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

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. AbstractRight 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.

Chronic Thromboembolic Pulmonary Hypertension – What Have We Learned From Large Animal Models

“…Consistent with the findings in a rat model of pulmonary artery banding (94), the mild RV dysfunction in swine with CTEPH was characterized by an increase in the stiff titin isoform N2BA but not with changes in myocardial fibrosis as measured histologically. Furthermore, there was a change in the ratio between Col1 and Col3 in the RV, suggesting relatively more expression of the stiff Col1 isoform (55), which is consistent with data from rats with PAH (94), and may have contributed to a stiffer RV. Although, neither SERCA nor phospholamban gene expression were changed in our CTEPH swine model, it is possible that changes in their phosphorylation may play a role in altered Ca 2+ handling, which is in turn implied to play a role in the development of RV dysfunction (93).…”

“…In the porcine studies from our laboratory, CTEPH was induced with multiple (up to 5) embolizations using an average of 9,000 microspheres of 600-710 µm in diameter per embolization procedure, hence 45,000 microspheres in total (37,55,56). This number is much higher than the number of order 3 and 4 pulmonary small arteries present in the porcine lung and hence should be able to obstruct a sufficiently large part of the pulmonary vasculature.…”

“…RV remodeling is associated with cardiomyocyte hypertrophy, interstitial fibrosis and changes in capillary density (48,55). RV hypertrophy, both in terms of RV weight and RV cardiomyocyte size was accompanied by activation of both pro-and antiapoptotic gene expression (upregulation of Caspase-3 and BCL2 mRNA, respectively).…”

“…RV hypertrophy, both in terms of RV weight and RV cardiomyocyte size was accompanied by activation of both pro-and antiapoptotic gene expression (upregulation of Caspase-3 and BCL2 mRNA, respectively). RV resting function is generally preserved, but BNP expression is increased (48,49,55), suggestive of an increased wall stress. The increased BNP showed a negative correlation with stroke volume and a positive correlation with global RV hypertrophy (48).…”

The Physiology, Pathology, and Therapeutic Interventions for ROCK Isoforms in Diabetic Kidney Disease

“…Initial insights linking ROCK2 to diseases were gleaned from studies implicating ROCK2 as a regulator of, among others, immunity, inflammation, and fibrosis (Yang et al, 2018;Stam et al, 2019;Ricker et al, 2020). With regard to the kidney, we provided the first evidence indicating ROCK2 to be a core component of signaling circuitry that governs DKD progression.…”