Background: 
Pulmonary hypertension (PH) frequently develops secondary to left heart disease (PH-LHD) and then contributes significantly to morbidity and mortality by increasing right ventricular (RV) afterload that ultimately results in RV failure. Although PH-LHD accounts for 65-80% of all PH cases, in comparison to other forms of PH pulmonary vascular remodeling in PH-LHD is little understood, and pharmacological interventions are lacking. In addition to increased pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), the stiffening of pulmonary arteries (PAs) can aggravate PH by amplifying systolic pulse pressure and reducing diastolic flow, thus causing a further increase in RV afterload and distal vessel injury. We hypothesized that PA stiffening could be not only a hallmark and pathomechanism, but also a therapeutic target in PH-LHD.

Results: 
In a prospective clinical trial, we assessed PA stiffening and underlying molecular mechanisms in PA samples of left heart disease (LHD) patients with and without PH. Ex vivo testing of PA biomechanical competences by uniaxial tensile test revealed increased stiffness of the elastic and collagen dominant components of PAs, respectively, and a load-bearing shift from elastin- to collagen-enriched material in PH-LHD patients as compared to LHD patients without PH and healthy controls. Altered PA mechanics correlated positively with mean PAP and PVR. Further analyses of PA samples using RNA sequencing, immunofluorescent and transmission electron microscopy revealed that extracellular matrix (ECM) remodeling in the PA wall precedes the onset of PH in LHD patients. Specifically, PAs of LHD patients without PH showed a marked dysregulation of genes implicated in elastic fiber fragmentation and degradation, while further deterioration of elastic fibers in PH-LHD patients was associated with increased expression of fibrillar collagens crosslinked by advanced glycation end-products. In ex vivo cultured human PAs, elastin stabilization with the polyphenolic compound pentagalloyl glucose (PGG) protected fibers from elastolysis and improved PA mechanical properties. In a rat model of PH-LHD secondary to aortic banding, nanoparticle-based targeted delivery of PGG reduced PA stiffness and normalized RV and pulmonary hemodynamics.

Conclusions: 
Our work provides the first evidence for pulmonary artery stiffening in patients with PH-LHD. We further show that therapeutic stabilization of elastic fibers rescues PA biomechanical competences and attenuates pulmonary hypertension in a preclinical model of PH-LHD. These results highlight the pathogenic significance of pulmonary artery stiffening and reveal the therapeutic potential of ECM-targeted interventions in PH treatment.

This research was supported by DZHK and BMBF