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

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.

Stam K ，Cai Z ，van der Velde N ，van Duin R ，Lam E ，van der Velden J ，Hirsch A ，Duncker DJ ，Merkus D ... -  《-》

Exercise facilitates early recognition of cardiac and vascular remodeling in chronic thromboembolic pulmonary hypertension in swine.

Stam K ，van Duin RWB ，Uitterdijk A ，Cai Z ，Duncker DJ ，Merkus D ... -  《-》

Right ventricular adaptation to pressure-overload: Differences between chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH. We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders. We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p < .01), and a lower RV relative wall thickness (0.6 ± 0,1 g/ml vs 0.7 ± 0,2 g/ml; p < .01). The correlation coefficient of RV diastolic stiffness to afterload was higher in CTEPH compared to iPAH (p < .05; independent of age and gender). Despite differences in patient characteristics, disease etiology and physiology, RV functional parameters in CTEPH and iPAH are mostly similar. The right ventricle in CTEPH is marginally more dilated, stiffer and less hypertrophic than in iPAH.

Braams NJ ，van Leeuwen JW ，Vonk Noordegraaf A ，Nossent EJ ，Ruigrok D ，Marcus JT ，Bogaard HJ ，Meijboom LJ ，de Man FS ... -  《-》

Early return of reflected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension.

Fukumitsu M ，Westerhof BE ，Ruigrok D ，Braams NJ ，Groeneveldt JA ，Bayoumy AA ，Marcus JT ，Meijboom LJ ，de Man FS ，Westerhof N ，Bogaard HJ ，Vonk Noordegraaf A ... -  《-》

Long-term changes of right ventricular myocardial deformation and remodeling studied by cardiac magnetic resonance imaging in patients with chronic thromboembolic pulmonary hypertension following pulmonary thromboendarterectomy.

Right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is associated with reduced myocardial contractility and ventriculoarterial coupling. The impact of increased afterload on RV myocardial deformation was assessed by comparing the characteristics of CTEPH patients to healthy controls at baseline, and by comparing characteristics of CTEPH patients before and 12 months after pulmonary endarterectomy (PEA). Cardiac deformation and function of CTEPH patients (n = 20) and healthy controls (n = 20) were assessed by cardiac magnetic resonance (CMR). CTEPH patients were also examined with right heart catheterization before and 12 months after PEA. PEA resulted in significant improvement of invasive hemodynamics and normalization of RV hypertrophy and right atrial, RV and left ventricular dimensions and volumes. RV ejection fraction improved from 30 ± 13% at baseline to 44 ± 10% at 12 months (p < 0.0001) but remained decreased compared with control subjects (54 ± 4%, p < 0.05). RV global circumferential strain (GCS) normalized 12 months after PEA, but RV global longitudinal strain (GLS) remained significantly lower in CTEPH patients than controls (baseline -12.9 ± 3.3% vs. -16.5 ± 3.6% at 12 months p < 0.01, vs. controls -19.3 ± 3.2%, p < 0.05). RV mass changes were significantly correlated with RV-ejection fraction, RV-GLS, and RV-GCS. RV-pulmonary arterial coupling with the volume method improved at 12 months (0.49 ± 0.30 vs. 0.84 ± 0.31, p < 0.0005), but remained significantly reduced compared with healthy controls (1.19 ± 0.20, p < 0.0005). RV global longitudinal and circumferential myocardial three-dimensional strain by CMR improved significantly in CTEPH patients 12 months after PEA. Improvements in myocardial deformation were associated with regression of RV hypertrophy and decrease in pulmonary artery pressure.

Waziri F ，Ringgaard S ，Mellemkjær S ，Bøgh N ，Kim WY ，Clemmensen TS ，Hjortdal VE ，Nielsen SL ，Poulsen SH ... -  《-》