Nickel Concentrations in Serum of Patients with Acute Myocardial Infarctionor Unstable Angina PectorisCharles N. Leach Jr.,1 Jeanne V. Linden,2 SidneySunderman Jr.23

M. Kopfer,2 M. Cristina Crisostomo,2 and F. William

CLIN.CHEM.31/4, 556-560 (1985)

556 CLINICALCHEMISTRY,Vol. 31, No. 4, 1985

Nickel was measured, by electrothermalatomic absorptionspectrophotometry, in sera from (a) 30 healthyadults,(b) 54patientswith acute myocardialinfarction,(C) 33 patientswithunstable angina pectoris without infarction, and (c fivepatientswith coronaryatherosclerosiswho developedcardi-ac ischemiaduringtreadmillexercise. Mean (and SD) con-centrationsin Group a were 0.3 (0.3) IL (range <0.05-1.1.zgJL).Within 72 h after hospitaladmission,hypemickelemia(Ni 1 .2 IL) was foundin41 patientsof groupb (76%) andin 16 patientsof group c (48%). Hypemickelemiawas foundbefore and after exercise in one patient of Group d (20%).Peak values averaged 3.0 i.zg/L (range 0.4-21 /L) inGroup b, 1.5 1.g/L (range <0.05-3.3 igJL) in Group c. InGroupb, the mean time intervalbetweenthe peak valuesforcreatinekinaseactivityand for nickelwas 18 h. Serum nickelconcentrations were unrelated to age, sex, time of day,cigarette smoking, medications, clinical complications, oroutcome. Mechanisms and sources of release of nickel intothe serum of patients with acute myocardial infarction orunstable angina pectoris are conjectural, but hypemickele-mia may be related to the pathogenesis of ischemic myocar-dial injury.

Additional Keyphrases: myocardial ischemia trace elementselectrothermalatomic absorptionspectrophotometry- refer-

ence interval

D’Alonzo and Pell (1) observed increased nickel concen-trations in sera from 19 of 20 patients with acute myocardialinfarction, sampled within 24 h after admission to thehospital; Sunderman et al. (2, 3) reported increased nickelconcentrations in serum of 25 of 35 patients with acutemyocardial infarction, sampled 12 to 36 h after onset ofsymptoms. Such frequent occurrence of hypernickelemiaafter acute myocardial infarction has been confirmed byinvestigators in England (4), Germany (5), the USSR (6),and Pakistan (7). McNeely et al. (8) showed that hypernick-elemia is not specific for myocardial infarction, becausenickel concentrations in serum are also increased in pa-tients with cerebral stroke and thermal burns, as well as insome patients with myocardial ischemia without infarction.

During the decades since the initial studies of serumnickel concentrations in patients with myocardial infarc-tion, the accuracy and precision of analyses for nickel inbody fluids have gradually been improved and the detectionlimits for nickel have steadily declined (9-11). It is nowfeasible to measure serum nickel concentrations in 1-mL

‘Department of Medicine, New Britain General Hospital, NewBritain, CT 06050.

2Department of Laboratory Medicine, University of ConnecticutMedical School, Farmington, CT 06032.

3To whom reprint requests should be addressed.Preliminary results of this study were presented at the Third mt.

Conf. on Nickel Metabolism and Toxicology, Paris, France, Septem-ber 4-7, 1984.

Received January 24, 1985; accepted January 29, 1985.

samples (12), as compared with 10-mL samples in 1970 (2).The techniques for collecting specimens and avoiding nickelcontamination during sample processing have also beensubstantially refined (9-12). As a consequence, referencevalues for nickel concentrations in sera of healthy personshave diminished from 2.6 (SD 0.8) .tg/L in 1970 (2) to 0.46(SD 0.26) ig/L in 1984 (12).

The principal goal of the present study was to reinvesti-gate the incidence, magnitude, and time-course of hyper-nickelemia in patients with acute myocardial infarction,with application of stringent clinical criteria, up-to-dateanalytical instrumentation, and utmost precautions to mini-mize contamination of samples with nickel. Additionalpopulations for this study included (a) healthy adult resi-dents of central Connecticut, (b) patients with unstableangina pectoris who were admitted to the cardiovascularintensive care unit, but who did not subsequently developelectrocardiographic or biochemical signs of acute myocardi-al infarction, and (c) patients with coronary atherosclerosis,who were tested before and after strenuous exercise on atreadmill.

Protocol and MethodsThe protocol for this study was approved by the Human

Experimentation Committees of the New Britain GeneralHospital and the University of Connecticut Health Center;each participant gave infonned consent in writing.

Blood specimens were collected with polyethylene intra-vascular cannulae, polypropylene syringes, and polyethyl-ene test tubes, with precautions to avoid contamination withnickel (10,12). Nickel-free heparin from bovine lung (SigmaChemical Co., St. Louis, MO 63178) was used as theanticoagulant for whole-blood specimens. Nickel concentra-tions in serum and whole blood were analyzed in duplicateby electrothermal atomic absorption spectrophotometry, asdescribed by Sunderman et al. (12), in a Model 5000spectrometer with automatic sampler, pyrolytic graphitetubes, and Zeeman background correction system (Perkin-Elmer Corp., Norwalk, CT 06856). The detection limit fornickel was 0.05 g/L; coefficients of variation for replicatenickel analyses averaged 3.8% (within-run) and 8.1% (day-to-day); analytical recovery of nickel, added to 16 sera togive a concentration of 8 pg/L, averaged 97% (SD ± 3%);analytical recovery of nickel similarly added to 13 samplesof whole blood averaged 103% (SD ±6%). Nickel concentra-tions in 30 sera, measured by the method of Sunderman etal. (12), did not differ significantly (r = 0.980) from resultsobtained by the IUPAC Reference Method (10). Nickel wasmeasured in urine specimens by electrothermal atomicabsorption spectrophotometry, after acid digestion, chela-tion, and solvent extraction, all according to the IUPACReference Method (10).

The healthy control subjects were 30 asymptomatic adultresidents of central Connecticut (15 men, 15 women, ages 23to 84 years), who were not receiving medications, includingoral contraceptives, and who gave no history of heart disease

To determine whether delay in serum separation from theblood might affect nickel concentrations in serum speci-mens, we collected four tubes of blood from each of fivehealthy subjects. The tubes were placed in a refrigerator(10 #{176}C),and one tube from each subject was centrifuged forserum separation at 1, 4, 8, and 20 h, respectively, aftervenepuncture. As indicated in Table 1, there were nosignificant changes from the initial values for serum nickelconcentrations by paired-sample t-test, indicating that bloodspecimens could be stored at 10 #{176}Cfor as long#{225}a20h beforeremoval of serum. This finding made it feasible to collectblood specimens for serum nickel analysis from patients inthe cardiovascular intensive-care unit during the nightwork-shifts.

To determine whether diurnal or post-prandial fluctua-tions of nickel metabolism might be confounding factors inthis study, we obtained nine specimens of serum and timedcollections of urine from two healthy subjects during a 36-hperiod. As shown in Table 2, there were no significantdiurnal or post-prandial variations of serum nickel concen-trations. We noted considerable fluctuation in the urinaryexcretion of nickel, but saw no clear-cut circadian pattern.

Table 1. Effect of Delay in Serum Separation onNickel Concentrations in Sera from Healthy

AdultsSsrum NI concn, ig/L

or occupational exposure to nickel. Specimens of serum andheparinized whole blood were obtained from these (nonfast-ing) subjects at various times during the working hours. Totest for circadian variations of nickel concentrations, speci-mens of serum and urine were collected from two healthycontrols on nine occasions during a 36-h period. To test forexercise-induced fluctuations of nickel concentrations, serawere obtained from seven healthy controls (four men, threewomen) before, immediately after, and 3 h after an 8-kmcross-country run, and from two healthy controls before andimmediately after maximal exertion for 15 mm on a tread-mill.

The patients included 87 adult residents of central Con-necticut (58 men, 29 women, ages 30 to 89 years), who wereadmitted to the cardiovascular intensive-care unit at NewBritain General Hospital with the provisional diagnosis ofsuspected myocardial infarction. Three to six blood speci-mens were collected for nickel analysis within 72 h ofadmission, including two or three specimens during the firsthospital day. In selected cases, blood sampling was contin-ued for five to seven days.

The first tube of blood, which was collected through thepolyethylene intravenous cannula, was used for routinediagnostic tests, including analyses for serum creatine ki-nase (CK; EC 2.7.3.2) activity and fractionations of CKisoenzymes (13, 14). The second tube of blood was used foranalysis for serum nickel; when feasible, a third tube wascollected for analysis for nickel in heparinized whole blood.The tubes of blood for nickel analysis were placed in acid-washed plastic containers and refrigerated (10 #{176}C)until theywere transported to the Trace-Metal Laboratory at theUniversity of Connecticut. Sera were separated by centrifu-gation in hermetically sealed, acid-washed trunnion cups, aspreviously described (12).

At the conclusion of the study, two of us (C.N.L., Jr., andJ.V.L.) reviewed the hospital charts of the 87 patients. Fifty-four of the patients (40 men, 14 women, ages 30 to 89 years)were diagnosed as having acute myocardial infarction,based upon at least two of the following three criteria: (a)severe, prolonged chest pain with typical clinical course, (b)development of new Q waves in the electrocardiogram (ortall R waves in the right precordial leads, in cases ofposterior wall infarction), and (c) characteristic temporalpattern of increased CK activity in serum, with an increasedproportion of the CK-MB isoenzyme. Thirty-three of thepatients (18 men, 15 women, ages 30 to 86 years) werediagnosed as having unstable angina pectons (acute myo-cardial ischemia without infarction) on the basis of severechest pain, with or without electrocardiographic changes;patients with new Q waves or their equivalent were notincluded in this group. The patients who were diagnosed ashaving unstable angina pectoris did not develop increasedserum CK activity or increased proportion of the CK-MBisoenzyme.

Five additional patients (men, ages 42 to 73 years) whohad unequivocal angiographic evidence of coronary athero-sclerosis were studied to determine the effects of exercise-induced cardiac ischemia on serum nickel concentrations.Sera for nickel analysis were obtained before and immedi-ately after an exercise tolerance test. These patients alldeveloped cardiac ischemia during maximal exertion on thetreadmill, as manifested by angina pectoria or electrocardio-graphic abnormalities, or both.

Statistical computations, including standard deviation,Student’s paired and non-paired t-test, the chi-square test,sign test, Mann-Whitney U test, linear regression, andcorrelation coefficient were performed as described by Gold-stein (15).

Subject

ABCDE

Mean (SD):

lii 4h 8h 20h

0.60.40.40.40.5

0.46 (0.09)

0.40.50.30.40.4

0.40 (0.07)

0.70.20.30.40.2

0.36 (0.21)

0.60.30.50.40.5

0.46 (0.11)‘Four blood specimensfromeach subject were storedat 10#{176}C.The tubes

were centrifuged and sera were separated at the specified intervals aftervenepuncture.No significantchanges from the Initialvalues were found by thepaired-samplet-testorthe sign test.

Table 2. Search for Clrcadian Variations of NickelMetabolism in Two Healthy Adults

Timeofday

Subject A’20:0000:0005:0009:0014:3016:0020:3023:3008:00

Mean (SD):

SubjectB#{176}20:0000:0005:0009:0014:3016:0020:3023:30

08:00Mean (SD):

Serum NIconcn,

UrInary NI concentration or excretion

P019pg/L 1ig/L creatlnlne pg/h

0.6 1.6 4,5 0.130.5 4.0 2.9 0.230.6 6.7 3.3 0.170.3 4.6 3.3 0.240.3 3.4 2.5 0.320.4 1.8 1.9 0.310.3 1.9 2.0 0.070.4 1.9 1.7 0.080.1 3.1 2.3 0.41

0.4 (0.2) 3.2 (1.7) 2.7 (0.9) 0.22 (0.11)

0.3 1.1 1.1 0.030.3 1.1 1.3 0.070.6 2.7 2.1 0.090.4 2.8 2.0 0.090.7 0.9 2.0 0.020.3 2.0 1.3 0.180.5 1.3 0.8 0.050.2 1.3 0.8 0.020.4 1.4 0.8 0.07

0.4 (0.2) 1.6 (0.7) 1.4 (0.5) 0.07 (0.05)‘Male, 45 years old. bFemale, 47 years old.

Results

CLINICALCHEMISTRY,Vol. 31, No. 4, 1985 557

Mean NI concn, .ug/L (and SD)

Men

Women

All subjects

No.subjects

87

105

30

Serum

0.24 (0.22)0.23 (0.20)0.29 (0.19)0.41 (0.40)0.28 (0.24)

Whole blood

0.20 (0.13)0.31 (0.26)0.48 (0.39)0.32 (0.16)0.34 (0.28)

-J

#{149}

20

- azE 0

U,U)

Ag. 1. Biphasic peaks of serum Ni concentrations in two patients withacute myocardial infarctionThese patients both had single peaks of serum creatine kinase activity(Panel A:E.B.,female,45 yr; Panel B: A.L, male,61 yr)

Days after admission

Table 4. Serum Nickel Concentrations in Patients with Acute Myocardlal Infarction or Unstable AnginaPectoris

Serum NI concn, pg/L

213331434054

212120181633

‘p <0.01 vs healthy controls (Table 3) by Mann-Whitney U test or chi-square test.

558 CLINICALCHEMISTRY,Vol. 31, No. 4, 1985

Nickel concentrations in specimens of serum and wholeblood from 30 healthy adults averaged 0.3 pg/L (SD 0.3,range <0.05-t.1 gfL). No significant influences of age orsex on serum nickel concentrations were noted (Table 3).The concentrations of nickel in whole-blood specimens wereslightly lower than previously reported (12), owing to theavailability of heparin that contained no detectable nickel.Nickel concentrations in sera collected from seven healthysubjects after an 8-km cross-country run, and in sera fromtwo healthy subjects after maximal exertion for 15 miii on atreadmill, did not reveal any significant differences from thecorresponding nickel concentrations in pre-exercise sera,based upon the paired-sample t-test (data not shown). Theserum nickel concentrations in the post-exertion specimenswere within the reference range (<0.05-1.1 zg/L).

In Table 4 we compare serum nickel concentrations inpatients with acute.myocardial infarction with the resultsfor patients with unstable angina pectoris. The peak valuefor serum nickel concentration averaged 3.0 ug/L (SD 3.4,range 0.4 to 21 .&gfL) in patients with acute myocardialinfarction, compared with 1.4 ig/L (SD 0.9, range <0.05 to3.3 g/L) in patients with unstable angina pectoris (p <0.01by the Mann-Whitney U test). During 72 h after admission,hypernickelemia (i.e., serum nickel concentration �1.2tg/L) was observed in 41 of 54 patients (76%) with acutemyocardial infarction as compared with 16 of 33 patients(48%) with unstable angina pectoris (p <0.01 by the chi-square test).

There were clear-cut peaks of serum CK activity, whichgenerally occurred within 6 to 18 h after admission, and ofserum nickel concentration, which generally occurred with-in 12 to 48 hours after admission, in 41 of the patients withacute myocardial infarction. The mean interval between the

Table 3. Nickel Concentrations in Specimens ofSerum and Whole Blood from Healthy Adults

Agerange,

Sex years25-3940-7223-3940-8423-84

Median (andrange) 0.3 (<0.05-1.1) 0.3 (<0.05-1.1)

peak value for serum CK activity and the peak value forserum nickel concentration was 18 h. The nickel concentra-tion in serum was greatest 8 to 48 h after the value forserum CK activity reached its maximum in 30 of the 41patients (73%); the two peak values occurred simultaneous-ly in eight patients (20%); the peak value for serum nickelconcentration occurred 8 to 24 h before the peak value forserum CK activity in three patients (7%). In two patients,biphasic increases of serum nickel concentration were ob-served, although there were only single peaks of serum CKactivity (Figure 1). Both patients experienced recurrentchest pain at rest after the second peak in serum nickel,although their electrocardiograms and serum CK activitiesdid not indicate extensions of the myocardial infarcta. Thebouts of recurrent chest pain were consistent with coronaryvasopasm.

Whole-bloodspecimens were obtained for nickel analysisfrom 16 patients with acute myocardial infarction. Figure 2shows comparisons of nickel concentrations in 50 pairedspecimens of whole blood and serum from these patients,collected during 72 h after admission. Blood hematocritvalues in these patients ranged from 45 to 50%, so theincreased concentrations of nickel in serum were associatedwith little, if any, increases of nickel concentrations inerythrocytes.

Hypernickelemia (�1.2 tgfL) occurred in 20 of 26 patients

96

Diagnosis andtime afteradmission

Acutemyocardialinfarction0- 8h9-16 h

17-24 h25-48 h49-72 h

PeakNi concn:Unstableanginapectoris

0- 8 h9-16 h

17-24 h25-48 h49-72 h

Peak Ni concn:

No.patients Mean (SD)

0.5 ± (0.7)0.9 ± (1.0)’2.8 ± (4.2)’2.0 ± (1.9)’1.6 ± (1.3)’3.0 ± (3.4)’

0.6 ± (0.7)0.9 ± (0.6)a0.9 ± (0.7)’1.1 ± (1.1)’1.0 ± (0.6)a1.4 ± (0.9)’

MOdlan(range)

0.3 (<0.05- 2.8)0.7 (<0.05- 5.5)1.3( 0.2 -21.2)1.6( 0.1 -8.3)1.2 (<0.05- 7.2)2.0 ( 0.4 -21.2)

0.5 (<0.05- 3.1)0.6 (<0.05- 2.0)0.8 (<0.05- 3.0)0.9 (<0.05- 3.3)1.0 (<0.05- 1.8)1.0 (<0.05- 3.3)

ProportIon ofpatients with

serum NI a 1.2pg/L

3/21 (14%)7/33 (21%)’

18/31 (58%)’24/43 (56%)’21/40 (53%)41/54 (76%)8

3/21 (14%)6/21 (29%)’4/20 (20%)’6/18 (33%)’6/16 (38%)’

16/33 (48%)’

3

zV00

01

Y=0:53x+0.21Corr.Coef.= 0.82N=50,p<0.001

.

#{149} S.

#{149}#{149}.3_.-

4,’-..’. S

..tqf

Table 5. Follow-up Measurements of Serum NiConcentrations in PatIents with Myocardial

InfarctionSerum NI canon, pg/I

.

0

Subject (age Peek valueIn years and Follow-up, withIn 3 days

sex) months post-Infarction

A(72,d) 1 0.6B(74,) 6 1.8C(67,d) 4 2.0D(74,d) 3 2.3E(41,) 1 3.4F(45,) 3 4.9G(63,d) 2 7.2All subjects: 1-6 3.2 (SD 2.2)3

Value observedat follow-up

0.10.20.20.20.80.70.3

0.36 (SD 0.28)

Dnos

-0.5-1.6-1.8-2.1-2.6-4.2-6.9

-2.8 + 2.1’

‘p <0.02 by paired-sample f-testand sign test.

Table 6. Effect of Exercise-Induced Cardiaclschemia in Five Men with Coronary

AtherosclerosisSerum NI conan, pg/t.

0.20.40.70.31.4

0.6(SD0.5)

0+0.2+0.5

0-2.4

-0.3 (SD 1.1)’

CLINICALCHEMISTRY,Vol. 31, No. 4, 1985 559

2

SerumNi (jigiL)

Fig. 2. Companson of Ni concentrations in 50 pairs of whole-blood andserum specimens collected from 16 patients with acute myocardialInfarction during 72 h afteradmission to thecardiovascular intensive-careunit.

(77%) with acute myocardial infarction who were treatedwith calcium-blocking drugs (nifedipine, diltiazem, or vera-pamil). This incidence did not differ significantly from theoccurrence of hypernickelemia in 21 of 28 patients (75%)with acute myocardial infarction who did not receive calci-um-blocking drugs. Hypernickelemia was observed in two ofthree patients with acute myocardial infarction who werebeing treated with streptokinase. There was no evidencethat hypernickelemia in patients with acute myocardialinfarction or unstable angina pectoris is associated withadministration of any other drug.

Serum nickel concentrations were unrelated to age, sex,race, occupation, time of day, cigarette smoking, hypoten-sion, arrhythmias, congestive heart failure, pulmonary ede-ma, or clinical complications. Hypernickelemia was found intwo of three patients who died within three weeks after anacute myocardial infarction.

Sera from seven patients, collected after their completerecovery from acute myocardial infarction and dischargefrom the hospital, showed normal nickel concentrations oneto six months post-infarction (Table 5).

We analyzed serum sampled from five men with angio-graphic evidence of advanced coronary atherosclerosis, be-fore and immediately after maximal exercise testing on atreadmill. These patients all developed angina pectoris ordiagnostic electrocardiographic abnormalities, or both, dur-ing the exercise tolerance test. One of the patients hadhyperrnckelemia (3.8 ig/L) before exercise; his serum nickelconcentration after exercise was lower, but still abovenormal (1.4 zg/L). In the other four subjects, serum nickelconcentrations were not significantly altered after exercise-induced cardiac ischemia (Table 6).

DiscussionThis study demonstrates that hypernickelemia develops

in three-fourths of patients with acute myocardial infarctionand in approximately half of patients with unstable anginapectoris, based upon analyses by a sensitive, precise, andspecific technique, with precautions to minimize nickelcontamination. Although nickel concentrations in sera fromhealthy control subjects are lower by the present techniquethan were obtained by earlier methods, the post-infarctionincrements in serum nickel concentrations that were ob-served in this study are similar to those reported by Sunder-man et al. (2), Howard (4), Vollkopfet al. (5), Kahn et al. (7),and McNeely et al. (8). Moreover, the time-course of hyper-nickelemia that was observed in this investigation is con-

Subjects Before Afterage, yr exercise exercise

59 0.270 0.273 0.272 0.357 3.8

Allsubjects: 0.9 (SD 1.6)a significantchanges from the pre-exercise values were found by the

paired-sample ftest or the sign test.

sistent with the reports of previous workers (2,4, 5, 7, 8).The present study indicates that therapy with calcium-blocking drugs does not affect the incidence of hypernickele-mia in patients with acute myocardial infarction.

On the basis of measurements of nickel concentrations inhearts from previously healthy subjects who died suddenlyfrom murder or suicide, Sunderman et al. estimated that thenormal human heart contains approximately 1.8 zg ofnickel. Even if nickel were to be completely released fromcardiac tissue after myocardial infarction and if the releasednickel were distributed solely within a serum volume of 2.5L, the resulting increase in serum nickel concentrationwould be only 0.7 .tg/L. Therefore, Sunderman et al. (3)suggested that hypernickelemia in patients with acutemyocardial infarction is unlikely to be caused by post-necrotic release of the nickel that normally is present in theheart. This deduction is strengthened by the present study,because we often observed hypernickelemia in patients withunstable angina pectoris, without electrocardiographic orbiochemical evidence of myocardial injury or necrosis.

We consider three hypotheses to explain the source andmechanism of hypernickelemia in patients with acute myo-cardial infarction or unstable angina pectoris:

First, the myocardiuni or coronary arteries of patientswith atherosclerotic heart disease (a) may contain abnor-mally increased concentrations of nickel and (b) whenstunned by ischemia, may release nickel into the circula-tion. Part a of this hypothesis is being tested by analyses fornickel in cardiac tissue samples obtained post-mortem frompatients with coronary atherosclerosis. Contrary to part b ofthis hypothesis, patients with coronary atherosclerosisfailed to develop hypernickelemia following exercise-in-duced myocardial ischemia.

Second, hypernickelemia may be a secondary phenome-non, mediated by release of nickel from another organ, in

560 CLINICALCHEMISTRY, Vol.31, No. 4, 1985

response to stress, hypotension, congestive heart failure, orpulmonary edema. The lung would be a likely source ofnickel, because human lung tissue accumulates nickel withadvancing age (11). However, correlation between occur-rence of hypernickelemia and presence of hypotension,congestive heart failure, or pulmonary edema was notevident in this study.

Third, nickel may be bound to clotting factors or comple-ment components, and released into serum during thecoagulation cascade that occurs during coronary thrombosisor during the activation of the alternative complementpathway that follows myocardial inflammation. These spec-ulations are prompted by recent findings that human factorVifi and C-3 convertase contain metal-binding sites thatmay form complexes with Ni2 (16, 17).

Rubanyi et al. (18-20) proposed that hypernickelemiacontributes to the pathogenesis of ischemic myocardialinjury, based upon their observation that Ni2 at lowconcentrations (106 to iO mol/L) induces coronary vaso-constriction in dog heart in vivo and in vitro. Rubanyi et al.(21) and Farago et al. (22) reported elevations of nickelconcentrations in serum and myocardium, as well as in-creased coronary resistance, in rats after acute burns orhemorrhagic shock, suggesting a role of nickel in thecoronary spasm that occurs in these disorders. This specula-tion is consistent with the possible occurrence of coronaryspasm following hypernickelemia in two of our patients(Figure 1). Recent studies by other workers (23-25) demon-strate that Ni2 can act directly upon the myocardium toinduce electrophysiological disturbances, possibly mediatedby inhibition of the slow inward Ca2 current.

We conclude that the mechanisms and sources of nickelrelease into sera of patients with acute myocardial infarc-tion or unstable angina pectoris are conjectural, but itappears that hyperrnckelemia may somehow be related tothe pathogenesis of ischemia myocardial injury.

This study was supported by Grant EV-03140 from the U.S. Dept.of Energy and by Grant ES-01337 from the National Institute ofEnvironmental Health Sciences, NIH.

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