Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Abstract

Duchenne muscular dystrophy (DMD) is a progressive disease of striated muscle deterioration. Respiratory and cardiac muscle dysfunction are particularly clinically relevant because they result in the leading causes of death in DMD patients. Despite the clinical and physiological significance of these systems, little has been done to understand the cardiorespiratory interaction in DMD. We show here that prior to the onset of global cardiac dysfunction, dystrophin-deficient mdx mice have increased cardiac fibrosis with the right ventricle being particularly affected. Using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing, we demonstrate that both the right and left ventricles have significant reductions in both systolic and diastolic function in response to dobutamine. Unstimulated cardiac function is relatively normal except for a significant reduction in the ventricular pressure transient duration compared with controls. These biventricular analyses also reveal the absence of a dobutamine-induced increase in isovolumic relaxation in the right ventricle of control hearts. Simultaneous assessment of biventricular pressure demonstrates a dobutamine-dependent enhancement of coupling between the ventricles in control mice, which is absent in mdx mice. Furthermore, studies probing the passive-extension properties of the left ventricle demonstrate that the mdx heart is significantly more compliant compared with age-matched C57BL/10 hearts, which have an age-dependent stiffening that is completely absent from dystrophic hearts. These new results indicate that right ventricular fibrosis is an early indicator of the development of dystrophic cardiomyopathy, suggesting a mechanism by which respiratory insufficiency may accelerate the development of heart failure in DMD.

Diastolic dysfunction precedes hypoxia-induced mortality in dystrophic mice

“…Furthermore, these mice have significant reductions in cardiac function (Lu and Hoey 2000; Quinlan et al. 2004; Meyers and Townsend 2015) and significant reductions in respiratory function (Farkas et al. 2007; Ishizaki et al.…”

Heart structural remodeling in a mouse model of Duchenne cardiomyopathy revealed using optical polarization tractography [Invited]

“…The group average of the slope was significantly smaller (p = 0.004, Student's t-test) in the mdx RV (20.3 ± 28.4°/mm) than in the BL6 RV (67.9 ± 12.6°/mm). The severe structural remodeling observed in the RV of the 7-month-old mdx mouse is most likely caused by the diaphragm degeneration related pulmonary dysfunction [17,18]. Deterioration of the respiratory function increases pulmonary vascular resistance which then leads to increased RV stress [17].…”

“…The severe structural remodeling observed in the RV of the 7-month-old mdx mouse is most likely caused by the diaphragm degeneration related pulmonary dysfunction [17,18]. Deterioration of the respiratory function increases pulmonary vascular resistance which then leads to increased RV stress [17]. This process eventually results in tissue damage in the RV [17,18].…”

“…Deterioration of the respiratory function increases pulmonary vascular resistance which then leads to increased RV stress [17]. This process eventually results in tissue damage in the RV [17,18]. The global heart structural remodeling can be a direct consequence of the myofiber damage in the RV.…”

Comparison of right and left ventricular function and size in Duchenne muscular dystrophy

“…They also demonstrated a trend toward a decrease with age for LVEF at rest (p = 0.051) but not for RVEF (p = 0.8). A recent study by Meyers et al using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing reported that in dystrophin deficient mdx mice the RV was particularly affected by cardiac fibrosis [22]. Although unstimulated cardiac function was relatively normal, there were significant reductions in RV and LV systolic and diastolic function in response to dobutamine.…”