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Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD) that significantly affects its prognosis. Down syndrome is a common comorbidity among patients with PAH associated with CHD. Children born in recent years with CHD have benefited from advances in pediatric cardiac surgery that have modified their evolution compared to adults with the same pathologies. Our objective was to know and compare the characteristics of the adult and pediatric population with DS and PAH associated with CHD. REHAP and REHIPED are Spanish, voluntary, multicenter registries that include patients with PAH associated with CHD. REHAP started in 2007 and includes patients over 18 years of age. Patients diagnosed with PAH after this time were prospectively included, until 2021. Patients who were followed in the participating centers and diagnosed after January 1998 were retrospectively included in the registry. REHIPED started in 2009 and collects patients between 2 months and 18 years of age. Patients diagnosed with PAH after this time were prospectively included, until 2021. Patients who were followed and diagnosed after January 1998 were retrospectively included. 131 adults and 47 children with DS and PAH associated with CHD were analyzed. Their baseline characteristics, hemodynamics, treatment, and 10-year survival were compared. Adult patients with DS presented more frequently complete atrioventricular canal defect as underlying heart disease and were mostly in Eisenmenger's situation (84%). In pediatric patients the largest group was post-repair PAH (50%). Functional class was similar in both groups, although adults presented significantly greater hemodynamic severity. Regarding medical treatment, no differences were observed between both groups: there was a very low use of prostanoids both at baseline and at follow-up, and a majority use of oral monotherapy. There were no significant differences in survival. Corrective surgery in patients with DS has become more frequent over the years: adults are mostly in Eisenmenger's situation, while post-repair PAH is the most numerous group in children. Although adults show greater hemodynamic severity, survival is similar in both groups. Medical treatment, which showed no differences between pediatric and adult age, is very conservative, with most patients on oral monotherapy and rare use of prostanoids. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Janssen MSD

Introduction Eisenmenger syndrome is the final clinical stage of different congenital heart diseases (CHD) associated with pulmonary arterial hypertension (PAH). Children born in recent years with CHD have benefited from advances in pediatric cardiac surgery that have modified their evolution compared to adults with the same pathologies. Purpose Our objective was to define and compare the characteristics and prognosis of the adult and pediatric population with Eisenmenger Syndrome. Methods REHAP and REHIPED are Spanish, voluntary, multicenter registries that include patients with PAH associated with CHD. REHAP started in 2007 and includes patients over 18 years of age. Patients diagnosed with PAH after this time were prospectively included, until 2020. Patients who were followed in the participating centres and diagnosed after January 1998 were retrospectively included in the registry. REHIPED started in 2009 and collects patients between 2 months and 18 years of age. Patients diagnosed with PAH after this time were prospectively included, until 2020. Patients who were followed and diagnosed after January 1998 were retrospectively included. The baseline characteristics, hemodynamic profile, treatment, and 10-year survival of the REHAP patients were compared to those included in the REHIPED. Results Eisenmenger syndrome is the main clinical group in adults (56% of patients with PAH associated with CHD enlisted in REHAP), 371 patients were included. On the other hand, Eisenmenger syndrome is the least frequent clinical group in childhood (21% of patients with PAH associated with CHD enlisted in REHIPED), 32 patients were included. Among adults, simple defects were significatively more common, whereas complex defects were more frequent in children (p 0.004). Half of the patients were in NYHA class III-IV, with no difference between groups. Adults presented greater hemodynamic severity, with higher mean pulmonary arterial pressure and greater pulmonary vascular resistance index. There were no differences in treatment: neither in first line therapy nor in the percentage of patients who received prostanoids at any time during follow up. The usage of prostanoids was very low in both groups. Two-thirds of the patients who died or underwent transplantation did so without taking prostanoids at any time. The 10-years survival analysis showed no significative difference between groups. Conclusions The prevalence of Eisenmenger syndrome is clearly lower in the pediatric population with CHD compared to the adult population. However, once Eisenmenger syndrome has developed, even though adults present greater hemodynamic severity, the clinical characteristics and the prognosis are similar in both groups. The usage of prostanoids is low in adulthood and in childhood, even in those with more severe forms of the disease. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ferrer, MSD, Janssen, GSK Table 1Figure 1

Background Pulmonary arterial hypertension (PAH) is a rare and severe disease, genetically predisposed in a high proportion of patients. PAH is subclassified in different subtypes depending on the underlying condition. Gene variants are more frequent among heritable or idiopathic forms. Nevertheless, pathogenic variants have been described across the entire spectrum of this disease. Evidence regarding genetics in pediatric PAH is scarce [1]. Purpose Our aim is to describe the prevalence of significant gene mutations among a pediatric PAH cohort and to define specific data in the different subtypes. Methods Samples for genetic studies were obtained from blood tests of patients included in the Spanish National Registry of Pediatric Pulmonary Hypertension (REHIPED). Guardians signed informed consent before the inclusion in the study. Qualitative variables were compared by Chi-square test. Quantitative variables were assessed by Kruskal-Wallis, considering the asymmetric distribution of variables. STATA 14.0 was used for analyses. Results Sixty four patients were included between 2011 and 2021. Median age of the entire sample was 7.1 years (2.0–12.6) and 42.2% of them were male. There were significant differences in the age at diagnosis and race between the different included groups (table). Pathogenic or likely pathogenic variants were more frequent in familial pulmonary venooclusive disease (PVOD) and familial PAH cases. A similar percentage of mutations were found in idiopathic cases and in PAH associated with congenital heart disease (Figure). Gene variants in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) were the most frequent mutations in the PAH familial cohort and there was also the most frequent finding in congenital heart disease and sporadic PAH, in conjunction with the TBX4 gene. Homozygous or compound heterozygous EIF2AK4 (eukaryotic translation initiation factor 2 a kinase 4) mutations were found in all the patients diagnosed with PVOD. Heritable PAH and PVOD cases were diagnosed more frequently after family screening. Conclusions This study shows a comparable proportion of pathogenic-likely pathogenic gene mutations in patients diagnosed of pulmonary arterial hypertension associated with congenital heart disease and idiopathic cases, with similar distribution of specific genes. BMPR2 and TBX 4 were the most frequent gene variants in this pediatric PAH population. BMPR2 and EIF2AK4 are the most common mutations in familial PAH and PVOD subtypes, respectively. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ACU holds a Rio Hortega Grant from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.JAT and NG hold grants from FEDER (Federaciόn Española de Enfermedades Raras) and from the FCHP. Table 1. Characteristics of PAH subtypesFigure 1. PAH and ACMG classification.

Background Pulmonary arterial hypertension (PAH) includes idiopathic PAH and congenital heart disease (CHD) related PAH. A wide variety of CHD can develop PAH, but their clinical characteristics define four large groups: Eisenmenger, PAH associated with non-restrictive shunt, severe PAH associated with restrictive shunt and postoperative PAH. Our aim was to study the clinical and prognostic differences between these groups and idiopathic PAH. Methods The REHIPED registry is a Spanish, multicenter, observational and prospective registry on pulmonary hypertension in the pediatric population ( Results 183 patients were analyzed, characteristics are detailed in the table. In patients with idiopathic PAH, treatment with prostanoids was more frequently used as first line therapy and during follow up. The average follow-up time was 9 years. There was not a statistically significant difference in survival among the 4 clinical groups of CHD related PAH. There was a borderline significant difference (logrank p 0.05) in survival between the group of CHD related PAH and idiopathic PAH. Conclusion Idiopathic PAH patients have worse outcome than CHD related PAH patients although they have less comorbidities, less severe hemodynamics and are treated more aggressively. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Janssen, Ferrer

Introduction Pulmonary arterial hypertension (PAH) is a rare disease that affects the small pulmonary arteries, producing gradual obliteration of arterial lumen leading to the progressive increase in pulmonary vascular resistance and, ultimately, right ventricular failure and death. Idiopathic PH refers to patients without an identifiable underlying cause, although some of them may have a genetic cause. Our aim was to define the baseline characteristics, initial therapy and risk factors for survival of patients with idiopathic PAH. Methods The REHIPED registry is a Spanish, multicenter, observational and prospective registry on pulmonary hypertension in the pediatric population ( Results The mean age at diagnosis was 4.5 years, and there was a similar proportion of both sexes. 64% of patients were in functional class I-II. The mean pulmonary arterial pressure was 47,3±16,3 mmHg, with mean pulmonary vascular resistance index of 12±8,3 WU·m2. Initial therapy was oral monotherapy in 67%, prostanoids monotherapy in 11% and combination therapy with prostanoids in 9%. At the end of follow up, 55% of patients had received prostanoids. The mean follow-up time was 8 years. The survival rates (free of death or transplantation) was 91% (95% confidence interval (CI): 79–97%), 82% (95% CI: 67–91%) and 70% (95% CI: 52–82%) at 1, 5 and 10 years. Lung transplantation was performed in 7 patients. The main factors influencing survival, after adjustment for pulmonary vascular resistance, were functional class III-IV (Hazard Ratio (HR) 4.6, p=0.022, 95% CI: 1.3–15.3) and diagnosis under the age of 2 (HR 4, p=0.031, 95% CI: 1.1–14.4). Conclusions Idiopathic Pulmonary hypertension in pediatric age affects both sexes equally and begins at a young age. Prostanoids were used in 55% of patients. The main factors influencing survival, after adjustment for pulmonary vascular resistance, were functional class III-IV and diagnosis under the age of 2. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Janssen, Ferrer

Background Different “ex vivo” studies have shown both a greater platelet activation and higher rates of resistance to clopidogrel in obese patients. Although there is less evidence, less prasugrel activity has also been observed in these patients. Our aim was to study the variability of the response to clopidogrel, ticagrelor and prasugrel in obese patients, defined as a body mass index ≥30. Methods Prospective, multicenter, observational, pharmacodynamic study, conducted in a Spanish population of patients with an acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI) and double anti-aggregation with acetylsalicylic acid and a P2Y12 receptor inhibitor. Platelet function tests were performed the morning after the ICP and 30 days after it, including: 1) VerifyNow P2Y12 assay; 2) multiple electrode aggreometry (Multiplate); and 3) VASP analysis. Results Of the total patients included (988), 300 were obese (30.3%). The obese group was younger (62.8±12 years vs 64.9±12), had a higher incidence of arterial hypertension (76.3% vs. 56.7%), diabetes mellitus (35% vs. 27.5%); and lower incidence of chronic kidney disease (7.7% vs. 17%). There were no differences in the acute phase (day 1 after PCI) in the pharmacodynamic response to any of the P2Y12 inhibitors used. After 30 days, greater platelet aggregation (decreased response) was documented in obese patients treated with prasugrel according to VASP tests (PRI in non-obese 23.9±13% vs. 30.4±14.7% in obese, p 0.035) and MEA (area under the aggregation units curve in non-obese 251.7±104.1 vs 320±166.7 in obese, p 0.007) and a numerical trend with VerifyNow. A trend in the same direction was also observed in patients treated with clopidogrel that did not reach statistical significance with all the platelet function tests used. No differences were observed in the ticagrelor group. Conclusion Obese patients with an ACS treated with PCI have a worse response to thienopyridines than non-obese patients in the maintenance phase of antiaggregant treatment, while the response to ticagrelor is not affected by obesity. Completing the clinical follow-up proposed by the registry is necessary to know if these differences have an implication in cardiovascular events. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)

Introduction Pulmonary arterial hypertension (PAH) is a common comorbidity in congenital heart disease (CHD) and significantly affects prognosis. Our aim was to investigate how the location of the shunt influences the outcome of these patients. Methods The REHAP registry is a Spanish multicentre voluntary registry of patients over 14 years of age, which includes patients with congenital heart disease and PAH, starting in 2007. Baseline characteristics, functional class, right catheterization data, treatment and survival were compared. We performed a cox regression model for assessing the impact of the type of shunt on prognosis, after looking for confusing and effect modifying variables. Results 664 patients were analyzed, their characteristics are detailed in the table. Mean follow up time was 10 years. We performed a survival analysis adjusted for the confounding variables: age (Hazard ratio (HR) 1.02 p Conclusion The type of shunt significantly affects prognosis in Eisenmenger patients, with a much worse outcome for those with pretricuspid shunts. Functional class and clinical group are also closely related to outcome. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): MSD, GSK

Background Several pharmacodynamic studies have shown the impact of smoking habit on platelet reactivity; with a reduction on platelet aggregation. Wether this inhibition in platelet reactivity is due to tobacco effects in platelet signaling pathways or due to a pharmacodynamic interaction with antiplatelet therapies is not well stablished. Purpose Our aim was to study the influence of smoking habit in platelet reactivity and in the response to P2Y12 inhibitors. Methods Patients admitted in four tertiary care hospitals due to an acute coronary syndrome that undergone percutaneous coronary intervention (PCI) were consecutively and prospectively recruited. All the patients received dual antiplatelet therapy with aspirin and a P2Y12 inhibitor following current European Guidelines. Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12, VASP (Vasodilator-stimulated phosphoprotein) y MEA (Multiple electrode aggregometry). Results A total of 1000 patients were enrolled, of whom 12 had to be excluded due to inaccurate processing of blood samples. 372 patients (37,6%) had smoking habit. Non-smoking patients showed higher prevalence of high blood pressure [423 (68.7%) vs 196 (52.7%)] and diabetes mellitus [213 (34.6%) vs 81 (21.8%)]. Smoking patients were younger [57.3 (9,6) years old vs 68.4 (11.1)], with higher incidence of acute coronary syndrome with ST segment elevation [184 patients (49,5%) vs 241 (39.1%), p Conclusion Smoking habit was associated with a lower response to prasugrel of borderline significance, and with higher response to clopidogrel, according with previous studies suggesting a pharmacodynamics interaction between tobacco use and P2Y12 inhibitors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)

Background Pulmonary arterial hypertension (PAH) is a common comorbidity in congenital heart disease (CHD) and significantly affects prognosis. There are four large clinical groups of CHD-related PAH: Eisenmenger syndrome, PAH associated with non-restrictive shunt, PAH associated with restrictive shunt and postoperative PAH. Our purpose was to study the clinical and prognostic differences among them. Methods The REHAP is a Spanish multicentre voluntary registry of patients over 14 years of age, which includes patients with CHD and PAH, starting in 2007. 664 patients were analyzed: Baseline characteristics, functional class, right catheterization data, treatment and survival were compared. Results 664 patients were analyzed: characteristics are detailed in the table. Patients with Eisenmenger were more frequently treated with oral monotherapy as a first line therapy and received less frequently prostanoids during the follow-up. Patients with Eisenmenger had significantly better prognosis, with the best long-term survival of the 4 groups. In a cox regression model, postoperative PAH has a 1.7 hazard ratio (HR) (reference group: Eisenmenger) after adjustment for age (HR 1.02 p 0,001), functional class (HR NYHA III-IV 2.3 p Conclusion The clinical classification of PAH associated with CHD defines both the baseline characteristics and the prognosis of patients. Outcome relates closely to functional class and type of PAH–CHD. Eisenmenger group, which has the most severe hemodynamics, is the one with the best prognosis despite a less aggressive treatment. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Ferrer, Janssen