Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women

Background: Epidemiological studies demonstrate an inverse association between serum magnesium and incidence of cardiovascular disease. Diuretics commonly cause hypomagneseamia. Method: We evaluated effects of magnesium supplementation on blood pressure (BP) and vascular function in thiazide-treated hypertensive women in a randomized, double-blind, clinical trial. Hypertensive women (40–65 years) on hydrochlorothiazide and mean 24-h BP at least 130/80 mmHg were divided into placebo and supplementation (magnesium chelate 600 mg/day) groups. Patients were evaluated for nutritional and biochemical parameters, office and ambulatory blood pressure monitoring, brachial flow-mediated dilatation (FMD), peripheral arterial tonometry, assessment of carotid intima–media thickness, central hemodynamic parameters and pulse wave velocity at inclusion and after 6-month follow-up. Results: The magnesium group had a significant reduction in SBP (144 ± 17 vs. 134 ± 14 mmHg, P = 0.036) and DBP (88 ± 9 vs. 81 ± 8 mmHg, P = 0.005) at 6 months, without effect on plasma glucose, lipids, or arterial stiffness parameters. The placebo group showed a significant increase in carotid intima-media thickness (0.78 ± 0.13 vs. 0.89 ± 0.14 mm, P = 0.033) without change in the magnesium group (0.79 ± 0.16 vs. 0.79 ± 0.19 mm, P = 0.716) after 6 months. The magnesium group demonstrated a significant increase in variation of FMD vs. the placebo group (+3.7 ± 2.1 vs. 2.4 ± 1.2%, P = 0.015). There was a significant correlation between the intracellular magnesium variation and FMD (r = 0.44, P = 0.011). Conclusion: Magnesium supplementation was associated with better BP control, improved endothelial function and amelioration of subclinical atherosclerosis in these thiazide-treated hypertensive women

Inter and intra-raters reproducibility of flow-mediated slowing using local estimates of brachial artery pulse wave velocity

INTRODUÇÃO: A desaceleração mediada pelo fluxo (DMF) mede de forma não invasiva a função endotelial braquial por meio de alterações na velocidade da onda de pulso (VOP) induzidas por uma hiperemia reativa, e é sugerido para mitigar as limitações bem conhecidas da dilatação mediada por fluxo (DMF), incluindo a reprodutibilidade subotima e a alta dependência da experiência do operador. No entanto, os poucos estudos que examinaram a reprodutibilidade da DMF mostraram resultados controversos, e usaram apenas medições regionais de VOP efetuadas por um único avaliador. Tal pode não refletir verdadeiramente as respostas exatas da rigidez da artéria braquial à hiperemia reativa e a sua aplicabilidade clínica. No presente trabalho avaliámos a reprodutibilidade inter- e intra- avaliadores das análises off-line do DMF através dos sinais brutos de distensibilidade arterial obtidos do procedimento DMF. MÉTODOS: Vinte e quatro participantes saudáveis do sexo masculino com idades entre 23-75 anos, foram examinados por 2 avaliadores, em dois dias separados, para avaliar a reprodutibilidade inter- e intra-dias. As alterações na rigidez beta braquial e na VOP beta (DMF) induzidas pela hiperemia reativa foram calculadas de acordo com as fórmulas do fabricante através da utilização de um script R personalizado. A reprodutibilidade inter- e intra- avaliador foi examinada com coeficiente de correlação intraclasse (ICC), coeficiente de variação (CV) e gráficos Bland-Altman. RESULTADOS: A reprodutibilidade inter- avaliador da DMS mostrou uma boa reprodutibilidade para as análises intra (bias: -0.12%; ICC: 0.84; 95% CI: 0.57 to 0.94; CV: 19%) e inter- dia (bias: -0.25%; ICC: 0.82; 95% CI: 0.57 to 0.92; CV: 16%). A reprodutibilidade intra avaliador mostrou uma reprodutibilidade moderada a boa para a análise inter- dia (1º Avaliador: bias: 0.39%; ICC: 0.78; 95% CI: 0.51 to 0.91; CV: 21%; 2º Avaliador: bias:0.14%; ICC: 0.53; 95% CI: -0.07 to 0.80; CV: 36%). CONCLUSÕES: As análises off-line do DMS através dos sinais brutos de ultrassonografia são reprodutíveis entre diferentes avaliadores.INTRODUCTION: Flow-mediated slowing (FMS) measures brachial endothelial function non-invasively through reactive hyperemia-induced changes on pulse wave velocity (PWV), and it is suggested to mitigate well-known pitfalls of flow-mediated dilation (FMD) including suboptimal reproducibility and high-operator dependency. However, the few studies that examined FMS reproducibility have shown controversial results and used only regional measurements of PWV performed by a single rater This might not truly reflect the exact stiffness responses of the brachial artery to reactive hyperemia and limit its clinical usefulness. In the present study we assessed inter- and intra-raters reproducibility of off-line analyses of FMS using the raw distensibility signals obtained from the FMD procedure. METHODS: Twenty-four healthy male participants aged 23 – 75 yr, were examined on two separate days to assess inter- and intra-day reproducibility. Reactive hyperemia-induced changes on brachial beta stiffness and beta PWV (FMS) were calculated according to the manufacturer's formulas using a tailored R-script. Inter- and int-rater reproducibility was examined with intraclass correlation coefficient (ICC), coefficient of variation (CV), and Bland-Altman plot estimates. RESULTS: Inter-rater reproducibility of FMS showed an overall good reproducibility for both intra (bias: -0.12%; ICC: 0.84; 95% CI: 0.57 to 0.94; CV: 19%) and inter-day (bias: -0.25%; ICC: 0.82; 95% CI: 0.57 to 0.92; CV: 16%) analyses. Intra-rater reproducibility showed an overall moderate-to-good reproducibility for inter-day (1st rater: bias: 0.39%; ICC: 0.78; 95% CI: 0.51 to 0.91; CV: 21%; 2nd rater: bias:0.14%; ICC: 0.53; 95% CI: -0.07 to 0.80; CV: 36%) analyses. CONCLUSIONS: Off-line analyses of FMS using raw signals from ultrasonography were reproducible among different raters

Circadian variations in aortic stiffness, sympathetic vasoconstriction, and post-ischemic vasodilation in adults with and without type 2 diabetes.

The current literature reveals a lack of information on the circadian variations of some important cardiovascular risk factors related to the work of the heart or the capacity to provide blood and oxygen to various tissues. These factors include aortic stiffness, peripheral vasoconstrictor responsiveness, and post-ischemic vasodilation capacity. Furthermore, it is not clear whether the impact of an external stressor capable of activating the sympathetic nervous system could have greater repercussions on the cardiovascular system in the morning than in the evening. Given the higher incidence of acute cardiovascular events in the morning than in the evening, the studies undertaken in this thesis aim to investigate the circadian variations of these factors that are linked to cardiovascular risk, both at rest and during acute activation of the sympathetic nervous system. Type 2 diabetes (T2DM) is a condition that induces deleterious changes in cardiovascular function, impacting cardiovascular mortality and morbidity. Thus, the impact of diabetes will be evaluated. As a secondary purpose, considering the sex differences in the incidence and prognosis of cardiovascular disease, the effect of sex will be evaluated. Aortic stiffness proved not to be increased in the morning compared to the evening at specific times when the cardiovascular risk is significantly different, both at rest and during sympathetic activation. However, while healthy older women show similar aortic stiffness values compared to their male counterparts during acute stress, older women with T2DM reported greater aortic stiffness compared to men with T2DM. The post-ischemic forearm vasodilation is blunted in the morning compared to the evening in healthy elderly and such an attenuated vasodilation capacity impairs blood flow supply towards the ischemic area. The presence of T2DM does not affect vasodilation capacity and reactive hyperemia, but induces circadian variations in arterial pressure. The peripheral vasoconstriction triggered by a standardized sympathetic stressor is similar between morning and evening, regardless of the presence of T2DM and reduced baseline vascular conductance values in the morning. However, the peripheral vasoconstriction responsiveness is blunted in individuals with T2DM than in healthy ones as sympathetic activation induces vasodilation on the contralateral forearm in individuals with T2DM and vasoconstriction in healthy age-matched subjects. This finding highlights a neurovascular response to an external stressor altered by T2DM. Taken together, our findings suggest that the baseline state of constriction of the peripheral vascular tissue is greater in the morning than in the evening, but this fact is not due to greater sympathetic vasoconstriction responsiveness in the morning. Higher morning vasoconstriction at baseline however affects the capacity of a vascular tissue to dilate and, in turn, to supply blood to an ischemic tissue. Similar sympathetic vasoconstriction responsiveness between morning and evening is a likely factor explaining similar or lower values of central artery stiffness in the morning than in the evening, not only at rest but also during sympathetic excitation. Paradoxically, adults with T2DM report an increase in sympathetic-mediated dilatation capacity on the vascular tissue, which might be a defense mechanism that allows to reduce the central pressor response during sympathetic excitation

The Markers of Endothelial Activation

Biomarkers are biological indicators of processes that are part of ethiopathogenesis of the diseases, and can, but do not have to be causal to diseases. One very important question is how specific and sensitive the marker is, since one molecule can appear in many conditions. Biomarkers of endothelial cell activation can be very diverse, from biochemical/metabolic to functional biomarkers. Activation of endothelial cells is part of physiological as well as pathophysiological response of cardiovascular system in conditions as physical activity, growth, pregnancy and in all cardiometabolic diseases (e.g., hypertension, diabetes mellitus, autoimmune inflammatory diseases, coronary artery disease, atherosclerosis, ischemia and reperfusion, etc.). During activation, there is a change in endothelial cell morphology and function, which could be a defensive response of endothelium to provoking factor or could lead to increased risk for the injury and end organ damage. This chapter aims to overview current knowledge on established biomarkers of normal and disease-related endothelial activation and to provide information on novel, potential biomarkers in common cardiometabolic diseases

Reproducibility and physiological factors pertinent to the study of the acute effects of exercise on traditional and alternative measures of vascular and autonomic function in young and older adults

Measuring age-related endothelial dysfunction may provide a prognostic marker of cardiovascular diseases beyond traditional cardiovascular risk factors. Flow-mediated slowing (FMS) may address flow-mediated dilation (FMD) major caveats including larger measurement and biological variability, still, applanation tonometry FMS reproducibility is unknown. The acute model permits investigating the mechanisms underlying aerobic exercise anti-atherogenic and sympatholytic effects which preserve neurovascular homeostasis through aging. Thus, this dissertation aimed to investigate the reproducibility and physiological factors relevant to the study of exercise acute effects on traditional and alternative measures of vascular and autonomic function in young and older adults. Reproducibility assessments of applanation tonometry FMS and FMD were conducted on twenty-four males (aged 23-75 years) healthy and active male adults. Participants also performed walking or running randomized acute bouts of high-intensity interval training (HIIT), moderate-intensity continuous training, or a non-exercise condition. FMS was not a reproducible method with poorer reproducibility (CV: 141%) than FMD (CV: 23%). We found no age-associated response patterns on FMD, and heart-rate variability indexes to exercise in active young and older adults. FMD remained unchanged following exercise, whilst only HIIT reduced cardiovagal modulation, likely representing the initial trigger for vagal adaptations, returning to baseline 60-min into recovery.A disfunção endotelial inerente ao envelhecimento pode ser preditiva de doenças cardiovasculares independentemente dos factores de risco tradicionais, assim a sua avaliação é crucial. A desaceleração fluxo-mediada (DFM) pretende colmatar as lacunas da vasodilatação fluxo-mediada (VFM): a elevada variabilidade biológica e de medição. Contudo, a reprodutibilidade da DFM medida por tonometria de aplanação é desconhecida. O modelo agudo possibilita investigar os mecanismos subjacentes aos efeitos ateroscleróticos e simpatolíticos do exercício aeróbio preservando a homeostasia neurovascular durante o envelhecimento. O objetivo desta dissertação consistiu em examinar a reprodutibilidade e os factores relevantes para o estudo dos efeitos agudos do exercício em medidas tradicionais e alternativas de função endotelial e autonómica em homens jovens e idosos. A reprodutibilidade da DFM e da VFM foi avaliada em 24 homens (23-75 anos), saudáveis e fisicamente ativos. Adicionalmente, duas sessões de treino aeróbio (contínuo vs intervalado) e uma de controlo foram ainda realizadas aleatoriamente. A DFM apresentou uma reprodutibilidade inferior (CV: 141%) à da VDM (CV: 23%). As respostas ao exercício da VFM e da variabilidade da frequência cardíaca não diferiram entre jovens e idosos. A VFM permaneceu inalterada no pós-exercício, já a modulação cardiovagal diminui apenas no pós-treino intervalado de alta intensidade retornando a níveis basais após 60-min de recuperação

Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.</p

The Effects of Aerobic Exercise Training on Arterial Stiffness in the Metabolic Syndrome

Background: Arterial dysfunction, due in part to arterial stiffening, is recognized as a surrogate end point for cardiovascular disease (CVD) and predicts the risk of future CV events. The metabolic syndrome (MetS) is a clustering of risk factors associated with increased stiffening and carotid artery thickening. Aerobic exercise is a well-established therapy that reduces CV events, and has proven to be an effective intervention against arterial stiffening and pathological wall remodeling in the healthy, hypertensive, and diabetic population.;Aims: The purpose of this thesis was to examine the impact of aerobic exercise training on arterial stiffness and wall remodeling in MetS individuals. We hypothesized that an 8-week exercise intervention would decrease stiffness and reduce carotid wall thickness, compared to inactive MetS participants.;Methods: We compared arterial stiffness (pulse wave velocity: PWV), carotid wall thickness (cIMT), central pulse pressure (cPP), and peak aerobic capacity (VO2peak) between healthy subjects (n=15) and MetS individuals (n=21), free of CV events. Further, we examined how 8 weeks of aerobic exercise training in MetS individuals (n=11) altered the above parameters, compared to MetS individuals (n=9) who remained inactive. Two MetS participants did not finish the 8-week intervention and were only included in the baseline analysis. Cross-sectional comparisons were analyzed using two-tailed independent t-tests. The intervention data was analyzed using repeated measures analysis of variance.;Results: Carotid-femoral PWV (PWVcf) and cPP were 26% (P=0.001) and 33% (p\u3c0.05) higher, respectively; in MetS individuals compared to healthy controls, and cIMT was 13% (p\u3c0.05) greater in the MetS group. There was no significant difference between the trained and non-trained group in all baseline indexes. The major finding of this study was that 8 weeks of aerobic exercise significantly attenuated PWVcf (8.1 +/- 0.5 vs. 7.2 +/- 0.4 m/s, p\u3c0.05) in the trained group, and no change was observed in the non-trained group (8.0 +/- 0.5 vs. 7.9 +/- 0.3 m/s, p=0.51). Carotid IMT did not change in the trained or non-trained group (0.58 +/- 0.03 vs. 0.58 +/- 0.03 mm, p=0.78 and 0.59 +/- 0.05 vs. 0.61 +/- 0.05 mm, p=0.92). Another discovery was the trained group increased VO 2peak (16.0 +/- 1.4 vs. 18.2 +/-1.7 ml/kg/min, p=0.05), and no change was seen in the non-trained group (19.0 +/- 1.9 vs. 18.7 +/- 1.3 ml/kg/min, p=0.76). Further, PWVcf and cPP were both negatively correlated (r=-.40 and r=-.51, p\u3c0.01 for both) with VO2peak.;Conclusions: Although the mechanisms underlying the improvement in arterial elasticity are not fully understood, there is strong evidence supporting an association with the improvement in peak aerobic capacity. Cross-sectional examination revealed increased stiffening and blunted VO2peak in the MetS individuals. Negative correlation was established between composite measures of stiffness and VO2peak. Following the aerobic exercise intervention, the trained group improved cardiorespiratory fitness, while reducing arterial stiffness. These are novel findings that indicate chronic, aerobic exercise is an effective therapeutic intervention that decreases arterial stiffness, but does not attenuate carotid wall thickening in the MetS