Abstract
The heart displays a well-described circadian rhythm in which heart rate, blood pressure and other important functional markers decrease during the inactive period. However, this circadian rhythm of the cardiovascular system is blunted, absent or even reversed in diabetes, which places those with diabetes at a far greater risk of developing cardiovascular disease. As there is a current epidemic of diabetes in New Zealand, this becomes especially important. Restoring cardiac circadian rhythmicity in these individuals would carry significant therapeutic benefit, but the origin of this rhythm and the mechanism by which it is deregulated in diabetes have not yet been found and thus confound the search for potential therapies.
A central circadian clock exists in the hypothalamus of the brain and was once thought to be the sole provider of circadian rhythmicity to the body. However, circadian clocks have since been found in almost all organs of the body, including the heart. The central circadian clock is connected to the cardiac circadian clock via the autonomic nervous system, and it has been shown that autonomic input can affect the transcription of key cardiac circadian clock proteins. Autonomic input could be a potential timekeeper for the intrinsic cardiac clock, creating the cardiac circadian rhythm. To understand this further, this study aimed to determine how the heart’s sensitivity to autonomic signalling varied between the active and inactive phase, and whether any such rhythms were disrupted in diabetes.
To this end, hearts of type 2 diabetic Zucker Diabetic Fatty (ZDF) rats and their non-diabetic littermates were isolated at the start of the rat’s active and inactive periods. The hearts were then mounted on a Langendorff rig and were allowed to beat at their intrinsic rate without external stimulation. Baseline function of the left ventricle was assessed, including chronotropic (rate), inotropic (contraction) and lusitropic (relaxation) measures. The hearts were then exposed to the effectors of the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) to determine changes in functional sensitivity of chronotropic, inotropic, and lusitropic responses. Following this, protein expression levels of the receptors for the PNS (muscarinic-2 cholinergic receptors) and SNS (beta-1 and beta-2 adrenergic receptors) as well as proteins of the circadian clock (BMAL1 and CLOCK) were determined in tissue homogenates collected at the same timepoints but from a different cohort of ZDF rat hearts free from experimental confounders, using Western blot.
While this study did not show a circadian rhythm in cardiac sensitivity to the PNS, there was evidence of a significant circadian rhythm in cardiac sensitivity to the SNS, with greater inotropic and lusitropic responses at the start of the rat’s active period. This was associated with no change in the protein expression of autonomic receptors between timepoints. This provides evidence that the SNS, but not the PNS, may act as a timekeeper for the intrinsic cardiac circadian clock. However, the diurnal rhythm in functional sensitivity to the SNS was maintained in diabetic hearts and so this process may not be the mechanism by which the cardiac circadian rhythm is disrupted in diabetes. Evidence of reduced responsiveness to the PNS in diabetic hearts was also found.
In conclusion, while this study did not find the mechanism of circadian dysregulation in diabetic hearts, it did find that the SNS is likely involved in the creation of the cardiac circadian rhythm, and that reduced sensitivity to the PNS in diabetic hearts could be contributing to the burden of disease seen in people with diabetes. These exciting and novel finings create the opportunity for potential therapeutic targets, as drugs that interfere with SNS signalling such as beta-blockers have the potential to either reinforce or weaken circadian rhythmicity in the heart. Depending on how they are prescribed, these medications could actually contribute to increased morbidity and mortality seen in people living with diabetes, highlighting the importance of chronotherapy research. The reduced PNS sensitivity in type 2 diabetes must also be explored further, as restoring normal sensitivity could be another treatment avenue to improve outcomes in the surging number of people living with diabetes in New Zealand.