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1.
J Clin Med ; 11(18)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36142926

RESUMO

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.

2.
Stem Cell Reports ; 17(7): 1536-1545, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35777360

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENGc.1678C>T) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1c.1678C>T-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays.


Assuntos
Células-Tronco Pluripotentes Induzidas , Telangiectasia Hemorrágica Hereditária , Receptores de Activinas Tipo II/genética , Endoglina/genética , Endoglina/metabolismo , Células Endoteliais/metabolismo , Humanos , Mutação , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/metabolismo
3.
J Heart Lung Transplant ; 41(6): 716-721, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35305871

RESUMO

EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH.


Assuntos
Fibrilação Atrial , Hipertensão Pulmonar , Administração Oral , Anticoagulantes/efeitos adversos , Estudos de Coortes , Hemorragia/induzido quimicamente , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/tratamento farmacológico , Estudos Prospectivos , Vitamina K
4.
Heart Lung Circ ; 30(10): 1502-1508, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33933365

RESUMO

BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and its aetiology is unclear. Different pathophysiological mechanisms in sarcoidosis-associated pulmonary hypertension (SAPH) are known. Clinical phenotyping can aid clinicians in choosing the optimal treatment strategy. This study aimed to describe clinical phenotypes of SAPH and their characteristics. METHODS: A retrospective cohort study was performed on all SAPH patients at a tertiary referral centre. All patients were extensively analysed and discussed case by case in a multidisciplinary expert team to determine the most likely pathophysiological mechanism of PH. Patients were then classified into conceptual clinical phenotypes. RESULTS: Forty (40) patients with SAPH were identified between 2010 and 2019. Three (3) patients were classified as the postcapillary phenotype. Of the remaining 37 patients with precapillary PH, six were classified as 'compression of pulmonary vasculature', 29 as 'parenchymal', one as 'suspected vasculopathy', and one as 'chronic pulmonary emboli' phenotypes. Of the patients with compression of pulmonary vasculature, four showed compression by fibrotic disease and two by active sarcoidosis-based disease. Within the parenchymal phenotype, 20 patients (69%) showed pulmonary vascular resistance >3.0 Wood Units (WU) and had significantly lower diffusing capacity of the lung for carbon monoxide compared with the nine patients (31%) with pulmonary vascular resistance ≤3.0 WU. CONCLUSION: SAPH had multiple pathophysiological mechanisms and clinical phenotypes in this retrospective study. Further studies are necessary to examine how these phenotypes can affect appropriate treatment and prognosis.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Sarcoidose , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Fenótipo , Estudos Retrospectivos
5.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801690

RESUMO

In this review, we discuss the role of transforming growth factor-beta (TGF-ß) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-ß signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-ß pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.


Assuntos
Pneumopatias/complicações , Telangiectasia Hemorrágica Hereditária/complicações , Doenças Vasculares/complicações , Receptores de Activinas Tipo II/metabolismo , Animais , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/genética , Endoglina/metabolismo , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/genética , Pneumopatias/genética , Mutação , Risco , Transdução de Sinais , Telangiectasia Hemorrágica Hereditária/genética , Fator de Crescimento Transformador beta/metabolismo , Doenças Vasculares/genética
6.
Respir Med ; 178: 106220, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33540340

RESUMO

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.


Assuntos
Análise de Dados , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sistema de Registros , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Segurança , Fatores de Tempo , Resultado do Tratamento
7.
Respir Med ; 177: 106241, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33422952

RESUMO

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. RESULTS: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. CONCLUSION: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.

8.
Eur Heart J Cardiovasc Imaging ; 22(10): 1190-1196, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-32667638

RESUMO

AIMS: Transthoracic contrast echocardiography (TTCE) is the recommended screening tool to detect pulmonary right-to-left shunt (RLS) caused by pulmonary arteriovenous malformations (PAVMs). We assessed a novel method to quantify the RLS using the change in echo density (ED) following contrast injection. METHODS AND RESULTS: An analysis of 437 consecutive patients [58% female, 47 years, interquartile range (IQR) 33-60] who underwent TTCE for the detection of a pulmonary RLS. Using ImageJ (National Institutes of Health), the change in ED was measured for each patient. This method was strongly correlated (Spearman's ρ = 0.89; P < 0.0001) with our standard method based on a four-point grading scale (no, mild, moderate, and severe RLS). In patients without a history of embolotherapy (n = 334), a PAVM was detected with chest computed tomography (CT) in 66 and embolotherapy was judged possible in 35 of these patients. The median increase in ED was higher in the latter: +20.1% (IQR 12.3-34.0) compared to non-treatable PAVM +0.2% (IQR -0.2 to 1.1). The specificity to detect treatable PAVMs increased from 87% to 90% when using the novel method without affecting the sensitivity (of 100%). Using the optimal cut-off value of +4.5% increase in ED, 8/74 (11%) needed chest CT-scans-individuals with a moderate or severe RLS-were no longer required without missing any treatable PAVM. CONCLUSIONS: The use of ED quantification for pulmonary RLS is promising; resulting in a substantial decrease in the number of chest CT scans needed. However, this method and the threshold should be validated in an independent study population.


Assuntos
Fístula Arteriovenosa , Malformações Arteriovenosas , Veias Pulmonares , Telangiectasia Hemorrágica Hereditária , Ecocardiografia , Feminino , Humanos , Masculino , Artéria Pulmonar/diagnóstico por imagem , Veias Pulmonares/diagnóstico por imagem
9.
J Clin Med ; 9(11)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202566

RESUMO

BACKGROUND: Computed tomography (CT) is considered the imaging modality of choice to diagnose pulmonary arteriovenous malformations PAVMs. The drawback of this technique is that it requires ionizing radiation. Magnetic resonance (MR) imaging does not have the limitation, but little is known about the performance of MR compared to CT for the detection of PAVMs. The aim of this study is to investigate the sensitivity of contrast-enhanced MR angiography (CE-MRA) in the detection of PAVMs with feeding artery diameters (FAD) > 2 mm. METHODS: Patients with a grade 2 or 3 shunt on screening transthoracic contrast echocardiography (TTCE) were asked to participate. Included patients underwent chest CT and CE-MRA. CT was considered the reference standard. CT and CE-MRA scans were anonymized and assessed for the presence of PAVMs with FAD > 2 mm by one and two readers respectively. Data analysis was performed on per patient and per PAVM basis. RESULTS: Fifty-three patients were included. 105 PAVMs were detected on CT, 45 with a FAD ≥ 2 mm. In per patient analysis, sensitivity and specificity of CE-MRA were 92% and 97% respectively for reader 1 and 92% and 62% for reader 2. Negative and positive predictive value (NPV/PPV) were 93% and 96% for R1 and 90% and 67% for R2. In per PAVM analysis, sensitivity, specificity, NPV and PPV were 96%, 99%, 100% and 86% for R1 and 93%, 96%, 100% and 56% for R2, respectively. CONCLUSIONS: CE-MRA has excellent sensitivity and NPV for detection of PAVMs with FAD ≥ 2 mm and can therefore be used to detect these PAVMs. We are hopeful that future advancements in CE-MRA technology will reduce false positive rates and allow for more broad use of CE-MRA in PAVM diagnosis and management.

10.
J Clin Med ; 9(11)2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33172103

RESUMO

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease, is characterized by telangiectases and arteriovenous malformations (AVMs). Untreated AVMs, especially in the lungs-pulmonary AVMs (PAVMs)-can result in morbidity with a decreased life expectancy. We have investigated whether HHT patients, systematically screened for HHT-related organ involvement and treated if needed, have a similar survival as persons without HHT. We included all individuals screened for HHT between 2004 and 2016 with a genetically or clinically confirmed diagnosis (HHT group) or excluded diagnosis (non-HHT control group). The social security number was used to confirm status as dead or alive in December 2019. We included 717 HHT patients and 471 controls. There was no difference in survival between the HHT and the non-HHT control group. The HHT group had a life expectancy of 75.9 years (95% confidence interval (CI) 73.3-78.6), comparable to the control group (79.3 years, 95% CI 74.8-84.0, Mantel-Cox test: p = 0.29). In conclusion, the life expectancy of HHT patients systematically screened for HHT-related organ involvement and treated if needed in an HHT center of excellence was similar compared to their controls, justifying systematic screening and treatment in HHT patients.

11.
Semin Respir Crit Care Med ; 41(5): 659-672, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32777851

RESUMO

Pulmonary hypertension (PH) is a well-known complication of sarcoidosis, defined by a mean pulmonary artery pressure of ≥25 mm Hg. Since both PH and sarcoidosis are rare diseases, data on sarcoidosis-associated PH (SAPH) is retrieved mostly from small retrospective studies. Estimated prevalence of SAPH ranges from 3% in patients referred to a tertiary center up to 79% in patients awaiting lung transplant. Most patients with SAPH show advanced parenchymal disease as the underlying mechanism. However, some patients have disproportional elevated pulmonary artery pressure, and PH can occur in sarcoidosis patients without parenchymal disease. Other mechanisms such as vascular disease, pulmonary embolisms, postcapillary PH, extrinsic compression, and other sarcoidosis-related comorbidities might contribute to SAPH. The diagnosis of PH in sarcoidosis is challenging since symptoms and signs overlap. Suspicion can be raised based on symptoms or tests, such as pulmonary function tests, laboratory findings, electrocardiography, or chest CT. PH screening mainly relies on transthoracic echocardiography. Right heart catheterization should be considered on a case-by-case basis in patients with clinical suspicion of PH, taking into account clinical consequences. Treatment options are considered on patient level in a PH expert center, and might include oxygen therapy, immunosuppressive, or PH-specific therapy. However, qualitative evidence is scarce. Furthermore, in a subset of patients, interventional therapy or eventually lung transplant can be considered. SAPH is associated with high morbidity. Mortality is higher in sarcoidosis patients with PH compared with those without PH, and increases in patients with more advanced stages of sarcoidosis and/or PH.


Assuntos
Hipertensão Pulmonar/etiologia , Sarcoidose Pulmonar/complicações , Cateterismo Cardíaco , Ecocardiografia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Transplante de Pulmão , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/fisiopatologia , Sarcoidose Pulmonar/terapia
12.
Vasc Med ; 25(4): 341-347, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32303156

RESUMO

Abnormal vasculature is a key feature of hereditary hemorrhagic telangiectasia (HHT) and can also present in the nail fold capillary beds. However, the exact prevalence and the clinical diagnostic value in HHT are still largely unknown. The nail fold can be easily and noninvasively inspected with a capillary microscope. We therefore retrospectively assessed the prevalence and diagnostic value of abnormal nail fold capillaries in all patients who were screened between January 2000 and July 2017 for the presence of HHT and underwent capillary microscopy in St Antonius Hospital, The Netherlands. Capillary microscopy results and clinical characteristics were extracted from medical files and the prevalence of abnormal nail fold capillaries was calculated and the diagnostic value of the Curaçao criteria with and without capillary microscopy results was assessed. Of the 1761 individuals screened, 923 (52%) were diagnosed with a clinical and/or genetic HHT diagnosis. In these patients, capillary microscopy was normal in 23% (n = 218), enlarged loops were seen in 11% (n = 99), and giant loops in 66% (n = 606). The sensitivity and specificity of the Curaçao criteria for the diagnosis of HHT without capillary microscopy results were 96% and 90%, respectively. The addition of the presence of giant loops to the Curaçao criteria led to a small increase in sensitivity to 97% without affecting the specificity. In conclusion, the prevalence of nail fold abnormalities in patients with HHT is high. Capillary microscopy can be a useful, easy, and noninvasive diagnostic tool in HHT.


Assuntos
Angioscopia Microscópica , Telangiectasia Hemorrágica Hereditária/diagnóstico por imagem , Telangiectasia Hemorrágica Hereditária/epidemiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Valor Preditivo dos Testes , Prevalência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
15.
Circulation ; 138(23): 2698-2712, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30571259

RESUMO

BACKGROUND: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. METHODS: We took advantage of Acvrl1+/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1+/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. RESULTS: Acvrl1+/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1+/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1+/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1+/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1+/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1+/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1+/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1+/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. CONCLUSIONS: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.


Assuntos
Telangiectasia Hemorrágica Hereditária/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptores de Ativinas Tipo I/genética , Receptores de Activinas Tipo II , Adulto , Animais , Anticorpos/administração & dosagem , Anticorpos/imunologia , Malformações Arteriovenosas/etiologia , Modelos Animais de Doenças , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Mycoplasma pulmonis/fisiologia , Neovascularização Fisiológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Vasos Retinianos/fisiologia , Transdução de Sinais , Pele/patologia , Telangiectasia Hemorrágica Hereditária/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia
16.
PLoS One ; 13(10): e0205196, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356250

RESUMO

BACKGROUND: The various conditions causing a chronic increase of RV pressure greatly differ in the occurrence of RV failure, and in clinical outcome. To get a better understanding of the differences in outcome, RV remodeling, longitudinal function, and transverse function are compared between patients with pulmonary stenosis (PS), those with a systemic RV and those with pulmonary hypertension (PH). MATERIALS AND METHODS: This cross-sectional study prospectively enrolled subjects for cardiac magnetic resonance imaging (CMR), functional echocardiography and cardiopulmonary exercise testing. The study included: controls (n = 37), patients with PS (n = 15), systemic RV (n = 19) and PH (n = 20). Statistical analysis was performed using Analysis of Variance (ANOVA) with posthoc Bonferroni. RESULTS: PS patients had smaller RV volumes with higher RV ejection fraction (61.1±9.6%; p<0.05) compared to controls (53.8±4.8%). PH and systemic RV patients exhibited dilated RVs with lower RV ejection fraction (36.9±9.6% and 46.3±10.1%; p<0.01 versus controls). PH patients had lower RV stroke volume (p = 0.02), RV ejection fractions (p<0.01) and VO2 peak/kg% (p<0.001) compared to systemic RV patients. Mean apical transverse RV free wall motion was lower and RV free wall shortening (p<0.001) was prolonged in PH patients-resulting in post-systolic shortening and intra-ventricular dyssynchrony. Apical transverse shortening and global longitudinal RV deformation showed the best correlation to RV ejection fraction (respectively r = 0.853, p<0.001 and r = 0.812, p<0.001). CONCLUSIONS: RV remodeling and function differed depending on the etiology of RV pressure overload. In contrast to the RV of patients with PS or a systemic RV, in whom sufficient stroke volumes are maintained, the RV of patients with PH seems unable to compensate for its increase in afterload completely. Key mediators of RV dysfunction observed in PH patients, were: prolonged RV free wall shortening, resulting in post-systolic shortening and intra-ventricular dyssynchrony, and decreased transverse function.


Assuntos
Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Estenose da Valva Pulmonar/fisiopatologia , Remodelação Ventricular , Adulto , Idoso , Débito Cardíaco , Ecocardiografia , Teste de Esforço , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Modelos Lineares , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estenose da Valva Pulmonar/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita
17.
Int J Mol Sci ; 19(10)2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30336550

RESUMO

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-ß) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.


Assuntos
Hipertensão Pulmonar Primária Familiar/complicações , Telangiectasia Hemorrágica Hereditária/complicações , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/terapia , Hemodinâmica , Humanos , Padrões de Herança/genética , Telangiectasia Hemorrágica Hereditária/genética
18.
Curr Opin Pulm Med ; 24(3): 260-268, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29470256

RESUMO

PURPOSE OF REVIEW: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterized by telangiectasia and arteriovenous malformations (AVMs). To date, five genetic types of HHT and one combined juvenile polyposis syndrome and HHT are known. Clinical and genetic screening of patients suspected with HHT is recommended to confirm the diagnosis and to prevent complications associated with HHT. The aim of this article is to give an overview of the evidence and to formulate a recommendation for clinicians concerning screening for HHT. RECENT FINDINGS: Complications of HHT such as stroke, brain abscess and intracranial hemorrhage are caused by pulmonary and cerebral AVMs (CAVMs) and can often be prevented by screening and treatment when possible. Screening and treatment of these AVMs will result in an increased life expectancy comparable with that of the general population as opposed to unscreened and untreated HHT patients. SUMMARY: Screening of HHT patients and their first-degree relatives is recommended to prevent severe complications including stroke, brain abscess and intracranial hemorrhage.


Assuntos
Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/terapia , Programas de Rastreamento , Telangiectasia Hemorrágica Hereditária/diagnóstico , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/genética
19.
J Cardiovasc Magn Reson ; 20(1): 5, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29332606

RESUMO

BACKGROUND: Tricuspid valve (TV) regurgitation (TR) is a common complication of pulmonary hypertension and right-sided congenital heart disease, associated with increased morbidity and mortality. Estimation of TR severity by echocardiography and conventional cardiovasvular magnetic resonance (CMR) is not well validated and has high variability. 4D velocity-encoded (4D-flow) CMR was used to measure tricuspid flow in patients with complex right ventricular (RV) geometry and varying degrees of TR. The aims of the present study were: 1) to assess accuracy of 4D-flow CMR across the TV by comparing 4D-flow CMR derived TV effective flow to 2D-flow derived effective flow across the pulmonary valve (PV); 2) to assess TV 4D-flow CMR reproducibility, and 3) to compare TR grade by 4D-flow CMR to TR grade by echocardiography. METHODS: TR was assessed by both 4D-flow CMR and echocardiography in 21 healthy subjects (41.2 ± 10.5 yrs., female 7 (33%)) and 67 RV pressure-load patients (42.7 ± 17.0 yrs., female 32 (48%)). The CMR protocol included 4D-flow CMR measurement across the TV, 2D-flow measurement across the PV and conventional planimetric measurements. TR grading on echocardiographic images was performed based on the international recommendations. Bland-Altman analysis and intra-class correlation coefficients (ICC) were used to asses correlations and agreement. RESULTS: TV effective flow measured by 4D-flow CMR showed good correlation and agreement with PV effective flow measured by 2D-flow CMR with ICC = 0.899 (p < 0.001) and mean difference of -1.79 ml [limits of agreement -20.39 to 16.81] (p = 0.084). Intra-observer agreement for effective flow (ICC = 0.981; mean difference - 1.51 ml [-12.88 to 9.86]) and regurgitant fraction (ICC = 0.910; mean difference 1.08% [-7.90; 10.06]) was good. Inter-observer agreement for effective flow (ICC = 0.935; mean difference 2.12 ml [-15.24 to 19.48]) and regurgitant fraction (ICC = 0.968; mean difference 1.10% [-7.96 to 5.76]) were comparable. In 25/65 (38.5%) TR grade differed by at least 1 grade using 4D-flow CMR compared to echocardiography. CONCLUSION: TV effective flow derived from 4D-flow CMR showed excellent correlation to PV effective flow derived from 2D-flow CMR, and was reproducible to measure TV flow and regurgitation. Twenty-five out of 65 patients (38.5%) were classified differently by at least one TR grade using 4D-flow CMR compared to echocardiography.


Assuntos
Ecocardiografia Quadridimensional , Cardiopatias Congênitas/diagnóstico por imagem , Hemodinâmica , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Imagem de Perfusão do Miocárdio/métodos , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/diagnóstico por imagem , Adolescente , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Estudos Transversais , Estudos de Viabilidade , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Estudos Prospectivos , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/etiologia , Insuficiência da Valva Tricúspide/fisiopatologia , Adulto Jovem
20.
Respiration ; 94(3): 242-250, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28743113

RESUMO

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations in the brain, liver, and lungs. Pulmonary hypertension (PH) is increasingly recognized as a severe complication of HHT. However, there are no studies describing the prevalence of PH in HHT compared to HHT-negative controls. OBJECTIVE: To assess the estimated prevalence of PH in patients with HHT compared to HHT-negative controls. METHODS: All consecutive subjects screened for HHT with available genetic testing and echocardiography-based peak tricuspid regurgitation velocity (TRV) measurement were included. Increased-probability PH was defined as a TRV >2.8 m/s. RESULTS: In 578 subjects, both echocardiography and genetic testing were available. A reliable TRV was measured in 383 (66.3%), of whom 127 had HHT type 1 (HHT1), 150 had HHT type 2 (HHT2), and 106 were HHT-negative controls, with a mean TRV of 2.3 ± 0.4, 2.4 ± 0.5, and 2.2 ± 0.3 m/s, respectively (p = 0.008 and p < 0.001 vs. controls). Increased-probability PH was found in 42 subjects (8.7% in HHT1, 18.0% in HHT2, and 3.8% in HHT-negative controls). HHT2 and hepatic arteriovenous malformations (HAVMs) were the most important predictors for increased-probability PH (odds ratio 5.6, p = 0.002, and odds ratio 11.3, p < 0.001, respectively). Heritable pulmonary arterial hypertension (HPAH) was diagnosed in 2 patients (0.7%) and only found in HHT2 (1.3%). CONCLUSION: The estimated prevalence of PH is higher in HHT patients compared to HHT-negative controls. This increase is especially present in HHT2 and mainly associated with the presence of HAVMs. HPAH appears to be rare in HHT patients and was only diagnosed in HHT2.


Assuntos
Hipertensão Pulmonar/etiologia , Telangiectasia Hemorrágica Hereditária/complicações , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Telangiectasia Hemorrágica Hereditária/epidemiologia
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