Reduced Cell Excitability of Cardiac Postganglionic Parasympathetic Neurons Correlates With Myocardial Infarction-Induced Fatal Ventricular Arrhythmias in Type 2 Diabetes Mellitus

Abstract

ObjectiveWithdrawal of cardiac vagal activity is considered as one of the important triggers for acute myocardial infarction (MI)-induced ventricular arrhythmias in type 2 diabetes mellitus (T2DM). Our previous study demonstrated that cell excitability of cardiac parasympathetic postganglionic (CPP) neurons was reduced in T2DM rats. This study investigated whether cell excitability of CPP neurons is associated with cardiac vagal activity and MI-induced ventricular arrhythmias in T2DM rats.MethodsRat T2DM was induced by a high-fat diet plus streptozotocin injection. MI-evoked ventricular arrhythmia was achieved by surgical ligation of the left anterior descending coronary artery. Twenty-four-hour, continuous ECG recording was used to quantify ventricular arrhythmic events and heart rate variability (HRV) in conscious rats. The power spectral analysis of HRV was used to evaluate autonomic function. Cell excitability of CPP neurons was measured by the whole-cell patch-clamp technique.ResultsTwenty-four-hour ECG data demonstrated that MI-evoked fatal ventricular arrhythmias are more severe in T2DM rats than that in sham rats. In addition, the Kaplan-Meier analysis demonstrated that the survival rate over 2 weeks after MI is significantly lower in T2DM rats (15% in T2DM+MI) compared to sham rats (75% in sham+MI). The susceptibility to ventricular tachyarrhythmia elicited by programmed electrical stimulation was higher in anesthetized T2DM+MI rats than that in rats with MI or T2DM alone (7.0 ± 0.58 in T2DM+MI group vs. 3.5 ± 0.76 in sham+MI). Moreover, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of increase of left ventricular pressure (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in T2DM rats. Furthermore, T2DM increased heterogeneity of ventricular electrical activities and reduced cardiac parasympathetic activity and cell excitability of CPP neurons (current threshold-inducing action potentials being 62 ± 3.3 pA in T2DM rats without MI vs. 27 ± 1.9 pA in sham rats without MI). However, MI did not alter vagal control of the ventricular function and CPP neuronal excitability, although it also induced cardiac autonomic dysfunction and enhanced heterogeneity of ventricular electrical activities.ConclusionThe reduction of CPP neuron excitability is involved in decreased cardiac vagal function, including cardiac parasympathetic activity and vagal control of ventricular function, which is associated with MI-induced high mortality and malignant ventricular arrhythmias in T2DM.

Hydrogen Peroxide Scavenging Restores N-Type Calcium Channels in Cardiac Vagal Postganglionic Neurons and Mitigates Myocardial Infarction-Evoked Ventricular Arrhythmias in Type 2 Diabetes Mellitus

“…Data from the power spectral analysis of the HRV demonstrated that HF power (an index of cardiac parasympathetic activation) was significantly reduced, whereas the LF power (a marker of cardiac sympathetic activation) was slightly reduced in T2DM rats, compared with sham rats ( Figure 7 ). These data are consistent with results from our recent publication ( 24 ) and one clinical report that vagal predominance was significantly impaired in proportion to a withdrawal of total autonomic activity ( 71 ). Ad.CAT gene transfection into CVP neurons partially restored T2DM-impaired cardiac vagal activation recorded in T2DM+Ad.CAT conscious rats ( Figures 7A,B ).…”

“…Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients ( 6 , 100 ). Our recent study found that the decrease in cell excitability of CVP neurons contributes to the withdrawal of cardiac vagal activity and MI-evoked ventricular arrhythmias and high mortality in T2DM rats ( 24 ). Our current study further demonstrated that endogenous H 2 O 2 elevation is a critical factor for dysfunction of CVP neurons and subsequent impairment of the cardiac vagal activity in the T2DM state.…”

“…Voltage-gated Ca 2+ currents and APs were recorded in CVP neurons by the whole-cell patch-clamp technique using Axopatch 200B patch-clamp amplifier (Axon Instruments) ( 20 , 23 , 24 ). Resistance of the patch pipette was 4–6 MΩ when filled with following solution (in mM): 120 CsCl, 1 CaCl2, 40 HEPES, 11 EGTA, 4 MgATP, 0.3 Tris-GTP, 14 creatine phosphate, and 0.1 leupeptin (pH 7.3; 305 mOsm/L).…”

“…Our previous study found that reduced N-type Ca 2+ channels (Ca v 2.2) and cell excitability of CVP neurons contribute to the withdrawal of ventricular vagal function in T2DM ( 23 ). More importantly, T2DM-reduced cell excitability of CVP neurons exacerbated MI-evoked ventricular arrhythmias and high mortality rate in T2DM ( 24 ). However, the mechanisms responsible for low-expression and inactivation of N-type Ca 2+ channels in CVP neurons are unclear.…”