Evaluation of the BMPR2-Activin Signaling Pathway in Group II Pulmonary Hypertension.

Heart Failure, Pulmonary Hypertension Due to Left Heart Disease, Pulmonary Hypertension (PH)

BMPR2, Activin, cardiac transplant, pulomnary hypertension II, gene expression, microRNAs

Previous data from our group showed reduced BMPR2 isoform A in pulmonary hypertension associated with left heart disease (PH-LHD) of valvular origin. Focusing on dysregulation of the BMPR2-activin pathway, a key regulator of vascular homeostasis, this project uses a multimodal approach combining molecular biology, advanced cardiac imaging, and histology. Its aim is to determine the role of the BMPR2-activin pathway in the development and regression of PH-LHD. We will conduct a prospective observational study with 1-year follow-up in 150 heart failure patients of different etiologies undergoing hemodynamic assessment. Clinical parameters, biomarkers, molecular profiles, and hemodynamic/echocardiographic variables will be analyzed. A nested substudy in 40 heart transplant candidates will include thoracic CT for vascular morphometric analysis and histological correlation in explanted hearts versus healthy controls. We will also assess reversibility of vascular remodeling one year after transplantation. Results may redefine PH-LHD classification, enable phenotypic precision-medicine models, guide targeted therapies such as activin inhibitors, and refine transplant criteria in combined pulmonary hypertension.

This is a longitudinal observational study involving patients with heart failure (HF), including a substudy of advanced HF patients awaiting heart transplantation (BREATHE-CT). The main cohort will include 150 HF patients of diverse etiologies undergoing invasive hemodynamic assessment by right heart catheterization. Approximately 70 patients are expected to have PH-LHD and 80 will not. Eligible participants include advanced HF patients assessed for heart transplantation or ventricular assist devices, patients hospitalized for severe acute HF decompensation, and those undergoing pre-valvular intervention evaluation. The BREATHE-CT substudy will include 40 advanced HF patients selected from the main cohort and listed for heart transplantation. Eligibility requires fulfillment of inclusion criteria and written informed consent. Advanced HF and pulmonary hypertension classification will follow current European Society of Cardiology guidelines. To improve representativeness, the study prioritizes inclusion of historically underrepresented groups, particularly women, given their increased risk for pulmonary hypertension.

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