The Cardiac Effects of d- and 1-Disopyramide in Normal Subjects: A Noninvasive Study CHARLES POLLICK, M.B., CH.B., KATHLEEN M. GIACOMINI, PH.D., TERRENCE F. BLASCHKE, M.D., WENDEL L. NELSON, PH.D., KATHLEEN TURNER-TAMIYASU, R.N., VIRGINIA BRISKIN, M.D., AND RICHARD L. Popp, M.D. SUMMARY Commercially available disopyramide is a racemic mixture of equal parts of dextrorotatory (d-) and levorotatory (1-) optical isomers. We studied the cardiac effects of i.v. adnministration of each isomer and the racemic mixture (dl-) in six normal males by digitized echocardiography, systolic time intervals and ECG. Both isomers and the racemic mixture produced equally marked dose-dependent negative inotropic effects (28.1 11.8% mean maximal reduction in fractional shortening of left ventricular dimension) and diastolic effects (28.6 + 24.1% mean maximal reduction in peak left ventricular filling rate). Howevet, only the d-isomer prolonged QTc duration (by 13.6 5.2% at maximum, p < 0.001 vs 1-isomer). We conclude that disopyramide, in the doses used, produces marked adverse effects on left ventricular systolic and diastolic function in normal subjects independent of optical rotation. The production of these effects bEy the 1-isomer without affecting QTc duration suggests different subcellular mechanisms for the myocardial depressant effects and some of the electrophysiologic effects of disopyramide. DISOPYRAMIDE [y disopropylamino-a-phenyl-a(2- pyridyl)-butyramide] was discovered 20 years ago to possess antiarrhythmic properties.' 2 Although it is usually well tolerated,3 it may precipitate heart fail- ure4 and cardiogenic shock6 as well as malignant ven- tricular arrhythmias.7 9 The commercially available compound (Norpace in the United States, Rhythmodan in other countries) is a racemic mixture, i.e., composed of equal amounts of dextrorotatory (d-) and levorotatory (1-) isomers,0 Op- tical isomers often differ pharmacologically."I Recent studies in isolated guinea pig ileum strips have shown differences between the 1- and d-disopyramide isomers in anticholinergic potencies. 12 In addition, in dogs, the 1-isomer cleared more slowly than the d-isomer.'3 Analysis of digitized M-mode echocardiographic records provides information on left ventricular sys- tolic and diastolic function beyond that given by stan- dard dimensions. We used this together with systolic time intervals and the 12-lead surface ECG to deter- mine if the cardiac effects of the two isomers in normal subjects are different. Methods Protocol Six healthy male subjects, ages 20-25 years (mean 23 years), were studied. On three occasions approxi- From the Divisions of Cardiology and Clinical Pharmacology, Stan- ford University School of Medicine, California, and the Department of Pharmaceutical Sciences, University of Washington, Seattle, Washington. Supported in part by USPHS grants GM-22209 and F32 GM07344. Dr. Pollick was supported by a grant from the Canadian Heart Foundation. Dr. Giacomini's present address: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Address for correspondence: Richard L. Popp, M.D., Cardiology Division, Stanford University Medical Center, Stanford, California 94305. Received September 9, 1981; revision accepted December 7, 1981. Circulation 66, No. 2, 1982. mately 1 week apart, a 1.5-mg/kg i.v. dose of either d-, 1- or dl- (racemic) disopyramide was infused over 10 minutes. One patient received the d- and 1-isomers but not the racemic mixture. Blood pressure, ECG, M- mode echocardiography of the left ventricle, systolic time intervals, and blood samples were taken at all or some of the following time periods: -30, - 20, - 10, 5, 15, 30, 45, 60, 120, and 180 minutes (0 minutes start of infusion). Echocardiographic Studies M-mode echocardiograms of the left ventricle were recorded at 100 mm/sec with a 2.25-MHz transducer and Irex system II echocardiograph. The echocardio- grams were digitized and the following standard mea- surements in diastole and systole were obtained: left ventricular internal dimension, interventricular septal thickness, and left ventricular posterior wall thickness. In addition, the peak rates of change (d/dt) of the left ventricle, interventricular septum and posterior wall were obtained for both diastole and systole. 14 Three to five beats were analyzed and averaged for each time period (nine to 15 beats before infusion). Systolic Time Intervals Systolic time intervals were calculated from the si- multaneous recording at 100 mm/sec of ECG lead IL, carotid pulse using a hand-held transducer, and phono- cardiogram from a microphone placed parastemally over the second right intercostal space. Left ventricular ejection time (LVET) and preejection period (PEP) were derived. '5 Three cycles were measured and aver- aged for each period. Electrocardiogram A 12-lead ECG was performed at each period. In three patients the ECG was obtained using the Hewlett Packard 5600C ECG management system. PR, QRS and QT intervals were derived by computer in these three patients and determined from an average of all 12 447 Downloaded from http://ahajournals.org by on May 29, 2020