Authorship：Lead author   Language：English   Publisher：Journal of Applied Physiology  

Adaptation of the right ventricle (RV) to a progressively increasing afterload is one of the hallmarks of pulmonary arterial hypertension (PAH). Pressure-volume loop analysis provides measures of load-independent RV contractility, i.e., end-systolic elastance, and pulmonary vascular properties, i.e., effective arterial elastance (Ea). However, PAH-induced RV overload potentially results in tricuspid regurgitation (TR). TR makes RV eject to both PA and right atrium; thereby, a ratio of RV end-systolic pressure (Pes) to RV stroke volume (SV) could not correctly define Ea. To overcome this limitation, we introduced a two-parallel compliance model, i.e., Ea = 1/(1/Epa 1/ETR), while effective pulmonary arterial elastance (Epa = Pes/PASV) represents pulmonary vascular properties and effective tricuspid regurgitant elastance (ETR) represents TR. We conducted animal experiments to validate this framework. First, we performed SV analysis with a pressure-volume catheter in the RV and a flow probe at the aorta in rats with and without pressure-overloaded RV to determine the effect of inferior vena cava (IVC) occlusion on TR. A discordance between the two techniques was found in rats with pressure-overloaded RV, not in sham. This discordance diminished after IVC occlusion, suggesting that TR in pressure-overloaded RV was diminished by IVC occlusion. Next, we performed pressure-volume loop analysis in rats with pressure-overloaded RVs, calibrating RV volume by cardiac magnetic resonance. We found that IVC occlusion increased Ea, suggesting that a reduction of TR increased Ea. Using the proposed framework, Epa was indistinguishable to Ea post-IVC occlusion. We conclude that the proposed framework helps better understanding of the pathophysiology of PAH and associated right heart failure.

DOI： 10.1152/japplphysiol.00081.2023

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PubMed

Authorship：Lead author,　Corresponding author   Language：English   Publisher：Pulmonary Circulation  

Vagal nerve stimulation (VNS) ameliorates pulmonary vascular remodeling and improves survival in a rat model of pulmonary hypertension (PH). However, the direct impact of VNS on right ventricular (RV) function, which is the key predictor of PH patients, remains unknown. We evaluated the effect of VNS among the three groups: pulmonary artery banding (PAB) with sham stimulation (SS), PAB with VNS, and control (no PAB). We stimulated the right cervical vagal nerve with an implantable pulse generator, initiated VNS 2 weeks after PAB, and stimulated for 2 weeks. Compared to SS, VNS increased cardiac index (VNS: 130 ± 10 vs. SS: 93 ± 7 ml/min/kg; p < 0.05) and end-systolic elastance assessed by RV pressure–volume analysis (VNS: 1.1 ± 0.1 vs. SS: 0.7 ± 0.1 mmHg/μl; p < 0.01), but decreased RV end-diastolic pressure (VNS: 4.5 ± 0.7 vs. SS: 7.7 ± 1.0 mmHg; p < 0.05). Furthermore, VNS significantly attenuated RV fibrosis and CD68-positive cell migration. In PAB rats, VNS improved RV function, and attenuated fibrosis, and migration of inflammatory cells. These results provide a rationale for VNS therapy as a novel approach for RV dysfunction in PH patients.

DOI： 10.1002/pul2.12154

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PubMed

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Authorship：Lead author   Language：English   Publishing type：Doctoral thesis  

Language：English   Publisher：Scientific Reports  

Moderate/severe anemia [hemoglobin (Hb) < 10 g/dL] is recommended to be treated in patients with renal anemia. However, the optimal therapeutic target for Hb levels in patients with heart failure (HF) is unknown. This study aimed to investigate the impact of severity of anemia, especially moderate/severe anemia, associated with renal dysfunction (RD: eGFR < 60 mL/min/1.73 m²) in HF patients. We analyzed 1,608 HF patients from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) database. Patients were classified based on the severity of admission anemia in the presence/absence of RD. Patients with RD and anemia were older, more likely to be female, and had a history of HF admission. The composite outcome was higher in RD and moderate/severe anemia (adjusted hazard ratio:2.120, 95% CI:1.559–2.881, p < 0.001) compared to RD and non/mild anemia (Hb ≥ 10 g/dL), non-RD and moderate/severe anemia, and non-RD and non/mild anemia (reference). During hospitalization, 6% and 10% of patients had improving and worsening RD and/or moderate/severe anemia, respectively. These status changes were associated with the post-discharge outcomes in HF patients. Moderate/severe anemia has a prognostic impact in HF patients with RD and may be an appropriate therapeutic target in HF.

DOI： 10.1038/s41598-025-87650-z

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PubMed

Language：English   Publisher：Pulmonary Circulation  

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by elevated pulmonary arterial pressure and organized thrombi within pulmonary arteries. Riociguat is a soluble guanylate cyclase stimulator and is approved for patients with inoperable CTEPH or residual pulmonary hypertension after pulmonary endarterectomy (PEA). Previous work suggested that riociguat treatment is associated with an increased risk of bleeding, although the mechanism is unclear. The aim of this study is to assess how riociguat affects primary hemostasis by studying its effect on the interaction between platelets and endothelial cells derived from CTEPH patients. Pulmonary artery endothelial cells (PAECs) were isolated from thrombus-free regions of PEA material. Purified PAECs were cultured in flow chambers and were stimulated with 0.1 and 1 µM riociguat for 24 h before flow experiments. After stimulation with histamine, PAECs were exposed to platelets under shear stress. Platelet adhesion and expression of von Willebrand Factor (VWF) were evaluated to assess the role of riociguat in hemostasis. Under dynamic conditions, 0.1 and 1.0 µM of riociguat suppressed platelet adhesion on the surface of PAECs. Although riociguat did not affect intracellular expression and secretion of VWF, PAECs stimulated with riociguat produced fewer VWF strings than unstimulated PAECs. Flow cytometry suggested that decreased VWF string formation upon riociguat treatment may be associated with suppressed cell surface expression of P-selectin, a protein that stabilizes VWF anchoring on the endothelial surface. In conclusion, Riociguat inhibits VWF string elongation and platelet adhesion on the surface of CTEPH-PAECs, possibly by reduced P-selectin cell surface expression.

DOI： 10.1002/pul2.12146

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PubMed

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DOI： 10.11272/jssabst.50.0_s64

CiNii Research

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