Pilar Escribano Subías

Pathogenic variants in PORCN cause focal dermal hypoplasia (FDH/Goltz syndrome), an X‐linked dominant disorder historically considered lethal in males, with milder presentations now recognized as PORCN non‐Goltz spectrum (PONGOS). We report three male patients identified by exome sequencing: one with a mosaic de novo variant (c.727C>T; p.Arg243*) showing FDH features, and two siblings with an inherited non‐mosaic variant (c.1315T>G; p.Trp439Gly) from their unaffected carrier mother with a PONGOS phenotype. These cases confirm that male survival is possible with both mosaic and non‐mosaic PORCN variants and expand the clinical and molecular spectrum of the disease. Our findings highlight the role of residual protein function in clinical variability and have important implications for diagnosis, genetic counseling, and management in families with apparently unaffected carrier mothers.

Rationale: While therapeutic advances have improved survival in Group 1 Pulmonary Arterial Hypertension (PAH), patients with Group 1.5 “PAH with features of venous/capillary involvement” (formerly Pulmonary Veno-Occlusive Disease or Pulmonary Capillary Hemangiomatosis, now collectively termed PVOD/PCH) remain underrecognized, develop serious complications from usual PAH therapy titrations, and suffer high mortality awaiting necessary lung transplant. Identifying PVOD/PCH early before therapy initiation could aid management and expedite transplant referral. Objective: We aimed to develop a likelihood score distinguishing PVOD/PCH from other forms of PAH using clinical variables. Methods: Due to low PVOD/PCH prevalence and no dedicated registries, we leveraged published case control/series studies to assess the ability of several clinical variables to discriminate PVOD/PCH from PAH. From pooled literature-derived data, we performed Sensitivity/Specificity and simulation-based Receiver Operator Characteristic (ROC) analyses to estimate variable performance. Top-performing variables formed a PVOD/PCH Likelihood score, which had its accuracy tested for distinguishing histopathology-confirmed PVOD/PCH cases (n = 37) from PAH controls (n = 60) in three cohorts of transplant-eligible patients from the United States, Spain, and the Netherlands. Measurements and Main Results: DLCO, six-minute walk desaturation, PaO2, sex, smoking history, CT septal line thickening, and CT lymphadenopathy had the highest sensitivity and specificity performance and were incorporated into the PVOD score. Across test cohorts, the score achieved a ROC area under the curve of 0.97 (95% CI 0.93-1.00) for discriminating PVOD/PCH and it retained accuracy when data were missing. Conclusions: This score could facilitate early PVOD/PCH identification in incident PAH, potentially helping expedite transplant referral and informing therapy initiation/titration decisions.

To delve deeper into the molecular mechanisms underlying pulmonary hypertension secondary to left heart disease (PH-LHD), an essential step toward developing a comprehensive classification, reliable biomarkers and targeted therapies. In this study, we analyzed the whole transcriptome (mRNA and microRNA) of a unique cohort of patients with persistent PH due to valvular heart disease (PH-VHD) to identify biological pathways associated with disease prognosis. The analysis was performed using the well-characterized SIOVAC (Sildenafil for Improving Outcomes after Valvular Correction) clinical trial cohort. We included 116 patients with demonstrated PH-LHD after valvular correction, and 30 VHD patients with no or mild PH (Control). The comparison between PH-LHD patients and controls of the whole blood transcriptome identified 3,217 differentially expressed genes. Unsupervised clustering in PH-VHD patients revealed three clusters (K1–K3), with K1 showing significantly worse 84-month survival (p = 0.017) despite no clinical or hemodynamic differences among clusters. Enrichment analysis identified 173 significantly altered canonical pathways, involved in inflammatory and stress-related networks (e.g., Granzyme A, IL-15, JAK/STAT, HIF1α) and inhibition of metabolic and translational processes (e.g., oxidative phosphorylation, EIF2). Circulating microRNA analysis identified 97 differentially expressed microRNAs; notably, BMPR2 was regulated by 22 of these and demonstrated significant downregulation of its functional isoform A in K1 patients. In conclusion PH-VHD transcriptomic signature identifies a cluster of patients associated with higher risk of mortality characterized by immune overactivation and a mitochondrial metabolic shift, with BMPR2 emerging as a key metabolic target.

Pregnancy poses substantial risks for women with Pulmonary Arterial Hypertension (PAH). This study aimed to evaluate maternal and neonatal outcomes in a contemporary PAH cohort under modern management, specifically investigating whether vasoreactive status warrants distinct clinical recommendations. We conducted a retrospective, longitudinal cohort study of PAH pregnancies managed at our institution between February 2010 and December 2023, comparing clinical characteristics, maternal complications, long‐term outcomes, and neonatal parameters between vasoreactive and non‐vasoreactive patients. Among 29 patients, 8 underwent pregnancy termination, and 21 proceeded with the pregnancy; 7 (33.3%) of whom were vasoreactive. Non‐vasoreactive patients experienced significantly higher rates of major complications (35.7% vs. 0%, p = 0.039) and minor complications (92.9% vs. 0%, p < 0.001). Complications in the non‐vasoreactive subgroup included prostacyclin initiation (78.6%), inotropic support (35.7%), mechanical circulatory support (14.3%), and one death (7.14%). All neonates born to non‐vasoreactive patients were delivered preterm and showed a trend toward higher complication rates (84.6% vs. 42.9%, p = 0.054). Over a median 5‐year follow‐up, two non‐vasoreactive patients died, whereas none of the vasoreactive patients lost their vasoreactive profile. In conclusion, despite advances in management, pregnancy in PAH remains associated with substantial maternal and neonatal morbidity. Vasoreactive patients, however, exhibit a distinctly favorable prognosis for both mother and offspring, which suggest the need for tailored recommendations for this subgroup.

Extract Pulmonary arterial hypertension (PAH) is a chronic, progressive disease in which increased pulmonary vascular resistance (PVR) and elevated mean pulmonary arterial pressure (mPAP) lead to right ventricular (RV) dysfunction, the major determinant of mortality [1]. Although advances in targeted therapies have improved survival, pragmatic and clinically meaningful haemodynamic treatment goals remain needed [2]. Reductions in PVR and mPAP correlate with RV recovery and better long-term outcomes, as described after the initiation of pulmonary vasodilators and specially after lung transplant in PAH, and in the context of chronic thromboembolic pulmonary hypertension after successful interventional treatment [3, 4, 5]. The concept of haemodynamic partial remission (PR)—a profound reduction of afterload without full normalisation—has gained interest, but its prevalence and prognostic relevance have not been well defined [6]. This study evaluates PR in a large contemporary cohort of patients with PAH.

Introduction: Pulmonary veno‐occlusive disease (PVOD) is a rare but severe form of pulmonary arterial hypertension (PAH), characterized by poor response to medical therapy. Lung transplantation is often the only therapeutic alternative. Methods: We analyzed a retrospective cohort of 58 patients with group 1 PAH who underwent lung transplantation between 2011 and 2024. Baseline characteristics, perioperative complications, and survival were compared between patients with and without PVOD. Statistical methods included descriptive analysis, Kaplan–Meier survival curves, log‐rank tests, and Cox regression. Results: Among the 58 patients, 21 (36.2%) had a diagnosis of PVOD before transplantation. PVOD patients were younger (median age 39.8 vs. 43.1 years, p = 0.03), had lower DLCO (32% vs. 66%, p < 0.001), shorter six‐minute walk distance (300 vs. 430 m, p < 0.001), and a higher COMPERA 2.0 four‐strata risk score (median 3 vs. 2, p = 0.035) tan non‐PVOD patients. Hemodynamically, PVOD patients showed lower systolic pulmonary artery pressure (78 vs. 98 mmHg, p = 0.038), lower pulmonary vascular resistance (9.2 vs. 10.6 Wood units, p = 0.03), and lower right atrial pressure (6.5 vs. 11.5 mmHg, p = 0.003). Time from diagnosis to transplantation was significantly shorter (23.8 vs. 69.6 months, p < 0.001), and extracorporeal membrane oxygenation (ECMO) as bridge to transplantation was more frequent (23.8% vs. 2.7%, p = 0.011). Survival did not differ significantly between groups (log‐rank p = 0.657). Postoperative need for non‐invasive ventilation (NIV) was independently associated with mortality (HR 3.15; 95% CI 1.00–9.83; p = 0.042). Conclusions: Lung transplantation in PVOD patients results in survival comparable to other group 1 PAH subtypes. Postoperative need for NIV identifies patients at higher risk of mortality.

Objectives: To assess the demographic and clinical characteristics (including the burden of comorbidities) and the survival rates of patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and to compare them with those of contemporary patients with idiopathic PAH (IPAH). We also evaluated the impact of emerging age-related comorbidities on survival. Methods: This was a retrospective cohort study based on data from patients included in the Spanish Registry of PAH (REHAP) during 2014–2023. Kaplan–Meier survival estimates were calculated (overall and according to ≥3 vs 1–2 or no comorbidities). Prognostic values were analysed using Cox proportional-hazards regression models. Results: A total of 340 CTD-PAH patients and 417 IPAH patients were included in the analysis (n = 757). CTD-PAH patients were older than IPAH patients [62 (14) vs 56 (17) years old] and showed lower comorbidity burden (17% vs 34% patients with ≥3 comorbidities), both P < 0.001. The 1-, 3- and 5-year survival rates were 97%, 76% and 55%, respectively, for CTD-PAH and 93%, 77% and 54%, respectively, for IPAH (P = 0.884). Of the seven comorbidities analysed, only chronic kidney disease (CKD) was associated with poor prognosis after adjustment for known PAH prognostic factors (hazard ratio 1.83; 95% CI: 1.19, 2.80), independently of aetiology. CTD-PAH received monotherapy more frequently (37% vs 52% in IPAH). Conclusion: Contemporary CTD-PAH patients included in REHAP are older and have a lower comorbidity burden than IPAH patients, while exhibiting similar survival rates up to 5 years. CKD is an independent prognostic factor in both aetiologies. CTD-PAH patients tend to receive a more conservative treatment approach.

Pulmonary embolism (PE) presents both acute and chronic complications that significantly affect patient outcomes. Acute complications include syncope or sudden death, often resulting from severe hypoxaemia or right ventricular failure; and early recurrence of the embolic event. Chronic complications, which can develop over time, are often grouped under post-embolic syndrome (PES), a condition affecting more than half of PE survivors. Symptoms of PES include persistent dyspnoea and reduced exercise tolerance. PES is associated with several serious conditions, such as chronic thromboembolic pulmonary hypertension, chronic thromboembolic pulmonary disease, right ventricular dysfunction, physical deconditioning, and psychological harm. Although promising catheter-directed therapies are under investigation for acute PE treatment, their effectiveness in preventing chronic complications has yet to be confirmed by large-scale randomised controlled trials.

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) represents a major health issue worldwide, accounting for nearly 75% of cases of PH. PH-LHD eventually develops in more than half of patients with heart failure and confers poor prognosis. It is recognised that targeted therapies are lacking partially because the underlying molecular mechanisms remain poorly understood [1, 2].