Abstract 13527: Inhibition of With-No-Lysine Kinase Improves Right Ventricular Function by Blunting Excess Protein O-GlcNAcylation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sasha Z Prisco ◽  
Megan Eklund ◽  
Kurt W Prins
Keyword(s):  
Cardiac Output ◽  
Right Ventricular ◽  
Vascular Disease ◽  
Disease Severity ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Pulmonary Vascular Disease ◽  
Post Translational Modification ◽  
Loop Analysis ◽  
Rv Function

Introduction: Pulmonary arterial hypertension (PAH) is caused by obstructive remodeling of the pulmonary arteries which ultimately causes right ventricle (RV) failure and death. Increased expression of the glucose membrane transporters Glut1 and Glut4 occurs in the failing RV, but the upstream regulators of these proteins are unknown. The With-no-Lysine (WNK) kinase-1, a kinase activated in low chloride conditions, promotes expression of Glut1/4 in skeletal muscle, but its regulation in the RV in PAH is unexplored. Furthermore, the relationship between WNK1 and protein O-GlcNAcylation, a glucose based post-translational modification, has not been examined. Methods: Immunoblots quantified the abundance of WNK1, Glut1, Glut4, and total protein O-GlcNAcylation in the RV of control, monocrotaline (MCT) rats, and MCT rats treated with a WNK inhibitor two weeks after MCT injection. Echocardiography and pressure-volume loop analysis assessed RV function and pulmonary vascular disease severity. Results: Treatment with WNK inhibitor improved TAPSE (2.4±0.1 vs 1.8±0.1 mm, p =0.0007), cardiac output (86.0±9.1 vs 52.5±5.6 ml/min, p =0.02), and cardiac output normalized body weight (0.26±0.03 vs 0.15±0.02 ml/min/g, p =0.0032). Importantly, the WNK inhibitor did not alter pulmonary vascular disease severity as there were no differences in pulmonary artery acceleration time (18.2±1.5 vs 14.2±0.9 sec, p =0.22), Ea (0.58±0.07 vs 0.58±0.08 mmHg/μL, p=1.00), or right ventricular systolic pressure (71.8±7.6 vs 72.0±4.0 mmHg, p =1.00) compared to MCT. At the molecular level, WNK1 inhibition decreased expression of WNK1 (MCT: 1.3±0.2 fold increase, MCT-WNK: 3.4±2.2 fold decrease), Glut1 (MCT: 2.7±0.9 fold increase, MCT-WNK: 1.2±0.2 fold increase), Glut4 (MCT: 1.7±0.4 fold increase, MCT-WNK: 1.0±0.2 fold increase), and protein O-GlcNAcylation (MCT: 2.4±0.7 fold increase, MCT-WNK: 1.1±0.1 fold increase). Conclusions: WNK inhibition normalized Glut1/4 expression and protein O-GlcNAcylation in the RV. These molecular changes resulted in improved RV function without a change in pulmonary vascular disease burden.

scholarly journals With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

2021 ◽  
Author(s):  
Sasha Z Prisco ◽  
Megan Eklund ◽  
Thenappan Thenappan ◽  
Kurt W Prins
Keyword(s):  
Right Ventricular ◽  
Right Ventricular Dysfunction ◽  
Glycolytic Flux ◽  
Pulmonary Vascular Disease ◽  
Acid Oxidation ◽  
Loop Analysis ◽  
Post Translational Modifications ◽  
Glut4 Expression ◽  
Systolic And Diastolic Function ◽  
Rv Function

Objectives: Investigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. Background: In PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. Methods: Rats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. Results: WNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. Conclusions: WNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function.

Increased Brain Natriuretic Peptide as a Marker for Right Ventricular Dysfunction in Acute Pulmonary Embolism

2001 ◽  
Vol 86 (11) ◽  
pp. 1193-1196 ◽  
Author(s):  
Igor Tulevski ◽  
Alexander Hirsch ◽  
Bernd-Jan Sanson ◽  
Hans Romkes ◽  
Ernst van der Wall ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Brain Natriuretic Peptide ◽  
Right Ventricular ◽  
Natriuretic Peptide ◽  
Acute Pulmonary Embolism ◽  
Prognostic Significance ◽  
Systolic Pressure ◽  
Clinical Importance ◽  
Acute Pe ◽  
Rv Function

SummaryRight ventricular (RV) function is of major prognostic significance in patients with acute pulmonary embolism (PE). The aim of the present study was to evaluate the role of neurohormone plasma brain natriuretic peptide (BNP) in assessing RV function in patients with acute PE.BNP levels were measured in 16 consecutive patients with acute PE as diagnosed by high probability lung scintigraphy or pulmonary angiography. Twelve healthy age-matched volunteers served as controls. All 16 patients underwent standard echocardiography and blood tests during the first hour of presentation. In the patient group, survival was studied for a period of 30 days. Plasma BNP levels in patients with acute PE were higher than in controls (7.2 [95% CI 0.4 to 144.6] versus 1.4[95% CI 0.4 to 4.6] pmol/L, p = 0.0008). Plasma BNP was significantly higher in 5 patients with RV dysfunction compared to 11 patients with normal RV function (40.2 [95% CI 7.5 to 214.9] versus 3.3 [95% CI 0.4 to 24.9] pmol/L, p = 0.0003). RV systolic pressure was not significantly correlated with BNP (r = 0.42, p = ns).In conclusion, plasma BNP neurohormone levels might be of clinical importance as a supplementary tool for assessment of RV function in patients with acute PE.

Abstract 16574: Heart Failure Biomarkers (NT-proBNP, Gal-3, sST2) Correlate With Right Ventricular Systolic Pressure and Provide Insight to Poor CRT Response: A BIOCRT Substudy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Roderick C Deaño ◽  
Jackie Szymonifka ◽  
Qing Zhou ◽  
Jigar H Contractor ◽  
Zachary Lavender ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Cardiac Transplant ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Crt Response

Objective: Patients with heart failure (HF) and pulmonary hypertension (PH) have worse outcomes after cardiac resynchronization therapy (CRT). The relationship of circulating HF biomarkers and right ventricular systolic pressure (RVSP) may provide insight to the mechanism between PH and poor CRT response. Methods: In 90 patients (age 65 ± 13, 78% male, EF 26 ± 8%, RVSP 44 ± 12 mmHg) undergoing CRT, we measured baseline RVSP by echocardiography and obtained peripheral blood samples drawn at the time of device implantation. We measured levels of established and emerging HF biomarkers (Table 1). CRT non-response was defined as no improvement of adjudicated HF Clinical Composite Score at 6 months. Major adverse cardiac event (MACE) was defined as composite endpoint of death, cardiac transplant, left ventricular assist device, and HF hospitalization within 2 years. Results: There were 34% CRT non-responders and 27% had MACE. Per 1 unit increase in log-transformed RVSP, there was an 11-fold increase risk of having CRT non-response (odd ratio [OR] 11.0, p=0.01) and over 5-fold increase of developing 2-year MACE (hazard ratio [HR] 5.8, p=0.02). When comparing patients with severe PH (RVSP>60 mmHg) to those without PH (RVSP < 35 mmHg), there was an 8-fold increase in CRT nonresponse (OR 8.4, p=0.03) but no difference in MACE (p=NS). RVSP was correlated with increased biomarker levels of myocardial stretch and fibrosis, but not myocardial necrosis (Table 1). Conclusions: Higher RVSP is associated with greater rates of CRT non-response and adverse clinical outcomes. The mechanistic association between severe PH and CRT nonresponse may be explained by the biomarker profile reflective of myocardial wall stretch and fibrosis.

Abstract 17209: Impaired Ventricular-Vascular Coupling in Young Adults Born Preterm

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Ashley Mulchrone ◽  
Alessandro Bellofiore ◽  
Arij G Beshish ◽  
Gregory Barton ◽  
Heather Shumaker ◽  
...  
Keyword(s):  
Young Adults ◽  
Preterm Birth ◽  
Right Ventricular ◽  
Very Low Birth Weight ◽  
Systolic Pressure ◽  
The United States ◽  
Pulmonary Vascular Disease ◽  
Heart Catheterization ◽  
Volume Data ◽  
Arterial Elastance

Background: Preterm birth affects 10% of live births in the United States, often requiring mechanical ventilation and oxygen supplementation. Although a known risk factor for neonatal and childhood pulmonary vascular disease, little is known regarding the long-term impact on the right ventricle (RV). Here, we utilize novel techniques to investigate RV afterload, contractility, and ventricular-vascular coupling (VVC) in young adults born preterm. Methods: Adults born premature (n=7; 4; current age 26.7±0.4 years; gestational age 28.6±1.1 weeks) born with very low birth weight (≤1500g) were recruited from the Newborn Lung Project. Control subjects (n=7; 2) from the same birth years were recruited from the general population. All subjects had no known cardiopulmonary disease. Right heart catheterization (RHC) and magnetic resonance imaging (MRI) were performed to assess right ventricular hemodynamics. Asynchronously acquired pressure and volume data (from RHC and MRI, respectively) were used to compute effective arterial elastance (Ea), end-systolic elastance (Ees), and VVC as: [ESP/SV], [(P max -ESP)/SV], and [Ees/Ea], respectively, where ESP is the end-systolic pressure, SV is the stroke volume, and P max is the maximum isovolumetric pressure estimated from a novel single-beat approach. Results were analyzed via two-sample t-test; p<0.05 was considered significant. Results: Preterm subjects had significantly increased Ea, a measure of RV afterload (Figure 1A). No difference Ees, a measure of RV contractility, was evident (Figure 1B), resulting in significantly impaired VVC in preterm subjects (Figure 1C). Conclusion: Otherwise healthy young adults born preterm have high resistance-low compliance pulmonary vascular beds with no RV adaptation, resulting in impaired right ventricular-pulmonary vascular coupling. These findings add to the growing literature that preterm birth has profound lifelong consequences that warrant further study.

Evidence for Pulmonary Vascular Disease Despite Absence of Overt Pulmonary Arterial Hypertension (PAH) in Myeloproliferative Disorders (MPD) (PV and ET).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4939-4939
Author(s):  
Jean-Jacques Kiladjian ◽  
Christine Lamberto ◽  
Thierry Laperche ◽  
Hilario Nunes ◽  
Hesham Mohamed ◽  
...  
Keyword(s):  
Gas Exchange ◽  
Pulmonary Function ◽  
Prospective Study ◽  
Vascular Disease ◽  
Dead Space ◽  
Pulmonary Function Tests ◽  
Systolic Pressure ◽  
Pulmonary Artery Systolic Pressure ◽  
Pulmonary Vascular Disease ◽  
Cell Counts

Abstract Background: Until recently, the association of PAH unrelated to thromboembolic events with MPD was occasionally reported, essentially in patients with myelofibrosis. In a large retrospective study, 26 cases of unexplained PAH associated with MPD (including 6 PV and 5 ET) were identified in the referral population of the Mayo Clinic (Chest, 2001;120:801). More recently, a prospective study found that 10 of 24 MPD patients (including 2 PV and 14 ET) had PAH (Haematologica, 2004;89:245). We prospectively evaluated the incidence of PAH in an unselected cohort of 45 consecutive MPD patients seen at our centre. In addition, evaluation of pulmonary function and gas exchange was performed. Methods: MPD diagnosis (WHO criteria) was polycythemia vera (PV) (n=25), and essential thrombocythemia (ET) (n=20). 9/11 patients tested had the V617F JAK2 mutation and 11/12 over-expressed PRV1. Evaluation was performed at time of MPD diagnosis (n=9) or during evolution (n=36, median from diagnosis 43 months, range 7–135). Doppler transthoracic echocardiography (TTE) was used to estimate pulmonary artery systolic pressure (PASP), PAH being defined as PASP &gt; 35 mmHg. Pulmonary function tests included slow vital capacity, total lung capacity, flow-volume curves, and lung diffusing capacity for carbon monoxide (DLCO and DLCOc when corrected for hemoglobin value). Gas exchange tests were performed using a treadmill exercise protocol allowing steady state alveolar-arterial differences measurement for rest and moderate exercise intensity. Results: PASP could be estimated by TTE in 36 patients and was normal in all cases (mean 28 ± 3.5 mmHg). Pulmonary volumes and flow were normal in all MPD patients. However, we observed significantly decreased DLCOc in 17/28 patients (9/14 ET, 8/14 PV). Mean DLCOc was 89% ± 15 of predicted value (based on sex, age, height and weight) for the whole cohort (p=0.0004 by paired t-test), 84% ± 16 in ET (p=0.005) and 93% ± 12 in PV (p=0.035). Dead space to tidal volume ratio (VD/VT) at exercise was significantly increased in 19/28 patients (10/14 ET, 9/14 PV). Mean VD/VT was 28% ± 7, 28% ± 9 and 27% ± 5 in the whole cohort, ET and PV patients respectively, and was 18% ± 4 in controls (p=0.001 for the 3 groups). A negative correlation was found between VD/VT and DLCO (r=0.47, p=0.02). In PV patients, no correlation was found between hemoglobin value and DLCOc (p=0.37) or VD/VT (p=0.87). Conclusion: Contrary to previous reports, in this prospective study in unselected MPD patients, no case of PAH was found. Yet, pulmonary function studies revealed in two third of MPD patients anomalies suggesting presence of pulmonary vascular disease a minima, with increased dead space at exercise correlated with decreased DLCO. These anomalies were similarly observed in PV and ET, and could be detected at diagnosis or during evolution in patients with normalized cell counts. A possible mechanism could be occlusion of the pulmonary micro-vascular bed, a phenomenon well described in terminal arterial circulation of MPD patients. Longer follow-up will show if abnormal dead space and DLCO are predictive of overt PAH development in MPD patients and could justify preventive measures.

scholarly journals Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis

2015 ◽  
Vol 308 (6) ◽  
pp. L523-L538 ◽  
Author(s):  
Tsutomu Shinohara ◽  
Hirofumi Sawada ◽  
Shoichiro Otsuki ◽  
Noriko Yodoya ◽  
Taichi Kato ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Pulmonary Vascular Disease ◽  
Ventricular Systolic Pressure ◽  
Targeting Therapy ◽  
Pulmonary Arterial ◽  
Medial Wall Thickness ◽  
Endothelial Growth Factor

It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3–5 wk (early study) or during 5–8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.

scholarly journals Immediate impact of percutaneous transvenous mitral commissurotomy on right ventricular function

2017 ◽  
Vol 14 (2) ◽  
pp. 19-24
Author(s):  
Bishal KC ◽  
Rabi Malla ◽  
Ram Kishore Shah ◽  
Anish Hirachan ◽  
Binay Kumar Rauniyar ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Clinical Symptoms ◽  
Longitudinal Velocity ◽  
Prognostic Significance ◽  
Systolic Pressure ◽  
Pulmonary Artery Systolic Pressure ◽  
Tei Index ◽  
Long Term Outcome ◽  
Rv Function

Background and Aims: Abnormal Right Ventricular (RV) function affects the long term outcome and clinical symptoms in patients with mitral stenosis (MS). This study evaluates the immediate effect of Percutaneous Transmitral Commisurotomy (PTMC) on RV function.Methods: An observational, cross sectional study was done on 50 patients with rheumatic MS who underwent PTMC at Shahid Gangalal National Heart Center from Dec 2015 –Dec 2016. All underwent clinical evaluation and echocardiogram before and immediately after PTMC.Results: There was female preponderance with 66% being female. The mean age was 37.26 ± 10.63 years. There was immediate increase in the mitral valve area (MVA) from 0.87 ± 0.12cm2 to 1.54 ± 0.27cm2(p< 0.001). There was significant decrease in mean mitral diastolic gradient from 16.4 ± 8.8mmHg to 5 ± 1.5mmHg (p< 0.001), in the pulmonary artery systolic pressure 53.6 ± 21.83mmHg to 39.5 ± 14.67mmHg (p< 0.001), in the RV Tei index from 0.56 ± 0.08 to 0.40 ± 0.08 (p< 0.001). There was significant increase in TAPSE from 16.0 ± 1.50 to 18.6 ± 1.70 mm, (p<0.001) and the longitudinal velocity of excursion of the RV at the tricuspid annulus (RV S’) from 13.69 ± 3.33 cm/sec to 15.31 ± 3.07 cm/sec (p< 0.001)Conclusions: Successful PTMC can improve RV function as shown by the improvement in PASP, RV Tei index, TAPSE and RV S’. Further larger population studies are required to confirm the findings. Long term studies are important to determine the prognostic significance of improvement in RV function.Nepalese Heart Journal 2017; 14(2): 19-24

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