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1.
Am J Med Genet A ; 185(7): 2180-2189, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33878224

RESUMO

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.


Assuntos
Aneurisma Aórtico/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Síndrome de Marfan/genética , Idoso , Idoso de 80 Anos ou mais , Aneurisma Aórtico/complicações , Aneurisma Aórtico/patologia , Éxons , Feminino , Testes Genéticos , Humanos , Imunoglobulina G/genética , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Mutação
2.
Circ Res ; 112(5): 781-91, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23303165

RESUMO

RATIONALE: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation. OBJECTIVE: To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways. METHODS AND RESULTS: We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin-angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension. CONCLUSIONS: Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gαq-coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Vasos Sanguíneos/fisiologia , Homeostase/fisiologia , Músculo Liso Vascular/fisiologia , Proteínas RGS/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Hipertensão/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase C/fisiologia , Proteínas RGS/deficiência , Proteínas RGS/genética , Transdução de Sinais/fisiologia , Vasoconstrição/fisiologia , Quinases Associadas a rho/fisiologia
3.
Lancet ; 390(10089): 26-27, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28677555

Assuntos
Hipertensão , Humanos
4.
JACC Clin Electrophysiol ; 8(2): 152-164, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35210071

RESUMO

OBJECTIVES: This study sought to evaluate the role of cardiac afferent reflexes in atrial fibrillation (AF). BACKGROUND: Efferent autonomic tone is not associated with atrial remodeling and AF persistence. However, the role of cardiac afferents is unknown. METHODS: Individuals with nonpermanent AF (n = 48) were prospectively studied (23 in the in-AF group and 25 in sinus rhythm [SR]) with 12 matched control subjects. We performed: 1) low-level lower body negative pressure (LBNP), which decreases cardiac volume, offloading predominantly cardiac afferent (volume-sensitive) low-pressure baroreceptors; 2) Valsalva reflex (predominantly arterial high-pressure baroreceptors); and 3) isometric handgrip reflex (both baroreceptors). We measured beat-to-beat mean arterial pressure (MAP) and heart rate (HR). LBNP elicits reflex vasoconstriction, estimated using venous occlusion plethysmography-derived forearm blood flow (∝1/vascular resistance), maintaining MAP. To assess reversibility, we repeated LBNP (same day) after 1-hour low-level tragus stimulation (in n = 5 in the in-AF group and n = 10 in the in-SR group) and >6 weeks post-cardioversion (n = 7). RESULTS: The 3 groups were well matched for age (59 ± 12 years, 83% male), body mass index, and risk factors (P = NS). The in-AF group had higher left atrial volume (P < 0.001) and resting HR (P = 0.01) but similar MAP (P = 0.7). The normal LBNP vasoconstriction (-49 ± 5%) maintaining MAP (control subjects) was attenuated in the in-SR group (-12 ± 9%; P = 0.005) and dysfunctional in the in-AF group (+11 ± 6%; P < 0.001), in which MAP decreased and HR was unchanged. Valsalva was normal throughout. Handgrip MAP response was lowest in the in-AF group (P = 0.01). Interestingly, low-level tragus stimulation and cardioversion improved LBNP vasoconstriction (-48 ± 15%; P = 0.04; and -32 ± 9%; P = 0.02, respectively). CONCLUSIONS: Cardiac afferent (volume-sensitive) reflexes are abnormal in AF patients during SR and dysfunctional during AF. This could contribute to AF progression, thus explaining "AF begets AF." (Characterisation of Autonomic function in Atrial Fibrillation [AF-AF Study]; ACTRN12619000186156).


Assuntos
Fibrilação Atrial , Idoso , Feminino , Força da Mão , Átrios do Coração , Humanos , Pressão Negativa da Região Corporal Inferior , Masculino , Pessoa de Meia-Idade , Pressorreceptores/fisiologia
6.
Health Serv Res ; 56(6): 1252-1261, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33723855

RESUMO

OBJECTIVE: To test relatively simple and complex models for examining model fit, higher-level variation in, and correlates of, GP consultations, where known nonhierarchical data structures are present. SETTING: New South Wales (NSW), Australia. DESIGN: Association between socioeconomic circumstances and geographic remoteness with GP consultation frequencies per participant was assessed using single-level, hierarchical, and multiple membership cross-classified (MMCC) models. Models were adjusted for age, gender, and a range of socioeconomic and demographic confounds. DATA COLLECTION/EXTRACTION METHODS: A total of 261,930 participants in the Sax Institute's 45 and Up Study were linked to all GP consultation records (Medicare Benefits Schedule; Department of Human Services) within 12 months of baseline (2006-2009). PRINCIPAL FINDINGS: Deviance information criterion values indicated the MMCC negative binomial regression was the best fitting model, relative to an MMCC Poisson equivalent and simpler hierarchical and single-level models. Between-area variances were relatively consistent across models, even when between GP variation was estimated. Lower rates of GP consultation outside of major cities were only observed once between-GP variation was assessed simultaneously with between-area variation in the MMCC models. CONCLUSIONS: Application of the MMCC model is necessary for estimation of variances and effect sizes in sources of big data on primary care in which complex nonhierarchical clustering by geographical area and GP is present.


Assuntos
Medicina Geral , Geografia Médica , Modelos Estatísticos , Encaminhamento e Consulta/estatística & dados numéricos , Idoso , Austrália , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales , Fatores Socioeconômicos
7.
Nat Commun ; 11(1): 6408, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328478

RESUMO

Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Histonas/metabolismo , Polímeros/farmacologia , Sepse/sangue , Sepse/tratamento farmacológico , Animais , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Feminino , Histonas/toxicidade , Humanos , Bicamadas Lipídicas , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Ativação Plaquetária/efeitos dos fármacos , Polieletrólitos , Polímeros/química , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Sepse/patologia
8.
J Mol Cell Cardiol ; 47(1): 49-56, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19328207

RESUMO

The capacity of mitochondria to respond to changes in oxygen delivery has the potential to affect the ability of the heart to tolerate decreased oxygen delivery. Respiration by mitochondria is typically regarded as independent of oxygen tension (pO(2)) until critically low oxygen concentrations limit the activity of cytochrome oxidase. Paradoxically, there is evidence that cellular and mitochondrial oxygen consumption (respiration) can decline at oxygen tensions well above this critical pO(2). We tested the hypothesis that oxygen sensitive decreases in mitochondrial hydrogen peroxide production can decrease cardiac mitochondrial respiration rate. Consistent with previous work, an acute decline in pO(2) from 146 mm Hg to 10-13 mm Hg in less than 10 min did not affect mitochondrial respiration rate. In contrast, sustained incubation of mitochondria at a pO(2) of 10-13 mm Hg for 30 min caused a 50% decrease in mitochondrial respiration rate. This decrease in mitochondrial respiration rate was mimicked by incubation with the hydrogen peroxide scavenger catalase and the decrease in mitochondrial respiration rate was fully reversible by reintroducing oxygen or by adding hydrogen peroxide. Incubation at low pO(2) was also associated with a decreased rate of mitochondrial reactive oxygen species production. These findings indicate that oxygen-dependent decreases in the rate of mitochondrial hydrogen peroxide production can decrease cardiac mitochondrial respiration.


Assuntos
Peróxido de Hidrogênio/metabolismo , Mitocôndrias Cardíacas/metabolismo , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Animais , Complexo I de Transporte de Elétrons , Complexo II de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons , Inibidores Enzimáticos/farmacologia , Masculino , Microscopia Eletrônica de Transmissão , Mitocôndrias Cardíacas/ultraestrutura , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Superóxidos/metabolismo
9.
Cerebrovasc Dis ; 27(3): 259-65, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19202330

RESUMO

BACKGROUND: Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall. B-vitamin supplements reduce total plasma homocysteine concentrations (tHcy), but it is not known whether the treatment also reduces arterial wall inflammation. We used (18)F-fluorodeoxygluose positron emission tomography ((18)F-FDG PET) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke. METHODS: 30 stroke patients were randomly assigned to B-vitamin therapy (folic acid 2 mg, vitamin B(6) 25 mg and vitamin B(12) 0.5 mg) or placebo in a double-blind clinical trial. After a mean treatment period of 4.0 +/- 0.7 years, all subjects had tHcy, carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery measured and underwent an (18)F-FDG PET scan. Standardised uptake values (SUV) were measured at six sites in the carotid, femoral and aortic arteries. Areas of locally increased tracer uptake in the arterial wall ('hot spots') were also identified and counted. RESULTS: Long-term B-vitamin treatment significantly reduced tHcy compared with placebo (8.4 micromol/l, 95% confidence interval, CI, 7.2-9.6 vs. 11.6 micromol/l, 95% CI 10.0-13.4, p = 0.002). The treatment did not affect mean arterial SUV (2.0 +/- 0.3 vitamins vs. 2.1 +/- 0.3 placebo, p = 0.65) or the number of hot spots (n = 1.1 +/- 1.0 vitamins vs. n = 1.2 +/- 1.0 placebo, p = 0.65). There was no significant correlation between mean arterial SUV and CIMT or FMD. CONCLUSIONS: These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by (18)F-FDG PET.


Assuntos
Arterite/etiologia , Aterosclerose/etiologia , Fluordesoxiglucose F18 , Homocisteína/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Complexo Vitamínico B/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aorta/diagnóstico por imagem , Arterite/diagnóstico por imagem , Arterite/tratamento farmacológico , Aterosclerose/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Artéria Braquial/fisiopatologia , Artérias Carótidas/diagnóstico por imagem , Estudos Transversais , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Artéria Femoral/diagnóstico por imagem , Ácido Fólico/uso terapêutico , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/complicações , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Vasodilatação , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico
10.
Arterioscler Thromb Vasc Biol ; 28(6): 1158-64, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18356552

RESUMO

OBJECTIVE: The purpose of this study was to determine whether adjustment for renal function eliminates the relationship between total plasma homocysteine (tHcy) and vascular risk, assessed by carotid intima medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery. METHODS AND RESULTS: We used cross-sectional data from 173 stroke patients treated with B-vitamins (folic acid 2 mg, vitamin B(6) 25 mg, and vitamin B(12) 0.5 mg) or placebo in a randomized double-blinded trial to test the relationships between posttreatment tHcy, cystatin C (a marker of glomerular filtration rate), estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease equation) creatinine, CIMT, and FMD in stepwise and multivariable regression models. The strong linear relationship between tHcy and cystatin C was not altered by long-term B-vitamin treatment. tHcy lost significance as a predictor of the vascular measurements after adjustment for any single marker of renal function. Cystatin C, but not tHcy, was a significant independent predictor of FMD after adjustment for age, sex, smoking, systolic blood pressure, high-density lipoprotein cholesterol, and treatment group. CONCLUSIONS: Adjusting for renal function eliminates the relationship between tHcy and CIMT and FMD, supporting the hypothesis that elevated tHcy is a marker for renal impairment rather than an independent cardiovascular risk factor.


Assuntos
Doenças Cardiovasculares/etiologia , Cistatinas/sangue , Homocisteína/sangue , Nefropatias/sangue , Nefropatias/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Artéria Braquial/fisiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Artérias Carótidas/patologia , Estudos Transversais , Cistatina C , Cistatinas/fisiologia , Feminino , Ácido Fólico/uso terapêutico , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Homocisteína/fisiologia , Humanos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fluxo Sanguíneo Regional/fisiologia , Análise de Regressão , Fatores de Risco , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico
11.
J Interv Card Electrophysiol ; 54(3): 299-307, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30661160

RESUMO

PURPOSE: The role of the autonomic nervous system in the genesis of atrial fibrillation (AF) has been well studied; however, the converse remains poorly understood. Pulmonary veins (PV) contain receptors important in cardiac reflexes. Here, we evaluated reflex responses in patients with paroxysmal AF (PAF) to lower body negative pressure (LBNP). METHODS: Thirty-four PAF patients (including 14 PAF patients post successful PV Isolation; PVI) were compared to 14 age and sex-matched controls. Mean arterial pressure (MAP), heart rate (HR), systemic vascular resistance index (SVRI), cardiac index (CI), and stroke volume index (SVI) were measured continuously during - 0, - 20, and - 40 mmHg LBNP. LBNP reduces venous return, deactivating atrial receptors, thereby eliciting a reflex increase in SVRI to maintain MAP. RESULTS: AF patients have higher BMI than the controls (p = 0.02). In control subjects, LBNP did not alter MAP as SVRI increased. In PAF patients, LBNP resulted in a reduction in MAP (- 4.8%) with attenuated SVRI response (+ 4.2%) compared to controls (p < 0.05). However, in the post-PVI group, SVRI increase was similar to controls (p = 0.12) although that was insufficient to maintain MAP. In all patients, both reduction in SVI and CI and increase in HR were similar in response to LBNP. CONCLUSIONS: This study provides novel clinical evidence of autonomic dysfunction in PAF patients. Successful PVI results in partial recovery of the cardiac reflex. Therefore, not only does autonomic disturbance predispose to AF but it is also a consequence of AF; potentially contributing to disease progression. This could help explain the dictum "AF begets AF."


Assuntos
Fibrilação Atrial/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Pressão Negativa da Região Corporal Inferior , Fibrilação Atrial/cirurgia , Estudos de Casos e Controles , Ablação por Cateter/métodos , Técnicas Eletrofisiológicas Cardíacas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/cirurgia
12.
J Biomed Sci ; 15(6): 801-12, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18604639

RESUMO

Functional evidence suggests that nitric oxide (NO) signalling in the rostral ventrolateral medulla (RVLM) is cGMP-dependent and that this pathway is impaired in hypertension. We examined cGMP expression as a marker of active NO signalling in the C1 region of the RVLM, comparing adult (>18 weeks) Wistar-Kyoto (WKY, n = 4) and spontaneously hypertensive rats (SHR, n = 4). Double label immunohistochemistry for cGMP-immunoreactivity (IR) and C1 neurons [as identified by phenylethanolamine N-methyltransferase (PNMT-IR) or tyrosine hydroxylase TH-IR)], or neuronal NO synthase (nNOS) neurones, failed to reveal cGMP-IR neurons in the RVLM of either strain, despite consistent detection of cGMP-IR in the nucleus ambiguus (NA). This was unchanged in the presence of isobutylmethylxanthine (IBMX; 0.5 mM, WKY, n = 4, SHR n = 2) and in young animals (WKY, 10-weeks, n = 3). Incubation of RVLM-slices (WKY, 10-weeks, n = 9) in DETA-NO (100 mum; 10 min) or NMDA (10 muM; 2 min) did not uncover cGMP-IR. In all studies, cGMP was prominent within the vasculature. Soluble guanylate cyclase (sGC)-IR was found throughout neurones of the RVLM, but did not co-localise with PNMT, TH or nNOS-IR neurons (WKY, 10-weeks, n = 6). Results indicate that within the RVLM, cGMP is not detectable using immunohistochemistry in the basal state and cannot be elicited by phosphodiesterase inhibition, NMDA receptor stimulation or NO donor application.


Assuntos
GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Bulbo/metabolismo , Animais , Tronco Encefálico/metabolismo , Imuno-Histoquímica , Masculino , Bulbo/citologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
13.
BMC Cardiovasc Disord ; 8: 24, 2008 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-18803866

RESUMO

BACKGROUND: Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown. METHODS: We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD. RESULTS: After a mean treatment period of 3.9 +/- 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 micromol/L, 95% CI 7.5 to 8.4 versus 11.8 micromol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 +/- 0.17 mm vitamins versus 0.83 +/- 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials. CONCLUSION: Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Suplementos Nutricionais , Homocisteína/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Túnica Íntima/efeitos dos fármacos , Túnica Média/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Complexo Vitamínico B/uso terapêutico , Idoso , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Método Duplo-Cego , Regulação para Baixo , Combinação de Medicamentos , Feminino , Ácido Fólico/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Túnica Média/patologia , Túnica Média/fisiopatologia , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico
14.
Cardiovasc Ultrasound ; 6: 6, 2008 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-18208623

RESUMO

BACKGROUND: Flow-mediated dilation (FMD) and carotid intima-medial thickness (CIMT), measured by ultrasound, are widely used to test the efficacy of cardioprotective interventions. Although assessment methods vary, automated edge-detecting image analysis software is routinely used to measure changes in FMD and CIMT. We aimed to quantify the effect that commonly adjusted ultrasound settings have on arterial lumen and wall thickness measurements made with CIMT measurement software. METHODS: We constructed phantom arteries from a tissue-mimicking agar compound and scanned them in a water bath with a 10 MHz multi-frequency linear-array probe attached to a high-resolution ultrasound machine. B-mode images of the phantoms were recorded with dynamic range (DR) and gain set at five decibel (dB) increments from 40 dB to 60 dB and -10 dB to +10 dB respectively. Lumen diameter and wall-thickness were measured off-line using CIMT measurement software. RESULTS: Lumen measurements: there was a strong linear relationship between DR and gain and measured lumen diameter. For a given gain level, a 5 dB increase in DR reduced the measured lumen diameter by 0.02 +/- 0.004 mm (p < 0.001). For a given DR level, a 5 dB increase in gain reduced measured lumen diameter by 0.04 +/- 0.004 mm (p < 0.001). A 5 mm increase in distance between the ultrasound probe and the artery reduced measured lumen diameter by 0.04 +/- 0.03 mm (p < 0.001)CIMT measurements: For a fixed gain level, a 5 dB increase in DR increased measured wall thickness by 0.003 +/- 0.002 mm (p < 0.001). The effects of increasing gain were not consistent and appeared to vary depending on the distance between the artery and the ultrasound probe and the thickness of the artery wall. CONCLUSION: DR, gain and probe distance significantly alter lumen diameter and CIMT measurements made using image analysis software. When CIMT and FMD are used to test the efficacy of cardioprotective interventions, the DR, gain and probe position used to record baseline scans should be documented and replicated in post-treatment scans in individual trial subjects. If more than one sonographer or imaging centre is used to collect data, the study protocol should document specific DR and gain settings to be used in all subjects.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Software , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Diagnóstico por Computador , Humanos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Ultrassonografia
15.
Kidney Blood Press Res ; 30(3): 129-44, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17446713

RESUMO

BACKGROUND/METHODS: We have examined the hypothesis that cyst formation is key in the pathogenesis of cardiovascular disease in a Lewis polycystic kidney (LPK) model of autosomal-recessive polycystic kidney disease (ARPKD), by determining the relationship between cyst development and indices of renal function and cardiovascular disease. RESULTS: In the LPK (n = 35), cysts appear at week 3 (1.1 +/- 0.1 mm) increasing to week 24 (2.8 +/- 2 mm). Immunostaining for nephron-specific segments indicate cysts develop predominantly from the collecting duct. Cyst formation preceded hypertension (160 +/- 22 vs. Lewis control 105 +/- 20 mm Hg systolic blood pressure (BP), n = 12) at week 6, elevated creatinine (109 +/- 63 vs. 59 +/- 6 micromol/l, n = 16) and cardiac mass (0.7 vs. 0.4% bodyweight, n = 15) at week 12, and left ventricular hypertrophy (2,898 +/- 207 vs. 1,808 +/- 192 mum, n = 14) at week 24 (all p < or = 0.05). Plasma-renin activity and angiotensin II were reduced in 10- to 12-week LPK (2.2 +/- 2.9 vs. Lewis 11.9 +/- 4.9 ng/ml/h, and 25.0 +/- 19.1 vs. 94.9 +/- 64.4 pg/ml, respectively, n = 26, p < or = 0.05). Ganglionic blockade (hexamethonium 3.3 mg/kg) significantly reduced mean BP in the LPK (52 vs. Lewis 4%, n = 9, p < or = 0.05). CONCLUSION: Cyst formation is a key event in the genesis of hypertension while the sympathetic nervous system is important in the maintenance of hypertension in this model of ARPKD.


Assuntos
Modelos Animais de Doenças , Hipertensão Renal/patologia , Hipertrofia Ventricular Esquerda/patologia , Rim Policístico Autossômico Recessivo/patologia , Ratos Mutantes , Animais , Anticorpos Monoclonais , Biomarcadores/metabolismo , Creatinina/sangue , Feminino , Hipertensão Renal/etiologia , Hipertensão Renal/genética , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/genética , Imuno-Histoquímica , Córtex Renal/inervação , Córtex Renal/metabolismo , Córtex Renal/patologia , Medula Renal/inervação , Medula Renal/metabolismo , Medula Renal/patologia , Túbulos Renais Distais/inervação , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/patologia , Túbulos Renais Proximais/inervação , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/genética , Valor Preditivo dos Testes , Ratos , Ratos Endogâmicos Lew , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Simpatolíticos/farmacologia , Fatores de Tempo , Ureia/sangue
16.
Cardiovasc Ultrasound ; 5: 29, 2007 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-17892537

RESUMO

BACKGROUND: Carotid intima-media thickness (CIMT) measured by B-mode ultrasonography is a marker of atherosclerosis and is commonly used as an outcome in intervention trials. We have developed DICOM-based software that measures CIMT rapidly on multiple end-diastolic image frames. The aims of this study were to compare the performance of our new software with older bitmap-based CIMT measurement software and to determine whether a ten-fold increase in the number of measurements used to calculate mean CIMT would improve reproducibility. METHODS: Two independent sonographers recorded replicate carotid scans in thirty volunteers and two blinded observers measured CIMT off-line using the new DICOM-based software and older bitmap-based software. A Bland-Altman plot was used to compare CIMT results from the two software programs and t-tests were used to compare analysis times. F-tests were used to compare the co-efficients of variation (CVs) from a standard six-frame measurement protocol with CVs from a sixty-frame measurement protocol. Ordinary least products (OLP) regression was used to test for sonographer and observer biases. RESULTS: The new DICOM-based software was much faster than older bitmap-based software (average measurement time for one scan 3.4 +/- 0.6 minutes versus 8.4 +/- 1.8 minutes, p < 0.0001) but CIMT measurements were larger than those made using the alternative software (+0.02 mm, 95%CI 0.01-0.03 mm). The sixty-frame measurement protocol had worse reproducibility than the six-frame protocol (inter-observer CV 5.1% vs 3.5%, p = 0.004) and inter and intra-observer biases were more pronounced in the sixty-frame than the six-frame results. CONCLUSION: While the use of DICOM-based software significantly reduced analysis time, a ten-fold increase in the number of measurements used to calculate CIMT did not improve reproducibility. In addition, we found that observer biases caused differences in mean CIMT of a magnitude commonly reported as significant in intervention trials. Our results highlight the importance of good study design with concurrent controls and the need to ensure that no observer drift occurs between baseline and follow-up measurements when CIMT is used to monitor the effect of an intervention.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Diagnóstico por Computador , Software , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Método Simples-Cego , Software/normas , Fatores de Tempo , Ultrassonografia
18.
J Comp Neurol ; 497(4): 566-74, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16739165

RESUMO

The sympathetic preganglionic neurons (SPN) of the intermediolateral cell column (IML) play a critical role in the maintenance of vascular tone. We undertook a comparative neuroanatomical analysis of neuronal nitric oxide synthase (nNOS) expression in the SPN of the mature normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR). The anatomical relationship between nNOS and the NO signaling molecule cyclic guanosine monophosphate (cGMP) was also determined. All animals were male, age > 6 months. Fluorogold (FG) retrograde labeling of SPN (detected with immunohistochemistry) was combined with NADPH-diaphorase histochemistry for NOS in the thoracic spinal cord (T1-11, n = 5 WKY, 5 SHR). There was no difference in the total number of FG-labeled SPN (WKY 6,542 +/- 828, SHR 6,091 +/- 820), but the proportion of FG-labeled cells expressing NOS was significantly less in the SHR (WKY 64.4 +/- 5.1 vs. SHR 55.6 +/- 2.1, P < 0.05). Fluorescence immunohistochemistry for nNOS/cGMP (n = 4 WKY, 4 SHR) was also performed. Confocal microscopy revealed that all nNOS-positive SPN contain cGMP and confirmed a strain-specific anatomical arrangement of SPN cell clusters. A novel subpopulation of cGMP-only cells were also identified. Double labeling for cGMP and choline acetyltransferase (n = 3 WKY, 3 SHR), confirmed these cells as SPN in both WKY and SHR. These results suggest that cGMP is a key signaling molecule in SPN, and that a reduced number of NOS neurons in the SHR may play a role in the increase in sympathetic tone associated with hypertension in these animals.


Assuntos
GMP Cíclico/metabolismo , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Medula Espinal/metabolismo , Sistema Nervoso Simpático/metabolismo , Acetilcolina/metabolismo , Animais , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiopatologia , Contagem de Células , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Histocitoquímica , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Imuno-Histoquímica , Masculino , NADPH Desidrogenase/metabolismo , Neurônios/citologia , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Especificidade da Espécie , Medula Espinal/citologia , Estilbamidinas , Sistema Nervoso Simpático/citologia , Vasoconstrição/fisiologia
19.
Med Sci Sports Exerc ; 38(1): 86-92, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16394958

RESUMO

BACKGROUND: Exercise training is a known stimulus for arteriogenesis, but it is unclear whether elite athletes, who exhibit increased conduit vessel diameter at rest, experience further structural vascular adaptations as a result of intense exercise training. METHODS: Cross-sectional comparisons were performed between elite rowers (N = 17), following a respite from training, and eight untrained age- and gender-matched controls to assess the effects of long-term exercise on vessel structure. To determine the impact of the resumption of intensive exercise training on conduit artery structure, measures were repeated following 3 and 6 months of training in the athletes; the controls remained inactive. Conduit vessel structure was assessed, using high-resolution B-mode ultrasound, as brachial artery diameter at rest (BADr) and in response to 5-min (BAD5) and 10-min (BAD10) periods of forearm cuff ischemia. Shear rate profiles were also analyzed following cuff deflation at all time points. RESULTS: At entry, all measures of BAD were greater (all P < 0.05) in the athletes relative to controls (athletes vs controls; BADr 4.47 +/- 0.10 vs 3.84 +/- 0.22 mm; BAD5 4.70 +/- 0.10 vs 4.05 +/- 0.36 mm, and BAD10 4.93 +/- 0.10 vs 4.07 +/- 0.25 mm). Resumption of exercise training caused a further increase in brachial artery diameters in the athletes at 3 months (BADr, 4.71 +/- 0.10 mm, P < 0.01; BAD5 4.94 +/- 0.10 mm, P < 0.05; BAD10 5.12 +/- 0.10 mm, P < 0.001), which were maintained, but not further increased, after 6 months of training. CONCLUSIONS: Athletes exhibit enhanced conduit artery diameters at rest and in response to vasodilator stimuli. Despite this long-term training effect on arterial structure, resumption of training further enhances diameter, an effect that occurs within 3 months.


Assuntos
Artéria Braquial/fisiologia , Exercício Físico/fisiologia , Vasodilatação , Adulto , Artéria Braquial/diagnóstico por imagem , Estudos Transversais , Humanos , Masculino , Esportes , Ultrassonografia , Austrália Ocidental
20.
Circulation ; 110(9): 1091-6, 2004 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-15302797

RESUMO

BACKGROUND: In chronic heart failure (CHF), elevated pulmonary microvascular pressure (P(mv)) results in pulmonary edema. Because elevated P(mv) may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. METHODS AND RESULTS: Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF (P<0.001), and levels increased with New York Heart Association classification (P<0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B (P<0.01) and NT-proBNP (P<0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization (P=0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% (P<0.001) and NT-proBNP had increased 32% (P<0.001). Conversely, at the next visit, SP-B fell 12% (P<0.001), whereas NT-proBNP fell 39% (P<0.001). CONCLUSIONS: Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised P(mv).


Assuntos
Insuficiência Cardíaca/sangue , Proteína B Associada a Surfactante Pulmonar/sangue , Idoso , Biomarcadores , Estudos de Coortes , Diuréticos/administração & dosagem , Diuréticos/uso terapêutico , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico , Proteínas do Tecido Nervoso/sangue , Pacientes Ambulatoriais , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Índice de Gravidade de Doença
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