Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the previous diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.

The factors that contribute to the occurrence of sudden cardiac death (SCD) in patients with chronic myocardial infarction (MI) are not entirely clear. The present study tests the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of ventricular tachycardia (VT), ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and complete atrioventricular (AV) block, we induced cardiac sympathetic nerve sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion (experimental group, n=9). Another 6 dogs with MI and complete AV block but without NGF infusion served as controls (n=6). Immunocytochemical staining revealed a greater magnitude of sympathetic nerve sprouting in the experimental group than in the control group. After MI, all dogs showed spontaneous VT that persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0 days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d, P<0.05). Four dogs in the experimental group but none in the control group died suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and AV block augments sympathetic nerve sprouting and creates a high-yield model of spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be an important determinant of SCD in chronic MI.

The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple hat propagate “shifting” foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H 2 O 2 ) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.

Early afterdepolarizations (EADs) are an important cause of lethal ventricular arrhythmias in long QT syndromes and heart failure, but the mechanisms by which EADs at the cellular scale cause arrhythmias such as polymorphic ventricular tachycardia (PVT) and Torsades de Pointes (TdP) at the tissue scale are not well-understood. Here we summarize recent progress in this area, discussing i) the ionic basis of EADs, ii) evidence that deterministic chaos underlies the irregular behavior of EADs, iii) mechanisms by which chaotic EADs synchronize in large numbers of coupled cells in tissue to overcome the source-sink mismatches, v) how this synchronization process allows EADs to initiate triggers and generate mixed focal-reentrant ventricular arrhythmias underlying PVT and TdP, and vi) therapeutic implications.

Abstract-In the heart, oxidative stress caused by exogenous H 2 O 2 has been shown to induce early afterdepolarizations (EADs) and triggered activity by impairing Na current (I Na ) inactivation. Because H 2 O 2 activates Ca 2ϩ /calmodulin kinase (CaMK)II, which also impairs I Na inactivation and promotes EADs, we hypothesized that CaMKII activation may be an important factor in EADs caused by oxidative stress. Using the patch-clamp and intracellular Ca (Ca i ) imaging in Fluo-4 AM-loaded rabbit ventricular myocytes, we found that exposure to H 2 O 2 (0.2 to 1 mmol/L) for 5 to 15 minutes consistently induced EADs that were suppressed by the I Na blocker tetrodotoxin (10 mol/L), as well as the I Ca,L blocker nifedipine. H 2 O 2 enhanced both peak and late I Ca,L , consistent with CaMKII-mediated facilitation. By prolonging the action potential plateau and increasing Ca influx via I Ca,L , H 2 O 2 -induced EADs were also frequently followed by DADs in response to spontaneous (ie, non-I Ca,L -gated) sarcoplasmic reticulum Ca release after repolarization. The CaMKII inhibitor (1 mol/L; nϭ4), but not its inactive analog (1 mol/L, nϭ5), prevented H 2 O 2 -induced EADs and DADs, and the selective CaMKII peptide inhibitor AIP (autocamtide-2-related inhibitory peptide) (2 mol/L) significantly delayed their onset. In conclusion, H 2 O 2 -induced afterdepolarizations depend on both impaired I Na inactivation to reduce repolarization reserve and enhancement of I Ca,L to reverse repolarization, which are both facilitated by CaMKII activation.