Role of parathyroid-hormone-related peptide in volume or pressure loaded pulmonary vasculature

Objectives

Parathyroid-hormone-related peptide (PTHrP) is a paracrine factor expressed throughout the body with vasodilatative qualities. In vitro, PTHrP is released from the endothelium via a mechano-sensitive mechanism. In vivo data on changes in PTHrP release were collected in two pediatric patient groups.

Methods

(A) Twenty patients (median age 6.1 years), pre- and postinterventional closure of an atrial septal defect (ASD), preclosure Qp/Qs 2.1 ± 0.24. (B) Twenty patients (median age 8.1 years) with pulmonary hypertension (PHT), Rp/Rs 0.36–1.79. (A) Blood samples from pulmonary artery (PA), left atrium (LA), systemic artery (SA) and superior vena cava (SVC); and (B) from PA and SA (baseline, after oxygen and after nebulized iloprost). Determination of PTHrP concentrations ([PTHrP]) by quantitative immunoblot, normalized to SA-[PTHrP], compared by Mann–Whitney U-test. Assessment of average peak (blood flow) velocity (APV) in the PA with intraluminal flow wire (FloMap, Cardiometrics).

Results PHT

In all 11/20 patients with significant oxygen- or ilo-prost-induced drop in Rp/Rs, a significant difference in baseline [PTHrP] was found (PA +43.4 ± 6.1% [P = 0.05] compared with SA). After pressure drop (induced by oxygen/iloprost) [PTHrP] decreased from PA/SA-[PTHrP] of 1.49 ± 0.27 → 1.02 ± 0.17 (P = 0.02) and 1.51 ± 0.21 → 0.88 ± 0.16 (P = 0.0001), respectively. In all patients with lack of inducible vascular reactivity (9/20) no difference was seen in [PTHrP] before (-6.5 ± 2.0%) or after drug application. In addition, an increase in APV after infusion of the endothelium-dependent vasodilator acetylcholine was only seen in patients with significant pressure-induced PTHrP release.

Results ASD

Preclosure [PTHrP] was 55 ± 14.4% higher in the PA than in the SA, further decreasing with distance from the PA: +11.5% ± 5.5% in the LA and -4.1 ± 6.4% in the SVC. Postclosure, the [PTHrP] decreased from +55% to +14.9 ± 4.1%.

Conclusions

There is a clear in vivo correlation between volume (ASD) and pressure (PHT) load and [PTHrP] in the PA system, with an acute decrease in [PTHrP] following drop in volume and/or pressure. In children with PHT, PTHrP may be useful for assessing PA endothelial function and may play a role as a diagnostic or prognostic marker. In patients with ASD the [PTHrP] gradient indicates a release from the right heart and/or proximal PA.