood pressure and on body mass index. Using the elementary and junior high school Coddington scales, life events occurring in the past 12 months were measured for students ages 9 to 14 years, no significant differences in life events were observed by age and sex. The number of life events was not related to blood pressure but was positively correlated to body mass index in children and adolescents. ^

Avaliação da aterosclerose subclínica em portadores de HDL-colesterol marcadamente elevado

O HDL-c é um fator de risco cardiovascular negativo e sua concentração plasmática apresenta relação inversa com a incidência de eventos cardiovasculares. Entretanto, as evidências relativas ao grupo de indivíduos com níveis de HDL-c acima do percentil 95 da população geral ainda são escassas e o impacto da hiperalfalipoproteinemia (HALP) sobre o risco cardiovascular continua representando motivo de controvérsia na literatura médica. Alguns estudos em populações específicas associam a HALP a aumento do risco cardiovascular. Ao mesmo tempo, outros estudos identificaram populações de indivíduos hipoalfalipoproteinêmicos com marcada longevidade. Assim, demonstrou-se aparente dissociação entre níveis de HDL-c e risco cardiovascular em determinadas populações, reconduzível a aspectos disfuncionais da HDL. O objetivo do presente estudo foi verificar o papel da HALP na determinação do risco cardiovascular; comparar a prevalência de doença cardiovascular subclínica, avaliada por meio da quantificação ultrassonográfica da Espessura Íntimo-Medial Carotídea (EIMC), entre portadores de HDL-c >= 90mg/dL (grupo HALP) e portadores de concentrações de HDL-c atualmente consideradas normais (entre 40 e 50mg/dL para os homens e entre 50 e 60mg/dL para as mulheres); e avaliar características e função da HDL em portadores de HALP por meio do estudo de sua composição, de sua capacidade de efluxo de colesterol, e de sua atividade anti-inflamatória e antioxidante, correlacionando estas características com a presença de doença cardiovascular subclínica avaliada por meio da determinação da EIMC, da Velocidade de Onda de Pulso (VOP) e da presença de Calcificação Arterial Coronariana (CAC) avaliada pela TCMD. Para responder estas perguntas, o presente estudo foi articulado em dois braços: Braço 1: Análise da coorte do estudo ELSA com o objetivo de determinar a prevalência de HALP em uma população geral; definir o perfil demográfico, antropométrico e metabólico dos portadores de HALP; e comparar a prevalência de doença vascular subclínica deste grupo com controles da mesma coorte com níveis normais de HDL-colesterol. Braço 2: Recrutamento de 80 voluntários hígidos e portadores de HALP para avaliação da correlação entre presença de doença vascular subclínica, e aspectos estruturais e funcionais da HDL. Em seus dois braços, o estudo levou a quatro conclusões principais: 1) Níveis marcadamente elevados de HDL-c estão associados a menor espessura íntimo-medial carotídea quando comparados a níveis de HDL-c considerados normais pelas diretrizes vigentes. Embora portadores do fenótipo HALP apresentem, como grupo, um perfil metabólico mais favorável que o encontrado em indivíduos com HDL-c normal, a associação entre EIMC e HALP foi independente dos fatores de risco tradicionais, indicando que a menor prevalência destes últimos em portadores de HDL-c marcadamente elevado justifica apenas parcialmente a menor prevalência de doença vascular subclínica neste grupo; 2) Embora a HALP se apresente como um fenótipo ateroprotetor, há indivíduos com níveis marcadamente elevados de HDL-c que evoluem com doença cardiovascular, clínica ou subclínica. Neste contexto, nossos resultados indicam correlação entre os três métodos avaliados para estudar doença vascular subclínica em portadores de HALP: EIMC, VOP e CAC; 3) Os fatores de risco tradicionais continuam exercendo seu peso na determinação do risco cardiovascular em portadores de HALP. Idade, tabagismo, hipertensão arterial, hipertrigliceridemia e altos níveis de LDL-c apresentaram associação estatisticamente significativa com a presença de doença vascular subclínica no grupo estudado; 4) A avaliação da composição e da função da HDL em portadores de HALP pode permitir identificar indivíduos especificamente mais suscetíveis à aterosclerose. Nossos resultados indicam que, em particular, a atividade anti-inflamatória da HDL, avaliada pela capacidade de inibição da produção de IL-6; o efluxo de colesterol e a capacidade de transferência de triglicérides apresentaram associação independente com menor espessura íntimo-medial carotídea em portadores de HALP, enquanto níveis mais altos de Apo A-IV se associaram a maior grau de doença cardiovascular subclínica

Reduced postprandial proinsulinaemia and 32-33 split proinsulinaemia after a mixed meal in type 2 diabetic patients following sensitization to insulin with pioglitazone

Objective: Reduced insulin sensitivity associated with fasting hyperproinsulinaemia is common in type 2 diabetes. Proinsulinaemia is an established independent cardiovascular risk factor. The objective was to investigate fasting and postprandial release of insulin, proinsulin (PI) and 32-33 split proinsulin (SPI) before and after sensitization to insulin with pioglitazone compared to a group treated with glibenclamide. Design and patients: A randomized double-blind placebo-controlled trial. Twenty-two type 2 diabetic patients were recruited along with 10 normal subjects. After 4 weeks washout, patients received a mixed meal and were assigned to receive pioglitazone or glibenclamide for 20 weeks, after which patients received another identical test meal. The treatment regimes were designed to maintain glycaemic control (HbA1c) at pretreatment levels so that ß-cells received an equivalent glycaemic stimulus for both test meals. Measurements: Plasma insulin, PI, SPI and glucose concentrations were measured over an 8-h postprandial period. The output of PI and SPI was measured as the integrated postprandial response (area under the curve, AUC). Results: Pioglitazone treatment resulted in a significant reduction in fasting levels of PI and SPI compared to those of the controls. Postprandially, pioglitazone treatment had no effect on the insulin AUC response to the meal but significantly reduced the PI and SPI AUCs. Glibenclamide increased fasting insulin and the postprandial insulin AUC but had no effect on the PI and SPI AUCs. Conclusions: Sensitization to insulin with pioglitazone reduces the amount of insulin precursor species present in fasting and postprandially and may reduce cardiovascular risk. © 2007 The Authors.

Air Pollution and High Density Lipoprotein Structure and Function

Thesis (Ph.D.)--University of Washington, 2016-06

The pathophysiology of CADASIL: studies in a Scottish cohort

Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest. This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland. Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis. 22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained. I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker. I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p <0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year. I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing. NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies. The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles. On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease.

Familial Hypercholesterolemia in Portugal: analysis of biomarkers

Aims of the study: 1) Cardiovascular risk assessment of a cohort of children with a clinical diagnosis of FH; 2) Identification of biomarkers to distinguish between monogenic and polygenic/environmental dyslipidemia in clinical settings; 3) Clinical criteria improvement to identify FH children.