Ankle-brachial index, high-sensitivity C-reactive protein and endothelial function in a cardiovascular risk population

Atherosclerotic vascular disease is the leading cause of death in the Western world. Its main three manifestations are coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Asymptomatic peripheral arterial disease is usually diagnosed using the ankle brachial index, and values ≤ 0.90 are used to determine the diagnosis. The classical risk factors of peripheral arterial disease, such as smoking and diabetes, are well known and early interventions are mandatory to improve the prognosis. What is not well known is the role of inflammation as a risk factor. Yet, a novel approach to cardiovascular diseases is the measurement of endothelial function. In this thesis, we studied the ankle-brachial index, C-reactive protein and endothelial function in a cardiovascular risk population. A total of 2856 subjects were invited to the study and 2085 (73%) responded. From these subjects, a cohort of 1756 risk persons was screened. We excluded the subjects with previously known cardiovascular disease or diabetes, because they were already under systematic follow-up. Out of the study subjects, 983 (56%) were women and 773 (44%) men. The ankle brachial index and high-sensitivity C-reactive protein were measured from 1047 subjects. Endothelial function was assessed by measuring reactive hyperemia pulse amplitude tonometry from 66 subjects with borderline peripheral arterial disease. In this study, smoking was a crucial risk factor for peripheral arterial disease. Subclinical peripheral arterial disease seems to be more common in hypertensive patients even without comorbidities. The measurement of the ankle brachial index is an efficient method to identify patients at an increased cardiovascular risk. High-sensitivity C-reactive protein did not correlate with the ankle brachial index or peripheral arterial disease. Instead, it correlated with measures of obesity. In a cardiovascular risk population with borderline peripheral arterial disease, nearly every fourth subject had endothelial dysfunction. This might point out a subgroup of individuals in need of more intensive treatment for their risk factors.

Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

Reflexões sobre o trauma cardiovascular civil a partir de um estudo prospectivo de 1000 casos atendidos em um centro de trauma de nível I: a prospective study from 1000 cases

OBJETIVO: Analisar os dados referentes a uma grande série de casos de traumas cardiovasculares exclusivamente civil operados em um único centro de trauma brasileiro. MÉTODO: Trata-se de um estudo de coorte, prospectivo, descritivo e analítico registrados entre os anos de 1998 - 2005. RESULTADOS: No período foram operados 1000 casos que acometeram principalmente homens jovens devido a armas de fogo, armas brancas/vidros e trauma contuso e cuja topografia das lesões se deu na seguinte ordem: abdominais, cervicais, torácicas e extremidades. As três síndromes mais comuns a admissão foram: hemorrágica, isquêmica e hemorrágica/isquêmica. No entanto, 34.6% dos pacientes estavam em choque hipovolêmico grave e em 85% da casuística havia lesões não cardiovasculares associadas. A maioria dos pacientes foi submetida a tratamento cirúrgico sem propedêutica específica, mas 14% destes foram reoperados devido à síndrome compartimental, trombose aguda e/ou hemorragia grave. A taxa de amputação foi de 5.5% e da mortalidade de 7.5%, estando correlacionada com choque hipovolêmico grave ou síndrome da resposta inflamatória sistêmica. Lesões CCV isoladas ocorreram em 15% dos casos com taxa de letalidade global de 41%, sendo 22% venosa, 47% arterial e 81% cardíaca, proporcionando diferença significativa entre lesões cardíacas versus arteriais e venosas associadas (p = 0,01; odds ratio de 7.37) e lesões arteriais versus venosas (p = 0,01; odds ratio de 3.17). CONCLUSÃO: Esta grande série de casos demonstrou ser o homem jovem o mais acometido devido principalmente à violência interpessoal e os acidentes automobilísticos, que envolvem na maioria das vezes as extremidades, associadas com lesões em outros órgãos ou sistemas. Os fatores preditivos de mau prognóstico foram choque hipovolêmico, lesão de grandes vasos arteriais e lesão cardíaca.

New perspectives on the melanocortins and their cardiovascular effects: Potential implications for the treatment of cardiovascular diseases with melanocortin analogues

The melanocortin peptides, including melanocyte-stimulating hormones, α-, β- and γ-MSH, are derived from the precursor peptide proopiomelanocortin and mediate their biological actions via five different melanocortin receptors, named from MC1 to MC5. Melanocortins have been implicated in the central regulation of energy balance and cardiovascular functions, but their local effects, via yet unidentified sites of action, in the vasculature, and their therapeutic potential in major vascular pathologies remain unclear. Therefore, the main aim of this thesis was to characterise the role of melanocortins in circulatory regulation, and to investigate whether targeting of the melanocortin system by pharmacological means could translate into therapeutic benefits in the treatment of cardiovascular diseases such as hypertension. In experiments designed to elucidate the local effects of α-MSH on vascular tone, it was found that α-MSH improved blood vessel relaxation via a nitric oxide (NO)-dependent mechanism without directly contracting or relaxing blood vessels. Furthermore, α-MSH was shown to regulate the expression and function of endothelial NO synthase in cultured human endothelial cells via melanocortin 1 receptors. In keeping with the vascular protective role, pharmacological treatment of mice with α-MSH analogues displayed therapeutic efficacy in conditions associated with vascular dysfunction such as obesity. Furthermore, α-MSH analogues elicited marked diuretic and natriuretic responses, which together with their vascular effects, seemed to provide protection against sodium retention and blood pressure elevation in experimental models of hypertension. In conclusion, the present results identify novel effects for melanocortins in the local control of vascular function, pointing to the potential future use of melanocortin analogues in the treatment of cardiovascular pathologies.

Resistência à insulina em mulheres com síndrome dos ovários policísticos modifica fatores de risco cardiovascular

OBJETIVO: avaliar se a presença de resistência à insulina (RI) modifica fatores de risco cardiovascular em mulheres com síndrome dos ovários policísticos (SOP). MÉTODOS: estudo transversal no qual 60 mulheres com SOP, com idade entre 18 e 35 anos e sem uso de hormônios, foram avaliadas. A RI foi avaliada por meio do quantitative insulin sensitivity check index (QUICKI). RI foi definida como QUICKI <0,33. As seguintes variáveis foram comparadas entre o grupo com e sem RI: antropométricas (peso, altura, circunferência da cintura, pressão arterial e frequência cardíaca), laboratoriais (homocisteína, interleucina-6, fator de necrose tumoral-α, testosterona, fração de androgênios livre, colesterol total e frações, triglicerídeos, proteína C reativa e insulina, glicose) e ultrassonográficas (distensibilidade e espessura íntima-média da carótida e dilatação mediada por fluxo da artéria braquial). RESULTADOS: Dezoito mulheres (30%) apresentaram RI. As mulheres com RI, comparadas às sem RI, apresentaram diferenças significativas nos seguintes marcadores antropométricos (SOP com RI e sem RI respectivamente): índice de massa corporal (35,5±5,6 versus 23,9±4,8 kg/m², p<0,01;), cintura (108,1±11,53 versus 79,5±11,1 cm, p<0,01) e pressão arterial sistólica (128,0±10,8 versus 114,0±8,9 mmHg, p<0,01) e pressão arterial diastólica (83,6±9,6 versus 77,0±7,5 mmHg, p=0,01). Também foram observadas diferenças significativas nos seguintes marcadores laboratoriais: triglicerídeos (120,0±56,5 versus 77,7±53,4 mg/dL, p=0,01), HDL (43,06±6,3 versus 40,4±10,8, p=0,01) e proteína C reativa (7,9±10,5 mg/L versus 2,6±3,2 mg/L, p<0,01), insulina (28,0±18,1 versus 5,3±2,4 µU/mL, p<0,01) e glicose (93,5±10,0 versus 87,5±8,7 mg/dL, p=0,02). Adicionalmente, dois dos três marcadores ultrassonográficos de risco cardiovascular também foram diferentes entre os grupos: distensibilidade carotídea (0,24±0,05 versus 0,30±0,08 mmHg-1, p<0,01) e espessura íntima-média da carótida (0,52±0,08 versus 0,43±0,09 mm, p<0,01). Além disso, a proporção de síndrome metabólica foi maior nas mulheres com RI (nove casos=50% versus três casos=7,1%, p<0,01). CONCLUSÕES: mulheres com SOP e RI apresentam diferenças significativas em vários marcadores ultrassonográficos, séricos e antropométricos que apontam para uma elevação no risco cardiovascular, quando comparadas a mulheres com SOP sem RI. Diante desses dados, a determinação sistemática da avaliação de RI em mulheres com SOP pode ajudar a identificar pacientes de risco cardiovascular.

Cardiovascular risk in middle-aged breast cancer survivors: a comparison between two risk models

PURPOSE: It was to assess the risk of cardiovascular disease (CVD) in breast cancer survivors (BCS).METHODS: This cross-sectional study analyzed 67 BCS, aged 45 -65 years, who underwent complete oncological treatment, but had not received hormone therapy, tamoxifen or aromatase inhibitors during the previous 6 months. Lipid profile and CVD risk were evaluated, the latter using the Framingham and Systematic COronary Risk Evaluation (SCORE) models. The agreement between cardiovascular risk models was analyzed by calculating a kappa coefficient and its 95% confidence interval (CI).RESULTS: Mean subject age was 53.2±6.0 years, with rates of obesity, hypertension, and dyslipidemia of 25, 34 and 90%, respectively. The most frequent lipid abnormalities were high total cholesterol (70%), high LDL-C (51%) and high non-HDL-C (48%) concentrations. Based on the Framingham score, 22% of the participants had a high risk for coronary artery disease. According to the SCORE model, 100 and 93% of the participants were at low risk for fatal CVD in populations at low and high risk, respectively, for CVD. The agreement between the Framingham and SCORE risk models was poor (kappa: 0.1; 95%CI 0.01 -0.2) for populations at high risk for CVD.CONCLUSIONS: These findings indicate the need to include lipid profile and CVD risk assessment in the follow-up of BCS, focusing on adequate control of serum lipid concentrations.

The effect of soy dietary supplement and low dose of hormone therapy on main cardiovascular health biomarkers: a randomized controlled trial

PURPOSE: To assess the effects of a soy dietary supplement on the main biomarkers of cardiovascular health in postmenopausal women compared with the effects of low-dose hormone therapy (HT) and placebo.METHODS: Double-blind, randomized and controlled intention-to-treat trial. Sixty healthy postmenopausal women, aged 40-60 years, 4.1 years mean time since menopause were recruited and randomly assigned to 3 groups: a soy dietary supplement group (isoflavone 90mg), a low-dose HT group (estradiol 1 mg plus noretisterone 0.5 mg) and a placebo group. Lipid profile, glucose level, body mass index, blood pressure and abdominal/hip ratio were evaluated in all the participants at baseline and after 16 weeks. Statistical analyses were performed using the χ2 test, Fisher's exact test, Kruskal-Wallis non-parametric test, analysis of variance (ANOVA), paired Student's t-test and Wilcoxon test.RESULTS: After a 16-week intervention period, total cholesterol decreased 11.3% and LDL-cholesterol decreased 18.6% in the HT group, but both did not change in the soy dietary supplement and placebo groups. Values for triglycerides, HDL-cholesterol, glucose level, body mass index, blood pressure and abdominal/hip ratio did not change over time in any of the three groups.CONCLUSION: The use of dietary soy supplement did not show any significant favorable effect on cardiovascular health biomarkers compared with HT. Clinical Trial Registry: The trial is registered at the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC), number RBR-76mm75.

Associação entre calcificações arteriais mamárias e fatores de risco para doença cardiovascular em mulheres menopausadas

OBJETIVO:Avaliar a presença de calcificações arteriais em mamografias de mulheres menopausadas e a sua associação com fatores de risco para doenças cardiovasculares.MÉTODOS:Trata-se de um estudo de corte transversal e retrospectivo, em que foram analisados as mamografias e os prontuários médicos de 197 pacientes atendidas no período entre 2004 e 2005. As variáveis do estudo foram: calcificação arterial mamária, acidente vascular cerebral, síndrome coronariana aguda, idade, obesidade, diabetes mellitus, tabagismo e hipertensão arterial sistêmica. Para a análise estatística dos dados, utilizaram-se os testes de Mann-Whitney, χ2 e Cochran-Armitage, sendo também avaliadas as razões de prevalência entre as variáveis descritas e calcificação arterial mamária. Os dados foram analisados com o software SAS, versão 9.1.RESULTADOS:Dos 197 exames e prontuários analisados, observou-se a prevalência de 36,6% para calcificações arteriais nas mamografias. Entre os fatores de risco para doença cardiovascular avaliados, os mais frequentes foram: hipertensão (56,4%), obesidade (31,9%), tabagismo (15,2%) e diabetes (14,7%). A síndrome coronariana aguda e o acidente vascular cerebral tiveram prevalências de 5,6 e 2,0% respectivamente. Entre as mamografias de mulheres diabéticas, a maior ocorrência foi de calcificação arterial mamária com razão de prevalência de 2,1 (IC95%1,0-4,1) e valor p de 0,02. Por outro lado, nas mamografias de pacientes fumantes, foi menor a ocorrência de calcificação arterial mamária com razão de prevalência de 0,3 (IC95% 0,1-0,8). Hipertensão arterial sistêmica, obesidade, diabetes mellitus, acidente vascular cerebral e síndrome coronariana aguda não apresentaram associação significativa com calcificações mamárias.CONCLUSÃO:A ocorrência de calcificação arterial mamária foi associada ao diabetes mellitus e mostrou associação negativa com o tabagismo. A presença de calcificação revelou-se independente dos demais fatores de risco para doença cardiovascular analisados.

Effects of Socioeconomic Status and Sociodemographic Features on Cardiovascular Disease. Mortality and Morbidity in Finland

Despite declining trends in morbidity and mortality, cardiovascular diseases have a considerable impact on Finnish public health. A goal in Finnish health policy is to reduce inequalities in health and mortality among population groups. The aim of this study was to assess inequalities in cardiovascular diseases according to socioeconomic status (SES), language groups and other sociodemographic characteristics. The main data source was generated from events in 35-99 year-old men and women registered in the population-based FINMONICA and FINAMI myocardial infarction registers during the years ranging from 1988-2002. Information on population group characteristics was obtained from Statistics Finland. Additional data were derived from the FINMONICA and FINSTROKE stroke registers and the FINRISK Study. SES, measured by income level, was a major determinant of acute coronary syndrome (ACS) mortality. Among middle-aged men, the 28-day mortality rate of the lowest group of six income groups was 5.2 times and incidence 2.7 times as high when compared to the highest income group. Among women, the differences were even larger. Among the unmarried, the incidence of ACS was approximately 1.6 times as high and their prognosis was significantly worse than among married persons - both in men and women and independent of age. Higher age-standardized attack rates of ACS and stroke were found among Finnish-speaking compared to Swedish-speaking men in Turku and these differences could not be completely explained by SES. In these language groups, modest differences were found in traditional risk factor levels possibly explaining part of the found morbidity and mortality inequality. In conclusion, there are considerable differences in the morbidity and mortality of ACS and stroke between socioeconomic and sociodemographic groups, in Finland. Focusing measures to reduce the excess morbidity and mortality, in groups at high risk, could decrease the economic burden of cardiovascular diseases and thus be an important public health goal in Finland.