INTRODUCTION:ESC/ERS guidelines recommend risk stratification of prevalent patients with pulmonary arterial hypertension (PAH) using noninvasive parameters, whereas right heart haemodynamic parameters are left to the clinician's discretion if deemed necessary. The study aimed to define the possible contribution of invasive haemodynamic parameters in predicting both the risk of death from all causes and the risk of clinical worsening (CW) in patients with PAH categorized at follow-up by the noninvasive ESC/ERS 4-strata risk stratification model. METHODS:We evaluated incident patients with PAH enrolled in 11 Italian centres between 2005 and 2021 who had a first follow-up right heart catheterization within 6-12 months of diagnosis. In each noninvasive risk category, patients were subsequently stratified in a subgroup with a good haemodynamic profile if stroke volume index was ⩾38 mL/m2 and right atrial pressure was <8 mmHg and a subgroup with a poor haemodynamic profile if stroke volume index <38 ml/m2 and/or right atrial pressure ⩾8 mmHg. Median follow-up was 3.7 years (interquartile range 1.2-6.8) months. RESULTS:Among low-risk patients (n = 162) survival was similar, but the CW rate was better in the good haemodynamic compared with the poor haemodynamic subgroup (P = .033). Among patients at intermediate-low risk (n = 240), both survival and CW rates were significantly better in the good haemodynamic subgroup compared with the poor haemodynamic subgroup (P = .028 and P = .011, respectively). Among patients at intermediate-high risk (n = 339), the CW rate was similar but survival was significantly better in the good haemodynamic than in the poor haemodynamic subgroup (P = .015). In the high-risk group, only 1 out of 28 patients had a good haemodynamic profile. CONCLUSION:In prevalent patients with PAH, a good haemodynamic profile predicts better survival in intermediate-risk patients and, importantly, a lower CW rate in low-risk patients.

BACKGROUND:The demographic shift of pulmonary arterial hypertension (PAH) patients, the expanding therapeutic armamentarium with new emerging drugs and the heterogenous experience in handling more complex therapies are making the management of PAH increasingly challenging. This project was developed to standardize PAH management across Italian centres and ensure timely access to the optimal therapeutic strategies. METHODS:A consensus document containing 10 statements, mainly focused on the use of parenteral prostanoids, was developed by eight experts in PAH during in-person and web-based meetings. Forty-six physicians were invited online to rate each statement, indicating their agreement, neutrality or disagreement. RESULTS:Forty physicians participated to the survey. There was strong agreement that age and comorbidities significantly influence the choice of PAH-targeted therapies. Agreement was also reached on the use of parenteral prostanoids in the following clinical scenarios: a) treatment-naive patients at high risk; b) newly diagnosed patients classified as intermediate-risk, with severe right ventricular dysfunction assessed invasively and c) prevalent high-risk patients, as defined by the 4-strata risk score. The use of parenteral prostanoids in selected newly diagnosed intermediate-risk patients with severe right ventricular dysfunction assessed by imaging achieved a mild agreement. Three statements did not meet the predefined threshold for consensus. CONCLUSIONS:These consensus statements are intended to support physicians in starting parenteral prostanoids, minimizing delays that could negatively affect patient prognosis.

Background and Aims The aim of this study was to evaluate whether echocardiography-derived phenotypes describing different degrees of right ventricular (RV) remodelling and dysfunction add prognostic information to that of current risk stratification tools in patients with pulmonary arterial hypertension (PAH) at first follow-up.Methods In 11 centres of the Italian Pulmonary Hypertension NETwork (IPHNET), data were prospectively collected from patients with PAH who underwent re-evaluation between 6 and 12 months after diagnosis. Echocardiographic variables were combined a priori to define four phenotypes representing different degrees of RV dilatation and right ventricular-pulmonary arterial (RV-PA) coupling: a mildly dilated right ventricle with preserved RV-PA coupling defined phenotype-1; a mildly dilated right ventricle with poor RV-PA coupling defined phenotype-2; a severely dilated right ventricle with preserved RV-PA coupling defined phenotype-3; a severely dilated right ventricle with poor RV-PA coupling, either with or without tricuspid regurgitation of moderate degree or more, defined phenotype-4. Patients were followed up for all-cause death for a median of 3.7 years.Results These echocardiographic phenotypes were present in all European Society of Cardiology/European Respiratory Society or REVEAL 2.0 risk groups except for the high-risk groups, which included only phenotype-3 and phenotype-4. In each risk group, RV phenotype-4 identified patients with a poorer prognosis; RV phenotype-1 identified patients with better survival in intermediate risk groups.Conclusions Echocardiography-derived phenotypes describing different degrees of RV remodelling and dysfunction provide prognostic information which is independent of and additional to the clinically defined risk in PAH patients at first follow-up.

BACKGROUND:The Venous Excess Ultrasound (VExUS) score is increasingly used to assess systemic venous congestion, yet direct validation against invasively measured right atrial pressure (RAP) in pulmonary hypertension (PH) remains limited. RESEARCH QUESTION:How accurate is the VExUS score to predict RAP in patients with established or suspected PH? METHODS:We conducted a multicenter observational study across 7 Italian reference centers including patients referred for PH and undergoing a VExUS assessment and right heart catheterization within 1 hour. A VExUS score was calculated with a 0 to 3 grading based on inferior vena cava (IVC) diameter and collapsibility, and Doppler assessment of hepatic, portal, and intrarenal venous flow patterns. The diagnostic performance of VExUS for identifying elevated RAP thresholds was compared with echocardiographic estimates based on IVC diameter and inspiratory collapse and RA surface areas using a multivariable analysis followed by receiver operator curves (ROC) calculations. Subgroup analyses were performed across pulmonary hemodynamic phenotypes (normal hemodynamics vs pre- vs postcapillary PH). RESULTS:The study included 145 patients with pre-capillary PH, most of whom with pulmonary arterial hypertension (PAH), 21 with post-capillary PH, and 21 with no PH. The VExUS score showed a strong graded association with RAP, with mean RAP increasing across VExUS grades (0: 3.9 mmHg; 1: 8.4 mmHg; 2: 13.5 mmHg; 3: 15.8 mmHg; p<0.001). The VExUS score demonstrated excellent discrimination for elevated RAP >12 mmHg (AUC 0.97, 95% CI 0.94-0.99), with higher diagnostic performance than isolated echocardiographic markers and performance comparable to echocardiographic RAP estimation. These findings were consistent across hemodynamic phenotypes.

BACKGROUND:The precise impact of cardiovascular risk factors (CVRFs) on the right ventricle-pulmonary circulation unit remains unclear. RESEARCH QUESTION:Are there any differences regarding resting and exercise right ventricular function in patients with CVRFs but without overt cardiovascular disease when compared with healthy control patients? STUDY DESIGN AND METHODS:We extracted from the RIGHT Heart International NETwork registry the data of 362 patients with at least 1 CVRF but no overt cardiovascular disease and 375 healthy control patients. All patients and control patients had undergone resting and exercise echocardiographic evaluations on a semirecumbent cycle ergometer. Right ventricular-pulmonary arterial coupling was assessed using the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary arterial systolic pressure (sPAP) and pulmonary vascular function through the slope of mean pulmonary arterial pressure (mPAP) to cardiac output (CO) relationship, or dynamic total pulmonary vascular resistance. All-cause mortality and hospitalization events at follow-up were analyzed. RESULTS:Patients with CVRFs had lower TAPSE/sPAP (P < .001) and a steeper mPAP/CO slope (P < .001) than control patients. A substantial proportion of patients with ≥ 2 CVRFs (38.2%) had mPAP/CO slopes ≥ 3 mm Hg/min/L. Patients with CVRFs also had worse exercise capacity with chronotropic incompetence. The presence of ≥ 2 CVRFs was associated with an additional negative impact on right ventricular systolic function as assessed by TAPSE. The presence of CVRFs affected outcome, with 1 event in healthy control patients compared with 12 events in patients with CVRFs (P < .001). However, no independent effect of TAPSE/sPAP or mPAP/CO was observed, likely due to the limited number of events. INTERPRETATION:Patients with CVRFs exhibited echocardiographic evidence of right ventricular-pulmonary arterial uncoupling at rest and during exercise, along with elevated dynamic pulmonary vascular resistance, all of which are relevant to exercise capacity. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03041337; URL: www. CLINICALTRIALS:gov.

Pulmonary arterial hypertension (PAH) is a rare, chronic and progressive disease with a significant clinical, social, and economic impact. Despite available therapies, none address the underlying cause but rather focus on symptom management. This study aims to estimate the economic and social burden of PAH in Italy, including direct healthcare costs, direct nonhealthcare costs, and indirect costs related to productivity loss. A bottom-up prevalence-based cost-of-illness model was developed using epidemiological data and healthcare resource consumption from national and international literature, validated by a panel of expert clinicians with extensive experience in the management of the condition across different regions of Italy. The analysis was conducted from a societal perspective over a 1-year horizon. The economic burden included direct healthcare costs (hospitalization, pharmaceuticals, and specialist care), direct nonhealthcare costs, and indirect costs related to productivity loss. In Italy, the prevalent population of patients with PAH is estimated between 2100 and 3500 individuals, with 2–5

BACKGROUND:Right ventricular functional adaptation to afterload is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to investigate if right ventricular-pulmonary artery (PA) coupling evaluated by the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (sPAP) improves risk assessment scores for survival prediction. METHODS:A total of 677 consecutive patients with PAH (55% idiopathic) were prospectively enrolled with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months (interquartile range, 180-344 days) after initiation of targeted therapies in 11 Italian centers. European Society of Cardiology/European Respiratory Society guidelines-derived risk scores and REVEAL 2.0 (US Registry to Evaluate Early and Long-Term PAH Disease Management 2.0) risk scores were collected at baseline and follow-up. 254 consecutive patients with PAH retrospectively enrolled in a German reference center served as a validation cohort. RESULTS:A low-risk status at a median of 3.7 years (interquartile range, 1.2-6.8) follow-up was significantly associated with each unit (0.1 mm/mm Hg) increase in TAPSE/sPAP under targeted therapies (European Society of Cardiology/European Respiratory Society score: odds ratio, 1.78; P≤0.001; REVEAL 2.0 score: odds ratio, 1.43; P≤0.001). At follow-up, the TAPSE/sPAP ratio increased the prognostic information of each risk stratum of the European Society of Cardiology/European Respiratory Society risk score, except the highest risk stratum, with 0.5 mm/mm Hg, 0.35 mm/mm Hg, and 0.30 mm/mm Hg, from the lowest to the intermediate-high risk score, identified as the best cutoff value. TAPSE/sPAP ratio increased the prognostic information of the REVEAL 2.0 score at follow-up, with 0.35 mm/mm Hg identified as the best cutoff value to discriminate within a score of 5 to 8, with no added value for scores <5 and >8. These results were confirmed in the validation cohort. CONCLUSIONS:Assessment of right ventricular-PA coupling by the TAPSE/sPAP ratio in PAH improves risk assessment scores except in the lowest or most advanced stage of the disease.

BACKGROUND:Our understanding of pulmonary arterial hypertension (PAH) pathophysiology and treatment has significantly improved over time. Within this scenario we established the Italian Network on Pulmonary Arterial Hypertension (IPHNET), promoting a national prospective registry (ASPYRE-1) to collect data on contemporary PAH patients and to define the baseline features of Italian PAH patients. The aim of our study is to show the clinical characteristics of the Italian PAH patients. This cohort of patients will be followed in the ongoing registry to provide important insight into risk stratification and mode of death. METHODS:Twenty-six PAH centers were initially involved in the registry. Data were collected on anthropometric measurements, medical history, vital signs, clinical signs of heart failure, physical examination, laboratory tests (hematology and clinical chemistry), WHO functional class evaluation, non-encouraged 6-min walk test (6MWT), echocardiographic imaging and right heart catheterization (RHC) of outpatients and inpatients with PAH (Group 1) diagnosis. All the centers shared a common database for the prospective follow-up of the patients. RESULTS:between May 2014 and January 2023, a total of 500 prevalent patients with clinical diagnosis of PAH were enrolled: idiopathic (40.6 %), heritable (4.6 %), associated with drug or toxins (0.8 %), associated with connective tissue disease (26.4 %), associated with HIV infection (4.8 %), associated with portal hypertension (3.8 %), associated with congenital heart disease (16,4 %), with features of venous/capillary involvement (1.4 %), others (1.2 %) were enrolled. According to the ERS/ESC guidelines risk assessment, 207 (41.4 %) patients were at low risk, and 286 (57.2 %) were at intermediate risk. According to the REVEAL 2.0 score, 352 (70.4 %) patients were at low risk (score < 7), 93 (18.6 %) were at intermediate risk (score 7-8), and 55 (11 %) were at high risk (score > 8), Of the total patient population, 177 (35.4 %) received monotherapy, 222 (44.4 %) received double combination therapy, and 101 (20.2 %) received triple combination therapy. CONCLUSION:Built as a collaborative registry of centers treating PAH patients in Italy, it holds significant promise for addressing several critical needs within the field, including patients' clinical trajectory and risk stratification.

Connective Tissue Diseases (CTD) are associated with severe cardiovascular and pulmonary complications. Right ventricular-pulmonary arterial coupling (RVPAC) plays a critical role in prognosis, yet the sex-based differences in right heart function during exercise in CTD patients remain poorly understood. This study aims to compare right heart function and RVPAC during exercise between males and females with SSc. We analyzed data from 872 CTD patients (756 females, 124 males, 98% with systemic sclerosis) without overt pulmonary hypertension, from the RIGHT Heart International NETwork (RIGHT-NET) database, and compared them to 375 healthy controls. All subjects underwent resting and exercise transthoracic echocardiography. Key echocardiographic parameters, including cardiac output (CO), pulmonary pressures (PASP, mPAP), and RVPAC (mPAP/CO slope), were assessed at rest and peak exercise. Female CTD patients exhibited reduced stroke volume (SV, p<0.001) and impaired RVPAC (TAPSE/PASP, p<0.001) during exercise, alongside higher pulmonary pressures (PASP, p<0.001; mPAP, p<0.001) compared to healthy females. Male CTD patients, larger right heart chambers (RVED, p<0.001), and higher pulmonary pressures (mPAP, p<0.01) during exercise compared to healthy males. Both sexes with CTD had reduced cardiac output reserve (CI, p<0.001). Notably, male CTD patients demonstrated a steeper increase in the mPAP/CO slope, indicating more severe impairment in RVPAC (p<0.001, see figure 1). CTD patients show significant sex differences in right heart function and exercise adaptation, with males exhibiting more severe cardiovascular impairment despite a lower disease prevalence. These findings emphasize the importance of considering sex-specific differences in the management of SSc-related cardiovascular complications.

Despite the innovations introduced in the 2022 European Society of Cardiology/European Respiratory Society Guidelines on Pulmonary Hypertension, risk discrimination and management of pulmonary arterial hypertension (PAH) patients at intermediate risk still represents a grey zone. Additionally, clinical evidence derived from currently available studies is limited. This expert panel survey intends to aid physicians in choosing the best therapeutic strategy for patients at intermediate risk despite ongoing oral therapy. An expert panel of 24 physicians, specialized in cardiology and/or pulmonology with expertise in handling all drugs available for the treatment of PAH participated in the survey. All potential therapeutic options for patients at intermediate risk were explored and analyzed to produce graded consensus statements regarding: the switch from endothelin receptor antagonist (ERA) or phosphodiesterase 5 inhibitor (PDE5i) to another oral drug of the same class; the addition of a drug targeting the prostacyclin pathway administered by different routes; the switch from PDE5i to riociguat.

BACKGROUND:Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools. METHODS:Consecutive incident PAH patients aged ≥18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n = 152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n = 143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n = 201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n = 519 patients). Risk stratification was based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) 3-strata model and Registry to Evaluate Early and Long-Term PAH disease Management (REVEAL) 2.0 score. RESULTS:These phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% CI 1.6-2.8, p < 0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% CI 0.18-0.47, p < 0.001). CONCLUSIONS:Echocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients.

Abstract Aims Recent studies have shown that lung ultrasound-assessed pulmonary congestion is worse in heart failure when pulmonary vascular resistance (PVR) is increased, suggesting a paradoxical relationship between right heart failure and increased lung water content. Accordingly, we wondered if lung ultrasound would reveal otherwise clinically silent pulmonary congestion in patients with pulmonary arterial hypertension (PAH). Methods and results All patients referred for suspicion of PAH in a tertiary center from January 2020 to December 2022 underwent a complete diagnostic work-up including echocardiography, lung ultrasound and right heart catheterization. Pulmonary congestion was identified by lung ultrasound B-lines using an 8-site scan. The study enrolled 102 patients with idiopathic PAH (mean age 53±13; 71% female). WHO functional classes I, II and III were found respectively in 2, 52 and 46% of them. The N-terminal-pro-brain natriuretic peptide (NT-proBNP) was 377 pg/mL [interquartile range, IQR 218, 906]. B-lines were identified in 77 out of 102 patients (75%), with a median of 3 [IQR: 1-5]. At univariable analysis B-lines were positively correlated to male sex, age, NT-proBNP, systolic PA pressure (sPAP), right atrial pressure (RAP), PVR, left ventricular end-diastolic volume and tricuspid annulus plane systolic excursion (TAPSE), and negatively to cardiac output and stroke volume. At multivariable analysis, RAP (p<0.001; Fig 1), TAPSE/sPAP (p=0.001), and NT-proBNP (p=0.04) were independent predictors of B-lines. Conclusion Lung ultrasound commonly discloses pulmonary congestion in PAH. This finding is related to right ventricle to pulmonary artery uncoupling, and may tentatively be explained by increased central venous pressure impeding lymphatic outflow.Figure 1

Background: Pulmonary hypertension (PH) is a pathophysiological problem that may involve several clinical symptoms and be linked to various respiratory and cardiovascular illnesses. Its diagnosis is made invasively by Right Cardiac Catheterization (RHC), which is difficult to perform routinely. Aim of the current study was to develop a Machine Learning (ML) algorithm based on the analysis of anamnestic data to predict the presence of an invasively measured PH. Methods: 226 patients with clinical indication of RHC for suspected PH were enrolled between October 2017 and October 2020. All patients underwent a protocol of diagnostic techniques for PH according to the recommended guidelines. Machine learning (ML) approaches were considered to develop classifiers aiming to automatically detect patients affected by PH, based on the patient's characteristics, anamnestic data, and non-invasive parameters, transthoracic echocardiography (TTE) results and spirometry outcomes. Results: Out of 51 variables of patients undergoing RHC collected, 12 resulted significantly different between patients who resulted positive and those who resulted negative at RHC. Among them 8 were selected and utilized to both train and validate an Elastic-Net Regularized Generalized Linear Model, from which a risk score was developed. The AUC of the identification model is of 83 % with an overall accuracy of 74 % [95 % CI (61 %, 84 %)], indicating very good discrimination between patients with and without the pathology. Conclusions: The PH-targeted ML models could streamline routine screening for PH, facilitating earlier identification and better RHC referrals.

A comprehensive evaluation of risk, using multiple indices, is necessary to provide reliable prognostic information and guide therapy in pulmonary arterial hypertension (PAH). The current ESC/ERS guidelines suggest using a three-strata model for incident (newly diagnosed) patients and a four-strata model for prevalent patients with PAH.The four-strata model serves as a fundamental risk-stratification tool and relies on a minimal dataset of indicators that must be considered during follow-up. Nevertheless, there are still areas of vagueness and ambiguity when classifying and managing patients in the intermediate-risk category. For these patients, considerations should include right heart imaging, hemodynamics, as well as individual factors such as age, sex, genetic profile, disease type, comorbidities, and kidney function.The aim of this report is to present case studies, with a specific focus on patients ultimately classified as intermediate risk. We aim to emphasize the challenges and complexities encountered in the realms of diagnosis, classification, and treatment for these particular patients.

AIMS:Recent studies have shown that lung ultrasound-assessed pulmonary congestion is worse in heart failure when pulmonary vascular resistance (PVR) is increased, suggesting a paradoxical relationship between right heart failure and increased lung water content. Accordingly, we wondered if lung ultrasound would reveal otherwise clinically silent pulmonary congestion in patients with pulmonary arterial hypertension (PAH).METHODS AND RESULTS:All patients referred for suspicion of PAH in a tertiary centre from January 2020 to December 2022 underwent a complete diagnostic work-up including echocardiography, lung ultrasound and right heart catheterization. Pulmonary congestion was identified by lung ultrasound B-lines using an 8-site scan. The study enrolled 102 patients with idiopathic PAH (mean age 53 ± 13 years; 71% female). World Health Organization functional classes I, II, and III were found in 2%, 52%, and 46% of them, respectively. N-terminal pro-brain natriuretic peptide (NT-proBNP) was 377 pg/ml (interquartile range [IQR] 218-906). B-lines were identified in 77 out of 102 patients (75%), with a median of 3 [IQR 1-5]. At univariable analysis, B-lines were positively correlated with male sex, age, NT-proBNP, systolic pulmonary artery pressure (sPAP), right atrial pressure (RAP), PVR, left ventricular end-diastolic volume and tricuspid annular plane systolic excursion (TAPSE), and negatively with cardiac output and stroke volume. At multivariable analysis, RAP (p < 0.001), TAPSE/sPAP (p = 0.001), and NT-proBNP (p = 0.04) were independent predictors of B-lines.CONCLUSION:Lung ultrasound commonly discloses pulmonary congestion in PAH. This finding is related to right ventricular to pulmonary artery uncoupling, and may tentatively be explained by increased central venous pressure impeding lymphatic outflow.

L’ipertensione polmonare (IP) è una patologia frequente in tutto il mondo, nella maggior parte dei casi secondaria a malattie cardiovascolari e respiratorie, con una prognosi infausta. L’ipertensione arteriosa polmonare (IAP) è una forma rara che colpisce il sistema vascolare arterioso polmonare. IP e IAP sono caratterizzate da sintomi aspecifici e da un progressivo aumento delle resistenze vascolari polmonari che determina disfunzione ventricolare destra, talvolta irreversibile. Negli ultimi anni, il crescente impegno dei sanitari e delle istituzioni ha consentito diagnosi più accurate in tempi più brevi. Tuttavia, il divario tra le linee guida e la pratica clinica rimane una sfida per tutti gli specialisti coinvolti nella gestione della malattia. Considerando la necessità di condividere e descrivere percorsi diagnostici e terapeutici, di valutare i risultati ottenuti e di affrontare i costi e le problematiche organizzative prodotte da questa malattia, tutte le figure coinvolte dovrebbero collaborare per migliorarne l’impatto prognostico e la spesa sanitaria. In questo documento di consenso, gli esperti dell’Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) e della Società Italiana di Cardiologia (SIC) sull’IP affrontano 1) definizione, classificazione e bisogni insoddisfatti dell’IP e IAP; 2) classificazione e caratteristiche dei centri coinvolti nella diagnosi e cura della malattia; 3) proposta di organizzazione di un percorso diagnostico-terapeutico, basato su robuste e recenti evidenze scientifiche.

Novel biomarkers are needed to better identify—and distinguish—heart failure with preserved ejection fraction (HFpEF) from other clinical phenotypes. The goal of our study was to identify epigenetic-sensitive biomarkers useful to a more accurate diagnosis of HFpEF. We performed a network-oriented genome-wide DNA methylation study of circulating CD4+ T lymphocytes isolated from peripheral blood using reduced representation bisulfite sequencing (RRBS) in two cohorts (i.e., discovery/validation) each of both male and female patients with HFpEF (n = 12/10), HF with reduced EF (HFrEF; n = 7/5), and volunteers lacking clinical evidence of HF (CON; n = 7/5). RRBS is the gold-standard platform for measuring genome-wide DNA methylation changes at single-cytosine resolution in hypothesis-generating studies. We identified three hypomethylated HFpEF-specific differentially methylated positions (DMPs) associated with FOXB1, ELMOD1, and DGKH genes wherein ROC curve analysis revealed that increased expression levels had a reasonable diagnostic performance in predicting HFpEF (AUC ≥ 0.8, p < 0.05). Network analysis identified additional three genes including JUNB (p = 0.037), SETD7 (p = 0.003), and MEF2D (p = 0.0001) which were significantly higher in HFpEF vs. HFrEF patients. ROC curve analysis showed that integrating the functional H2FPEF classification with the expression levels of the FOXB1, ELMOD1, and DGKH as well as the JUNB, SETD7, and MEF2D genes improved diagnostic accuracy, with AUC = 0.8 (p < 0.0001) as compared to H2FPEF score alone (p > 0.05). Besides, increased expression levels of SETD7-RELA-IL6 axis significantly discriminated overweight/obese HFpEF vs. HFrEF patients (AUC = 1; p = 0.001, p = 0.006, p = 0.006, respectively). We support an emerging dogma that indirect epigenetic testing via high-resolution RRBS methylomics represents a non-invasive tool that may enable easier access to both diagnostic and mechanistic insights of HFpEF. An epigenetic-oriented dysregulation of network-derived SETD7-RELA-IL6 axis in circulating CD4+ T lymphocytes may drive pro-inflammatory responses which, in turn, may lead to cardiac remodeling in overweight/obese HFpEF.

Pulmonary hypertension (PH) is a frequent pathological condition worldwide, mainly secondary to cardiovascular and respiratory diseases, with a poor prognosis. Pulmonary arterial hypertension (PAH) is a rare form that affects the arterial pulmonary vasculature. PH and PAH are characterized by non-specific symptoms and a progressive increase of pulmonary vascular resistance that results in progressive, sometimes irreversible, right ventricular dysfunction. In recent years, a growing medical and social commitment on this disease allowed more accurate diagnosis in shorter times. However, the gap between guidelines and clinical practice remains a challenge for all medical doctors involved in the disease management. Considering the needs to share and describe diagnostic and therapeutic pathways, to measure the results obtained and to address the economical and organizational problems of this disease, all involved figures should collaborate to improve its prognostic impact and health expenses. In this consensus document, the PH experts of the Italian Association of Hospital Cardiologists (ANMCO) together with those of the Italian Society of Cardiology (SIC), address 1) definition, classification and unmet needs of PH and PAH; 2) classification and characteristics of centers involved in the diagnosis and treatment of the disease; 3) proposal of organization of a diagnostic-therapeutic pathway, based on robust and recent scientific evidence.

Pulmonary arterial hypertension (PAH) is defined as increase in mean pulmonary arterial pressure and pulmonary vascular resistance (PVR). It can be associated with congenital heart disease (CHD) with the following subtypes: 1) uncorrected left-to-right (L-R) intracardiac shunt leading to overload of the pulmonary circulation and a progressive increase of PVR; 2) Eisenmenger syndrome, appearing when a large post-tricuspid shunt is left uncorrected and pulmonary vascular disease (PVD) is severe, so the shunt becomes bidirectional or right-to-left, causing cyanosis; 3) PAH after shunt closure, when PVR arises after a defect correction; and 4) PAH associated with small or coincidental defects. While the treatment of patients with Eisenmenger syndrome is well established, the treatment of patients with PAH in whom there is a L-R shunt (with no cyanosis) remains unclear and requires expertise. In such patients, correction of the defect may be contemplated if there is mild PVD and a significant L-R shunt. Others may benefit from a "treat and repair" strategy, which involves the use of PAH therapy to achieve a drop in PVR, with the aim of achieving operability criteria. Cardiac catheterization is at the center of the evaluation and follow-up of these patients, collecting “baseline” data and providing the opportunity to challenge the pulmonary circulation, manipulate the loading status, or temporarily occlude the defect. This article provides a detailed overview of the pathophysiology and treatment options for patients with PAH associated with a L-R congenital shunt, including current approaches to operability and the use of PAH therapies.