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. 2021 Oct 1;321(4):H702-H715.
doi: 10.1152/ajpheart.00046.2021. Epub 2021 Aug 27.

Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension

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Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension

Ethan D Kwan et al. Am J Physiol Heart Circ Physiol. .

Abstract

Although pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening.NEW & NOTEWORTHY Using a novel combination of hemodynamic and morphological measurements over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we found that compensated systolic function was almost entirely explained by RV hypertrophy, but subsequently altered RV end-diastolic mechanics were primarily explained by passive myocardial stiffening that was not associated with significant collagen extracellular matrix accumulation.

Keywords: diastolic function; mathematical modeling; pulmonary arterial hypertension; sugen-hypoxia; systolic function.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1.
Figure 1.
In vivo hemodynamic measurements in SuHx rats through the 10-wk time course of the study showed significant increases by week 3 in end-systolic (ES) right ventricular pressure (A) and total pulmonary vascular resistance (C), and significant increases by week 5 in end-diastolic (ED) pressure (B) and peak positive time derivative of right ventricular pressure (F). Although ES volume (D) increased significantly, ED volume (E) was preserved throughout the study apart from a small but significant increase at week 3, and stroke volume (G) was only significantly lower than control after week 6. Mean ejection fraction (H) decreased significantly by week 4 but did not change after week 4 (P > 0.05, comparison not shown). The magnitude of peak negative time derivative of pressure (I) increased significantly at week 3 and after week 4. Data are shown as means ± SE, *P < 0.05 and #P < 0.01 compared with the control group. SuHx, sugen-hypoxia.
Figure 2.
Figure 2.
Masses of right ventricle (A), left ventricle plus septum (B), and their mass ratio (C), and right ventricular wall thickness (D) and estimated V0 (E). Data are shown as means ± SE, *P < 0.05 and #P < 0.01 compared with the control group. LV, left ventricle; S, septum; RV, right ventricle; V0, unloaded volume.
Figure 3.
Figure 3.
Pressure-volume (P-V) during caval occlusion to determine end-systolic (ES) and end-diastolic (ED) P-V relations for a control (A, green) and a 6-wk SuHx (B, blue) animal. ES elastance Ees (C), ED elastance Eed (D), arterial elastance Ea (E), and ventricular-vascular coupling Ees/Ea (F). Data are shown as means ± SE, *P < 0.05 and #P < 0.01 compared with the control group. SuHx, sugen-hypoxia.
Figure 4.
Figure 4.
Measurements of control (white bars) and SuHx (gray bars) RV pressure for end systole (A) and end diastole (B) compared with model predictions of pressure using SuHx volume with control geometry and material properties (green); SuHx volume and geometries with control material properties (black); and SuHx volume, geometries, and material properties (blue). Green bars with * indicate a significant contribution of RV volume to increased ES or ED pressure compared with control (white bars). Black bars with # indicate a significant contribution of RV hypertrophy to increased ES (A) or ED (B) pressure compared with the contributions of volume alone (green bars). Blue bars with £ indicate a significant contribution of altered myofilament activation (A) or myocardial resting stiffness (B) to increased ES or ED pressure compared with volume and geometry (black bars). Data are shown as means ± SE, P < 0.05. ED, end-diastolic; ES, end-systolic; RV, right ventricle; SuHx, sugen-hypoxia.
Figure 5.
Figure 5.
Model-predicted mean active end-systolic (top) and passive end-diastolic (bottom) fiber stress-sarcomere length relations for control (green) and SuHx (blue) rats at weeks 3 (A), 4 (B), 5 (C), 6 (D), 8 (E), and 10 (F). The slope of the active stress-sarcomere length relation was only significantly higher than control in week 5 (P < 0.05). Predicted mean passive stress-sarcomere length relations were significantly stiffer in SuHx than in control rats at weeks 5, 8, and 10 (*P < 0.05). SuHx, sugen-hypoxia.
Figure 6.
Figure 6.
Histological collagen to myocyte area fraction (A) from Masson’s trichrome-stained RV sections in control (D) rats and SuHx rats at weeks 3 (E), 4 (F), 6 (G), 8 (H), and 10 (I) was only significantly different from control at week 6 (*P < 0.05). RV myocardial total collagen content (B) and collagen type I to III ratio (C) showed no significant changes throughout the study (P > 0.05). Data are shown as means ± SE compared with the control group. RV, right ventricle; SuHx, sugen-hypoxia.

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