Cardiac remodelling in a swine model of chronic thromboembolic pulmonary hypertension: comparison of right vs. left ventricle.

Kelly Stam,Zongye Cai,Richard Van Duin,Dirk J Duncker,Esther Lam,Nikki Van Der Velde,Daphne Merkus,Jolanda Van Der Velden,Alexander Hirsch

doi:10.1113/jp277896

Abstract

Key points Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH).The changes in right and left ventricle gene expression that contribute to ventricular remodelling are incompletely investigated.RV remodelling in our CTEPH swine model is associated with increased expression of the genes involved in inflammation (TGFβ), oxidative stress (ROCK2, NOX1 and NOX4), and apoptosis (BCL2 and caspase‐3).Alterations in ROCK2 expression correlated inversely with RV contractile reserve during exercise.Since ROCK2 has been shown to be involved in hypertrophy, oxidative stress, fibrosis and endothelial dysfunction, ROCK2 inhibition may present a viable therapeutic target in CTEPH. Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The present study investigated whether the increased cardiac afterload is associated with (i) cardiac remodelling and hypertrophic signalling; (ii) changes in angiogenic factors and capillary density; and (iii) inflammatory changes associated with oxidative stress and interstitial fibrosis. CTEPH was induced in eight chronically instrumented swine by chronic nitric oxide synthase inhibition and up to five weekly pulmonary embolizations. Nine healthy swine served as a control. After 9 weeks, RV function was assessed by single beat analysis of RV–pulmonary artery (PA) coupling at rest and during exercise, as well as by cardiac magnetic resonance imaging. Subsequently, the heart was excised and RV and left ventricle (LV) tissues were processed for molecular and histological analyses. Swine with CTEPH exhibited significant RV hypertrophy in response to the elevated PA pressure. RV–PA coupling was significantly reduced, correlated inversely with pulmonary vascular resistance and did not increase during exercise in CTEPH swine. Expression of genes associated with hypertrophy (BNP), inflammation (TGFβ), oxidative stress (ROCK2, NOX1 and NOX4), apoptosis (BCL2 and caspase‐3) and angiogenesis (VEGFA) were increased in the RV of CTEPH swine and correlated inversely with RV–PA coupling during exercise. In the LV, only significant changes in ROCK2 gene‐expression occurred. In conclusion, RV remodelling in our CTEPH swine model is associated with increased expression of genes involved in inflammation and oxidative stress, suggesting that these processes contribute to RV remodelling and dysfunction in CTEPH and hence represent potential therapeutic targets.

Highlights

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism (Lang et al 2016; Simonneau et al 2017)
The main findings were that chronic thromboembolic pulmonary hypertension (CTEPH) resulted in (i) Right ventricle (RV) hypertrophy, both at the global and the myocyte level; (ii) mild RV dysfunction, as indicated by decreased RV–pulmonary artery (PA) coupling and elevated BNP expression, with trends towards an increased RV EDVi and a lower ejection fractions (EF); (iii) a further decrease in RV–PA coupling during exercise that correlated with an increase in ROCK2, NOX1 and NOX4 expression; and (iv) increased VEGFA expression that was accompanied by an increased capillary density in the RV
We previously showed that this combination was required because neither NOS-inhibition, nor embolization alone were sufficient to induce chronically elevated pulmonary artery pressures, whereas the combination of NOS-inhibition and embolization resulted in a progressive increase in Total pulmonary vascular resistance index (tPVRi) that continued to increase after the last embolization and was accompanied by pulmonary microvascular remodelling (Stam et al 2018a,b)

Summary

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism (Lang et al 2016; Simonneau et al 2017). In CTEPH, pulmonary vascular resistance, which is initially elevated because of obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodelling (Lang et al 2016; Simonneau et al 2017). This increased pulmonary vascular resistance augments afterload of the right ventricle (RV), thereby resulting in RV dilatation and RV hypertrophy. RV structural and functional adaptability are important determinants of functional capacity and survival in patients with CTEPH (Hardziyenka et al 2011; van de Veerdonk et al 2016; Claeys et al 2018). It is increasingly recognized that RV dysfunction may influence the left ventricle (LV), both mechanically, via direct mechanical interaction and changes in LV filling, by inducing interventricular asynchrony (Marcus et al 2008; Vonk Noordegraaf et al 2017), as well as via activation of inflammatory pathways, which may be the result of low grade systemic inflammation in combination with neurohumoral activation because of reduced cardiac output (Dell’Italia, 2011; Hardziyenka et al 2011; Naeije & Badagliacca, 2017)

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