Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock

Abstract

BACKGROUND: Succinate (SI) is a citric acid cycle metabolite that accumulates in tissues during hemorrhagic shock (HS) due to electron transport chain uncoupling. Dimethyl malonate (DMM) is a competitive inhibitor of SI dehydrogenase, which has been shown to reduce SI accumulation and protect against reperfusion injury. Whether DMM can be therapeutic after severe HS is unknown. We hypothesized that DMM would prevent SI buildup during resuscitation (RES) in a swine model of HS, leading to better physiological recovery after RES. METHODS:The carotid arteries of Yorkshire pigs were cannulated with a 5-Fr catheter. After placement of a Swan-Ganz catheter and femoral arterial line, the carotid catheters were opened and the animals were exsanguinated to a mean arterial pressure (MAP) of 45 mm. After 30 minutes in the shock state, the animals were resuscitated to a MAP of 60 mm using lactated ringers. A MAP above 60 mm was maintained throughout RES. One group received 10 mg/kg of DMM (n = 6), while the control received sham injections (n = 6). The primary end-point was SI levels. Secondary end-points included cardiac function and lactate. RESULTS:Succinate levels increased from baseline to the 20-minute RES point in control, while the DMM cohort remained unchanged. The DMM group required less intravenous fluid to maintain a MAP above 60 (450.0 vs. 229.0 mL; p = 0.01). The DMM group had higher pulmonary capillary wedge pressure at the 20-minute and 40-minute RES points. The DMM group had better recovery of cardiac output and index during RES, while the control had no improvement. While lactate levels were similar, DMM may lead to increased ionized calcium levels. DISCUSSION:Dimethyl malonate slows SI accumulation during HS and helps preserve cardiac filling pressures and function during RES. In addition, DMM may protect against depletion of ionized calcium. Dimethyl malonate may have therapeutic potential during HS.

Dimethyl malonate protects the lung in a murine model of acute respiratory distress syndrome

“…[8][9][10][11][12] In both small and large animal models of hemorrhagic shock and resuscitation, our group showed that DMM can protect against damage to the pulmonary endothelial glycocalyx. 2,5 This study is the first to examine the therapeutic use of a malonate ester in an acute lung injury model.…”

“…2 This may be related to using a direct lung injury model, rather than an ischemia-reperfusion model, as seen with myocardial infarction or hemorrhagic shock injury models. 2,8 However, the present study is the first to show that succinate is produced in the pulmonary vasculature endothelium in a model of acute lung injury and that DMM reduces succinate accumulation in this model (Fig. 1).…”

“…This study agrees with our prior work that has shown that succinate is injurious to the endothelial glycocalyx. 2,5 In a rat hemorrhagic shock and resuscitation model, succinate accumulation led to damage to the endothelial glycocalyx. Treatment of animals with DMM preserved the endothelial glycocalyx.…”

“…T he importance of succinate as a proinflammatory metabolite of hypoxia and driver of reactive oxygen species formation in critically injured patients has recently come to light. [1][2][3][4][5] Studies have shown that succinate is a better marker of shock than lactate in critically ill patients. 1 Succinate levels correlate with mortality in patients with combat-related injuries.…”

“…7 In ischemia-reperfusion models, during the reperfusion phase, there is increased availability of oxygen, and the excess succinate that accumulates in tissues during hypoxia becomes rapidly oxidized by succinate dehydrogenase, leading to a large mitochondrial membrane change and reversal of the electron transport change, which drives generation of reactive oxygen species. 2,7 Elevated succinate and reactive oxygen species have been linked to endothelial glycocalyx damage and coagulopathy. 5 Malonate esters have been used to inhibit succinate accumulation and decrease ischemia-reperfusion in several tissue beds such as the kidney, brain, liver, and heart.…”