Acute Biomechanical Effects of Empagliflozin on Living Isolated Human Heart Failure Myocardium

Abstract

Purpose Multiple randomized controlled trials have presented SGLT2 inhibitors (SGLT2i) as novel pharmacological therapy for patients with heart failure, resulting in reductions in hospitalization for heart failure and mortality. Given the absence of SGLT2 receptors in the heart, mechanisms of direct cardioprotective effects of SGLT2i are complex and remain to be investigated. In this study, we evaluated the direct biomechanical effects of SGLT2i empagliflozin on isolated myocardium from end-stage heart failure patients. Methods Ventricular tissue biopsies obtained from 7 patients undergoing heart transplantation or ventricular assist device implantation surgery were cut into 27 living myocardial slices (LMS) and mounted in custom-made cultivation chambers with mechanical preload and electrical stimulation, resulting in cardiac contractions. These 300 µm thick LMS were subjected to 10 µM empagliflozin and with continuous recording of biomechanical parameters. Results Empagliflozin did not affect the maximum contraction force of the slices, however, increased total contraction duration by 13% (p = 0.002) which was determined by prolonged time to peak and time to relaxation (p = 0.009 and p = 0.003, respectively). Conclusion The addition of empagliflozin to LMS from end-stage heart failure patients cultured in a biomimetic system improves contraction and relaxation kinetics by increasing total contraction duration without diminishing maximum force production. Therefore, we present convincing evidence that SGLT2i can directly act on the myocardium in absence of systemic influences from other organ systems.

Effects of empagliflozin on right ventricular adaptation to pressure overload

“…More knowledge is needed to elucidate whether this single increase in Tau logistic depicts a potential worsening of diastolic function at this disease stage. Accordingly, the diuretic effect may explain some of the RV effects seen in present study, but we cannot exclude other mechanisms might play a role, as recent studies describe a direct cardiac effect of empagliflozin on cardio myocytes and SGLT2-knock out mice without affecting systemic SGLT2 function (36)(37)(38). Either way, we solely see a slight disease reduction and not a normalization of RV function in present study, emphasizing the need for further investigation of empagliflozin's role as a potentially new therapy complimenting current RV failure management.…”

Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects

“…Thus, the beneficial effects of empagliflozin on the heart are unlikely to involve angiotensin. Yet, importantly, SGLT2 expression in the heart is absent [6,32], and thus any local cardiac effect of empagliflozin must be due to an off-target effect. Indeed, empagliflozin did improve contraction and relaxation kinetics in human left ventricular tissue slices, and reduced infarct size in the isolated Langendorff-perfused mouse heart exposed to 30 min of global ischemia [6,32].…”

“…Yet, importantly, SGLT2 expression in the heart is absent [6,32], and thus any local cardiac effect of empagliflozin must be due to an off-target effect. Indeed, empagliflozin did improve contraction and relaxation kinetics in human left ventricular tissue slices, and reduced infarct size in the isolated Langendorff-perfused mouse heart exposed to 30 min of global ischemia [6,32]. It has also been shown to suppress inflammation and sympathetic activity in the rat heart [33].…”

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

“…In view of a lack of effect of OM on intracellular Ca-transients, the functional significance of this change is not clear. Moreover, tests of effects of OM in living tissue slices from human HF patients showed that although there was an increase in contractility and duration of contraction time, relaxation was impaired [103]. The relaxation prolongation worsened with increased beating rates and was suggested to possibly promote arrhythmias.…”