250 JACC Vol. 5, No.2 February 1985:250-8

Clinical Superiority of a New Nonionic Contrast Agent (Iopamidol) for Cardiac Angiography

EDWARD W. GERTZ, MD, FACC, JUDITH A. WISNESKI, MD, FACC, DAVID CHlU,

JOHN R. AKIN, MD, CHARLOTTE HU, MD

San Francisco, Cal(f(Jrnia

The hemodynamic and electrophysiologic alterations in­duced by ionic contrast agents during cardiac angiog­raphy are well described. Recently nonionic contrast agents have become available for cardiac angiography. To evaluate the safety of these new agents, a double­blind randomized study was performed comparing a new nonionic agent (iopamidol) with a commonly used ionic contrast agent (Renografin-76). Eighty-one patients undergoing left ventriculography and coronary angi­ography were included; 41 received iopamidol and 40 received sodium meglumine diatrizoate (Renografin-76).

After left ventriculography, there was a decrease in the arterial pressure with both contrast agents. How­ever, the severity and the duration of hypotension were both significantly greater with Renografin-76 compared with the new non ionic agent (p < 0.001). After selective injections of the coronary arteries, electrocardiographic

Numerous animal and human studies (1-18) have docu­mented the deleterious effects of ionic contrast media on the myocardium immediately after contrast ventriculog­raphy and coronary angiography, Decreases in systemic ar­terial pressure and myocardial contractility and alterations in the ventricular pressure-volume relation after the use of ionic contrast agents are well described ( I A-IS), Although the intensity and duration of these changes are known. the mechanisms responsible for these alterations of myocardial function remain controversial. The contribution of various factors. such as contrast-induced hypocalcemia. osmolality of the agent or a direct effect of the contrast molecule or

From the Departments of Medicine and Radiology and the Cardiovas­cular Research Institute. University of California and the Veterans Admin­istration Medical Center, San Francisco, California. This study was sup­ported in part by the Medical Research Service of the Veterans Administration, San Francisco, California. lopamidol was supplied by E.R. Squibb and Sons, Inc. Manuscript received April 30, 1984: revised manuscript received July 3, 1984, accepted September 20, 1984.

Address for reprints: Edward W. Gertz. MD, Veterans Administration Medical Center, (II1CI). 4150 Clement Street. San Francisco, California 94121.

~) 1985 by the American College of Cardiology

analysis demonstrated that the increase in the QT in­terval (p < 0.0002) and the changes in both the ST segment and T wave amplitude (p < 0.001) were sig­nificantly greater in the Renografin-76 group compared with the iopamidol group. During coronary angiogra­phy, 8 of the 40 patients receiving Renografin-76 re­quired temporary pacing for sinus pauses of 2.5 seconds or more, and 2 of the 40 also developed ventricular fibrillation. None of the 41 patients receiving iopamidol had these complications.

This report demonstrates that the electrocardio­graphic changes, the severity and duration of hypoten­sion and the incidence of serious arrhythmias are sig­nificantly greater with Renografin-76 than with iopamidol. Thus, this new nonionic agent appears to enhance the safety of cardiac angiography.

(J Am Coli Cardiol 1985;5:250-8)

anion. to these hemodynamic and physiologic alterations is unclear (5.7.11-13.15.19-27).

Sodium meglumine diatrizoate (Renografin-76) is a com­monly used contrast agent for cardiac angiography. Several studies (1.8.15.17.20) have demonstrated the adverse ef­fects of this standard ionic agent on myocardial function. metabolism and electrophysiology. Metrizamide was the first commercially available nonionic contrast agent. Animal and human studies (15.20.28-32) demonstrated that its ad­verse hemodynamic and physiologic effects were signifi­cantly less than those of ionic agents. In addition. it reduced the discomfort experienced by the patient during intravas­cular angiography (32). However, metrizamide is unstable in aqueous solution; therefore, it must be reconstituted from the lyophilized form immediately before intravascular in­jection. Recently, nonionic contrast agents that are hydro­lytic ally stable have been developed and are being evaluated for use in coronary angiography (33-40).

The purpose of this investigation was to evaluate one of these new nonionic agents. iopamidol. in human subjects in a randomized double-blind study. The electrocardio-

07.'S-I097/8S/$3.30

250 lACC Vol. 5, No.2February 1985:250-8

Clinical Superiority of a New Nonionic Contrast Agent (Iopamidol) forCardiac Angiography

EDWARD W. GERTZ, MD, FACC, JUDITH A. WISNESKI, MD, FACC, DAVID CHlU,

JOHN R. AKIN, MD, CHARLOTTE HU, MD

San Francisco, Cal(f{Jrnia

The hemodynamic and electrophysiologic alterations in­duced by ionic contrast agents during cardiac angiog­raphy are well described. Recently nonionic contrastagents have become available for cardiac angiography.To evaluate the safety of these new agents, a double­blind randomized study was performed comparing a newnonionic agent (iopamidol) with a commonly used ioniccontrast agent (Renografin-76). Eighty-one patientsundergoing left ventriculography and coronary angi­ography were included; 41 received iopamidol and 40received sodium meglumine diatrizoate (Renografin-76).

After left ventriculography, there was a decrease inthe arterial pressure with both contrast agents. How­ever, the severity and the duration of hypotension wereboth significantly greater with Renografin-76 comparedwith the new nonionic agent (p < 0.001). After selectiveinjections of the coronary arteries, electrocardiographic

Numerous animal and human studies (1-18) have docu­mented the deleterious effects of ionic contrast media onthe myocardium immediately after contrast ventriculog­raphy and coronary angiography. Decreases in systemic ar­terial pressure and myocardial contractility and alterationsin the ventricular pressure-volume relation after the use ofionic contrast agents are well described (I A-IS). Althoughthe intensity and duration of these changes are known. themechanisms responsible for these alterations of myocardialfunction remain controversial. The contribution of variousfactors, such as contrast-induced hypocalcemia, osmolalityof the agent or a direct effect of the contrast molecule or

From the Departments of Medicine and Radiology and the Cardiovas­cular Research Institute. University of California and the Veterans Admin­istration Medical Center. San Francisco. California. This study was sup­ported in part by the Medical Research Service of the Veterans Administration.San Francisco. California. lopamidol was supplied by E.R. Squibb andSons. Inc. Manuscript received April 30. 1984: revised manuscript receivedJuly 3. 1984. accepted September 20. 1984.

Address for reprints: Edward W. Gertz. MD. Veterans AdministrationMedical Center. (1IICI). 4150 Clement Street, San Francisco. California94121.

~) 1985 by the American College of Cardiology

analysis demonstrated that the increase in the QT in­terval (p < 0.0002) and the changes in both the STsegment and T wave amplitude (p < 0.001) were sig­nificantly greater in the Renografin-76 group comparedwith the iopamidol group. During coronary angiogra­phy, 8 of the 40 patients receiving Renografin-76 re­quired temporary pacing for sinus pauses of 2.5 secondsor more, and 2 of the 40 also developed ventricularfibrillation. None of the 41 patients receiving iopamidolhad these complications.

This report demonstrates that the electrocardio­graphic changes, the severity and duration of hypoten­sion and the incidence of serious arrhythmias are sig­nificantly greater with Renografin-76 than with iopamidol.Thus, this new nonionic agent appears to enhance thesafety of cardiac angiography.

(J Am Coli Cardiol 1985;5:250-8)

anion, to these hemodynamic and physiologic alterations isunclear (5,7,11-13.15,19-27).

Sodium meglumine diatrizoate (Renografin-76) is a com­monly used contrast agent for cardiac angiography. Severalstudies (\.8,15,17,20) have demonstrated the adverse ef­fects of this standard ionic agent on myocardial function,metabolism and electrophysiology. Metrizamide was thefirst commercially available nonionic contrast agent. Animaland human studies (\5.20,28-32) demonstrated that its ad­verse hemodynamic and physiologic effects were signifi­cantly less than those of ionic agents. In addition, it reducedthe discomfort experienced by the patient during intravas­cular angiography (32). However, metrizamide is unstablein aqueous solution; therefore, it must be reconstituted fromthe lyophilized form immediately before intravascular in­jection. Recently, nonionic contrast agents that are hydro­lytically stable have been developed and are being evaluatedfor use in coronary angiography (33-40).

The purpose of this investigation was to evaluate one ofthese new nonionic agents, iopamidol. in human subjectsin a randomized double-blind study. The electrocardio-

07.'5-1097/85/$3.30

lACC Vol. 5. No.2 February 1985:250--8

graphic and hemodynamic alterations induced by this new agent during left ventriculography and selective coronary angiography were measured and compared with those In­

duced by Renografin-76.

Methods Patient selection. All patients undergoing left ventric­

ulography and selective coronary angiography at the San Francisco Veterans Administration Medical Center were el­igible for this study except for I) patients with a history of adverse reactions to contrast media or iodine compounds, 2) patients with bleeding disorders, 3) patients with creat­inine clearance below 25 mllmin, and 4) patients receiving intravascular or orally absorbable contrast material within I week of the study.

The study was of a randomized double-blind design for comparison of iopamidol and sodium meglumine diatrizoate (Renografin-76) as the contrast agent used for left ventric­ulography and selective coronary angiography. Iopamidol and Renografin-76 both contain 37% iodine. The viscosities of iopamidol and Renografin-76 are similar at 37°C, 9.4 cp and 8.4 cp, respectively.

Procedure. All patients received oral diazepam ( 10 mg) as premedication. No medications were withheld before the catheterization. No patient received atropine. Electrocar­diographic leads I and II were monitored continuously dur­ing the procedure. An 8F USCI sheath was placed in the femoral artery. For the treatment of bradyarrhythmias or complete heart block which may develop during coronary angiography, a temporary pacing catheter was inserted through a femoral venous sheath and positioned at the apex of the right ventricle. For asystolic episodes lasting 2.5 seconds or more, pacing was performed at 60 beats/min until the pa­tient's intrinsic rhythm returned. The left ventriculogram was performed using a 7F Cordis high flow pigtail catheter; 0.5 ml/kg of contrast medium was injected at 12 mils. The amount of contrast agent injected for the left ventriculogram was 40.5 :i: 5.7 ml in the iopamidol group and 37.4 :i: 4.9 ml in the Renografin-76 group. Left ventricular volumes and ejection fraction were calculated using a calibrated grid and the method of Kennedy et al. (41). The electrocardio­gram, left ventricular pressure and femoral artery pressure were recorded continuously for 6 seconds before the left ventriculogram and for the first 2 minutes after the injection. In all patients, the left ventriculogram preceded the selective injections of the right and left coronary arteries. Similarly, the electrocardiogram and aortic pressure were recorded before and for the first 2 minutes after the first selective injection of the right and left coronary arteries. All record­ings were made at a strip chart speed of 100 mm/s. There were no test injections of contrast agent preceding the left ventriculogram or the first selective injection of the coronary arteries. Immediately after the procedure, each patient was

GERTZ ET AL. 251 NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

asked to grade on a 0 to 10 scale subjective feelings of pain and warmth that occurred during and after the contrast injections.

The cineangiograms were reviewed by an independent observer with regard to quality of contrast, definition and opacification of coronary vessels and were graded as poor, adequate, good or excellent.

Blood for determination of urea nitrogen and serum cre­atinine was obtained at baseline (before angiography) and at 24 and 48 hours after the procedure. If the values were abnormal at 48 hours, these tests were repeated I week after angiography and, if abnormal, repeated until the values returned to baseline levels. The protocol was approved by the Human Research Committees of the University of Cal­ifornia and the Veterans Administration Medical Center at San Francisco. Informed written consent was obtained from each patient.

Statistics. All hemodynamic and electrocardiographic variables were analyzed by repeated measures analysis of variance using Tukey's tests to determine whether there was a difference between the changes induced by the two contrast agents (42). The unpaired t test was used to determine whether there was a difference between the hemodynamic and electrocardiographic variables of the iopan;idol and Reno­grafin-76 groups at baseline. The chi-square test was used to compare discrete variables. The nonparametric variables such as cineangiographic quality and subjective response of the patients to the contrast agent were compared using the Mann-Whitney test. The data in the text and tables are presented as mean :i: I standard deviation. The mean values :i: I standard error are shown in the figures.

Results Patient characteristics. The study group consisted of

81 male patients. Seventy-nine patients underwent left ven­triculography and selective coronary angiography for symp­toms of ischemic heart disease and two underwent the pro­cedure for evaluation of valvular heart disease. Forty-one patients received iopamidol and 40 received Renografin-76.

The patient characteristics in these two groups are listed in Tahle I. A coronary lesion was considered significant if 75% or more of the cross-sectional luminal area of the vessel was obstructed. There was no significant difference between the two groups in the number of patients with significant left main lesions and with no, one, two or three vessel disease. Two patients receiving Renografin-76 had aortic valve disease; one had significant aortic regurgitation re­quiring valve replacement and the other had mild aortic stenosis. One patient in the iopamidol group had significant aortic stenosis requiring valve replacement. In each group, there was one patient with mild mitral regurgitation.

Indexes ollefi ventricular function are also listed in Table I. There was no significance difference in ejection fraction,

lACC Vol. 5. No.2February 1985:250-8

GERTZ ET AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

251

graphic and hemodynamic alterations induced by this newagent during left ventriculography and selective coronaryangiography were measured and compared with those in­duced by Renografin-76.

MethodsPatient selection. All patients undergoing left ventric­

ulography and selective coronary angiography at the SanFrancisco Veterans Administration Medical Center were el­igible for this study except for I) patients with a history ofadverse reactions to contrast media or iodine compounds,2) patients with bleeding disorders, 3) patients with creat­inine clearance below 25 mllmin, and 4) patients receivingintravascular or orally absorbable contrast material withinI week of the study.

The study was of a randomized double-blind design forcomparison of iopamidol and sodium meglumine diatrizoate(Renografin-76) as the contrast agent used for left ventric­ulography and selective coronary angiography. Iopamidoland Renografin-76 both contain 37% iodine. The viscositiesof iopamidol and Renografin-76 are similar at 37°C, 9.4 cpand 8.4 cp, respectively.

Procedure. All patients received oral diazepam ( 10 mg)as premedication. No medications were withheld before thecatheterization. No patient received atropine. Electrocar­diographic leads I and II were monitored continuously dur­ing the procedure. An 8F USCI sheath was placed in thefemoral artery. For the treatment of bradyarrhythmias orcomplete heart block which may develop during coronaryangiography, a temporary pacing catheter was inserted througha femoral venous sheath and positioned at the apex of theright ventricle. For asystolic episodes lasting 2.5 seconds ormore. pacing was performed at 60 beats/min until the pa­tient's intrinsic rhythm returned. The left ventriculogramwas performed using a 7F Cordis high flow pigtail catheter;0.5 ml/kg of contrast medium was injected at 12 mils. Theamount of contrast agent injected for the left ventriculogramwas 40.5 :i: 5.7 ml in the iopamidol group and 37.4 :i: 4.9ml in the Renografin-76 group. Left ventricular volumesand ejection fraction were calculated using a calibrated gridand the method of Kennedy et al. (41). The electrocardio­gram, left ventricular pressure and femoral artery pressurewere recorded continuously for 6 seconds before the leftventriculogram and for the first 2 minutes after the injection.In all patients. the left ventriculogram preceded the selectiveinjections of the right and left coronary arteries. Similarly.the electrocardiogram and aortic pressure were recordedbefore and for the first 2 minutes after the first selectiveinjection of the right and left coronary arteries. All record­ings were made at a strip chart speed of 100 mm/s. Therewere no test injections of contrast agent preceding the leftventriculogram or the first selective injection of the coronaryarteries. Immediately after the procedure, each patient was

asked to grade on a 0 to 10 scale subjective feelings of painand warmth that occurred during and after the contrastinjections.

The cineangiograms were reviewed by an independentobserver with regard to quality of contrast. definition andopacification of coronary vessels and were graded as poor.adequate. good or excellent.

Blood for determination of urea nitrogen and serum cre­atinine was obtained at baseline (before angiography) andat 24 and 48 hours after the procedure. If the values wereabnormal at 48 hours. these tests were repeated I week afterangiography and, if abnormal. repeated until the valuesreturned to baseline levels. The protocol was approved bythe Human Research Committees of the University of Cal­ifornia and the Veterans Administration Medical Center atSan Francisco. Informed written consent was obtained fromeach patient.

Statistics. All hemodynamic and electrocardiographicvariables were analyzed by repeated measures analysis ofvariance using Tukey's tests to determine whether there wasa difference between the changes induced by the two contrastagents (42). The unpaired t test was used to determine whetherthere was a difference between the hemodynamic andelectrocardiographic variables of the iopan;idol and Reno­grafin-76 groups at baseline. The chi-square test was usedto compare discrete variables. The nonparametric variablessuch as cineangiographic quality and subjective response ofthe patients to the contrast agent were compared using theMann-Whitney test. The data in the text and tables arepresented as mean :i: I standard deviation. The mean values:i: I standard error are shown in the figures.

ResultsPatient characteristics. The study group consisted of

81 male patients. Seventy-nine patients underwent left ven­triculography and selective coronary angiography for symp­toms of ischemic heart disease and two underwent the pro­cedure for evaluation of valvular heart disease. Forty-onepatients received iopamidol and 40 received Renografin-76.

The patient characteristics in these two Rroups are listedin Tahle I. A coronary lesion was considered significant if75% or more of the cross-sectional luminal area of the vesselwas obstructed. There was no significant difference betweenthe two groups in the number of patients with significantleft main lesions and with no. one. two or three vesseldisease. Two patients receiving Renografin-76 had aorticvalve disease; one had significant aortic regurgitation re­quiring valve replacement and the other had mild aorticstenosis. One patient in the iopamidol group had significantaortic stenosis requiring valve replacement. In each group,there was one patient with mild mitral regurgitation.

Indexes oj"lefi ventricular function are also listed in TableI. There was no significance difference in ejection fraction.

252 GERTZ ET AL. NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

Table 1. Characteristics of Patients

No. of patients Age (yr) Severity of CAD

(no. of patients with "'75';' obstruction) No ves,el disease One vessel disea,e Two vessel disea,e Three vessel disease Left main lesion

Valvular heart disease (no. of patients)

Aortic stenosis/aortic regurgitation Mitral regurgitation

Left ventricular function Ejection fraction (%)

Left ventricular end-diastolic volume index (011/01')

Left ventricular end-diastolic pressure (mm HI')

lopamidol

41 57 :t: 10

5 7 X

21 7

59 :t: 10 XO :±: 19

13 :t: 6

Renografin-76

40 60 :±: 7

4 7 7

22 II

2

62 :±: 13 75 :t: IX

12 :t: 6

p Value

NS

NS NS NS NS NS

NS NS

NS NS

NS

JACC Vol. 5. No.2 February 19S5:250-8

Data are presented a, mean :±: I standard deviation. CAD = coronary artery disease: NS = no significant difference between the iopamidol and Renografin-76 groups.

left ventricular end-diastolic volume index and baseline left ventricular end-diastolic pressure between the two groups.

The medications received hy the patients hellJre the an­xioxraphic study are listed in Tahle 2. There was no sig­nificant difference in the types of medications prescribed for the patients in the two groups.

The haseline (hellJre contrast medium) systolic arterial pressure, le.lf ventricular end-diastolic pressure and electro­cardioxraphic data for these two xroups ol paticnts arc xivcn in Tahle 3. There was no significant difference in any of these measurements at baseline between the two groups.

Hemodynamic alterations. The baseline (before con­trast medium) systolic arterial pressure was 146 ± 22 mm Hg in the Renografin-76 group and 141 ± 24 mm Hg in the iopamidol group (p = NS). After left ventriculography, there was a decrease in the arterial pressure in both groups (Fig. 1). The average decrease in systolic pressure was 48 ± 14 mm Hg in the Renografin-76 group and 19 ± II mm Hg in the iopamidol group (p < 0.001). The duration

Table 2. Medications Administered Immediately Before Angiography

Long-acting nitrates Beta-adrenergic blocking agents Calcium channel blocking agents Digoxin Antiarrhythmic agents Diuretic drugs Antihypertensive agents

Data represent number of patients.

lopamidol

30 35 21

5 5

16 2

Renografin-76

33 35 16 4

14 3

of the decrease in systolic pressure (decrease in systolic pressure > 10% of control) was 45 ± 25 seconds in the Renografin-76 group compared with 9 ± 10 seconds in the iopamidol group (p < 0.00 I). Thus, not only was the de­crease in arterial pressure greater after Renografin-76 but also the duration of these changes was significantly longer compared with iopamidol. The change in left ventricular end-diastolic pressure induced by ventriculography is also shown in Figure 1. After injection of Renografin-76, the average increase in end-diastolic pressure at 90 seconds after the ventriculogram was 9 ± 7 mm Hg compared with 1 ± 5 mm Hg for iopamidol. This difference was highly sig­nificant (p < 0.001).

Thc systolic artcrial prcssurc durinx the control period and alter the .first selcctive injection ()l the riXht and le.li coronary arteries is shown in Fixure 2. There was no sig­nificant difference between the two groups in the arterial pressure during the control period. After selective injection of either the right or the left coronary artery, arterial pressure did not change in the iopamidol group but decreased sig­nificantly in the Renografin-76 group (p < 0.001).

Electrocardiographic changes. Figure 3 compares the electrocardiographic changes induced by selective contrast injections of the left and right coronary arteries and left ventriculography in the Renografin-76 and iopamidol groups. Data are shown for the control period and for the 60 second period after the contrast injection. With selective left coro­nary injection, there was a marked prolongation of the QT interval. from 394 ± 32 to 482 ± 56 ms, in the Renografin-76 group (p < 0.001), but only a slight increase, from 386 ± 33 to 393 ± 36 ms, in the iopamidol group (p = NS). A repeated measures analysis of variance showed that there

252 GERTZ ET AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

Table 1. Characteristics of Patients

lACC Vol. 5. No.2February 19S5:250-S

No. of patientsAge (yr)Severity of CAD

(no. of patients with "'75';' obstruction)No vessel diseaseOne vessel diseaseTwo vessel diseaseThree vessel diseaseLeft main lesion

Valvular heart disease(no. of patients)

Aortic stenosis/aortic regurgitationMitral regurgitation

Left ventricular functionEjection fraction (%)

Left ventricular end-diastolicvolume index (ml/m')

Left ventricular end-diastolicpressure (mm HI')

lopamidol

4157 :t: 10

57X

217

59 :t: 10XO :±: 19

13 :t: 6

Renografin-76 p Value

4060 :±: 7 NS

4 NS7 NS7 NS

22 NSII NS

2 NSNS

62 :±: 13 NS75 :t: IX NS

12 :t: 6 NS

Data arc presented as mean :±: I standard deviation. CAD = coronary artery disease: NS = no significantdifference between the iopamidol and Renografin-76 groups.

left ventricular end-diastolic volume index and baseline leftventricular end-diastolic pressure between the two groups.

The medications received by the patients be/fIre the an­xioxraphic study are listed in Table 2. There was no sig­nificant difference in the types of medications prescribedfor the patients in the two groups.

The baseline (be/f)re contrast medium) systolic arterialpressure, left ventricular end-diastolic pressure and electro­cardiof,?raphic data F)r these two xroups ol patients arexiven in Table 3. There was no significant difference in anyof these measurements at baseline between the two groups.

Hemodynamic alterations. The baseline (before con­trast medium) systolic arterial pressure was 146 ± 22 mmHg in the Renografin-76 group and 141 ± 24 mm Hg inthe iopamidol group (p = NS). After left ventriculography,there was a decrease in the arterial pressure in both groups(Fig. I). The average decrease in systolic pressure was48 ± 14 mm Hg in the Renografin-76 group and 19 ± IImm Hg in the iopamidol group (p < 0.001). The duration

Table 2. Medications Administered ImmediatelyBefore Angiography

Long-acting nitratesBeta-adrenergic blocking agentsCalcium channel blocking agentsDigoxinAntiarrhythmic agentsDiuretic drugsAntihypertensive agents

Data represent number of patients.

lopamidol

303521

55

162

Renografin-76

3335164I

143

of the decrease in systolic pressure (decrease in systolicpressure > 10% of control) was 45 ± 25 seconds in theRenografin-76 group compared with 9 ± 10 seconds in theiopamidol group (p < 0.00 I). Thus, not only was the de­crease in arterial pressure greater after Renografin-76 butalso the duration of these changes was significantly longercompared with iopamidol. The change in left ventricularend-diastolic pressure induced by ventriculography is alsoshown in Figure I. After injection of Renografin-76, theaverage increase in end-diastolic pressure at 90 seconds afterthe ventriculogram was 9 ± 7 mm Hg compared with I ±5 mm Hg for iopamidol. This difference was highly sig­nificant (p < 0.00 I).

The systolic arterial pressure durinx the control periodand alter the .first selective injection ()l the riXht and le.licoronary arteries is shown in Fixure 2. There was no sig­nificant difference between the two groups in the arterialpressure during the control period. After selective injectionof either the right or the left coronary artery, arterial pressuredid not change in the iopamidol group but decreased sig­nificantly in the Renografin-76 group (p < 0.001).

Electrocardiographic changes. Figure 3 compares theelectrocardiographic changes induced by selective contrastinjections of the left and right coronary arteries and leftventriculography in the Renografin-76 and iopamidol groups.Data are shown for the control period and for the 60 secondperiod after the contrast injection. With selective left coro­nary injection, there was a marked prolongation of the QTinterval. from 394 ± 32 to 482 ± 56 ms, in the Renografin­76 group (p < 0.001), but only a slight increase, from 386± 33 to 393 ± 36 ms, in the iopamidol group (p = NS).A repeated measures analysis of variance showed that there

lACC Vol. 5. No.2 February 19H5:250~H

(iERTZ ET At.. 253 NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

Table 3. Baseline Hemodynamic and Electrocardiographic Variable~

lopan1ldol l{~no~ralil1- 76 p Value

Systolic arterial pressure (111111 H~)

Left ventricular end-diastolic 141 • 24 I~ + 6

NS NS

pressure (mm H~) OT interval (ms) .lX6 -I .' I ~X6 + 2X

O.lJX + 0.14 (l.1l + Il'i

14 1 1.2

NS NS NS NS

RR interval (seconds) ST segment displacement (mm) T wave amplitude (mm)

100 + 0 II (l.O + (U

1.6 + 1.6

All electrocardiographic variahles were measured in lead II One millivolt = 10 n1l11. NS no slgnilieant difference hetween the iopamidol and Renogralil1-76 groups. Data are presented as mean + 1 standard deviation.

was a significant difference in the prolongation of the QT interval produced by two contrast agents (p < 0.0001). At the end of the 60 second period. there was still a significant increase in the QT interval in the Renografin-76 group com­pared with the control value (p < 0.001). and a significant difference between the two contrast agent groups (p < 0.00 I). Selective injections of the right coronary artery produced a similar change in the QT interval; the difference between

Figure l. The systolic arterial pressure (top) is shown for control (time 0) and for the 2 minute period after left ventriculography for the 41 iopamidol (£---£) and 40 Renogratin-76 ( ________ ) patients. The left ventricular end-diastolic pressure (bottom) is also shown for the control period and after the left ventriculogram. The left ventriculogram was performed immediately after the con­trol values (time 0). The data are presented as mean::+:: I standard error. II p < 0.05 iopamidol versus Renogratin-76: * p < (J.OI iopamidol versus Renogratin-76: ~ p < 0.005 iopamidol versus Renogratin-76: :j: p < 0.00 I iopamidol versus Renogratin-76: 'I- p < 0.05 versus control; H p < 0.0 I versus control: * p < 0.005 versus control: ** p < 0.001 versus control.

..J < a:

160

~ w ..... 140 II: II: en

< ~ ~ 120 ~ :3 E ..JII: o Q. ...... 100 l-I/)

> I/) 80

25

20

15

10

5

o

LEFT VENTRICULOGRAPHY

i I * T I ___ r-----. " \\.** l",-"'--'t .. t'i··- t *

** t

** **

---t""

**

**

** .. + + t +

" + t---t---t-----t------f

~~~~--+-~~I~'~~

o 20 40 60 90 120 TIME (seconds)

the two contrast agents was again highly significant (p < 0.0002).

There Ims no significlInt chllnge ill the RR illlerva/ in the ioparnidol-treated patients after selective injections of either the right or left coronary artery. However, in the patients receiving Renogrann-76 there was a significant in­crease in the RR interval from O. 9K :+:: 0.15 to 1.32 :+:: 0.46 seconds after left coronary angiography (p < 0.0(1) and a similarincreasefromO.9K:+:: O.15to 1.26:+:: 0.44 seconds after right coronary angiography (p < 0.(01) (Fig. 3). The QRS duration was (l.OK :+:: OJ)I second in the Renografin-

Figure 2. The systolic arterial pressures immediately before (time 0) and for the :2 minute~ after the tirst selective contrast inject jon of the right coronary artery (top) and the len coronary artery (bottom) are plotted. The data arc presented as mean ± I standard error. £---£ represent the values in the jopamidol group and ............. in the Renogratin-76 )!roup. Symbols for probability (p) values as in Figure I.

160 en J: 140 E E

120 W II: 100 ::> I/) I/) w 80 II: Q.

..J 160 < 0: w 140 I-0:: <

~ 120

..J 0 100 l-I/) > I/) 80

,.*

0

RIGHT CORONARY ANGIOGRAPHY

"~~

LEFT CORONARY ANGIOGRAPHY

"~~ 20 40 60 90 120 TIME ( seconds)

lACC Vol. 5. No.2February 19H5:250~H

(iERTZ ET At..NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

253

Table 3. Baseline Hemodynamic and Electrocardiographic Variables

lopal111dol 1{cl1()~ralil1- 76 p Valuc

Systolic arterial pressure (111111 H~)

Left ventricular cl1d-diastolicpressurc (mm H~)

QT intcrval (ms)RR intcrval (seconds)ST se~ment displacement (mm)T wave amplitudc (mm)

141 • 24

I~ + 6

.'X6 -I .' I100 + 0 II

0.0 + (U

1.6 + 1.6

146 ~ "12 ~ 6

~X6 + 2XO.lJX + 0.14

0.0 + O'i14 1 1.2

NSNS

NSNSNSNS

All c1ectrocardio~raphic variahles wcrc mcasured in lead II Onc millivolt = 10111111. NS no sl~nilicant

differcncc hetwccn the iopamidol and Reno~ralin-76 ~rolipS. Data arc prcscntcd as mcan + I standard dcviation.

was a significant difference in the prolongation of the QTinterval produced by two contrast agents (p < 0.0001). Atthe end of the 60 second period. there was still a significantincrease in the QT interval in the Renografin-76 group com­pared with the control value (p < 0.001). and a significantdifference between the two contrast agent groups (p < 0.00 I).Selective injections of the right coronary artery produced asimilar change in the QT interval; the difference between

Figure l. The systolic arterial pressure (top) is shown for control(time 0) and for the 2 minute period after left ventriculographyfor the 41 iopamidol (£---£) and 40 Renogratin-76 (-------.)patients. The left ventricular end-diastolic pressure (bottom) isalso shown for the control period and after the left ventriculogram.The left ventriculogram was performed immediately after the con­trol values (time 0). The data are presented as mean::+:: I standarderror. II p < 0.05 iopamidol versus Renogratin-76: *p < (U) Iiopamidol versus Renogratin-76: ~ p < 0.005 iopamidol versusRenogratin-76; :j: p < 0.00 I iopamidol versus Renogratin-76: 'I- p< 0.05 versus control; H p < 0.0 I versus control: * p < 0.005versus control: ** p < 0.001 versus control.

the two contrast agents was again highly significant (p <0.0002).

There Ims no significant change in the RR interval inthe iopamidol-treated patients after selective injections ofeither the right or left coronary artery. However. in thepatients receiving Renografin-76 there was a significant in­crease in the RR interval from O. 9K :+:: 0.15 to 1.32 :+:: 0.46seconds after left coronary angiography (p < 0.0(1) and asimilarincreasefromO.9K:+:: 0.15to 1.26:+:: 0.44 secondsafter right coronary angiography (p < 0.(01) (Fig. 3). TheQRS duration was O.OK :+:: 0.01 second in the Renografin-

Figure 2. Thc systolic arterial pressurcs immediately before (time0) and for the :2 minutes after the tirst selective contrast injectionof thc right coronary artery (top) and the leli coronary artery(bottom) are plotted. The data are presented as mean ± I standardcrror. £---£ represent the values in the iopamidol group and............. in thc Renogratin-76 group. Symbols for probability (p)valucs as in Figure I.

RIGHT CORONARYANGIOGRAPHY160

CIl

J: 140EE

120WI%: 100::>I/)I/)UJ 80I%: "~~Q.

...l 160 LEFT CORONARY< ANGIOGRAPHYii:UJ 140I-0::<

~120

...l0 100 ••l-I/)>I/) 80

"~~0 20 40 60 90 120

TIME ( seconds )

••..**..

••

....

.. ++ t +

" +t---t---t-----t------f---t'/

••

LEFT VENTRICULOGRAPHY

>----+--+---l-+--+---+o'""",~~

20 40 60 90 120TIME (seconds)

i I • T I r-----. " \\." 1.···...···t.. t'i·'- t •.. t

o

25

20

15

10

5

o

80

160...l<a:~ w ..... 140I%:I%:CIl

< ~ ~ 120~ :3 E...ll%:o Q. ...... 100l-I/)

>I/)

254 GERTZ ET AL. NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

500 .... ..-, c( In > '0

ffi 8 450 I- (,)

Z = - .-I- ~ 400 0 .....

.... c(

350

1.4

~ ~ 1.2 w c I- 0 ~ (,)

cu 1.0 a: In ..... a:

0.8

1.0

!z 0.6 w_ ~E O.g wE 0_ -0.2

I- -0.6

W Q ::l I-

4.0 3.0 2.0

:J A. - 1.0 :IE E 0 c(E w- -1.0 > c( -2.0 ~ -3.0

LEFT CORONARY

ANGIOGRAPHY

••

••

••

••

o 20 40 60

76 group and 0.08 ± 0.02 second in the ioparridol group (p = NS). After selective coronary injection of the contrast agents, 19 of the 40 patients treated with Renografin-76 developed an intraventricular conduction defect with the duration of the QRS complex greater than 0.10 second, whereas only 3 of the 41 iopamidol-treated patients had prolongation of the QRS complex (p < 0.01).

RIGHT CORONARY

ANGIOGRAPHY

• •

+ ++

••

+ + + + +

+ + t t ~ ,t-t,-1''i---1----t,---i---i

••

•• I I I

o 20 40 6Q

TIME (seconds)

lACC Vol. 5. No.2 February 1985:250-8

LEFT

VENTRICULOGRAPHY

• •• t ·~J... ___ L __ ... ---~---i

! , t t ~

** ** ** I ,

~t·-j---t---i---i

I I

o 20 40 60

Figure 3. The changes in the QT intervals, RR intervals, ST segments and T wave amplitudes induced by the contrast injections of the left coronary artery (left) and right coronary artery (middle) and by left ventriculography (right) are shown. The data are pre­sented as mean ;:t:: I stal1dard error. 6.---6. represent the changes after iopamid!,>1 injection and ~ after Renografin-76 injec­tion. Measurements and symbols for probability (p) values as in Figures I and 2.

254 GERTZ ET ALNONIONIC CONTRAST CARDIAC ANGIOGRAPHY

lACC Vol. 5. No.2February 1985:250-8

LEFT CORONARY

ANGIOGRAPHY

500 ••••

LEFT

VENTRICULOGRAPHY

++++ +

+ + ++ + t ~ ~

,t-t,'1''i- --1' ._-t,-.-i---i

RIGHT CORONARY

ANGIOGRAPHY

+++

++++

+ ~ + + ++ + +

~'±"t'i"i--''t---''i---'i--''i

350

... ....,c( In> '0ffi 8 450I- (,)

Z =- .-I- ~ 4000 .....

.....

** ** **I ,

• •• t·~"'. L __...---~---i

I , t t ~

••••

••

1.2

1.4

1.0

0.8

...c(

> Ina: '0w cI- 0~ (,)

cua: In

a:

1.0

!Z 0.6w....,~E O.gwE0 ..... - 0 .2

... -0.6UJ

_ I

4.0wQ 3.0::;)

I- 2.0:JA."'" 1.0:lEEc( E 0w..... -1.0>c( -2.0~ -3.0...

••

o 20 40 60

.1. I.1--1---~---1.--.1---.l+ + "+ +-_.......------.,.

.,.*

••.*••I ~ I I I

o 20 40 6Q

TIME (seconds)

oI I

20 40 60

76 group and 0.08 ± 0.02 second in the ioparridol group(p = NS). After selective coronary injection of the contrastagents, 19 of the 40 patients treated with Renografin-76developed an intraventricular conduction defect with theduration of the QRS complex greater than 0.10 second.whereas only 3 of the 41 iopamidol-treated patients hadprolongation of the QRS complex (p < 0.01).

Figure 3. The changes in the QT intervals, RR intervals, STsegments and T wave amplitudes induced by the contrast injectionsof the left coronary artery (left) and right coronary artery (middle)and by left ventriculography (right) are shown. The data are pre­sented as mean ± I staI1dard error. A.---A. represent the changesafter iopamid!,>1 injection and~ after Renografin-76 injec­tion. Measurements and symbols for probability (p) values as inFigures I and 2.

lACC Vol. 5, No.2 f'cbruary 1985: 250--8

With riRht coronar\' arter\' injectiolls or RelloRrajill-76. electrocardiographic analysis of lead II demonstrated sig­nificant ST segment depre~sion from 0.0 ± 0.5 to -0,9 ± I, I Iilm (p < 0.00 I) and marked T wave inversion from an amplitude of 1.4 ± 1,2 to - 2,2 ± 2,6 mm (p < (LOOI) (Fig, 3), At the end of 60 seconds. there was still a signif­icant decrease in T wave amplitude compared with the con­trol value in the Reriografin-76 group (p < (U)OI). With iopamidol. there was ST segment depression from 0,0 ± 0,3 to - 0,3 ± 0,6 mm at 5 seconds after the contrast injection (p < 0,0(5). but there was no significant change in T wave amplitude, A repeated measures analysis of var­iance showed that there was a significant difference in the ST segment and T wave amplitude response for the two contrast agents (p < 0,05 and p < (U)OOI. respectively),

With the left corollary injections there was a significant elevation in the ST segment and a significant increase in T wave amplitude in lead II with Renografin-76, With iopam­idol. there was no significant change in these two variables (Fig, 3).

Serious arrhythmias. Two of the patients in the Ren­ografin-76 group developed ventricular fibrillation during selective injection of the right coronary artery: the arrhyth­mia was immediately treated with electrical cardioversion and there were no iate sequelae in either patient. There were no episodes of ventricular tachycardia or fibrillation in the iopamidol group.

There was 0 siRnijiCllflt hut hrier tJecreose ill the hearl rate immediately after injections of I:Jbth the right and left coronary arteries with Renografin-76 (Fig. 3). whereas with iopamidol there was no significant change in the heart rate. All patients in this study had a temporary pacing catheter placed in the right ventricle which wa~ used for periods of asystole lasting 2.5 seconds or more. Eight of the 40 patients receiving Renografin-76 required pacing during the coronary injections. However. none of the 41 patients in the iopam­idol group was paced during the procedure. This difference in the development of serious bradyarrhythmias during coro­nary injections is significant (p < 0.(1).

Chest pain. It is not uncommon for patients to experi­ence transient chest pain and feelings of warmth during and immediately after selective contrast injections of the coro­nary arteries and during left ventriculography. After the procedure. each patient was asked to grade these subjective feelings of pain and warrhth that occurred during angiog­raphy. Thirty-three of the 40 patiertts receiving Renografin-76 had no chest pain during the irltravascular bolus injection for the left ventriculogram. Likewise. 37 of the 41 patients in the iopamidol group had no pain. There was no significant difference between the two groups for chest pain induced by the left ventriculogram. However. on a scale of 0 to 10 for the sensation of warmth associated with the left ven­triculogram. the mean score was 7.0 ± 2.5 for the Reno­grafin-76 group and 4.2 ± 2.3 for the iopamidol group; this difference was significant (p < (l05).

GERTZ ET AL. 255 NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

DuriflR selective COroflOr\' aflMioMraphv. 25 of the 40 patients treated with Renografin-76 had chest pain. whereas only II of the 41 iopamidol-treated patients had pain (p < 0.0(5). In the Renografin-76 group. the mean score for pain during the selective coronary angiography was 3.1 ± 3.0 and the score for warmth was 2.8 ± 2.7. In comparison. the mean scores for the iopamidol group were 0.8 ± 1.6 and 1.1 ± 2.0. respectively. The differences for both pain and warmth during coronary angiography were significant (p < (LOS). In most patients. the chest pain associated with the contrast injection was very transient and required no treatment. However. 13 of the patients treated with Reno­grafin-76 required nitroglycerin for their chest pain asso­ciated with coronary angiography, Only five of the iopam­idol-treated patients had chest pain requiring treatment with nitroglycerin during the study.

Other side effects. Two of the patients receiving Ren­ografin-76 developed nausea and vomiting after contrast injection. None of the patients in the iopamidol group had gastrointestinal symptoms during or after the procedure.

There was flO difference in the mean creatinine clearance hetweefl the two groups; the mean value for the calculated creatinine clearance was 81 ± 23 ml/min in the patients treated with Renografin-76 and 85 ± 25 mllmin in the iopamidol-treated patients. Two patients receiving Reno­grafin-76 had deterioration of their renal function after an­giography. as defined by a 0.5 mg/dl increase in serum creatinine. In these patients, the creatinine increased from 1.3 and 1.2 mg/dl (control) to 2.3 and 2.6 mg/dl. respec­tively, 48 hours after angiography. In the iopamidol group. only one patient had a similar increase in serum creatinine from 1.2 to 1.7 mg/dl. In all three patients. the deterioration in renal function was transient.

Quality of cineangiograms. Both contrast agents con­tain 370 mg iodine/ml and produced very good to excellent visuali/.ation of the coronary anatomy. We could not detect a difference in the cineangiographic quality of the left ven­triculograms and the selective coronary angiograms between iopamidol and Renografin-76.

Discussion Safety of cardiac angiography. Morbidity and mortal­

ity associated with selective coronary angiography and left ventriculography have decreased in the last decade (43-45). Many of the remaining complications are directly related to the contrast medium. There is a decrease in systemic ar­terial pressure and an increase in left ventricular end-dia­stolic pressure immediately after an intravascular bolus injection of an ionic contrast medium for the left ventric­ulogram (5.7-9.13.31.34.35). Selective coronary injections of these ionic agents are associated with bradyarrhythmias. prolongation of the QRS complex. increase in the QT in­tervaL marked shifts in the ST segment and T wave changes ( 1-3, 10.29.31.34,46). Development of contrast agents that

lACC Vol. 5, No, 2f'cbruary 1985: 250--8

GERTZ ET AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

255

With riRht coronan' arten' injections or Renografin-76.electrocardiographic analysis of lead II demonstrated sig­niticant ST segment depre~sion from 0,0 ± 0,5 to -0.9± 1.1 Jilm (p < 0.00 I) and marked T wave inversion froman amplitude of 1.4 ± 1,2 to - 2.2 ± 2.6 mm (p < (l.001)(Fig. 3). At the end of 60 seconds. there was still a signif­icant decrease in T wave amplitude compared with the con­trol value in the Renogratin-76 group (p < 0,(01). Withiopamidol, there was ST segment depression from 0.0 ±0.3 to - 0.3 ± 0.6 mm at 5 seconds after the contrastinjection (p < 0.0(5), but there was no significant changein T wave amplitude, A repeated measures analysis of var­iance showed that there was a signiticant difference in theST segment and T wave amplitude response for the twocontrast agents (p < 0,05 and p < 0,0001. respectively),

With the left coronary injections there was a significantelevation in the ST segment and a significant increase in Twave amplitude in lead II with Renogratin-76. With iopam­idol, there was no significant change in these two variables(Fig. 3).

Serious arrhythmias. Two of the patients in the Ren­ogratin-76 group developed ventricular tibrillation duringselective injection of the right coronary artery: the arrhyth­mia was immediately treated with electrical cardioversionand there were no iate sequelae in either patient. There wereno episodes of ventricular tachycardia or tibrillation in theiopamidol group.

There was a significant hut hrier tJecrease in the !lmrtrate immediately after injections of I:Jbth the right and leftcoronary arteries with Renogratin-76 (Fig. 3). whereas withiopamidol there was no signiticant change in the heart rate.All patients in this study had a temporary pacing catheterplaced in the right ventricle which wa~ used for periods ofasystole lasting 2.5 seconds or more. Eight of the 40 patientsreceiving Renogratin-76 required pacing during the coronaryinjections. However. none of the 41 patients in the iopam­idol group was paced during the procedure. This differencein the development of serious bradyarrhythmias during coro­nary injections is significant (p < 0.01).

Chest pain. It is not uncommon for patients to experi­ence transient chest pain and feelings of warmth during andimmediately after selective contrast injections of the coro­nary arteries and during left ventriculography. After theprocedure. each patient was asked to grade these subjectivefeelings of pain and warrhth that occurred during angiog­raphy. Thirty-three of the 40 patiertts receiving Renogratin­76 had no chest pain during the irltravascular bolus injectionfor the left ventriculogram. Likewise, 37 of the 41 patientsin the iopamidol group had no pain. There was no significantdifference between the two groups for chest pain inducedby the left ventriculogram. However, on a scale of 0 to 10for the sensation of warmth associated with the left ven­triculogram, the mean score was 7.0 ± 2.5 for the Reno­gratin-76 group and 4,2 ± 2.3 for the iopamidol group;this difference was significant (p < (l05).

During selective coronan' angiography. 25 of the 40patients treated with Renogratin-76 had chest pain, whereasonly II of the 41 iopamidol-treated patients had pain (p <0.005). In the Renogratin-76 group, the mean score fix painduring the selective coronary angiography was 3.1 ± 3,0and the score for warmth was 2,8 ± 2.7. In comparison,the mean scores for the iopamidol group were 0.8 ± 1.6and \.\ ± 2.0, respectively. The differences for both painand warmth during coronary angiography were signiticant(p < (l.05). In most patients, the chest pain associated withthe contrast injection was very transient and required notreatment. However, 13 of the patients treated with Reno­gratin-76 required nitroglycerin for their chest pain asso­ciated with coronary angiography. Only five of the iopam­idol-treated patients had chest pain requiring treatment withnitroglycerin during the study.

Other side effects. Two of the patients receiving Ren­ografin-76 developed nausea and vomiting after contrastinjection. None of the patients in the iopamidol group hadgastrointestinal symptoms during or after the procedure.

There was no difference in the mean creatinine clearancehetween the two groups; the mean value for the calculatedcreatinine clearance was 81 ± 23 ml/min in the patientstreated with Renografin-76 and 85 ± 25 mllmin in theiopamidol-treated patients. Two patients receiving Reno­gratin-76 had deterioration of their renal function after an­giography, as defined by a 0.5 mg/dl increase in serumcreatinine. In these patients, the creatinine increased from1.3 and 1.2 mg/dl (control) to 2,3 and 2.6 mg/dl, respec­tively. 48 hours after angiography. In the iopamidol group,only one patient had a similar increase in serum creatininefrom 1.2 to 1.7 mg/dl. In all three patients, the deteriorationin renal function was transient.

Quality of cineangiograms. Both contrast agents con­tain 370 mg iodine/ml and produced very good to excellentvisuali/.ation of the coronary anatomy. We could not detecta difference in the cineangiographic quality of the left ven­triculograms and the selective coronary angiograms betweeniopamidol and Renogratin-76.

DiscussionSafety of cardiac angiography. Morbidity and mortal­

ity associated with selective coronary angiography and leftventriculography have decreased in the last decade (43-45).Many of the remaining complications are directly related tothe contrast medium. There is a decrease in systemic ar­terial pressure and an increase in left ventricular end-dia­stolic pressure immediately after an intravascular bolusinjection of an ionic contrast medium for the left ventric­ulogram (5,7-9.13,31,34,35). Selective coronary injectionsof these ionic agents are associated with bradyarrhythmias,prolongation of the QRS complex. increase in the QT in­terval, marked shifts in the ST segment and T wave changes( 1-3. 10,29,31 ,34.46). Development of contrast agents that

256 GERTZ ET AL. NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

are less toxic to the myocardium than these standard ionic agents should enhance the safety of angiographic procedures.

Animal studies (15.28-31.38) have shown that the new nonionic agents arc associated with fewer hemodynamic and electrocardiographic changes compared with ionic contrast media. Measurements of myocardial contractility have shown that these new agents have a small positive inotropic effect as opposed to the negative inotropic effects of the ionic agents (15.20.33.35). These non ionic agents have been evaluated in several human studies (32,34,39.40), and their results corroborate the findings of the animal studies, sug­gesting that these new agents are safer.

This is the first large study that compares iopamidol and Renografin-76 in human subjects in a double-blind random­ized fashion. Our data demonstrate that the hemodynamic and electrocardiographic changes induced by contrast left ventriculography and coronary angiography were signifi­cantly less when the nonionic agent. iopamidol. was com­pared with a standard ionic contrast medium. The incidence and severity of bradyarrhythmias and systemic hypotension were greater with Renografin-76 compared with iopamidol. Prolongation of the QT interval. widening of the QRS com­plex and ST and T wave changes were also significantly greater in the Renografin-76 group compared with the io­pam idol group. These findings indicate that iopamidol is less toxic to the myocardium compared with Renografin-76.

Ventricular fibrillation. Ventricular fibrillation is one of the most serious complications associated with coronary angiography and is directly associated with injections of contrast agent. Although there is no direct relation between development of ventricular fibrillation and changes in the QT interval. prolongation of the QT interval is considered a risk factor for ventricular arrhythmia (46-49). In this study, the increase in the QT interval was significantly greater with Renografin-76 than with iopamidol (p < 0.0(02). If there were a direct relation between prolongation of QT interval and ventricular fibrillation. one might expect a higher incidence of ventricular fibrillation in the Renografin-76 group. In our study, 2 of the 40 patients in the Renografin-76 group developed ventricular fibrillation during selective coronary angiography, whereas none of the 41 patients receiving iopamidol had this complication. Although the number of patients in this study is too small to determine the true incidence of ventricular fibrillation for each contrast agent. our data suggest that the incidence of ventricular fibrillation may be higher for Renografin-76 than for io­pamidol. Using Renografin-76 as the contrast agent. the incidence in our laboratory of ventricular tachycardia­fibrillation is 1.5%. This was determined in 260 consecutive cases petformed after the completion of this double-blind study.

Heterogeneity of depolarization and repolarization within adjacent areas of the myocardium is one of the proposed

JACC Vol. 5. No.2 February 1985:250-8

mechanisms of contrast-induced ventricular fibrillation. Franz et al. (50) measured indexes of depolarization and repolar­ization during the coronary injections of iopamidol and Ren­ografin-76 in dogs. They found that Renografin-76 caused a significantly greater prolongation of the monophasic action potential compared with iopamidol. Their findings also sug­gest that the risks of ventricular arrhythmias are higher with Renografin-76 than with iopamidol.

Biochemical data. We (17) and Visioli et al. (18) have demonstrated that contrast ventriculography with Reno­grafin-76 induces changes in myocardial metabolism. Re­cently (51). we have investigated the myocardial metabolic effects of iopamidol and have shown that the decrease in myocardial lactate extraction that occurs after injection of Renografin-76 did not occur with this new nonionic agent. Using [1- '4Cllactate as a tracer, we measured the amount of lactate released by the myocardium before and after an injection of Renografin-76 and iopamidol. After injection of Renografin-76, there was a 54 ± 38% increase in myo­cardial lactate release, whereas after iopamidol there was no significant change in the amount of lactate released (52). These biochemical data suggest that contrast angiography with the standard ionic agents induces myocardial cellular ischemia and that the newer non ionic agent. iopamidoJ, does not produce these changes.

Factors influencing contrast medium toxicity. In ad­dition to the contrast ion or molecule, there are a number of other important differences between these two contrast agents, such as osmolality and cation composition and con­tent. The contribution of these factors to the electrocardio­graphic and hemodynamic differences observed in this study is unclear. Many reports (5.7,12,13,15,19,20,28,35,53) have indicated that the toxicity of a contrast agent is directly related to the osmolality. The osmolality of Renografin-76 ( 1,680 mosm/kg) is approximately twice that of iopamidol (796 mosm/kg) (34,36,38). Recently, an ionic contrast agent (ioxaglate) has been developed which has an osmolality similar to iopamidol (20,31,38,53). Tragardh and Lynch (31) compared the effects of ioxaglate, diatrizoate (Reno­grafin-76) and two nonionic compounds during coronary angiography in animals. Their study demonstrated that both nonionic agents were associated with fewer hemodynamic and electrophysiologic changes than the new ionic low os­molality contrast agent. Although osmolality plays an im­portant role in contrast agent toxicity, the study by Tragardh and Lynch (31) suggests that it is not the only factor. The cation composition and content of the contrast agent also appear to be important factors (15,19,20,22,23,46,54-56). lopamidol has negligible amounts of sodium compared with 190 mEq/liter in Renografin-76. Renogratin-76 has no cal­cium and iopamidol contains only negligible amounts of calcium. Contrast agents with varying sodium and calcium contents have been evaluated (15,20,22,23,56). Although the addition of calcium appears to decrease the toxicity, the

256 GERTZ ET AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

JACC Vol. 5. No.2February 1985:250-8

are less toxic to the myocardium than these standard ionicagents should enhance the safety of angiographic procedures.

Animal studies (15.28-31.38) have shown that the newnonionic agents are associated with fewer hemodynamic andelectrocardiographic changes compared with ionic contrastmedia. Measurements ofmyocardial contractility have shownthat these new agents have a small positive inotropic effectas opposed to the negative inotropic effects of the ionicagents (15.20.33.35). These non ionic agents have beenevaluated in several human studies (32,34.39.40). and theirresults corroborate the findings of the animal studies. sug­gesting that these new agents are safer.

This is the first large study that compares iopamidol andRenografin-76 in human subjects in a double-blind random­ized fashion. Our data demonstrate that the hemodynamicand electrocardiographic changes induced by contrast leftventriculography and coronary angiography were signifi­cantly less when the nonionic agent. iopamidol. was com­pared with a standard ionic contrast medium. The incidenceand severity of bradyarrhythmias and systemic hypotensionwere greater with Renografin-76 compared with iopamidol.Prolongation of the QT interval. widening of the QRS com­plex and ST and T wave changes were also significantlygreater in the Renografin-76 group compared with the io­pam idol group. These findings indicate that iopamidol isless toxic to the myocardium compared with Renografin­76.

Ventricular fibrillation. Ventricular fibrillation is oneof the most serious complications associated with coronaryangiography and is directly associated with injections ofcontrast agent. Although there is no direct relation betweendevelopment of ventricular fibrillation and changes in theQT interval. prolongation of the QT interval is considereda risk factor for ventricular arrhythmia (46-49). In thisstudy. the increase in the QT interval was significantly greaterwith Renografin-76 than with iopamidol (p < 0.0002). Ifthere were a direct relation between prolongation of QTinterval and ventricular fibrillation. one might expect a higherincidence of ventricular fibrillation in the Renografin-76group. In our study. 2 of the 40 patients in the Renografin­76 group developed ventricular fibrillation during selectivecoronary angiography. whereas none of the 41 patientsreceiving iopamidol had this complication. Although thenumber of patients in this study is too small to determinethe true incidence of ventricular fibrillation for each contrastagent. our data suggest that the incidence of ventricularfibrillation may be higher for Renografin-76 than for io­pamidol. Using Renografin-76 as the contrast agent. theincidence in our laboratory of ventricular tachycardia­fibrillation is 1.5%. This was determined in 260 consecutivecases performed after the completion of this double-blindstudy.

Heterogeneity of depolarization and repolarization withinadjacent areas of the myocardium is one of the proposed

mechanisms of contrast-induced ventricular fibrillation. Franzet a!. (50) measured indexes of depolarization and repolar­ization during the coronary injections of iopamidol and Ren­ografin-76 in dogs. They found that Renografin-76 causeda significantly greater prolongation of the monophasic actionpotential compared with iopamidol. Their findings also sug­gest that the risks of ventricular arrhythmias are higher withRenografin-76 than with iopamidol.

Biochemical data. We (17) and Visioli et a!. (18) havedemonstrated that contrast ventriculography with Reno­grafin-76 induces changes in myocardial metabolism. Re­cently (51). we have investigated the myocardial metaboliceffects of iopamidol and have shown that the decrease inmyocardial lactate extraction that occurs after injection ofRenografin-76 did not occur with this new nonionic agent.Using [1- '4Cjlactate as a tracer, we measured the amountof lactate released by the myocardium before and after aninjection of Renografin-76 and iopamidoJ. After injectionof Renografin-76. there was a 54 ± 38% increase in myo­cardial lactate release. whereas after iopamidol there wasno significant change in the amount of lactate released (52).These biochemical data suggest that contrast angiographywith the standard ionic agents induces myocardial cellularischemia and that the newer nonionic agent, iopamidol. doesnot produce these changes.

Factors influencing contrast medium toxicity. In ad­dition to the contrast ion or molecule. there are a numberof other important differences between these two contrastagents. such as osmolality and cation composition and con­tent. The contribution of these factors to the electrocardio­graphic and hemodynamic differences observed in this studyis unclear. Many reports (5,7,12,13,15,19,20,28.35,53) haveindicated that the toxicity of a contrast agent is directlyrelated to the osmolality. The osmolality of Renografin-76( 1.680 mosm/kg) is approximately twice that of iopamidol(796 mosm/kg) (34.36,38). Recently, an ionic contrast agent(ioxaglate) has been developed which has an osmolalitysimilar to iopamidol (20,31.38,53). Tragardh and Lynch(31) compared the effects of ioxaglate. diatrizoate (Reno­grafin-76) and two nonionic compounds during coronaryangiography in animals. Their study demonstrated that bothnoniohic agents were associated with fewer hemodynamicand electrophysiologic changes than the new ionic low os­molality contrast agent. Although osmolality plays an im­portant role in contrast agent toxicity. the study by Tragardhand Lynch (31) suggests that it is not the only factor. Thecation composition and content of the contrast agent alsoappear to be important factors (15,19,20.22,23,46,54-56).lopamidol has negligible amounts of sodium compared with190 mEg/liter in Renografin-76. Renogratin-76 has no cal­cium and iopamidol contains only negligible amounts ofcalcium. Contrast agents with varying sodium and calciumcontents have been evaluated (15,20.22.23,56). Althoughthe addition of calcium appears to decrease the toxicity, the

lACC Vol. S. No.2 Fehruary I9KS: 250-S

entire cardiodepressant effect of the contrast medium is not eliminated. Further studies are needed to elucidate the mech­anisms for the differences in the toxicity we observed be­tween iopamidol and Renografin-76.

Clinical implications. This study has shown that the incidence of malignant bradyarrhythmias and the severity and duration of hypotension after left ventriculography and coronary angiography is significantly less with iopamidol than with the standard ionic agent. Renogratin-76. The in­cidence of ventricular fibrillation may also be less with iopamidol compared with Renografin-76. Other electrocar­diographic and hemodynamic variables measured in this study indicate that iopamidol is less toxic to the myocar­dium. Therefore. this nonionic agent appears to increase the safety of cardiac angiography. In addition. the discomfort experienced by the patient was considerably less with io­pamidol compared with the ionic agent. The cineangio­graphic quality of the two contrast agents was similar. In­creasing the safety of cardiac angiography without compromising excellent cineangiographic results makes this new nonionic contrast agent. iopamidol. superior to the standard ionic agents.

The cost of this new nonionic contrast medium will prob­ably be greater than the standard ionic contrast agents. Fur­ther studies are needed to address the cost/benefit ratio of these new agents. Although the costs may preclude their use in all patients undergoing angiography. we believe that patients at high risk. such as those with impending myo­cardial infarction, unstable angina, impaired ventricular function or recurrent ventricular arrhythmias. will benefit greatly through the use of these nonionic agents in cardiac angiography.

We expre" appreciation to Mary Parks and Lucinda Li,ton. RN for tech­nical as,istance in the Cardiac Catheterization Lahoratory. Gunnard Modin. BS ror assi,tance in the stati,tical analy,i, and Patricia Paulson for ,ec­retarial assistance.

References I. Gensini GG. DiGiorgi S. Myocardial toxicity of contrast agen" used

in angiography. Radiology IIJ64JQ:24-34.

2. Coskey RL. Magidson O. Electrocardiographic response to selective coronary arteriography. Br Heart J 1967;29:512-IJ.

3. May tin O. Castillo C. Castellanos A Jr. The genesis of QRS changes produced hy selective coronary arteriography. Circulation 1970AI:247-55.

4. Rahimtoola SH. Gau GT. Raphael MJ. Cardiac performance arter diagnm,tic coronary arteriography. Circulation 1970:41537-44.

5. Friesinger C;c, Schaffer J. eriley JM. Gaertner RA. Rms RS. Hemo­dynamic consequence, of the injection of radiopaque material. Cir­culation 1'>6531 :730-40.

b. Brown R. Rahimtoola SH. Davis GD. Swan HJC. The effect of an­giocardiographic contrast medium on circulatory dynami" in man: cardiac output during angiocardiography. Circulation 196):31 :2J4-40.

7. Gootman N. Rudolph AM. Buckley NM. ElTech of angi0t'raphic contrast media on cardiac function. Am J Cardiol I <J70:25:5IJ-fl5.

GERTZ lOT AL. 257 NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

X. Brundage BH. Cheitlin MD. Ventricular function curves from the cardiac response to angiographic contra,t: a sensitive detector of ven­tricular dysfunction in coronary artery disease. Am Heart J 1974:XX:2XI-X.

9. Hamhy RI. Aintahlian A. WisolT BG. Hartstein ML. Effects of con­trast medium on lert ventricular pressure and volume with emphasi, on coronary artery di,ease. Am Heart J 1977:IJ3:9-IX.

10. Fi,cher HW. ThOlmon KR. Contrast media in coronary arteriography: a review. Inve,t Radiol 197X: 13:450-9.

I I. Lindgren P. Hemodynamic responses to contrast media. Inve,t Radiol 1970:5:424-35.

12. Fi"her HW. Hemodynamic reaction, to ant'iographic media. Ra­diolot'y I%X:91:bb-73.

13. Klmter FE. Bri,tow JD. Jacohs WR. Porter GA. Griswold HE. Hemo­dynamic elTech of angiocardiography. Invest Radiol 1966: I :39X-406.

14. Karliner JS. Bouchard RJ. Gault JH. Haemodynamic effects of an­t'iographic contrast material in man: a heat-hy-heat analysis. Br Heart J 1972:34:347-55.

15. Higt'ins CB. EITeds of contrast materials on Iert ventricular function. Invest Radiol 19XO: 15:S220-31.

lb. Bassan M. Ganz W. Marcus HS. Swan HJC. The effect of intracor­onary injection of contrast medium upon coronary blood flow. Cir­culation 1975;51 :442-5.

17. Wisneski lA. Gertz EW. Neese R. et al. Myocardial metaholic al­terations after contrast angiography. Am J Cardiol 19X2:50:239-45.

IX. Visioli O. Bongrani S. Cu(Chini F. DiDonato M. Ferrari R. Myo­cardial lactic acid halance after left ventriculography. Eur J Cardiol 19XO: 11.357-65.

19. Popio KA. Ross AM. Oravec JM, Ingram JT. Identification and de­scription of separate mechanisms for two components of Renografin cardiotoxicity. Circulation 1978;58:520-8.

20. I)euhch AL. Gerher KH. Haigler FH. Higgins CB. Effects of low osmolality contrast materials on coronary hemodynamics. myocardial function. and coronary silll" o,molality in normal and ischemic statcs. Invest Radiol 19X2:17:2X4-91.

21. Higgins CB. Schmidt W. Alterations in calcium levels of coronary sinus hlood during coronary arteriography in the dog. Circulation 1')7X:58:512-IJ.

22. Tragardh B. Heckman lL. Lym:h PRo Coronary arteriography in ca­nines with calcium-enriched ioxaglate and diatrimate. Invest Radiol 1982:17:66-9.

23. Trat'anlh B. Lynch PRo Vinciguerra T. Cardia, function during coro­nary arteriography with calcium enriched diatriwate and metril.amide. Invest Radiol 197b: II :569-76.

24. Lohr L. Reidmeister JC. Popitz G. Otto H, Timmermann J. Myo­cardial response to contrast media: effect, on electrolyte metaholi,m and suhcellular structures. Invest Radiol 1'J77; 12: 135-41.

25. Lipton MJ. Higgins CB. Wiley AA. Angell WW. Barry WHo The effect of contrast media on the isolated perfused canine heart. Invest Radiol 1978:13:519-22.

2b. Refsum H. Passwal M. Arrhythmogenic and cardiodepressivc effects of contra,t media on isolateu rat atria. Invest Radiol I97X; 13:444-9.

27. Konnano M. Frey H. Toxicity of x-ray contra,t media in cell culture,. Invest Radiol 19XO:15:6X--71.

2X. Tragardh B. Bove AA. Lynch PRo Cardiac conduction ahnormalities during coronary arteriography in dol!': reduced effects of a new con­trast medium. Invest Radiol 1974;9:340-5.

29. Tragardh B. Lynch PRo ITCJ changes and arrhythmias induced hy ionic and non-ionic contrast media during coronary arteriography in dog, Invest Radiol 1978: 1.l:233-7.

30. Tragardh B. Lynch PRo Vinciguerra T. Effects of metrizamide. a new non ionic conlra:-.l mediulll. on cardiac function during coronary an­giography in the dog. Radiology 1975:115:59-62.

31. Tragardh B. Lynch PRo Cardiac function during left coronary artc-

lACC Vol. 5. No.2Fehruary 19K5: 250-S

GERTZ lOT AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

257

entire cardiodepressant effect of the contrast medium is noteliminated. Further studies are needed to elucidate the mech­anisms for the differences in the toxicity we observed be­tween iopamidol and Renogratin-76.

Clinical implications. This study has shown that theincidence of malignant bradyarrhythmias and the severityand duration of hypotension after left ventriculography andcoronary angiography is significantly less with iopamidolthan with the standard ionic agent. Renografin-76. The in­cidence of ventricular fibrillation may also be less withiopamidol compared with Renografin-76. Other electrocar­diographic and hemodynamic variables measured in thisstudy indicate that iopamidol is less toxic to the myocar­dium. Therefore, this nonionic agent appears to increase thesafety of cardiac angiography. in addition. the discomfortexperienced by the patient was considerably less with io­pamidol compared with the ionic agent. The cineangio­graphic quality of the two contrast agents was similar. in­creasing the safety of cardiac angiography withoutcompromising excellent cineangiographic results makes thisnew nonionic contrast agent. iopamidoL superior to thestandard ionic agents.

The cost of this new nonionic contrast medium will prob­ably be greater than the standard ionic contrast agents. Fur­ther studies are needed to address the cost/benefit ratio ofthese new agents. Although the costs may preclude theiruse in all patients undergoing angiography. we believe thatpatients at high risk, such as those with impending myo­cardial infarction, unstable angina, impaired ventricularfunction or recurrent ventricular arrhythmias, will benefitgreatly through the use of these nonionic agents in cardiacangiography.

We express appreciation to Mary Parks and Lucinda Liston. RN for tech­nical assistance in the Cardiac Catheterization Lahoratory. Gunnard Modin.HS for assistance in the statistical analysis and Patricia Paulson for sec­retarial assistance.

ReferencesI. Gensini GG. DiGiorgi S. Myocardial toxicity of contrast agents used

in angiography. Radiology IlJ64JQ:24-34.

2. Coskey RL. Magidson O. Electrocardiographic response to selectivecoronary arteriography. Br Heart J 1967:29:512-lJ.

3. Maytin O. Castillo C. Castellanos A Jr. The genesis of QRS changesproduced hy selective coronary arteriography. Circulation1970AI:247-55.

4. Rahimtoola SH. Gau GT. Raphael MJ. Cardiac pcrformance anerdiagnostic coronary arteriography. Circulation 1970:415.\7-44.

5. Friesinger GC, Schaffcr J. Crilcy JM. Gaertner RA. Ross RS. Hemo­dynamic consequences of the injection of radiopaque material. Cir­culation 1'>65:31 :730-40.

6. Brown R. Rahimtoola SH. Davis GD. Swan HJC. The effect of an­giocardiographic contrast medium on circulatory dynamics in man:cardiac output during angiocardiography. Circulation 1%5:31 :2.'4-40.

7. Gootman N. Rudolph AM. Huckley NM. Effects of angiographiccontrast media on cardiac function. Am J Cardiol 1lJ70:25:5lJ-1l5

X. Hrundage BH. Cheitlin MD. Ventricular function curves from thecardiac response to angiographic contrast: a sensitive detector of ven­tricular dysfunction in coronary artery disease. Am Heart J1974:XX:2XI-X.

9. Hamhy RI. Aintahlian A. WisolT BG. Hartstein ML. Effects of con­trast medium on len ventricular pressure and volume with emphasison coronary artery disease. Am Heart J 1977:lJ3:9-IX.

10. Fischer HW. Thomson KR. Contrast media in coronary arteriography:a review. Invest Radiol 197X: 13:450-9.

I I. Lindgren P. Hemodynamic responses to contrast media. Invest Radiol1970:5 :424-35.

12. Fischer HW. Hemodynamic reactions to angiographie media. Ra­diology I%X:91:66-73.

13. Kloster FE. Bristow JD. Jacohs WR. Porter GA. Griswold HE. Hemo­dynamic elTccts of angiocardiography. Invest Radiol 1966: I:39X-406.

14. Karliner JS. Bouchard RJ. Gault JH. Haemodynamie effects of an­giographic contrast material in man: a heat-hy-heat analysis. Br HeartJ 1972:34:347-55.

15. Higgins CB. Effects of contrast materials on Icn ventricular function.Invest Radiol IlJXO: 15:S220·31.

16. Bassan M. Ganz W. Marcus HS. Swan HJC. The effect of intracor­onary injection of contrast medium upon coronary blood flow. Cir­culation 1lJ75:51 :442-5.

17. Wisneski JA. Gertz EW. Neese R. et al. Myocardial metaholie al­terations after contrast angiography. Am J Cardiol 19X2:50:239-45.

IX. Visioli O. Hongrani S. Cucchini F. DiDonato M. Ferrari R. Myo­cardial lactic acid halance after left ventriculography. Eur J CardiolIlJXO: I 1.357-65.

19. Popio KA. Ross AM. Oravec JM. Ingram JT. Identification and de­scription of separate mechanisms for two components of Renografincardiotoxicity. Circulation 1978:58:520-8.

20. Deutsch AL. Gerher KH. Haigler FH. Higgins CB. Effects of lowosmolality contrast materials on coronary hemodynamics. myocardialfunction. and coronary sinus osmolality in normal and ischemic states.Invest Radiol 19X2:17:2X4-91.

21. Higgins CB. Schmidt W. Alterations in calcium levels of coronarysinus hlood during coronary arteriography in the dog. Circulation1'!7X:5X:512-lJ.

22. Tragardh B. Heckman JL. Lynch PRo Coronary arteriography in ca­nines with calcium-enriched ioxaglate and diatriwate. Invest Radiol19X2:17:66-9.

23. Tragardh B. Lynch PRo Vinciguerra T. Cardiac: function during coro­nary arteriography with calcium enriched diatriwate and metrizamide.Invest Radiol 1976: II :569-76.

24. Lohr L. Reidmeister JC. Popitz G. Otto H. Timmermann J. Myo­cardial response to contrast media: effects on electrolyte metaholismand suhcellular structures. Invest Radiol 1'177: 12: 135-41.

25. Lipton MJ. Higgins CB. Wilcy AA. Angell WW. Barry WHo Theeffect of contrast media on the isolated perfused canine heart. InvestRadiol 1'!7X:I3:519-22

26. Refsum H. Passwal M. Arrhythmogenic and cardiodepressive effectsof contrast media on isolated rat atria. Invest Radiol 1lJ78: 13:444-9.

27. Kormano M. Prey H. Toxicity of x-ray contrast media in cell cultures.Invest Radiol 19XO:15:6X--71.

2X. Tragardh B. Bove AA. Lynch PRo Cardiac conduction ahnormalitiesduring coronary arteriography in dogs: reduced effects of a new con­trast medium. Invest Radiol 1974:9:340-5.

29. Tragardh B. Lynch PRo ITG changes and arrhythmias induced hyionic and non-ionic contrast media during coronary arteriography indogs Invest Radiol 197X: 13:233-7.

30. Tragardh B. Lync:h PRo Vinciguerra T. Effects of metrizamide. a newnon ionic conlrast mediulll. on cardiac function during coronary an­giography in the dog. Radiology 1975:115:5<)-62.

31. Tragardh B. Lynch I'R. Cardiac function during left coronary arte-

258 GERTZ ET AL. NON IONIC CONTRAST CARDIAC ANGIOGRAPHY

riography in canines with ioxaglate. nonionic compounds. and dia­trizoate. Invest Radiol 1980;15:449-51.

32. Enge I, Nitter-Hauge S. Andrew E. Levorstad K. Amipaque: a new contrast medium in coronary angiography. Radiology 1977: 125:317-22.

33. Gerber KH, Higgins CB, Yuh YS, Koziol lA. Regional myocardial hemodynamic and metabolic effects of ionic and non ionic contrast media in normal and ischemic states. Circulation 1982:65: 1307-14.

34. Mancini GB1, Bloomquist IN. Bhargava V, et a!. Hemodynamic and e1ectrocar~iographic effects in man of a new nonionic contrast agent (Iohexol): advantages over standard ionic agents. Am 1 Cardiol 1983:51: 1218-22.

35. Higgins CB. Sovak M. Schmidt WS. Kelley Ml, Newell 10. Direct myocardial effects of intracoronary administration of new contrast materials with low osmolality. Invest Radiol 1980:15:39-46.

36. DiDonato M, Bongrani S, Cucchini F. et al. Cardiovascular effects induced by the injection of a new non ionic contrast medium (iopam­idol): experimental study in dogs. Invest Radiol 1979: 14:309-15.

37. Sink lD, Wechsler AS. Pellom GL. Thompson WM. Effect of B-15,000 (iopamidol), a new non ionic contrast agent. on cardiac function of the isolated rat heart. Invest Radiol 1979: 14:508-12.

38. Thomson KR, Evill CA, Fritzsche 1, Benness GT. Comparison of iopamidol, ioxaglate, and diatrizoate during coronary arteriography in dogs. Invest Radiol 1980;15:234-41.

39. PaJ1ridge lB. Robinson P1. Turnbull CM, Stoker lB, Boyle RM. Morrison GW. Clinical cardiovascular experiences with iopamidol: a new non-ionic contrast medium. Clin Radiol 1981:32:451-5.

40. Mancini GB1, Atwood lE, Bhargava V, Slutsky RA. Grover M. Higgins CB. Comparative effects of ionic and non ionic contrast ma­terials on indexes of isovolumic contradion and relaxation in humans. Am 1 Cardiol 1984:53:228-33.

41. Kennedy lW. Baxley WA, Figley MM. Dodge HT. Blackmon lR. Quantitative angiocardiography. I. The normal left ventricle in man. Circulation 1966:34:272-8.

42. Dixon Wl. ed. BMDP Statistics Software. Berkeley: University of Calili)rnia Press, 1981 :359-86.

43. Adams DF, Fraser DB. Abrams HL. The complications of coronary aJ1eriography. Circulation 1973:48:609-18.

44. Adams OF. Abrams HL. Complications of coronary arteriography: a follow-up repOJ1. Cardiovasc Radiol 1 <J79:2:89-96.

lACC Vol. 5. No.2 February 1985:250--8

45. Gwost 1. Stoebe T, Chesler E. Weir EK. Analysis of the complications of cardiac catheterization over nine years. Cathet Cardiovasc Diagn 1982:8: 1 3-21.

46. Wolf GL, Hirshfeld lW lr. Changes in QTc interval induced with Renografin-76 and Hypaque-76 during coronary arteriography. 1 Am Coli Cardiol 1983; I: 1489-92.

47. lervell A, Lange NF. Congenital deaf-mutism, functional heaJ1 disease with prolongation of QT interval, and sudden death. Am Heart 1 1957;54:59-68.

48. Levine SA, Woodworth CR. Congenital deaf-mutism, prolonged QT interval, syncopal attacks, and sudden death. N Engl 1 Med 1958;259:412-7.

49. DiSegni E. Klein HO. David D. Libhaber e. Kaplinsky E. Overdrive pacing in quinidine syncope and other long QT-interval syndromes. Arch Intern Med 1980: 140: 1036-40.

50. Franz R. Gottlieb SO. Brinker lA. Renografin-76 but not iopamidol produces marked local prolongation of canine monophasic action po­tential duration (abstr). Circulation 1983:68(suppl 1l1):11l-350.

51. Gem EW, Wisneski lA, Neese R, Silverstein D, Akin lR, Morris DL. The effects of iopamidol on myocardial metabolism: a comparison with Renografin-76. Invest Radiol 1984; 19:5 191-6.

52. Wisneski lA. Gertz EW. Neese R. Non-ionic contrast agents do not induce biochemical ischemia during cardiac angiography (abstr). 1 Am Coli Cardiol 1984:3:598.

53. Hirshfeld lW lr. Laskey W. Martin JL. Groh We. Untereker W, Wolf GL. Hemodynamic changes induced by cardiac angiography with iox­aglate: comparison with diatrizoate. 1 Am Coli Cardiol 1983;2:954-7.

54. Wolf GL, LeVeen RF, Malry C, Kilzer K. The influence of contrast media additives upon ventricular fibrillation thresholds during coro­nary angiography in ischemic and normal canine heaJ1s. Cardiovasc Intervent Radiol 1981 ;4: 145-7.

55. Wolpers HG, Baller 0, Ensink FBM, Schroter W, Zipfel 1, Hellige G. Influence of aJ1eriographic contrast media on the Na + ICa + + -ratio in blood. Cardiovasc Intervent Radiol 1981;4:8-13.

56. Hildner Fl. Scherlag B. Samet P. Evaluation of Renografin M-76 as a contrast agent lilr angiocardiography. Radiology 1971: I 00:329-34.

258 GERTZ ET AL.NONIONIC CONTRAST CARDIAC ANGIOGRAPHY

JACC Vol. 5. No.2February 1985:250--8

riography in canines with ioxaglate. nonionic compounds. and dia­trizoate. Invest Radiol 1980;15:449-51.

32. Enge I. Nitter-Hauge S. Andrew E. Levorstad K. Amipaque: a newcontrast medium in coronary angiography. Radiology 1977:125:317-22.

33. Gerber KH, Higgins CB, Yuh YS, Koziol lA. Regional myocardialhemodynamic and metabolic effects of ionic and non ionic contrastmedia in normal and ischemic states. Circulation 1982:65: 1307-14.

34. Mancini GB1. Bloomquist IN. Bhargava V. et al. Hemodynamic ande1ectrocar~iographic effects in man of a new nonionic contrast agent(Iohexol): advantages over standard ionic agents. Am 1 Cardiol1983;51: 1218-22.

35. Higgins CB. Sovak M. Schmidt WS. Kelley Ml. Newell 10. Directmyocardial effects of intracoronary administration of new contrastmaterials with low osmolality. Invest Radiol 1980:15:39-46.

36. DiDonato M. Bongrani S. Cucchini F. et al. Cardiovascular effectsinduced by the injection of a new nonionic contrast medium (iopam­idol): experimental study in dogs. Invest Radiol 1979;14:309-15.

37. Sink lD. Wechsler AS. Pellom GL. Thompson WM. Effect of B­15.000 (iopamidol), a new non ionic contrast agent. on cardiac functionof the isolated rat heart. Invest Radiol 1979; 14:508-12.

38. Thomson KR, Evill CA, Fritzsche 1, Benness GT. Comparison ofiopamidol, ioxaglate, and diatrizoate during coronary arteriography indogs. Invest Radiol 1980;15:234-41.

39. PaJ1ridge lB. Robinson P1. Turnbull CM. Stoker JB. Boyle RM.Morrison GW. Clinical cardiovascular experiences with iopamidol: anew non-ionic contrast medium. Clin Radiol 1981:32:451-5.

40. Mancini GB1. Atwood lE. Bhargava V. Slutsky RA. Grover M.Higgins CB. Comparative effects of ionic and nonionic contrast ma­terials on indexes of isovolumic contraction and relaxation in humans.Am 1 Cardiol 1984:53:228-33.

41. Kennedy lW. Baxley WA. Figley MM. Dodge HT. Blackmon lR.Quantitative angiocardiography. I. The normal left ventriclc in man.Circulation 1966;34:272-8.

42. Dixon Wl. ed. BMDP Statistics Software. Berkeley: University ofCalifi)rnia Press. 1981 :359-86.

43. Adams DF. Fraser DB. Abrams HL. The complications of coronaryaJ1eriography. Circulation 1973:48:609-18.

44. Adams OF. Abrams HL. Complications of coronary arteriography: ali)lIow-up repOJ1. Cardiovasc Radiol 1'J79:2:89-96.

45. Gwost 1. Stoebe T. Chesler E. Weir EK. Analysis of the complicationsof cardiac catheterization over nine years. Cathet Cardiovasc Diagn1982:8: I3-21.

46. Wolf GL, Hirshfeld JW Jr. Changes in QTc interval induced withRenografin-76 and Hypaque-76 during coronary arteriography. 1 AmColi Cardiol 1983; I: 1489-92.

47. lervell A, Lange NF. Congenital deaf-mutism, functional heaJ1 diseasewith prolongation of QT interval, and sudden death. Am Heart 11957;54:59-68.

48. Levine SA, Woodworth CR. Congenital deaf-mutism, prolonged QTinterval, syncopal attacks, and sudden death. N Engl 1 Med1958;259:412-7.

49. DiSegni E. Klein HO. David 0, Libhaber e. Kaplinsky E. Overdrivepacing in quinidine syncope and other long QT-interval syndromes.Arch Intern Med 1980: 140: 1036-40.

50. Franz R. Gottlieb SO. Brinker JA. Renogratin-76 but not iopamidolproduces marked local prolongation of canine monophasic action po­tential duration (abstr). Circulation 1983:68(suppl 111):111-350.

51. GeJ1Z EW, Wisneski JA, Neese R, Silverstein D, Akin JR, MorrisDL. The effects of iopamidol on myocardial metabolism: a comparisonwith Renogratin-76. Invest Radiol 1984; 19:5 191-6.

52. Wisneski JA. Gertz EW. Neese R. Non-ionic contrast agents do notinduce biochcmical ischemia during cardiac angiography (abstr). J AmColi Cardiol 1984:3:598.

53. Hirshfeld JW Jr. Laskey W. Martin JL, Groh We. Untereker W. WolfGL. Hemodynamic changes induccd by cardiac angiography with iox­aglate: comparison with diatrizoate. J Am Coli Cardiol 1983;2:954-7.

54. Wolf GL, LeVeen RF, Malry C, Kilzer K. The influence of contrastmedia additives upon ventricular fibrillation thresholds during coro­nary angiography in ischemic and normal canine heaJ1s. CardiovascIntervent Radiol 1981 ;4: 145-7.

55. Wolpers HG, Baller 0, Ensink FBM, Schroter W, Zipfel J, HelligeG. Influence of aJ1eriographic contrast media on the Na + ICa + + -ratioin blood. Cardiovasc Intervent Radiol 1981;4:8-13.

56. Hildner FJ. Scherlag B. Samct P. Evaluation of Renogratin M-76 asa contrast agent lilr angiocardiography. Radiology 1971: 100:329-34.