Left ventricular and aortic dysfunction in cystic fibrosis mice

Abstract

Background: Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease.

Methods: Using gut-corrected F508del CFTR mutant mice (ΔF508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization.

Results: ΔF508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (-dP/dt, Tau). Aortas displayed increased stiffness and altered diastolic flow. β-adrenergic stimulation revealed diminished cardiac reserve (attenuated +dP/dt,-dP/dt, LV pressure).

Conclusions: In a mouse model of CF, CFTR mutation leads to LV remodeling with alteration of cardiac and aortic functions in the absence of lung disease. As CF patients live longer, more active lives, their risk for cardiovascular disease should be considered.

Keywords: Aorta; CFTR; Cystic fibrosis; Left ventricular function.

Figure 1. ΔF508 CFTR mice show increased baseline cardiac activity

LV hemodynamic measurements were performed in WT (n=9) and ΔF508 (n=12) mice via catheterization. Each circle represents a single mouse, while the line represents the mean.

Figure 2. CFTR mutation causes increases aortic stiffness

In vivo, aortic compliance was measured using echocardiography in WT and ΔF508 mice (n=10). A. Representative images of WT and ΔF508 aortic arches using M-mode images presented with values for mean internal diameters (ID) of aorta (Ao) during diastole (d) and systole (s). B. Distensibility was calculated as the relative change in diameter between systole and diastole. C. Pulse wave velocity-measured aortic stiffness. D. Representative Doppler flow images during 2 cycles of systole and diastole through the aortic arches of WT and ΔF508 mice. The straight line represents zero blood velocity with below the line showing velocity of forward flow as blood moves away from probe and above the line showing velocity of retrograde flow as blood moves towards probe. Values for the mean forward and retrograde velocities are presented. All values are presented as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. WT by Student’s t-test.

Figure 3. Decreased cardiac reserve in ΔF508 mice during β-adrenergic stimulation

LV catheterization-measured hemodynamic changes following stimulation with serial concentrations of the β₁-adrenergic agonist dobutamine in WT (n=9) and ΔF508 (n=12) mice. Data are shown as percent change from the respective baseline (Figure 1) for each concentration. Values are expressed as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. WT by Student’s t-test.