The storm of controversy surrounding cardiovascular risks of the glucose-lowering drug rosiglitazone (1) triggered a series of obligatory trials on cardiovascular safety of new glucose-lowering drugs (2). After years of neutral trial outcomes (3), a substantial lowering of cardiovascular risk in subjects with type 2 diabetes was shown for the sodium-glucose transporter 2 (SGLT2) inhibitor Empagliflozin, with particularly strong effects on heart failure (4). While the glucose-lowering effect of SGLT2 inhibition is primarily mediated by inhibiting glucose resorption in the distal tubule (5), a variety of pleiotropic effects underlying its cardiovascular benefits have been proposed, including lowering of blood volume and blood pressure (6). In further support of glucose-independent cardioprotective effects of SGLT2 inhibitors, the SGLT2 inhibitor Dapagliflozin exerted similar beneficial effects on heart failure in people with and without diabetes (7).
In heart failure associated with type 2 diabetes, especially with preserved ejection fraction (HFpEF), microvascular endothelial dysfunction has been proposed to drive myocardial dysfunction (8). Endothelial properties related to progression to HFpEF are reduced NO synthesis, increased production of reactive oxygen species and inflammation (8, 9). This hypothesis recently received strong experimental support by the demonstration that a combination of diet-induced obesity and inhibition of NO synthesis was sufficient to cause HFpEF in mice (10).
In the paper of the months, Juni et al. provide further proof of concept for a clinically relevant role of microvascular endothelium in myocardial function and dysfunction. Using an elegant co-culture approach, they demonstrate that NO synthesis by cardiac microvascular endothelial cells (CMEC) enhances cardiomyocyte contraction and relaxation. Cytokine exposure of CMEC impairs cardiomyocyte function by enhancing mitochondrial synthesis of reactive oxygen species (ROS) and scavenging NO. Empagliflozin reversed the effects of inflammation on endothelial function, resulting in restored cardiomyocyte contraction and relaxation (11). Of note, Empagliflozin did not act as a simple ROS scavenger, leaving the question how it decreases mitochondrial ROS production unanswered. A second unanswered question is how NO is transferred to the cardiomyocytes, as endothelium-conditioned medium retained its effect on cardiomyocyte function. The latter effect may be exerted through endothelial microvesicles, which have demonstrated capacity to transfer NO (12, 13).
In conclusion, the data of Juni et al. strongly support the concept that endothelial dysfunction links inflammation to heart failure, and that endothelial effects of Empagliflozin contribute to cardioprotection independently from blood glucose. While the exact target(s) of Empagliflozin in cardiac microvascular endothelial cells remain elusive, the identification of microvascular endothelium as a clinically relevant target in heart failure opens much-needed new avenues for treatment. An indirect result from the Rosiglitazone controversy as terrific as it was unforeseen in 2007.
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- Hiatt WR, Kaul S and Smith RJ. The Cardiovascular Safety of Diabetes Drugs - Insights from the Rosiglitazone Experience. N Engl J Med. 2013;369:1285-1287.
- Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M and Drucker DJ. Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors. Circulation. 2017;136:849-870.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC and Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373:2117-2128.
- van Baar MJB, van Ruiten CC, Muskiet MHA, van Bloemendaal L, RG IJ and van Raalte DH. SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management. Diabetes Care. 2018;41:1543-1556.
- Bertero E, Prates Roma L, Ameri P and Maack C. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res. 2018;114:12-18.
- McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M and Langkilde A-M. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine. 2019;381:1995-2008.
- Paulus WJ and Tschöpe C. A Novel Paradigm for Heart Failure With Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation. Journal of the American College of Cardiology. 2013;62:263-271.
- Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ and Hamdani N. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2016;4:312-24.
- Schiattarella GG, Altamirano F, Tong D, French KM, Villalobos E, Kim SY, Luo X, Jiang N, May HI, Wang ZV, Hill TM, Mammen PPA, Huang J, Lee DI, Hahn VS, Sharma K, Kass DA, Lavandero S, Gillette TG and Hill JA. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. 2019.
- Juni R, Kuster DW, Goebel M, Helmes M, Musters RJ, van der Velden J, Koolwijk P, Paulus WJ and van Hinsbergh VW. Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin. JACC: Basic to Translational Science. 2019;4:575-591.
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The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.