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BACKGROUND: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF. METHODS: Eight-week-old male and female C57BL/6J mice received either Nγ-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1ß (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1ß antibody were utilized to deplete macrophages and IL-1ß, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models. RESULTS: Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1ß in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1ß depletion also attenuated PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice. CONCLUSIONS: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1ß as an important contributor to PH in HFpEF.
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Insuficiência Cardíaca , Hipertensão Pulmonar , Animais , Feminino , Humanos , Masculino , Camundongos , Ácido Clodrônico , Insuficiência Cardíaca/metabolismo , Hipertensão Pulmonar/etiologia , Interleucina-1beta , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Volume Sistólico/fisiologiaRESUMO
The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology, and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science, and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH) the current approach to patient phenotyping integrates clinical, hemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iteration of the PH clinical classification is likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools, clinical trial design, and improve treatment selection in clinical practice.
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BACKGROUND: Early diagnosis of pulmonary hypertension (PH) is critical for effective treatment and management. We aimed to develop and externally validate an artificial intelligence algorithm that could serve as a PH screening tool, based on analysis of a standard 12-lead ECG. METHODS: The PH Early Detection Algorithm (PH-EDA) is a convolutional neural network developed using retrospective ECG voltage-time data, with patients classified as "PH-likely" or "PH-unlikely" (controls) based on right heart catheterisation or echocardiography. In total, 39 823 PH-likely patients and 219 404 control patients from Mayo Clinic were randomly split into training (48%), validation (12%) and test (40%) sets. ECGs taken within 1â month of PH diagnosis (diagnostic dataset) were used to train the PH-EDA at Mayo Clinic. Performance was tested on diagnostic ECGs within the test sets from Mayo Clinic (n=16 175/87 998 PH-likely/controls) and Vanderbilt University Medical Center (VUMC; n=6045/24 256 PH-likely/controls). In addition, performance was tested on ECGs taken 6-18â months (pre-emptive dataset), and up to 5â years prior to a PH diagnosis at both sites. RESULTS: Performance testing yielded an area under the receiver operating characteristic curve (AUC) of 0.92 and 0.88 in the diagnostic test sets at Mayo Clinic and VUMC, respectively, and 0.86 and 0.81, respectively, in the pre-emptive test sets. The AUC remained a minimum of 0.79 at Mayo Clinic and 0.73 at VUMC up to 5â years before diagnosis. CONCLUSION: The PH-EDA can detect PH at diagnosis and 6-18â months prior, demonstrating the potential to accelerate diagnosis and management of this debilitating disease.
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Algoritmos , Diagnóstico Precoce , Eletrocardiografia , Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/diagnóstico , Eletrocardiografia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Inteligência Artificial , Curva ROC , Ecocardiografia , Adulto , Redes Neurais de Computação , Cateterismo CardíacoRESUMO
Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption affects development.
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Proteínas com Domínio T , Fatores de Transcrição , Animais , Humanos , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , FenótipoRESUMO
AIMS: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.
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Anemia Ferropriva , Insuficiência Cardíaca , Hipertensão Pulmonar , Deficiências de Ferro , Humanos , Anemia Ferropriva/complicações , Hemoglobinas , TransferrinasRESUMO
Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/complicações , Cinurenina , Triptofano , Escleroderma Sistêmico/complicações , Hipertensão Pulmonar Primária Familiar , BiomarcadoresRESUMO
BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.
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Aromatase/genética , Doença Hepática Terminal/complicações , Estrogênios/metabolismo , Hipertensão Portal/genética , Hipertensão Pulmonar/genética , Idoso , Aromatase/metabolismo , Estudos de Casos e Controles , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Ecocardiografia , Doença Hepática Terminal/sangue , Doença Hepática Terminal/genética , Doença Hepática Terminal/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/sangue , Estrogênios/urina , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/metabolismo , Hipertensão Portal/urina , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/urina , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Transdução de Sinais/genética , Resistência Vascular/genéticaRESUMO
BACKGROUND: Study of pulmonary arterial hypertension (PAH) in claims-based (CB) cohorts may facilitate understanding of disease epidemiology, however previous CB algorithms to identify PAH have had limited test characteristics. We hypothesized that machine learning algorithms (MLA) could accurately identify PAH in an CB cohort. METHODS: ICD-9/10 codes, CPT codes or PAH medications were used to screen an electronic medical record (EMR) for possible PAH. A subset (Development Cohort) was manually reviewed and adjudicated as PAH or "not PAH" and used to train and test MLAs. A second subset (Refinement Cohort) was manually reviewed and combined with the Development Cohort to make The Final Cohort, again divided into training and testing sets, with MLA characteristics defined on test set. The MLA was validated using an independent EMR cohort. RESULTS: 194 PAH and 786 "not PAH" in the Development Cohort trained and tested the initial MLA. In the Final Cohort test set, the final MLA sensitivity was 0.88, specificity was 0.93, positive predictive value was 0.89, and negative predictive value was 0.92. Persistence and strength of PAH medication use and CPT code for right heart catheterization were principal MLA features. Applying the MLA to the EMR cohort using a split cohort internal validation approach, we found 265 additional non-confirmed cases of suspected PAH that exhibited typical PAH demographics, comorbidities, hemodynamics. CONCLUSIONS: We developed and validated a MLA using only CB features that identified PAH in the EMR with strong test characteristics. When deployed across an entire EMR, the MLA identified cases with known features of PAH.
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Hipertensão Arterial Pulmonar , Algoritmos , Registros Eletrônicos de Saúde , Hipertensão Pulmonar Primária Familiar , Humanos , Aprendizado de Máquina , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/epidemiologiaRESUMO
PURPOSE OF REVIEW: While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science findings to human disease and even led to recently published studies of metabolic therapy in pulmonary arterial hypertension that are discussed here. RECENT FINDINGS: Progress has been made in four key areas including mechanisms of insulin resistance in pulmonary arterial hypertension, the role of obesity in pulmonary vascular disease, novel clinical trials targeting metabolism in pulmonary hypertension, and the role of metabolism in chronic thromboembolic pulmonary hypertension. SUMMARY: : Insulin resistance in pulmonary arterial hypertension is primarily in the lipid axis. There are systemic manifestations of insulin resistance including right ventricular lipotoxicity. Obesity is associated with elevation of right ventricular systolic pressure even in a healthy population and therapies in pulmonary arterial hypertension that target metabolism hold promise for improving exercise, right ventricular function, and visceral adiposity. Finally, there are emerging data that chronic thromboembolic pulmonary hypertension is similarly characterized by metabolic alterations, though the specific metabolites may be different from pulmonary arterial hypertension.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Ventrículos do Coração , Humanos , Artéria Pulmonar , Circulação Pulmonar , Função Ventricular DireitaRESUMO
Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating AktSer473 via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.
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Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Antígenos de Superfície/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Antígenos CD36/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Resistência à Insulina , Camundongos , Proteínas do Leite/metabolismo , Mitocôndrias/metabolismo , Mutação/genética , Consumo de Oxigênio , Ácido Palmítico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Superóxidos/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Purpose: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial-venous ratio (PR) could substitute for the transpulmonary ratio (TPR).Materials and methods: Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH (n = 18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH; n = 7) and isolated post-capillary PH (Ipc-PH; n = 9). Bland-Altman comparisons were made between peripheral venous and PA samples and between peripheral arterial and PAW samples. TPR was defined as [PAW]/[PA].Results: For ET-1, Bland-Altman analysis indicated negative bias (-24%) in peripheral arterial compared to PAW concentration and positive bias (23%) in peripheral venous compared to PA concentration. There was <10% absolute bias for NT-pro-BNP and cAMP. For ET-1, there was no difference in PR between Cpc-PH and Ipc-PH (0.87 ± 0.4 vs. 0.94 ± 0.6, p = 0.8), whereas there was a difference in TPR (2.2 ± 1.1 vs. 1.1 ± 0.2, p < 0.05).Conclusions: In PH-LHD, peripheral samples may be inadequate surrogates for transpulmonary samples, particularly when measuring mediators with prominent pulmonary secretion or clearance, such as ET-1.
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Biomarcadores/sangue , Hipertensão Pulmonar/sangue , Adulto , Artérias , Coleta de Amostras Sanguíneas , Estudos de Casos e Controles , AMP Cíclico/sangue , Endotelina-1/sangue , Feminino , Cardiopatias/sangue , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Artéria Pulmonar , VeiasRESUMO
The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.
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Hipertensão Pulmonar/fisiopatologia , Circulação Pulmonar , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Adaptação Fisiológica , Animais , Cateterismo Cardíaco , Ecocardiografia , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/terapia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/terapiaRESUMO
BACKGROUND: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies. METHODS: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations. RESULTS: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes. CONCLUSIONS: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.
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Pesquisa , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita/fisiologia , Animais , Humanos , Sociedades Médicas , Estados UnidosRESUMO
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4â mg·kg-1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4â h and increased SOD2 plasma protein at 2â weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
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Citocinas/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Peptidil Dipeptidase A/farmacologia , Artéria Pulmonar/fisiopatologia , Adulto , Idoso , Enzima de Conversão de Angiotensina 2 , Animais , Biomarcadores , Citocinas/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudo de Prova de Conceito , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Superóxido Dismutase/metabolismo , Suínos , Resistência Vascular/efeitos dos fármacosRESUMO
The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.
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Hipertensão Pulmonar/terapia , Medicina de Precisão/métodos , Educação , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Estados UnidosRESUMO
BACKGROUND: The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. METHODS AND RESULTS: We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4±1.3% triglyceride versus 0.22±0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV. CONCLUSIONS: Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation.