Open Access

ARTICLE

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease

Mariana M. Clavé¹, Nair Y. Maeda², Ana M. Thomaz¹, Sergio P. Bydlowski³, Antonio A. Lopes¹

1 Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil
2 Pró‐Sangue Foundation, São Paulo, Brazil
3 LIM‐31, University of São Paulo School of Medicine, São Paulo, Brazil

* Corresponding Author: Antonio A. Lopes, MD, PhD, FAHA, FPVRI, Department of Pediatric Cardiology and Adult Congenital Heart Disease, Heart Institute (InCor), University of São Paulo School of Medicine, Av. Dr. Enéas de Carvalho Aguiar, 44, 05403‐000, São Paulo, Brazil. Email:

Congenital Heart Disease 2019, 14(2), 246-255. https://doi.org/10.1111/chd.12688

Abstract

Background: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient’s physical capacity.
Methods: We analyzed circulating (plasma) markers of endothelial and platelet activation/dys‐ function (enzyme‐linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty‐one patients were enrolled (age 10‐54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tada‐ lafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days.
Results: Compared to controls, patients had elevated baseline β‐thromboglobulin (β‐TG, P = .002), P‐selectin (P = .027), tissue‐type plasminogen activator (t‐PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of β‐TG (P = .004), t‐PA (P = .003) and TM (P = .046) levels, while P‐selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6‐minute test, P < .05), he‐ matocrit and hemoglobin level (P < .05), and health‐related quality of life (physical and mental components, P < .05).
Conclusion: In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

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