RESUMO
BACKGROUND: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function. METHODS: We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV-arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism. RESULTS: RV mass significantly decreased from 43±15 to 27±11g/m2 (-15.9 g/m2 [95% CI, -21.4 to -10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 in healthy controls [95% CI, 2.1 to 9.8]; P<0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2-6.1]; P=0.013) as a result of a larger reduction in cellular volume than in matrix volume (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-ß (transforming growth factor-ß) were elevated at baseline and remained elevated post-PEA. CONCLUSIONS: Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover.
Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Disfunção Ventricular Direita , Humanos , Hipertensão Pulmonar/cirurgia , Hipertensão Pulmonar/complicações , Inibidor Tecidual de Metaloproteinase-1 , Fibrose , Biomarcadores , Endarterectomia , Colágeno , Hipertrofia/complicações , Função Ventricular Direita , Disfunção Ventricular Direita/cirurgia , Disfunção Ventricular Direita/complicações , Artéria Pulmonar/cirurgiaRESUMO
Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families. Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis. Results: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH. Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.
RESUMO
Background Recognition of precapillary pulmonary hypertension (PH) has significant implications for patient management. However, the low a priori chance to find this rare condition in community hospitals may create a barrier against performing a right heart catheterization (RHC). This could result in misclassification of PH and delayed diagnosis/treatment of precapillary PH. Therefore, we investigated patient characteristics and echocardiographic parameters associated with the decision whether to perform an RHC in patients with incident PH in 12 Dutch community hospitals. Methods and Results In total, 275 patients were included from the OPTICS (Optimizing PH Diagnostic Network in Community Hospitals) registry, a prospective cohort study with patients with incident PH; 157 patients were diagnosed with RHC (34 chronic thromboembolic PH, 38 pulmonary arterial hypertension, 81 postcapillary PH, 4 miscellaneous PH), while 118 patients were labeled as probable postcapillary PH without hemodynamic confirmation. Multivariable analysis showed that older age (>60 years), left ventricular diastolic dysfunction grade 2-3, left atrial dilatation were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilatation, and tricuspid regurgitation velocity ≥3.7 m/s favor an RHC performance. Conclusions Older age and echocardiographic parameters of left heart disease were independently associated with the decision to not perform an RHC, while presence of prior venous thromboembolic events or pulmonary arterial hypertension-associated conditions, right atrial dilation, and severe PH on echocardiography favored an RHC performance. As such, especially elderly patients may be at an increased risk of diagnostic delays and missed diagnoses of treatable precapillary PH, which could lead to a worse prognosis.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Idoso , Cateterismo Cardíaco/efeitos adversos , Hipertensão Pulmonar Primária Familiar , Hospitais Comunitários , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Estudos ProspectivosRESUMO
Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
Assuntos
Mutação com Ganho de Função , Pneumopatias , Humanos , Proteínas com Domínio T/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Fenótipo , Pneumopatias/genética , Mutação/genética , GenótipoRESUMO
Rationale: Pulmonary hypertension encompasses progressive disorders leading to right ventricular dysfunction and early death. Late detection is an important cause of poor clinical outcomes. However, biomarkers that accurately predict the presence of pulmonary hypertension are currently lacking. Objectives: In this study, we provide evidence that blood platelets contain a distinctive ribonucleic acid (RNA) profile that may be exploited for the detection of pulmonary hypertension. Methods: Blood platelet RNA was isolated prospectively from 177 prevalent patients with different subtypes of pulmonary hypertension as well as 195 control subjects clinically not suspected of pulmonary hypertension. Sequencing libraries were created using SMARTer (Switching Mechanism at 5' end of RNA Template) copy desoxyribonucleic acid amplification and sequenced on the Illumina High Throughput Sequencing platform. RNA-sequencing reads were mapped to the human reference genome, and intron-spanning spliced RNA reads were selected. Differential spliced RNA panels were calculated by analysis of variance statistics. A particle swarm optimization-enhanced classification algorithm was built employing a development (n = 213 samples) and independent validation series (n = 159 samples). Results: We detected a total of 4,014 different RNAs in blood platelets from patients with pulmonary hypertension (n = 177) and asymptomatic control subjects (n = 195). Gene ontology analysis revealed enhanced RNA concentrations for genes related to RNA processing, translation, and mitochondrial function. A particle swarm optimization-selected RNA panel of 408 distinctive differentially spliced RNAs mediated detection of pulmonary hypertension with 93% sensitivity, 62% specificity, 77% accuracy, 0.89 (95% confidence interval, 0.83-0.93) area under the curve, and a negative predictive value of 91% in the independent validation series. The prediction score was independent of age, sex, smoking, pulmonary hypertension subtype, and the use of pulmonary hypertension-specific medication or anticoagulants. Conclusions: A platelet RNA panel may accurately discriminate patients with pulmonary hypertension from asymptomatic control subjects. In the light of current diagnostic delays, this study is the starting point for further development and evaluation of a platelet RNA-based blood test to ultimately improve early diagnosis and clinical outcomes in patients with pulmonary hypertension.
Assuntos
Plaquetas , Hipertensão Pulmonar , Anticoagulantes , Biomarcadores , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , RNA/genéticaRESUMO
BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAH-patients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females ≤45years had best prognosis in comparison to females ≥55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females ≤45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females ≤45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAH-patients. DHEA-S appeared to be lower in male and female PAH-patients. Females ≤45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.
Assuntos
Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Hipertensão Pulmonar Primária Familiar , Feminino , Hormônios Esteroides Gonadais , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Função Ventricular DireitaRESUMO
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity. METHODS: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP ≥30 and ≤50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging. RESULTS: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52±11 versus PAH: 36±12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3±0.2 versus PAH: 1.2±0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg). CONCLUSIONS: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/fisiopatologia , Função Ventricular Direita/fisiologia , Adulto , Idoso , Cateterismo Cardíaco/métodos , Feminino , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda/fisiologiaRESUMO
For young adults with end-stage idiopathic pulmonary hypertension, a valved graft connecting the central pulmonary artery to the distal aortic arch can provide substantial palliation of symptoms and may defer lung transplantation https://bit.ly/2TvMFFC.
RESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) has an identifiable genetic cause in 5% of all PAH cases. Due to health benefits conferred by the early detection of PAH and the recent identification of additional PAH-associated genes, we decided to offer (extended) genetic testing to all incident and prevalent idiopathic PAH (iPAH) and pulmonary veno-occlusive disease (PVOD) patients in our clinic. Here, we report the lessons learned from (re-)contacting iPAH/PVOD patients concerning the uptake and analysis of identified PAH-associated genes and patient perspectives of the approach. METHODS: Between January 2018 and April 2020, all iPAH/PVOD patients who were not previously genetically tested (contact group) and those who tested negative on prior analysis of BMPR2 and SMAD9 variants (re-contact group) were (re-)contacted for (additional) genetic testing. RESULTS: With our approach, 58% of patients (84 out of 165) opted for genetic counselling, and a pathogenic variant was found in 12% of cases (n = 10) (re-contact group, 11%, and contact group, 13%). Eighty-six percent of participants of the survey study appreciated being (re-)contacted for genetic testing. Mild psychosocial impacts were observed. CONCLUSIONS: Our report shows the importance of (re-)contact and interest of patients (as indicated by the uptake, mild psychosocial impact and appreciation) in PAH.
Assuntos
Atitude , Testes Genéticos/métodos , Hipertensão Pulmonar/genética , Pacientes/psicologia , Adulto , Idoso , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Feminino , Testes Genéticos/ética , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/psicologia , Masculino , Pessoa de Meia-Idade , Proteína Smad8/genéticaRESUMO
Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18FLT-PET scanning in three patients demonstrated uneven regional distribution in 18FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18FLT report may be explained by a small sample size previously and we observed large variation of lung 18FLT signals between patients, challenging the application of 18FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.
RESUMO
Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH.
Assuntos
Predisposição Genética para Doença , Fator 2 de Diferenciação de Crescimento/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Hipertensão Arterial Pulmonar/genética , Pneumopatia Veno-Oclusiva/genética , Proteínas com Domínio T/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Família , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Hipertensão Arterial Pulmonar/epidemiologia , Pneumopatia Veno-Oclusiva/epidemiologia , Adulto JovemRESUMO
Background Although most newly presenting patients with pulmonary hypertension (PH) have elevated pulmonary artery wedge pressure, identification of so-called postcapillary PH can be challenging. A noninvasive tool predicting elevated pulmonary artery wedge pressure in patients with incident PH may help avoid unnecessary invasive diagnostic procedures. Methods and Results A combination of clinical data, ECG, and echocardiographic parameters was used to refine a previously developed left heart failure risk score in a retrospective cohort of pre- and postcapillary PH patients. This updated score (renamed the OPTICS risk score) was externally validated in a prospective cohort of patients from 12 Dutch nonreferral centers the OPTICS network. Using the updated OPTICS risk score, the presence of postcapillary PH could be predicted on the basis of body mass index ≥30, diabetes mellitus, atrial fibrillation, dyslipidemia, history of valvular surgery, sum of SV1 (deflection in V1 in millimeters) and RV6 (deflection in V6 in millimeters) on ECG, and left atrial dilation. The external validation cohort included 81 postcapillary PH patients and 66 precapillary PH patients. Using a predefined cutoff of >104, the OPTICS score had 100% specificity for postcapillary PH (sensitivity, 22%). In addition, we investigated whether a high probability of heart failure with preserved ejection fraction, assessed by the H2FPEF score (obesity, atrial fibrillation, age >60 yrs, ≥2 antihypertensives, E/e' >9, and pulmonary artery systolic pressure by echo >35 mmHg), similarly predicted the presence of elevated pulmonary artery wedge pressure. High probability of heart failure with preserved ejection fraction (H2FPEF score ≥6) was less specific for postcapillary PH. Conclusions In a community setting, the OPTICS risk score can predict elevated pulmonary artery wedge pressure in PH patients without clear signs of left-sided heart disease. The OPTICS risk score may be used to tailor the decision to perform invasive diagnostic testing.