Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but data regarding the safety and efficacy of BPA in patients with CTED are lacking. We report a prospective series of ten consecutive patients with CTED who underwent 35 BPA interventions (median of four per patient) at two German institutions. All patients underwent a comprehensive diagnostic workup at baseline and 24 weeks after their last intervention. BPA was safe, with one pulmonary vascular injury and subsequent self‐limiting pulmonary bleeding as the only complication (2.9% of the interventions, 10% of the patients). After the procedures, World Health Organization functional class, 6‐min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT‐proBNP concentrations declined in 9/10 patients. BPA may be a new treatment option for carefully selected patients with CTED. A larger, prospective, international registry is required to confirm these results.

Riociguat is the treatment of choice for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). We addressed here whether additional balloon pulmonary angioplasty (BPA) provides further benefits. A prospective series of 36 consecutive patients with inoperable CTEPH were treated with riociguat at least three months before BPA. All patients underwent diagnostic workup at baseline, before BPA treatments, and six months after final intervention. The main outcome measures were pulmonary hemodynamic parameters and World Health Organization (WHO) functional class (FC). Significant improvements in pulmonary hemodynamics and physical capacity were observed for riociguat treatment, and subsequent BPA interventions yielded further benefits. With targeted medication, WHO FC improved by at least one class in 13 (36.1%) patients (P = 0.01). Hemodynamic assessment showed significant improvements in mean pulmonary arterial pressure (mPAP) (49 ± 12 mmHg vs. 43 ± 12 mmHg; P = 0.003) and PVR (956 ± 501 dyn·s·cm^–5 vs. 517 ± 279 dyn·s·cm^–5; P = 0.0001). Treatment with a combination of targeted medication and BPA resulted in WHO FC improvement in 34 (94.4%) patients. Hemodynamic assessment showed significant improvement in mPAP (43 ± 12 mmHg vs. 34 ± 14 mmHg; P = 0.0001) and PVR (517 ± 279 dyn·s·cm^–5 vs. 360 ± 175 dyn·s·cm^–5; P = 0.0001). These findings provide, for the first time, support for the therapeutic strategy recommended by current guidelines.

Extracellular vesicles are released by numerous cell types of the human body under physiological but also under pathophysiological conditions. They are important for cell–cell communication and carry specific signatures of peptides and RNAs. In this study, we aimed to determine whether extracellular vesicles isolated from patients with pulmonary hypertension show a disease specific signature of small non-coding RNAs and thus have the potential to serve as diagnostic and prognostic biomarkers. Extracellular vesicles were isolated from the serum of 23 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and 23 controls using two individual methods: a column-based method or by precipitation. Extracellular vesicle- associated RNAs were analyzed by next-generation sequencing applying molecular barcoding, and differentially expressed small non-coding RNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). We identified 18 microRNAs and 21 P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) or piRNA clusters that were differentially expressed in CTEPH patients compared with controls. Bioinformatic analysis predicted a contribution of these piRNAs to the progression of cardiac and vascular remodeling. Expression levels of DQ593039 correlated with clinically meaningful parameters such as mean pulmonary arterial pressure, pulmonary vascular resistance, right ventricular systolic pressure, and levels of N-terminal pro-brain natriuretic peptide. Thus, we identified the extracellular vesicle- derived piRNA, DQ593039, as a potential biomarker for pulmonary hypertension and right heart disease.