Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation

Abstract

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM ( db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control. NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.

Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy

“…Reentry can arise from abnormalities in conduction, repolarization, or both (Tse et al, 2016). In diabetic cardiomyopathy both abnormalities are present, establishing a powerful arrhythmogenic substrate, further strengthened by systemic factors, like autonomic neuropathy or inflammation [ 139 , 196 ] and associated heart diseases like coronary artery disease [ 69 , 126 , 198 , 260 , 312 ]. Moreover, altered ionic currents and Ca 2+ mishandling favor EADs, DADs, and spontaneous APs and constitute the arrhythmogenic trigger.…”

Stop the beat to see the rhythm: excitation-contraction uncoupling in cardiac research

“…As shown in Figure 1, since its first use for optical mapping in 2007, blebbistatin has all but replaced the other available EC uncouplers. In fact, in the last three years alone, blebbistatin was used twice as often (1,29,36,41,51,56,59,69,74,76,78,83,85,87) as any other uncoupler for imaging applications (25,27,33,46,54,55,80). The use of BDM/DAM and CytoD for optical mapping has essentially ceased, yet due to its lower cost, BDM/DAM may still be a reasonable choice for larger animal (i.e., non-rodent) studies (10,23,25,35,52,70,77), which require larger amounts of an EC uncoupler (72).…”

Novel cardiac cell subpopulations: Pnmt-derived cardiomyocytes

“…The release of catecholamines increases myocardial oxygen demand [ 91 ], exacerbates heterogeneity in underlying conduction pathways [ 92 , 93 ], and can lead to CM calcium handling dysregulation [ 54 , 94 ]—alongside other mechanisms, these underlie the contribution of excessive catecholamines to precipitating potentially fatal cardiac dysrhythmias [ 51 , 94 , 95 ]. Furthermore, excessive catecholaminergic activity is associated with several chronic cardiac pathologies such as heart failure [ 96 – 98 ], stress-induced cardiomyopathy [ 99 , 100 ] and diabetic cardiomyopathy [ 101 ]. The mechanisms underlying the contributions of catecholamines to the cardiovascular pathophysiology of these conditions are complex and active areas of research beyond the scope of this chapter.…”