Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date

Abstract

The prevalence of type 2 diabetes (T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms, with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.

Keywords: Cardiac metabolism; Diabetic cardiomyopathy; Myocardial steatosis; Myocardial strain.

Figure 1

An overview of myocardial energy substrate utilization. Fatty acids and glucose are the major substrates used for ATP generation. The pyruvate generated from glycolysis is metabolised within the mitochondria to produce the majority of carbohydrate-derived ATP while fatty acids undergo β-oxidation. The majority of myocardial ATP originates from the mitochondria via the Krebs Cycle. A preferential increase of activity in one pathway over the other can result in imbalances in substrate uptake and utilization by the mitochondria[151]. GLUT 1: Glucose Transporter 1; GLUT 4: Glucose Transporter 4; FATP: Fatty Acid Transport Protein; CAC: Citric Acid Cycle; ATP: Adenosine Triphosphate; CPT-1: Carnitine palmitoyltransferase-1; CPT-2: Carnitine palmitoyltransferase-2.

Figure 2

Carnitine shuttle system. This summarises the role of carnitine in the mitochondrial oxidation of fatty acids; contained within Figure 1[152]. CPT-1: Carnitine palmitoyltransferase-1; CPT-2: Carnitine palmitoyltransferase-2; OM: Outer mitochondrial membrane; IM: Inner mitochondrial membrane.

Figure 3

Randle cycle. The glucose-fatty acid (Randle) cycle in muscle. Oxidation of fatty acids inhibits pyruvate dehydrogenase. Citrate inhibits phosphofructokinase. The rise in glucose-6-phosphate inhibits hexokinase[153]. FFA: Fatty acids; HK: Hexokinase; PDH: Pyruvate dehydrogenase; PFK: Phosphofructokinase; UDP: Uridine diphosphate; GLUT 4: Glucose transporter 4; OOA: Oxaloacetic acid.

Figure 4

Pathways of cardiac dysfunction leading to diabetic cardiomyopathy. Pathways leading to the development of diabetic cardiomyopathy[154]. AGE: Advanced glycation end products; FA: Fatty acids; FFA: Free fatty acids; GLUT: Glucose transporters; PKC: Protein kinase C; PPARα: Peroxisome proliferator-activated receptor alpha; ROS: Reactive oxygen species.

Figure 5

Major cardiovascular outcome trials using GLP1 receptor antagonists.

Figure 6

Major cardiovascular outcome trials examining SGLT2 inhibitors.