SUMMARY Accumulation of polymorphonuclear neutrophils during the acute inflammatory response may exacerbate tissue injury through the release of activated oxygen products or proteolytic enzymes or both. To assess the role of neutrophils in acute myocardial infarction, circulating neutrophil levels in dogs were reduced by 77 + 2% (mean SEM) by administering rabbit antiserum to dog neutrophils. Acute myocardial infarction was induced in open-chest anesthetized dogs by 90 minutes of left circumflex coronary artery occlusion followed by 6 hours of reperfusion. Dogs treated with neutrophil antiserum (n = 8) developed myocardial infarcts that were an average of 43% smaller' than infarcts in dogs treated with nonimmune rabbit serum (n = 7) (27.0 ± 4.5% vs 47.1% 7.5% of the area at risk, p < 0.05). In a salinetreated control group (n = 8), infarct size was 48.0 ± 4.7% of the area at risk, a value not significantly different from that of the nonimmune serum group but significantly greater than that in the neutrophil antiserum dogs (p < 0.05). There were no major hemodynamic differences between groups. Histopathologic examination revealed that infarcted myocardium from dogs given saline or treated with nonimmune serum had a substantial neutrophilic infiltrate, which was virtually absent in infarcted tissue from dogs treated with neutrophil, antiserum. These observations suggest that neutrophil accumulation in response to myocardial ischemia may be responsible for a substantial portion of the irreversible myocardial' injury resulting from temporary coronary artery occlusion.THE MIGRATION of polymorphonuclear neutrophils into recently infarcted myocardium represents the initial phase of a process that leads to demolition and subsequent organization of injured tissue and culminates in the replacement of necrotic myocardium with fibrous scar." 2 Infiltration of neutrophils into irreversibly injured myocardium facilitates the breakdown of necrotic myocardium, which promotes resorbtion or phagocytosis by macrophages.2 After the removal of tissue debris, capillaries and fibroblasts invade the infarcted area and lead to the formation of collagen-rich scar tissue, which replaces the necrotic area.2 During the early acute inflammatory response, polymorphonuclear neutrophils undergo a complex series of functional and biochemical alterations that promote tissue lysis. Although these events are important to the repair process, they may also result in the destruction of potentially viable tissue elements. Stimulated neutrophils release highly reactive and cytotoxic activated oxygen species such as superoxide anion, hydroxyl radical, hydrogen peroxide and singlet oxygen. These activated oxygen radicals degrade extracellular macromolecules, attack membrane phospholipids and, thus, promote cell injury or death. idonic acid, which is converted by specific lipoxygenases to potent chemotactic hydroxy-eicosatetraenoic acids (HETEs).6 These chemoattractant substances promote the further recruitment of neutrophils into the acute inflammatory re...

Background - The limited effectiveness of endocardial catheter ablation (CA) for persistent and long-standing persistent atrial fibrillation (Ps/LSP-AF) treatment led to the development of a minimally-invasive epicardial/endocardial ablation approach (Hybrid Convergent) to achieve a more comprehensive lesion set with durable transmural lesions. The multi-center randomized controlled CONVERGE trial (NCT01984346) evaluated the safety of Hybrid Convergent and compared its effectiveness to CA for Ps/LSP-AF treatment. Methods - One-hundred fifty-three patients were randomized 2:1 to Hybrid Convergent vs. CA. Primary effectiveness was freedom from AF/AFL/AT absent new/increased dosage of previously failed/intolerant class I/III anti-arrhythmic drugs (AADs) through 12-months. Primary safety was major adverse events through 30 days. CONVERGE permitted left atrium size up to 6cm and imposed no limits on AF duration, making it the only ablation trial to substantially include LSP-AF i.e. 42% patients with LSP-AF. Results - Of 149 evaluable patients at 12 months, primary effectiveness was achieved in 67.7% (67/99) patients with Hybrid Convergent and 50.0% (25/50) with CA (p=0.036) on/off previously failed AADs and in 53.5% (53/99) versus 32.0% (16/50) (p=0.0128) respectively off AADs. At 18-months using 7-day Holter, 74.0% (53/72) Hybrid Convergent and 55% (23/42) CA patients experienced ≥90% AF burden reduction. A total of 2.9% (3/102) patients had primary safety events within 7 days, and 4.9% (5/102) between 8-30 days post-procedure. No deaths, cardiac perforations or atrioesophageal fistulas occurred. All but one primary safety event resolved. Conclusions - The Hybrid Convergent procedure has superior effectiveness compared to the CA for the treatment of Ps/LSP-AF.

Experiments were performed in the dog to examine the effects of neutropenia on ultimate infarct size resulting from short (90 minutes) or prolonged (4 hours) circumflex coronary artery occlusion. Sheep antiserum to canine neutrophils was used to produce neutropenia. Control animals received nonimmune serum. Neutrophil infiltration into myocardial infarcts was examined using histopathologic techniques and a semiquantitative scoring system. In 90-minute occlusions with 24-hour reperfusion, neutropenia was associated with the development of significantly smaller infarcts: normopenic group, 43.2% +/- 3.3% (n = 7) vs. neutropenic group, 26.6% +/- 3.7% (n = 10) of the area at risk, means +/- SEM. However, in 4-hour occlusion with 6-hour reperfusion experiments, the tendency of neutrophil depletion to reduce infarct size did not reach statistical significance (46.4% +/- 7.2% vs. 31.5% +/- 6.0% of the area at risk, normopenic vs. neutropenic) despite differences in neutrophil infiltration into the reperfused region. The observed differences in ultimate infarct size could not be attributed to differences in myocardial oxygen consumption. The results suggest that a significant amount of myocardial infarction induced by a limited duration of coronary artery occlusion followed by reperfusion is neutrophil dependent and appears to be less important in determining the fate of myocardium subjected to more prolonged periods of ischemia followed by reperfusion.

SUMMARY To assess the ability of ibuprofen to influence the extent of platelet aggregation and leukocyte infiltration during acute myocardial infarction, autologous indium-111 ("IIn)-labeled platelets or leukocytes were injected before 60 minutes of left circumflex coronary artery (LCx) occlusion, followed by 24 hours of reperfusion in the canine heart. Myocardial infarct size, as a percent of the area at risk, was reduced in the ibuprofen-treated group (12.5 mg/kg i.v. every 4 hours beginning 30 minutes before LCx occlusion) by 40%, from 48 4% in control animals to 29 4% in ibuprofen-treated dogs (p = 0.005).Quantification of the platelet-associated "l'In radioactivity in irreversibly injured myocardium indicated that ibuprofen did not alter the accumulation of platelets in infarcted myocardium. In contrast, leukocyte accumulation in infarcted tissue was reduced significantly. In tissue samples with 0.414.60 gram infarct, the in'farcted/normal ratio of leukocyte radioactivity was 12 ± 2 in control dogs and 4 + 1 in ibuprofentreated dogs, which represents a 67% reduction in leukocyte accumulation in ibuprofen-treated compared with control dogs. Similar reductions were found in other gram-infarct-weight categories. Although both platelets and leukocytes accumulate in infarcted canine myocardium, ibuprofen may exert its beneficial effect on ischemic myocardium by suppressing the inflammatory response associated with myocardial ischemia and infarction.THE GOAL of much cardiovascular research has been to develop pharmacologic means of managing patients before or soon after an acute ischemic insult to minimize the extent of irreversible myocardial injury and subsequent loss of ventricular function. Several agents are effective in reducing the extent of myocardial infarction resulting from experimentally induced acute myocardial ischemia in a variety of animal models.1 One such agent, ibuprofen, is a nonsteroidal antiinflammatory compound that has been reported to exert cardioprotective effects by significantly reducing the extent of irreversible myocardial injury to experimental ischemia in the dog,2'3 the cat,4 and the rat.5 Ibuprofen renders its cardioprotective effects administered orally,3 intravenously2 or intramuscularly.5Several independent investigators have demonstrated protective effects in a variety of experimental models of myocardial ischemia and infarction, but little is known about ibuprofen's mechanism of action. Apparently, the beneficial effects of ibuprofen do not derive from alteration of the balance of myocardial oxygen supply and demand in a favorable manner. Intravenous ibuprofen reportedly has negligible hemodynamic effects2' 6 and almost no effect on the calculated ratepressure product, an accepted approximation of myocardial oxygen consumption,7 during myocardial ischemia in the dog.6 Moreover, in the nonischemic, isolated, blood-perfused cat heart, an animal model that permits careful control of hemodynamic variables, ibuprofen did not alter myocardial oxygen consumption as measured by art...

An antitachycardia pacemaker-cardioverter-defibrillator that is capable of storing ventricular electrograms before and after delivery of device shock therapy was implanted in 16 patients. Three of the patients experienced out-of-hospital device shock therapy preceded by minimal symptoms. Although limitations of electrogram analysis exist and are discussed, careful analysis and registration of electrograms during all supraventricular and ventricular rhythms observed during in-hospital testing served as an important reference for subsequent arrhythmia diagnosis. By analyzing the electrogram rate and RR interval stability and configuration, a definitive diagnosis was established in all three patients (atrial fibrillation, polymorphic ventricular tachycardia and rate-sensing lead disruption, respectively). Thus, the ability to store ventricular electrograms before shock therapy represents a major advance in the management of patients who receive an electrical device to treat ventricular tachyarrhythmia.

Retrograde atrial activation over the fast pathway is heterogeneous within Koch's triangle and the coronary sinus, both for the entire population and for individual patients during different modes of activation. These data do not support the concept of an anatomically discrete retrograde fast pathway.

Background-Cardiologists often use clinical variables to determine the need for electrophysiological studies to stratify patients for risk of sudden death. It is not clear whether this is rational in patients with coronary artery disease, left ventricular dysfunction, and nonsustained ventricular tachycardia. Methods and Results-We analyzed the first 1721 patients enrolled in the Multicenter UnSustained Tachycardia Trial to determine whether clinical variables could predict which patients would have inducible sustained monomorphic ventricular tachycardia. The rate of inducibility of sustained ventricular tachycardia was significantly higher in patients with a history of myocardial infarction and in men compared with women. There was a progressively increased rate of inducibility with increasing numbers of diseased coronary arteries. There was a significantly lower rate of inducibility in patients with prior coronary artery bypass surgery and in patients who also had noncoronary cardiac disease. The rate of inducibility was higher in patients of white race, patients with recent (Յ6 weeks) angina, left ventricular dyskinesis, and in patients with greater numbers of fixed thallium defects. Inducibility was more likely in patients who had a prior myocardial infarction complicated by congestive heart failure, ventricular tachycardia, or fibrillation Յ48 hours after the onset of infarction. Although these associations are statistically significant, the accuracy of the clinical variables in discriminating between patients with and those without inducible ventricular tachycardia is only modest (receiver operator characteristic area Ͻ0.70). Conclusions-Multiple clinical variables are independently associated with inducible sustained ventricular tachycardia.However, they have limited utility to guide clinical decisions regarding the use of electrophysiological testing for risk stratification in this patient population.

BACKGROUND Resetting and entrainment have both been used to characterize the electrophysiological properties of the reentrant circuit in ventricular tachycardia. Several entrainment studies have suggested that the circuit has decremental properties, because the return cycle increases at faster pacing rates. Resetting, however, demonstrates a fully excitable gap in the majority of tachycardias. METHODS AND RESULTS The response to resetting and overdrive pacing was analyzed in 18 ventricular tachycardias. Resetting demonstrated some duration of a fully excitable gap in 14 of 18 tachycardias. Overdrive pacing was performed at several cycle lengths with an incremental number of stimuli (1-15 beats) such that the first beat that interacted with the tachycardia (the nth beat) could be identified. The return cycles measured during resetting and the nth beat of pacing were identical (r = 0.99). At relatively long paced cycle lengths, paced beats after the nth beat resulted in a constant return cycle in most tachycardias with a fully excitable gap. At rapid paced cycle lengths, an increase in the return cycle from the nth to the nth + 1 beat was associated with progressive prolongation in the return cycle with each incremental paced beat until a longer equilibrium return cycle was reached or the tachycardia terminated in response to pacing. CONCLUSIONS We propose that the responses to resetting and overdrive pacing with or without entrainment appear to provide conflicting information about the characteristics of the circuit because they in fact measure entirely different electrophysiological parameters. The nth beat of pacing foreshortens the excitable gap to the extent that it arrives prematurely. Subsequent paced beats interact with an altered tachycardia circuit that has had less time to recover excitability. Resetting is the interaction of a single paced beat with the tachycardia and, as such, provides a more accurate assessment of the characteristics of the unaltered tachycardia circuit.