BACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with... Show moreBACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function.METHODS:We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV–arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism.RESULTS:RV mass significantly decreased from 43±15 to 27±11g/m2 (−15.9 g/m2 [95% CI, −21.4 to –10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 in healthy controls [95% CI, 2.1 to 9.8]; P<0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2–6.1]; P=0.013) as a result of a larger reduction in cellular volume than in matrix volume (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-β (transforming growth factor-β) were elevated at baseline and remained elevated post-PEA.CONCLUSIONS:Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover. Show less
Wessels, J.N.; Wezenbeek, J. van; Rover, J. de; Smal, R.; Llucià-Valldeperas, A.; Celant, L.R.; ... ; Man, F.S. de 2023
Background: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness.Objectives: This study aimed to investigate... Show moreBackground: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness.Objectives: This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses.Methods: RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis.Results: RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2- to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm2 accompanied by interstitial and perivascular fibrosis.Conclusions: RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis. Show less
Wezenbeek, J. van; Groeneveldt, J.A.; Llucia-Valldeperas, A.; Bruggen, C.E. van der; Jansen, S.M.A.; Smits, A.J.; ... ; Man, F.S. de 2022
BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of... Show moreBACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAHpatients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females < 45years had best prognosis in comparison to females & GE;55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females < 45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females < 45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAHpatients. DHEA-S appeared to be lower in male and female PAH-patients. Females < 45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.J Heart Lung Transplant 2022;41:445-457 (c) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Wezenbeek, J. van; Kianzad, A.; Bovenkamp, A. van de; Wessels, J.; Mouratoglou, S.A.; Braams, N.J.; ... ; Man, F.S. de 2022
Background: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and... Show moreBackground: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity. Methods: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP >= 30 and <= 50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging. Results: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52 +/- 11 versus PAH: 36 +/- 12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3 +/- 0.2 versus PAH: 1.2 +/- 0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg). Conclusions: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity. Show less
BACKGROUND: Between 16% and 51% of patients with chronic thromboembolic pulmonary hypertension will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual... Show moreBACKGROUND: Between 16% and 51% of patients with chronic thromboembolic pulmonary hypertension will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual PH is related to remaining (sub-)segmental macrovascular lesions or to microvascular disease is unknown. New imaging techniques can provide detailed information about (sub-)segmental pulmonary arteries and parenchymal perfusion. The aim of this study was to describe the prevalence after PEA of remaining (sub-)segmental vascular lesions on electrocardiogram-gated computed tomography pulmonary angiography (CTPA) and parenchymal hypoperfusion on magnetic resonance imaging (MRI) and to relate these imaging abnormalities to the presence or absence of residual PH after PEA.METHODS: In a prospective cohort of patients with operable chronic thromboembolic pulmonary hypertension, hemodynamics, CTPA, and lung perfusion MRI were performed before and 6 months after PEA. The percentage of (sub-)segmental vascular lesions was calculated on CTPA and parenchymal hypoperfusion on lung perfusion MRI.RESULTS: PEA led to significant improvements in hemodynamics and a reduction of imaging abnormalities. Residual PH was present in 45% of patients after PEA, whereas remaining (sub-)segmental vascular lesions and parenchymal hypoperfusion were present in 20% and 21% of the pulmonary vasculature, respectively. Patients with and without residual PH after PEA had similar percentages of remaining (sub-)segmental vascular lesions (25% +/- 14% vs 17% +/- 15%; p = 0.16) and similar degrees of parenchymal hypoperfusion (20% +/- 7% vs 19% +/- 6%; p = 0.63).CONCLUSIONS: After successful PEA, advanced imaging shows that around 20% of the pulmonary vasculature remains abnormal, independent of the presence of residual PH. This may suggest that microvascular disease, rather than residual macrovascular lesions, plays a prominent role in residual PH after PEA. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved. Show less
Bruggen, C.E. van der; Happe, C.M.; Dorfmuller, P.; Trip, P.; Spruijt, O.A.; Rol, N.; ... ; Man, F.S. de 2016
