Rate-Dependent Effects ofDiltiazem on Human Atrioventricular NodalProperties

Background. Tachycardia enhances thechannel-blocking effects ofantiarrhythmic drugs. Incontrast to theextensive dataregarding therate-dependent effects ofsodiumchannel blockers inhumans, little is knownaboutthefrequency-dependent effects ofcalcium channel blockers on humanatrioventricular (AV)nodal properties. Accordingly, thepurposeofthis study was toevaluate theimportance ofheart rate inmodulating theelectrophysiological effects ofdiltiazem inhumans. Methods andResults. Electrophysiological studies wereperformed in25patients. Sinusnode, atrial, and AVnodalfunction were evaluated atmultiple atrial ratesundercontrol conditions andafter administration ofone ofthree intravenous dosesofdiltiazem designed toproduce low,intermediate, andhigh stable plasma concentrations (designated doses1,2,and3,respectively). Results wereanalyzed interms ofthelongest andshortest cycle lengths obtainable ineachpatient undercontrol anddrugconditions. Plasmaconcentrations ofdiltiazem werestable andaveraged 43+4,73±6,and136±11ng/mlfordoses 1,2,and3,respectively. Sinusnoderecoverytime, intra-atrial conduction time, atrial effective refractory period, andHV interval wereunaffected bydiltiazem infusion. Effects ofdiltiazem werelimited tochanges inAVnodal parameters. Stable, dose-dependent increases inWenckebach cycle length wereobserved after allthreedosesofdiltiazem (increases of54±f13, 84±18,and174±33msec fordoses1,2,and3, respectively). Smallnonsignificant increases inAH interval andatrioventricular effective refractory period (AVERP) wereobserved after dose1ofdiltiazem. Atlongcycle lengths, diltiazem caused modest increases inAHlinterval (3±4and25±8msec fordoses 2and3,respectively) andAVERP(36±f12 and 70±25msec). Drugeffects werefargreater atshortcycle lengths (45±17 msec,58±+12 msec forAH interval and80±24msec,163±41 msec forAVERP;p<0.05 versusvalues atlongcycle lengths). Atrapid rates, effects ofdiltiazem on AVERP substantially exceeded those on AVconduction, a result thatcould account forthebeneficial effects ofdiltiazem during paroxysmal AVreentrant tachycardia bydecreasing theexcitable gap. Conclusions. Depressant effects ofdiltiazem onhumanAVnodalfunction arehighly dependent on atrial rate; therate-dependent actions on AV nodalrefractoriness probably contribute tobeneficial effects of diltiazem inpatients withsupraventricular arrhythmias. (Circulation 1992;86:870-877)