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Background: Pulmonary hypertension (PH) can lead to congestive hepatopathy, known as cardiohepatic syndrome (CHS). Hepatic congestion is associated with increased liver stiffness, which can be quantified using shear wave elastography. We aimed to investigate whether hepatic shear wave elastography detects patients at risk in the early stages of PH., Methods: Sixty-three prospectively enrolled patients undergoing right heart catheterization (52 diagnosed with PH and 11 with invasive exclusion of PH) and 52 healthy volunteers underwent assessments including echocardiography and hepatic shear wave elastography. CHS was defined as increased levels of ≥2 of the following: gamma-glutamyl transferase, alkaline phosphatase, and bilirubin. Liver stiffness was defined as normal (≤5.0 kPa) or high (>5.0 kPa)., Results: Compared with normal liver stiffness, high liver stiffness was associated with impaired right ventricular (RV) and right atrial (RA) function (median [interquartile range] RV ejection fraction: 54 [49; 57]% vs 45 [34; 51]%, p < 0.001; RA reservoir strain: 49 [41; 54]% vs 33 [22; 41]%, p < 0.001), more severe tricuspid insufficiency (p < 0.001), and higher prevalence of hepatovenous backflow (2% vs 29%, p < 0.001) and CHS (2% vs 10%, p = 0.038). In the patient subgroup with precapillary PH (n = 48), CHS and high liver stiffness were associated with increased European Society of Cardiology/European Respiratory Society 2022 risk scores (p = 0.003)., Conclusions: Shear wave liver elastography yields important information regarding right heart function and may complement risk assessment in patients with (suspected) PH., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP - end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH.Trial registration. NCT04663217., (© 2024. The Author(s).)

Background: The right ventricle has a complex contraction pattern of uncertain clinical relevance. We aimed to assess the relationship between right ventricular (RV) contraction pattern and RV-pulmonary arterial (PA) coupling defined by the gold-standard pressure-volume loop-derived ratio of end-systolic/arterial elastance (Ees/Ea)., Methods: Prospectively enrolled patients with suspected or confirmed pulmonary hypertension underwent three-dimensional echocardiography, standard right heart catheterization, and RV conductance catheterization. RV-PA uncoupling was categorized as severe (Ees/Ea < 0.8), moderate (Ees/Ea 0.8-1.29), and none/mild (Ees/Ea ≥ 1.3). Clinical severity was determined from hemodynamics using a truncated version of the 2022 European Society of Cardiology/European Respiratory Society risk stratification scheme., Results: Fifty-three patients were included, 23 with no/mild, 24 with moderate, and 6 with severe uncoupling. Longitudinal shortening was decreased in patients with moderate vs no/mild uncoupling (p <0.001) and intermediate vs low hemodynamic risk (p < 0.001), discriminating low risk from intermediate/high risk with an optimal threshold of 18% (sensitivity 80%, specificity 87%). Anteroposterior shortening was impaired in patients with severe vs moderate uncoupling (p = 0.033), low vs intermediate risk (p = 0.018), and high vs intermediate risk (p = 0.010), discriminating high risk from intermediate/low risk with an optimal threshold of 15% (sensitivity 100%, specificity 83%). Left ventricular (LV) end-diastolic volume was decreased in patients with severe uncoupling (p = 0.035 vs no/mild uncoupling)., Conclusions: Early RV-PA uncoupling is associated with reduced longitudinal function, whereas advanced RV-PA uncoupling is associated with reduced anteroposterior movement and LV preload, all in a risk-related fashion., Clinicaltrials: GOV: NCT04663217., Competing Interests: Disclosure statement This study was funded by Deutsche Forschungsgesellschaft, Grant Agreement Number CRC 1213, Project B08. Dr Rako, Ms Yildiz, Mr da Rocha, Dr Kremer and Dr Vadász report nonfinancial support from the University of Giessen during the conduct of the study. Dr Yogeswaran reports nonfinancial support from the University of Giessen during the conduct of the study and personal fees from MSD outside the current study. Dr Lakatos, Dr Fábián, and Dr Kovács report personal fees from Argus Cognitive, Inc. during the conduct of the study. Dr Ghofrani reports nonfinancial support from the University of Giessen and grants from the German Research Foundation during the conduct of the study and personal fees from Bayer, Actelion, Pfizer, Merck, GSK and Takeda, grants and personal fees from Novartis, Bayer HealthCare and Encysive/Pfizer, and grants from Aires, the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the German Ministry of Education and Research outside the current study. Dr Seeger reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the current study and personal fees from Pfizer and Bayer Pharma AG outside the submitted work. Dr Gall reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the current study and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics outside the current study. Dr Richter reports nonfinancial support from the University of Giessen during the conduct of the current study and research support from United Therapeutics and Bayer, speaker honoraria from Bayer, Actelion, Mundipharma, Roche, and OMT, and consultancy fees from Bayer outside the submitted work. Dr Bauer reports consultancy fees from Bristol Myers Squibb/Pfizer and speaker fees from Bristol Myers Squibb/Pfizer, AstraZeneca and Amgen. Dr Tedford reports no direct conflicts of interest during the conduct of the current study and consulting relationships with Abiomed (research advisory board), Medtronic, Abbott (steering committee), Aria CV Inc., Acceleron/Merck (steering committee and hemodynamic core lab work for Merck), Alleviant, CareDx, Cytokinetics, Itamar, Edwards LifeSciences (national principal investigator for the RIGHT-FLOW clinical trial), Eidos Therapeutics, Lexicon Pharmaceuticals, and Gradient outside the submitted work. Dr Naeije reports relationships including consultancies, speaker’s fees and membership of advisory boards with AOP Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation and United Therapeutics. Dr Tello reports nonfinancial support from the University of Giessen during the conduct of the current study and speaker honoraria from Actelion and Bayer outside the submitted work. We thank Claire Mulligan, PhD (Beacon Medical Communications Ltd, Brighton, UK) for editorial assistance, funded by the University of Giessen., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo-based myocardial work (MW) module] vs. gold-standard invasive right ventricular (RV) pressure-volume (PV) loops., Methods and Results: From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure-strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop-derived RV SW in the overall cohort [rho = 0.546 (P < 0.001)] and the PAH/CTEPH subgroup [rho = 0.568 (P < 0.001)]. Overall, RVGWW correlated with invasive measures of arterial elastance (Ea), the ratio of end-systolic elastance (Ees)/Ea, and end-diastolic elastance (Eed) significantly., Conclusions: Integrated echo measurement of pressure-strain loop-derived SW correlates with PV loop-based assessment of RV SW. Wasted work correlates with invasive measures of load-independent RV function. Given the methodological and anatomical challenges of RV work assessment, evolution of this approach by incorporating more elaborated echo analysis data and an RV reference curve might improve its reliability to mirror invasively assessed RV SW., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In this study we investigated the effects of alpha-ketoisocaproic (KIC), alpha-ketoisovaleric (KIV) and alpha-keto-beta-methylvaleric (KMV) acids on the phosphorylation of intermediate filament (IF) proteins of cerebral cortex of rats. Tissue slices were incubated with [32P] orthophosphate in the presence or absence of the acids. The intermediate filament enriched cytoskeletal fraction was isolated and the radioactivity incorporated into neurofilament subunits, vimentin and glial fibrillary acidic protein was measured. Results demonstrated that KIC significantly increased phosphorylation of these proteins whereas the other acids had no effect. Experiments using protein kinase inhibitors indicated that the effect of KIC was mediated by Ca2+/calmodulin- and cAMP-dependent protein kinases. This study provides evidence that KIC, a key metabolite accumulating in maple syrup urine disease, increases phosphorylation of IF proteins.

Background: Phenylalanine has been considered the main responsible agent for the brain damage that occurs in phenylketonuria., Methods and Results: In this work we studied the effect of this amino acid on the in vitro phosphorylation of cytoskeletal proteins of the cerebral cortex of rats. We observed that 2 mM phenylalanine, a concentration usually found in the plasma of phenylketonuric patients, decreased the in vitro 32P incorporation into these proteins. In addition, we investigated the effect of alanine on the inhibition of 32P incorporation into cytoskeletal proteins caused by phenylalanine. We observed that 0.5 mM alanine did not alter 32P incorporation but prevented the inhibition provoked by phenylalanine., Conclusion: In case the inhibition of cytoskeletal protein phosphorylation by phenylalanine also occurs in human phenylketonuria, it is possible that alanine supplementation to the phenylalanine-restricted diet may be beneficial to these patients.