RESUMO
BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy-related gene 7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.
Assuntos
Apoptose , Autofagia , Células Endoteliais , Hipertensão Pulmonar , Artéria Pulmonar , Animais , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Camundongos , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Proliferação de Células , Masculino , Remodelação Vascular , Camundongos Knockout , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Modelos Animais de Doenças , Hipóxia/metabolismo , Hipóxia/patologia , Células Cultivadas , Camundongos Endogâmicos C57BLRESUMO
AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.
Assuntos
Insuficiência Cardíaca , Hemodinâmica , Pirimidinas , Volume Sistólico , Humanos , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Idoso , Pirimidinas/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Seguimentos , Cateterismo Cardíaco/métodos , Resultado do Tratamento , Pressão Propulsora Pulmonar/fisiologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Compostos Heterocíclicos com 2 AnéisRESUMO
Background: The contemporary outcome of balloon pulmonary angioplasty (BPA) and pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are unclear. Objectives: This study aimed to clarify the characteristics and outcomes of CTEPH patients treated with BPA and PEA in Japan. Methods: Among 1,270 participants enrolled between 2018 and 2023 in the CTEPH AC (Chronic Thromboembolic Pulmonary Hypertension Anticoagulant) registry, a Japanese nationwide CTEPH registry, 369 treatment-naive patients (BPA strategy: n = 313; PEA strategy: n = 56) and 690 on-treatment patients (BPA strategy: n = 561; PEA strategy: n = 129) were classified according to the presence of prior reperfusion therapy. Morbidity and mortality events (all-cause death, rescue mechanical reperfusion therapy, and/or initiation of parenteral pulmonary vasodilators), pulmonary hemodynamics, exercise tolerance, and relevant laboratory test results were evaluated. Results: The BPA strategy was chosen in older patients than the PEA strategy (mean age, BPA vs PEA: 66.5 ± 12.6 years vs 62.5 ± 11.8 years; P = 0.028). Median follow-up period was 615 (Q1-Q3: 311-997) days in treatment-naive patients and 1,136 (Q1-Q3: 684-1,300) days in on-treatment patients. BPA strategy had as acceptable morbidity and mortality as PEA strategy (5-year morbidity and mortality event rate, BPA vs PEA: 10.2% [95% CI: 5.2%-19.5%] vs 16.1% [95% CI: 4.3%-50.6%] in treatment-naive patients; 9.7% [95% CI: 6.7%-13.8%] vs 6.9% [95% CI: 2.7%-17.3%] in on-treatment patients), with greater improvement of renal function; glomerular filtration rate in propensity score-matched population (difference between change: 4.9 [95% CI: 0.5-9.3] mL/min/1.73 m2; P = 0.030). Conclusions: BPA strategy was more frequently chosen in older patients compared with PEA strategy and showed acceptable outcomes for efficacy with greater advantage for improvement in renal function. (Multicenter registry of chronic thromboembolic pulmonary hypertension in Japan; UMIN000033784).
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Background: Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR. Objectives: To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics. Methods: Moderate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed. Results: At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%). Conclusion: Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.
RESUMO
Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease. Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome. Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis. Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (rs = 0.470, P < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively. Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses.