Introduction: Diabetic cardiomyopathy is a manifestation of the effects of diabetes on cardiac function. Given the ongoing challenges in elucidating the complex mechanisms underlying this disease at the cell and tissue levels, we have integrated advanced experimental and modelling techniques to further our understanding. Here we present the first instance of applying our previously published methodology to human cardiac tissues.
Methods: Human atrial trabeculae (10 diabetic patients and 10 non-diabetic patients) were chemically skinned to identify the effects of type 2 diabetes on passive and active mechanical properties. Using a purpose-built device, the sensitivity of cross-bridge cycling kinetics to [ATP] and [Pi] was probed using small-amplitude sinusoidal perturbations at a range of frequencies to quantify muscle complex moduli. Our experimental data were then used to parameterise mechanistic metabolite-sensitive cross-bridge models representing diabetic and non-diabetic cohorts. These cross-bridge models were integrated within a muscle model to simulate twitch dynamics and stress-length work-loops. Calcium transient dynamics were kept the same between the two models to isolate the effects of diabetes on cross-bridge function.
Results: Diabetic trabeculae produced lower active stresses, passive stresses and had complex moduli with slower cross-bridge cycling kinetics. Model simulations of isometric twitches predicted slower twitch kinetics and reduced twitch amplitude in diabetes. In work-loop simulations, the diabetic model had reduced shortening velocity and shortening power. Simulation of increased [Pi] predicted lower shortening power and work output in both groups. However, the reduction was less pronounced in the diabetic model, suggesting a lower sensitivity to Pi.
Conclusions: Our mechanistic model reveals that a decline in cross-bridge stiffness and cycling rates drives the attenuating effect of diabetes on muscle shortening velocity and power output. However, a reduced sensitivity to Pi suggests the presence of a compensatory mechanism to mitigate the effects of metabolic dysfunction in the diabetic heart.