The expression status of proinflammatory cytokines in high-altitude pulmonary arterial hypertension (PAH) has been well studied. However, the changes in interleukin (IL)-8 and tumor necrosis factor α ...(TNF-α) during the reversible changes in pulmonary vascular remodeling (PVR) in PAH after detaching from a hypobaric hypoxic environment have not been elucidated. This investigation elucidated a high-altitude PAH rat model. Then, PAH rats in the high-altitude group were maintained in the high-altitude area, and rats in the low-altitude group returned to the low-altitude area. After 0, 10, 20, and 30 days of PAH modeling, right ventricular systolic pressure (RVSP) and the mean pulmonary arterial pressure (mPAP) were assessed. Right ventricular (RV) hypertrophy was reflected by the ratio of RV/left ventricle + interventricular septum (S). Pathological changes in PVR were accessed by hematoxylin-eosin staining, and medial wall thickness (WT%) and medial wall area (WA%) were measured. TNF-α and IL-8 levels in pulmonary artery tissues and blood were measured with Western blot assay and enzyme-linked immunosorbent assay, respectively. Our results showed that PAH rats exhibited a substantial increase in RVSP and mPAP, RV hypertrophy, PVR, and enhanced generation of TNF-α and IL-8. Then, we found that these pathological changes were gradually aggravated and TNF-α and IL-8 levels were increased in rats in the high-altitude group after 10, 20, and 30 days of PAH modeling. In contrast, the mPAP was decreased and PVR was alleviated in rats in the low-altitude group, accompanying with reduced TNF-α and IL-8 production. In conclusion, our study demonstrated that the generation of TNF-α and IL-8 was also reversible during the reversible changes in PVR after detaching from a hypobaric hypoxic environment. Thus, proinflammatory cytokine TNF-α and IL-8 levels are positively correlated with PVR severity.
At the 6th World Symposium on Pulmonary Hypertension (PH), it was proposed that the mean pulmonary arterial pressure (mPAP) threshold used to define PH should be lowered from ≥25 mmHg to >20 mmHg. ...The rationale for this change is that the ≥25 mmHg threshold is arbitrary, whereas the revised threshold is based on scientific evidence. For the definition of all forms of pre-capillary PH, the inclusion of a pulmonary vascular resistance (PVR) ≥3 Wood Units was also proposed, placing greater emphasis on an elevated PVR to identify pulmonary vascular disease. Here, we discuss the possible impact of the revised definition of PH on future clinical management. This change may facilitate earlier PH detection, particularly in at-risk patient groups that are already undergoing screening programmes, e.g. those with systemic sclerosis or mutations associated with PH. As an mPAP above the upper limit of normal (>20 mmHg) but <25 mmHg is associated with increased risk of morbidity and mortality compared with a normal mPAP, early identification of patients in this group is important to enable close monitoring and timely treatment initiation once clinically indicated. Treatments currently approved for PH are not necessarily suitable for patients with an mPAP 21-24 mmHg, as the management of this group has not been widely examined. The revised definition may facilitate inclusion of these patients in prospective trials, allowing the evaluation of appropriate management strategies.
Background:
The World Symposium on Pulmonary Hypertension (WSPH) in 2018 recommended new definitions of pulmonary hypertension (PH). We investigated the impact of the updated definition on prevalence ...of PH due to left heart disease (PH-LHD).
Methods:
The data of right heart catheterizations in patients with suspected PH-LHD between January 2008 and July 2015 was retrospectively analyzed applying different definitions. The number of patients diagnosed by the updated WSPH hemodynamic criteria of a mean pulmonary artery pressure (mPAP) > 20 mmHg was compared to the number of patients using mPAP ≥ 25 mmHg. The differentiation between patients with isolated post-capillary (Ipc) and combined post-capillary and pre-capillary (Cpc) PH was analyzed comparing the ESC/ERS guidelines, the recommendation of Cologne Consensus Conference (CCC) and WSPH.
Results:
Of the 726 patients with a suspected PH, 58 patients met the diagnostic criteria of the ESC/ERS guidelines for PH-LHD with 32.8% Ipc-cases, 34.4% Cpc-PH-cases and 32.8% unclassifiable cases. Overall, 58 patients were diagnosed by the CCC criteria, with 34.5% classified as Cpc-PH and 65.5% as Icp-PH. Using the criteria of WSPH, the number of PH-LHD rose by one patient. According to the new definition, 64.4% of the patients were classified as Cpc-PH and had a significantly higher right to left atrial area (RA/LA) ratio than Ipc-PH patients.
Conclusion:
Applying the new recommendation, the number of diagnosed patients with PH-LHD increases marginally. There is, however, a relevant shift in the number of Cpc-PH cases. An elevated RA/LA ratio might help to identify patients for invasive diagnostic work-up.
•The updated hemodynamic definition did have minor impact on the number of PH-LHD.•The use of DPG in the definition of PH-LHD underestimated the number of Cpc-PH cases.•The updated hemodynamic definition causes a shift in the number of Cpc-PH cases.•Cpc-PH group showed a significantly higher right to left atrial area (RA/LA)-ratio.
The classic definition of pulmonary arterial hypertension (PAH) is a mean pulmonary artery pressure (mPAP) of 20 mmHg. The gold standard for assessing pulmonary hemodynamics is right heart ...catheterization (RHC), which is necessary to confirm the diagnosis of PH. In some instances, RHC evaluates the degree of hemodynamic dysfunction and performs vasoreactivity tests. Measurement of the hepatic venous pressure gradient remains the gold standard diagnostic for identifying portal hypertension. This review aims to describe the procedure of RHC and the hemodynamic measurement in patients with PAH and Portopulmonary hypertension (PoPH). The RHC remains the gold standard for diagnosing PAH and PoPH.
Pulmonary hypertension (PH) is a highly prevalent and important condition in adults with chronic kidney disease (CKD). In this review, we summarize the definition of PH, discuss its pathophysiology ...and classifications, and describe diagnostic and management strategies in patients with CKD, including those with kidney failure treated by kidney replacement therapy. In the general population, PH is classified into 5 groups based on clinical presentation, pathology, hemodynamics, and management strategies. In this classification system, PH in CKD is placed in a diverse group with unclear or multifactorial mechanisms, although underlying cardiovascular disease may account for most cases. CKD may itself directly incite pulmonary circulatory dysfunction and remodeling through uremic toxins, inflammation, endothelial dysfunction, and altered vasoregulation. Despite several studies describing the higher prevalence of PH in CKD and kidney failure, along with an association with poor outcomes, high-quality evidence is not available for its diagnostic and management strategies in those with CKD. In CKD not requiring kidney replacement therapy, volume management along with treatment of underlying risk factors for PH are critical. In those receiving hemodialysis, options are limited and transition to peritoneal dialysis may be considered if recurrent hypotension precludes optimal volume control.
The development of pulmonary arterial hypertension (PAH) can complicate many interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). We sought to characterize the prevalence of PAH ...and its impact on survival in patients with advanced IPF.
Retrospective analysis of consecutive IPF patients undergoing pretransplantation right heart catheterization.
Lung transplant and IPF referral center.
PAH was defined as a mean pulmonary artery pressure (mPAP) of > 25 mm Hg. We compared demographic, spirometric, 6-min walk test (6MWT) results, and survival outcomes between those with PAH and those without PAH.
Seventy-nine patients were included in the study. PAH was present in 31.6% of patients (mean ± SD mPAP, 29.5 ± 3.3 vs 19.1 ± 3.7 mm Hg, respectively). Those patients with PAH had a lower mean diffusing capacity of the lung for carbon monoxide (Dlco) (37.6 ± 11.3% vs 31.1 ± 10.1%, respectively; p = 0.04) and were more likely to require supplemental oxygen (66.7% vs 17.6%, respectively; p < 0.0001). Mean distance walked (143.5 ± 65.5 vs 365.9 ± 81.8 m, respectively; p < 0.001) and mean pulse oximetric saturation nadir (80.1 ± 3.7% vs 88.0 ± 3.5%, respectively; p < 0.001) during the 6MWT were also lower among those with PAH. PAH was associated with a greater risk of death during the study period (mortality rate, 60.0% vs 29.9%, respectively; odds ratio, 2.6; 95% confidence interval CI, 2.3 to 3.1; p = 0.001). One-year mortality rates were higher in those with PAH (28.0% vs 5.5%, respectively; p = 0.002). As a predictor of mortality, PAH had a sensitivity, specificity, and accuracy of 57.1%, 79.3%, and 73.4%, respectively. There was a linear correlation between mPAP and outcomes with higher pressures associated with a greater risk of mortality (hazard ratio, 1.09; 95% CI, 1.02 to 1.16). FVC and Dlco did not predict outcomes.
PAH is common in advanced cases of IPF and significantly impacts survival. A reduced Dlco, supplemental oxygen requirement, or poor 6-min walk performance should raise suspicion of the presence of underlying PAH. Identifying PAH might be an important adjunct in monitoring disease progression, triaging for transplantation, and guiding therapy.
Limited medical therapies have been implemented for the treatment of the devastating cardiorespiratory disease of pulmonary hypertension (PH) while none of which is sufficiently effective to stop or ...regress development of PH. We have previously shown that netrin-1, an axon-guiding protein during development, protects against ischemia reperfusion injury induced myocardial infarction via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. Since NO deficiency and oxidative stress-mediated vascular remodeling play important roles in the pathogenesis of PH, our present study investigated therapeutic effects on PH of netrin-1 and its derived small peptides. Infused into mice for 3 weeks during exposure to hypoxia, netrin-1 and netrin-1 derived small peptides V1, V2 or V3 substantially alleviated pathophysiological and molecular features of PH, as indicated by abrogated increases in mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), attenuated right ventricular hypertrophy, diminished vascular remodeling of medial thickening and upregulation in smooth muscle alpha-actin (SMA) and proliferative cell nuclear antigen (PCNA), and alleviated perivascular and peribronchial fibrosis reflected by collagen deposition. NO bioavailability was substantially improved by treatment with netrin-1 and netrin-1 derived small peptides, while hypoxia induced increases in total superoxide production and eNOS uncoupling activity were all attenuated. These dual mechanisms of increasing NO bioavailability and decreasing oxidative stress at the same time, underlie robust protective effects on PH of netrin-1 and its derived small peptides, which are different from existing medications that primarily target NO signaling alone. Our data for the first time demonstrate intriguing findings that netrin-1 and netrin-1 derived small peptides can be used as novel and robust therapeutics for the treatment of PH.
Pulmonary hypertension (PH) is a group of pulmonary vascular disorders in which mean pulmonary arterial pressure (mPAP) becomes abnormally high because of various pathological conditions, including ...remodeling of the pulmonary arteries, lung and heart disorders, or congenital conditions. Various animal models, including mouse and rat models, have been used to recapitulate elevated mPAP observed in PH patients. However, the measurement and recording of mPAP and mean systemic arterial pressure (mSAP) in small animals require microsurgical procedures and a sophisticated data acquisition system. In this paper, we describe the surgical procedures for right heart catheterizations (RHC) to measure mPAP in rats. We also explain the catheterization of the carotid artery for simultaneous measurement of mPAP and mSAP using the PowerLab Data Acquisition system. We enumerate the surgical steps involved in exposing the jugular vein and the carotid artery for catheterizing these two blood vessels. We list the tools used for microsurgery in rats, describe the methods for preparing catheters, and illustrate the process for inserting the catheters in the pulmonary and carotid arteries. Finally, we delineate the steps involved in the calibration and setup of the PowerLab system for recording both mPAP and mSAP. This is the first protocol wherein we meticulously explain the surgical procedures for RHC in rats and the recording of mPAP and mSAP. We believe this protocol will be essential for PH research. Investigators with little training in animal handling can reproduce this microsurgical procedure for RHC in rats and measure mPAP and mSAP in rat models of PH. Further, this protocol is likely to help master RHC in rats that are performed for other conditions, such as heart failure, congenital heart disease, heart valve disorders, and heart transplantation.
Pulmonary hypertension (PH) is a chronic and progressive disease. We introduced a novel automated self-organized feature engineering architecture for PH detection, which was trained and refined using ...a new thoracic CT image dataset. This study's dataset includes 807 transverse contrast-enhanced CT images from 313 patients, categorized into four groups: Group 1 with 20 mmHg ≤ mean pulmonary artery pressure (mPAP) < 25 mmHg; Group 2 with 25 mmHg ≤ mPAP ≤ 30 mmHg; Group 3 where mPAP > 30 mmHg; and a control group with no PH. Our model consists of four primary stages: (i) generation of features based on combinations from nested patches, (ii) feature selection, (iii) classification and (iv) majority voting. CT images were segmented into nested patches, each being processed through pretrained EfficientNetB0 and DenseNet201 to derive four deep feature vectors, utilizing both the global average pooling and fully connected layers of these networks. These four extracted features underwent combinatorial operations, resulting in 15 feature vectors. Subsequently, these vectors were introduced to neighborhood component analysis, ReliefF, and Chi2 feature selectors. This process yielded 45 refined feature vectors with diminished data dimensions. These selected vectors were then processed through support vector machine and k-nearest neighbors classifiers, producing 90 predictive vectors. By applying mode-based iterative majority voting to these vectors, an additional 88 voted prediction vectors were generated, leading to a total of 178 classifier-generated and voted prediction vectors. The optimal classification result was selected from these 178 vectors. With the use of 10-fold cross-validation, our model achieved a remarkable 97.27% overall accuracy for the 4-class classification on the study dataset. Owing to its reduced time complexity, this model is practical for CT-based PH screenings.
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