Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

Sudden cardiac death as a result of lethal ventricular arrhythmias is a major cause of death in cardiac diseases such as heart failure and prior myocardial infarct. Activity of the autonomic nervous system is often abnormal where sympathetic activity is upregulated and vagal activity reduced in these conditions. The abnormal autonomic state has been shown to be a strong prognostic marker of increased mortality and propensity to lethal arrhythmias, for which there is no effective prevention. Research effort over the years has established good evidence for a causal link between autonomic disturbance and ventricular arrhythmias. However, the detailed electrophysiological mechanisms by which ventricular fibrillation occurs are still not clear and molecular processes which are modulated by autonomic nerve influences that either predispose the heart to or protect it from these arrhythmias are not fully understood. This review presents data from studies investigating the link between activity of the autonomic nervous system and ventricular arrhythmias, from seminal findings in classical studies to ongoing investigations, in the quest for a better understanding of the arrhythmogenic mechanisms underlying neurocardiac interactions with a view to the development of effective preventative and therapeutic strategies which are very much needed

Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice.

Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS-/- mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after beta-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after beta-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 microgram/kg i.p.). At baseline, nNOS-/- mice had higher mean HR (711+/-8 vs. 650+/-8 bpm, P = 0.0004) and lower HR variance (424+/-70 vs. 1,112+/-174 bpm2, P = 0.001) compared with WT mice. In nNOS-/- mice, atropine administration led to a much smaller change in mean HR (-2+/-9 vs. 49+/-5 bpm, P = 0.0008) and in HR variance (64+/-24 vs. -903+/-295 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After beta-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS-/- mice before PTX administration was similar to that in WT mice. However, PTX-treated nNOS-/- mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex-mediated cardioinhibition unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse

Statistical model of paroxysmal atrial fibrillation catheter ablation targets for pulmonary vein isolation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pulmonary vein isolation (PVI) by catheter ablation is a cornerstone treatment of paroxysmal AF. Low success rates are mainly due to reconnecting tissue. Local myocardial wall-thickness (WT) information is missing; lesion transmurality is impossible to estimate. WT information can be obtained from pencil beam high-resolution MRI, a time-consuming protocol. To reduce scan time, automatic selection of regions of interest is proposed. We developed a left atrial target probability model for paroxysmal AF ablation, based on intraprocedural ablation targeting data of fifteen patients, to support the selection of these regions. A common mesh serves as a reference for registration of the electroanatomical meshes and ablation targets using landmark registration and the Iterative Closest Points algorithm. This is followed by projection of the ablation targets onto the mean mesh model, closure of isolated ablation voids on the surface and Gaussian smoothing of the probability distribution. The final probability distribution clearly shows PVI contours as suggested in the consensus statement by European associations. The right inferior pulmonary vein (RIPV) shows a lower ablation probability, which may be due to limited maneuverability of the ablation catheter and the proximity of the RIPV ostium and the transseptal puncture, where the catheter enters the left atrium

Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S-methyl-L-thiocitrulline and L-NAME, in conscious rats

1. The regional haemodynamic effects of the putative nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), were compared with those of the nonselective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in conscious, male Sprague–Dawley rats. 2. SMTC (0.3 mg kg(−1) bolus) produced a significant, short-lived, pressor effect associated with renal, mesenteric and hindquarters vasoconstriction; the same dose of L-NAME did not affect mean blood pressure (BP), although it caused bradycardia and mesenteric vasoconstriction. 3. At the highest dose tested (10 mg kg(−1)), L-NAME produced a significantly greater bradycardia and fall in mesenteric vascular conductance than SMTC, although the initial pressor response to SMTC was greater, but less sustained, than that to L-NAME. 4. Infusion of SMTC or L-NAME (3 mg kg(−1) h(−1)) induced rises in BP and falls in renal, mesenteric and hindquarters vascular conductances, but the effects of L-NAME were greater than those of SMTC, and L-NAME also caused bradycardia. 5. The renal vasodilator response to acetylcholine was markedly attenuated by infusion of L-NAME, but unaffected by SMTC. The hindquarters vasodilatation induced by salbutamol was attenuated by L-NAME, but not by SMTC. The mesenteric vasodilator response to bradykinin was modestly enhanced by SMTC, but not by L-NAME. The depressor and renal, mesenteric and hindquarters vasodilator responses to sodium nitroprusside were enhanced by L-NAME, whereas SMTC modestly enhanced the hypotensive and renal vasodilator effects of sodium nitroprusside, but attenuated the accompanying tachycardia. 6. The results are consistent with the cardiovascular effects of low doses of SMTC being attributable to nNOS inhibition