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. 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. We completed 2 further studies using MRI and CT to describe changes in cardiac chamber dimension and function during sepsis. In the first, we found the cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death. In the second study, we found cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion. In conclusion, the septic cardiomyopathy constitutes a diffuse ultrastructural injury to myocytes with three phases. Initially, there is a decrease in Left Ventricular end Diastolic Volume, and ejection Fraction due to myocyte damage within 6h of bacterial challenge; next, the patient sees a passive Left ventricular end-diastolic volume recovery from 6-30h, where Left ventricle mass loss increases relative wall percent water content, which facilitates wall compliance and LVEDV; and lastly, the patient sees mass loss beyond 30h consistent with an active repair mechanism of myocytes, returning systolic function to normal. Therefore, end-diastolic volume changes are a pathophysiological biomarker for sepsis outcomes. A lower Left Ventricular end Diastolic Volume indicates persistent unrepairable ultrastructure damage with worsening wall compliance and poorer outcomes. Left Ventricular end Diastolic Volume dilation is a sign of near-full recovery of ultrastructure injury, augmenting wall compliance and improving outcomes.