scholarly journals IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2280
Author(s):  
Siladitta Biswas ◽  
Baktybek Kojonazarov ◽  
Stefan Hadzic ◽  
Michael Majer ◽  
Ganimete Bajraktari ◽  
...  
Keyword(s):  
Systolic Pressure ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Inositol Trisphosphate Receptor ◽  
Kinase Substrate ◽  
Signaling Complex ◽  
Hypoxic Conditions ◽  
Pulmonary Artery Smooth Muscle ◽  
Trisphosphate Receptor

PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP3R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP3RI, which mediates intracellular Ca2+ release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O2) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice.

Abstract 17168: Myocardial Natriuretic Peptide Expression in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Virginia S Hahn ◽  
Hildur Knutsdottir ◽  
Kenneth C Bedi ◽  
Kenneth B Margulies ◽  
Saptarsi M Haldar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Renal Function ◽  
Ejection Fraction ◽  
Systolic Pressure ◽  
Principal Component ◽  
Serum Levels ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Preserved Ejection Fraction

Introduction: Serum natriuretic peptides (NP) are reduced in heart failure with preserved ejection fraction (HFpEF) compared to HFrEF; however, myocardial NP expression in HFpEF is unknown. We analyzed serum NTproBNP and myocardial RNAseq data to test the hypothesis that 1) lower myocardial NP expression in HFpEF drives the difference in serum levels, and 2) HFpEF with higher NP expression have transcriptomic signatures more similar to HFrEF. Methods: HFpEF patients (n=41) with clinical HF, LVEF≥50%, and meeting current consensus criteria for HFpEF underwent right heart catheterization and right ventricular (RV) endomyocardial biopsy. We performed differential gene expression analysis of RV septal tissue from HFpEF and compared to explanted HFrEF (n=30) and unused donor hearts (n=24, Control). Results: Myocardial NPPB expression was 5-fold higher in HFrEF vs Control (p<0.001) and unchanged in HFpEF vs Control, while NPPA expression was 9-fold higher in HFrEF and 5-fold higher in HFpEF vs Control (p<0.0001 for both comparisons). After adjustment for renal function and BMI, myocardial NPPB expression was significantly associated with serum NTproBNP in HFpEF (R 2 0.68; p<0.0001 for renal function, NPPB expression; p=0.03 for BMI). Pulmonary artery (PA) systolic pressure and PA wedge pressure correlated with myocardial NPPB expression (PASP R 2 0.45, p<0.0001; PAWP R 2 0.25, p=0.01), even after adjustment for comorbidities. HFpEF patients with high (≥ median NPPB expression in HFpEF) vs low NPPB expression had transcriptomic signatures more similar to HFrEF using ~13,000 genes in a Principal Component Analysis (Figure), quantified by vector distance from HFrEF (p=0.017). Conclusions: HFpEF patients have reduced serum NTproBNP due to lower myocardial NPPB gene expression. HFpEF patients with higher NPPB expression have transcriptomic signatures more similar to HFrEF, highlighting a HFpEF subgroup that may benefit from targeted therapies.

Sleep-Related Breathing Disorders

2016 ◽  
pp. 773-774
Author(s):  
Mithri R. Junna
Keyword(s):  
Systolic Pressure ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Lower Extremity Edema ◽  
Right Ventricular Systolic Pressure ◽  
Sleep Related Breathing Disorders ◽  
Transthoracic Doppler Echocardiography ◽  
Ventricular Systolic Pressure ◽  
Progressive Dyspnea ◽  
The Many

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure of at least 25 mm Hg at rest, as measured during right heart catheterization (RHC). The many causes of PH are classified into 5 groups. The clinical presentation of patients with PH is nonspecific: progressive dyspnea, chest pain, lower extremity edema, and fatigue. Typically, a diagnosis of PH is suggested by an increased right ventricular systolic pressure on transthoracic Doppler echocardiography and is confirmed with RHC.

scholarly journals Investigating Cardiac MRI Based Right Ventricular Contractility as a Novel Non-Invasive Metric of Pulmonary Arterial Pressure

2014 ◽  
Vol 8s1 ◽  
pp. CMC.S15711 ◽  
Author(s):  
Prahlad G. Menon ◽  
Srilakshmi M. Adhypak ◽  
Ronald B. Williams ◽  
Mark Doyle ◽  
Robert W. W. Biederman
Keyword(s):  
Systolic Pressure ◽  
Right Heart Catheterization ◽  
Three Dimensions ◽  
Heart Catheterization ◽  
Ventricular Contractility ◽  
Shape Variation ◽  
Predictive Values ◽  
Non Invasive ◽  
Pulmonary Arterial ◽  
Rv Function

Background We test the hypothesis that cardiac magnetic resonance (CMR) imaging-based indices of four-dimensional (4D) (three dimensions (3D) + time) right ventricle (RV) function have predictive values in ascertaining invasive pulmonary arterial systolic pressure (PASP) measurements from right heart catheterization (RHC) in patients with pulmonary arterial hypertension (PAH). Methods We studied five patients with idiopathic PAH and two age and sex-matched controls for RV function using a novel contractility index (CI) for amplitude and phase to peak contraction established from analysis of regional shape variation in the RV endocardium over 20 cardiac phases, segmented from CMR images in multiple orientations. Results The amplitude of RV contractility correlated inversely with RV ejection fraction (RVEF; R2 = 0.64, P = 0.03) and PASP ( R2 = 0.71, P = 0.02). Phase of peak RV contractility also correlated inversely to RVEF ( R2 = 0.499, P = 0.12) and PASP ( R2 = 0.66, P = 0.04). Conclusions RV contractility analyzed from CMR offers promising non-invasive metrics for classification of PAH, which are congruent with invasive pressure measurements.

scholarly journals EXPRESS: Mouse Model of Experimental Pulmonary Hypertension: Lung Angiogram and Right Heart Catheterization

2021 ◽  
pp. 204589402110415
Author(s):  
Jason X.-J. Yuan ◽  
Mingmei Xiong ◽  
Pritesh Prakash Jain ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Ex Vivo ◽  
Systolic Pressure ◽  
Right Heart Catheterization ◽  
Mouse Lung ◽  
Heart Catheterization ◽  
Right Heart ◽  
Pulmonary Hemodynamics ◽  
Pulmonary Vascular Remodeling

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness. The peripheral lung vascular images were selected to determine the total length of lung vascular branches, the number of branches and the number of junctions in a given area (mm-2). We found that the three parameter determined by angiogram were not significantly different among the apical, middle and basal regions of the mouse lung from normal mice, and were not influenced by gender (no significant difference between female and male mice). We conducted RHC in mice to measure right ventricular systolic pressure (RVSP), a surrogate measure for pulmonary artery (PA) systolic pressure and right ventricle (RV) contractility (RV-±dP/dtmax) to estimate RV function. RHC, a short time (4-6 min) procedure, did not alter the lung angiography measurements. In summary, utilizing ex vivo angiogram to determine peripheral vascular structure and density in the mouse lung and utilizing in vivo RHC to measure pulmonary hemodynamics are reliable readouts to phenotype normal mice and mice with experimental PH. Lung angiogram and RHC are also reliable approaches to examine pharmacological effects of new drugs on pulmonary vascular remodeling and hemodynamics.

scholarly journals Preoperative Evaluation of Pulmonary Hypertension in Lung Transplant Candidates: Echocardiography Versus Right Heart Catheterization

2021 ◽  
Author(s):  
Tal Abu ◽  
Amos Levi ◽  
David Hasdai ◽  
Mordechai R. Kramer ◽  
Tamir Bental ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Preoperative Evaluation ◽  
Systolic Pressure ◽  
Area Under The Curve ◽  
Right Heart Catheterization ◽  
Mean Value ◽  
Pulmonary Artery Systolic Pressure ◽  
Heart Catheterization ◽  
Right Heart

Abstract Background - Right heart catheterization (RHC) and echocardiography are both routinely used for pulmonary artery systolic pressure (PASP) assessment in lung transplantation (LT) candidates, although this is not mandated by current guidelines. We aimed to explore the correlation between PASP estimated by echocardiography to that measured by RHC, in this population in order to assess the necessity of RHC. Methods - From a retrospective registry of 393 LT candidates undergoing RHC and echocardiography during 2015-2019, patients were assessed for the presence of pulmonary hypertension (PH), defined as mean pulmonary artery pressure (mPAP) above 20 mmHg, according to two methods – echocardiography and RHC. The primary outcome was the correlation between the PASP estimated by echocardiography to that measured by RHC. Secondary outcomes were the prediction value of the echocardiographic evaluation and its accuracy. Results - The mean value of PASP estimated by echocardiography was 49.5±20.0 mmHg, compared to 42.5±18.0 mmHg measured by RHC. The correlation between the two measurements was moderate (Pearson’s correlation: r=0.609, p<0.01). Echocardiography PASP measurements were moderately discriminative to diagnose PH, with an area under the curve (AUC) of 0.72 (95% CI 0.66-0.76). Echocardiographic overestimation of PASP of more than 10 mmHg was found in 35.0% of the patients, and underestimation was found in 11.6% of the patients.Conclusion - In the pre-surgical evaluation of LT candidates, echocardiographic estimation of PASP had moderate correlation and limited accuracy compared to the PASP measured by RHC. We thus recommend performing routine RHC to all LT candidates, regardless of the echocardiographic estimation of PASP.

scholarly journals Role of Pulmonary Artery Wedge Pressure Saturation During Right Heart Catheterization

2020 ◽  
Vol 13 (11) ◽  
Author(s):  
Michael C. Viray ◽  
Eric L. Bonno ◽  
Nicholas D. Gabrielle ◽  
Bradley A. Maron ◽  
Jessica Atkins ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Pulmonary Artery Wedge Pressure ◽  
Right Heart ◽  
Wedge Pressure
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