Right ventricular diastolic adaptation to pressure overload in different rat strains

Abstract

Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age-matched male rat weanlings were randomized to sham surgery (W-sham, n = 5; SD-sham, n = 4; F-sham, n = 4) or PTB (W-PTB, n = 8; SD-PTB, n = 8; F-PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure and increased RV systolic pressures four-fold in all three PTB groups compared with sham. W- and SD-PTB had a 2.4-fold increase in RV end-systolic volume index compared with sham, while F-PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end-diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F-PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F-PTB rats showed less RV dilatation and a more preserved diastolic function compared with W- and SD-PTB.

Keywords: diastolic dysfunction; pulmonary trunk banding; rat strains; right ventricular failure.

FIGURE 1

Study design. Male Wistar, Sprague Dawley, and Fischer344 rats were randomized to either sham or pulmonary trunk banding (PTB) surgery. One week after the surgery, an echocardiography (echo) was performed on all the rats. Five weeks after surgery, cardiac function was evaluated by echocardiography, magnetic resonance imaging (MRI), and invasive pressure‐volume (PV) measurements. Afterwards the rats were euthanized, and histochemical and molecular analyses were performed on the hearts. Figure created with BioRender.com.

FIGURE 2

Pulmonary trunk banding caused right ventricular systolic dysfunction at end‐of‐study. W: Wistar; SD: Sprague Dawley; F: Fischer344; PTB: Pulmonary trunk banding. Hemodynamic results from pressure‐volume loops: (a) Arterial elastance; (b) End‐systolic elastance, one outlier excluded in F‐sham; (c) Ventriculo‐arterial coupling, one excluded in F‐sham. (d) Tricuspid annular plane systolic excursion (TAPSE) from echocardiography. Following results derived from MRI: (e) Cardiac index as cardiac output/body surface area (BSA); (f) Right ventricular (RV) end‐systolic volume index (index = volume/BSA); (g) RV end‐diastolic volume index. (h) short‐axis RV global circumferential strain (GCS). (i) Long‐axis RV global longitudinal strain. Results are expressed as scatterplots with mean ± SD.

FIGURE 3

Effects of pulmonary trunk banding on heart failure markers, RV fibrosis, and RV histology. W: Wistar; SD: Sprague Dawley; F: Fischer344; PTB: Pulmonary trunk banding. (a) mRNA expression of brain natriuretic peptide (BNP). (b) mRNA expression of transforming growth factor‐β (TGF‐β). (c) mRNA expression of collagen 1. (d) mRNA expression of collagen 3. (e) collagen 1/collagen3 ratio. (f) Fulton index: Right ventricular (RV) weight/(Left ventricular (LV) + septum (S) weight). (g) RV cardiomyocyte cross sectional area (CSA). (h) RV capillary density. (i) RV fibrosis. In G‐I, one W‐sham rat is missing, further one W‐sham and W‐PTB rat are missing in H. Histological sections stained with hematoxylin and eosin from (j, l) W‐sham and (k, m) W‐PTB. Black scale bar equals 50 μm. Gene expression levels quantified by real‐time polymerase chain reaction (PCR) and normalized to 18 s and HPRT. Results presented by box plots. Anatomy and histology data are expressed as scatterplots with mean ± SD.

FIGURE 4

Right ventricular diastolic dysfunction is evident 5 weeks after pulmonary trunk banding surgery. W: Wistar; SD: Sprague Dawley; F: Fischer344; PTB: Pulmonary trunk banding. Hemodynamic results from pressure‐volume loops: (a) Right ventricular (RV) filling pressure as (end‐diastolic pressure)–(beginning of diastolic pressure); (b) RV end‐diastolic elastance; (c) First derivative (minimal) of RV systolic pressure (absolute values); (d) The relaxation time constant, Tau logistic. Following results derived from echocardiography: (e) Early peak of RV relaxation velocity, one rat is missing in W‐sham due to low quality; (f) Late peak of RV relaxation velocity, two rats are missing in W‐sham due to low quality; (g) Early peak of diastolic transtricuspid valve (TV) inflow; (h) RV filling pressure as TVE/e'; (i) Ratio of transtricuspid valve flow velocities. (j) Tricuspid S′/right atrial area index (RAAi). In G‐I, one W‐PTB rat missing due to EA fusion. Results are expressed as scatterplots with mean ± SD.

FIGURE 5

Effects of pulmonary trunk banding on RA function at end‐of‐study. W: Wistar; SD: Sprague Dawley; F: Fischer344; PTB: Pulmonary trunk banding. (a) Right atrial (RA) weight/body surface area (BSA). (b) RA ejection fraction. (c) RA end‐systolic volume index (index = volume/BSA). (d) RA end‐diastolic volume index. Due to low scanning quality one W‐sham, F‐sham, and F‐PTB are missing in RA volume index' and RA‐EF. Results are expressed as scatterplots with mean ± SD.