Seminars in respiratory and critical care medicine
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Tremendous progress has been made in understanding the genetics of heritable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). Recent advancements in gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH (CAV1, KCNK3). ⋯ The reduced penetrance makes genetic counseling complex, as the majority of carriers of PAH-related mutations will never be diagnosed with the disease. This issue is increasingly important, as clinical testing for BMPR2 and other mutations is now available for the evaluation of patients and their at-risk kin. The possibilities to avoid mutation transmission, such as the rapidly advancing field of preimplantation genetic testing, highlight the need for all clinicians to understand the genetic features of PAH risk.
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Semin Respir Crit Care Med · Oct 2013
ReviewTyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword?
New treatments for pulmonary arterial hypertension (PAH) are a crucial need. The increased proliferation, migration, and survival of pulmonary vascular cells within the pulmonary artery wall in PAH have allowed successful transposition of pathophysiological elements from oncologic researches. Next steps will require translation of these biological advances in PAH therapeutic arsenal and guidelines. ⋯ These safety issues raise concern about a potential amplified harmful effect in PAH, a pathology characterized by an underlying cardiac dysfunction. In addition, analyses of PAH registries shed light on a selective pulmonary vascular toxicity triggered by TKIs, especially dasatinib. These possible dual effects of the TKIs in PAH need to be taken in account for future pharmacological development of this therapeutic class in PAH.
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Semin Respir Crit Care Med · Oct 2013
ReviewPulmonary Hypertension Complicating Interstitial Lung Disease and COPD.
Pulmonary hypertension (PH) may complicate parenchymal lung disease, specifically interstitial lung diseases and chronic obstructive pulmonary disease, and uniformly increases the mortality risk. The epidemiology and degree of PH is variable and unique to the underlying lung disease. ⋯ In general, PH-specific therapies in this setting have been poorly studied, with concern for increased shunting and/or ventilation/perfusion (V/Q) mismatch and resultant hypoxemia. A better understanding of the mechanisms underlying PH related to parenchymal lung disease may lead to novel pharmacological targets to prevent or treat this serious complication.
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Semin Respir Crit Care Med · Oct 2013
ReviewPulmonary hypertension associated with left heart disease.
Left heart disease (LHD) is probably the most frequent cause of pulmonary hypertension (PH). Although rheumatic mitral valve stenosis has been in the past the most common cause of this condition, PH-LHD mainly results from heart failure related to systolic and/or diastolic dysfunction of the left ventricle and is associated with elevated left-sided cardiac filling pressures. Most patients have passive increase in pulmonary arterial pressure because of backward transmission of the elevated left atrial pressure, whereas a small subset develop severe PH with elevated transpulmonary gradient and pulmonary vascular resistance. ⋯ Although PH-LHD may evolve to right ventricular failure and is associated with some changes in the pulmonary vascular bed similar to pulmonary arterial hypertension (PAH), there is no evidence-based data to support the use of PAH-specific therapies in the setting of PH-LHD. However, recent studies suggest the usefulness of sildenafil, a phosphodiesterase-5 inhibitor. This review addresses the epidemiology, pathophysiology, risk factors, and treatment controversies of PH due to LHDs.
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Pulmonary hypertension is a devastating, life-threatening disorder with no curative options, characterized by elevated pulmonary vascular resistance and secondary right ventricular failure. Although the etiologies of pulmonary arterial hypertension are multiple and its pathogenesis is complex, there is growing evidence that inflammation, endothelial dysfunction, aberrant vascular wall cell proliferation, as well as mutations in the bone morphogenetic protein receptor type 2 gene play a crucial role in triggering pathological vascular remodeling. The present article outlines the current understanding of this disease from the point of view of pathology and pathobiology.