Risk Stratification and Prognosis of Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background:Current guidelines for managing pulmonary arterial hypertension(PAH)recommend a risk strati-fication approach.However,the applicability and accuracy of these strategies for PAH associated with congenital heart disease(PAH-CHD)require further validation.This study aims to validate the reliability and predictive accuracy of a simplified stratification strategy for PAH-CHD patients over a three-year follow-up.Additionally,new prognostic variables are identified and novel risk stratification methods are developed for assessing and managing PAH-CHD patients.Methods:This retrospective study included 126 PAH-CHD patients.Clinical and biochemical variables across risk groups were assessed using Kruskal-Wallis and Fisher’s exact tests.Indepen-dent risk factors were identified using ordered logistic regression,while Kaplan-Meier and Cox proportional hazards regression analyses evaluated their impact on all-cause mortality.A new stratification model for the PAH-CHD population was constructed based on these analyses.Results:Significant survival differences across stratified risk groups were observed(p<0.001),validating the effectiveness of the simplified risk stratification method in PAH-CHD patients.Prothrombin activity was a strong independent predictor of adverse outcomes of PAH-CHD patients(Hazard ratio 0.95,p<0.001,C-index 0.70).A model combining N-terminal pro-brain natriuretic peptide,prothrombin activity,albumin,and right atrial area achieved an area under the curve of 0.89 and a C-index of 0.85.Conclusions:The simplified risk stratification method is applicable to PAH-CHD patients.Prothrombin activity is a strong independent predictor of adverse outcomes.A comprehensive risk stratification approach,incorporating both established and novel biomarkers,enhances accessibility and offers predictive efficacy during follow-up for PAH-CHD patients,comparable to established models.

Selexipag as Add-on Therapy for Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease:A Single-Center Retrospective Study

Purpose:This study examined the efficacy and safety of selexipag in treating pulmonary arterial hypertension(PAH)associated with congenital heart disease(CHD).Materials and Methods:We conducted a retrospective study of patients with CHD-associated PAH,treated with selexipag since December 2017.Thirteen adult patients(mean age,45.4 years;women,77%)were treated with selexipag as add-on therapy.Baseline characteristics,World Health Organization functional class,6-minute walking distance(6MWD)test results,N-terminal pro-B-type natriuretic peptide levels,echocardiographic data,and incidence of side effects were assessed.Results:The majority of patients(12/13,92.3%)experienced more than one treatment-associated complication;one patient dropped out of the study due to intolerable myalgia.The results of 6MWD test(from 299.2±56.2 m to 363.8±86.5 m,p=0.039)and tricuspid regurgitation(TR)pressure gradient(from 84.7±20.5 mmHg to 61.6±24.0 mmHg,p=0.018)improved and remained improved after selexipag treatment in 12 patients.Based on the results of a non-invasive risk assessment,8(66.7%)patients showed improvement,3(25.0%)showed no interval change,and the status of one patient(8.3%)deteriorated.Moreover,compared to patients treated with a low dosage,patients treated with a medium-to-high dosage showed a greater increase in 6MWD results(88.3±26.4 m vs.55.3±27.6 m,p=0.043)and a greater reduction in the TR pressure gradient(-33.7±10.9 mmHg vs.-12.5±12.0 mmHg,p=0.015).Conclusion:Selexipag is an efficient pulmonary vasodilator as add-on therapy in treating CHD-associated PAH.

NOTCH3 Mutations and CADASIL Phenotype in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background:The etiology of pulmonary arterial hypertension associated with congenital heart disease(PAHCHD)is complicated and the phenotype is heterogeneous.Genetic defects of NOTCH3 were associated withcerebral disease and pulmonary hypertension.However,the relationship between NOTCH3 mutations and theclinical phenotype has not been reported in CHD-PAH.Methods:We eventually enrolled 142 PAH-CHD patientsfrom Fuwai Hospital.Whole exome sequencing(WES)was performed to screen the rare deleterious variants ofNOTCH3 gene.Results:This PAH-CHD cohort included 43(30.3%)men and 99(69.7%)women with the meanage 29.8±10.9 years old.The pathogenic or likely pathogenic mutations of NOTCH3 were identified in five cases.Patients 2,5,8 and 11 carried the same NOTCH3 mutation c.1630C>T(pArg544Cys),which is the hot-spotmutation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL).Patient 3 carried the NOTCH3 mutation p.Arg75Gln that has also been reported to be associatedwith the CADASIL.Patients 2,5,8,11 took the examination of the cerebral magnetic resonance imaging(MRI)and confirmed the phenotype of CADASIL.Conclusions:We first reported the NOTCH3 rare mutationsand CADASIL phenotypes in CHD-PAH patients.The NOTCH3 rare variants were with a relatively high positiverate and CADASIL phenotypes were likely enriched in PAH-CHD patients.The preoperative neurological examinationmight be recommended for PAH-CHD patients to determine the surgical contraindications and reduceintraoperative neurological complications.

Transgelin as a potential target in the reversibility of pulmonary arterial hypertension second to congenital heart disease

Background The reversibility of pulmonary arterial hypertension(PAH)in congenital heart disease(CHD)is of great importance for the operability of CHD.Proteomics analysis found that transgelin was significantly upregulated in the lung tissue of CHD-PAH patients,especially in the irreversible group.However,how exactly it participated in CHD-PAH development is unknown.

Correlation between endothelia cells activation and imbalance of cytokines in pulmonary hypertension of congenital heart disease

Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.

Pulmonary Arterial Hypertension Medical Management of the Adult Patient with Congenital Heart Disease

Congenital heart disease(CHD)-associated pulmonary arterial hypertension(PAH)includes a heterogeneous patient population that can be characterized by the underlying cardiac malformation.CHD-associated PAH has an estimated prevalence of 5– 10% in adult patients,with an increasing number of patients surviving to adulthood because of advances in the surgical management and the development of pulmonary arterial hypertension(PAH)-targeted pharmacotherapy.Although limited data exist,targeted PAH pharmacotherapy has proven to be benefi cial in patients with CHD-associated PAH,with observed improvement in functional class,increase in exercise capacity,and improvement in quality of life and cardiopulmonary hemodynamics.Additionally,there has been increasing interest in the“treat-to-close”strategy.PAH-targeted pharmacotherapy may be used to optimize cardiopulmonary hemodynamics so as to improve patients’operability in repairing the cardiac defect.Although there have been signifi cant advances in the management of this disease state in the past 2 decades,mortality remains high,and ongoing clinical trials are needed to better understand the treat-to-close strategy.

Perioperative Nursing for Adult Congenital Heart Disease with Severe Pulmonary Arterial Hypertension

Objectives: To explore the main points of perioperative nursing for adult congenital heart disease with severe pulmonary arterial hypertension. Methods: A retrospective study of 13 patients with congenital heart disease and severe pulmonary arterial hypertension who admitted to the perioperative period of care from January 2018 to December 2019. To prevent perioperative complications of the patients, the focus is on respiratory and circulatory system care, followed by blood coagulation monitoring, digestive system protection and psychological care. Results: All 13 patients passed the perioperative period and were discharged from ICU. Conclusion: Adult congenital heart disease with severe pulmonary arterial hypertension has high perioperative risk, respiratory and circulatory system care is the key.

Plasma HGF and OPN as Potential Biomarkers of Pulmonary Arterial Hypertension in Congenital Heart Disease

Objectives:Pulmonary arterial hypertension in congenital heart disease(PAH-CHD)is the most common type of PAH and increases morbidity and mortality in patients with CHD.Right heart catheterization(RHC)is the standard method to diagnose PAH.However,RHC is an invasive and complicated method with relatively high cost.Noninvasive,feasible,and cost-efficient methods are urgently needed.The objective of this study was to evaluate three potential biomarkers of PAH-CHD:Hepatocyte growth factor(HGF),osteopontin(OPN),and suppression of tumorigenicity 2(ST2).Methods:Plasma samples were collected from patients with CHD(n=46)and healthy individuals(n=22)and divided into four groups according to the severity of PAH.The levels of HGF,OPN,and ST2 were then analyzed using an enzyme-linked immunosorbent assay.Correlations between HGF,OPN,ST2,and clinical parameters of PAH-CHD were analyzed.Results:The plasma HGF levels in the moderate to the severe group were significantly higher than those in the mild group,nonPAH group,and healthy control group(p<0.05).Derived from a receiver operating characteristic(ROC)curve analysis,a cut-off value of 356.75 ng/ml for the HGF concentration was able to predict PAH-CHD with 53%sensitivity and 89%specificity.The HGF level was positively related to pulmonary arterial systolic pressure(PASP)(r=0.36,p<0.05)and pulmonary vascular resistance(PVR)(r=0.36,p<0.05).Plasma OPN levels in the mild group were significantly higher than other groups and positively correlated with the pulmonary-systemic shunt ratio(Qp/Qs)(r=0.33,p<0.05).There was no statistically significant between-group difference in plasma soluble ST2(sST2)levels.Conclusion:The plasma HGF level was elevated in PAH-CHD patients and can be used as a potential biomarker.The plasma OPN level was positively correlated with the Qp/Qs.

Clinical Effect of an Improved Post-Operative Feeding Protocol“in Transition”Infants of Congenital Heart Disease with Pulmonary Hypertension

Background:To achieve successful management of infants with congenital heart disease(CHD)together with pulmonary hypertension(PH),postoperative care,especially feeding care is vital in addition to surgery.Postoperative feeding is comprised of three stages:feeding in the intensive care unit,feeding in the general ward and family feeding,in which the general ward is considered as the“transitional stage”.At present,there is little research on the optimal mode of feeding care for the transitional stage,and there is no universally recognized and accepted protocol.Methods:We retrospectively analyzed 114 CHD infants with PH who underwent family-centered(FC)feeding care from July 2017 to December 2018,and prospectively studied 122 CHD infants with the same baseline level who adopted the improved mode,nurse-parent-driven(NPD)feeding mode from January 2019 to June 2020.The feasibility and efficacy of NPD as a“transitional”feeding nursing mode in CHD infants with PH were compared with the FC cohort by observing and analyzing the stress of family caregivers,feedingrelated complications,the proportion of breastfeeding,improvement of nutritional status,acquisition of knowledge and skills of feeding care,inpatient’s satisfaction rating and prognosis.Results:When compared with the FC feeding care,the NPD mode significantly reduced the burden of family caregivers,improved the rate of feeding care knowledge and skills and inpatient’s satisfaction rating,reduced the incidence of improper feeding-related complications,and enhanced the proportion of breastfeeding and nutritional status of infants at the“transitional stage”(all P<0.05).The self-assessment score of care ability of family caregivers and weight gain of children in the NPD group were significantly higher than those in the FC group(all P<0.05)during the follow-up.Conclusions:As a transitional mode of feeding in CHD infants with PH,NPD feeding care is superior to the conventional FC mode,which therefore can be adopted as a standard protocol in clinical practice.

Assessment of Reversibility in Pulmonary Hypertension Related to Congenital Heart Disease by Using Biomarkers and Clinical Features

Background:Reversibility of pulmonary hypertension(PH)is closely related to the treatment options for and prognosis of children with congenital heart disease.Objective:We combined patient-specific clinical features including diagnosis,age and echocardiographic results,and biomarkers of pulmonary vascular dysfunction to explore the noninvasive methods that can be used to accurately evaluate the reversibility of pulmonary hypertension in congenital heart disease(PH-CHD).Methods:Based on the preoperative systolic pulmonary arterial pressure(sPAP),70 CHD patients were divided into normal,PH-CHD suspected,and confirmed groups.Additionally,biomarkers of circulating endothelial cells(CECs),endothelin-1(ET-1),and endothelial nitric oxide synthase(eNOS)were detected.Patients were categorized into reversible(RPH)and irreversible(IRPH)groups according to the sPAP 6 months after surgery.Risk stratification was performed according to the clinical features and biomarkers.Results:CECs and ET-1 levels in the confirmed group were significantly higher.eNOS was higher in the confirmed and suspected groups than that in the normal group.CECs in the IRPH group were significantly higher compared to the RPH group.No such intergroup differences were observed with respect to ET-1 and eNOS levels.The ROC curve showed that the risk stratification was of high diagnostic value to evaluate reversibility.Conclusion:The CECs,eNOS,and ET-1 were closely related with PH-CHD.CECs and risk stratification have high practical value in assessing the reversibility of PH-CHD.

Development of pulmonary hypertension remains a major hurdle to corrective surgery in Down syndrome

Down syndrome is the most common chromosomal abnormality encountered in clinical practice with 50%of them having associated congenital heart disease(CHD).Shunt lesions account for around 75%of all CHDs in Down syndrome.Down syndrome patients,especially with large shunts are particularly predisposed to early development of severe pulmonary hypertension(PH)compared with shunt lesions in general population.This necessitates timely surgical correction which remains the only viable option to prevent long term morbidity and mortality.However,despite clear recommendations,there is wide gap between actual practice and fear of underlying PH which often leads to surgical refusals in Down syndrome even when the shunt is reversible.Another peculiarity is that Down syndrome patients can develop PH even after successful correction of shunt.It is not uncommon to come across Down syndrome patients with uncorrected shunts in adulthood with irreversible PH at which stage intracardiac repair is contraindicated and the only option available is a combined heartlung transplant.However,despite the guidelines laid by authorities,the rates of cardiac transplant in adult Down syndrome remain dismal largely attributable to the high prevalence of intellectual disability in them.The index case presents a real-world scenario highlighting the impact of severe PH on treatment strategies and discrimination driven by the fear of worse outcomes in these patients.

Congenital heart“Challenges”in Down syndrome

In this editorial,we comment on the article by Kong et al published in the recent issue of the World Journal of Cardiology.In this interesting case,the authors present the challenges faced in managing a 13-year-old patient with Down syndrome(DS)and congenital heart disease(CHD)associated with pulmonary arterial hypertension.In this distinct population,the Authors underscore the need for early diagnosis and management as well as the need of a multidisciplinary approach for decision making.It seems that the occurrence of CHD in patients with DS adds layers of complexity to their clinical management.This editorial aims to provide a comprehensive overview of the intricate interplay between DS and congenital heart disorders,offering insights into the nuanced diagnostic and therapeutic considerations for physicians.

Treatment of patients with bosentan in postoperation of congenital heart disease with pulmonary arterial hypertension:a double-blind,randomized controlled trial

Objective Endothelin is a key role in the pathogenic of pulmonary arterial hypertension. High concentrations of endothelin 1 have been recorded in plasma and lungs of patients with pulmonary artery hypertension associated with congenital heart disease,and the concentrations of endothelin-1 was correlated with severity degree

Twin pregnancy with sudden heart failure and pulmonary hypertension after atrial septal defect repair: A case report

BACKGROUND Pulmonary arterial hypertension(PAH)in pregnancy is one of the major obstetric complications and is considered a contraindication to pregnancy as it is classified as a class IV risk in the revised risk classification of pregnancy by the World Health Organisation.Pregnancy,with its adaptive and expectant mechanical and hormonal changes,negatively affects the cardiopulmonary circulation in pregnant women.Do patients with repaired simple congenital heart disease(CHD)develop other pulmonary and cardiac complications during pregnancy?Can pregnant women with sudden pulmonary hypertension be treated and managed in time?In this paper,we present a case of a 39-year-old woman who underwent cesarean section at 33 wk'gestation and developed PAH secondary to repaired simple CHD.Our research began by a PubMed search for"pulmonary hypertension"and"pregnancy"and"CHD"case reports.Three cases were selected to review PAH in pregnancy after correction of CHD defects.These studies were reviewed,coupled with our own clinical experience.CASE SUMMARY Herein,a case involving a woman who underwent atrial septal defect repair at the age of 34,became pregnant five years later,and had a sudden onset of PAH and right heart failure secondary to symptoms of acute peripheral edema in the third trimester of her pregnancy.As a result,the patient underwent a cesarean section and gave birth to healthy twins.Within three days after cesarean delivery,her cardiac function deteriorated as the pulmonary artery pressure increased.Effec-tive postpartum management,including diuresis,significant oxygen uptake,vasodilators,capacity and anticoagulants management,led to improvements in cardiac function and oxygenation.The patient was discharged from hospital with a stable recovery and transferred to local hospitals for further PAH treatment.CONCLUSION This case served as a reminder to obstetricians of the importance of pregnancy after repair of CHD.It is crucial for patients with CHD to receive early correction.It suggests doctors should not ignore edema of twin pregnancy.Also,it provides a reference for the further standardization of antenatal,in-trapartum and postpartum management for patients with CHD worldwide.

Bosentan Is Associated with a Reduction in Right Ventricular Systolic Pressure N-Terminal Pro-Hormone B-Type Natriuretic Peptide Levels in Young Patients with Pulmonary Hypertension

Pulmonary hypertension is a rare and potentially fatal disease in children if left untreated. Emerging therapies, including Bosentan, a dual endothelin receptor antagonist, have shown significant benefits in the adult pulmonary hypertension population;however, few studies have assessed the efficacy and safety of endothelin receptor antagonists in infants and young children. Our study was a single-center retrospective analysis of patients less than two years of age with a confirmed diagnosis of pulmonary hypertension and initiated on Bosentan therapy between 2017 and 2020. Twelve cases met eligibility criteria. Demographic data, laboratory data, echocardiographic, and cardiac catheterization data were analyzed. With treatment, there was a statistically significant decrease in mean right ventricular systolic pressure estimated by the tricuspid regurgitation jet (79 ± 23 mmHg reduced to 52 ± 25 mmHg;p < 0.001) N-terminal pro-hormone B-type natriuretic peptide levels (21,071 reduced to 2,037;p < 0.001). Additionally, improvement and eventual normalization of right ventricular function and septal geometry was seen within the first four months of therapy. Patients who underwent cardiac catheterization after therapy initiation (n = 4) demonstrated hemodynamic improvements;however, only the decrease in diastolic pulmonary artery pressure was statistically significant (p = 0.018). No significant differences in hemoglobin, platelet count, or liver function tests were observed between groups. In conclusion, these data suggest that Bosentan may be an effective and relatively safe treatment option for children less than two years of age with pulmonary hypertension. Further long-term randomized control studies are necessary to validate the potential clinical benefit of utilizing this drug therapy in young children.

Animal models of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease(PH-LHD) is regarded as the most prevalent form of pulmonary hypertension(PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease(LHD). Clinically, there are no drugs or treatments that directly address PH-LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH-LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH-LHD are required. There are several available models for PH-LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH-LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH-LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH-LHD. Therefore, this review will summarize the characteristics of each PH-LHD animal model and discuss the advantages and limitations of the different models.

Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease

BACKGROUND Despite major advances in pharmacologic treatment,patients with pulmonary arterial hypertension(PAH)still have a considerably reduced life expectancy.In this context,chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH,thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.AIM To evaluate the application and prognostic effect of neurohormonal inhibitors(NEUi)in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.METHODS We analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1,2005 to October 31,2018.Patients on beta-blocker,angiotensin-converting enzyme inhibitor,angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi nonrecipients.RESULTS Complete data were available for 57 PAH subjects:27 of those(47.4%)were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients.NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients.Additionally,NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients(56.7%vs 25.9%,log-rank P=0.020).CONCLUSION The above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival.Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

CORRELATION OF vWF： Ag LEVELS WITH PULMONARY HYPERTENSION IN CONGENITAL HEART DEFECTS

vWF: Ag is an important factor reflecting the injury of pulmonary vascular endothelium. We measured plasma concentrations of vWF: Ag in 89 patients with congenital heart defects (left to right shunting) by quantitative immunoelectrophoresis and assessed endothelial vWF: Ag directly by an immunoperoxidase stain applied io lung biopsy tissue in 10 patients. The patients with pulmonary hypertension had significanthigher vWF: Ag levels, the elevation was associated with the elevation of PVR (P<0.01). The vWF: Ag levels varied directly with PVR and PAR (r=0.89, 0.82, P<0.05).The regression equations of vWF: Ag-PVR. vWF: Ag-PAR we made cam help us to estimate PVR noninvasiverly. Our study will provide us a theoretical basis to choose an appropriate occasion for corrective suryery.

The Potential of Circular RNAs as Biomarkers in Pulmonary Arterial Hypertension Related to Congenital Heart Disease

A particular type of endogenous noncoding RNAs known as circular RNAs(circRNAs)has now become possible biomarkers for several diseases because of their stability and tissue-specific expression patterns.CircRNAs might play a role in various of biological processes.The identification of particular circRNAs dysregulated in pulmonary arterial hypertension(PAH)raises the possibility of these molecules serving as biomarkers for the disease’s early diagnosis and treatment.This review mainly summarizes the role and potential of circRNA as a future biomarker in PAH related to congenital heart disease.This study presented several potential circRNA targets as diagnostic biomarkers for PAH,discussed their biological functions,and addressed the challenges that need to be considered for their application in clinical settings.