The Comparative Pathobiology of Stress-induced and Sepsis-induced Cardiomyopathy

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Abstract

One of the primary treatments of septic shock to maintain blood pressure is with fluids (colloids and crystalloids), and catecholamines. Paradoxically, catecholamines administered to treat sepsis-induced low blood pressure, and released within the vasculature as part of the stress response to shock, could be responsible for or contribute to, the worsening of cardiac dysfunction during sepsis (i.e. stress-induced cardiomyopathy). Consistent with the notion that sepsis is at least in part a stress-induced cardiomyopathy, we have shown in our large animal septic shock model that epinephrine can worsen cardiac function during sepsis. In this protocol, we tested this hypothesis directly in a 2 by 2 factorial design using animals randomized to receive a bacterial inoculation to develop a pneumonia model of septic shock (or not) and then further randomized to receive a 40 h epinephrine infusion (or not). Hemodynamic parameters included serial echocardiograms, central and peripheral pressures and cardiac output. Unexpectedly, the epinephrine infusion was found to mitigate the myocardial depression of septic shock and promote a quicker functional recovery. We then investigated whether this new finding can provide novel insights about underlying causes of myocardial depression in septic shock and if there are beneficial effects associated with epinephrine in sepsis. Using cardiac MRI, the effects of sepsis on the heart in our sedated and ventilated pneumonia model of sepsis that simulates the cardiac dysfunction seen during human septic shock confirmed the well characterized reversible cardiac dysfunction leading to a reduced ability of the heart to contract (ejection fraction) and an increase in the size of the ventricle. (1) When comparing the heart injury in survivors to non-survivors, the critical factor associated with survival we showed for the first time appeared to be solely the left ventricles ability to fully dilate during recovery. These changes in ventricular size had previously been wrongly explained by either increases in the filling of the heart (preload) or increased resistance to outflow (afterload). We have shown that changes in loading and afterload conditions are not responsible in this study and by exclusion, are related rather to sepsis induced changes in the wall of the heart itself. Associated with recovery of the hearts ability to eject blood or contract, we surprisingly showed for the first time, the left ventricular wall was found to lose mass (15%) and develops an increased percentage of water (edema) over 92 h (2 to 3%). This degree of edema is enough to fully explain the cardiac dysfunction seen during sepsis. There is no biochemical (troponin levels) or histological (light and electron microscopy) evidence that this loss of mass is due to muscle cell loss (myocyte drop out) or damage from decrease tissue perfusion (ischemia). The loss of mass occurs as the heart is recovering (the ejection fraction is returning to normal) suggesting that it may represent a reparative remodeling of the heart.