Robert C. Kowal

Use of Automated External Defibrillators by a U.S. Airline

BACKGROUND Passengers who have ventricular fibrillation aboard commercial aircraft rarely survive, owing to the delay in obtaining emergency care and defibrillation. METHODS In 1997, a major U.S. airline began equipping its aircraft with automated external defibrillators. Flight attendants were trained in the use of the defibrillator and applied the device when passengers had a lack of consciousness, pulse, or respiration. The automated external defibrillator was also used as a monitor for other medical emergencies, generally at the direction of a passenger who was a physician. The electrocardiogram that was obtained during each use of the device was analyzed by two arrhythmia specialists for appropriateness of use. We analyzed data on all 200 instances in which the defibrillators were used between June 1, 1997, and July 15, 1999. RESULTS Automated external defibrillators were used for 200 patients (191 on the aircraft and 9 in the terminal), including 99 with documented loss of consciousness. Electrocardiographic data were available for 185 patients. The administration of shock was advised in all 14 patients who had electrocardiographically documented ventricular fibrillation, and no shock was advised in the remaining patients (sensitivity and specificity of the defibrillator in identifying ventricular fibrillation, 100 percent). The first shock successfully defibrillated the heart in 13 patients (defibrillation was withheld in 1 case at the familys request). The rate of survival to discharge from the hospital after shock with the automated external defibrillator was 40 percent. A total of 36 patients either died or were resuscitated after cardiac arrest. No complications arose from use of the automated external defibrillator as a monitor in conscious passengers. CONCLUSIONS The use of the automated external defibrillator aboard commercial aircraft is effective, with an excellent rate of survival to discharge from the hospital after conversion of ventricular fibrillation. There are not likely to be complications when the device is used as a monitor in the absence of ventricular fibrillation.

The low-density lipoprotein receptor-related protein: Double agent or decoy?

The low-density lipoprotein receptor-related protein, a large cell-surface molecule with a multidomain structure, apparently serves a dual function, acting as a clearance receptor for two ligands that undergo activation during circulation in plasma. Chylomicron remnants (activated by apolipoprotein E enrichment) and α2-macroglobulin (activated by serum proteases) both bind avidly to this novel molecule.

Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.

EVEC, a Novel Epidermal Growth Factor–Like Repeat-Containing Protein Upregulated in Embryonic and Diseased Adult Vasculature

A hallmark of vascular lesions is the phenotypic modulation of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a more primitive, proliferative phenotype with a more fetal pattern of gene expression. Using subtraction hybridization to identify genes that may regulate this transition, we cloned a novel gene named EVEC, an acronym for its expression in the embryonic vasculature and the presence of Ca2+ binding epidermal growth factor-like repeats contained in the predicted protein structure. Although these repeats are characteristic of the extracellular matrix proteins, fibrillin, fibulin, and the latent transforming growth factor-beta binding proteins, EVEC most closely resembles the H411 and T16/S1-5 gene products, the latter of which are believed to regulate DNA synthesis in quiescent fibroblasts. Using in situ hybridization, we demonstrated that EVEC is expressed predominantly in the VSMCs of developing arteries in E11.5 through E16.5 mouse embryos. Lower levels of expression are also observed in endothelial cells, perichondrium, intestine, and mesenchyme of the face and kidney. EVEC mRNA expression is dramatically downregulated in adult arteries, except in the uterus, where cyclic angiogenesis continues; however, EVEC expression is reactivated in 2 independent rodent models of vascular injury. EVEC mRNA is observed in cellular elements of atherosclerotic plaques of LDL receptor-deficient, human apolipoprotein B transgenic mice and in VSMCs of the media and neointima of balloon-injured rat carotid arteries. These data suggest that EVEC may play an important role in the regulation of vascular growth and maturation during development and in lesions of injured vessels.

Effect of Atrial Fibrillation and an Irregular Ventricular Response on Sympathetic Nerve Activity in Human Subjects

Background—Although the hemodynamic changes associated with atrial fibrillation (AF) have been extensively studied, the neural changes remain unclear. We hypothesized that AF is associated with an increase in sympathetic nerve activity (SNA) and that the irregular ventricular response contributes to this state of sympathoexcitation. Methods and Results—In 8 patients referred for an electrophysiological study, SNA, blood pressure (BP), central venous pressure (CVP), and heart rate were recorded during 3 minutes of normal sinus rhythm (NSR) and 3 minutes of induced AF. In 5 of 8 patients who converted to NSR, right atrial (RA) pacing was performed for 3 minutes in atrial pacing triggered by ventricular sensing mode triggered by playback of an FM tape previously recorded from the right ventricle during AF (RA-irregular) and atrial pacing inhibited by atrial sensing mode at a rate equal to the mean heart rate obtained during AF (RA-regular). SNA data were expressed as percentage of baseline during NSR. SNA increased in all 8 patients during induced AF compared with NSR (171±40% versus 100%, respectively;P <0.01). This was associated with a trend for a decrease in BP and an increase in CVP (P =0.02). Similarly, SNA was significantly higher during RA-irregular pacing compared with RA-regular pacing (124±24% versus 91±20%, respectively;P =0.03). BP and CVP were not significantly different between the 2 pacing modes. Conclusions—Induced AF results in a significant increase in SNA, which is in part attributable to the irregular ventricular response. Our findings suggest that restoring NSR or regularity might be beneficial, particularly in patients with heart failure.

Effects of resynchronization therapy on sympathetic activity in patients with depressed ejection fraction and intraventricular conduction delay due to ischemic or idiopathic dilated cardiomyopathy

This study assesses the effect of biventricular pacing on sympathetic nerve activity (SNA) in patients with depressed ejection fraction and intraventricular conduction delay (IVCD). Biventricular pacing has been shown to result in hemodynamic improvement in patients with depressed ejection fraction and IVCD. The effect of biventricular pacing on SNA, however, remains unclear. A total of 15 men with a mean ejection fraction of 25 +/- 4% were enrolled. Arterial pressure, central venous pressure and SNA were recorded during 3 minutes of right atrial (RA) pacing and RA-biventricular pacing. Pacing was performed at a rate 5 to 10 beats faster than sinus rhythm, with an atrioventricular interval equal to 100 ms during RA-biventricular pacing. RA-biventricular pacing resulted in greater arterial pressures (p <0.05) than RA pacing (146 +/- 15/83 +/- 11 vs 141 +/- 15/80 +/- 10 mm Hg). There were no differences in central venous pressures between the 2 pacing modes (p = 0.76). SNA was significantly less during RA-biventricular pacing (727 +/- 242 U) than during RA pacing (833 +/- 332 U) (p <0.02). Furthermore, there was a positive correlation between baseline QRS duration and the decrease in SNA noted with RA-biventricular pacing (r = 0.58, p = 0.03). Biventricular pacing results in improved hemodynamics and a decrease in SNA compared with intrinsic conduction in patients with left ventricular dysfunction and IVCD. If the current findings are also present with chronic biventricular pacing, then this form of therapy may have a positive impact on mortality.

Serotonin Reuptake Inhibitor (Paxil) Does Not Prevent the Vasovagal Reaction Associated With Carotid Sinus Massage and/or Lower Body Negative Pressure in Healthy Volunteers

Background—The purpose of this study was to assess the effect of the serotonin reuptake inhibitor paroxetine hydrochloride (Paxil, SmithKline Beecham) on cardiovascular reflexes. We hypothesized that Paxil prevents neurally mediated syncope (NMS) by attenuating the sympathoinhibition and vagotonia associated with a vasovagal reaction. Methods and Results—In a double-blind randomized study, 25 healthy subjects with a positive response to either carotid sinus massage (CSM) or lower body negative pressure (LBNP) received Paxil (20 mg/d) or placebo for 6 weeks. Arterial baroreflex sensitivity (BRS), muscle sympathetic nerve activity (SNA), baroreflex control of SNA, blood pressure, and heart rate responses to CSM and LBNP were measured at baseline and at 6 weeks. Nineteen subjects completed the study (Paxil, n=9; placebo, n=10). In the Paxil group, BRS decreased significantly compared with baseline (15.8±4.0 ms/mm Hg versus 11.0±2.6 ms/mm Hg, P =0.05); however, all 9 subjects continued to have a positive response to LBNP with presyncope. Paxil did not attenuate the sympathoinhibition or vagotonia associated with a positive LBNP response and had no significant effect on baroreflex control of SNA. In the control group, no significant change in BRS was noted compared with baseline. Seven out of 9 subjects who had a positive LBNP response at baseline had a repeat positive LBNP response, and the subject with a positive CSM at baseline had a negative response at 6 weeks. Conclusions—Paxil decreases arterial BRS but does not prevent the presyncope associated with LBNP. The effect of Paxil on the autonomic reflexes in patients with neurally mediated syncope remains unclear.

Estimation of the optimal VV delay by an IEGM-based method in cardiac resynchronization therapy

Determination of the optimal interventricular (VV) delay in cardiac resynchronization therapy currently relies on costly, time‐consuming echocardiographic (ECHO) methods. This study evaluated the performance of a new intracardiac electrogram (IEGM)‐based VV method compared to the aortic velocity time integral (AVTI) method of VV delay optimization. The study included two patient groups. Eleven patients enrolled by a single center in the Rhythm II ICD trial underwent prospective comparisons of the AVTI at the VV interval determined by the IEGM VV method versus the maximum AVTI at the echocardiographically determined optimal VV delay. In 61 patients enrolled in the RHYTHM VV trial, the same testing methods were compared retrospectively. In the prospective study, the maximum AVTI by the ECHO‐based method (24.3 ± 7.9 cm), was closely correlated with maximum AVTI by the IEGM‐based method (23.9 ± 7.9 cm; concordance correlation coefficient = 0.99; 95% confidence, lower limit of 98%. Likewise, in the retrospective analysis, the ECHO‐determined maximum AVTI (22.1 ± 8.2 cm) was similar to that determined by the IEGM‐based method (20.9 ± 8.3 cm; concordance correlation coefficient = 0.98; 95% confidence, lower limit of 97%).

Electrical cardioversion of atrial fibrillation

External direct current cardioversion remains the most common and effective method for restoration of normal sinus rhythm in patients with persistent AF. The development of biphasic defibrillators allows for higher success rates of conversion using standard energy levels. For persistent AF, an initial energy of 200 J is recommended for biphasic defibrillators, and 300 to 360 J are recommended for monophasic defibrillators, with the electrodes placed in the anterior posterior position. For refractory cases, alternatives are available such as dual defibrillators or internal cardioversion. Antiarrhythmic drugs may enhance the results of cardioversion by helping overcome shock failure or by preventing immediate recurrence of AF. Thromboembolism is the most important complication associated with cardioversion, but it can be prevented by providing 3 weeks of anticoagulation before the procedure or by excluding the presence of thrombi by transesophageal echocardiography, followed by an additional 4 weeks of anticoagulation.

Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation

D the frequent use of amiodarone, questions about the effect of this drug on the defibrillation threshold (DFT) have not been fully answered. Previous clinical investigations have shown this drug to increase the DFT when using monophasic shocks,1–3 whereas other studies showed no effect.4 Implantable cardioverter-defibrillators (ICDs) now use biphasic waveforms because they are more effective in terminating ventricular fibrillation. Several recent uncontrolled studies comparing biphasic DFTs in populations of patients on and off amiodarone suggested no difference in the DFT between the 2 groups.5,6 Pelosi et al7 recently reported an increase in the biphasic DFT with chronic amiodarone use, measured on average 2 to 3 months after drug initiation, but provided no data regarding acute effects of the drug. We examined the immediate effects of in-hospital oral amiodarone loading on the biphasic DFT. • • • This study compared the DFTs of 18 patients (16 men and 2 women, mean age 63 6 10 years) at the time of initial implantation and after receiving an in-hospital load of oral amiodarone for clinically indicated reasons. The initial indication for ICD implantation was ventricular tachycardia in 17 patients and resuscitated cardiac death in 1 patient. Ten patients had underlying coronary artery disease, and 8 had dilated cardiomyopathy. Left ventricular function was severely depressed (,30%) in 15 patients; in 3 other patients it was moderately depressed (30% to 39%), mildly depressed (40% to 49%), and preserved (.50%). The implanted ICD models included the 7223Cx (n 5 7) and 7227Cx (n 5 6) manufactured by Medtronic, Inc. (Minneapolis, Minnesota), and the 1763 (n 5 1), 1782 (n 5 2), 1790 (n 5 1), and 1831 (n 5 1) manufactured by Guidant Corp. (St. Paul, Minnesota). All patients had DFTs determined at the time of device implant using a sequential “change in delivered energy” protocol from an initial delivered energy of 15 J with decrements or increments of 5 J. Ventricular fibrillation was induced using a T-wave shock. The lowest energy required for cardioversion was considered the DFT.8 No patient was receiving antiarrhythmic drugs other than b blockers (10 patients) at the time of initial device implant. The indication for amiodarone was recurrent ventricular tachycardia in 12 patients and atrial fibrillation in 6. The drug was loaded orally in the hospital for a total dose of 8 to 12 g over 6 to 10 days, followed by maintenance doses. Follow-up DFT determination was performed after the oral load using the same protocol used at device implant. The Student’s t test for paired data was used to compare the DFTs from implant and after amiodarone loading. Data are expressed as mean 6 SD. A p value ,0.05 was considered statistically significant. The time between initial DFT determination and the DFT after amiodarone loading ranged from 1 to 32 months. The average time between studies was 226 6 248 days, with a median time of 146 days. In the overall group, the DFT increased significantly after amiodarone loading, from 10.5 6 4.7 to 15.2 6 7.8 J (p ,0.0015). In the subgroup of patients in whom the time between initial DFT determination and initiation of amiodarone was ,6 months (12 of the 18 patients), the DFT also increased from 10.8 6 5.3 to 16.1 6 8.6 J (p 5 0.005). The mean changes in DFT are shown in Figure 1. After loading, 11 of 18 patients had an increase in the DFT, 6 had no change, and 1 patient had a decrease from 10 to 5 J. In 1 patient, termination of amiodarone was required because the DFT after drug loading was unacceptably high (25 J). Individual changes in the DFT are displayed in Figure 2. • • • The main finding of our study was the demonstration of higher DFTs using biphasic energy waveforms after in-hospital oral amiodarone loading over several days. To our knowledge, this is the first time that the effect of short-term amiodarone oral loading on the biphasic DFT has been examined in humans. Although the results observed in our study could be attributed to other long-term physiologic differences (such as changes in ventricular size and ventricular function), we doubt this to be the case. Three of 6 patients who began therapy with amiodarone within 1 month of the initial device implantation had an increase in the DFT after drug loading, including 1 patient whose DFT was raised enough to render an inadequate safety margin. The difference in DFT was also significant in the group of patients in whom amiodarone was started within 6 months of implant. Although the increase in defibrillation energy requirements was statistically significant, it was not universal. One third of patients studied had no change in the DFT after drug initiation, and 1 patient had a From the Department of Internal Medicine (Cardiology, Clinical Cardiac Electrophysiology), The University of Texas Southwestern Medical Center; and The Dallas Veterans Affairs Medical Center, Dallas, Texas. Dr. Joglar’s address is: Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Room CS7.102, 5323 Harry Hines Boulevard, Dallas, Texas 753909047. E-mail: jajogl@parknet.pmh.org. Manuscript received September 14, 2000; revised manuscript received and accepted March 27, 2001.