BACKGROUND: Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide, endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). We hypothesized that distinct and overlapping gene expression patterns in SSc-PAH versus IPAH lung tissues could inform the investigation of precision-targeted therapies. METHODS: Lung tissue samples from 4 SSc-PAH, 4 IPAH, and 4 failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative lung tissue bank. Single-cell RNA sequencing was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis, transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. RESULTS: SSc-PAH samples showed a higher proportion of fibroblasts compared with failed donors and a higher proportion of dendritic cells/macrophages compared with IPAH. Gene set enrichment analysis revealed enriched pathways related to epithelial-to-mesenchymal transition, apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial-to-endothelial cell signaling observed. Macrophage-to-endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. CONCLUSIONS: Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve outcomes in patient with SSc-PAH. Future studies should validate these targets and explore their therapeutic efficacy.

Pericardial cysts (PCs) are rare, benign congenital abnormalities that are encountered as mediastinal lesions. Despite their rarity, they remain clinically important due to their potential to mimic other mediastinal or cardiac pathologies and their capacity, in select cases, to cause significant complications. PCs are typically identified incidentally on imaging studies such as chest x-ray or transthoracic echocardiography, as most patients remain asymptomatic throughout their lives. When symptoms do occur, they are often nonspecific and related to compression of adjacent structures. Serious complications—including infection, rupture, and, rarely, cardiac tamponade—have been reported, underscoring the importance of accurate diagnosis and appropriate follow-up. Definitive characterization of PCs is best achieved using advanced imaging modalities such as cardiac computed tomography or cardiac magnetic resonance imaging, which help differentiate PCs from other mediastinal masses. While many PCs remain stable or even regress spontaneously, intervention may be warranted for symptomatic patients, enlarging cysts, or when the diagnosis remains uncertain. Therapeutic options include percutaneous aspiration, which carries a risk of recurrence, and surgical resection, which offers definitive treatment with excellent outcomes. This review provides a comprehensive overview of the etiology, clinical manifestations, diagnostic evaluation, differential diagnosis, complications, and management strategies for PCs.

Cystic fibrosis (CF) has undergone a remarkable transformation from a fatal childhood disease to a chronic adult condition, with a median predicted survival now exceeding 50 years following the introduction of highly effective CFTR modulator therapy (HEMT). This demographic shift has unmasked cardiovascular complications that were previously unrecognized due to premature mortality. In a multinational propensity-matched cohort, CF conferred a 65% higher risk of major adverse cardiac events (MACEs), including myocardial infarction, heart failure, and atrial fibrillation, versus matched controls (Frost et al., HR 1.65). In a separate Canadian population-based cohort, cardiovascular disease occurred at 2.9 times the rate of the general population and at least 20 years earlier (Arya et al., RR 2.9). Cardiac involvement extends beyond the traditional paradigm of cor pulmonale. CFTR is expressed in cardiomyocytes, vascular endothelium, and smooth muscle, where its dysfunction disrupts ion homeostasis, impairs nitric oxide-dependent vasodilation, and promotes oxidative stress. Clinically, these mechanisms manifest as biventricular dysfunction detectable by strain echocardiography and cardiac MRI even when ejection fraction is preserved, diffuse myocardial fibrosis, endothelial dysfunction and accelerated arterial stiffness from childhood, increased arrhythmia susceptibility, and, in a single-center cohort, an unexpectedly high prevalence of pericardial calcification (18%) on chest CT that awaits independent replication. Paradoxically, while HEMT has dramatically improved pulmonary outcomes, it introduces new cardiovascular considerations including hypertension, dyslipidemia, and obesity, and cross-sectional data in modulator-treated cohorts show persistent cardiac abnormalities, though whether these predate treatment or would differ without it is unknown. This review synthesizes the genetic, molecular, and clinical dimensions of cardiovascular disease in CF; distinguishes direct CFTR-mediated cardiac effects from indirect consequences of chronic lung disease; examines vascular, electrophysiological, valvular, and pericardial manifestations; and discusses management implications including CFTR modulator therapy, exercise, nutritional paradigm shifts, and transplantation considerations.