IONTOPHORETIC TRANSMYOCARDIAL DRUG DELIVERY - A NOVEL-APPROACH TO ANTIARRHYTHMIC DRUG-THERAPY

Background. Antiarrhythmic drugs often fail to achieve therapeutic effects without toxic systemic levels. Direct transport of drugs into the myocardium may circumvent this problem and may also provide new insights into antiarrhythmic drug effect on arrhythmogenic tissues. In a canine model, procainamide (PA) was delivered iontophoretically using pulsed current synchronized with the ventricular depolarization via an implantable defibrillator patch electrode that was modified to contain a 3.6-ml chamber. Myocardial tissue concentrations of PA were evaluated in 7-day myocardial infarcts (n = 16) that were exposed to 10 minutes of iontophoretic PA delivery and compared with passive diffusion (n = 5) and intravenous (n = 16) PA. These dogs were followed for 3 hours. The infarcted tissue PA levels were compared with normal myocardium. Coronary and systemic blood levels of PA, effective refractory period (ERP), diastolic threshold, and efficacy of ventricular tachycardia (VT) suppression were evaluated throughout the follow-up period. Methods and Results. Three hours after 10 minutes of iontophoretic, passive, and intravenous PA, the epicardial layer concentration in the center of the infarcted zone was 840 +/- 853-mu-g/g, 93 +/- 90-mu-g/g, and 15 +/- 8-mu-g/g of tissue, respectively. In the endocardial layer, the PA concentrations with iontophoresis were 38 +/- 57-mu-g/g and were significantly higher than those achieved with either passive diffusion (4 +/- 2-mu-g/g) or with intravenous delivery (11 +/- 5-mu-g/g) (p < 0.05). Epicardial tissue PA concentrations 3 hours after iontophoresis, passive diffusion, and intravenous PA in the normally perfused tissues were 14 +/- 13-mu-g/g, 3 +/- 2-mu-g/g, and 16 +/- 8-mu-g/g of PA, respectively. Venous blood levels were 2 +/- 3-mu-g/ml 3 hours after iontophoresis, 1 +/- 1-mu-g/ml 3 hours after passive PA delivery, and 11 +/- 7-mu-g/ml with intravenous administration (p < 0.05 intravenous versus passive and iontophoresis). Iontophoretic delivery of PA resulted in 22 +/- 29 msec ERP prolongation intramurally in the infarcted zone with no significant normal tissue ERP prolongation. Passive delivery of PA produced no significant changes in ERP. After intravenous infusion, the ERP in the infarcted zone increased by 35 +/- 29 msec and 13 +/- 12 msec in the normal tissue. Sustained monomorphic VT was induced in 20 animals. In one of these animals, only nonsustained VT could be induced at baseline; however, after intravenous PA, VT could be induced and remained inducible throughout the 3-hour follow-up period. In the iontophoretic delivery group, PA suppressed VT in all of the animals, with termination time ranging from 20 seconds to 7 minutes. In three cases, sustained monomorphic VT could be reinduced, two after 60 minutes and one after 120 minutes. However, in seven dogs, VT could not be induced during the 3-hour follow-up period. None of the dogs in which PA was delivered iontophoretically into the infarcted myocardium developed VT that was not induced before delivery of the drug. Intravenous PA administration resulted in VT suppression in one of 10 dogs. In two dogs, VT could not be induced before intravenous infusion of PA. However, after intravenous PA, VT could be induced. Immunohistochemical mapping of the PA within the infarcted tissue revealed transmural PA distribution. Conclusions. These data show that 1) the delivery of high transmural concentrations of PA directly into infarcted myocardium is both feasible and effective. PA concentrations in the infarcted tissues were significantly above therapeutic levels for over 3 hours after 10 minutes of iontophoretic drug exposure, with only minimal levels detected in the circulation, 2) PA delivery into the infarcted myocardium using iontophoresis is much more effective than either passive diffusion or intravenous administration, and 3) in this model, VT is rapidly suppressed by the iontophoretic delivery of PA into the infarcted area; however, effective refractory period and diastolic threshold did not increase dramatically with iontophoretic PA delivery.