Kan Kikuchi

Targeted Modification of Atrial Electrophysiology by Homogeneous Transmural Atrial Gene Transfer

Background—Safe and effective myocardial gene transfer remains elusive. Heterogeneous ventricular gene delivery has been achieved in small mammals but generally with methods not readily transferable to the clinic. Atrium-specific gene transfer has not yet been reported. We hypothesized that homogeneous atrial gene transfer could be achieved by direct application of adenoviral vectors to the epicardial surface, use of poloxamer gel to increase virus contact time, and mild trypsinization to increase virus penetration. Methods and Results—We “painted” recombinant adenovirus encoding the reporter gene Escherichia coli &bgr;-galactosidase directly onto porcine atria. Investigational variables included poloxamer use, trypsin concentration, and safety. Using the painting method, we modified the atrial phenotype with an adenovirus expressing HERG-G628S, a long-QT-syndrome mutant. Our results showed that application of virus with poloxamer alone resulted in diffuse epicardial gene transfer with negligible penetration into the myocardium. Dilute trypsin concentrations allowed complete transmural gene transfer. After trypsin exposure, echocardiographic left atrial diameter did not change. Left atrial function decreased on postoperative day 3 but returned to baseline by day 7. Tissue tensile strength was affected only in the 1% trypsin group. HERG-G628S gene transfer prolonged atrial action potential duration and refractory period without affecting ventricular electrophysiology. Conclusions—We show complete transmural atrial gene transfer by this novel painting method. Adaptation of the method could allow application to other tissue targets. Use with functional proteins in the atria could cure or even prevent diseases such as atrial fibrillation or sinus node dysfunction.

Molecular ablation of ventricular tachycardia after myocardial infarction.

Ventricular tachycardia is a common and lethal complication after myocardial infarction. Here we show that focal transfer of a gene encoding a dominant-negative version of the KCNH2 potassium channel (KCNH2-G628S) to the infarct scar border eliminated all ventricular arrhythmias in a porcine model. No proarrhythmia or other negative effects were discernable. Our results demonstrate the potential viability of gene therapy for ablation of ventricular arrhythmias.

Selective Molecular Potassium Channel Blockade Prevents Atrial Fibrillation

Background— Safety and efficacy limit currently available atrial fibrillation (AF) therapies. We hypothesized that atrial gene transfer would allow focal manipulation of atrial electrophysiology and, by eliminating reentry, would prevent AF. Methods and Results— In a porcine AF model, we compared control animals to animals receiving adenovirus that encoded KCNH2-G628S, a dominant negative mutant of the IKr potassium channel &agr;-subunit (G628S animals). After epicardial atrial gene transfer and pacemaker implantation for burst atrial pacing, animals were evaluated daily for cardiac rhythm. Electrophysiological and molecular studies were performed at baseline and when animals were euthanized on either postoperative day 7 or 21. By day 10, none of the control animals and all of the G628S animals were in sinus rhythm. After day 10, the percentage of G628S animals in sinus rhythm gradually declined until all animals were in AF by day 21. The relative risk of AF throughout the study was 0.44 (95% confidence interval 0.33 to 0.59, P<0.01) among the G628S group versus controls. Atrial monophasic action potential was considerably longer in G628S animals than in controls at day 7, and KCNH2 protein levels were 61% higher in the G628S group than in control animals (P<0.01). Loss of gene expression at day 21 correlated with loss of action potential prolongation and therapeutic efficacy. Conclusions— Gene therapy with KCNH2-G628S eliminated AF by prolonging atrial action potential duration. The effect duration correlated with transgene expression.

Gene transfer techniques for cardiac arrhythmias

Therapy for cardiac arrhythmias is inadequate, based on current options. Gene therapy has shown tremendous potential to investigate pathophysiology and potential therapies for cardiac diseases. The current work reviews the possibilities for application of in vivo gene transfer to treatment of common arrhythmias, including vector selection, delivery technique, and data on in vivo gene transfer for rate control in atrial fibrillation and for pacemaking activity. Arrhythmia gene therapy is a field in its infancy, and future human applications are dependent on solutions to the problems discussed in this review.

Superior Rhythm Discrimination With the SmartShock Technology Algorithm ― Results of the Implantable Defibrillator With Enhanced Features and Settings for Reduction of Inaccurate Detection (DEFENSE) Trial ―

BACKGROUND Shocks delivered by implanted anti-tachyarrhythmia devices, even when appropriate, lower the quality of life and survival. The new SmartShock Technology®(SST) discrimination algorithm was developed to prevent the delivery of inappropriate shock. This prospective, multicenter, observational study compared the rate of inaccurate detection of ventricular tachyarrhythmia using the SST vs. a conventional discrimination algorithm.Methods and Results:Recipients of implantable cardioverter defibrillators (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) equipped with the SST algorithm were enrolled and followed up every 6 months. The tachycardia detection rate was set at ≥150 beats/min with the SST algorithm. The primary endpoint was the time to first inaccurate detection of ventricular tachycardia (VT) with conventional vs. the SST discrimination algorithm, up to 2 years of follow-up. Between March 2012 and September 2013, 185 patients (mean age, 64.0±14.9 years; men, 74%; secondary prevention indication, 49.5%) were enrolled at 14 Japanese medical centers. Inaccurate detection was observed in 32 patients (17.6%) with the conventional, vs. in 19 patients (10.4%) with the SST algorithm. SST significantly lowered the rate of inaccurate detection by dual chamber devices (HR, 0.50; 95% CI: 0.263-0.950; P=0.034). CONCLUSIONS Compared with previous algorithms, the SST discrimination algorithm significantly lowered the rate of inaccurate detection of VT in recipients of dual-chamber ICD or CRT-D.

Modification of cellular communication by gene transfer

Abstract: Hope has been expressed that gene and cell therapies will one day reduce the morbidity and mortality associated with cardiovascular diseases. Work in these fields has shown that the road from bench to bedside is filled with obstacles. Still, the possibility for treatment or even cure of cardiac disease is real. Continuing work will improve understanding of the underlying physiology and vector biology. The current review focuses on the potential use of gene therapy to affect cellular communication. Included is a review of communication effects on a transcellular level with angiogenesis, AV nodal conduction and sinus nodal automaticity, and effects on an intracellular level with cardiac myocyte repolarization. Challenges facing the field of gene therapy are also reviewed. If these problems can be solved, gene therapy will become a viable alternative for clinical use.