The many-faced hurdle of cardiac involvement in diabetes: where to focus?

Today, cardiovascular disease in diabetes is a hot topic on the major international scene – both in cardiology and in diabetes – owing to the results of the past years’ Cardiovascular Outcome Trials (CVOT), which have shown decreases in cardiovascular morbidity and mortality in patients randomized to sodium-glucose transport-2 (SGLT-2) inhibitors or glucagon-like peptide-1 receptor agonists (GLP1-RA).^1,2 But, despite their ability to reduce cardiovascular disease in patients with type 2 diabetes, no one really knows the mechanisms underlying this obvious positive effect. So, even though we now have pharmacological ways of preventing cardiovascular disease, we really need to learn even more about diabetes and its effect on the cardiovascular system in general, and the heart in particular. In this special issue on Cardiovascular Disease and Diabetes: Risk Factors, Prevention and Management, we address some important aspects of the ongoing research areas trying to establish the mechanisms of cardiac and cardiovascular involvement in type 2 diabetes, and, in addition, provide novel insight in to the cardiac remodeling exerted by type 2 diabetes.

The ability of SGLT-2 inhibitors to reduce heart failure events has attracted immense focus on the ailing diabetic myocardium. The notion of a specific cardiac involvement in diabetes, however, is not new. Since it is years underway, the advent of insulin was needed for it to become apparent. The idea was first introduced by the Danish researcher Lundbæk in 1954 ³ ; however, many also credit Rubler’s post-mortem studies of the diabetic heart as the first evidence of the specific ‘diabetic cardiomyopathy’ that is defined as cardiac involvement in diabetes without concomitant coronary artery disease. ⁴ Indeed, a lot has happened since! In this issue, Gulsin et al. unravel the most important of the immense number of studies that have examined the characteristics of myocardial involvement in diabetes. It is generally accepted that the end-product of longstanding diabetic influence of the myocardium is primarily diastolic dysfunction, or, to be more precise, heart failure with preserved ejection fraction (HFpEF). This state is characterized by thickening of the left ventricle, reduced longitudinal function, and, consequently, decreased compliance resulting in increased left ventricular filling pressures which, in turn, cause symptoms. ⁵ But what are the causes for this? In this issue, Gulsin et al. impressively review the data supporting type 2 diabetes-related myocardial alterations in energy metabolism, myocardial steatosis, coronary microvascular dysfunction, myocardial fibrosis, and aortic stiffening as – at least partly – responsible for these changes. Beyond this comprehensive review, Gulsin et al. also contribute to this special issue with an original paper examining the differential cardiac remodeling and causes for this in HFpEF patients with and without type 2 diabetes. Among the interesting findings in this study were increased markers of systemic inflammation in patients with type 2 diabetes as well as a marked increase in left ventricular concentric remodeling. These findings, the authors state, suggest a differential pathophysiology between HFpEF patients with type 2 diabetes compared with those without type 2 diabetes.

The clinical entity HFpEF presents a, so far, insurmountable obstacle, as no clinical trial has provided convincing evidence of improved prognosis with medical treatment in these patients. Recently, the PARAGON trial disappointingly demonstrated no benefit for patients with HFpEF treated with Sacubitril/Valsartan compared with Valsartan alone, ⁶ and the results were similar in the diabetes subgroup in prespecified analyses. However, we know from the PARADIGM trial, ⁷ that treatment with Sacubitril/Valsartan resulted in a greater decrease in hemoglobin A1c compared with treatment with enalapril alone. This interesting finding suggest a possible role for Sacubitril/Valsartan in treatment of type 2 diabetes; however, the mechanisms are only poorly elucidated. In this issue, Seferovic et al. review the possible mechanisms for this surprising effect in type 2 diabetes, and find that the effect is most likely related to the inhibition of neprilysin causing a cascade of downstream substrate changes. However, much is still needed to fully understand this phenomenon.

The deleterious effect of diabetes on the heart is not limited to the myocardium alone. Arrhythmias, as well, might also be responsible for some of the excess cardiovascular mortality in type 2 diabetes. In the pre-CVOT era, the ACCORD trial showed that intensive glucose control, especially in patients established cardiovascular disease, was associated with increased mortality driven mainly by an increase in cardiovascular mortality. ⁸ This has been accredited to a higher incidence of severe hypoglycemia inducing fatal arrhythmias in susceptible patients. In this issue, Andersen et al. thoroughly review the potential mechanisms behind hypoglycemia and fatal cardiac arrhythmias. According to present data, there is a possible role of the autonomic nervous system with effects varying from daytime to night. However, despite the considerable amount of data suggesting a link between cardiac arrhythmias and hypoglycemia, future research with long-term simultaneous monitoring of glucose levels and heart rhythm is needed.

Finally, epicardial fat has emerged as an important player in the struggle to understand diabetic heart disease. Acting both through paracrine secretion of inflammatory cytokines and through application of direct mechanical stress on the myocardium, epicardial fat is both related strongly to heart disease and a powerful predictor of future cardiovascular disease. In this special collection, Christensen et al. reviews the role of cardiac adipose tissues in cardiac disease, and, importantly, its potential as a target for both lifestyle and pharmacological therapeutic interventions.

So, to summarize, while much effort has been invested in examining the cardiac and cardiovascular involvement in type 2 diabetes, much work still needs to done in this area. In this special issue, we have addressed this conundrum by presenting a subject that we believe deserve special attention. We hope that readers will share our enthusiasm while reading the articles of this special issue on Cardiovascular Disease and Diabetes: Risk Factors, Prevention and Management in Therapeutic Advances in Endocrinology and Metabolism.