Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Archer SL
PROVIDER: S-EPMC2869481 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
Publications
Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies.
Archer Stephen L SL Weir E Kenneth EK Wilkins Martin R MR
Circulation 20100501 18
Similar Datasets
Project description:Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.
| S-EPMC8380049 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
| S-EPMC7735523 | biostudies-literature
Project description:Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.
| S-EPMC10058689 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is an enigmatic and deadly vascular disease with no known cure. Recent years have seen rapid advances in our understanding of the molecular underpinnings of PAH, with an expanding knowledge of the molecular, cellular, and systems-level drivers of disease that are being translated into novel therapeutic modalities. Simultaneous advances in clinical technology have led to a growing list of tools with potential application to diagnosis and phenotyping. Guided by fundamental biology, these developments hold the potential to usher in a new era of personalized medicine in PAH with broad implications for patient management and great promise for improved outcomes.
| S-EPMC9980296 | biostudies-literature
Project description:Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.
| S-EPMC6351342 | biostudies-literature
Project description:Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current diagnostic strategies are suboptimal for detecting early-stage disease. Thus, there is a substantial need to develop new diagnostics and therapies that target the molecular origins of PH. Emerging investigations have defined metabolic aberrations as fundamental and early components of disease manifestation in both pulmonary vasculature and the right ventricle. As such, the elucidation of metabolic dysregulation in pulmonary hypertension allows for greater therapeutic insight into preventing, halting, or even reversing disease progression. This review will aim to discuss (1) the reprogramming and dysregulation of metabolic pathways in pulmonary hypertension; (2) the emerging therapeutic interventions targeting these metabolic pathways; and (3) further innovation needed to overcome barriers in the treatment of this devastating disease.
| S-EPMC5406775 | biostudies-literature
Project description:Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration-approved medications. Although the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of pulmonary arterial hypertension, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Because only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease.
| S-EPMC6032070 | biostudies-literature
Project description:Pulmonary hypertension (PH) is an often-fatal vascular disease of unclear molecular origins. The pulmonary vascular remodelling which occurs in PH is characterised by elevated vasomotor tone and a pro-proliferative state, ultimately leading to right ventricular dysfunction and heart failure. Guided in many respects by prior evidence from cancer biology, recent investigations have identified metabolic aberrations as crucial components of the disease process in both the pulmonary vessels and the right ventricle. Given the need for improved diagnostic and therapeutic options for PH, the development or repurposing of metabolic tracers and medications could provide an effective avenue for preventing or even reversing disease progression. In this review, we describe the metabolic mechanisms that are known to be dysregulated in PH; we explore the advancing diagnostic testing and imaging modalities that are being developed to improve diagnostic capability for this disease; and we discuss emerging drugs for PH which target these metabolic pathways.
| S-EPMC5842433 | biostudies-literature
Project description:Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.
| S-EPMC7731052 | biostudies-literature
Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
2003-11-15 | GSE703 | GEO