Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 211
Filtrar
1.
Eur Respir J ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38964779

RESUMO

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.

2.
Eur Respir J ; 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38936966

RESUMO

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 electrocardiogram (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 1 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). Performance was also tested on ECGs taken 6-18 months (pre-emptive dataset), and up to 5 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 set at Mayo Clinic and VUMC, respectively, and 0.86 and 0.81, respectively, in the pre-emptive test set. The AUC remained a minimum of 0.79 at Mayo Clinic and 0.73 at VUMC up to 5 years before diagnosis. CONCLUSION: The PH-EDA can detect PH at diagnosis and 6-18 months prior, demonstrating the potential to accelerate diagnosis and management of this debilitating disease.

3.
Eur J Heart Fail ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38837273

RESUMO

AIMS: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized. METHODS AND RESULTS: Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86). CONCLUSIONS: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02980887.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38747680

RESUMO

RATIONALE: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. OBJECTIVES: We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH). METHODS: We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. MEASUREMENTS AND MAIN RESULTS: Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups. CONCLUSIONS: Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03229499.

5.
Lancet Respir Med ; 12(7): 523-534, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38705167

RESUMO

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.


Assuntos
Hipertensão Arterial Pulmonar , Humanos , Masculino , Método Duplo-Cego , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Idoso , Hipertensão Arterial Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Resistência Vascular/efeitos dos fármacos , Administração por Inalação , Hipertensão Pulmonar/tratamento farmacológico
6.
Pulm Circ ; 14(2): e12361, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38800494

RESUMO

Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1-year mortality risk. PAH patients (n = 223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R 2 = 0.82, p < 0.001), whereas the relationship between TAPSE and RVFWS was weaker (R 2 = 0.28, p < 0.001). Death or lung transplantation at 5 years occurred in 78 patients (35%). Guided by outcome analysis, we ascertained a uniform set of parameter thresholds for grading the severity of right heart adaptation in PAH. Using these quantitative thresholds, we, then, validated the recently reported REVEAL-echo score (AUC 0.68, p < 0.001). This study proposes a consistent echocardiographic grading system for right heart adaptation in PAH guided by outcome analysis.

7.
Eur J Heart Fail ; 26(4): 707-729, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38639017

RESUMO

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Circulação Pulmonar , Função Ventricular Direita , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Função Ventricular Direita/fisiologia , Circulação Pulmonar/fisiologia
9.
J Am Heart Assoc ; 13(7): e031796, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38533961

RESUMO

BACKGROUND: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio. METHODS AND RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all). CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier: NCT00763867.


Assuntos
Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Humanos , Biomarcadores , Estudos Transversais , GMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Fragmentos de Peptídeos , Citrato de Sildenafila/farmacologia , Volume Sistólico/fisiologia
10.
Chest ; 165(6): 1493-1504, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38354903

RESUMO

BACKGROUND: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH). RESEARCH QUESTION: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system? STUDY DESIGN AND METHODS: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups. RESULTS: Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3. INTERPRETATION: HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH.


Assuntos
Hipertensão Pulmonar , Qualidade de Vida , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/psicologia , Estudos Transversais , Idoso , Inquéritos e Questionários
11.
bioRxiv ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38328113

RESUMO

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.

12.
Med Phys ; 51(7): 4759-4766, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38277476

RESUMO

BACKGROUND: Oscillating x-ray attenuation in the lungs provides an opportunity to evaluate pulmonary perfusion without contrast. Recent intensity-based methods have been compared to pulmonary scintigraphy and CT angiography but lack rigorous phantom studies. PURPOSE: A new method to quantify the periodic signal amplitude was employed using spectral analysis. Performance was characterized using a water phantom capable of creating an oscillating x-ray attenuation at physiologic amplitudes. Feasibility in detecting abnormal perfusion was performed on a volunteer with pulmonary vascular disease and compared to pulmonary angiography, the clinical gold standard. METHODS: For each fluoroscopic acquisition, the normalized temporal signal from each pixel was decomposed into its frequency components using Fourier transformation, and the spectral amplitude, defined as the x-ray pulsatility index (XPI), was determined at the desired frequency using a band-pass filter. XPI was displayed as a pixel-wise parametric colormap. Based on XPI maps generated using two human volunteers, a water bath phantom was constructed with a fluctuating fluid height and a 1 cm diameter pulsatility defect. Contrast-to-noise (CNR) of the defect was measured using fluoroscopy images acquired at variable fluid height fluctuation (0.1-1.9 mm) and oscillation frequency (30-60 bpm). Various sampling frame rates (3-30 fps) and acquisition durations (1.8-8 s) using truncated datasets were reconstructed from full datasets. Fluoroscopic images were obtained in a patient just prior to pulmonary angiography in the same projection. RESULTS: XPI maps in human subjects showed high signal to background contrast with high central XPI measuring up to 0.5. Phantom experiments revealed CNR was linearly correlated to fluid height change (r2 = 0.998). CNR is proportional to increasing sampling frame rate and increasing acquisition duration as expected with Fourier analysis. XPI map displayed multifocal perfusion defects in good agreement with pulmonary angiography. CONCLUSION: Spectral analysis is an accurate and sensitive method to detect small changes in periodic x-ray attenuation using a short fluoroscopic acquisition. This method demonstrated good agreement to pulmonary angiography and shows promise for clinical imaging of pulmonary perfusion using standard fluoroscopic methods.


Assuntos
Estudos de Viabilidade , Pulmão , Imagens de Fantasmas , Fluoroscopia , Humanos , Pulmão/diagnóstico por imagem , Razão Sinal-Ruído , Imagem de Perfusão/métodos , Processamento de Imagem Assistida por Computador/métodos
13.
J Heart Lung Transplant ; 43(2): 272-283, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37778526

RESUMO

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals.


Assuntos
Acetamidas , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Pirazinas , Adulto , Humanos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Anti-Hipertensivos , Estudos Prospectivos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico
14.
Circ Res ; 133(11): 885-898, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37929582

RESUMO

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.


Assuntos
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/fisiologia
15.
J Am Coll Cardiol ; 82(21): 1989-2005, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37968017

RESUMO

BACKGROUND: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear. OBJECTIVES: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival. METHODS: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses. RESULTS: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation. CONCLUSIONS: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Cardíaca/complicações , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/etiologia , Oxigênio , Sono , Disfunção Ventricular Direita/epidemiologia , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita
16.
Front Med (Lausanne) ; 10: 1276422, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37869164

RESUMO

Introduction: Pulmonary arterial hypertension is a fatal cardiopulmonary disease. Leptin, a neuroendocrine hormone released by adipose tissue, has a complex relationship with cardiovascular diseases, including PAH. Leptin is thought to be an important factor linking metabolic syndrome and cardiovascular disorders. Given the published association between metabolic syndrome and RV dysfunction in PAH, we sought to determine the association between leptin and RV dysfunction. We hypothesized that in PAH-RV, leptin influences metabolic changes via leptin receptors, which can be manipulated by metformin. Methods: Plasma leptin was measured in PAH patients and healthy controls from a published trial of metformin in PAH. Leptin receptor localization was detected in RV from PAH patients, healthy controls, animal models of PH with RV dysfunction before and after metformin treatment, and cultured cardiomyocytes with two different BMPR2 mutants by performing immunohistochemical and cell fractionation studies. Functional studies were conducted in cultured cardiomyocytes to examine the role of leptin and metformin in lipid-driven mitochondrial respiration. Results: In human studies, we found that plasma leptin levels were higher in PAH patients and moderately correlated with higher BMI, but not in healthy controls. Circulating leptin levels were reduced by metformin treatment, and these findings were confirmed in an animal model of RV dysfunction. Leptin receptor expression was increased in PAH-RV cardiomyocytes. In animal models of RV dysfunction and cultured cardiomyocytes with BMPR2 mutation, we found increased expression and membrane localization of the leptin receptor. In cultured cardiomyocytes with BMPR2 mutation, leptin moderately influences palmitate uptake, possibly via CD36, in a mutation-specific manner. Furthermore, in cultured cardiomyocytes, the Seahorse XFe96 Extracellular Flux Analyzer and gene expression data indicate that leptin may not directly influence lipid-driven mitochondrial respiration in BMPR2 mutant cardiomyocytes. However, metformin alone or when supplemented with leptin can improve lipid-driven mitochondrial respiration in BMPR2 mutant cardiomyocytes. The effect of metformin on lipid-driven mitochondrial respiration in cardiomyocytes is BMPR2 mutation-specific. Conclusion: In PAH, increased circulating leptin can influence metabolic signaling in RV cardiomyocytes via the leptin receptor; in particular, it may alter lipid-dependent RV metabolism in combination with metformin in a mutation-specific manner and warrants further investigation.

17.
Am J Physiol Lung Cell Mol Physiol ; 325(5): L617-L627, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37786941

RESUMO

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.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/complicações , Cinurenina , Triptofano , Escleroderma Sistêmico/complicações , Hipertensão Pulmonar Primária Familiar , Biomarcadores
18.
Pulm Circ ; 13(3): e12285, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37701142

RESUMO

Pulmonary arterial hypertension (PAH) patients have low activity. Activity intensity or duration could be a measure of clinical status or improvement. We aimed to determine whether standard or novel actigraphy measures could detect increases in activity after adding therapy. This was a prospective, single-center observational study evaluating activity after adding therapy in Group 1 PAH; we also report a validation cohort. For our study, two different accelerometers were used, a wrist (ActiGraph) and chest (MC10) device. Patients were analyzed in two groups, Treatment Intensification (TI, adding therapy) or Stable. Both groups had baseline monitoring periods of 7 days; the TI group had follow-up at 3 months, while Stables had follow-up within 4 weeks to assess stability. Activity time and steps were reported from both devices' proprietary algorithms. In ActiGraph only, steps in 1-min intervals throughout the day were ranked (not necessarily contiguous). Average values for each week were calculated and compared using nonparametric testing. Thirty patients had paired data (11 Stable and 19 TI). There was no between-group difference at baseline; we did not observe therapy-associated changes on average daily steps or activity time/intensity. The top 5 min of steps (capacity) increased after adding therapy; there was no difference in the stable group. This key finding was validated in a previously reported randomized trial studying a behavioral intervention to increase exercise. Total daily activity metrics are influenced by both disease and non-disease factors, making therapy-associated change difficult to detect. Peak minute steps were a treatment-responsive marker in both a pharmacologic and training intervention.

20.
Circ Heart Fail ; 16(10): e010555, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37664964

RESUMO

BACKGROUND: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. METHODS: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. RESULTS: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. CONCLUSIONS: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Humanos , Hipertensão Arterial Pulmonar/diagnóstico , Imageamento por Ressonância Magnética , Ventrículos do Coração/diagnóstico por imagem , Função Ventricular Direita , Artéria Pulmonar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...