Current Management and Future Directions for Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.
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SUBMITTER: Mahmoud AK
PROVIDER: S-EPMC10817644 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
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Current Management and Future Directions for Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.
Mahmoud Ahmed K AK Abbas Mohammed Tiseer MT Kamel Moaz A MA Farina Juan M JM Pereyra Milagros M Scalia Isabel G IG Barry Timothy T Chao Chieh-Ju CJ Marcotte Francois F Ayoub Chadi C Scott Robert L RL Majdalany David S DS Arsanjani Reza R
Journal of personalized medicine 20231220 1
Current management of patients with congenital heart disease has increased their survival into adulthood. This is accompanied by potential cardiac complications, including pulmonary hypertension associated with congenital heart disease (PAH-CHD). PAH-CHD constitutes a challenging subgroup of pulmonary hypertension and requires expert management to improve quality of life and prognosis. Novel agents have shown a significant improvement in morbidity and mortality in patients with pulmonary arteria ...[more]
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Project description:ObjectiveThe Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, double-blind, placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies.MethodsIn PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect.ResultsIn PATENT-1, riociguat increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (-250±410 vs -66±632 dyn·s/cm(5)), NT-proBNP (-164±317 vs -46±697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years.ConclusionsRiociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP.Trial registration numberThe clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2.
| S-EPMC4680166 | biostudies-literature
Project description:During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.
| S-EPMC4452016 | biostudies-literature
Project description:Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) has serious consequence and plasma protein profiles in CHD-PAH are unknown. We aimed to reveal the differential plasma proteins in 272 CHD patients with or without PAH. Various types of CHD-PAH were studied. Differential plasma proteins were first detected by iTRAQ proteomic technology and those with significant clinical relevance were selected for further ELISA validation in new cohort of patients. Among the 190 differential plasma proteins detected by iTRAQ, carbamoyl-phosphate synthetase I (CPSI, related to urea cycle and endogenous nitric oxide production) and complement factor H-related protein 2 (CFHR2, related to complement system and coagulant mechanism) were selected for further ELISA validation in new cohort of 152 patients. Both CPSI and CFHR2 were down-regulated with decreased plasma levels (p < 0.01). Thus, we for the first time in CHD-PAH patients identified a large number of differential plasma proteins. The decreased CPSI expression in CHD-PAH patients may reveal a mechanism related to endogenous nitric oxide and the decrease of CFHR2 protein may demonstrate the deficiency of the immune system and coagulation mechanism. The findings may open a new direction for translational medicine in CHD-PAH with regard to the diagnosis and progress of the disease.
| S-EPMC5122864 | biostudies-literature
Project description:With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267; p = 0.00799). Sensitivity analyses including various cis-SNPs, provided consistent estimates for S100A3 (inverse variance weighted (IVW) OR: 0.085, 95% CI: 0.032-0.225; p = 7.5 × 10-7 and MR-Egger OR: 0.212, 95% CI: 0.013-3.376; p = 0.387). Colocalization analyses confirmed a shared genetic signal for S100A3 and PAH, with a posterior probability of 99.9%. Transcriptomic investigations further highlighted S100A3's protective role in CHD-PAH. Our study using SMR and GEO data identified S100A3 as a gene associated with a reduced risk of PAH in CHD patients. Elevated circulating levels of S100A3 were linked to a reduced PAH risk, and transcriptomic evidence further supported its protective function in CHD-PAH.
| S-EPMC11878227 | biostudies-literature
Project description:Background: As the most common types of pulmonary arterial hypertension (PAH) in childhood, the similarities and differences in clinical characteristics and prognosis between idiopathic PAH (IPAH) and PAH associated with congenital heart disease (PAH-CHD) are not well-known. This study describes and compares clinical features of pediatric IPAH and PAH-CHD in a single center of China during an 11-year period and explores the prognostic factors. Methods: Twenty-five children with IPAH and 60 children with PAH-CHD, diagnosed in West China Second Hospital of Sichuan University from January 2008 to December 2018, were chosen as study objects. The follow-up deadline was June 2019, and the end-point was all-cause death. The baseline data, results of auxiliary examinations, treatment strategies, and follow-up outcomes were recorded and compared between IPAH and PAH-CHD patients to explore the similarities, differences, and prognostic factors. Results: The median diagnostic age for PAH-CHD patients was 2.3 years, which was younger than IPAH patients (7.3 years; p = 0.009). Sixty-eight percent of the IPAH patients presented with exercise-induced symptoms at initial diagnosis, whereas 58.3% of the PAH-CHD patients were asymptomatic (p < 0.001). Sixty percent of the IPAH patients were in World Health Organization-functional class (WHO-FC) III or IV, which was significantly worse than those of the PAH-CHD patients (p = 0.002). The incidence of ST-segment and T-wave (ST-T) change in children with IPAH (76.0%) was significantly higher than that (28.3%) in children with PAH-CHD (p < 0.001). Mean corpuscular volume (MCV), mean platelet volume (MPV), and platelet distribution width were larger in IPAH patients than those in PAH-CHD patients (p < 0.01). The 1-, 3-, and 5-year survival rates of IPAH and PAH-CHD patients were 53.5, 46.5, and 31.2% and 96.5, 93.1, and 77.6%, respectively (p < 0.05). WHO-FC III-IV [relative risk (RR) = 2.750, p = 0.008] and higher MPV (RR = 1.657, p = 0.006) predicted poor prognosis for pediatric PAH. Conclusion: We showed that there are more differences than similarities between IPAH and PAH-CHD patients in clinical characteristics. PAH-CHD patients have a better prognosis than IPAH patients. WHO-FC III-IV and higher MPV at initial diagnosis are independent risk factors for poor prognosis.
| S-EPMC7137755 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a serious complication of congenital heart disease (CHD). Without early surgical repair, around one-third of paediatric CHD patients develop significant PAH. Recent data from the Netherlands suggest that >4% of adult CHD patients have PAH, with higher rates in those with septal defects. A spectrum of cardiac defects is associated with PAH-CHD, although most cases develop as a consequence of large systemic-to-pulmonary shunts. Eisenmenger's syndrome, characterised by reversed pulmonary-to-systemic (right-to-left) shunt, represents the most advanced form of PAH-CHD and affects as many as 50% of those with PAH and left-to-right shunts. It is associated with the poorest outcome among patients with PAH-CHD. 40 yrs ago, ∼50% of children with CHD requiring intervention died within the first year, and <15% survived to adulthood. Subsequent advances in paediatric cardiology have seen most patients with CHD survive to adulthood, with resulting shifts in the demographics of CHD and PAH-CHD. The number of adults presenting with CHD is increasing and, although mortality is decreasing, morbidity is increasing as older patients are at increased risk of arrhythmia, heart failure, valve regurgitation and PAH. Data show that probability of PAH increases with age in patients with cardiac defects.
| S-EPMC9487491 | biostudies-literature
Project description:BackgroundPulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.MethodsTo identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene.ResultsWe identified SOX17 as a novel candidate risk gene (p = 5.5e-7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases.ConclusionsThese data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.
| S-EPMC6054746 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.
| S-EPMC10349598 | biostudies-literature
Project description:BackgroundPulmonary arterial hypertension (PAH) is a common complication among patients with congenital heart disease (CHD). Despite advances in PAH treatment, evidence for the benefits of PAH therapies in CHD-PAH is limited.ObjectivesThis analysis aimed to evaluate outcomes in patients with repaired PAH-CHD receiving an approved PAH drug.MethodsThis was a pooled analysis including CHD-PAH patients whose CHD was repaired ≥1 year prior from 3 randomized, placebo-controlled, event-driven studies: GRIPHON (NCT01106014), SERAPHIN (NCT00660179), and COMPASS-2 (NCT00303459). The primary endpoint was time to first confirmed morbidity/mortality (M/M) event. HRs with 95% CIs were determined with random effects models.ResultsThe analysis included 1,982 patients with PAH, 177 (8.9%) with CHD-PAH. In the overall PAH cohort, the mean age was 48 and 49 years in treatment and placebo groups; 80% and 77% were female. In the CHD-PAH cohort, the mean age was 41 and 39 years; 70% and 66% were female. Overall, ≥98% in each group were World Health Organization functional class II and III at baseline. There was a significant reduction in risk of M/M events vs placebo in the overall PAH and CHD-PAH cohorts: 37% reduction in the overall PAH cohort (HR: 0.63; 95% CI: 0.52-0.77) and 50% reduction in the CHD-PAH population (HR: 0.50; 95% CI: 0.26-0.94).ConclusionsTreatment with approved PAH drugs provided a similar reduction in M/M risk in patients with repaired CHD-PAH when compared with the overall PAH population. This pooled analysis provides important evidence to guide medical management in this patient population.
| S-EPMC11908551 | biostudies-literature
Project description:Hypoplastic left heart syndrome (HLHS) is one of the most complex forms of congenital heart disease, characterized by an underdeveloped left ventricle, outflow tract and aorta. Current surgical and medical treatment for this disease remains palliative. As a result of the multi-step surgery, the right ventricle plays the role of the systemic ventricle, which inevitably leads to its failure. There is an urgent need to develop new treatments to ameliorate the right ventricle failure. Stem cell therapy may represent a new approach to single ventricle pathology. Great numbers of small and large animal studies have proven this therapy to be safe and effective in hypoplastic left heart syndrome. Several clinical trials have been designed to investigate the potential of mesenchymal stem cells in univentricular heart physiology. With increasing evidence, understanding of the mechanism of stem cells' action has shifted from the concept of differentiation into various heart cell types to paracrine activity playing the major role. The secretome of stem cells has been identified as their functional unit. In this review, we present different types of stem cells used in single ventricle diseases in children as well as their preclinical investigations. We also summarize clinical applications of stem cells in children with HLHS.
| S-EPMC10031672 | biostudies-literature