Advertisement

Sodium-glucose cotransporter-2 inhibitors: A treatment option for recurrent vasovagal syndrome?

  • Despina Sanoudou
    Correspondence
    Corresponding author at: Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Affiliations
    Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, "Attikon" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Biomedical Research Foundation of the Academy of Athens, Athens, Greece

    Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
    Search for articles by this author
  • Christos S. Mantzoros
    Affiliations
    Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, United States

    Section of Endocrinology, VA Boston Healthcare System, Jamaica Plain, MA 02130, United States
    Search for articles by this author
  • Michael A. Hill
    Affiliations
    Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, United States
    Search for articles by this author
Published:September 02, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155309
      The increasing prevalence of metabolic disease, along with cardiometabolic multimorbidity remains a leading healthcare challenge, despite advances in biomarker discovery and a broad pharmacological armamentarium [
      • Katsiki N.
      • Mantzoros C.
      • Mikhailidis D.P.
      Adiponectin, lipids and atherosclerosis.
      ,
      • Mantzoros C.S.
      • Flier J.S.
      Insulin resistance: the clinical spectrum.
      ,
      • Pilitsi E.
      • Farr O.M.
      • Polyzos S.A.
      • Perakakis N.
      • Nolen-Doerr E.
      • Papathanasiou A.E.
      • et al.
      Pharmacotherapy of obesity: available medications and drugs under investigation.
      ,
      • Polyzos S.A.
      • Kountouras J.
      • Mantzoros C.S.
      Adipose tissue, obesity and non-alcoholic fatty liver disease.
      ]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors introduced a paradigm shift in the management of diabetes. They have been shown to lower glycated hemoglobin, fasting and postprandial plasma glucose levels, body weight, and blood pressure, while also offering cardio- and nephroprotection (Fig. 1) [
      • Caruso I.
      • Giorgino F.
      SGLT-2 inhibitors as cardio-renal protective agents.
      ,
      • Giorgino F.
      • Caruso I.
      • Moellmann J.
      • Lehrke M.
      Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure.
      ,
      • Liu H.
      • Sridhar V.S.
      • Boulet J.
      • Dharia A.
      • Khan A.
      • Lawler P.R.
      • et al.
      Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
      ,
      • Prattichizzo F.
      • de Candia P.
      • Ceriello A.
      Diabetes and kidney disease: emphasis on treatment with SGLT-2 inhibitors and GLP-1 receptor agonists.
      ].
      Fig. 1
      Fig. 1SGLT2 inhibition impacts a broad range of functions across different organs and systems, jointly contributing to a multitude of benefits for the cardiovascular system, including reduced cardiac denervation, cardiac autonomic dysfunction and vaso-vagal syncope recurrence. (Abbreviations: CKD: chronic kidney disease, NHE: Na+/H+ exchanger, O2: oxygen, RAAS: renin-angiotensin-aldosterone system).

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Katsiki N.
        • Mantzoros C.
        • Mikhailidis D.P.
        Adiponectin, lipids and atherosclerosis.
        Curr Opin Lipidol. 2017; 28: 347-354
        • Mantzoros C.S.
        • Flier J.S.
        Insulin resistance: the clinical spectrum.
        Adv Endocrinol Metab. 1995; 6: 193-232
        • Pilitsi E.
        • Farr O.M.
        • Polyzos S.A.
        • Perakakis N.
        • Nolen-Doerr E.
        • Papathanasiou A.E.
        • et al.
        Pharmacotherapy of obesity: available medications and drugs under investigation.
        Metabolism. 2019; 92: 170-192
        • Polyzos S.A.
        • Kountouras J.
        • Mantzoros C.S.
        Adipose tissue, obesity and non-alcoholic fatty liver disease.
        Minerva Endocrinol. 2017; 42: 92-108
        • Caruso I.
        • Giorgino F.
        SGLT-2 inhibitors as cardio-renal protective agents.
        Metabolism. 2022; 127154937
        • Giorgino F.
        • Caruso I.
        • Moellmann J.
        • Lehrke M.
        Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure.
        Metabolism. 2020; 104154045
        • Liu H.
        • Sridhar V.S.
        • Boulet J.
        • Dharia A.
        • Khan A.
        • Lawler P.R.
        • et al.
        Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
        Metabolism. 2022; 126154918
        • Prattichizzo F.
        • de Candia P.
        • Ceriello A.
        Diabetes and kidney disease: emphasis on treatment with SGLT-2 inhibitors and GLP-1 receptor agonists.
        Metabolism. 2021; 120154799
        • Sardu C.
        • Massimo Massetti M.
        • Rambaldi P.
        • Gatta G.
        • Cappabianca S.
        • Sasso F.C.
        • et al.
        SGLT2-inhibitors reduce the cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus: the SCAN study.
        Metabolism. 2022; 155243
        • Gallo L.A.
        • Wright E.M.
        • Vallon V.
        Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences.
        Diab Vasc Dis Res. 2015; 12: 78-89
        • Wilding J.P.
        The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors.
        Metabolism. 2014; 63: 1228-1237
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • Fitchett D.
        • Bluhmki E.
        • Hantel S.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • de Zeeuw D.
        • Fulcher G.
        • Erondu N.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • Mosenzon O.
        • Kato E.T.
        • Cahn A.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Hallow K.M.
        • Helmlinger G.
        • Greasley P.J.
        • McMurray J.J.V.
        • Boulton D.W.
        Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.
        Diabetes Obes Metab. 2018; 20: 479-487
        • Ehrenkranz J.R.
        • Lewis N.G.
        • Kahn C.R.
        • Roth J.
        Phlorizin: a review.
        Diabetes Metab Res Rev. 2005; 21: 31-38
        • Washburn W.N.
        • Poucher S.M.
        Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus.
        Expert Opin Investig Drugs. 2013; 22: 463-486
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • Kober L.
        • Kosiborod M.N.
        • Martinez F.A.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • Ferreira J.P.
        • Bocchi E.
        • Bohm M.
        • et al.
        Empagliflozin in heart failure with a preserved ejection fraction.
        N Engl J Med. 2021; 385: 1451-1461
        • Cherney D.Z.I.
        • Udell J.A.
        • Drucker D.J.
        Cardiorenal mechanisms of action of glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors.
        Med (N Y). 2021; 2: 1203-1230
        • Vallon V.
        • Thomson S.C.
        Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.
        Diabetologia. 2017; 60: 215-225
        • Ferrannini E.
        Sodium-glucose co-transporters and their inhibition: clinical physiology.
        Cell Metab. 2017; 26: 27-38
        • Gill A.
        • Gray S.P.
        • Jandeleit-Dahm K.A.
        • Watson A.M.D.
        SGLT-2 inhibition: novel therapeutics for reno-and cardioprotection in diabetes mellitus.
        Curr Diabetes Rev. 2019; 15: 349-356
        • van Ruiten C.C.
        • Hesp A.C.
        • van Raalte D.H.
        Sodium glucose cotransporter-2 inhibitors protect the cardiorenal axis: update on recent mechanistic insights related to kidney physiology.
        Eur J Intern Med. 2022; 100: 13-20
        • Lopaschuk G.D.
        • Verma S.
        Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review.
        JACC Basic Transl Sci. 2020; 5: 632-644
        • Verma S.
        • Rawat S.
        • Ho K.L.
        • Wagg C.S.
        • Zhang L.
        • Teoh H.
        • et al.
        Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors.
        JACC Basic Transl Sci. 2018; 3: 575-587
        • Koenen M.
        • Hill M.A.
        • Cohen P.
        • Sowers J.R.
        Obesity, adipose tissue and vascular dysfunction.
        Circ Res. 2021; 128: 951-968
        • Uthman L.
        • Homayr A.
        • Juni R.P.
        • Spin E.L.
        • Kerindongo R.
        • Boomsma M.
        • et al.
        Empagliflozin and dapagliflozin reduce ROS generation and restore NO bioavailability in tumor necrosis factor alpha-stimulated human coronary arterial endothelial cells.
        Cell Physiol Biochem. 2019; 53: 865-886
        • Mancini S.J.
        • Boyd D.
        • Katwan O.J.
        • Strembitska A.
        • Almabrouk T.A.
        • Kennedy S.
        • et al.
        Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms.
        Sci Rep. 2018; 8: 5276
        • Durante W.
        • Behnammanesh G.
        • Peyton K.J.
        Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and arterial remodeling.
        Int J Mol Sci. 2021; 22
        • Gaspari T.
        • Spizzo I.
        • Liu H.
        • Hu Y.
        • Simpson R.W.
        • Widdop R.E.
        • et al.
        Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: a potential mechanism for inhibition of atherogenesis.
        Diab Vasc Dis Res. 2018; 15: 64-73
        • Han Y.
        • Cho Y.E.
        • Ayon R.
        • Guo R.
        • Youssef K.D.
        • Pan M.
        • et al.
        SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery.
        Am J Physiol Lung Cell Mol Physiol. 2015; 309: L1027-L1036
        • El-Daly M.
        • Pulakazhi Venu V.K.
        • Saifeddine M.
        • Mihara K.
        • Kang S.
        • Fedak P.W.M.
        • et al.
        Hyperglycaemic impairment of PAR2-mediated vasodilation: prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress.
        Vascul Pharmacol. 2018; 109: 56-71
        • Aroor A.R.
        • Das N.A.
        • Carpenter A.J.
        • Habibi J.
        • Jia G.
        • Ramirez-Perez F.I.
        • et al.
        Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury.
        Cardiovasc Diabetol. 2018; 17: 108
        • Lee D.M.
        • Battson M.L.
        • Jarrell D.K.
        • Hou S.
        • Ecton K.E.
        • Weir T.L.
        • et al.
        SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice.
        Cardiovasc Diabetol. 2018; 17: 62
        • Chilton R.
        • Tikkanen I.
        • Cannon C.P.
        • Crowe S.
        • Woerle H.J.
        • Broedl U.C.
        • et al.
        Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.
        Diabetes Obes Metab. 2015; 17: 1180-1193
        • Striepe K.
        • Jumar A.
        • Ott C.
        • Karg M.V.
        • Schneider M.P.
        • Kannenkeril D.
        • et al.
        Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus.
        Circulation. 2017; 136: 1167-1169
        • Bosch A.
        • Ott C.
        • Jung S.
        • Striepe K.
        • Karg M.V.
        • Kannenkeril D.
        • et al.
        How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial.
        Cardiovasc Diabetol. 2019; 18: 44
        • Patoulias D.
        • Papadopoulos C.
        • Kassimis G.
        • Fragakis N.
        • Vassilikos V.
        • Karagiannis A.
        • et al.
        Effect of sodium-glucose co-transporter-2 inhibitors on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials.
        Vasc Med. 2022; https://doi.org/10.1177/1358863X221101653
        • Wei R.
        • Wang W.
        • Pan Q.
        • Guo L.
        Effects of SGLT-2 inhibitors on vascular endothelial function and arterial stiffness in subjects with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.
        Front Endocrinol (Lausanne). 2022; 13826604
        • Behnammanesh G.
        • Durante Z.E.
        • Peyton K.J.
        • Martinez-Lemus L.A.
        • Brown S.M.
        • Bender S.B.
        • et al.
        Canagliflozin inhibits human endothelial cell proliferation and tube formation.
        Front Pharmacol. 2019; 10: 362
        • Nguyen T.
        • Wen S.
        • Gong M.
        • Yuan X.
        • Xu D.
        • Wang C.
        • et al.
        Dapagliflozin activates neurons in the central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice.
        Diabetes Metab Syndr Obes. 2020; 13: 2781-2799
        • Pawlos A.
        • Broncel M.
        • Wozniak E.
        • Gorzelak-Pabis P.
        Neuroprotective effect of SGLT2 inhibitors.
        Molecules. 2021; 26
        • Khemais-Benkhiat S.
        • Belcastro E.
        • Idris-Khodja N.
        • Park S.H.
        • Amoura L.
        • Abbas M.
        • et al.
        Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence.
        J Cell Mol Med. 2020; 24: 2109-2122
        • Pulakazhi Venu V.K.
        • El-Daly M.
        • Saifeddine M.
        • Hirota S.A.
        • Ding H.
        • Triggle C.R.
        • et al.
        Minimizing hyperglycemia-induced vascular endothelial dysfunction by inhibiting endothelial sodium-glucose cotransporter 2 and attenuating oxidative stress: implications for treating individuals with type 2 diabetes.
        Can J Diabetes. 2019; 43: 510-514
        • De Pascalis A.
        • Cianciolo G.
        • Capelli I.
        • Brunori G.
        • La Manna G.
        SGLT2 inhibitors, sodium and off-target effects: an overview.
        J Nephrol. 2021; 34: 673-680
        • Baartscheer A.
        • Schumacher C.A.
        • Wust R.C.
        • Fiolet J.W.
        • Stienen G.J.
        • Coronel R.
        • et al.
        Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits.
        Diabetologia. 2017; 60: 568-573
        • Chung Y.J.
        • Park K.C.
        • Tokar S.
        • Eykyn T.R.
        • Fuller W.
        • Pavlovic D.
        • et al.
        Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart.
        Cardiovasc Res. 2021; 117: 2794-2806
        • Mustroph J.
        • Wagemann O.
        • Lucht C.M.
        • Trum M.
        • Hammer K.P.
        • Sag C.M.
        • et al.
        Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes.
        ESC Heart Fail. 2018; 5: 642-648
        • Li X.
        • Flynn E.R.
        • do Carmo J.M.
        • Wang Z.
        • da Silva A.A.
        • Mouton A.J.
        • et al.
        Direct cardiac actions of sodium-glucose cotransporter 2 inhibition improve mitochondrial function and attenuate oxidative stress in pressure overload-induced heart failure.
        Front Cardiovasc Med. 2022; 9: 859253
        • Vinik A.I.
        • Casellini C.
        • Parson H.K.
        • Colberg S.R.
        • Nevoret M.L.
        Cardiac autonomic neuropathy in diabetes: a predictor of cardiometabolic events.
        Front Neurosci. 2018; 12: 591
        • Dimova R.
        • Tankova T.
        Does SGLT2 inhibition affect sympathetic nerve activity in type 2 diabetes?.
        Horm Metab Res. 2021; 53: 75-84
        • Herat L.Y.
        • Magno A.L.
        • Rudnicka C.
        • Hricova J.
        • Carnagarin R.
        • Ward N.C.
        • et al.
        SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection.
        JACC Basic Transl Sci. 2020; 5: 169-179
        • Nashawi M.
        • Sheikh O.
        • Battisha A.
        • Ghali A.
        • Chilton R.
        Neural tone and cardio-renal outcomes in patients with type 2 diabetes mellitus: a review of the literature with a focus on SGLT2 inhibitors.
        Heart Fail Rev. 2021; 26: 643-652
        • Verma S.
        Are the cardiorenal benefits of SGLT2 inhibitors due to inhibition of the sympathetic nervous system?.
        JACC Basic Transl Sci. 2020; 5: 180-182
        • Sato D.
        • Nakamura T.
        • Amarume J.
        • Yano M.
        • Nishina A.
        • Feng Z.
        • et al.
        Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load.
        J Pharmacol Sci. 2022; 148: 86-92
        • Hamaoka T.
        • Murai H.
        • Hirai T.
        • Sugimoto H.
        • Mukai Y.
        • Inoue O.
        • et al.
        Different responses of muscle sympathetic nerve activity to dapagliflozin between patients with type 2 diabetes with and without heart failure.
        J Am Heart Assoc. 2021; 10e022637
        • Gueguen C.
        • Burke S.L.
        • Barzel B.
        • Eikelis N.
        • Watson A.M.D.
        • Jha J.C.
        • et al.
        Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.
        Diabetologia. 2020; 63: 1424-1434
        • Jordan J.
        • Tank J.
        • Heusser K.
        • Heise T.
        • Wanner C.
        • Heer M.
        • et al.
        The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus.
        J Am Soc Hypertens. 2017; 11: 604-612
        • Lambert E.
        • Lambert G.W.
        Sympathetic dysfunction in vasovagal syncope and the postural orthostatic tachycardia syndrome.
        Front Physiol. 2014; 5: 280
        • Jardine D.L.
        • Wieling W.
        • Brignole M.
        • Lenders J.W.M.
        • Sutton R.
        • Stewart J.
        The pathophysiology of the vasovagal response.
        Heart Rhythm. 2018; 15: 921-929
        • Brown E.
        • Wilding J.P.H.
        • Barber T.M.
        • Alam U.
        • Cuthbertson D.J.
        Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities.
        Obes Rev. 2019; 20: 816-828
        • Donnan J.R.
        • Grandy C.A.
        • Chibrikov E.
        • Marra C.A.
        • Aubrey-Bassler K.
        • Johnston K.
        • et al.
        Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.
        BMJ Open. 2019; 9e022577
        • Klen J.
        • Dolzan V.
        Treatment response to SGLT2 inhibitors: from clinical characteristics to genetic variations.
        Int J Mol Sci. 2021; 22
        • Hoeben E.
        • De Winter W.
        • Neyens M.
        • Devineni D.
        • Vermeulen A.
        • Dunne A.
        Population pharmacokinetic modeling of canagliflozin in healthy volunteers and patients with type 2 diabetes mellitus.
        Clin Pharmacokinet. 2016; 55: 209-223
        • Gkouskou K.
        • Vlastos I.
        • Karkalousos P.
        • Chaniotis D.
        • Sanoudou D.
        • Eliopoulos A.G.
        The "Virtual digital Twins" concept in precision nutrition.
        Adv Nutr. 2020; 11: 1405-1413
        • Stouras I.
        • Papaioannou T.G.
        • Tsioufis K.
        • Eliopoulos A.G.
        • Sanoudou D.
        The challenge and importance of integrating drug-nutrient-genome interactions in personalized cardiovascular healthcare.
        J Pers Med. 2022; 12
        • Hong D.
        • Si L.
        • Jiang M.
        • Shao H.
        • Ming W.K.
        • Zhao Y.
        • et al.
        Cost effectiveness of sodium-glucose Cotransporter-2 (SGLT2) inhibitors, glucagon-like Peptide-1 (GLP-1) receptor agonists, and dipeptidyl Peptidase-4 (DPP-4) inhibitors: a systematic review.
        Pharmacoeconomics. 2019; 37: 777-818
        • Rahman W.
        • Solinsky P.J.
        • Munir K.M.
        • Lamos E.M.
        Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
        Expert Opin Pharmacother. 2019; 20: 151-161
        • Esler M.
        Clinical application of noradrenaline spillover methodology: delineation of regional human sympathetic nervous responses.
        Pharmacol Toxicol. 1993; 73: 243-253
        • Esler M.
        • Jennings G.
        • Lambert G.
        • Meredith I.
        • Horne M.
        • Eisenhofer G.
        Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions.
        Physiol Rev. 1990; 70: 963-985
        • Kalozoumi G.
        • Yacoub M.
        • Sanoudou D.
        MicroRNAs in heart failure: small molecules with major impact.
        Glob Cardiol Sci Pract. 2014; 2014: 79-102
        • Sanoudou D.
        • Gkouskou K.K.
        • Eliopoulos A.G.
        • Mantzoros C.S.
        Epitranscriptomic challenges and promises in metabolic diseases.
        Metabolism. 2022; 132155219
        • Sanoudou D.
        • Vafiadaki E.
        • Arvanitis D.A.
        • Kranias E.
        • Kontrogianni-Konstantopoulos A.
        Array lessons from the heart: focus on the genome and transcriptome of cardiomyopathies.
        Physiol Genomics. 2005; 21: 131-143
        • Mathew H.
        • Farr O.M.
        • Mantzoros C.S.
        Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients.
        Metabolism. 2016; 65: 73-80
        • Raji A.
        • Gerhard-Herman M.D.
        • Warren M.
        • Silverman S.G.
        • Raptopoulos V.
        • Mantzoros C.S.
        • et al.
        Insulin resistance and vascular dysfunction in nondiabetic Asian Indians.
        J Clin Endocrinol Metab. 2004; 89: 3965-3972
        • Deveau A.P.
        • Sheldon R.
        • Maxey C.
        • Ritchie D.
        • Doucette S.
        • Parkash R.
        Sex differences in vasovagal syncope: a post hoc analysis of the prevention of syncope trials (POST) I and II.
        Can J Cardiol. 2020; 36: 79-83
        • Bhave G.
        • Neilson E.G.
        Volume depletion versus dehydration: how understanding the difference can guide therapy.
        Am J Kidney Dis. 2011; 58: 302-309
        • Zelniker T.A.
        • Bonaca M.P.
        • Furtado R.H.M.
        • Mosenzon O.
        • Kuder J.F.
        • Murphy S.A.
        • et al.
        Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights from the DECLARE-TIMI 58 trial.
        Circulation. 2020; 141: 1227-1234
        • Ong H.T.
        • Teo Y.H.
        • Teo Y.N.
        • Syn N.L.
        • Wee C.F.
        • Leong S.
        • et al.
        Effects of Sodium/Glucose cotransporter inhibitors on atrial fibrillation and stroke: a meta-analysis.
        J Stroke Cerebrovasc Dis. 2022; 31106159