Abnormal Pulmonary Artery Pressure Response in Asymptomatic Carriers of Primary Pulmonary Hypertension Gene

Grünig, Ekkehard; Janssen, Bart; Mereles, Derliz; Barth, Ulrike; Borst, Mathias M.; Vogt, Ina R.; Fischer, Christine; Olschewski, Horst; Kuecherer, Helmut F.; Kübler, W.

doi:10.1161/01.cir.102.10.1145

Cited by 232 publications

(155 citation statements)

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“…Abnormal exercise physiology has been recognized in SSc, idiopathic PAH, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (21,28,(34)(35)(36)(37)(38)(39)(40). Studies have described exerciseinduced PH in 46-59% of patients with scleroderma spectrum disorders, characterized by Doppler echocardiogram pulmonary artery systolic pressure Ͼ40 mm Hg during exercise (23,41,42).…”

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confidence: 99%

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Saggar

Khanna

Fürst

et al. 2010

Arthritis & Rheumatism

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Objective. Exercise-induced pulmonary hypertension (PH) may represent an early but clinically relevant phase in the spectrum of pulmonary vascular disease. There are limited data on the prevalence of exerciseinduced PH determined by right heart catheterization in scleroderma spectrum disorders. We undertook this study to describe the hemodynamic response to exercise in a homogeneous population of patients with scleroderma spectrum disorders at risk of developing pulmonary vascular disease. Methods.Patients with normal resting hemodynamics underwent supine lower extremity exercise testing. A classification and regression tree (CART) analysis was used to assess combinations of variables collected during resting right heart catheterization that best predicted abnormal exercise physiology, applicable to each individual subject.Results. Fifty-seven patients who had normal resting hemodynamics underwent subsequent exercise right heart catheterization. Four distinct hemodynamic groups were identified during exercise: a normal group, an exercise-induced pulmonary venous hypertension (ePVH) group, an exercise out of proportion PH (eoPH) group, and an exercise-induced PH (ePH) group. The eoPH and ePVH groups had higher pulmonary capillary wedge pressure (PCWP) than the ePH group (P < 0.05). The normal and ePH groups had exercise PCWP <18 mm Hg, which was lower than that in the ePVH and eoPH groups (P < 0.05). During submaximal exercise, the transpulmonary gradient and pulmonary vascular resistance (PVR) were elevated in the ePH and eoPH groups as compared with the normal and ePVH groups (P < 0.05). CART analysis suggested that resting mean pulmonary artery pressure (mPAP) >14 mm Hg and PVR >160 dynes/seconds/cm ؊5 were associated with eoPH and ePH (positive predictive value 89% for mPAP 14-20 mm Hg and 100% for mPAP >20 mm Hg).Conclusion. We characterized the exercise hemodynamic response in at-risk patients with scleroderma spectrum disorders who did not have resting PH. Four distinct hemodynamic groups were identified during exercise. These groups may have potentially different prognoses and treatment options.

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confidence: 99%

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Saggar

Khanna

Fürst

et al. 2010

Arthritis & Rheumatism

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“…This important information tells us either that having the FPPH gene confers, at most, a mild-to-moderate disease, or is sufficient to cause a progressive disease in patients whose malignant progression has not yet occurred [11]. Whether an abnormal vasoreactivity or early pulmonary vascular lesions can explain the exerciseinduced pulmonary hypertension in these patients is unclear and requires further study.…”

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Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene

Tuder

Yeager²,

Geraci³

et al. 2001

Eur Respir J

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Research regarding understanding of the molecular mechanisms of pulmonary hypertension (PH) has experienced great progress in the last 3 yrs. Efforts to map the genetic susceptibility of familial primary pulmonary hypertension (FPPH) succeeded in localizing the gene site to the region 2q32-33, or so-called PPH1 gene site, which encompasses y3 centimorgan [1,2]. This finding raised the hope that important information could be generated since the prevailing concepts concerning the pathogenesis of primary pulmonary hypertension (PPH) have revolved around the pathophysiological roles of cellular components of vascular remodelling and abnormalities of pulmonary vascular tone control. The importance of the alterations of pulmonary vascular morphology was felt, by some, to be minimal, since they were interpreted to occur late in the disease process. Clearly, concepts were borrowed from hypoxic pulmonary vasoconstriction, yet severe PH is an irreversible disease with a magnitude of pulmonary hypertension not usually seen in acute or chronic hypoxia. Shortly after the FPPH locus had been announced, plexiform lesions in PPH were characterized to represent a tumour-like proliferation of a monoclonal population of endothelial cells, indicating that the endothelial cells arose from a selective growth of a single cell, whereas, in secondary PH, endothelial cells in plexiform lesions were polyclonal [3,4]. This finding in turn pointed towards mutational events, such as involving activation of growth-inducing kinase receptors or loss of tumour suppressor genes, as being responsible for the clonal expansion of endothelial cells in PPH [5].Recently, germline mutations in the bone morphogenetic protein receptor II (BMPR-II) (coded within the 2q32-33 region of the PPH1 gene site) were identified in a cohort of patients with FPPH [6,7] (fig. 1) and somatic losses of nucleotides in short stretches of repetitive mono-or dinucleotide sequences of the transforming growth factor-b receptor II (TGF-b RII) and Bax genes were found in endothelial cells in PPH, but not in secondary PH [9]. These findings lead to a novel hypothesis that germline and/or somatic mutations in key cell growth regulatory genes play a critical role in the development of idiopathic sporadic and familial PH. There is growing support of the concept that the dysregulation of endothelial cell growth in PPH has several fundamental properties in common with those seen in neoplastic processes.The present authors believe that these recent discoveries have opened a molecular/genetic perspective for research in severe PH. However, several important questions about how these findings relate to the mechanisms, the clinical presentation, and pulmonary haemodynamics of severe PH still remain unanswered.Bone morphogenetic protein receptor-II mutations in familial primary pulmonary hypertension: can they explain the disease process?Two groups almost simultaneously reported that BMP-RII mutations occur in a cohort of patients with FPPH [6,7]. BMPR-II mutations were identified in nin...

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“…A family history of pulmonary hypertension may lead to early recognition of clinical disease in other persons (17). A history of use of fenfluramine appetite suppressants (18,19) and current or previous use of amphetamines or cocaine should be explored, because these factors have been implicated in the development of PAH in some users.…”

Section: When Should Pah Be Suspected?mentioning

confidence: 99%

Evaluation and Management of the Patient with Pulmonary Arterial Hypertension

Rubin

Badesch²

2005

Ann Intern Med

126

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Increased pressure in the pulmonary circulation, or pulmonary hypertension, is a common disorder that may complicate various cardiopulmonary conditions, including severe obstructive airways disease and left ventricular dysfunction. An increase in pulmonary arterial pressure that is not due to coexistent cardiopulmonary disease, known as pulmonary arterial hypertension, may occur in the absence of a demonstrable cause (idiopathic or familial); as a complication of systemic conditions, such as connective tissue disease, HIV infection, or chronic liver disease; or as a result of the use of fenfluramine anorexigens, amphetamines, or cocaine. The development of disease-specific therapies for pulmonary arterial hypertension over the past decade underscores the importance of diagnosing pulmonary hypertension early in the course of the condition and implementing a treatment strategy that is based on the condition's cause and severity. In this review, the authors present approaches to the diagnosis and management of pulmonary arterial hypertension, using a hypothetical case to highlight the key management points. U ntil recently, management of pulmonary arterial hypertension (PAH) was generally ineffective in alleviating symptoms or improving survival. However, the past decade has witnessed remarkable advances in our understanding of the pathogenesis of PAH, advances that have led to the development of disease-specific treatments. Despite these achievements, PAH remains a challenging condition to diagnose and manage. This article reviews recent developments in the diagnosis and management of PAH in the context of a typical case, illustrating the importance of collaboration between the internist and the specialist in patient care.

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Abnormal Pulmonary Artery Pressure Response in Asymptomatic Carriers of Primary Pulmonary Hypertension Gene

Cited by 232 publications

References 24 publications

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene

Evaluation and Management of the Patient with Pulmonary Arterial Hypertension

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