Diastolic dysfunction precedes hypoxia-induced mortality in dystrophic mice

Abstract

Duchenne muscular dystrophy (DMD) is a progressive striated muscle disease that is characterized by skeletal muscle weakness with progressive respiratory and cardiac failure. Together respiratory and cardiac disease account for the majority of mortality in the DMD patient population. However, little is known regarding the effects of respiratory dysfunction on the dystrophic heart. The studies described here examine the effects of acute hypoxia on cardiac function. These studies demonstrate, for the first time, that a mouse model of DMD displays significant mortality following acute exposure to hypoxia. This mortality is characterized by a steady decline in systolic function. Retrospective analysis reveals that significant decreases in diastolic dysfunction, especially in the right ventricle, precede the decline in systolic pressure. The initial hemodynamic response to acute hypoxia in the mouse is similar to that observed in larger species, with significant increases in right ventricular afterload and decreases in left ventricular preload being observed. Significant increases in heart rate and contractility suggest hypoxia-induced activation of the sympathetic nervous system. These studies provide evidence that while hypoxia presents significant hemodynamic challenges to the dystrophic right ventricle, global cardiac dysfunction precedes hypoxia-induced mortality in the dystrophic heart. These findings are clinically relevant as the respiratory insufficiency evident in patients with DMD results in significant bouts of hypoxia. The results of these studies indicate that hypoxia may contribute to the acceleration of the heart disease in DMD patients. Importantly, hypoxia can be avoided through the use of ventilatory support.

Hypoxia-induced cardiac injury in dystrophic mice

“…In the studies presented here, the mdx mouse is used to assess the pathophysiological importance of hypoxia. Recent studies have demonstrated that acute exposure of anesthetized mdx mice to hypoxia is associated with acute myocardial decompensation, characterized by initial diastolic and subsequent systolic dysfunction (65). In the present study, it is shown that this acute hypoxia-induced mortality in anesthetized mice is associated with the development of metabolic acidosis.…”

“…This observation is particularly important because of the frequency with which patients with DMD are subjected to bouts of hypoxia. Studies in anesthetized mdx mice monitoring hemodynamic function of the dystrophic heart during hypoxia exposure reveal that hypoxia-induced mortality is preceded initially by diastolic dysfunction, which transitions into a gradual decline in systolic function (65). The present studies provide important mechanistic insight into the potential causes of this hypoxia-induced mortality.…”

“…Dystrophic mice have increased mortality and metabolic acidosis following hypoxia. Previous studies have demonstrated that anesthetized dystrophic mice exposed to acute hypoxia display increased mortality linked to the initial development of diastolic dysfunction followed by cardiac decompensation and death (65). These prior studies used invasive cardiac catheterization featuring a thoracotomy and artificial ventilation, which may have contributed to the increased mortality.…”

“…For these studies, death was defined as a heart rate of Ͻ200 beats/min, coupled with the loss of pulse measurements by the pulse oximeter. Previous studies have indicated that heart rates of Ͻ200 beats/min in the mouse are associated with pulseless electrical activity and occur following hemodynamic collapse (65).…”

Smooth Muscle Cells of Dystrophic (mdx) Mice Are More Susceptible to Hypoxia; The Protective Effect of Reducing Ca2+ Influx

“…The elevation in [Ca 2+ ] i induced by hypoxia may be a common mediator contributing to cell injury in VSMCs and other tissues, such as cardiac cells and neurons. In mdx cardiac cells, acute hypoxia causes diastolic and systolic dysfunction [11].…”