Intravesical nerve growth factor antisense therapy for bladder hypersensitivity induced by psychological stress.

This study assessed the relationship between NGF expression in the bladder and bladder hypersensitivity caused by psychological stress using water avoidance stress (WAS) in rats by modulating the NGF expression using intravesical liposome-complexed NGF antisense oligonucleotide (OND) therapy on WAS-induced bladder dysfunction. Female Wistar rats were divided into control and WAS groups, the latter of which received WAS sessions for 10 days with or without the OND pretreatment. Rats underwent cystometry with or without intravesical application of low-dose protamine sulfate (LD-PS), or pain behavior measurements after LD-PS application. After functional evaluations, the bladder was harvested for histology and molecular studies. WAS rats with or without LD-PS showed shortened intercontraction intervals and increased pain behaviors compared to control rats, which was improved by OND-treatment. Histological studies revealed that LD-PS provoked urothelial exfoliation in WAS rats. Compared to controls, protein assay showed increased NGF levels, and RT-PCR showed increases of TRPV1 and TRPA1 and a decrease in Cx43 in WAS rat bladders, which were improved by OND-treatment. WAS caused bladder hypersensitivity, which was improved by NGF antisense OND treatment. NGF upregulation in the bladder may be a therapeutic target for the treatment of psychological stress-induced bladder dysfunction.

Case-control study of IL23R rs76418789 polymorphism, smoking, and ulcerative colitis in Japan.

BACKGROUND: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. METHODS: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. RESULTS: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. CONCLUSION: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

Sexual Dimorphism of Spinal Neural Circuits Controlling the Mouse External Urethral Sphincter With and Without Spinal Cord Injury.

Spinal cord injury (SCI) disrupts coordination between the bladder and the external urinary sphincter (EUS), leading to transient or permanent voiding impairment, which is more severe in males. Male versus female differences in spinal circuits related to the EUS as well as post-SCI rewiring are essential for understanding of sex-/gender-specific impairments and possible recovery mechanisms. To quantitatively assess differences between EUS circuits in males versus females and in spinal intact (SI) versus SCI animals, we retrogradely traced and counted EUS-related neurons. In transgenic ChAT-GFP mice, motoneurons (MNs), interneurons (INs), and propriospinal neurons (PPNs) were retrogradely trans-synaptically traced with PRV614-red fluorescent protein (RFP) injected into EUS. EUS-MNs in dorsolateral nucleus (DLN) were separated from other GFP+ MNs by tracing them with FluoroGold (FG). We found two morphologically distinct cell types in DLN: FG+ spindle-shaped bipolar (SB-MNs) and FG- rounded multipolar (RM-MNs) cholinergic cells. Number of MNs of both types in males was twice as large as in females. SCI caused a partial loss of MNs in all spinal nuclei. After SCI, males showed a fourfold rise in the number of RFP-labeled cells in retro-DLN (RDLN) innervating hind limbs. This suggests (a) an existence of direct synaptic interactions between spinal nuclei and (b) a post-SCI increase of non-specific inputs to EUS-MNs from other motor nuclei. Number of INs and PPNs deferred between males and females: In SI males, the numbers of INs and PPNs were ∼10 times larger than in SI females. SCI caused a twofold decrease of INs and PPNs in males but not in females.

Water-avoidance stress aggravates prostatic inflammation in a murine model of chronic prostatitis.

OBJECTIVES: To date, few studies have considered the influence of psychological factors on chronic prostatitis (PRO) models. Here, we aimed to refine a murine PRO model combining chemically induced prostatitis with psychological stress. METHODS: A total of 40 mice were randomly divided into four groups: normal control (NC) group, PRO group, water avoidance stress (WAS) group, and PRO + WAS group. Ten mice were assigned to each group: five for cystometrograms (CMGs) and five for von Frey testing and histological analysis. PRO was induced through a prostatic injection of 10% paraformaldehyde. The WAS mice were placed on the middle platform for 1 h per day for 10 consecutive days. RESULTS: The results of the von Frey test demonstrated that both WAS and PRO induced bladder hyperalgesia in mice, and the WAS + PRO group showed significant pelvic pain symptoms either. The CMG results suggested that the PRO group, the WAS group, and the PRO + WAS group all exhibited bladder overactivity, presented as a shortened micturition interval and decreased threshold pressure evoking bladder contraction. The symptoms of the PRO group and the PRO + WAS group were more severe than those of the WAS group. The tissue staining results indicated that WAS itself caused only mild prostatic inflammation but could significantly aggravate chemical-induced prostatic inflammation, as well as the total number of mast cells and proportion of activated mast cells. CONCLUSIONS: Our refined murine PRO model could manifest persistent bladder overactivity, pelvic hyperalgesia and prostatic inflammation. WAS could induce mild prostatic inflammation and aggravate primary prostatic inflammation.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

Primary obsessive slowness in a young woman who benefited from continuous psychoeducation and modeling with video recordings during hospitalization: a case report.

BACKGROUND: Obsessive slowness, a symptom of obsessive-compulsive disorder (OCD), is characterized by compulsive behavior and significant slowness of movement. Primary obsessive slowness (POS) is defined as a condition in which a series of actions are segmented, and the patient spends an unlimited amount of time performing each action while checking each action, resulting in cessation or slowness of movement. It is often difficult to treat POS with exposure and response prevention, which is considered effective in general OCD, and no treatment has been established. Here, we discuss the effectiveness of psychoeducation and modeling using video recordings in the treatment of POS. CASE PRESENTATION: We report a case of POS in a 19-year-old woman. Each action was subdivided and ordered, and the patient could not proceed to the next action without confirming that the previous step had been performed. Therefore, she could not live her daily life independently; for instance, toileting and bathing required more than 1 h, even with assistance. After more than 5 months of long-term treatment, including pharmacotherapy, psychoeducation, and modeling with video recordings, she recovered to live her daily life independently. CONCLUSION: Psychoeducation and behavioral therapy can effectively treat POS. Particularly, modeling with video recordings would be an easy-to-use option for POS treatment.

Quantifying Smooth Muscles Regional Organization in the Rat Bladder Using Immunohistochemistry, Multiphoton Microscopy and Machine Learning.

The smooth muscle bundles (SMBs) in the bladder act as contractile elements which enable the bladder to void effectively. In contrast to skeletal muscles, these bundles are not highly aligned, rather they are oriented more heterogeneously throughout the bladder wall. In this work, for the first time, this regional orientation of the SMBs is quantified across the whole bladder, without the need for optical clearing or cryosectioning. Immunohistochemistry staining was utilized to visualize smooth muscle cell actin in multiphoton microscopy (MPM) images of bladder smooth muscle bundles (SMBs). Feature vectors for each pixel were generated using a range of filters, including Gaussian blur, Gaussian gradient magnitude, Laplacian of Gaussian, Hessian eigenvalues, structure tensor eigenvalues, Gabor, and Sobel gradients. A Random Forest classifier was subsequently trained to automate the segmentation of SMBs in the MPM images. Finally, the orientation of SMBs in each bladder region was quantified using the CT-FIRE package. This information is essential for biomechanical models of the bladder that include contractile elements.

Probiotics may alleviate intestinal damage induced by cardiopulmonary bypass in children.

OBJECTIVES: Intestinal ischaemia-reperfusion injury induced by cardiopulmonary bypass causes intestinal epithelial barrier dysfunction, leading to dysbiosis and bacterial translocation. We conducted a randomized prospective study with 2 objectives: (i) to investigate epithelial barrier dysfunction and bacterial translocation induced by cardiopulmonary bypass and changes in the gut microbiota and (ii) to verify whether probiotics can improve these conditions. METHODS: Between 2019 and 2020, patients 0-15 years old scheduled to undergo cardiac surgery using cardiopulmonary bypass were enrolled and randomly allocated to 2 groups: the intervention group received probiotics and the control group did not receive probiotics. We analysed the microbiota in faeces and blood, organic acid concentrations in faeces, plasma intestinal fatty acid-binding protein and immunological responses. RESULTS: Eighty-two patients were enrolled in this study. The characteristics of the patients were similar in both groups. The total number of obligate anaerobes was higher in the intervention group than in the control group after postoperative day 7. We identified 4 clusters within the perioperative gut microbiota, and cluster changes showed a corrective effect of probiotics on dysbiosis after postoperative day 7. Organic acid concentrations in faeces, incidence of bacterial translocation, intestinal fatty acid-binding protein levels and immunological responses, except for interleukin -17A, were not markedly different between the 2 groups. CONCLUSIONS: Administration of probiotics was able to correct dysbiosis but did not sufficiently alleviate the intestinal damage induced by cardiopulmonary bypass. More effective methods should be examined to prevent disturbances induced by cardiac surgery using cardiopulmonary bypass. CLINICAL TRIAL REGISTRATION NUMBER: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037174 UMIN000035556.

Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including ß3-Adrenoceptor Agonists -Basic Research Perspectives.

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. ß3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a ß3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial ß3-AR.

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury.

AIMS: Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). METHODS: Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. RESULTS: In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. CONCLUSIONS: MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.

Review: Lower urinary tract dysfunction in animal models of Parkinson's disease (PD): Translational aspects for the treatment of PD patients with overactive bladder.

Although the loss of dopaminergic neurons in the substantia nigra and consequent motor symptoms are the hallmarks of Parkinson's disease (PD), several non-motor symptoms may appear prior to these typical motor symptoms. While a variety of non-motor symptoms have emerged as the primary predictor of PD patients' quality of life, even though motor symptoms are undoubtedly distressing. According to a study, the prevalence of lower urinary tract symptoms (LUTS) varies between 27% and 64%, suggesting that PD-related lower urinary tract dysfunction may be affected by the disease stage, the presence of concomitant conditions affecting the lower urinary tract, and other autonomic dysfunctions. Animal models can serve as a platform for research into the causes of PD-related dysfunction and the evaluation of cutting-edge therapeutic approaches although the majority of animal research have been directed toward motor symptoms of PD. At present, the cause of lower urinary tract dysfunction in PD has not been fully clarified although the increasing evidence showing the multiple mechanisms underlying PD-related LUTS has emerged. In this chapter we summarize the findings of basic research in the studies of the lower urinary tract dysfunction using with different animal PD models and we try to shed light on the translational aspects for the development of future treatment modalities in PD patients with LUTS.

Sex differences in lower urinary tract function in mice with or without spinal cord injury.

OBJECTIVES: We examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI). METHODS: SCI was induced by Th8-9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6-S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme-linked immunosorbent assay. RESULTS: Sex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice. CONCLUSIONS: We demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6-S1 DRG and NGF in the bladder could be involved in SCI-induced lower urinary tract dysfunction in both sexes of mice.

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

[Postoperative Management for Severe Pulmonary Hypertension Associated with Congenital Heart Disease].

Preoperative and postoperative management in patients with pulmonary hypertension associated with congenital heart disease is improving by understanding of pathophysiology of pulmonary arterial hypertension (PAH) and several types of pulmonary vasodilators. While the irreversible PAH in untreated lesions has become rare in Japan, persisting/progressive PAH even after timely surgery remain challenging. To optimize preoperative and postoperative management in patients with PAH associated with congenital heart disease, adequate indication and treatment algorithms should be constructed.