Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Thromb Haemost ; 18(1): 114-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31557382

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, few data exist on the safety and efficacy of vitamin K antagonists (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs). OBJECTIVES: To evaluate outcomes and complication rates in CTEPH following pulmonary endarterectomy (PEA) for individuals receiving VKAs or DOACs. METHODS: Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Postoperative outcomes, recurrent venous thromboembolism (VTE), and bleeding events were obtained from patient medical records. RESULTS: Seven hundred ninety-four individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (standard deviation: 702) days. Significant improvements in hemodynamics and functional status were observed in both groups following PEA (P < .001). Major bleeding events were equivalent (P = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). The VTE recurrence was proportionately higher (P = .008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ. CONCLUSIONS: Post-PEA functional and hemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31661308

RESUMO

OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised plasma BMP9 and BMP10 levels in patients with idiopathic PAH. METHODS: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. CONCLUSIONS: Our findings demonstrate that GDF2 mutations result in BMP9 loss-of-function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH.

3.
Arthritis Res Ther ; 21(1): 217, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655622

RESUMO

OBJECTIVE: The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). METHODS: Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5-10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. RESULTS: After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP - 1 ± 6.4 mmHg vs. placebo - 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. - 0.31 ± 0.71 l/min/m2, p = 0.010; PVR - 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. - 0.45 ± 1.36 l/min/m2, p = 0.015; PVR - 0.84 ± 0.48 WU vs. - 0.0032 ± 0.34 WU, p < 0.0001). CONCLUSION: This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. TRIAL REGISTRATION: www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14th of November 2014.

4.
J Clin Med ; 8(4)2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970653

RESUMO

Prostacyclin mimetics (PMs) are effective for the treatment of pulmonary arterial hypertension (PAH). However, their clinical use may be limited by their adverse events. This study aims to quantify the different PM adverse events (AEs) with regard to their selectivity towards the prostacyclin (IP) receptor and their administrative routes. The study included randomised, placebo-controlled trials comparing iloprost, beraprost, treprostinil, and selexipag to placebo (published 2002­2016). We report the group efficacy differences between treatment and placebo by weighted and standardised mean difference. The probability of adverse events was determined by the odds ratio (OR). Of the 14 randomised clinical trials involving 3518 PAH patients, outcome and adverse event data were meta-analysed by drug type and route of administration. Prostacyclin mimetics comparison demonstrated a more significant discontinuation of the IP-selective agonist, selexipag, due to an adverse event (OR = 2.2; 95% CI: 1.5, 3.3). Compared to placebo, site pain associated with subcutaneously administered treprostinil was the most significant likely adverse event (OR = 17.5; 95% CI: 11.1, 27.1). Parenteral PMs were associated with fewer adverse effects overall. The overall efficacy of PMs to improve 6-minute walk distance by 16.3 meters was significant (95% CI: 13.0, 19.7). Decreases in pulmonary vascular resistance index (SMD = -5.5; 95% CI: -10.1, -0.9; I² = 98%) and mean pulmonary arterial pressure (SMD = -1.0; 95% CI: -2.6, -0.7; I² = 99%) in treatment groups were found to be significant. Adverse event profiles varied in response to administration route and PM type but were not negated by use of a selective IP agonist. Prostacyclin mimetics exposure to non-target IP receptors may underpin some AEs reported.

5.
Eur Respir J ; 53(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30923185

RESUMO

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a prioriHigher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 µg·m-3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 µg·m-3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

6.
JACC Cardiovasc Imaging ; 12(10): 1958-1969, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30772231

RESUMO

OBJECTIVES: This study sought to assess the performance of cardiovascular magnetic resonance (CMR) myocardial perfusion mapping against invasive coronary physiology reference standards for detecting coronary artery disease (CAD, defined by fractional flow reserve [FFR] ≤0.80), microvascular dysfunction (MVD) (defined by index of microcirculatory resistance [IMR] ≥25) and the ability to differentiate between the two. BACKGROUND: Differentiation of epicardial (CAD) and MVD in patients with stable angina remains challenging. Automated in-line CMR perfusion mapping enables quantification of myocardial blood flow (MBF) to be performed rapidly within a clinical workflow. METHODS: Fifty patients with stable angina and 15 healthy volunteers underwent adenosine stress CMR at 1.5T with quantification of MBF and myocardial perfusion reserve (MPR). FFR and IMR were measured in 101 coronary arteries during subsequent angiography. RESULTS: Twenty-seven patients had obstructive CAD and 23 had nonobstructed arteries (7 normal IMR, 16 abnormal IMR). FFR positive (epicardial stenosis) areas had significantly lower stress MBF (1.47 ± 0.48 ml/g/min) and MPR (1.75 ± 0.60) than FFR-negative IMR-positive (MVD) areas (stress MBF: 2.10 ± 0.35 ml/g/min; MPR: 2.41 ± 0.79) and normal areas (stress MBF: 2.47 ± 0.50 ml/g/min; MPR: 2.94 ± 0.81). Stress MBF ≤1.94 ml/g/min accurately detected obstructive CAD on a regional basis (area under the curve: 0.90; p < 0.001). In patients without regional perfusion defects, global stress MBF <1.82 ml/g/min accurately discriminated between obstructive 3-vessel disease and MVD (area under the curve: 0.94; p < 0.001). CONCLUSIONS: This novel automated pixel-wise perfusion mapping technique can be used to detect physiologically significant CAD defined by FFR, MVD defined by IMR, and to differentiate MVD from multivessel coronary disease. A CMR-based diagnostic algorithm using perfusion mapping for detection of epicardial disease and MVD warrants further clinical validation.

7.
Br J Pharmacol ; 176(9): 1251-1267, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30761523

RESUMO

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. EXPERIMENTAL APPROACH: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δmax ), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers. KEY RESULTS: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects. CONCLUSIONS AND IMPLICATIONS: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial.

8.
Arthritis Rheumatol ; 71(5): 805-816, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30615302

RESUMO

OBJECTIVE: This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). METHODS: Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. RESULTS: Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). CONCLUSION: The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.


Assuntos
Débito Cardíaco/fisiologia , Artéria Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Resistência Vascular/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Cateterismo Cardíaco , Estudos de Casos e Controles , Complacência (Medida de Distensibilidade) , Ecocardiografia Doppler , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Teste de Caminhada
9.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545974

RESUMO

Pulmonary hypertension (PH) is frequent in left heart disease (LHD), as a consequence of the underlying condition. Significant advances have occurred over the past 5 years since the 5th World Symposium on Pulmonary Hypertension in 2013, leading to a better understanding of PH-LHD, challenges and gaps in evidence. PH in heart failure with preserved ejection fraction represents the most complex situation, as it may be misdiagnosed with group 1 PH. Based on the latest evidence, we propose a new haemodynamic definition for PH due to LHD and a three-step pragmatic approach to differential diagnosis. This includes the identification of a specific "left heart" phenotype and a non-invasive probability of PH-LHD. Invasive confirmation of PH-LHD is based on the accurate measurement of pulmonary arterial wedge pressure and, in patients with high probability, provocative testing to clarify the diagnosis. Finally, recent clinical trials did not demonstrate a benefit in treating PH due to LHD with pulmonary arterial hypertension-approved therapies.

10.
Eur Respir J ; 53(2)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30578391

RESUMO

Objectives of this European Respiratory Society task force were to summarise current studies, to develop strategies for future research and to increase availability and awareness of exercise training for pulmonary hypertension (PH) patients.An evidence-based approach with clinical expertise of the task force members, based on both literature search and face-to-face meetings was conducted. The statement summarises current knowledge and open questions regarding clinical effects of exercise training in PH, training modalities, implementation strategies and pathophysiological mechanisms.In studies (784 PH patients in total, including six randomised controlled trials, three controlled trials, 10 prospective cohort studies and four meta-analyses), exercise training has been shown to improve exercise capacity, muscular function, quality of life and possibly right ventricular function and pulmonary haemodynamics. Nevertheless, further studies are needed to confirm these data, to investigate the impact on risk profiles and to identify the most advantageous training methodology and underlying pathophysiological mechanisms.As exercise training appears to be effective, cost-efficient and safe, but is scarcely reimbursed, support from healthcare institutions, commissioners of healthcare and research funding institutions is greatly needed. There is a strong need to establish specialised rehabilitation programmes for PH patients to enhance patient access to this treatment intervention.

11.
J Am Coll Cardiol ; 72(22): 2778-2788, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30497564

RESUMO

Echocardiography is the mainstay in screening for pulmonary hypertension (PH). International guidelines suggest echocardiographic parameters for suspecting PH, but these may not apply to many adults with congenital heart disease (ACHD). PH is relatively common in ACHD patients and can significantly affect their exercise capacity, quality of life, and prognosis. Identification of patients who have developed PH and who may benefit from further investigations (including cardiac catheterization) and treatment is thus extremely important. A systematic review and survey of experts from the United Kingdom and Ireland were performed to assess current knowledge and practice on echocardiographic screening for PH in ACHD. This paper presents the findings of the review and expert statements on the optimal approaches when using echocardiography to assess ACHD patients for PH, with particular focus on major subgroups: patients with right ventricular outflow tract obstruction, patients with systemic right ventricles, patients with unrepaired univentricular circulation, and patients with tetralogy of Fallot with pulmonary atresia.


Assuntos
Ecocardiografia/métodos , Cardiopatias Congênitas/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Programas de Rastreamento/métodos , Ecocardiografia/tendências , Cardiopatias Congênitas/epidemiologia , Humanos , Hipertensão Pulmonar/epidemiologia , Imagem Cinética por Ressonância Magnética/métodos , Imagem Cinética por Ressonância Magnética/tendências , Programas de Rastreamento/tendências
12.
Circ Genom Precis Med ; 11(10): e002087, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354297

RESUMO

BACKGROUND: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. METHODS: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. RESULTS: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. CONCLUSIONS: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.


Assuntos
Exoma , Hipertensão Pulmonar Primária Familiar/genética , Mutação de Sentido Incorreto , Receptores Sulfonilureia/genética , Adulto , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Humanos , Masculino
13.
Echo Res Pract ; 5(3): G11-G24, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30012832

RESUMO

Pulmonary hypertension is defined as a mean arterial pressure of ≥25 mmHg as confirmed on right heart catheterisation. Traditionally, the pulmonary arterial systolic pressure has been estimated on echo by utilising the simplified Bernoulli equation from the peak tricuspid regurgitant velocity and adding this to an estimate of right atrial pressure. Previous studies have demonstrated a correlation between this estimate of pulmonary arterial systolic pressure and that obtained from invasive measurement across a cohort of patients. However, for an individual patient significant overestimation and underestimation can occur and the levels of agreement between the two is poor. Recent guidance has suggested that echocardiographic assessment of pulmonary hypertension should be limited to determining the probability of pulmonary hypertension being present rather than estimating the pulmonary artery pressure. In those patients in whom the presence of pulmonary hypertension requires confirmation, this should be done with right heart catheterisation when indicated. This guideline protocol from the British Society of Echocardiography aims to outline a practical approach to assessing the probability of pulmonary hypertension using echocardiography and should be used in conjunction with the previously published minimum dataset for a standard transthoracic echocardiogram.

14.
Nat Commun ; 9(1): 1416, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650961

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.


Assuntos
Adenosina Trifosfatases/química , Aquaporina 1/química , Hipertensão Pulmonar Primária Familiar/genética , Fatores de Diferenciação de Crescimento/química , Proteínas de Membrana Transportadoras/química , Mutação , Fatores de Transcrição SOXF/química , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Adulto , Aquaporina 1/genética , Aquaporina 1/metabolismo , Sequência de Bases , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Estudos de Casos e Controles , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/metabolismo , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Células HEK293 , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Modelos Moleculares , Prognóstico , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Sequenciamento Completo do Genoma
15.
J Intensive Care Soc ; 18(2): 138-142, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28979560

RESUMO

We present the case of an 88-year-old gentleman who presented to hospital septic with bilateral leg cellulitis, pulmonary oedema and hypotension. He had no history of heart disease but had had bilateral carpal tunnel releases. His condition deteriorated with refractory hypotension in spite of fluid filling, inotropic and vasopressor support. His echocardiogram showed an infiltrative cardiomyopathy with a speckled myocardium, severe concentric left and right ventricular increased wall thickness, diastolic dysfunction, biatrial dilatation and restrictive physiology in keeping with cardiac amyloidosis. He developed atrial fibrillation and worsening respiratory failure due to fluid overload and was intubated and ventilated but continued to decline and passed away. The degree of heart failure in the absence of ischaemia, the patient's advanced age, echocardiographic findings and past history of carpal tunnel syndrome in a male are strongly indicative of a diagnosis of wild-type cardiac transthyretin amyloidosis. We discuss the key features and intensive care management of this disease.

16.
Circulation ; 136(21): 2022-2033, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-28972005

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.


Assuntos
Pressão Arterial/genética , Hipertensão Pulmonar/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Artéria Pulmonar/fisiopatologia , Adulto , Idoso , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Análise Mutacional de DNA , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto Jovem
17.
Thorax ; 72(11): 1035-1045, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28904006

RESUMO

Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the 'most common' emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis ('CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate.


Assuntos
Cuidados Críticos , Hipertensão Pulmonar/terapia , Papel do Médico , Arritmias Cardíacas/etiologia , Bacteriemia/microbiologia , Dor no Peito/etiologia , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Hemoptise/etiologia , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/mortalidade , Irlanda , Guias de Prática Clínica como Assunto , Prognóstico , Fatores de Risco , Resultado do Tratamento , Reino Unido , Disfunção Ventricular Direita/etiologia
18.
Eur Respir J ; 50(2)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28818881

RESUMO

Patients with connective tissue disease-associated pulmonary arterial hypertension (PAH-CTD) have a poor prognosis compared with other aetiologies. The underlying CTD can influence treatment response and outcomes. We characterised the GRIPHON study PAH-CTD subgroup and evaluated response to selexipag.Of 334 patients with PAH-CTD, PAH was associated with systemic sclerosis (PAH-SSc) in 170, systemic lupus erythematosus (PAH-SLE) in 82 and mixed CTD/CTD-other in 82. For the primary composite endpoint of morbidity/mortality, hazard ratios (HR) and 95% CI were calculated using Cox proportional hazard models.Compared with the overall GRIPHON population, the CTD subgroup was slightly older with a greater proportion of females and shorter time since diagnosis. Patients with PAH-SSc appeared to be more impaired at baseline, with a more progressive disease course. The converse was observed for PAH-SLE. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41-0.85). Treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype (interaction p=0.87 and 0.89, respectively). Adverse events were predominately prostacyclin-related and known for selexipag treatment.GRIPHON has allowed the comprehensive characterisation of patients with PAH-CTD. Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH-SSc and PAH-SLE.


Assuntos
Acetamidas , Hipertensão Pulmonar , Lúpus Eritematoso Sistêmico/complicações , Pirazinas , Escleroderma Sistêmico/complicações , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Medição de Risco , Análise de Sobrevida
19.
Rheumatology (Oxford) ; 56(6): 912-921, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28160468

RESUMO

Objective: Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods: The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results: A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion: The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.


Assuntos
Cardiomiopatias/terapia , Escleroderma Sistêmico/terapia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/terapia , Biomarcadores/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Fármacos Cardiovasculares/efeitos adversos , Eletrocardiografia , Medicina Baseada em Evidências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Humanos , Angiografia por Ressonância Magnética , Anamnese/métodos , Monitorização Ambulatorial/métodos , Equipe de Assistência ao Paciente/organização & administração , Pericardite/diagnóstico , Pericardite/etiologia , Pericardite/terapia , Exame Físico/métodos , Fatores de Risco , Escleroderma Sistêmico/diagnóstico
20.
Circulation ; 135(5): 460-475, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-27881557

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. RESULTS: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. CONCLUSIONS: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.


Assuntos
Hipertensão Pulmonar/genética , Metabolômica/métodos , RNA de Transferência/metabolismo , Adulto , Idoso , Metabolismo Energético , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA