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Potent antifibrillatory effects of intrapericardial nitroglycerin in the ischemic porcine heart

Kapil Kumar, MD^*, Khanh Nguyen, BA, Sergio Waxman, MD^*, Bruce D. Nearing, PhD^*, Gregory A. Wellenius, MSc, Susan X. Zhao, MS^* and Richard L. Verrier, PhD, FACC^*,*

^* Harvard Medical School, Boston, Massachusetts, USA
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Harvard School of Public Health, Boston, Massachusetts, USA

View larger version (131K): [in a new window]   Figure 1 Fluoroscopic image of experimental setup for electrophysiology studies. Infusion catheter (A) in the pericardial space conforms to the contour of the heart. Angioplasty balloon (B) completely occludes the left anterior descending coronary artery as demonstrated by dye injection into the left main coronary artery. Intracoronary guidewire (C) monitors the intracoronary electrocardiogram (ECG). Electrocatheter (D) positioned in the left ventricular (LV) ischemic zone records the LV ECG. Pacing catheter (E) is in the right atrium, positioned via the right internal jugular vein; 8F multipurpose guide catheter (F) in the right atrial appendage is used for introducing the pericardial infusion catheter.

View larger version (21K): [in a new window]   Figure 2 Suppression of ischemia-induced arrhythmias with intrapericardial nitroglycerin. (Top) Coronary artery occlusion consistently provoked severe arrhythmias after intrapericardial saline rather than nitroglycerin administration (n = 5). (Bottom) Arrhythmia severity was reduced 45 min after intrapericardial nitroglycerin (4,000 µg bolus) compared with control (p < 0.05). This reduction in arrhythmia grade appeared as early as 15 min and lasted up to 75 min in four of six animals. Each line type represents an individual experiment. VF = ventricular fibrillation; VPB = ventricular premature beats; VT = ventricular tachycardia (<10-s duration).

View larger version (20K): [in a new window]   Figure 3 Ischemia-induced T-wave alternans (TWA) in intracoronary electrocardiogram tracings in a representative experiment; TWA was not evident at baseline, before occlusion of the left anterior descending coronary artery (left). Marked TWA (105.26 µV) appeared just before ventricular fibrillation onset during occlusion without drug (middle) but was minimized (42.10 µV) during the occlusion at 45 min after intrapericardial nitroglycerin (4,000 µg bolus) (right).

View larger version (14K): [in a new window]   Figure 4 Intrapericardial nitroglycerin significantly attenuated the magnitude of ischemia-induced T-wave alternans (TWA) in the intracoronary lead at 45 min after delivery (*p < 0.05), in parallel with the agent’s effect on arrhythmias; TWA recovered to pre-drug levels by 75 min after intrapericardial nitroglycerin.

View larger version (14K): [in a new window]   Figure 5 Effect of intrapericardial nitroglycerin on the rise in contractility in response to intracoronary bolus injections of dobutamine. At 15 min after intrapericardial nitroglycerin, the rise in contractility induced by intracoronary dobutamine was significantly blunted (*p < 0.05). Thereafter, nitroglycerin’s effect did not achieve statistical significance. LV dP/dt max = maximum of the first time derivative of left ventricular pressure.

View larger version (29K): [in a new window]   Figure 6 Heart rate and hemodynamic response to intravenous (IV) (open circles) as compared with intrapericardial (IPC) (filled circles) nitroglycerin administration. The period of IV monitoring was 40 min, corresponding to a time when the effect of IV nitroglycerin would be expected to be completely dissipated, and, in fact, the values had all returned to baseline at that point. The effects of IPC nitroglycerin were monitored for 75 min, the anticipated period of action and potential antiarrhythmic effects. *p = difference from pre-drug baseline, <0.05. The results were obtained in a total of eight animals, four of which received both IV and IPC nitroglycerin, and the remaining four received the drug through either the IV or IPC route. Randomizing the protocol was intended to reduce possible sequence-related effects.