Pressure-based estimation of right ventricular ejection fraction: Validation as a clinically relevant target for drug development in a rodent model of pulmonary hypertension

Elassal, Ahmed; Steppan, Jochen; Charania, Sofia; Santhanam, Lakshmi; Singh, Inderjit; Heerdt, Paul M.

doi:10.1016/j.vascn.2021.107102

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…Pressure volume loops: Right ventricular function and pressures were analyzed by pressure volume loops as described previously (25)(26)(27). Briefly, animals were anesthetized with isoflurane via vaporizer (2%) and placed on a heating pad.…”

Section: Rat Pulmonary Hypertension Modelsmentioning

confidence: 99%

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

Steppan,

Wang,

Nandakumar

et al. 2023

Preprint

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Background: Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study. Methods and Results: Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in-vivo with PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Conclusion: Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 is a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH.

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Section: Rat Pulmonary Hypertension Modelsmentioning

confidence: 99%

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

Steppan,

Wang,

Nandakumar

et al. 2023

Preprint

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“…14 As an alternative, our group recently described a method based entirely on analysis of the RV pressure waveform that can effectively track acute changes in RVEF in animal models. 15,16 This methodology raises the possibility of rapidly gauging functional impairment of the RV during RHC and allowing for rapid bedside assessment of a diagnostic or therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Pressure‐based estimation of right ventricular ejection fraction

et al. 2022

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Aims A method for estimating right ventricular ejection fraction (RVEF) from RV pressure waveforms was recently validated in an experimental model. Currently, cardiac magnetic resonance imaging (MRI) is the clinical reference standard for measurement of RVEF in pulmonary arterial hypertension (PAH). The present study was designed to test the hypothesis that the pressure-based method can detect clinically significant reductions in RVEF as determined by cardiac MRI in patients with PAH. Methods and results RVEF estimates derived from analysis of RV pressure waveforms recorded during right heart catheterization (RHC) in 25 patients were compared with cardiac MRI measurements of RVEF obtained within 24 h. Three investigators blinded to cardiac MRI results independently performed pressure-based RVEF estimation with the mean of their results used for comparison. Linear regression was used to assess correlation, and a receiver operator characteristic (ROC) curve was derived to define ability of the pressure-based method to detect a maladaptive RV response, defined as RVEF <35% on cardiac MRI. In 23 patients, an automated adaptation of the pressure-based RVEF method was also applied as proof of concept for beat-to-beat RVEF monitoring. The study cohort was comprised of 16 female and 9 male PAH patients with an average age of 53 ± 13 years. RVEF measured by cardiac MRI ranged from 16% to 57% (mean 37.7 ± 11.6%), and estimated RVEF from 15% to 54% (mean 36.2 ± 11.2%; P = 0.6). Measured and estimated RVEF were significantly correlated (r 2 = 0.78; P < 0.0001). ROC curve analysis demonstrated an area under the curve of 0.94 ± 0.04 with a sensitivity of 81% and specificity of 85% for predicting a maladaptive RV response. As a secondary outcome, with the recognized limitation of non-coincident measures, Bland-Altman analysis was performed and indicated minimal bias for estimated RVEF (À1.5%) with limits of agreement of ± 10.9%. Adaptation of the pressure-based estimation method to provide beat-to-beat RVEF also demonstrated significant correlation between the median beat-to-beat value over 10 s with cardiac MRI (r 2 = 0.66; P < 0.001), and an area under the ROC curve of 0.94 ± 0.04 (CI = 0.86 to 1.00) with sensitivity and specificity of 78% and 86%, respectively, for predicting a maladaptive RV response. Conclusions Pressure-based estimation of RVEF correlates with cardiac MRI and detects clinically significant reductions in RVEF. Study results support potential utility of pressure-based RVEF estimation for assessing the response to diagnostic or therapeutic interventions during RHC.

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Right Ventricular Pressure Waveform Analysis—Clinical Relevance and Future Directions

Heerdt,

Kheyfets,

Oakland

et al. 2024

Journal of Cardiothoracic and Vascular Anesthesia

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Pressure-based estimation of right ventricular ejection fraction: Validation as a clinically relevant target for drug development in a rodent model of pulmonary hypertension

Cited by 4 publications

References 19 publications

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

Pressure‐based estimation of right ventricular ejection fraction

Right Ventricular Pressure Waveform Analysis—Clinical Relevance and Future Directions

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