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The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. (89 and 470). and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive xray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages. blood neutrophils. and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with aniodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung. Circulation 72, No. 5, 1064-1075, 1985 AMIODARONE is recognized as an orally effective agent in the treatment of atrial and ventricular arrhythmias refractory to conventional therapy. It is a benzofuran derivative containing two iodine atoms per molecule. In man, only one major metabolite has been identified, desethylamiodarone.' During long-term therapy this compound reaches similar plasma concentrations to amiodarone, and both compounds show long terminal elimination half-lives reflecting a com-

SUMMARY Epicardial activation and repolarisation sequences were investigated in patients with upright or inverted T waves in left ventricular leads of the surface electrocardiogram. Fifteen patients were studied: 10 were undergoing coronary artery bypass grafting (upright T waves) and five aortic valve replacement (four patients with T inversion). Monophasic action potentials were recorded intraoperatively from eight to 10 left ventricular sites in each patient. In patients with upright T waves there was an inverse relation between the duration of the monophasic action potential and the activation time (mean slope -1-44). As a consequence, activation and repolarisation proceeded in opposite directions. Dispersion of repolarisation time (14 ms) was less than dispersion of activation time (23 ms). In patients with T wave inversion caused by aortic stenosis there was no relation between the duration of action potential and activation time; the repolarisation sequence resembled the activation sequence, and the dispersion of repolarisation time was greater than the dispersion of activation time (31 and 26 ms respectively).These results show that there are epicardial repolarisation gradients in man and that these are related to the configuration of the T wave. In patients with upright T waves an inverse relation between the duration of the action potential and the activation time reduces the dispersion of the repolarisation time. When the T wave was inverted this relation was no longer found and the dispersion of repolarisation increased.

Objective-To quantify the errors associated with manual measurement of QT intervals and to determine the source of the errors. Design-A randomised study of QT measurement by four cardiologists of electrocardiograms plotted on paper in presentations with different noise levels, paper speeds, amplifier gains, and with and without a second QRST complex to indicate the RR interval. Subjects-Four electrocardiograph leads (I, aVR, VI, V5) recorded in eight healthy people relaxing in a semirecumbent position. Main outcome measures-Manual measurement of QT interval in 512 electrocardiograms (eight subjects x four leads x eight presentations x two repeats) by each of four cardiologists. Results-QT intervals measured were significantly longer with greater amplifier gain: by 8 ms for a doubling of gain (p < 0.005), equivalent to a doubling of T wave height. QT intervals measured were significantly longer at slower paper speeds: by 11 ms when paper speed was reduced from 100 to 50 mmis (p < 0.001) and by 16 ms when speed was further reduced from 50 to 25 mmis (p < 0 001).Neither the presence of noise nor the presence of a second QRST complex altered the mean QT measurements. There were consistent differences in the measurements between cardiologists, amounting to a maximum mean difference of 20 ms.

Different QT measurement techniques produced results which were influenced, to varying degrees, by filtering and technique variables. This is relevant for the inter-comparison of studies using different techniques. Technique TH, a common approach, is not recommended.