Abstract
Empagliflozin is a newly developed antidiabetic drug to reduce hyperglycaemia by highly selective inhibition of sodium–glucose co-transporter 2. Hyperglycaemia is commonly seen in patients after cardiac arrest (CA) and is associated with worse outcomes. In this study, we examined the effects of empagliflozin on cardiac function in rats with myocardial dysfunction after CA. Non-diabetic male Sprague–Dawley rats underwent ventricular fibrillation to induce CA, or sham surgery. Rats received 10 mg/kg of empagliflozin or vehicle at 10 min after return of spontaneous circulation by intraperitoneal injection. Cardiac function was assessed by echocardiography, histological analysis, molecular markers of myocardial injury, oxidative stress, mitochondrial ultrastructural integrity and metabolism. We found that empagliflozin did not influence heart rate and blood pressure, but left ventricular function and survival time were significantly higher in the empagliflozin treated group compared to the group treated with vehicle. Empagliflozin also reduced myocardial fibrosis, serum cardiac troponin I levels and myocardial oxidative stress after CA. Moreover, empagliflozin maintained the structural integrity of myocardial mitochondria and increased mitochondrial activity after CA. In addition, empagliflozin increased circulating and myocardial ketone levels as well as heart β-hydroxy butyrate dehydrogenase 1 protein expression. Together, these metabolic changes were associated with an increase in cardiac energy metabolism. Therefore, empagliflozin favorably affected cardiac function in non-diabetic rats with acute myocardial dysfunction after CA, associated with reducing glucose levels and increasing ketone body oxidized metabolism. Our data suggest that empagliflozin might benefit patients with myocardial dysfunction after CA.
Highlights
Cardiac arrest (CA) is an important public health challenge, and it seems to account for approximately 50% of all cardiovascular deaths (Fishman et al, 2010)
Our results found that the number of IMJs in cardiomyocytes was significantly decreased after CA, but empagliflozin treatment significantly increased the number of IMJs after CA (1.6 ± 0.4 versus 1.3 ± 0.4, FIGURE 5 | Effect of empagliflozin (EMP) on structural integrity of the myocardial mitochondria after cardiac arrest in rats. (A) Representative heart transmission electron microscopy (TEM) images of heart mitochondria at 24 h after return of spontaneous circulation (ROSC)
In addition to its excellent glucose-lowering effect, recent studies demonstrated that empagliflozin markedly improved myocardial function in diabetic and non-diabetic heart failure (Fitchett et al, 2016; Santos-Gallego et al, 2019; Yurista et al, 2019; Packer et al, 2020)
Summary
Cardiac arrest (CA) is an important public health challenge, and it seems to account for approximately 50% of all cardiovascular deaths (Fishman et al, 2010). Patients who initially achieve ROSC after CA have high morbidity and mortality rates due to post-CA syndrome, including brain injury, myocardial dysfunction, and systemic inflammatory responses (Nolan et al, 2008; Girotra et al, 2012). Post-CA myocardial dysfunction, including arterial hypotension, ventricular arrhythmias, and recurrent CA has been recognized as the leading cause of early death after ROSC (Nolan et al, 2008; Patil et al, 2015). Therapeutic hypothermia has proved effective in clinical studies, pharmacological treatment options presently for post-CA myocardial dysfunction are limited (Hypothermia after Cardiac Arrest Study, 2002). Several clinical studies have suggested that treatment of hyperglycemia may improve morbidity and mortality in critically-ill patients (Van den Berghe et al, 2006; Vogt et al, 2014). Some other studies have shown that tight glucose control through intensive insulin therapy may not necessarily improve outcomes in CA patients (Oksanen et al, 2007; Losert et al, 2008)
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