scholarly journals Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Ahmed Zaky ◽  
Iram Zafar ◽  
Juan Xavier Masjoan-Juncos ◽  
Maroof Husain ◽  
Nithya Mariappan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Disease Onset ◽  
P Wave ◽  
Transmitral Flow ◽  
Fatty Acid Binding ◽  
Eccentricity Index ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy associated with mechanical and electrical changes, culminating in increased vascular resistance, right ventricular (RV) failure, and death. With a main focus on invasive tools, there has been an underutilization of echocardiography, electrocardiography, and biomarkers to non-invasively assess the changes in myocardial and pulmonary vascular structure and function during the course of PAH.Methods: A SU5416-hypoxia rat model was used for inducing PAH. Biventricular functions were measured using transthoracic two-dimensional (2D) echocardiography/Doppler (echo/Doppler) at disease onset (0 week), during progression (3 weeks), and establishment (5 weeks). Similarly, electrocardiography was performed at 0, 3, and 5 weeks. Invasive hemodynamic measurements and markers of cardiac injury in plasma were assessed at 0, 3, and 5 weeks.Results: Increased RV systolic pressure (RVSP) and rate of isovolumic pressure rise and decline were observed at 0, 3, and 5 weeks in PAH animals. EKG showed a steady increase in QT-interval with progression of PAH, whereas P-wave height and RS width were increased only during the initial stages of PAH progression. Echocardiographic markers of PAH progression and severity were also identified. Three echocardiographic patterns were observed: a steady pattern (0–5 weeks) in which echo parameter changed progressively with severity [inferior vena cava (IVC) expiratory diameter and pulmonary artery acceleration time (PAAT)], an early pattern (0–3 weeks) where there is an early change in parameters [RV fractional area change (RV-FAC), transmitral flow, left ventricle (LV) output, estimated mean PA pressure, RV performance index, and LV systolic eccentricity index], and a late pattern (3–5 weeks) in which there is only a late rise at advanced stages of PAH (LV diastolic eccentricity index). RVSP correlated with PAAT, PAAT/PA ejection times, IVC diameters, RV-FAC, tricuspid systolic excursion, LV systolic eccentricity and output, and transmitral flow. Plasma myosin light chain (Myl-3) and cardiac troponin I (cTnI) increased progressively across the three time points. Cardiac troponin T (cTnT) and fatty acid-binding protein-3 (FABP-3) were significantly elevated only at the 5-week time point.Conclusion: Distinct electrocardiographic and echocardiographic patterns along with plasma biomarkers were identified as useful non-invasive tools for monitoring PAH progression.

scholarly journals Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension

2011 ◽  
Vol 39 (4) ◽  
pp. 939-944 ◽  
Author(s):  
G.A. Heresi ◽  
W.H.W. Tang ◽  
M. Aytekin ◽  
J. Hammel ◽  
S.L. Hazen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
Pulmonary Arterial ◽  
Poor Outcomes

Abstract 14880: Single-cell Transcriptomes Identify Unique Endothelial Subpopulation (FABP4 + TMEM100 - ) With Lipid Metabolism Dysfunction in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
BIN LIU ◽  
Jingbo Dai ◽  
Li Shuai ◽  
Dan Yi ◽  
Youyang Zhao ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Single Cell ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Premature Death ◽  
Right Heart Failure ◽  
Fatty Acid Binding ◽  
Pulmonary Arterial ◽  
Endothelial Plasticity

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial plasticity or distinct cell populations are critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: Here we applied single-cell RNA sequencing (ScRNA-seq) to profile the pulmonary cells in a severe mouse model ( Egln1 Tie2Cre mice) of PAH. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure FABP4 and FABP5 expression. siRNA mediated knockdown of FABP4 and FABP5 was performed to study cell proliferation and apoptosis. Mice with Fabp4 and Fabp5 deletion ( Fabp45 -/- ) and wild type (WT) mice were incubated with hypoxia (10% O 2 ) to induced PAH. Egln1 Tie2Cre mice were bred with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. Results: We identified five distinct EC subpopulations in both WT and Egln1 Tie2Cre mice via scRNA-seq. Unexpectedly, the number of Cluster (EC2, 49.8%) was markedly increased in Egln1 Tie2Cre lung compared with WT lung (2.8%). EC2 cluster (mainly from Egln1 Tie2Cre lung) was characterized by little expression of Tmem100 , Cldn5 , Tspan7 , Calcrl and Foxf1 and high expression of Fabp4, Cdh13, Sparl1 and Fabp5 . Fatty acid-binding protein (FABP) 4 and FABP5 (FABP4-5) were highly induced in PAECs from IPAH patients. Knockdown of FABP4-5 reduced EC proliferation and starvation-induced Caspase 3/7 activity. Fabp45 -/- mice were protected from hypoxia-induced PAH compared to WT mice. Moreover, Egln1 Tie2Cre / Fabp45 -/- mice also exhibited a reduction of RVSP and RV hypertrophy compared to Egln1 Tie2Cre mice. Conclusions: ScRNA-seq analysis identifies a unique endothelial population (FABP4 + TMEM100 - ) highly enriched in the lung of severe PAH mice. Knockdown of FABP4-5 reduces EC proliferation starvation-induced injury. Genetic deletion of FABP4-5 protects from hypoxia and Egln1 deficiency-induced PAH in mice.

scholarly journals Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

2021 ◽  
pp. jmedgenet-2021-107831
Author(s):  
Rajiv Machado ◽  
Carrie L Welch ◽  
Matthias Haimel ◽  
Marta Bleda ◽  
Elizabeth Colglazier ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Autosomal Recessive ◽  
Disease Onset ◽  
Compound Heterozygous ◽  
Childhood Onset ◽  
Catalytic Phosphorylation ◽  
Childhood All ◽  
Pulmonary Arterial ◽  
Dose Dependent

BackgroundThe molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and resultsWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent–offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.ConclusionOur findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

scholarly journals Epigenetic Inheritance Underlying Pulmonary Arterial Hypertension

2019 ◽  
Vol 39 (4) ◽  
pp. 653-664 ◽  
Author(s):  
Claudio Napoli ◽  
Giuditta Benincasa ◽  
Joseph Loscalzo
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Disease Onset ◽  
Later Life ◽  
Epigenetic Changes ◽  
Apoptosis Resistance ◽  
Integrated Network ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial

In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.

High-sensitive troponin T: a novel biomarker for prognosis and disease severity in patients with pulmonary arterial hypertension

2010 ◽  
Vol 119 (5) ◽  
pp. 207-213 ◽  
Author(s):  
Arthur Filusch ◽  
Evangelos Giannitsis ◽  
Hugo A. Katus ◽  
Franz J. Meyer
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Troponin T ◽  
Functional Class ◽  
World Health ◽  
Fourth Generation ◽  
Walk Distance ◽  
Fatty Acid Binding ◽  
Pulmonary Arterial

PAH (pulmonary arterial hypertension) is the leading cause of fatal right ventricular failure. However, rarely detectable, cTnT [cardiac TnT (troponin T)] is a significant prognostic marker. Therefore the aim of the present study was to evaluate the usefulness of a novel high-sensitive cTnT (hsTnT) assay as a parameter for functional and prognostic evaluation of PAH patients. In 55 PAH patients (idiopathic, n=20; chronic thromboembolic, n=30; and interstitial lung disease, n=5) with a mean pulmonary artery pressure of 45±18 mmHg, cTnT was measured by a fourth-generation conventional assay and a novel hsTnT assay with a lower detection limit at 2 pg/ml [total imprecision <10% at the 99th percentile value (13.4 pg/ml)]. In 90.9% of patients, cTnT was detectable using the hsTnT assay and in 30.9% using the fourth-generation assay. Concentrations >99th percentile were observed in 27.3% using hsTnT compared with 10.9% using the fourth-generation assay. A total of five out of six patients with cTnT values >30 pg/ml (fourth-generation assay) or >29.5 pg/ml (hsTnT assay) died during the 12-month follow-up. There was a correlation between hsTnT and 6-min walk distance (r=−0.92, P=0.0014), right ventricular systolic strain (r=0.95, P=0.0018) and strain rate (r=0.82, P=0.0021). In AUC (area under the curve) analysis, hsTnT predicted death at least as effectively as hFABP (heart-type fatty-acid-binding protein) or NT-proBNP (N-terminal pro-brain natriuretic protein). Moreover, hsTnT predicted a WHO (World Health Organization) functional class >II better than NT-proBNP or hFABP. In conclusion, in PAH patients, the novel biomarker hsTnT is associated with death and advanced WHO functional class, and is related to systolic right ventricular dysfunction and an impaired 6-min walk distance.

A Case of Pulmonary Arterial Hypertension Improved with Normalization of a Prominent Negative Component of P Wave in Lead V1

2012 ◽  
Vol 18 (10) ◽  
pp. S184
Author(s):  
Hiroaki Obata ◽  
Hiromi Kayamori ◽  
Masato Oda ◽  
Takeshi Kashimura ◽  
Haruo Hanawa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
P Wave ◽  
Negative Component ◽  
Pulmonary Arterial
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