First identification of Krüppel-like factor 2 mutation in heritable pulmonary arterial hypertension

2017 ◽  
Vol 131 (8) ◽  
pp. 689-698 ◽  
Author(s):  
Christina A. Eichstaedt ◽  
Jie Song ◽  
Rebecca Rodríguez Viales ◽  
Zixuan Pan ◽  
Nicola Benjamin ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Family Members ◽  
B Cell Lymphoma ◽  
Genetic Diagnostics ◽  
Heart Catheterization ◽  
Specific Gene ◽  
Inherited Disease ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene and/or genes of its signalling pathway in approximately 85% of patients. We clinically and genetically analysed an HPAH family without mutations in previously described pulmonary arterial hypertension (PAH) genes. Clinical assessment included electrocardiogram, lung function, blood gas analysis, chest X-ray, laboratory testing, echocardiography and right heart catheterization in case of suspected disease. Genetic diagnostics were performed using a PAH-specific gene panel including all known 12 PAH genes and 20 further candidate genes by next-generation sequencing (NGS). HPAH was invasively confirmed in two sisters and their father who died aged 32 years. No signs of HPAH were detected in five first-degree family members. Both sisters were lung transplanted and remained stable during a follow-up of >20 years. We detected a novel missense mutation in the Krüppel-like factor 2 (KLF2) likely leading to a disruption of gene function. The same KLF2 mutation has been described as a recurrent somatic mutation in B-cell lymphoma. Neither the healthy family members carried the mutation nor >120000 controls. These findings point to KLF2 as a new PAH gene. Further studies are needed to assess frequency and implication of KLF2 mutations in PAH patients.

scholarly journals Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

2018 ◽  
Vol 19 (10) ◽  
pp. 3203 ◽  
Author(s):  
Veronique Vorselaars ◽  
Anna Hosman ◽  
Cornelis Westermann ◽  
Repke Snijder ◽  
Johannes Mager ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Clinical Signs ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Inherited Disease ◽  
Vascular Dysplasia ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.

A new gene for heritable pulmonary arterial hypertension: Krüppel-like factor 2

Pneumologie ◽  
2017 ◽  
Vol 71 (S 01) ◽  
pp. S1-S125
Author(s):  
C Eichstaedt ◽  
J Song ◽  
R Rodríguez Viales ◽  
Z Pan ◽  
N Benjamin ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
New Gene ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

scholarly journals SAT0240 THE PROGNOSIS OF TWO DISTINCT CLINICAL PHENOTYPES OF SLE-PAH

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1063.2-1063
Author(s):  
J. Wang ◽  
Y. Feng ◽  
Y. Lei ◽  
X. Zhang
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lupus Erythematosus ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Systemic Lupus ◽  
Clinical Phenotypes ◽  
Weighted Score ◽  
Pulmonary Arterial

Background:Based on the characteristics of systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH), Sunet alhas put forward a scoring system to distinguish two clinical phenotypes as vasculitic and vasculopathic subtypes[1]. A weighted score ≥2 suggested a vasculitic subtype by combining two factors: The time interval between SLE and PAH diagnosis <2 years and ≥2 years were 1 and 0 point; SLE Disease Activity Index (SLEDAI) >9, 5-9 and <5 were 2, 1, 0 point, respectively. While the vasculitic subtype seemed to have poorer prognosis in Sun’s research, other study has shown controversial result[2].Objectives:To find out the prognosis of two distinct clinical phenotypes of SLE-PAH.Methods:Between 2008 and 2019, a SLE-PAH cohort confirmed by right heart catheterization (RHC) from Guangdong Provincial People’s Hospital was included. Other groups of pulmonary hypertension were excluded. Based on the scoring system, patients were divided into vasculitic (weighted score≥2) and vasculopathic subtypes (weighted score<2). The endpoint was PAH-related mortality. Survival status were confirmed by clinic follow-up data or phone call.Results:A total of 53 SLE-PAH patients were enrolled. The cases of vasculitic and vasculopathic subtype were 14 and 39, respectively. Ten endpoint events occurred. Eight attributed to PAH and the cause could not be traced in two which were still included in study. The pooled 1-, 3-, 5-year survival rates were 85.7%, 78.6%, 65.5% in vasculitic subtype, and 93.9%, 87.5%, 87.5% in vasculopathic subtype, respectively. Kaplan-Meier analysis showed vasculitic subtype tended to have a poorer prognosis than vasculopathic subtype (p=0.16, HR 2.4, 95%CI 0.5-13.8, figure 1).Figure 1.Survival curves for patients with systemic lupus erythematosus-pulmonary arterial hypertension (SLE-PAH) in two distinct subtypes. RHC, Right Heart Catheterization.Conclusion:The prognosis of the two phenotypes of SLE-PAH was statistically indifferent while the vasculitic subtype showed a trend of worse prognosis. Further studies are needed.References:[1]F. Sun, Y. Lei, W. Wu, L. Guo, K. Wang, Z. Chen, W. Xu, X. Wang, T. Li, X. Zhang, S. Ye, Two distinct clinical phenotypes of pulmonary arterial hypertension secondary to systemic lupus erythematosus, Ann Rheum Dis 78(1) (2019) 148-150.[2]J. Qian, M. Li, J. Zhao, Q. Wang, Z. Tian, X. Zeng, Inflammation in SLE-PAH: good news or not?, Ann Rheum Dis (2018).0:1–2. doi:10.1136/annrheumdis-2018-214605Disclosure of Interests:None declared

Abstract 16667: Computed Tomography-Based Pulmonary Vascular Tortuosity as a Marker in Resting and Exercise Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Eileen M Harder ◽  
Pietro Nardelli ◽  
Gonzalo Sanchez-Ferrero ◽  
James Ross ◽  
Sam Y Ash ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Early Form ◽  
Arterial Tortuosity ◽  
Vascular Tortuosity ◽  
Measure Analysis ◽  
Pulmonary Arterial

Introduction: Increased vascular tortuosity has been proposed as a marker of pulmonary arterial hypertension (PAH). In this analysis, we compared arterial and venous vascular tortuosity between controls and subjects with resting PAH. Furthermore, we examined if abnormalities could be detected in exercise PAH (EPAH), thought to be an early form of PAH. Methods: From an institutional registry, 388 patients with both right heart catheterization and computed tomography angiography (CTA) data were selected. Within this cohort, three distinct groups were identified: 1) controls, who had no cardiopulmonary disease and normal resting and exercise hemodynamics; 2) EPAH, with normal resting hemodynamics but age-adjusted pre-capillary pulmonary hypertension on exertion, and 3) PAH, defined as resting mPAP >20mmHg, pulmonary vascular resistance >3 Wood Units, and pulmonary capillary wedge pressure <15mmHg. Tortuosity was defined as the actual path length of a vessel divided by the linear distance between the two farthest endpoints of the vessel segment on CTA. AV>10% was defined as the number of arterial segments with tortuosity >10% divided by the same venous measure. Analysis was performed with Wilcoxon rank sum tests in R 3.5. Results: There were 99 patients in the final cohort, including 47 (47.4%) with PAH, 12 (12.1%) with EPAH, and 40 (40.4%) without disease. Compared to controls, median arterial tortuosity was increased in PAH (3.3 ± 0.1% vs. 3.4 ± 0.1%, p=0.0009; Figure 1) but not in EPAH (3.3 ± 0.1%, p=0.82). Median venous tortuosity did not differ between groups. AV>10% was increased in EPAH (vs. controls, 1.86 ± 0.38 vs. 1.56 ± 0.44, p=0.03) and resting PAH (2.0 ± 1.2 p=2e-6). Conclusions: Increased arterial tortuosity on CTA is a biomarker of resting PAH. When corrected for venous tortuosity, arterial tortuosity also appears to be abnormal in EPAH. Figure 1 . Arterial vessels in PAH, EPAH, and control subjects. Red segments have tortuosity > 10%.

Transition from IV epoprostenol to oral treprostinil in a patient with group 1 pulmonary arterial hypertension

2021 ◽  
Author(s):  
Preeyaporn Sarangarm ◽  
Kirsten Elwood
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Altered Mental Status ◽  
Direct Conversion ◽  
Central Line ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Final Titration ◽  
Rapid Transition ◽  
Pulmonary Arterial

Abstract Purpose Epoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. Summary A 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart catheterization four months prior found severe PAH with a pulmonary arterial pressure of 79/32 mmHg (mean, 49 mmHg) and pulmonary vascular resistance of 10.6 Wood units. To expedite the transition, the patient was directly converted from IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. A target oral treprostinil dose of 5 mg TID was calculated based on 110% of the IV epoprostenol dose (19 ng/kg/min) utilizing the conversion recommended by the medication manufacturer. Every 8 hours, IV epoprostenol was decreased by 2 ng/kg/min and oral treprostinil was increased by 0.5 mg. The target oral treprostinil dose of 5 mg TID was reached 72 hours after conversion initiation. Three hours after the final titration, the patient was discharged home on room air. Conclusion In this case, rapid transition from IV epoprostenol to oral treprostinil was achieved in 72 hours without reported adverse effects.

Pulmonary arterial hypertension associated with connective tissue disease

ESC CardioMed ◽  
2018 ◽  
pp. 2531-2534
Author(s):  
Christopher P. Denton
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Connective Tissue Disease ◽  
Lupus Erythematosus ◽  
Heart Catheterization ◽  
Pulmonary Arterial ◽  
Detection And Diagnosis ◽  
Health Organization

Connective tissue disease-associated pulmonary arterial hypertension (PAH) falls within World Health Organization group 1. These patients are treated as others in this group, but there are important considerations regarding detection and diagnosis. Patients with connective tissue disease are at risk of PAH and should be screened with confirmation of diagnosis by right heart catheterization. Treatment follows the European Society of Cardiology guidelines for other forms of PAH. However, more information is available for systemic sclerosis PAH regarding screening, including the DETECT algorithm, and also in terms of long-term outcome of patients with borderline elevation of mean pulmonary arterial pressure. In cases of systemic lupus erythematosus or mixed connective tissue disease, immunosuppression should be given in conjunction with targeted PAH-specific therapy. Long-term outcomes for PAH in patients with connective tissue disease have improved since targeted specific therapies became available. Recent trials with morbidity–mortality endpoints and a high proportion of patients receiving combination treatment have shown comparable benefits for patients with connective tissue disease and PAH as for those with idiopathic PAH in contrast to the blunted response that was characteristic of earlier short-term studies assessing improvement in 6 min walk test distance.

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