Models and Molecular Mechanisms of World Health Organization Group 2 to 4 Pulmonary Hypertension.
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ABSTRACT:
SUBMITTER: Xiong PY
PROVIDER: S-EPMC5777609 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Models and Molecular Mechanisms of World Health Organization Group 2 to 4 Pulmonary Hypertension.
Xiong Ping Yu PY Potus Francois F Chan Winnie W Archer Stephen L SL
Hypertension (Dallas, Tex. : 1979) 20171120 1
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Project description:World Health Organization (WHO) group 2 pulmonary hypertension (PH) due to left-side heart disease (ie, heart failure or left-sided valvular heart disease) is the most common form of PH in western countries. Distinguishing patients with WHO group 2 PH, particularly the subset of patients with PH due to heart failure with preserved ejection fraction (HFpEF), from those with WHO group 1 pulmonary arterial hypertension (PAH) is challenging. Separating the two conditions is of vital importance because treatment strategies differ completely. Furthermore, therapies that are indicated for WHO group 1 PAH may be harmful in patients with WHO group 2 PH. We review the somewhat confusing PH nomenclature and the WHO classification system and rationale behind it. We then focus on left-side heart disorders that cause PH. An aging population and advances in the medical management of common cardiovascular disorders have caused the prevalence of heart failure to rise significantly, with more than one-half of patients having HFpEF. We review contemporary studies that focus on clinical and echocardiographic findings that help to distinguish HFpEF from PAH in the patient with PH. We discuss the typical, and sometimes atypical, hemodynamic profiles that characterize these two groups, review challenges in the interpretation of data obtained by right-sided heart catheterization, and highlight special maneuvers that may be required for accurate diagnosis. Finally, we review the largely disappointing studies on the use of PAH-specific therapies in patients with WHO group 2 PH, including the use of prostacyclins, endothelin receptor antagonists, and the more promising phosphodiesterase-5 inhibitors.
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Project description:Pulmonary hypertension (PH) complicating chronic obstructive pulmonary disease (COPD-PH) and interstitial lung disease (ILD-PH) (World Health Organization [WHO] Group III PH) increases medical costs and reduces survival. Despite limited data, many clinicians are using pulmonary arterial hypertension (PAH)-specific therapy to treat WHO Group III PH patients. To further investigate the utility of PAH-specific therapy in WHO Group III PH, we performed a systematic review and meta-analysis. Relevant studies from January 2000 through May 2016 were identified in the MEDLINE, EMBASE, and COCHRANE electronic databases and www.clinicaltrials.gov. Change in six-minute walk distance (6MWD) was estimated using random effects meta-analysis techniques. Five randomized controlled trials (RCTs) in COPD-PH (128 placebo or standard treatment and 129 PAH-medication treated patients), two RCTs in ILD-PH (23 placebo and 46 treated patients), and four single-arm clinical trials (50 patients) in ILD-PH were identified. Treatment in both COPD-PH and ILD-PH did not worsen hypoxemia. Symptomatic burden was not consistently reduced but there were trends for reduced pulmonary artery pressures and pulmonary vascular resistance with PAH-specific therapy. As compared to placebo, 6MWD was not significantly improved with PAH-specific therapy in the five COPD-PH RCTs (42.7 m; 95% confidence interval [CI], -1.0 - 86.3). In the four single-arm studies in ILD-PH patients, there was a significant improvement in 6MWD after PAH-specific treatment (46.2 m; 95% CI, 27.9-64.4), but in the two ILD-PH RCTs there was not an improvement (21.6 m; 95% CI, -17.8 - 61.0) in exercise capacity when compared to placebo. Due to the small numbers of patients evaluated and inconsistent beneficial effects, the utility of PAH-specific therapy in WHO Group III PH remains unproven. A future clinical trial that is appropriately powered is needed to definitively determine the efficacy of this widely implemented treatment approach.
| S-EPMC5448533 | biostudies-literature
Project description:Pulmonary hypertension (PH) stands as a tumor paradigm cardiovascular disease marked by hyperproliferation of cells and vascular remodeling, culminating in heart failure. Complex genetic and epigenetic mechanisms collectively contribute to the disruption of pulmonary vascular homeostasis. In recent years, advancements in research technology have identified numerous gene deletions and mutations, in addition to bone morphogenetic protein receptor type 2, that are closely associated with the vascular remodeling process in PH. Additionally, epigenetic modifications such as RNA methylation, DNA methylation, histone modification, and noncoding RNAs have been shown to precisely regulate PH molecular networks in a cell-type-specific manner, emerging as potential biomarkers and therapeutic targets. This review summarizes and analyzes the roles and molecular mechanisms of currently identified genes and epigenetic factors in PH, emphasizing the pivotal role of long ncRNAs in its regulation. Additionally, it examines current clinical and preclinical therapies for PH targeting these genes and epigenetic factors and explores potential new treatment strategies.
| S-EPMC11892029 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.
| S-EPMC4881582 | biostudies-literature
Project description:ObjectiveTo assess interrater reliability of the New York Heart Association/World Health Organization functional classification as applied by clinicians (defined as both physicians and nurses in this article) to patients with pulmonary arterial hypertension (PAH).Patients and methodsBetween March 16 and August 31, 2007, a survey that described 10 hypothetical patients was completed by physicians and nurses attending a conference on PAH. Results were subsequently validated with physicians and nurses who were contacted online through the Pulmonary Hypertension Association. Respondents were asked to assign each patient's functional class as they would normally in clinical practice.ResultsThe functional class evaluations were completed by 113 clinicians, 87 (77%) of whom had participated in PAH trials; 106 (94%) reported using functional class when determining therapy. Clinicians reported a broad range of factors they considered when evaluating functional class, and their assessments of functional class varied widely. The intraclass correlation coefficient was 0.58 for the initial patient survey and 0.62 for the online survey. At best, one patient was ranked as either class II (by 60 clinicians [53%]) or class III (by 53 [47%]). Clinicians' rankings spanned at least 3 functional classes for each of the other patients. Equally divergent rankings were observed among nurses and physicians. Cluster analysis identified clinicians' tendencies toward "higher" or "lower" functional class rankings. Of the 113 clinicians, 101 (89%) thought that the patients described resembled those seen in their practices.ConclusionDespite the wide use of the New York Heart Association/World Health Organization functional class in clinical care and as a research tool, interrater agreement may be inadequate. Efforts to promote a uniform approach to evaluating functional class might help to standardize PAH care and research.
| S-EPMC2704130 | biostudies-literature
Project description:BackgroundThe World Health Organization recognizes 5 groups of pulmonary hypertension (PH), categorized by pathogenesis or comorbidity: 1-pulmonary arterial hypertension 2-left-heart disease, 3-lung disease and hypoxia 4-chronic thromboembolic disease, and 5-miscellaneous. The epidemiology of PH, apart from group 1, is largely unknown.Methods and resultsWe describe incidence, prevalence, comorbidities, mortality and prescribing patterns for groups 1 to 4 PH from 1993 to 2012. Case definitions are based on hospitalizations and emergency department visits, using the Institute for Clinical Evaluative Sciences data, which comprises linked databases of universal coverage health service records for Ontario residents. This cohort included 50 529 patients with PH. The annual incidence of adult PH increased from 2003 to 2012 from 24.1 to 28.7 cases/100 000 population and the annual prevalence from 1993 to 2012 from 99.8 to 127.3 cases/100 000 population, respectively. The most common form of adult PH was group 2, alone (34.2%) or combined with group 3 PH (29.3%). A diagnosis of PH increased the 1-year standardized mortality ratio 7.2-fold. Mortality in adults with PH was 13.0%, 36.4%, and 62.4%, at 30 days, 1 year, and 5 years, respectively. Mortality was highest in groups 2 and 3 and lowest in group 1. PH was present in only 3.6% of people with left heart disease, 0.7% with lung disease, and 1.4% with thromboembolic disease, suggesting that PH is a relatively rare complication of these common diseases. Children (age<16 years) accounted for 3.6% of the cohort. In children group 1 PH was most common (65.2%), and 5-year mortality was lower (21.4%) than in adults. Group 1-specific PH therapies were increasingly prescribed over time and paradoxically were often used in patients who seemed to have group 2, PH based on diagnostic codes indicating left heart disease.ConclusionsThe incidence and prevalence of adult PH are increasing. Groups 2 and 3 are the most common and lethal forms of PH. This study identifies an emerging epidemic of PH that likely has substantial adverse health and economic implications.
| S-EPMC5819352 | biostudies-literature
Project description:ObjectiveTo characterise the degree of disability in pulmonary hypertension (PH) patients based on the World Health Organisation Disability Assessment Schedule 2.0 (WHODAS 2.0).MethodA prospective and observational study of patients with documented PH (N = 46). Patients completed the WHODAS 2.0 questionnaire during a scheduled routine clinical visit, and their demographic and clinical characteristics were retrieved from electronic medical records (EMR). In subsequent visits, selected clinical variables were registered to assess disease progression.ResultsWHODAS 2.0 scores were indicative of mild to moderate disability for the domains of mobility (22.0 ± 23.2), life activities (23.7 ± 25.5), and participation in society (17.2 ± 15.9), as well as total WHODAS 2.0 score (15.3 ± 15.2). For the domains of cognition (9.1 ± 14.1), self-care (8.3 ± 14.4), and interpersonal relationships (11.7 ± 15.7), scores were lower. Disability scores were, generally, proportional to the PH severity. The main baseline correlates of disability were World Health Organisation (WHO) functional class, fatigue, dyspnoea, 6-minute walking distance (6MWD), and N-terminal pro b-type natriuretic peptide (NTproBNP). Baseline WHODAS 2.0 scores showed significant associations with disease progression. However, this effect was not transversal to all domains, with only a few domains significantly associated with disease progression variables.ConclusionsThis PH population shows mild disability, with higher degree of disability in the domains of mobility and life activities. This study is the first one to assess disability in PH using WHODAS 2.0. Further studies should apply this scale to larger PH populations with suitable representations of more severe PH forms.
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Project description:The objective of this project is to identify relevant mechanisms associated to maladaptive right ventricular hypertrophy (RV) in pulmonary hypertension (PH), beyond pressure overload. For that, we analyzed plasma samples from PH pig models by high-throughput proteomics. Four different experimental models in 48 Yucatan pigs were developed: chronic postcapillary PH by pulmonary vein banding (M1); chronic PH by aorto-pulmonary shunting (M2); RV pressure overload by pulmonary artery banding, thus without PH (M3); and a sham procedure (M0). Animals were evaluated at months 1, and 8 after surgery with right heart catheterization, cardiac magnetic resonance (CMR), and blood sampling, and myocardial tissue was analyzed with histology and molecular biology. Unbiased proteomic and metabolomic analyses were performed and compared among experimental groups and related to the severity of PH and RV dysfunction through integrative interactome networking.
2025-01-20 | PXD041643 | Pride
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