Fibrillation and defibrillation
Electrical shock is the only effective therapy of ventricular fibrillation. I received the training from Dr Ray Ideker to map ventricular fibrillation (VF) and defibrillation, and continued that line of research throughout my career. The central findings include: (1) reentrant wavefronts (rotors) underlie the mechanisms of VF and vulnerability. (2) Flattening action potential duration (ADP) restitution curve presents VF. (3) Unsuccessful epicardial shocks of greater than or equal to 1 J halt all activation fronts after which VF regenerates. (4) Upper limit of vulnerability (ULV) correlates with ventricular defibrillation threshold (DFT). These findings improved the understanding of the mechanisms of cardiac fibrillation and defibrillation. The correlation of ULV and defibrillation threshold has led to a number of clinical studies that documented ULV as an effective method in estimating defibrillation efficacy in human patients.
Radiofrequency (RF) catheter ablation
As a clinical cardiac electrophysiologist, I have contributed to the field by the following discoveries. (1) RF catheter ablation of atrial flutter. (2) Ligament of Marshall as a source of paroxysmal atrial fibrillation. (3) Eccentric retrograde activation in patients with atypical atrioventricular nodal reentrant tachycardia (AVNRT). These discoveries have become part of the knowledge base for interventional electrophysiologists when performing catheter ablation procedures. The isthmus ablation of atrial flutter is now one of the most commonly practiced procedures in clinical cardiac electrophysiology. Because roughly 6% of paroxysmal atrial fibrillation originates from the ligament of Marshall, it is a standard target for atrial fibrillation ablation. The discovery of eccentric retrograde activation in AVNRT is important in the differential diagnosis with atrioventricular reentrant tachycardia, which also has an eccentric retrograde activation sequence.
Cardiac nerve sprouting
Nerve sprouting hypothesis was established in 1980s as a fundamental mechanism that underlies epilepsy. I applied this concept to the mechanisms of cardiac arrhythmias after myocardial infarction. We found that in addition to electrophysiological and structural remodeling, there is also significant neural remodeling after myocardial infarction. The neural remodeling results in cardiac nerve sprouting, which causes regional myocardial hyperinnervation. Nerve growth factor infusion into the left stellate ganglion causes myocardial hyperinnervation, which results in increased incidence of ventricular tachyarrhythmias in a canine model. Using this canine model of sudden death, we were able to perform direct stellate ganglion nerve recording to document the relationship between stellate ganglion nerve activity and sudden cardiac death. These findings provided insights into the mechanisms by which beta blocker therapy prevents sudden death after myocardial infarction. It also provided further support for using neuromodulation to manage cardiac arrhythmias.
Small conductance Ca activated K (SK) channel and ventricular repolarization
The SK channel was first cloned in 1996 and is known to be responsible for afterhyperpolarization the controls neuronal discharges. It is also known to be present in the atria, but its function in the ventricles was unclear. Studies from my laboratory documented that the SK current is upregulated in failing rabbit ventricles. SK current activation during ventricular fibrillation shortens the APD and is responsible for inducing recurrent VF in failing rabbit ventricles. We then performed studies in failing human ventricles to document the presence of SK current upregulation. In the failing ventricles, SK current is important in steepening the action potential duration restitution curve at rapid rates, which help induce VF. On the other hand, the SK current is also upregulated in failing ventricles during bradycardia, and help maintain the repolarization reserve and prevent afterdepolarization and torsades de pointes ventricular arrhythmia. These findings provided new insights into the mechanisms of cardiac repolarization during heart failure. They suggest that SK current is important in cardiac arrhythmogenesis in diseased ventricles. It may also have significant implications in drug safety.
Nerve recording and neuromodulation in ambulatory dogs
I developed methods to record nerve activities in ambulatory dogs, and showed a direct relationship between nerve discharges and cardiac arrhythmias. Studies from our laboratory also documented the importance of nerve activities in controlling ventricular rate during atrial fibrillation. Low level vagal nerve stimulation can cause stellate ganglion remodeling and suppress spontaneous atrial fibrillation in dogs with intermittent pacing. Recently, we reported that it is feasible to record sympathetic nerve activity directly from the subcutaneous space, and that the subcutaneous nerve activity can be used to estimate the stellate ganglion nerve activity. Our most recent works focused on translating these findings to humans by using electrocardiographic electrodes to directly record sympathetic nerve activities from humans.