Ventricular tachycardia or fibrillation appears to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. In high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the primary and secondary prevention of sudden death.

Background-DNA variants appearing to predispose to drug-associated "acquired" long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K ϩ channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results-The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (nϭ92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (nϭ67) and cross sections of the Middle Tennessee (nϭ71) and US populations (nϭ90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K ϩ currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter I Na , which argues that they played no role in the aLQTS phenotype. Conclusions-DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in Ϸ10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits. (Circulation. 2002; 105:1943-1948.)

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Dramatic increases in both magnetic resonance imaging (MRI) usage and cardiac device-based therapy have resulted in an estimated 50-75% probability of a patient being indicated for an MRI over the lifetime of their device. Some recent studies have demonstrated "safe procedures" and "no adverse events" in the limited populations, clinical situations, and specific devices and lead orientations tested. While these investigations are useful to help ascertain the hazards for patients with cardiac devices, they do not demonstrate clear freedom from risk. All components of active implantable systems must be engineered during the design stage to provide safety in current and evolving MR environments. Device manufacturers need to secure regulatory approval to confirm their products' safety under multiple clinical and technical variables.

The incidence and clinical predictors of amiodarone pulmonary toxicity were examined in 573 patients treated with amiodarone for recurrent ventricular (456 patients) or supraventricular (117 patients) tachyarrhythmias. Amiodarone pulmonary toxicity was diagnosed in 33 of the 573 patients (5.8%), based on symptoms and new chest radiographic abnormalities (32 of 33 patients) and supported by abnormal pulmonary biopsy (13 of 14 patients), low pulmonary diffusion capacity (DLCO) (nine of 13 patients), and/or abnormal gallium lung scan (11 of 16 patients). Toxicity occurred between 6 days and 60 months of treatment for a cumulative risk of 9.1%, with the highest incidence occurring during the first 12 months (18 of 33 patients).Older patients developed it more frequently (62.7± 1.7 versus 57.4±0.5 years,p=0.018), with no cases diagnosed in patients who started therapy at less than 40 years of age. Gender, underlying heart disease, arrhythmia, and pretreatment chest radiographic, spirometric, or lung volume abnormalities did not predict development of amiodarone pulmonary toxicity, whereas pretreatment DLCO was lower in the group developing it (76.0+5.5% versus 90.4±-1.4%, p=0.01). There was a higher mean daily amiodarone maintenance dose in the pulmonary toxicity group (517±25 versus 409±6 mg, p<0.001) but no difference in loading dose. No patient receiving a mean daily maintenance dose less than 305 mg developed pulmonary toxicity. Patients who developed toxicity had higher plasma desethylamiodarone (2.34±0.18 versus 1.92+±0.04 Jg/ml, p=0.009) but not amiodarone concentrations during maintenance therapy. Death due to pulmonary toxicity occurred in three of 33 patients (9.1%). In conclusion: 1) amiodarone pulmonary toxicity occurred in 5.8% of patients and was more common with a higher amiodarone maintenance dose, advanced age, lower pretreatment DLCO, and higher plasma desethylamiodarone concentrations; and 2) pretreatment chest radiographic, spirometric, and lung volume abnormalities were not predictive for development of amiodarone pulmonary toxicity. (Circulation 1990;82:51- The present study was undertaken to determine the incidence and clinical features associated with amiodarone-induced pulmonary toxicity in a large series of patients treated at a single medical center. Also examined were the relations of preexisting pulmonary abnormalities, drug doses, and plasma drug concentrations to the development of amiodarone pulmonary toxicity. Methods PatientsThe study population comprised 573 patients who were treated at the Indiana University Medical Center and initiated amiodarone therapy between April

(1) A functional line of block is seen at the posteromedial (sinus venosa region) right atrium during counterclockwise and clockwise atrial flutter. (2) All lateral wall right atrial activation can be uniform during flutter, without linear block or double potentials in the region of the crista terminalis. (3) Activation at the site of posteromedial right atrial functional block can organize to subsequently initiate isthmus-dependent atrial flutter.

Transmural myocardial infarction in dogs produces denervation of sympathetic nerves in viable myocardium apical to the infarct that may be arrhythmogenic. It is unknown whether sympathetic denervation occurs in humans. The purpose of this study was to use iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals, to image noninvasively the cardiac sympathetic nerves in patients with and without ventricular arrhythmias after myocardial infarction. Results showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake indicating viable perfused myocardium, with no MIBG uptake. Such a finding is consistent with sympathetic denervation. One patient had frequent episodes of nonsustained ventricular tachycardia induced at exercise testing that was eliminated by beta-adrenoceptor blockade. Eleven of the 12 patients had ventricular tachycardia induced at electrophysiologic study and metoprolol never prevented induction. Sympathetic denervation was also detected in two of seven postinfarction patients without ventricular arrhythmias. Normal control subjects had no regions lacking MIBG uptake. This study provides evidence that regional sympathetic denervation occurs in humans after myocardial infarction and can be detected noninvasively by comparing MIBG and thallium-201 images. Although the presence of sympathetic denervation may be related to the onset of spontaneous ventricular tachyarrhythmias in some patients, it does not appear to be related to sustained ventricular tachycardia induced at electrophysiologic study.

Background-Approximately 25% of patients who receive an implantable cardioverter-defibrillator (ICD) to treat ventricular tachyarrhythmias have documented atrial tachyarrhythmias before implantation. This study assessed the ability of device-based prevention and termination therapies to reduce the burden of spontaneous atrial tachyarrhythmias. Methods and Results-Patients with a standard indication for the implantation of an ICD and 2 episodes of atrial tachyarrhythmias in the preceding year received a dual-chamber ICD (Medtronic 7250 Jewel AF) that uses pacing and shock therapies for prevention and/or termination of atrial tachyarrhythmias. In a multicenter trial, patients were randomized to 3-month periods with atrial therapies "on" or "off" and subsequently crossed over. Analysis was performed on the 52 of 269 patients who had episodes of atrial tachyarrhythmia and had Ն30 days of follow-up with atrial therapies on and off. The atrial therapies resulted in a reduction of atrial tachyarrhythmia burden from a mean of 58.5 to 7.8 h/mo. A paired analysis (Wilcoxon signed-rank test) showed that the median difference in burden (1.1 h/mo) was highly significant (Pϭ0.007). When the subgroup of 41 patients treated only with atrial pacing therapies was analyzed, the reduction in burden persisted (Pϭ0.01). Conclusions-In this study, patients with a standard ICD indication and atrial tachyarrhythmias had a significant reduction in atrial tachyarrhythmia burden with use of atrial pacing and shock therapies.