Introduction:

DMD is an X-linked genetic disorder resulting from the loss of the muscle protein dystrophin. In DMD patients, the progressive deterioration at the cardiac and diaphragm muscles worsens cardio-pulmonary function. Muscle membranes from fibers deficient in dystrophin are more susceptible to contraction-induced injury. Consequently, cycles of injury and repair occur, resulting in progressive muscle weakness and fibrosis, especially in the heart and diaphragm. One of the consequences of ventilatory failure is hypoxemia, which leads to hypoxia-induced diaphragm damage. Moreover, ECGs of DMD patients show tall right precordial R-waves, arrhythmias, conduction abnormalities, left ventricular dilation and cardiac autonomic dysfunction. However, little is known about the basic cardio-respiratory physiology in the mdx mouse. All this evidence lead us to hypothesize that the necrosis on cardio-ventilatory muscles in mdx mice leads to 1) abnormalities in ECG and in Vectorcardiogram (VCG) and 2) lower PaO₂ due to ventilatory insufficiency, hasting the muscle damage, which turns into a vicious cycle that worsens the ventilatory parameters. To test our hypothesis, we measured cardio-ventilatory parameters by studying the ECG and VCG parameters, arterial blood gas pressures, and by exposing the animals to different levels of oxygen and CO₂ in a whole body plethysmograph. We observed that mdx model have chronically lower levels of PaO₂ and higher levels of PaCO₂, a blunted response to mild hypoxia which would explain the progressive necrosis of the diaphragm. Furthermore, we extended the ECG knowledge in mdx mouse and provided new evidence of cardiac function through VCG analysis.

Material & Methods:

Age matched mouse male C57BL/10ScSnJ (normal) and C57BL/10ScSn-DMD ^mdx /J (mdx) were used. In order to measure the hypoxic ventilatory responses (HVR), we custom built a whole body plethysmograph (WBP) chamber (150 mL). The animals were exposed to graded levels of hypoxia to determine respiratory rate (f_R), V _T , and minute ventilation (V _E ) to characterize the HVR. The phrenic nerve activity was recorded from bipolar platinum electrode and lifted on mineral oil. The electrical activity of the heart was obtained using leads I and II. To calculate the VCG, the leads III, aVR, aVL and aVF ECG were obtained mathematically.

Conclusion:

The absence of dystrophin impairs the normal ventilation and the response to mild hypoxia, characterizing this response as a blunted or hypoxic desensitization to new hypoxic stimuli.The mentioned blunted HVR in mdx mice was reflected in the arterial blood gas concentration, resulting in animals being hypoxemic and hypercapnic.The time increase of the P-wave, PR interval and QRS complex suggest several cardiac abnormalities.The increase on QTc interval, ST height and T-wave amplitude suggest myocardial ischemia focus.The changes in VCG suggest radical alteration on the electrical activity and support the ECG findings.