Diabetes Mellitus and Heart Failure

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 type 2 DM (T2DM), against a background of overweight/obesity. HF prevention in DM is feasible with rigorous treatment of cardiovascular risk factors and selective antidiabetic agents. Conversely, development of new-onset T2DM in HF (cardiogenic DM) is common and has been attributed to an increase in the resistance to insulin, especially in the skeletal muscle, liver, and adipose tissue as well as in diminished insulin secretory response to hyperglycemia by pancreatic β-cells. Cardiogenic DM further deteriorates cardiac dysfunction and adversely affects outcome in HF. Novel 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 cardiogenic diabetes. Whether mitigation of cardiogenic DM should be a treatment target in HF deserves further investigation.

Keywords: diabetes; diabetic cardiomyopathy; heart failure.

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.

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]).

Figure 3

A model to demonstrate the metabolic vicious cycle whereby hyperglycemia-mediated stimulation of NOGPs fuels oxidative stress and further NOGP activation. The ROS produced by activation of the various NOGPs play a central role in fueling this vicious metabolic cycle. ROS produced by each pathway will further stimulate the respective NOGP as indicated, while also fueling the other NOGPs. The ROS produced will inhibit flux through the glycolytic pathway to further increase NOGP activation. In addition, higher ROS levels will deplete glutathione (GSH) and thus increase polyol pathway flux. Greater ROS availability will result in glucose autoxidation and lipid peroxidation that will generate increased AGEs. Increased ROS such as H2O2 can also directly cause activation of PKC. In addition, the polyol pathway plays a key role by activating other NOGPs. Here, it can generate fructose that can be further metabolized to produce AGEs and fructose-6-phosphate, which can lead to activation of the HBP, PKC, and AGEs. Mapanga, R.F., Essop MF. Am J Physiol Heart Circ Physiol 2016; 310: H153–H173 (Ref. [38]).

Figure 4

A simplified model of insulin resistance. The loss of suppressive effects of insulin on lipolysis in adipocytes increases free fatty acids. Increased free fatty acids flux to the liver stimulates the assembly and secretion of VLDL resulting in hypertriglyceridemia. Triglycerides (TG) in VLDL are transferred to both HDL and LDL through the action of cholesteryl ester transfer protein (CETP). This process results in a triglyceride-enriched HDL and LDL particle. Triglyceride-enriched HDL is more rapidly cleared from the circulation by the kidney, leaving fewer HDL particles to accept cholesterol from the vasculature. In the glucose metabolism, the insulin resistance results in decreased hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, increased hepatic gluconeogenesis, and glucose delivery by the liver. Ormazabal, V. et al., Cardiovasc Diabetol 2018; 17:122 (Ref. [39]).

Figure 5

Early cardiac changes in morphology and function related to diabetes. Diabetes mellitus affects all 4 chambers of the heart. While right ventricular ejection fraction (RVEF) and left ventricular ejection fraction (LVEF) are preserved with no difference between diabetes mellitus and no diabetes mellitus, RV and LV chamber sizes are decreased. This occurs before increase in LV mass can be detected but is represented by an increased LV mass-to-volume ratio, suggesting early cardiac remodeling. Deformation imaging shows subtle impairment in LV function related to diabetes despite similar LVEF. The smaller ventricular volumes are accompanied by smaller right atrium (RA) and left atrium (LA) volumes. For both RA and LA, emptying function is impaired, which may represent an early marker of dysfunction occurring before impairments in LV or RV function. Figure based on data from: Steele, J.M. et al. Cardiovasc Diabetol 2020; 19:163 (Ref. [47]); Jensen, M.T. et al. Circ Cardiovasc Imaging 2019; 12:e009476 (Ref. [49]); Kumric, M., et al. World J Diabetes 2021; 12: 685–705 (Ref. [50]).

Figure 6

Spectrum of cardiac phenotypes and their determinants in new-onset heart failure (HF) in diabetes mellitus. New-onset HF in DM is a heterogeneous syndrome depending on diverse factors in which disease progression is associated with a dynamic evolution of functional and structural changes, leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics.

Figure 7

Sodium glucose cotransporter 2 (SGLT2) inhibition has pleiotropic effects on multiple organ systems. Hoong, C.W.S. et al. Endocrinology 2021 (Ref. [97]).

Figure 8

Heart failure (HF) leads to the development of cardiogenic diabetes, which subsequently adversely affects cardiac function and HF outcome.

Figure 9

Incidence of new-onset type 2 diabetes mellitus (T2DM) in dapagliflozin vs. placebo groups in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. The hazard ratio (HR) for incident T2DM in the dapagliflozin group compared with placebo was 0.68 (95% CI 0.50–0.94; P50.019), with an early divergence of the event curves. Inzucchi, S.E. et al., Diabetes Care 2021; 44:586–594 (Ref. [126]).