A paradigm shift in pulmonary arterial hypertension management.
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ABSTRACT:
SUBMITTER: Rubin LJ
PROVIDER: S-EPMC9639191 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
A paradigm shift in pulmonary arterial hypertension management.
Rubin Lewis J LJ Galiè Nazzareno N Simonneau Gérald G McLaughlin Vallerie V
European respiratory review : an official journal of the European Respiratory Society 20131201 130
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Project description:Purpose of Review:This review focuses on the therapeutic management and individualized approach to Group 1 pulmonary arterial hypertension (PAH), utilizing Food and Drug Administration-approved PAH-specific therapies and various interventional and surgical options for PAH. Recent Findings:The paradigm for the optimal management of PAH has shifted in recent years. Upfront combination therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor is now widely accepted as standard of care. In addition, there is increasing emphasis on starting prostanoids early in order to delay time to clinical worsening. However, less is known regarding which prostanoid agent to initiate and the optimum time to do so. In order to facilitate shared decision-making, there is an increasing need for decision tools based on guidelines and collective clinical experiences to navigate between pharmacologic and interventional treatments, as well as explore innovative, therapeutic pathways for PAH. Summary:The management of PAH has become increasingly complex. With a growing number of PAH-specific therapies, intimate knowledge of the therapeutics and the potential barriers to adherence are integral to providing optimal care for this high-risk patient population. While current PAH-specific therapies largely mediate their effects through pulmonary vasodilation, ongoing research efforts are focused on ways to disrupt the mechanisms leading to pulmonary vascular remodeling. By targeting aberrations identified in the metabolism and proliferative state of pulmonary vascular cells, novel PAH treatment pathways may be just on the horizon.
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Project description:Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.
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Project description:During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.
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Project description:The management of pulmonary arterial hypertension (PAH) has significantly evolved over the last decades in the wake of more sensitive diagnostics and specialized clinical programs that can provide focused medical care. In the current era of PAH care, 1-year survival rates have increased to 86%-90% from 65% in the 1980s, and average long-term survival has increased to 6 years from 2.8 years. The heterogeneity in the etiology and disease course has opened doors to focusing research in phenotyping the disease and understanding the pathophysiology at a cellular and genetic level. This may eventually lead to precision medicine and the development of medications that may prevent or reverse pulmonary vascular remodeling. With more insight, clinical trial designs and primary end-points may change to identify the true survival benefit of pharmacotherapy. Identifying responders from non-responders to therapy may help provide individualized patient-centered care rather than an algorithm-based approach. The purpose of this review is to highlight the latest advances in screening, diagnosis, and management of PAH.
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Project description:The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.
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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
Project description:Over the past 20 years, there has been an explosion in the development of therapeutics to treat pulmonary arterial hypertension (PAH), a rare but life-threatening disorder associated with progressive elevation of pulmonary pressures and severe right heart failure. Recently, the field has seen the introduction of riociguat, a soluble guanylate cyclase stimulator, a new endothelin receptor antagonist (macitentan), and oral prostanoids (treprostinil and selexipag). Besides new drugs, there have been significant advances in defining the role of upfront combination therapy in treatment-naïve patients as well as proposed methods to deliver systemic prostanoids by use of implantable pumps. In this review, we will touch upon the most important developments in PAH therapeutics over the last three years and how these have changed the guidelines for the treatment of PAH. These exciting developments herald a new era in the treatment of PAH which will be punctuated by the use of more clinically relevant endpoints in clinical research trials and a novel treatment paradigm that may involve upfront double- or triple-combination therapy. We anticipate that the future will make use of these strategies to test the efficacy of upcoming new drugs that aspire to reduce disease progression and improve survival in patients afflicted with this devastating disease.
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Project description:Purpose of reviewPediatric pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. Herein we review the diagnosis and classification for pediatric PAH and detail the current therapeutic options available for use in the pediatric PAH population.Recent findingsClassification and treatment of pediatric PAH is guided by adult criteria and treatment algorithms, yet the distribution of factors contributing to PAH in children differs significantly from that seen in adults. It is necessary to understand these differences in order to appropriately tailor therapy to the needs of the child or adolescent. An expanding array of targeted PAH drugs are now approved for use in adults, and many of these drugs are used "off-label" to treat children and adolescents with PAH. Use of these novel therapies has coincided with marked improvement in outcomes, suggesting significant benefit. However, because most of these drugs have not been studied in rigorous randomized, controlled trials in children, it is critical that physicians understand their mechanisms of action, potential benefits, and safety profiles. Pediatric PAH outcomes have improved substantially in the modern era, coinciding with the "off-label" use of targeted PAH drugs in children and adolescents. Ideally, care should be provided at centers with specialized expertise in the diagnosis and treatment of pediatric PAH by providers who understand the appropriate diagnostic algorithms, classification schemes, and treatment approaches.
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