Diabetic cardiomyopathy: the need for adjusting experimental models to meet clinical reality

Abstract

Diabetic cardiomyopathy (CM), occurring in the absence of hypertension, coronary artery disease and valvular or congenital heart disease, is now recognized as a distinct, multifactorial disease leading to ventricular hypertrophy and abnormal myocardial contractility that correlates with an array of complex molecular and cellular changes. Animal models provide the unique opportunity to investigate mechanistic aspects of diabetic CM, but important caveats exist when extrapolating findings obtained from preclinical models of diabetes to humans. Indeed, animal models do not recapitulate the complexity of environmental factors, most notably the duration of the exposure to insulin resistance that may play a crucial role in the development of diabetic CM. Moreover, most preclinical studies are performed in animals with uncontrolled or poorly controlled diabetes, whereas patients tend to undergo therapeutic intervention. Finally, whilst T2DM prevalence trajectory mainly increases at 40- < 75 years (with a currently alarming increase at younger ages, however), it is a legitimate concern how closely rodent models employing young animals recapitulate the disease developing in old people. The aim of this review is to identify the current limitations of rodent models, and to discuss how future mechanistic and preclinical studies should integrate key confounding factors to better mimic the diabetic CM phenotype.

Early longitudinal changes in left ventricular function and morphology in diabetic pigs: evaluation by 3.0T magnetic resonance imaging

“…The success rate of modelling in this experiment was similar to that of different breeds of pigs in other experiments, but hyperglycaemia was maintained for a longer time [ 16 , 18 ]. The heart anatomy and the electrophysiological characteristics of pigs are more similar to those of humans than rodents, making pigs an ideal animal model for simulating human heart disease [ 19 ]. However, previous studies have lacked longitudinal studies on cardiac function and structure in diabetic pigs.…”

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats

“…Nevertheless, inconsistencies regarding the potential of HFD to induce LV cardiac dysfunction remain, as different studies have failed to identify cardiac complications whereas others have shown structural remodeling and diastolic dysfunction [ 44 , 45 , 46 , 47 ]. These conflicting data presumably arise from differences in rodent strains, timing and duration of the dietary interventions and diet composition, also making comparison difficult and outcome variability higher [ 48 ]. In addition, preclinical studies on the HFD regime mainly fail to account for later systolic dysfunction or reduced EF [ 18 , 49 ].…”

“…Particularly, T2DM and its cardiovascular complications develop in a chronic manner most often in middle-aged or older adults [ 66 ]. Contrary to the clinical scenario, the majority of studies on diet-induced diabetic cardiomyopathy models last a few weeks and/or employ young rodents [ 48 ]. The little evidence regarding the chronic impact of diet on cardiometabolic outcomes emphasizes the need for preclinical investigation at different life stages.…”

Effects of diabetes mellitus and glycemic traits on cardiovascular morpho-functional phenotypes

“…Diabetic patients have a high prevalence of heart failure, termed diabetic cardiomyopathy, with rates between 19% and 26% [ 46 ]. This disease is often asymptomatic in early stages, first showing as a thickening of the left ventricular wall, causing isolated diastolic dysfunction [ 47 , 48 ]. Our study revealed that higher FIns levels, when genetically predicted, could notably increase the thickness of myocardial-wall thickness at end-diastole and regional peak circumferential strain, leading to changes in left ventricular characteristics, echoing prior studies [ 49 – 51 ].…”