Empagliflozin restores chronic kidney disease–induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction

Abstract

Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure, particularly in those with preserved ejection fraction. CKD is associated with endothelial dysfunction, however, whether CKD can induce impairment of endothelium-to-cardiomyocyte crosstalk leading to impairment of cardiomyocyte function is not known. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, reduced cardiovascular events in diabetic patients with or without CKD, suggesting its potential as a new treatment for heart failure with preserved ejection fraction. We hypothesized that uremic serum from patients with CKD would impair endothelial control of cardiomyocyte relaxation and contraction, and that empagliflozin would protect against this effect. Using a co-culture system of human cardiac microvascular endothelial cells with adult rat ventricular cardiomyocytes to measure cardiomyocyte relaxation and contraction, we showed that serum from patients with CKD impaired endothelial enhancement of cardiomyocyte function which was rescued by empagliflozin. Exposure to uremic serum reduced human cardiac microvascular endothelial cell nitric oxide bioavailability, and increased mitochondrial reactive oxygen species and 3-nitrotyrosine levels, indicating nitric oxide scavenging by reactive oxygen species. Empagliflozin attenuated uremic serum-induced generation of endothelial mitochondrial reactive oxygen species, leading to restoration of nitric oxide production and endothelium-mediated enhancement of nitric oxide levels in cardiomyocytes, an effect largely independent of sodium-hydrogen exchanger-1. Thus, empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells on cardiomyocyte function by reducing mitochondrial oxidative damage, leading to reduced reactive oxygen species accumulation and increased endothelial nitric oxide bioavailability. Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure, particularly in those with preserved ejection fraction. CKD is associated with endothelial dysfunction, however, whether CKD can induce impairment of endothelium-to-cardiomyocyte crosstalk leading to impairment of cardiomyocyte function is not known. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, reduced cardiovascular events in diabetic patients with or without CKD, suggesting its potential as a new treatment for heart failure with preserved ejection fraction. We hypothesized that uremic serum from patients with CKD would impair endothelial control of cardiomyocyte relaxation and contraction, and that empagliflozin would protect against this effect. Using a co-culture system of human cardiac microvascular endothelial cells with adult rat ventricular cardiomyocytes to measure cardiomyocyte relaxation and contraction, we showed that serum from patients with CKD impaired endothelial enhancement of cardiomyocyte function which was rescued by empagliflozin. Exposure to uremic serum reduced human cardiac microvascular endothelial cell nitric oxide bioavailability, and increased mitochondrial reactive oxygen species and 3-nitrotyrosine levels, indicating nitric oxide scavenging by reactive oxygen species. Empagliflozin attenuated uremic serum-induced generation of endothelial mitochondrial reactive oxygen species, leading to restoration of nitric oxide production and endothelium-mediated enhancement of nitric oxide levels in cardiomyocytes, an effect largely independent of sodium-hydrogen exchanger-1. Thus, empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells on cardiomyocyte function by reducing mitochondrial oxidative damage, leading to reduced reactive oxygen species accumulation and increased endothelial nitric oxide bioavailability. Translational StatementChronic kidney disease is associated with a high incidence of heart failure, particularly heart failure with preserved ejection fraction. Sodium-glucose co-transporter 2 inhibitors improve cardiovascular outcome in chronic kidney disease. Using a co-culture system of cardiac microvascular endothelial cells and cardiomyocytes, we show that serum from patients on dialysis impairs endothelium-mediated enhancement of cardiomyocyte relaxation and contraction, which is restored by a sodium-glucose co-transporter 2 inhibitor, empagliflozin. Empagliflozin alleviates uremic serum–induced mitochondrial oxidative damage, restoring the endothelium ability to enhance nitric oxide in cardiomyocytes. Collectively, our results provide a novel mechanism underlying cardiac impairment in chronic kidney disease, and even more importantly, they establish a cardiovascular protective mechanism of empagliflozin and possibly sodium-glucose co-transporter 2 inhibitors in general, which is independent of the presence of diabetes or residual kidney function. Future clinical trials should address this concept in patients with advanced kidney failure. Chronic kidney disease is associated with a high incidence of heart failure, particularly heart failure with preserved ejection fraction. Sodium-glucose co-transporter 2 inhibitors improve cardiovascular outcome in chronic kidney disease. Using a co-culture system of cardiac microvascular endothelial cells and cardiomyocytes, we show that serum from patients on dialysis impairs endothelium-mediated enhancement of cardiomyocyte relaxation and contraction, which is restored by a sodium-glucose co-transporter 2 inhibitor, empagliflozin. Empagliflozin alleviates uremic serum–induced mitochondrial oxidative damage, restoring the endothelium ability to enhance nitric oxide in cardiomyocytes. Collectively, our results provide a novel mechanism underlying cardiac impairment in chronic kidney disease, and even more importantly, they establish a cardiovascular protective mechanism of empagliflozin and possibly sodium-glucose co-transporter 2 inhibitors in general, which is independent of the presence of diabetes or residual kidney function. Future clinical trials should address this concept in patients with advanced kidney failure. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular complications. It is common in patients with heart failure (HF), in particular HF with preserved ejection fraction (HFpEF), and is associated with worse clinical outcomes.1Mavrakanas T.A. Khattak A. Wang W. et al.Association of chronic kidney disease with preserved ejection fraction heart failure is independent of baseline cardiac function.Kidney Blood Press Res. 2019; 44: 1247-1258Crossref PubMed Scopus (3) Google Scholar, 2Ter Maaten J.M. Voors A.A. Renal dysfunction in heart failure with a preserved ejection fraction: cause or consequence?.Eur J Heart Fail. 2016; 18: 113-114Crossref PubMed Scopus (9) Google Scholar, 3Unger E.D. Dubin R.F. Deo R. et al.Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction.Eur J Heart Fail. 2016; 18: 103-112Crossref PubMed Scopus (91) Google Scholar A causal relationship between CKD and HFpEF have been reported in pre-clinical4Sarkozy M. Gaspar R. Zvara A. et al.Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.Sci Rep. 2019; 9: 1302Crossref PubMed Scopus (12) Google Scholar,5Yousefi K. Irion C.I. Takeuchi L.M. et al.Osteopontin promotes left ventricular diastolic dysfunction through a mitochondrial pathway.J Am Coll Cardiol. 2019; 73: 2705-2718Crossref PubMed Scopus (14) Google Scholar as well as in clinical settings. The majority of patients on hemodialysis develop this feature, whereas the phenotype of HF with reduced ejection fraction was found only in a minority of cases.6Antlanger M. Aschauer S. Kopecky C. et al.Heart failure with preserved and reduced ejection fraction in hemodialysis patients: prevalence, disease prediction and prognosis.Kidney Blood Press Res. 2017; 42: 165-176Crossref PubMed Scopus (30) Google Scholar,7Hickson L.J. Negrotto S.M. Onuigbo M. et al.Echocardiography criteria for structural heart disease in patients with end-stage renal disease initiating hemodialysis.J Am Coll Cardiol. 2016; 67: 1173-1182Crossref PubMed Scopus (48) Google Scholar Despite the increasing prevalence of HFpEF, which accounts for 65% of HF cases to date,8Lund L.H. Savarese G. Global public health burden of heart failure.Card Fail Rev. 2017; 03: 7-11Crossref Google Scholar there is no effective treatment available. Multimorbidity-induced cardiac microvascular dysfunction is proposed to play an important role in the development of diastolic impairment in HFpEF.9Yancy C.W. Jessup M. Bozkurt B. et al.2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.Circulation. 2013; 128: e240-e327Crossref PubMed Scopus (1423) Google Scholar,10Paulus W.J. Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol. 2013; 62: 263-271Crossref PubMed Scopus (1592) Google Scholar However, the mechanism underlying the contribution of CKD to the pathogenesis of HF is not completely known. Understanding this mechanism may provide insights to develop novel therapeutic strategies for HF, including HFpEF. CKD is associated with left ventricular hypertrophy, a stiffer myocardium and diastolic dysfunction, the CKD-related cardiac abnormalities often referred to as uremic cardiomyopathy, which shares several characteristics of HFpEF.3Unger E.D. Dubin R.F. Deo R. et al.Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction.Eur J Heart Fail. 2016; 18: 103-112Crossref PubMed Scopus (91) Google Scholar,11Wang X. Shapiro J.I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy.Nat Rev Nephrol. 2019; 15: 159-175Crossref PubMed Scopus (39) Google Scholar,12Faul C. Amaral A.P. Oskouei B. et al.FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011; 121: 4393-4408Crossref PubMed Scopus (1286) Google Scholar Renal impairment leads to the accumulation of uremic solutes and pro-inflammatory mediators in plasma, which promote oxidative damage and impair endothelial function.13Dou L. Sallee M. Cerini C. et al.The cardiovascular effect of the uremic solute indole-3 acetic acid.J Am Soc Nephrol. 2015; 26: 876-887Crossref PubMed Scopus (148) Google Scholar,14Verkaik M. Juni R.P. van Loon E.P.M. et al.FGF23 impairs peripheral microvascular function in renal failure.Am J Physiol Heart Circ Physiol. 2018; 315: H1414-H1424Crossref PubMed Scopus (11) Google Scholar We have previously shown in an endothelial-cardiomyocyte (CM) coculture system that cardiac microvascular endothelial cells (CMECs) enhance relaxation and contraction, the that by of to the pro-inflammatory R.P. M. et microvascular endothelial enhancement of cardiomyocyte function is impaired by and restored by 2019; PubMed Scopus Google Scholar Sodium-glucose co-transporter 2 as empagliflozin and have been shown to cardiovascular and HF in patients with 2 diabetes with or without B. C. et al.Heart failure outcomes with empagliflozin in patients with 2 diabetes high cardiovascular results of the Heart 2016; PubMed Scopus Google Scholar, C. J.M. et and of kidney disease in 2 J 2016; PubMed Scopus Google Scholar, B. C. J.M. et cardiovascular and in 2 J 2015; PubMed Scopus Google Scholar, B. et and renal outcomes in 2 diabetes and J 2019; PubMed Scopus Google Scholar and of in Chronic R. et in patients with chronic kidney J PubMed Scopus Google Scholar and and of in Heart et in patients with heart failure and reduced ejection J 2019; PubMed Scopus Google Scholar trials have shown that from cardiovascular in patients with CKD and HF with reduced ejection of the Empagliflozin in with Chronic Heart and a M. et and renal outcomes with empagliflozin in heart J PubMed Scopus Google Scholar showed that empagliflozin the risk of cardiovascular and HF in patients with HF without a cardiac of this of The and of empagliflozin in the heart the of in cardiac et of and in human kidney and of in human and 2015; PubMed Scopus Google A. M. 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M. et microvascular endothelial enhancement of cardiomyocyte function is impaired by and restored by 2019; PubMed Scopus Google Scholar of with the endothelial enhancement of relaxation and R.P. M. et microvascular endothelial enhancement of cardiomyocyte function is impaired by and restored by 2019; PubMed Scopus Google Scholar been shown to induce in increasing levels, leading to of G. the of several including and leading to an of the and reduced of L. W.J. Understanding heart failure with preserved ejection fraction: we Heart 2016; PubMed Scopus Google Scholar, in cardiac PubMed Scopus Google Scholar, and function through and Res. PubMed Scopus Google Scholar, C. S. A. et microvascular endothelial in heart failure with preserved ejection Heart Fail. 2016; PubMed Scopus Google Scholar The function of co-culture with was by a in in which was not co-culture with uremic of for the function of It been reported that can in leading to accumulation and in impaired diastolic et heart failure with preserved ejection 2019; PubMed Scopus Google Scholar However, we found no in which is as our with that from the in in by function in our The uremic serum–induced in oxidative and leads to is in with as a of oxidative uremic serum C. et mitochondrial and the to promote and mitochondrial J PubMed Scopus Google et as a and a for uremic J 2019; Scopus (12) Google Scholar which can to an in and a in et as a and a for uremic J 2019; Scopus (12) Google et as a potential to the oxidative by uremic serum in the 2015; 121: PubMed Scopus (14) Google Scholar is highly reactive and can with to which can cause damage, including of the of as a of nitric 2015; PubMed Scopus Google M. et and of in and renal Physiol. 2018; 9: PubMed Scopus Google Scholar was in and suggesting that the in our is not to to scavenging by We showed that generation with an of mitochondrial suggesting mitochondrial induces of Wang S. et diabetic myocardial microvascular of mitochondrial 2018; 15: PubMed Scopus Google et as a and a for uremic J 2019; Scopus (12) Google A.A. et of mitochondrial and cell and protective of and PubMed Scopus Google Scholar, G. R. in Rev 9: PubMed Scopus Google Scholar, et of mitochondrial by endothelial Rep. 2018; PubMed Scopus Google Scholar The role of in uremic serum–induced endothelial oxidative is as the reduced production and restored the beneficial effect of the endothelium on function. the mitochondrial oxidative damage by uremic serum was by empagliflozin, indicating as a of this is in with the effect of empagliflozin on reducing mitochondrial in diabetic with this Wang S. et diabetic myocardial microvascular of mitochondrial 2018; 15: PubMed Scopus Google X. et and through 2019; PubMed Scopus Google Scholar empagliflozin been reported to to its effect on Wang S. et diabetic myocardial microvascular of mitochondrial 2018; 15: PubMed Scopus Google X. et and through 2019; PubMed Scopus Google Scholar of as shown by the of was not our been reported that empagliflozin can cells and by to mitochondrial and reducing cell a inhibitor, cardiomyocytes by of 2019; inhibitors play a role in heart failure of the mitochondrial 2019; PubMed Scopus Google Scholar empagliflozin may endothelial mitochondrial damage by uremic serum by of serum uremic that can endothelial as advanced and pro-inflammatory S. et as uremic 2017; 9: Scopus (39) Google Scholar, C. K. et in uraemic serum promotes and of cells and of 2018; PubMed Scopus Google Scholar, et with endothelial induce of cell in human endothelial cells and in a potential mechanism for the of Clin Invest. PubMed Scopus Google Scholar we showed that increased and levels in the effect of uremic in uremic serum in the presence and in the of L. of high and its in diabetic kidney 2019; Scopus (9) Google J.M. S. G. G. and the J Physiol Renal Physiol. PubMed Scopus Google Scholar It may to the effect of uremic an effect that may in our diabetic empagliflozin treatment been shown to the of by of as well as the of S. M. A. et al.The empagliflozin the diabetic in 2017; PubMed Scopus Google Scholar can induce of endothelial cells et with endothelial induce of cell in human endothelial cells and in a potential mechanism for the of Clin Invest. PubMed Scopus Google Scholar or by of in which they and and pro-inflammatory for advanced and for the pathogenesis and treatment of on the 2017; PubMed Scopus Google Scholar shown that empagliflozin restores the beneficial effect of the endothelium on relaxation and to pro-inflammatory and in a R.P. M. et microvascular endothelial enhancement of cardiomyocyte function is impaired by and restored by 2019; PubMed Scopus Google Scholar indicating a effect of empagliflozin. have to cardiac of empagliflozin, the of in the et of and in human kidney and of in human and 2015; PubMed Scopus Google A. M. A. et the production of reactive oxygen species by in the Rep. 2017; PubMed Scopus Google A. M. of a in the heart Heart 2015; Scholar the of the been L. A. Juni R.P. et and generation and in factor human coronary endothelial Physiol 2019; PubMed Scopus Google Scholar several reported of in the et and in endothelial cells by and Rep. 2018; PubMed Scopus Google M. 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We showed that the of production by empagliflozin in the of the was the effect of is highly for on to et al.The and and in the Rep. 2019; 9: PubMed Scopus Google Scholar However, in the presence of empagliflozin reduced endothelial by indicating that the effect of empagliflozin in is largely independent of is in with a report no of by empagliflozin or inhibitors in et of empagliflozin not or in the heart of Res. Scholar and the outcome of the clinical with et of the sodium-hydrogen with to myocardial in results of the PubMed Scopus Google Scholar empagliflozin alleviates HF of was in an in system with which only the of the cells in the our co-culture human and rat this to the important role of in may the of Future human and to an in of CKD with HF this of patients with HF have L. et dysfunction in patients with heart failure with preserved reduced ejection fraction: of the new Chronic Heart Fail. PubMed Scopus Google Scholar provide insights the pathogenesis of in CKD, that uremic serum impairs in patients with A. et microvascular a in the development of uraemic 2019; PubMed Scopus (9) Google et of uremic by cardiac PubMed Scopus Google Scholar and often as left ventricular and diastolic dysfunction, which common of X. Shapiro J.I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy.Nat Rev Nephrol. 2019; 15: 159-175Crossref PubMed Scopus (39) Google Scholar and W.J. Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol. 2013; 62: 263-271Crossref PubMed Scopus (1592) Google Scholar and S. et microvascular and myocardial in heart failure with preserved ejection 2015; PubMed Scopus Google et of heart failure with preserved ejection fraction in for 2017; PubMed Scopus Google Scholar proposed that an of the cardiac microvascular endothelium by as diabetes and CKD, is an mechanism diastolic dysfunction in HFpEF. the we that serum from patients with end-stage kidney failure leading to the impairment of the endothelial enhancement of relaxation and provide a mechanism to HF development in to the underlying cardiac dysfunction, we that empagliflozin can crosstalk uremic serum a that to the beneficial effect of this on the of the Empagliflozin in 2 and and Renal in 2 and Chronic trials on the effect of on the of HF and in patients with diabetes and kidney B. C. et al.Heart failure outcomes with empagliflozin in patients with 2 diabetes high cardiovascular results of the Heart 2016; PubMed Scopus Google B. et and renal outcomes in 2 diabetes and J 2019; PubMed Scopus Google Scholar several clinical trials to the effect of in patients with HF with reduced ejection fraction and HFpEF the of R. et in patients with chronic kidney J PubMed Scopus Google et in patients with heart failure and reduced ejection J 2019; PubMed Scopus Google M. et and of the and trials of empagliflozin in patients with chronic heart J Heart Fail. 2019; PubMed Scopus Google Scholar the shown that empagliflozin HF and cardiovascular in patients with HF with reduced ejection fraction of the presence of M. et and renal outcomes with empagliflozin in heart J PubMed Scopus Google Scholar in patients with HFpEF in the in a mechanism by which empagliflozin HF in patients with end-stage kidney disease, of the of or kidney function. show that serum of patients with CKD the endothelium-mediated enhancement of relaxation and by endothelial mitochondrial generation and the ability of the endothelium to enhance the in we provide of a effect of empagliflozin on the uremic serum–induced impairment of Empagliflozin the endothelial mitochondrial and the of in the of relaxation and of provide new insights the pathogenesis of HF, including HFpEF, in patients with CKD and on the mechanism of restoration of myocardial function in this

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