Zongye Cai

Background: Activation of the plasma kynurenine pathway (KP) may contribute to the progression of pulmonary arterial hypertension (PAH). We investigated the functional role and molecular mechanisms of KP activation in PAH. Methods: KP activity was measured in the lungs and plasma of humans and rodents with pulmonary hypertension (PH). KP activity was modulated in lung microvascular endothelial cells in vitro, and through daily oral administration of epacadostat, an inhibitor of IDO‐1 (indoleamine 2,3‐dioxygenase), the rate‐limiting enzyme of the KP, in rats with monocrotaline‐induced PH. Results: IDO‐1 expression was increased in peripheral blood mononuclear cells but not in lung tissue of patients with PAH and in rats with monocrotaline‐induced PH. Epacadostat prevented KP activation and the development of monocrotaline‐induced PH, significantly reduced right ventricular systolic pressure (58±9 versus 42±4 and 46±6 mm Hg for placebo versus epacadostat 50 and 100 mg/kg, respectively, P P P + synthesis, increased mitochondrial membrane potential, and endothelial cell proliferation. Inhibition of IDO‐1 using siRNA or epacadostat reversed these effects and inhibited the inflammatory response. Conclusions: Increased IDO‐1 expression in peripheral blood mononuclear cells may drive KP activation and promote pulmonary vascular remodeling in PAH. Epacadostat prevents the development of monocrotaline‐induced PH. These findings suggest a novel approach for the treatment of PAH.

Background: Tryptophan and its kynurenine pathway (KP) metabolites play key roles in modulating the immune system and vasculature, and exhibit both pro- and antioxidant properties, making them crucial for a healthy pregnancy and fetal development. Disruptions in the KP may impact both prenatal and postnatal health, however, data on fetal KP metabolite concentrations and their alterations in pregnancy-related disorders remain scarce. This study aims to investigate the association between pregnancy complications and KP metabolite concentrations in umbilical cord blood. Methods: Pregnancies complicated by preeclampsia (n = 40), fetal growth restriction (FGR, n = 33), pregestational diabetes mellitus (DM, n = 42), gestational diabetes mellitus (GDM, n = 61), and amniotic infection syndrome (AIS, n = 47) were included, along with 410 controls matched in a 1:2 ratio using Mahalanobis nearest-neighbor matching from a prospective birth cohort study. Tryptophan, kynurenine, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, xanthurenic acid, quinolinic acid, picolinic acid, and nicotinic acid were measured in umbilical cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differences in metabolite concentrations were analyzed using unpaired t-tests and linear regression models to control for potential confounders. Results: Tryptophan concentrations were decreased in cases of preeclampsia and DM. We identified elevated levels of 3-hydroxykynurenine in preeclampsia, kynurenine in GDM, and nicotinic acid in both FGR and DM. Quinolinic acid levels were also higher in preeclampsia and GDM, although this was not significant after adjusting for confounding variables. We observed no changes in KP metabolites in AIS. Conclusion: This study identified distinct alterations in umbilical cord blood KP metabolite concentrations in pregnancies with preeclampsia, FGR, DM, and GDM, but not AIS. This suggests differential regulation and activation of the KP depending on the pregnancy disorder. Such changes may influence maternal and infant health and could play a role in fetal programming, with potential long-term effects on child development and health.

In a recent study conducted by Laura Stourm et al., the authors identified that patients with pulmonary hypertension (PH) harboring loss‐of‐function variants in the Filamin A (FLNA) gene exhibit a unique spectrum of phenotypes. These include pulmonary involvement with lung parenchymal abnormalities and emphysema, as well as a range of extrapulmonary manifestations such as dysmorphic facial features, epilepsy, congenital heart defects, valvular and aortic diseases, thrombocytopenia, and periventricular nodular heterotopia (PVNH). Based on these findings, the study advocates for FLNA genetic screening in patients with PH who present with these specific phenotypic features. Here, we describe a clinical case that aligns closely with the observations reported in their study.

Background: Balloon pulmonary angioplasty (BPA) has emerged as an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Recent studies have reported progressive improvements in hemodynamic and clinical parameters during follow‐up, even without additional interventions. However, the exact mechanisms underlying these delayed effects remain unclear.Methods: This retrospective study analyzed 114 lesions from 31 CTEPH patients who underwent initial BPA with undersized balloons. Quantitative pulmonary angiography analysis was performed at three time points: pre‐procedure, immediately post‐procedure, and at follow‐up. Vessel diameters were measured and compared across different lesion types.Results: Among the analyzed lesions, 78.2% demonstrated spontaneous pulmonary artery enlargement at a median follow‐up of 56 days. The median enlargement in diameter increased by 0.16 (0.00–0.36) mm from pre‐procedure to immediately post‐procedure, and further increased by 0.31 (0.03–0.76) mm at follow‐up. The magnitude of spontaneous enlargement during follow‐up was significantly greater than immediate post‐procedural changes (p = 0.003). Web lesions showed the highest rate of spontaneous enlargement (77.7%), compared to ring‐like stenosis lesions (57.1%). No restenosis was observed during the follow‐up period.Conclusions: In the initial BPA for CTEPH patients, even with the use of small balloons, the treated vessels demonstrated significant spontaneous enlargement from post‐procedure to follow‐up without additional interventions, particularly in web lesions.

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed. An alteration of nucleotide‐ and nucleoside‐activated purinergic signaling has been proposed as a potential contributor in the pathogenesis of PAH. Adenosine‐mediated purinergic 1 receptor activation, particularly A_2AR activation, reduces pulmonary vascular resistance and attenuates pulmonary vascular remodeling and right ventricle hypertrophy, thereby exerting a protective effect. Conversely, A_2BR activation induces pulmonary vascular remodeling, and is therefore deleterious. ATP‐mediated P2X₇R activation and ADP‐mediated activation of P2Y₁R and P2Y₁₂R play a role in pulmonary vascular tone, vascular remodeling, and inflammation in PAH. Recent studies have revealed a role of ectonucleotidase nucleoside triphosphate diphosphohydrolase, that degrades ATP/ADP, in regulation of pulmonary vascular remodeling. Interestingly, existing evidence that adenosine activates erythrocyte A_2BR signaling, counteracting hypoxia‐induced pulmonary injury, and that ATP release is impaired in erythrocyte in PAH implies erythrocyte dysfunction as an important trigger to affect purinergic signaling for pathogenesis of PAH. The present review focuses on current knowledge on alteration of nucleot(s)ide‐mediated purinergic signaling as a potential disease mechanism underlying the development of PAH.

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.

Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O₂) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O₂ delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility ( E_es and dP/d t_max) were higher in PH compared with control with preserved cardiac index and RV O₂ delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/d t_max, and end-systolic elastance ( E_es), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O₂ delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O₂ content was not significantly altered in PH. Moreover, RV O₂ delivery reserve correlated with RV functional reserve, Δcardiac index ( r² = 0.85), ΔdP/d t_max ( r² = 0.49), and Δ E_es ( r² = 0.70), all P < 0.05. The inability to sufficiently increase RV O₂ supply to meet the increased O₂ demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH. NEW & NOTEWORTHY Impaired right ventricular (RV) O₂ delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O₂ delivery.