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Background-The mechanisms that sustain ventricular fibrillation (VF) in the human heart remain unclear. Experimental models have demonstrated either a periodic source (mother rotor) or multiple wavelets as the mechanism underlying VF. The aim of this study was to map electrical activity from the entire ventricular epicardium of human hearts to establish the relative roles of these mechanisms in sustaining early human VF. Methods and Results-In 10 patients undergoing cardiac surgery, VF was induced by burst pacing, and 20 to 40 seconds of epicardial activity was sampled (1 kHz) with a sock containing 256 unipolar contact electrodes connected to a UnEmap system. Signals were interpolated from the electrode sites to a fine regular grid (100ϫ100 points), and dominant frequencies (DFs) were calculated with a fast Fourier transform with a moving 4096-ms window (10-ms increments). Epicardial phase was calculated at each grid point with the Hilbert transform, and phase singularities and activation wavefronts were identified at 10-ms intervals. Early human VF was sustained by large coherent wavefronts punctuated by periods of disorganized wavelet behavior. The initial fitted DF intercept was 5.11Ϯ0.25 (meanϮSE) Hz (PϽ0.0001), and DF increased at a rate of 0.018Ϯ0.005 Hz/s (PϽ0.01) during VF, whereas combinations of homogeneous, heterogeneous, static, and mobile DF domains were observed for each of the patients. Epicardial reentry was present in all fibrillating hearts, typically with low numbers of phase singularities. In some cases, persistent phase singularities interacted with multiple complex wavelets; in other cases, VF was driven at times by a single reentrant wave that swept the entire epicardium for several cycles. Conclusions-Our data support both the mother rotor and multiple wavelet mechanisms of VF, which do not appear to be mutually exclusive in the human heart. (Circulation. 2006;114:536-542.)

BackgroundBradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption.ObjectivesThe purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia.MethodsWe assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the “funny” current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1–30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography).ResultsIn mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% ± 3% and 15% ± 2% at 3 and 10 µM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% ± 6%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% ± 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function.ConclusionsWe have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If.

1. Positron emission tomography (PET) was used to identify the neuroanatomical correlates underlying 'central command' during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback.2. Three cognitive conditions were used: condition I, imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V I ): condition II, imagination of exercise, cycling uphill (increased HR by 12 % and V I by 30 % of the actual exercise response): condition III, volitionally driven hyperventilation to match that achieved in condition II (no change in HR).3. Subtraction methodology created contrast A (II minus I) highlighting cerebral areas involved in the imagination of exercise and contrast B (III minus I) highlighting areas activated in the direct volitional control of breathing (n = 4 for both; 8 scans per subject). End-tidal P CO 2 (P ET,CO 2 ) was held constant throughout PET scanning.4. In contrast A, significant activations were seen in the right dorso-lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), superolateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In contrast B, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso-lateral prefrontal cortex and the cerebellum are concerned with volitional/motor control, including that of the respiratory muscles.5. The neuroanatomical areas activated suggest that a significant component of the respiratory response to 'exercise', in the absence of both movement feedback and an increase in CO 2 production, can be generated by what appears to be a behavioural response.

Steep action potential duration (APD) restitution has been shown to facilitate wavebreak and ventricular fibrillation. The global APD restitution properties in cardiac patients are unknown. We report a combined clinical electrophysiology and computer modelling study to: (1) determine global APD restitution properties in cardiac patients; and (2) examine the interaction of the observed APD restitution with known arrhythmia mechanisms. In 14 patients aged 52-85 years undergoing routine cardiac surgery, 256 electrode epicardial mapping was performed. Activation-recovery intervals (ARI; a surrogate for APD) were recorded over the entire ventricular surface. Mono-exponential restitution curves were constructed for each electrode site using a standard S1-S2 pacing protocol. The median maximum restitution slope was 0.91, with 27% of all electrode sites with slopes < 0.5, 29% between 0.5 and 1.0, and 20% between 1.0 and 1.5. Eleven per cent of restitution curves maintained slope > 1 over a range of diastolic intervals of at least 30 ms; and 0.3% for at least 50 ms. Activation-recovery interval restitution was spatially heterogeneous, showing regional organization with multiple discrete areas of steep and shallow slope. We used a simplified computer model of 2-D cardiac tissue to investigate how heterogeneous APD restitution can influence vulnerability to, and stability of re-entry. Our model showed that heterogeneity of restitution can act as a potent arrhythmogenic substrate, as well as influencing the stability of re-entrant arrhythmias. Global epicardial mapping in humans showed that APD restitution slopes were organized into regions of shallow and steep slopes. This heterogeneous organization of restitution may provide a substrate for arrhythmia.

We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n = 8) or 3-morpholinosydnonimine (SIN-1, n = 6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n = 6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 mumol/L, n = 6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 mumol/L, n = 6), and (3) mimicked by 8-bromo-cGMP (n = 6) with no additional positive chronotropic effect of SIN-1 (n = 5). The response to 10 mumol/L SNP (n = 28) or 50 mumol/L SIN-1 (n = 16) was unaffected by IcaL antagonism with nifedipine (0.2 mumol/L) but was abolished after blockade of the hyperpolarization-activated inward current (I(f)) by Cs+ (2 mmol/L) or 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 mumol/L). The effect on I(f) was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n = 21), where we found that 5 mumol/L SNP or SIN-1 caused a reversible Cs(+)-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of I(f) via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.

Research into cardiac autonomic control has received an explosion of interest in the past 20 years, and we are now at a critical juncture with regard to the clinical translation of the experimental findings.There has been a rush to develop clinical interventions and implant a range of devices aimed at cardiac neuromodulation therapy. This interest has been driven by research, superimposed on commercial opportunities and perhaps the more relaxed regulatory framework governing implantable devices and interventions compared with that for pharmacotherapy. However, many of the results of the clinical trials into these therapies have been disappointing or conflicting. This lack of positive results is partly due to a scramble to find simple solutions for complex problems that we do not yet fully understand. Are there reasons to be optimistic? In this Review, we highlight areas in the field of cardiac autonomic control that we feel show most promise for clinical translation, and areas where our current range of blunt tools need to be refined to bring about long-term success in treating arrhythmia.

We tested the hypothesis that nitric oxide (NO) augments vagal neurotransmission and bradycardia via phosphorylation of presynaptic calcium channels to increase vesicular release of acetylcholine. The effects of enzyme inhibitors and calcium channel blockers on the actions of the NO donor sodium nitroprusside (SNP) were evaluated in isolated guinea‐pig atrial‐right vagal nerve preparations. SNP (10 μm) augmented the heart rate response to vagal nerve stimulation but not to the acetylcholine analogue carbamylcholine (100 nm). SNP also increased the release of [3H]acetylcholine in response to field stimulation. No effect of SNP was observed on either the release of [3H] acetylcholine or the HR response to vagal nerve stimulation in the presence of the guanylyl cyclase inhibitor 1H‐(1,2,4)‐oxadiazolo‐(4,3‐a)‐quinoxalin‐1‐one (ODQ, 10 μm). The phosphodiesterase 3 (PDE 3) inhibitor milrinone (1 μm) increased the release of [3H] acetylcholine and the vagal bradycardia and prevented any further increase by SNP. SNP was still able to augment the vagal bradycardia in the presence of the protein kinase G inhibitor KT5823 (1 μm) but not after protein kinase A (PKA) inhibition with H‐89 (0.5 μm) or KT5720 (1 μm) had reduced the HR response to vagal nerve stimulation. Neither milrinone nor H‐89 changed the HR response to carbamylcholine. SNP had no effect on the magnitude of the vagal bradycardia after inhibition of N‐type calcium channels with ω‐conotoxin GVIA (100 nm). These results suggests that NO acts presynaptically to facilitate vagal neurotransmission via a cGMP‐PDE 3‐dependent pathway leading to an increase in cAMP‐PKA‐dependent phosphorylation of presynaptic N‐type calcium channels. This pathway may augment the HR response to vagal nerve stimulation by increasing presynaptic calcium influx and vesicular release of acetylcholine.