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Diabetes Mellitus and Heart Failure Journal of Clinical Medicine Review Diabetes Mellitus and Heart Failure Filippos Triposkiadis 1,* , Andrew Xanthopoulos 1 , Alexandra Bargiota 2, Takeshi Kitai 3 , Niki Katsiki 4, Dimitrios Farmakis 5, John Skoularigis 1, Randall C. Starling 6 and Efstathios Iliodromitis 7 1 Department of Cardiology, University General Hospital of Larissa, 411 10 Larissa, Greece; [email protected] (A.X.); [email protected] (J.S.) 2 Department of Endocrinology and Metabolic Diseases, University General Hospital of Larissa, 411 10 Larissa, Greece; [email protected] 3 National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan; [email protected] 4 Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, 54124 Thessaloniki, Greece; [email protected] 5 University of Cyprus Medical School, P.O. Box 20537, Nicosia 1678, Cyprus; [email protected] 6 Kaufman Center for Heart Failure Treatment and Recovery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA; [email protected] 7 Second Department of Cardiology, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece; [email protected] * Correspondence: [email protected] Abstract: Diabetes mellitus (DM) is a major risk factor for new-onset heart failure (HF) and vice versa. The pathogenesis of new-onset HF in DM is complex and has been largely attributed to the toxic cardiovascular effects of hyperglycemia and relevant metabolic abnormalities (diabetic cardiomyopathy) as well as the frequently coexisting morbidities such as hypertension (HTN), coronary artery disease (CAD), and diabetic nephropathy. In patients with type 1 DM (T1DM), HF develops in the setting of a dysregulated immune response, whereas in most patients with Citation: Triposkiadis, F.; type 2 DM (T2DM), against a background of overweight/obesity. HF prevention in DM is feasible Xanthopoulos, A.; Bargiota, A.; Kitai, with rigorous treatment of cardiovascular risk factors and selective antidiabetic agents. Conversely, T.; Katsiki, N.; Farmakis, D.; Skoularigis, J.; Starling, R.C.; development of new-onset T2DM in HF (cardiogenic DM) is common and has been attributed Iliodromitis, E. Diabetes Mellitus and to an increase in the resistance to insulin, especially in the skeletal muscle, liver, and adipose Heart Failure. J. Clin. Med. 2021, 10, tissue as well as in diminished insulin secretory response to hyperglycemia by pancreatic β-cells. 3682. https://doi.org/10.3390/ Cardiogenic DM further deteriorates cardiac dysfunction and adversely affects outcome in HF. Novel jcm10163682 lifesaving medications employed in HF management such as sacubitril/valsartan and sodium glucose cotransporter 2 inhibitors (SGLT-2i) have a favorable metabolic profile and lower the incidence of Academic Editor: Christian Sohns cardiogenic diabetes. Whether mitigation of cardiogenic DM should be a treatment target in HF deserves further investigation. Received: 29 July 2021 Accepted: 17 August 2021 Keywords: diabetes; heart failure; diabetic cardiomyopathy Published: 19 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Diabetes mellitus (DM) is a major risk factor for several cardiovascular (CV) outcomes, including heart failure (HF) [1,2]. Epidemiological and observational studies have demon- strated that DM increases the risk for new-onset HF independent of other traditional risk factors. Each 1% increase in glycated hemoglobin A1c is associated with a 30% increase for risk of HF in Type 1 DM (T1DM) [3] and an 8% increase for HF risk in T2DM, the Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. most common type of DM occurring in approximately 90% of diabetes patients [4]. The This article is an open access article prevalence of cardiac dysfunction in people with T1DM and T2DM has been demonstrated distributed under the terms and to be as high as 14.5% and 35.0%, respectively [5,6]. conditions of the Creative Commons Conversely, HF is a major risk factor for the pathogenesis of new-onset T2DM (car- Attribution (CC BY) license (https:// diogenic diabetes). In a study including more than 100,000 patients with HF, the annual creativecommons.org/licenses/by/ incidence of new-onset T2DM was approximately 2% in the first years after HF diagnosis 4.0/). and rose to around 3% after 5 years of HF duration [7]. J. Clin. Med. 2021, 10, 3682. https://doi.org/10.3390/jcm10163682 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 3682 2 of 21 The present work summarizes the mechanisms and prevention of HF development in DM and vice versa. The metabolic abnormalities underlying both disease states will be emphasized both in the context of pathogenesis and as treatment targets. Gaps of knowledge will also be discussed. 1.1. New-Onset Heart Failure in Diabetes 1.1.1. Epidemiology The Framingham Heart Study, which enrolled 5209 men and women who were followed up for 18 years, reported a higher incidence of HF in women (5-fold) than men (2.4-fold) with DM after adjustment for other risk factors, including age, coronary artery disease (CAD), and hypertension (HTN) [8]. A recent meta-analysis assessed the risk of new-onset and recurrent HF according to the presence or absence of DM. For new-onset HF, the pooled risk ratio (RR) 95% confidence interval (CI) of 69 studies that examined HF as a whole (both HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)) was 2.14 (1.96–2.34). The risk magnitudes between HFpEF and HFrEF were not significantly different in studies that examined the risk in both syndromes (p = 0.86), whereas for recurrent HF, the pooled RR (95% CI) of 38 studies was 1.39 (1.33–1.45). These data indicate that, in patients with DM, the magnitude of risk for new-onset HF and recurrent HF is large and DM is associated with a high incidence of both HFpEF and HFrEF [9]. 1.1.2. Pathogenesis The pathogenesis of new-onset HF in DM is complex and has been attributed to the direct toxic effect of hyperglycemia and relevant metabolic effects on the myocardium (diabetic cardiomyopathy) as well as the frequently coexisting HTN, CAD, coronary mi- crovascular dysfunction (CMD), and diabetic nephropathy [10,11]. In patients with T1DM, HF develops in the setting of a dysregulated immune response, whereas in most patients with T2DM, against a background of overweight/obesity (Figure1). Figure 1. The pathogenesis of new-onset heart failure in diabetes mellitus (DM) is complex and has been largely attributed to the direct toxic effect of hyperglycemia and relevant metabolic effects on the myocardium (diabetic cardiomyopathy) as well as the frequently coexisting hypertension, coronary artery disease, coronary microvascular dysfunction, and diabetic nephropathy. In patients with type 1 DM, HF develops in the setting of a dysregulated immune response, whereas in most patients with T2DM, against a background of overweight/obesity. J. Clin. Med. 2021, 10, 3682 3 of 21 1. Immune dysregulation. T1DM results from the body’s immune system, which targets insulin-producing β-cells within the pancreatic islets. Patients with T1DM are also at increased risk of developing other autoimmune disorders, including cardiac au- toimmunity [12]. Immune-mediated destruction of β-cells in pancreatic islets results in diminished or absent release of insulin and consequent hyperglycemia. Both in patients with T1DM and those with T2DM, chronic hyperglycemia causes subclin- ical myocardial injury, leading to leakage and exposure of heart muscle proteins, including α-myosin, to the immune system. However, in T1DM patients with poor glycemic control, the dysregulated adaptive immune system is overreactive to my- ocardial injury, leading to a build-up of proinflammatory CD4+ T cells specific to α-myosin and the development of autoantibodies to MYH6 and other cardiac antigens (Figure2)[13] . This proinflammatory state leads to myocarditis resembling that seen in Chagas disease, and potentially a more generalized state of low-grade vascular inflammation, facilitating the development of atherosclerotic lesions and HF [14]. Figure 2. Proposed scheme of how chronic hyperglycemia is associated with cardiac autoimmunity and increased risk of cardiovascular disease (CVD) in patients with type 1 diabetes mellitus (T1DM). A: Absent thymic expression of the full-length α-cardiac myosin heavy chain (α-myosin; encoded by MYH6) is associated with high frequencies of CD4+ T cells specific to α-myosin in the peripheral blood of individuals in the general population. B: In both patients with T1DM and patients with type 2 diabetes mellitus (T2DM), chronic hyperglycemia causes subclinical myocardial injury, leading to leakage and exposure of heart muscle proteins, including α-myosin, to the immune system. C: In patients with T1DM, with poor glycemic control, the dysregulated adaptive immune system overreacts to myocardial injury, leading to the expansion of proinflammatory CD4+ T cells specific to α-myosin and the development of autoantibodies to MYH6 and other cardiac antigens. This proinflammatory state is associated with elevated levels of the inflammatory marker, high-sensitivity C-reactive protein (hsCRP), and increased risk for accelerated atherosclerosis and CVD events. Sousa, GR et al. Circulation 2019; 139:730–43 (Ref. [13]). 2. Obesity. Obesity is a major risk factor for the development of T2DM,
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