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AIMS: Antihypertensive drugs have been implicated in coronavirus disease 2019 (COVID-19) susceptibility and severity, but estimated associations may be susceptible to bias. We aimed to evaluate antihypertensive medications and COVID-19 diagnosis and mortality, accounting for healthcare-seeking behaviour. METHODS: A population-based case-control study was conducted including 16 866 COVID-19 cases and 70 137 matched controls from the UK Clinical Practice Research Datalink. We evaluated all-cause mortality among COVID-19 cases. Exposures were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (B), calcium-channel blockers (C), thiazide diuretics (D) and other antihypertensive drugs (O). Analyses were adjusted for covariates and consultation frequency. RESULTS: ACEIs were associated with lower odds of COVID-19 diagnosis (adjusted odds ratio [AOR] 0.82, 95% confidence interval [CI] 0.77-0.88) as were ARBs (AOR 0.87, 95% CI 0.80-0.95) with little attenuation from adjustment for consultation frequency. C and D were also associated with lower odds of COVID-19 diagnosis. Increased odds of COVID-19 for B (AOR 1.19, 95% CI 1.12-1.26) were attenuated after adjustment for consultation frequency (AOR 1.01, 95% CI 0.95-1.08). Patients treated with ACEIs or ARBs had similar odds of mortality (AOR 1.00, 95% CI 0.83-1.20) to patients treated with classes B, C, D or O or patients receiving no antihypertensive therapy (AOR 0.99, 95% CI 0.83-1.18). CONCLUSIONS: There was no evidence that antihypertensive therapy is associated with increased risk of COVID-19 diagnosis or mortality; most classes of antihypertensive therapy showed negative associations with COVID-19 diagnosis.
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COVID-19 , Hipertensão , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Teste para COVID-19 , Estudos de Casos e Controles , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , SARS-CoV-2RESUMO
RATIONALE: One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways. OBJECTIVE: The main objective of this study is to assess the role of a comprehensive panel of IgG glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA. METHODS AND RESULTS: We measured 76 IgG glycosylation traits in 2970 women (age range, 40-79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease risk score and their carotid and femoral plaque measured by ultrasound imaging. Eight IgG glycan traits are associated with the 10-year atherosclerotic cardiovascular disease risk score after adjusting for multiple tests and for individual risk factors-5 with increased risk and 3 with decreased risk. These glycans replicated in 967 women from ORCADES cohort (Orkney Complex Disease Study), and 6 of them were also associated in 845 men. A linear combination of IgG glycans and GlycA is also associated with presence of carotid (odds ratio, 1.55; 95% confidence interval, 1.25-1.93; P=7.5×10-5) and femoral (odds ratio, 1.32; 95% confidence interval, 1.06-1.64; P=0.01) plaque in a subset of women with atherosclerosis data after adjustment for traditional risk factors. One specific glycosylation trait, GP18-the percentage of FA2BG2S1 glycan in total IgG glycans, was negatively correlated with very-low-density lipoprotein and triglyceride levels in serum and with presence of carotid plaque (odds ratio, 0.60; 95% confidence interval, 0.50-0.71; P=5×10-4). CONCLUSIONS: We find molecular pathways linking IgG to arterial lesion formation. Glycosylation traits are independently associated with subclinical atherosclerosis. One specific trait related to the sialylated N-glycan is negatively correlated with cardiovascular disease risk, very-low-density lipoprotein and triglyceride serum levels, and presence of carotid plaque.
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Aterosclerose/complicações , Doenças Cardiovasculares/etiologia , Doenças em Gêmeos/etiologia , Imunoglobulina G/metabolismo , Adulto , Idoso , Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/metabolismo , Estudos de Coortes , Intervalos de Confiança , Doenças em Gêmeos/metabolismo , Feminino , Artéria Femoral/diagnóstico por imagem , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Polissacarídeos/metabolismo , Medição de Risco , Fatores de Risco , UltrassonografiaRESUMO
BACKGROUND: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia. STUDY DESIGN: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. CONCLUSION: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations.
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Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Adolescente , Adulto , Idoso , Anlodipino/uso terapêutico , Povo Asiático , População Negra , Clortalidona/uso terapêutico , Estudos Cross-Over , Esquema de Medicação , Quimioterapia Combinada , Hemodinâmica , Humanos , Hipertensão/fisiopatologia , Lisinopril/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Reino Unido , População Branca , Adulto JovemRESUMO
Patient-specific one-dimensional (1D) blood flow modeling requires estimating model parameters from available clinical data, ideally acquired noninvasively. The larger the number of arterial segments in a distributed 1D model, the greater the number of input parameters that need to be estimated. We investigated the effect of a reduction in the number of arterial segments in a given distributed 1D model on the shape of the simulated pressure and flow waveforms. This is achieved by systematically lumping peripheral 1D model branches into windkessel models that preserve the net resistance and total compliance of the original model. We applied our methodology to a model of the 55 larger systemic arteries in the human and to an extended 67-artery model that contains the digital arteries that perfuse the fingers. Results show good agreement in the shape of the aortic and digital waveforms between the original 55-artery (67-artery) and reduced 21-artery (37-artery) models. Reducing the number of segments also enables us to investigate the effect of arterial network topology (and hence reflection sites) on the shape of waveforms. Results show that wave reflections in the thoracic aorta and renal arteries play an important role in shaping the aortic pressure and flow waves and in generating the second peak of the digital pressure and flow waves. Our novel methodology is important to simplify the computational domain while maintaining the precision of the numerical predictions and to assess the effect of wave reflections.
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Aorta/fisiologia , Pressão Sanguínea/fisiologia , Simulação por Computador , Hemodinâmica , Modelos Cardiovasculares , Artéria Renal/fisiologia , Artérias/fisiologia , Velocidade do Fluxo Sanguíneo , HumanosRESUMO
Introduction: Aortic root dilatation is a reported cardiovascular sequela seen in children and young people (CYP) with chronic kidney disease (CKD) but has yet to be described in those with autosomal dominant polycystic kidney disease (ADPKD). Methods: Single center, cross-sectional study in a dedicated ADPKD clinic. Echocardiograms were evaluated for the presence of dilatation (defined by a z-score ≥2 [≥99th percentile] SDs from the mean) at 4 standardized locations, namely the aortic valve annulus, sinuses of Valsalva (SoV), sinotubular junction (STJ), and the ascending aorta. Measurements were compared with a control group to assess prevalence, severity, and determinants of aortic dilatation. Results: Ninety-seven children, median age (interquartile range) of 9.3 (6.1, 13.6) years were compared with 19 controls without ADPKD or other CKD. The prevalence of dilatation ranged from 5.2% to 17% in ADPKD, depending on anatomical location with no aortic dilatation identified in the control group. In multivariable regression, aortic root dilatation was significantly associated with cyst burden at the aortic valve annulus and SoV (ß = 0.42 and ß = 0.39, both P < 0.001), with age at SoV (ß = -0.26, P = 0.02), systolic blood pressure (SBP) z-score at SoV (ß = -0.20, P = 0.04) and left ventricular mass index (LVMI) at SoV and STJ (ß = 0.24, P = 0.02 and ß = 0.25, P = 0.03, respectively) following adjustment for age, sex (male or female), body mass index (BMI) z-score, estimated glomerular filtration rate (eGFR), SBP z-score, and LVMI. Conclusion: Our data suggests increased prevalence of aortic root and ascending aortic dilatation in CYP with ADPKD compared with controls. Further studies are needed to understand the pathogenesis and its contribution to the high cardiovascular morbidity in ADPKD.
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We performed a systematic review and meta-analysis to determine the relative contributions of elevated cardiac output and systemic vascular resistance to hypertension in children and adults. This included 27 studies on 11 765 hypertensive and normotensive children and adults in whom cardiac output was measured. Cardiac output but not systemic vascular resistance was elevated in hypertensive compared to normotensive children and young adults (difference in means 1.15 [0.78-1.52] l/min, P < 0.001). In older hypertensive adults, both were elevated compared to normotensive individuals (0.40 [0.26-0.55] l/min, P < 0.001 and 3.21 [1.91-4.51] mmHg min/l, P < 0.001 for cardiac output and systemic vascular resistance, respectively). The main haemodynamic alteration in primary hypertension (including obesity-hypertension) in both children and young to middle-aged adults is an elevation of cardiac output. With longer duration and greater severity of hypertension there may be progression from a 'cardiac' to a 'vascular' phenotype with increased systemic vascular resistance.
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Hipertensão Essencial , Hemodinâmica , Humanos , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Hipertensão Essencial/fisiopatologia , Hemodinâmica/fisiologia , Resistência Vascular/fisiologia , Criança , Adulto , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Supressed plasma renin in patients with primary hypertension is thought to be an indirect marker of sodium-induced volume expansion which is associated with more severe hypertension and hypertension-mediated organ damage. A novel test for erythrocyte glycocalyx sensitivity to sodium (eGCSS) has been proposed as a direct measure of sodium-induced damage on erythrocyte surfaces and a marker of sensitivity of the endothelium to salt in humans. Here we explore if eGCSS relates to plasma renin and other clinical and biochemical characteristics in a cohort of patients with primary hypertension. Hypertensive subjects (n = 85, 54% male) were characterised by blood biochemistry (including plasma renin/aldosterone), urine analysis for albumin-creatinine ratio (ACR), 24-h urine sodium/potassium excretion. eGCSS was measured using a commercially available kit. Correlations between eGCSS and clinical and biochemical characteristics were explored using Spearman's correlation coefficient and characteristics compared across tertiles of eGCSS. eGCSS was inversely correlated with renin (p < 0.05), with renin 17.72 ± 18 µU/l in the highest tertile of eGCSS compared to 84.27 ± 146.5 µU/l in the lowest (p = 0.012). eGCSS was positively correlated with ACR (p < 0.01), with ACR 7.37 ± 15.29 vs. 1.25 ± 1.52 g/mol for the highest vs. lowest tertiles of eGCSS (p < 0.05). eGCSS was not correlated with other clinical characteristics or biochemical measures. These results suggests that sodium retention in hypertension characterised by a low-renin state is associated with cell membrane damage reflected by eGCSS. This may contribute to the hypertension-mediated organ damage and the excess mortality associated with sodium overload and "salt sensitivity".
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Hipertensão , Sódio , Humanos , Masculino , Feminino , Sódio/urina , Projetos Piloto , Renina , Glicocálix/metabolismo , Pressão Sanguínea , Hipertensão/complicações , Cloreto de Sódio , Cloreto de Sódio na Dieta , Eritrócitos/metabolismo , Aldosterona , Hipertensão Essencial/complicaçõesRESUMO
AIM: The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown. METHODS: Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample. RESULTS: One hundred and one participants (60 men) aged 47.8â±â14.1 (meanâ±âSD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n â=â34) and those recovered from mild symptoms of COVID-19 ( n â=â34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P â=â0.001). In a sub-sample ( n â=â22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P â=â0.006) with no significant difference between hospitalized ( n â=â12) and nonhospitalized participants ( n â=â10). CONCLUSIONS: In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications.
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COVID-19 , Hipertensão , Masculino , Humanos , Vasodilatação , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Adrenérgicos/farmacologia , Endotélio Vascular , COVID-19/complicações , Vasodilatadores/farmacologia , Albuterol/farmacologia , Albuterol/uso terapêuticoRESUMO
BACKGROUND: Optimal target blood pressure to reduce adverse cardiac remodelling in children with chronic kidney disease is uncertain. We hypothesised that lower blood pressure would reduce adverse cardiac remodelling. METHODS: HOT-KID, a parallel-group, open-label, multicentre, randomised, controlled trial, was done in 14 clinical centres across England and Scotland. We included children aged 2-15 years with stage 1-4 chronic kidney disease-ie, an estimated glomerular filtration rate (eGFR) higher than 15 mL/min per 1·73 m2-and who could be followed up for 2 years. Children on antihypertensive medication were eligible as long as it could be changed to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) if they were not already receiving these therapies. Participants were randomly assigned (1:1) to standard treatment (auscultatory office systolic blood pressure target between the 50th and 75th percentiles) or intensive treatment (systolic target <40th percentile) by the chief investigator using a rapid, secure, web-based randomisation system. ACE inhibitors or ARBs were used as first-line agents, with the dose titrated every 2-4 weeks to achieve the target blood pressure levels. The primary outcome was mean annual difference in left ventricular mass index (LVMI) by echocardiography measured by a masked observer and was assessed in the intention-to-treat population, defined as all the children who underwent randomisation irrespective of the blood pressure reached. Secondary and safety outcomes were the differences between groups in mean left ventricular relative wall thickness, renal function, and adverse effects and were also assessed in the intention-to-treat population. This trial is registered with ISRCTN, ISRCTN25006406. FINDINGS: Between Oct 30, 2012, and Jan 5, 2017, 64 participants were randomly assigned to the intensive treatment group and 60 to the standard treatment group (median age of participants was 10·0 years [IQR 6·8-12·6], 69 [56%] were male and 107 [86%] were of white ethnicity). Median follow-up was 38·7 months (IQR 28·1-52·2). Blood pressure was lower in the intensive treatment group compared with standard treatment group (mean systolic pressure lower by 4 mm Hg, p=0·0012) but in both groups was close to the 50th percentile. The mean annual reduction in LVMI was similar for intensive and standard treatments (-1·9 g/m2·7 [95% CI -2·4 to -1·3] vs -1·2 g/m2·7 [-1·5 to 0·8], with a treatment effect of -0·7 g/m2·7 [95% CI -1·9 to 2·6] per year; p=0·76) and mean value in both groups at the end of follow-up within the normal range. At baseline, elevated relative wall thickness was more marked than increased LVMI and a reduction in relative wall thickness was greater for the intensive treatment group than for the standard treatment group (-0·010 [95% CI 0·015 to -0·006] vs -0·004 [-0·008 to 0·001], treatment effect -0·020 [95% CI -0·039 to -0·009] per year, p=0·0019). Six (5%) participants reached end-stage kidney disease (ie, an eGFR of <15 mL/min per 1·73 m2; three in each group) during the course of the study. The risk difference between treatment groups was 0·02 (95% CI -0·15 to 0·19, p=0·82) for overall adverse events and 0·07 (-0·05 to 0·19, p=0·25) for serious adverse events. Intensive treatment was not associated with worse renal outcomes or greater adverse effects than standard treatment. INTERPRETATION: These results suggest that cardiac remodelling in children with chronic kidney disease is related to blood pressure control and that a target office systolic blood pressure at the 50th percentile is close to the optimal target for preventing increased left ventricular mass. FUNDING: British Heart Foundation.
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Inibidores da Enzima Conversora de Angiotensina , Insuficiência Renal Crônica , Masculino , Criança , Humanos , Feminino , Pressão Sanguínea , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Remodelação Ventricular , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Objectives: We investigated the sensitivity and reproducibility of inferior vena cava (IVC) diameters and superior vena cava (SVC) flow velocities in detecting changes in cardiac preload in clinically euvolemic subjects with hypertension. Methods: Measurements were obtained during passive leg raising (PLR) and lower limb venous occlusion (LVO), interventions which respectively transiently increase and decrease cardiac preload. Measurements were made in 36 subjects and repeated on two separate occasions to examine reproducibility. Results: During PLR, there was no significant change in IVC diameters, but peak flow velocity of the SVC S wave increased by 6.5 (95% confidence interval 1.6-11.3) cm/s (P = 0.01). During LVO, IVC diameter in expiration decreased by 3.2 (1.7-4.7) mm and the SVC S wave decreased by 9.7 (4.4-14.7) cm/s (P < 0.001). Venae cavae-derived indices can be used to assess changes in preload within the physiological range in euvolemia. Conclusions: Despite suboptimal reproducibility of baseline measurements, high agreeability between the changes in IVC diameter and SVC flow after LVO suggests that these indices can be used to monitor changes in cardiac preload.
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[Figure: see text].
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Anti-Hipertensivos/uso terapêutico , Hipertensão , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Viés , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Conduta do Tratamento Medicamentoso/normas , Método de Monte Carlo , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Melhoria de Qualidade , Medição de Risco/métodos , TempoRESUMO
OBJECTIVES: Hypertension phenotypes differ between Africans and Europeans, with a greater prevalence of low renin salt-sensitive hypertension and greater predisposition to adverse cardiac remodelling in Africans. To elucidate the roles of inheritance and environment in determining hypertension phenotypes in sub-Saharan Africans and white-Europeans, we compared phenotypes in white individuals in the UK (nâ=â132) and in African individuals in the UK (nâ=â158) and Nigeria (nâ=â179). METHODS: Biochemistry, blood pressure, left ventricular structure (echocardiography) and 24-h urinary collections of sodium and potassium were measured. RESULTS: Twenty-four-hour urinary sodium/potassium ratio was lower in individuals living in Europe (both African and white: 2.32â±â0.15 and 2.28â±â0.17) than in individuals in Nigeria (4.09â±â0.26, both Pâ<â0.001) reflecting proportionately higher potassium intake in Europeans (African or white) than African residents. Plasma renin was lower in Africans irrespective of residency than white Europeans, but aldosterone was higher in Africans in Europe than those in Africa (466.15â±â32.95 vs. 258.60â±â17.42âpmol/l, Pâ<â0.001). Left ventricular mass index adjusted for blood pressure and other confounders was greatest in Africans in Europe (103.27â±â2.32âg/m) compared with those in Africa (89.28â±â1.98âg/m) or white Europeans (86.77â±â2.63âg/m, both Pâ<â0.001). CONCLUSION: Despite a similar low renin state in African origin individuals living in Europe and Africa, a higher aldosterone level, possibly related to higher potassium intake or other environmental factors, may contribute to greater cardiac remodelling in Africans in Europe.
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Pressão Sanguínea , Hipertensão/etnologia , Aldosterona/sangue , População Negra , Ecocardiografia , Etnicidade , Europa (Continente) , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nigéria , Fenótipo , Renina/sangue , Sódio , Cloreto de Sódio na Dieta , Reino Unido , População BrancaRESUMO
OBJECTIVES: To assess the impact of variable drug response and measurement error on SBP control. METHODS: We simulated a treat-to-target strategy for populations with different pretreatment SBP, whereby medications were added sequentially until measured SBP (mSBP) less than 140âmmHg. Monte Carlo simulations determined variability of both drug response (drugeffâ±âσdrug; 10â±â5âmmHg base case) and measurement error (σmeas; 10âmmHg base case) of true SBP (tSBP). The primary outcome measure was the proportion of individuals who achieved target less than 140âmmHg. RESULTS: Decision-making based on mSBP resulted in 35.0% of individuals with initial tSBP 150âmmHg being either inappropriately given, or inappropriately denied a second drug. When the simulation was run for multiple drug titrations, measurement error limited tSBP control for all populations tested. A strategy of drug titration based on a second measurement for individuals at risk of incorrect decisions (mSBP 120-150âmmHg; σmeas 15âmmHg) reduced the proportion above target from 40.1 to 30.0% when initial tSBP 160âmmHg. When the measurement variability for the second reading was reduced below that usually seen in clinical practice (σmeas 5âmmHg), the proportion above target decreased further to 17.4%. CONCLUSION: In this simulation, measurement error had the greatest impact on the proportion of individuals achieving their SBP target. Efforts to reduce this error through repeated measures, alternative measurement techniques or changing thresholds, are promising strategies to reduce cardiovascular morbidity and mortality and should be investigated in clinical trials. Here we have shown that Monte Carlo simulations are a useful technique to investigate the influence of uncertainty for different hypertension management strategies.
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Anti-Hipertensivos , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Hipertensão , Método de Monte Carlo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , IncertezaRESUMO
We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39-81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean±SD follow-up of 4.3±1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase (P=0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (ß=0.19, P=0.008) and collagen type IV α 1 (ß=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (ß=-0.20, P=0.005), angiotensin-converting enzyme (ß=-0.15, P=0.035), and B-cell CLL/lymphoma11B (ß=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (ß=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV α 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.
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Arteriosclerose/genética , Pressão Sanguínea/fisiologia , Expressão Gênica , Gêmeos/genética , Rigidez Vascular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Arteriosclerose/diagnóstico por imagem , Arteriosclerose/fisiopatologia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/fisiopatologia , Estudos Transversais , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/fisiopatologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Ultrassonografia , Reino UnidoRESUMO
Myocardial wall stress (MWS) is thought to be the mechanical stimulus to ventricular hypertrophy. The objective of this study was to examine whether MWS is elevated in children with chronic kidney disease (CKD) who are at high risk of developing adverse cardiovascular events related to left ventricular (LV) hypertrophy. MWS, a function of left ventricular pressure, myocardial wall volume, and cavity volume, was obtained using carotid tonometry to estimate ventricular pressure and 2-dimensional transthoracic echocardiographic wall-tracking to obtain LV cavity and wall volumes. Ninety-two children (50 boys) aged 11.2±3.2 (mean±SD) years, including healthy controls (n=16), and those with CKD disease divided into 3 groups according to estimated glomerular filtration rate (mL/min per 1.73 m2) >90 (CKD 1, n=26), 60 to 90(CKD 2, n=23), and <60 (CKD≥3, n=27) were studied. There was no significant difference in age, height, weight, central or peripheral blood pressure, LV mass, or mass index in the 4 study groups. By contrast, peak, mean, and end-systolic MWS were higher in children with CKD and increased across stages of CKD (peak MWS, 338.8±18.5 and 397.5±14.3 s/cm2 in controls and CKD≥3, respectively; P=0.01). Higher systolic MWS was explained by a form of LV dysfunction whereby dynamic values of the ratio of wall volume/cavity size during systole were lower in children with CKD than in those without (P=0.001). Children with CKD exhibit blood pressureindependent LV dysfunction which results in increased systolic MWS and which may predispose to LV hypertrophy in later life.
Assuntos
Pressão Sanguínea/fisiologia , Ventrículos do Coração/fisiopatologia , Hipertensão/etiologia , Hipertrofia Ventricular Esquerda/complicações , Insuficiência Renal Crônica/complicações , Volume Sistólico/fisiologia , Função Ventricular Esquerda , Criança , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Estudos Prospectivos , Insuficiência Renal Crônica/fisiopatologiaRESUMO
We compared large artery mechanical properties in children with nondialysis stages of chronic kidney disease with those in children with normal renal function, examining the potential effect of blood pressure (BP) components and level of renal dysfunction. Common carotid artery mechanical properties, carotid-femoral pulse wave velocity, and carotid and peripheral BP were measured in children (n=226) with nondialysis chronic kidney disease (n=188; 11.9±3.7 years; 26%, 25%, 30%, 16%, and 3% in stages 1, 2, 3, 4 and 5, respectively) and healthy controls (n=38; 11.5±3.3 years). In children with nondialysis chronic kidney disease when compared with healthy controls, at similar levels of peripheral and carotid BP, carotid artery diastolic diameter and wall thickness were similar. In those with suboptimal BP (≥75th percentile), indices of arterial elasticity indicated greater stiffness than in healthy normotensive controls (distensibility: 92±31 versus 114±33 kPa(-1)×10(-3), P=0.03; compliance: 2.1±0.7 versus 2.6±0.7 m(2) kPa(-1)×10(-6), P=0.02; Young elastic modulus: 0.151±0.068 versus 0.109±0.049 kPa×10(3), P=0.02; and wall stress: 83.6±23.5 versus 68.7±14.9 kPa, P=0.02). In all children, mechanical properties were independently related to carotid and peripheral BP components but not to estimated glomerular filtration rate. In children with nondialysis chronic kidney disease, changes in elastic properties of the carotid artery are primarily related to BP and not to glomerular renal function.
Assuntos
Pressão Sanguínea/fisiologia , Artérias Carótidas/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adolescente , Criança , Pré-Escolar , Elasticidade , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Análise de Onda de Pulso , Diálise RenalRESUMO
Differences between central aortic root (c) and peripheral (p) systolic blood pressure (SBP) may be particularly marked in children, but noninvasive methods for assessing cSBP in children have not been validated. We compared estimates of cSBP obtained from radiofrequency ultrasound wall tracking of the carotid artery (ART.LAB system) with that measured directly by a catheter in the aortic root at the time of arterial cannulation. Carotid waveforms were calibrated from invasive measurements of mean and diastolic pressures. In 9 children aged 10.5 ± 5.0 years (mean ± SD), cSBP obtained from carotid wall tracking was highly correlated with invasive measures of cSBP (r=0.99) with mean (± SD) difference 3.9 ± 2.5 mm Hg. Second, we compared values of cSBP obtained from the carotid with those obtained using noninvasive applanation tonometry at the radial artery and a radial-to-aortic transfer function (SphygmoCor). Both carotid and radial tonometric measurements were calibrated from the same peripheral mean and diastolic measurements of blood pressure obtained by sphygmomanometry. In 84 children aged 13.2 ± 3.2 years, there was excellent agreement between the 2 methods (r=0.95; P<0.001) with mean difference 0.71 ± 3.7 mm Hg (95% confidence interval =-1.53 to 1.01). This invasive validation study confirms that cSBP as estimated by carotid wall tracking provides an acceptable measurement of true cSBP when calibration is from true mean and diastolic pressures. Close agreement of cSBP obtained by carotid wall tracking and radial tonometry suggests that these provide similar results when calibrated from the same peripheral blood pressure measurements.
Assuntos
Pressão Arterial/fisiologia , Determinação da Pressão Arterial/métodos , Artéria Carótida Primitiva/diagnóstico por imagem , Hipertensão/fisiopatologia , Adolescente , Artéria Carótida Primitiva/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Masculino , Artéria Radial , Reprodutibilidade dos Testes , UltrassonografiaAssuntos
Anti-Hipertensivos/efeitos adversos , Hidroclorotiazida/efeitos adversos , Hipertensão/tratamento farmacológico , Neoplasias Cutâneas/induzido quimicamente , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Medição de Risco , Fatores de Risco , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Sociedades MédicasRESUMO
OBJECTIVES: Our aim was to examine the relationship of arterial stiffness to measures of atherosclerosis, arterial calcification, and bone mineral density (BMD); the heritability of these measures; and the degree to which they are explained by common genetic influences. BACKGROUND: Arterial stiffening relates to arterial calcification, but this association could result from coexistent atherosclerosis. A reciprocal relationship between arterial stiffening/calcification and BMD could explain the association between cardiovascular morbidity and osteoporosis. METHODS: We examined, in 900 women from the Twins UK cohort, the relationship of carotid-femoral pulse wave velocity (cfPWV) to measures of atherosclerosis (carotid intima-media thickening; carotid/femoral plaque), calcification (calcified plaque [CP]; aortic calcification by computed tomography, performed in subsample of 40 age-matched women with low and high cfPWV), and BMD. RESULTS: The cfPWV independently correlated with CP but not with intima-media thickness or noncalcified plaque. Total aortic calcium, determined by computed tomography, was significantly greater in subjects with high cfPWV (median Agatston score 450.4 compared with 63.2 arbitrary units in subjects with low cfPWV, p = 0.001). There was no independent association between cfPWV and BMD. Adjusted heritability estimates of cfPWV and CP were 0.38 (95% confidence interval: 0.19 to 0.59) and 0.61 (95% confidence interval: 0.04 to 0.83), respectively. Shared genetic factors accounted for 92% of the observed correlation (0.38) between cfPWV and CP. CONCLUSIONS: These results suggest that the association between increased arterial stiffness and the propensity of the arterial wall to calcify is explained by a common genetic etiology and is independent of noncalcified atheromatous plaque and independent of BMD.
Assuntos
Aterosclerose/patologia , Calcinose/patologia , Fatores Etários , Aortografia , Aterosclerose/genética , Velocidade do Fluxo Sanguíneo , Glicemia , Pressão Sanguínea , Densidade Óssea , Calcinose/genética , Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Artéria Femoral/diagnóstico por imagem , Frequência Cardíaca , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Fluxo Pulsátil , Tomografia Computadorizada por Raios X , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01). CONCLUSIONS/SIGNIFICANCE: These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.