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As far back as the ancient Egyptians and Greeks, physicians have observed and interpreted the arterial pulse to diagnose disease. In the last 20 years, advances in modern engineering have rendered quantitative pulse wave analysis widely available, reliable, and reproducible. To date, measurement of arterial stiffness has remained almost exclusively a research activity. However, ongoing technological improvements coupled with already strong and growing evidence of clinical value should facilitate integration of arterial stiffness measures into clinical practice in the near future. This brief review will highlight clinical areas where arterial stiffness measures are likely to be the most informative in clinical practice.
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Arterias/fisiopatología , Enfermedades Cardiovasculares/diagnóstico , Análisis de la Onda del Pulso , Rigidez Vascular , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE: Obesity and hypertension share a well known association. However, the mechanisms underlying their relationship are not well understood. Our goal was to assess the feasibility of a longitudinal, interventional weight gain study with detailed cardiovascular measurements in humans. METHODS: Sixteen healthy, normotensive, young, male volunteers (28â±â7âyears) were enrolled. Body composition, biochemical and cardiovascular data were obtained at baseline, and after an 8-week period of overfeeding (800-1000âkcal/day). Blood pressure (BP), cardiac output (CO) and peripheral vascular resistance (PVR) were determined, as were the minimum forearm vascular resistance (MFVR), forearm blood flow (FBF) response to mental stress and heart rate variability (HRV) parameters. RESULTS: Overfeeding resulted in a median weight gain of 5.6âkg [interquartile range (IQR) 4.6-6.4âkg; Pâ<â0.001]. Seated systolic and diastolic BP were significantly increased by 10â±â9 and 4â±â6âmmHg, respectively after weight gain (Pâ<â0.001 and Pâ=â0.011, respectively). CO also increased and PVR decreased significantly as a result of weight gain (Pâ=â0.032 and Pâ=â0.044, respectively). MFVR was also significantly decreased after weight gain (Pâ=â0.023). The FBF response to mental stress was blunted significantly (Pâ=â0.002), and sympathovagal balance and responsiveness to orthostatic challenge altered moderately after weight gain. CONCLUSION: Our overfeeding regimen resulted in moderate weight gain and significant increases in BP. An increase in CO is likely to be the dominant mechanism underlying the observed BP changes, with decreases in PVR partially compensating for these effects. Experimental weight gain, coupled with detailed cardiovascular phenotyping, is a feasible model to examine potential mechanisms underlying obesity-associated hypertension in young adults.
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BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. METHODS AND RESULTS: Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using (18)F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). CONCLUSIONS: This study demonstrates that RA patients have increased aortic (18)F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.
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Aorta Torácica/patología , Aorta/patología , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Rigidez Vascular/fisiología , Vasculitis/tratamiento farmacológico , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Aorta/efectos de los fármacos , Aorta Torácica/efectos de los fármacos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/patología , Etanercept , Femenino , Humanos , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Tomografía Computarizada por Rayos X/métodos , Vasculitis/epidemiología , Vasculitis/patologíaRESUMEN
BACKGROUND: Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38α/ß MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. METHODS AND RESULTS: Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol >4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (n=27) or placebo (n=29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (P=0.01 and P=0.03) compared with responses in control subjects (n=12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; P=0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; P=0.02), and to L-NMMA by 10% (95% confidence interval, -1 to 23; P=0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, -81 to -6%; P<0.05) in patients treated with losmapimod compared with placebo. CONCLUSIONS: Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease.
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Hipercolesterolemia/tratamiento farmacológico , Inflamación/prevención & control , Óxido Nítrico/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Vasodilatación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Acetilcolina/farmacología , Antebrazo/irrigación sanguínea , Humanos , Hipercolesterolemia/patología , Inflamación/tratamiento farmacológico , Infusiones Intraarteriales , Nitroprusiato/farmacología , Pletismografía , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Vasodilatadores/farmacología , omega-N-Metilarginina/farmacologíaRESUMEN
RATIONALE: COPD and smoking are characterised by pulmonary inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging may improve knowledge of pulmonary inflammation in COPD patients and aid early development of novel therapies as an imaging biomarker. OBJECTIVES: To evaluate pulmonary inflammation, assessed by FDG uptake, in whole and regional lung in "usual" (smoking-related) COPD patients, alpha-1 antitrypsin deficiency (α1ATD) COPD patients, smokers without COPD and never-smokers using FDG PET/CT. Secondly, to explore cross-sectional associations between FDG PET/CT and systemic inflammatory markers in COPD patients and repeatability of the technique in COPD patients. METHODS: Data from two imaging studies were evaluated. Pulmonary FDG uptake (normalised Ki; nKi) was measured by Patlak graphical analysis in four subject groups: 84 COPD patients, 11 α1ATD-COPD patients, 12 smokers and 10 never-smokers. Within the COPD group, associations between nKi and systemic markers of inflammation were assessed. Repeatability was evaluated in 32 COPD patients comparing nKi values at baseline and at 4-month follow-up. RESULTS: COPD patients, α1ATD-COPD patients and smokers had increased whole lung FDG uptake (nKi) compared with never-smokers (0.0037±0.001, 0.0040±0.001, 0.0040±0.001 versus 0.0028±0.001 mL·cm-3·min-1, respectively, p<0.05 for all). Similar results were observed in upper and middle lung regions. In COPD participants, plasma fibrinogen was associated with whole lung nKi (ß=0.30, p=0.02) in multivariate analysis adjusted for current smoking, forced expiratory volume in 1â s % predicted, systemic neutrophils and C-reactive protein levels. Mean percentage difference in nKi between the baseline and follow-up was 3.2%, and the within subject coefficient of variability was 7.7%. CONCLUSIONS: FDG PET/CT has potential as a noninvasive tool to enable whole lung and regional quantification of FDG uptake to assess smoking- and COPD-related pulmonary inflammation.
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[Figure: see text].
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Inhibidores de la Angiogénesis/efectos adversos , Endotelio Vascular/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipertensión/inducido químicamente , Indazoles/efectos adversos , Pirimidinas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sulfonamidas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Gasto Cardíaco/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Humanos , Hipertensión/fisiopatología , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Rigidez Vascular/efectos de los fármacosRESUMEN
AIMS: The aim of this study was to determine whether simvastatin would protect against inflammation-induced aortic stiffening and endothelial dysfunction. METHODS: Aortic pulse wave velocity (aPWV) and flow-mediated dilatation (FMD) were assessed three times, at baseline, after a 14 day administration of simvastatin or placebo and 8 h after Salmonella typhi vaccination in 50 healthy subjects. RESULTS: Following vaccination there was a significant increase in aPWV in the placebo group (5.80 ± 0.87 vs. 6.21 ± 0.97 m s⻹, 95% CI 0.19, 0.62, P= 0.002) but not the simvastatin group (5.68 ± 0.73 vs. 5.72 ± 0.74 m s⻹, 95% CI -0.19, 0.27, P= 0.9; P= 0.016 for comparison). Whereas FMD response was reduced in the placebo group (6.77 ± 4.10 vs. 5.27 ± 2.88%, 95% CI -2.49, -0.52, P= 0.02) but not in the simvastatin group (7.07 ± 4.37 vs. 7.17 ± 9.94%, 95% CI -1.1, 1.3. P= 0.9, P < 0.001 for comparison). There was no difference in the systemic inflammatory response between groups following vaccination. However, there was a significant reduction in serum apolipoprotein A-I (Apo A-I) in the placebo, but not in the simvastatin, group. CONCLUSIONS: Simvastatin prevents vaccination-induced aortic stiffening and endothelial dysfunction. This protective mechanism may be due to preservation of the Apo A-I lipid fraction, rather than pleiotropic anti-inflammatory effects of statins.
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Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/tratamiento farmacológico , Simvastatina/uso terapéutico , Adulto , Aorta/fisiopatología , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/fisiopatología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Método Doble Ciego , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inflamación/complicaciones , Inflamación/fisiopatología , Interleucina-6/biosíntesis , Lípidos/sangre , Masculino , Vacunas contra la Salmonella , Salmonella typhi , Simvastatina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Adulto JovenRESUMEN
Background Two individuals can have a similar pulse pressure (PP) but different levels of systolic blood pressure (SBP), although the underlying mechanisms have not been described. We hypothesized that, for a given level of PP, differences in SBP relate to peripheral vascular resistance (PVR); and we tested this hypothesis in a large cohort of healthy young adults. Methods and Results Demographic, biochemical, and hemodynamic data from 3103 subjects were available for the current analyses. In both men and women, for a given level of PP, higher SBP was associated with significantly higher body weight, body mass index, heart rate, and PVR (P<0.05 versus those with lower BP for all comparisons). Moreover, stratifying individuals by quartiles of PP and PVR revealed a stepwise increase in SBP from the lowest to highest quartile for each variable, with the highest SBP occurring in those in the highest quartile of both PP and PVR (P<0.001 for overall trend for both sexes). PVR was also increased with increasing tertile of minimum forearm vascular resistance, in both men (P=0.002) and women (P=0.03). Conclusions Increased PVR, mediated in part through altered resistance vessel structure, strongly associates with the elevation of SBP for a given level of PP in young adults. An impaired ability to adapt PVR appropriately to a given level of PP may be an important mechanism underlying elevated SBP in young adults.
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Presión Sanguínea , Extremidad Superior/irrigación sanguínea , Resistencia Vascular , Adaptación Fisiológica , Adolescente , Adulto , Factores de Edad , Estudios Transversales , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
: Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue damage and an alteration of arterial structure and function. Increased arterial stiffness is a well recognized cardiovascular risk factor independent of blood pressure levels and an intermediate endpoint for cardiovascular events. In the present review, we discuss immune-mediated mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening. We also show that acute inflammation predisposes the vasculature to arterial dysfunction and stiffening, and alteration of endothelial function and that chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis are accompanied by profound arterial dysfunction which is proportional to the severity of inflammation. Current findings suggest that treatment of inflammation by targeted drugs leads to regression of arterial dysfunction. There is hope that these treatments will improve outcomes for patients.
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Arterias/fisiopatología , Inflamación , Enfermedades Vasculares , Artritis Reumatoide , Aterosclerosis , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Enfermedades Inflamatorias del Intestino , Rigidez VascularRESUMEN
OBJECTIVES: Although cardiovascular disease (CVD) is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), it is unknown how to improve prediction of cardiovascular (CV) risk in individuals with COPD. Traditional CV risk scores have been tested in different populations but not uniquely in COPD. The potential of alternative markers to improve CV risk prediction in individuals with COPD is unknown. We aimed to determine the predictive value of conventional CVD risk factors in COPD and to determine if additional markers improve prediction beyond conventional factors. DESIGN: Data from the Evaluation of the Role of Inflammation in Chronic Airways disease cohort, which enrolled 729 individuals with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II-IV COPD were used. Linked hospital episode statistics and survival data were prospectively collected for a median 4.6 years of follow-up. SETTING: Five UK centres interested in COPD. PARTICIPANTS: Population-based sample including 714 individuals with spirometry-defined COPD, smoked at least 10 pack years and who were clinically stable for >4 weeks. INTERVENTIONS: Baseline measurements included aortic pulse wave velocity (aPWV), carotid intima-media thickness (CIMT), C reactive protein (CRP), fibrinogen, spirometry and Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) Index, 6 min walk test (6MWT) and 4 m gait speed (4MGS) test. PRIMARY AND SECONDARY OUTCOME MEASURES: New occurrence (first event) of fatal or non-fatal hospitalised CVD, and all-cause and cause-specific mortality. RESULTS: Out of 714 participants, 192 (27%) had CV hospitalisation and 6 died due to CVD. The overall CV risk model C-statistic was 0.689 (95% CI 0.688 to 0.691). aPWV and CIMT neither had an association with study outcome nor improved model prediction. CRP, fibrinogen, GOLD stage, BODE Index, 4MGS and 6MWT were associated with the outcome, independently of conventional risk factors (p<0.05 for all). However, only 6MWT improved model discrimination (C=0.727, 95% CI 0.726 to 0.728). CONCLUSION: Poor physical performance defined by the 6MWT improves prediction of CV hospitalisation in individuals with COPD. TRIAL REGISTRATION NUMBER: ID 11101.
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Enfermedades Cardiovasculares , Enfermedad Pulmonar Obstructiva Crónica , Enfermedades Cardiovasculares/epidemiología , Grosor Intima-Media Carotídeo , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Rendimiento Físico Funcional , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Análisis de la Onda del Pulso , Factores de RiesgoRESUMEN
AIMS: (i) To compare the effects of intra-arterial administration of urotensin II in patients with CVD with healthy volunteers, and (ii) to study the haemodynamic effects of intra-arterial infusion of the urotensin II receptor antagonist, urantide. METHODS: Ten healthy volunteers and 10 patients with CVD received a dose-ramped brachial artery infusion of urotensin II. A further six healthy male volunteers received a prolonged urotensin II infusion and 11 healthy male volunteers received a dose-ramped infusion of urantide. Forearm blood flow (FBF) was measured every 20 min and blood pressure and heart rate were assessed every 20 min. RESULTS: In healthy volunteers and patients with CVD, intra-arterial infusion of urotensin II had no effect on FBF ratio. A dose-ramped infusion of urantide similarly had no effect on FBF ratio. During dose-ramped infusions of urotensin II and urantide, systolic and mean arterial blood pressure increased significantly. In healthy volunteers, urotensin II and urantide, respectively, increased systolic blood pressure from 133 +/- 6 to 137 +/- 5 mmHg (P < 0.01) and from 113 +/- 4 to 120 +/- 4 mmHg (P < 0.01). In patients with CVD, heart rate also significantly increased during dose-ramped infusion of urotensin II from 59 +/- 3 to 62 +/- 4 bpm (P < 0.05). CONCLUSIONS: We have shown no in vivo effect of urotensin II or urantide on human forearm resistance vessels. Previous discrepancies do not seem to relate to either the age or CVD status of subjects. Changes in systemic cardiovascular haemodynamics during the dose-ramped infusion studies are unlikely to be caused by urotensin II receptor modulation.
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Presión Sanguínea/efectos de los fármacos , Antebrazo/irrigación sanguínea , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Fragmentos de Péptidos/efectos de los fármacos , Urotensinas/efectos de los fármacos , Adulto , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios de Casos y Controles , Humanos , Infusiones Intraarteriales , Masculino , Fragmentos de Péptidos/administración & dosificación , Flujo Sanguíneo Regional/efectos de los fármacos , Resultado del Tratamiento , Urotensinas/administración & dosificación , Adulto JovenRESUMEN
The aim of this study was to evaluate an inert gas rebreathing method (Innocor) for measurement of cardiac output and related haemodynamic variables and to provide robust normative data describing the influence of age, gender and body size on these variables. Four separate studies were conducted: measurement repeatability (study 1, n = 45); postural change (study 2, n = 40); response to submaximal cycling exercise (study 3, n = 20); and the influence of age, gender and body size (study 4, n = 1400). Repeated measurements of cardiac output, stroke volume and heart rate were similar, with low mean (±SD) differences (0.26 ± 0.53 L/min, 0 ± 11 mL and 2 ± 6beats/min, respectively). In addition, cardiac output and stroke volume both declined progressively from supine to seated and standing positions (P < 0.001 for both) and there was a stepwise increase in both parameters moving from rest to submaximal exercise (P < 0.001 for both). In study 4, there was a significant age-related decline in cardiac output and stroke volume in males and females, which remained significant after adjusting for body surface area (BSA, P < 0.001 for all comparisons). Both parameters were also significantly higher in those with high body mass index (BMI; P < 0.01 versus those with normal BMI for all comparisons), although indexing cardiac output and stroke volume to BSA reversed these trends. Inert gas rebreathing using the Innocor device provides repeatable measurements of cardiac output and related indices, which are sensitive to the effects of acute physiological manoeuvres. Moreover, inert gas rebreathing is a suitable technique for examining chronic influences such as age, gender and body size on key haemodynamic components of the arterial blood pressure.
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Gasto Cardíaco , Gases Nobles , Adulto , Envejecimiento , Ciclismo/fisiología , Tamaño Corporal , Superficie Corporal , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Postura , Valores de Referencia , Reproducibilidad de los Resultados , Caracteres Sexuales , Sedestación , Posición de Pie , Volumen Sistólico , Posición Supina , Adulto JovenRESUMEN
Blood pressure (BP) in young adults predicts BP in later life. We aimed to identify metabolic, hemodynamic, and autonomic characteristics associated with raised BP in young adults and whether these differ between males and females. Three thousand one hundred forty-five healthy subjects, aged 18 to 40 years, were grouped according to sex and BP category following the recent reclassification of BP as part of American Heart Association/American College of Cardiology 2017 guidelines. All individuals undertook a lifestyle and medical history questionnaire and detailed metabolic, hemodynamic, and autonomic assessments. Stage 1 hypertension and normal BP were the most common BP phenotypes in males (29%) and females (68%), respectively. In both sexes, cardiac output was positively associated with increasing BP category (P<0.001 for both). Similar positive trends were observed for heart rate and stroke volume in males (P<0.001 for both) and heart rate in females (P<0.001). Unlike in males, peripheral vascular resistance, aortic pulse wave velocity, and augmentation index were significantly increased in hypertensive females (P<0.001 for all) compared with the other BP categories. Most heart rate variability indices decreased across the BP categories, particularly in males. In young adults, metabolic and hemodynamic abnormalities associated with hypertension are already present at the elevated BP stage and the overall phenotype differed markedly between sexes. Whereas a cardiac phenotype was associated with elevated BP and hypertension in males, a vascular phenotype, characterized by elevated peripheral vascular resistance, aortic pulse wave velocity, and augmentation index, was dominant in females.
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Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Hipertensión/fisiopatología , Adolescente , Adulto , Femenino , Humanos , Masculino , Análisis de la Onda del Pulso , Caracteres Sexuales , Volumen Sistólico/fisiología , Resistencia Vascular/fisiología , Rigidez Vascular/fisiología , Adulto JovenRESUMEN
BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. OBJECTIVES: This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). METHODS: This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). RESULTS: We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. CONCLUSIONS: In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.
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Ciclopropanos/administración & dosificación , Fibrinógeno/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Piridinas/administración & dosificación , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/mortalidadRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-alpha therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P = 0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2 = 0.701; P < 0.0001). Aortic PWV was reduced significantly by anti-TNF-alpha therapy (8.82+/-2.04 versus 7.94+/-1.86 versus 7.68+/-1.56 m/s at weeks 0, 4, and 12, respectively; P < 0.001); concomitantly, endothelial function improved. CONCLUSIONS: RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-alpha therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.
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Aorta/fisiopatología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Aterosclerosis/fisiopatología , Proteínas de Neoplasias/uso terapéutico , Receptores Tipo II del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antirreumáticos/uso terapéutico , Aorta/efectos de los fármacos , Artritis Reumatoide/fisiopatología , Aterosclerosis/etiología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea , Susceptibilidad a Enfermedades/fisiopatología , Elasticidad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Etanercept , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Inflamación/complicaciones , Inflamación/fisiopatología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/farmacología , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Análisis de Regresión , Factores de Riesgo , Receptores Señuelo del Factor de Necrosis TumoralRESUMEN
High dietary sodium intake triggers increased blood pressure (BP). Animal studies show that dietary salt loading results in dermal Na+ accumulation and lymphangiogenesis mediated by VEGF-C (vascular endothelial growth factor C), both attenuating the rise in BP. Our objective was to determine whether these mechanisms function in humans. We assessed skin electrolytes, BP, and plasma VEGF-C in 48 healthy participants randomized to placebo (70 mmol sodium/d) and slow sodium (200 mmol/d) for 7 days. Skin Na+ and K+ concentrations were measured in mg/g of wet tissue and expressed as the ratio Na+:K+ to correct for variability in sample hydration. Skin Na+:K+ increased between placebo and slow sodium phases (2.91±0.08 versus 3.12±0.09; P=0.01). In post hoc analysis, there was a suggestion of a sex-specific effect, with a significant increase in skin Na+:K+ in men (2.59±0.09 versus 2.88±0.12; P=0.008) but not women (3.23±0.10 versus 3.36±0.12; P=0.31). Women showed a significant increase in 24-hour mean BP with salt loading (93±1 versus 91±1 mm Hg; P<0.001) while men did not (96±2 versus 96±2 mm Hg; P=0.91). Skin Na+:K+ correlated with BP, stroke volume, and peripheral vascular resistance in men but not in women. No change was noted in plasma VEGF-C. These findings suggest that the skin may buffer dietary Na+, reducing the hemodynamic consequences of increased salt, and this may be influenced by sex.
Asunto(s)
Dieta Hiposódica/métodos , Hipertensión , Potasio , Piel/metabolismo , Cloruro de Sodio , Sodio , Factor C de Crecimiento Endotelial Vascular/sangre , Adulto , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Método Doble Ciego , Inglaterra , Femenino , Hemodinámica/fisiología , Humanos , Hipertensión/diagnóstico , Hipertensión/dietoterapia , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Potasio/análisis , Potasio/metabolismo , Eliminación Renal/fisiología , Factores Sexuales , Sodio/análisis , Sodio/metabolismo , Cloruro de Sodio/metabolismo , Cloruro de Sodio/farmacología , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
OBJECTIVE: Nitrates are used widely in clinical practice. However, the mechanism underlying the bioactivation of nitrates to release NO remains unclear. Recent animal data suggest that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in nitrate bioactivation, but its role in humans is not known. We investigated the role of ALDH2 in the vascular effects of nitroglycerin (NTG) in humans in vivo. METHODS AND RESULTS: Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33% reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu504lys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu504lys mutation compared with East Asian and non-Asian wild-type control subjects (40% reduction in AUC; P=0.02). CONCLUSIONS: The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.
Asunto(s)
Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Nitroglicerina/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Vasodilatadores/metabolismo , Adulto , Aldehído Deshidrogenasa/antagonistas & inhibidores , Aldehído Deshidrogenasa Mitocondrial , Estudios Cruzados , Disulfiram/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Femenino , Antebrazo/irrigación sanguínea , Genotipo , Humanos , Masculino , Nitroglicerina/administración & dosificación , Nitroprusiato/administración & dosificación , Vasodilatadores/administración & dosificación , Verapamilo/administración & dosificaciónRESUMEN
OBJECTIVES: The positive association between adiposity and hypertension is well recognized. However, not all overweight individuals have elevated blood pressure (BP). Moreover, different factors may be associated with high BP in normal-weight versus overweight individuals. The aim of the current study was to examine the influence of adiposity on the relationship between SBP and underlying haemodynamic mechanisms in young adults. METHOD: Data from 2502 patients were available from the Enigma study. Detailed demographic, biochemical, and haemodynamic data were obtained in all individuals. Data were analysed between lower and upper tertiles of BMI and SBP, separately for each sex. RESULTS: In normal-weight individuals, cardiac output (CO) was elevated in those with higher SBP, independently of body size. Moreover, higher CO was associated with an increased stroke volume in men (Pâ<â0.001), but an increased heart rate in women (Pâ=â0.002). In contrast, in overweight individuals, peripheral vascular resistance (PVR) was elevated in men with higher SBP (Pâ=â0.02) and those with lower SBP had the lowest PVR of all groups. In linear regression analyses, there was a stronger association between SBP and CO in normal-weight individuals, but a stronger association between SBP and PVR in overweight individuals. CONCLUSION: Different haemodynamic mechanisms are associated with elevated SBP in young adults, depending on body size and sex. These data suggest the need for differential approaches to the identification and management of young adults with elevated BP.
Asunto(s)
Adiposidad/fisiología , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Sobrepeso/fisiopatología , Adulto , Índice de Masa Corporal , Tamaño Corporal , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Factores Sexuales , Volumen Sistólico , Resistencia Vascular , Adulto JovenRESUMEN
BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Biopterinas/análogos & derivados , Fármacos Cardiovasculares/administración & dosificación , Suplementos Dietéticos , Endotelio Vascular/efectos de los fármacos , Enfermedades Vasculares/prevención & control , Rigidez Vascular/efectos de los fármacos , Administración Oral , Adulto , Anciano , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/fisiopatología , Biomarcadores/sangre , Biopterinas/administración & dosificación , Biopterinas/efectos adversos , Fármacos Cardiovasculares/efectos adversos , Estudios Cruzados , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Inglaterra , Femenino , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proyectos Piloto , Análisis de la Onda del Pulso , Factores de Tiempo , Resultado del Tratamiento , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/fisiopatología , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
The autonomic nervous system is important in regulating blood pressure, but whether it regulates aortic stiffness is more contentious. We conducted 3 studies in young, healthy individuals to address this important question. Study 1 was a cross-sectional study of 347 subjects with detailed measurements of hemodynamics and heart rate variability. In study 2, 9 subjects were given a bolus of intravenous nicotinic ganglion blocker, pentolinium, or saline in a random order and hemodynamics and heart rate variability were assessed before and after. In study 3, changes in hemodynamics and heart rate variability were assessed during stimulation of the sympathetic nervous system with the use of isometric handgrip exercise in 12 subjects. Study 1: aortic pulse wave velocity (P=0.003) was lowest in the subjects with the highest parasympathetic activity, but after adjusting for mean arterial pressure, the effect was abolished (P=0.3). Study 2: after pentolinium, sympathetic and parasympathetic activity fell (P=0.001 for both), mean arterial pressure, and heart rate increased (P=0.004 and P=0.04, respectively), but there was no change in pulse wave velocity in comparison to placebo (P=0.1). Study 3: during handgrip exercise, sympathetic activity (P=0.003), mean arterial pressure (P<0.0001), and aortic pulse wave velocity increased (P=0.013). However, pulse wave velocity adjusted for mean arterial pressure did not change (P=0.1). The main finding of these studies is that in young healthy subjects, the autonomic nervous system does not have a pressure-independent role in the regulation of aortic stiffness. However, these findings may not apply to patients with increased sympathetic tone or hypertension.