Cardiovascular Drugs and Therapy 4: 909-914, 1990 ,~ Kluwer Academic Publishers, Boston. Printed in U.S.A.

Intravenous Nifedipine Prevents Ergonovine-Induced Myocardial Ischemia in Patients with Stable Effort Angina

Claudio Brunelli, Paolo Spallarossa, Giorgio Ghigliotti, Michelangelo Caudullo, Mario lannetti, Salvatore Caponnetto Department of Cardiology, University of Genova, Italy

Summary. Twelve of 40 consecutive patients with effort an- gina, documented coronary artery disease, and a positive ex- ercise stress test had a positive ergonovine test. ST-segment depression (0.1 mV) occurred in ten and ST elevation (0.1 mV) in two patients. During the ergonovine maleate test the rate-pressure product recorded at the onset of ischemia (ST -> 0.1 mV) was significantly lower than that recorded during the exercise stress test. The reproducibility of the rate-pressure product at ischemia was displayed in every patient with a second test; then, a third test "after intravenous nifedipine infusion (1 mg over 5 minutes + 1 mg over 55 minutes) was performed. Six patients had negative results; out of the re- maining six, three exhibited a significant increase in the dos- age required for provoking ischemia. Both systolic and dia- stolic blood pressure were reduced by nifedipine, while only a slight increase in heart rate occurred, so that the rate- pressure product at any ergonovine dosage was decreased by nifedipine. No differences in the ischemic threshold during exercise and during the ergonovine maleate tests (in washout and after nifedipine) were found in patients with a positive or negative response to nifedipine. The ergonovine test was posi- tive in a sizable (30%) number of patients with stable effort angina. In these patients nifedipine was effective in prevent- ing ergonovine-induced myocardial ischemia.

Key Words. intravenous nifedipine, ergonovine test, effort angina, myocardial ischemia, coronary vasomotion

F o r many years coronary atherosclerosis was consid- ered to be the only pathogenetic mechanism in stable effort angina [1]. Subsequently the role of dynamic changes in the coronary arteries (i.e., coronary spasm) was demonstrated in variant angina [2]. More recently the occurrence of coronary vasomotion disorders has also been proposed and demonstrated in patients with chronic stable angina [3].

The clinical evidence of a variable ischemic threshold in patients with effort angina has been ex- plained on the basis of discrete alterations in coronary tone superimposed on atherosclerotic plaque [4].

To confirm the susceptibility of coronary arteries to vasomotion in the clinical setting, ergonovine maleate

administration has been used as a provocative test in patients with both variant and stable effort angina [5-8].

Nifedipine has been shown to be effective in the treatment of variant [9-11] and effort angina [12,13]. In variant angina the benefit is due to its dilating ef- fect at the level of the large coronary arteries [14,15], while in effort angina either systemic [16,17] or coro- nary hemodynamic effects [17-19] have been consid- ered as possible effective mechanisms in preventing myocardial ischemia. The aim of the study is to evalu- ate whether intravenous nifedipine is able to prevent ergonovine-induced myocardial ischemia in patients with stable effort angina.

Methods

Patient selection Forty consecutive patients with a diagnosis of stable effort angina were studied. The inclusion criteria were positive exercise stress test and angiographically doc- umented coronary ar tery disease. The exclusion crite- ria were worsening or recent onset angina, recent myocardial infarction (less than 3 months), basal elec- trocardiographic abnormalities that made the diag- nosis of transient myocardial ischemia unreliable, and left main coronary ar tery disease.

On admission all patients discontinued cardiac medications. After exercise testing and coronary an- giography, patients underwent ergonovine maleate testing in the catheterization laboratory. If the first test was positive, the test was repeated 24 hours later to evaluate reproducibility. A third test was carried out during nifedipine infusion.

Address for correspondence and reprint requests: Claudio Brunelli, MD, Salita San Gerolamo, 4, 16124 Genova, Italy.

909

910 Bru,nelli, Spallarossa, Ghigliotti, Caudullo, lannett i a . d Capon.etto

Bicycle exercise test The protocol consisted of an initial work load of 25 W, with successive increments of 25 W every 2 minutes. Standard 12-lead electrocardiogram and blood pres- Patients sure recordings were obtained every minute during Age the test and every 2 minutes during the recovery pe- Sex

Exerc ise Test riod. ST-segment shifts of 0.1 mV or greater were �9 Pain considered to be diagnostic of myocardial ischemia. �9 RPP"

�9 W a t C

Coronary angiography Coronary ar ter iography with multiple orthogonal views and left ventricular angiography was performed using Judkins' technique. A stenosis diameter > 50% was considered to signify coronary atherosclerosis.

Ergonovine test All patients had a stable intravenous plastic cammla in place and a three-lead electrocardiogram was moni- tored. At 1-minute intervals, cuff blood pressure and a 12-lead electrocardiogram were recorded. Ergonovine was injected at an increasing dosage (12.5, 25, 50, 100, 200, up to 400 p.g) at 5-minute intervals. The test was defined to be positive when ischemic ST changes (ST

or T -> 0.1 mV) were associated with angina and reproducible when positive at the same or at the next dosage.

Intravenous nifedipine was administered over 55 minutes (1 mg over 5 minutes + 1 nag over 50 min- utes) using an infusion pump under electrocardio- graphic and blood pressure control; the third er- gonovine maleate test was started 25 minutes after the beginning of nifedipine infusion.

Data analysis Continuous data are presented as the mean -+ SD. Statistical analysis was performed using Student's t test for paired and unpaired data, as appropriate. A Wilcoxon rank test was used to evaluate the change fi'om the ergonovi.ne dosage required to provoke isch- emia in pharmacologic washout to the maximal er- gonovine dosage administered after nifedipine infu- sion. A value of p < 0.05 was considered statistically significant.

Results

Twelve of 40 patients (mean age, 52.6 -+ 5.4 years) with a positive exercise stress test had a positive er- gonovine maleate test. The clinical data for these pa- tients were not different from the remaining group (Table 1). The dosage levels of the positive test were 25 txg (two patients), 50 ~g (one patient), 100 ~g (six patients), and 200 ~g (three patients). All but two patients had ST-segment depression. Typical angina

Table 1. Cli.ical f i .d ings

Positive EMT Negat ive EMT

12 28

52.6 -+ 5.4 55.1 -+ 6 1F 1F

9 19 21733 -+ 6237 21945 -+ 5921

81.2 +- 34 84.8 -+ 30

EMT = ergonovine maleate test; RPP" = rate-pressure product.

WATT" Recorded at ischemia (ST => 0.1 mV).

~ - 1 ~ 2 ~ TEST 3 ~ TEST Dur ing n i f e d i p i n e

i n f u s i o n

NEGATIVE

400 ,.g

'. 200 ,"g

m :> ' lOOgg j _ ,

o 50 gg D_

25 ..g

12.5 !~g

R e p r o d u o b l e in al l p a t i e n t s

. - p < 005

( W i l c o x o n )

~ 0

Fig. 1. Data are c.cpr(,.ssed u.s chauges itt re,slmwse betwecu the two washo.t tests and the third with ,li/~,dipi~w i~/'.sion.

was always associated with ischemic changes. All patients had a reproducible ECG response to er- gonovine: Ten patients had a positive result at the same dosage, while one step variation occurred in two patients. Both the direction of the ST-segment shift and the ECG lead involved in ischemic changes were the same in two repeated tests. After nifedipine infu- sion, six patients had a negative ergonovine maleate test at a maximal dosage, while six still had a positive test. In three cases the test was positive at a signifi- cantly higher dosage (one step variation gTeater than the higher basal test), while the other three had one step variation (Figure 1). No variability in ST- segment changes was found in the tests, which were still positive.

Ischemic changes were promptly relieved by IV administration of a bolus of nitroglycerin (0.5-1 ~g). During the ergonovine test performed in the catheter- ization laboratory, 3 of 12 patients had coronary vaso-

Ergo~mvine and IV Nifedipine 911

Fig. 2. A~giograms in temporal seque~tce showi~g a critical ste~osis o~ the proximal portiol~ of the left anterior descendi~g artery (A) and the it~crease of ste~msis (B) associated zttith the intrave~m~ts h~jectio~ of ergo~mvine maleate darStg paitz at~d electrocardio- graphic cha~ges.

constriction (two on the left anterior descending and one on the right coronary artery) documented by in- jecting contrast medium in the involved coronary artery soon after the onset of pain and electrocar- diographic changes (Figures 2A and 2B). No complica- tions occm~-ed during or after ergonovine and nifedipine infusions.

Systolic and diastolic blood pressure, heart rate, and the rate-pressure product, both in washout and after nifedipine for each dosage of ergonovine adminis- tration, are shown in Figure 3. The ischemic threshold during the exercise stress test and the ergonovine maleate test are shown in Figure 4.

The rate-pressure product values recorded at the

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HEART RATE

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EnC.ONO'r {::,O~4,C,E (~gJ

�9 WASH = 0%11

'C' NIFEOI?INE

150 I

~oo[

so~

BLOOD P'~ESSUnE

,~s A so ,m ~ .5o E~GONOVINE {)OSAGE ( -gl

s,~,lOll( BP Ola$lOl,( BP �9 ~&SH-OUI �9 WI~-r'p,UT ,5 NI~'EOIPlNE 0 NIFEOII~NE

RaTE PI~ESSURE F"~OOUCI

150 f

~00p

rTs s ~ ~ z~ EPlG'ONOV~NE 0OS.AC'.E (ug~

�9 WASH - 0UI

C) NIFE01pBNE

J~

Fig. 3. T ime course vah. ,x qf hcart rntc, blood pressure, atvt the r . tc- t . 'cssure tu'~dm't i . p ti .Hs i . ,dbrmit~g ergo.for'ant tc,st.s HI the washo~d phase versus on n(fedil)h~e. Sl(tlisticnl anal!isis lW~:lbrmed i~si~tg Sh.h,~H'.~ t tcst.lbr p~fir,'d d .h t shuu'cd ~t de('reas(' q f systolic a . d diastolic blood pressure. (Hid the ratc-prcssttre prod~wt qlb'r ~llJ?'dipi~w . l "~qt d .sc h'rcl. ,\',, dil?i're~ce w(~s./bu~ld i~t hea~4 rate cah(es.

(3- n-

t~ D g EE (3.

1,1 rr D If) u3 LU pc. EL

LU

DE

300

200

100 i / i

, , a

Z;;q

EST EMT BASAL

D POSITIVE TEST

] NEGATIVE TEST

EMT NIFED~PtNE

Fig. 4. Ischemic tl reshoht (hr exercise stress test (EST) a~d ergonoui .e maleate test (EMT) .

onset of ischemia (ST-segment shift -> 0.1 mV) were sigmificantly lower during the ergonovine test per- formed in washout than during the exercise test (13083 _+ 3126 vs. 21733 _+ 6237; p < 0.001).

After nifedipine infusion the rate-pressure l)roduct at ischemia or at the maximal ergonovine dosage in the case of a negative test were sig~fificantly lower than the values recorded during the washout period (from 13083 -+ 3126 to 9558 _+ 2403; p < 0.01). How- ever, in comparing patients who after nifedipine showed a negative ergonovine test with those with a still positive test, no difference was ibund in the isch- emic threshold during exercise or ergonovine tests.

Discussion

The beneficial effects [21-23] of nifedipine are exten- sively documented in patients with both exertional and variant angina. In patients with effort angina, the variable threshold of effort myocardial ischemia can be explained on the basis of dynamic coronary stenosis [24-25] superimposed on fixed obstruction [4]. Spec- chia et al. demonstrated that after nifedipine 7 of 14 patients with stable effort angina--despite an in- crease in the rate-pressm-e product--showed an in- crease in exercise capacity and a reduction in ST- segment depression, due to an increase in coronary flow; while the remaining patients without significant coronary hemodynamic changes did not improve their exercise tolerance [181. However, both systemic and coronary circulation effects might explain the benefits of nifedipine in effort angina. Moreover, they might

Ergr a~d [I" Nil~dipi,e 913

play a different role in different groups of patients, even though it seems reasonable to assume that in some subjects an interplay between the two mecha- nisms may exist.

Hence, to select patients with evidence of an exces- sive tendency to coronary vasoconstriction and to evaluate the efficacy of intravenous nifedipine in an- tagonizing vigorous stimuli to vasomotion, we per- formed repeated provocative tests with intravenous ergonovine, a potent vasoconstrictive agent. Ergo- novine elicited myocardial ischemia in 12 patients (30c~), most of whom (83~) showed ST-segment de- pression. Because we did not perform coronary an- giog~'aphy during the ergonovine test in all patients, we cannot exclude that the ventricular stiffness pro- duced by ergonovine administration could lead to myo- cardial ischemia in some of our patients. However, bearing in mind that heart rate and blood pressure increased only slightly after ergonovine administra- tion, and the rate-pressm'e product at the onset of ischemic ECG changes was significantly lower than the same value recorded during exercise testing, a primary reduction of myocardial oxygen supply should be considered as a possible cause of myocardial isch- emia, as documented in three of ore" patients. The high prevalence of ST-segment depression suggests that in the majority of patients coronary constriction (lid not reach total occlusion. Ore" findings confirm that, even if patients with stable effort angina had a lower sen- sitivity to ergonovine 'than patients with variant an- g-ina when studied in the active phase of the disease, a sizable number of patients with effort angina are prone to enhanced vasomotion [4,81.

In this selected population, intravenous nifedipine prevented ergonovine-induced ischemia in six patients and increased the necessary dosage to elicit ECG changes in six other patients. This result could be explained on the basis of both direct eardiac effects and coronary [27,28] or systemic hemodynamic [29] changes, as previously considered. The oxygen- consumption-saving effect mediated by peripheral vasodilation might also be involved in the beneficial effect of nifedipine. In fact, at any ergonovine dosage, the rate-pressure product was significantly decreased by the drug, as well as the maximal rate-pressure product obtained by each patient. However, certain facts led us to believe that afterload reduction played a marginal role only. In fact, the two groups of patients who after intravenous nifedipine administration had either a negative or a continuing positive ergonovine test exhibited no difference in the effort myocardial ischemic threshold during the exercise test or in the ergonovine test isehemic threshold evaluated in the washout period. Since the rate-pressure product ob-

tained in the third test was similar in both gn'oups, it is difficult to explain in terms of oxygen consumption only how the same extent of reduction in peripheral resistances may present ischemia in some patients udthout producing benefits in others. Moreover, it is interesting to note that in the latter gq'oup of patients myocardial ischemia occurred despite a significant re- duction in metabolic demand.

There is thereibre evidence that nifedipine was able to relieve ergonovine-induced myocardial isch- emia. In unresponsive patients, it reduced the ten- dency to vasomotion but was unable to counteract the effect of a higher ergonovine dosage.

Conclusions

Nifedipine has different effects on subgq'oups of pa- tients with stable effort angina according to the pathogenetic mechanism of effort ischemia. In pa- tients with a documented tendency to vasomotion, nifedipine is effective in preventing coronary constric- tion. In patients unresponsive to constrictive stimuli, it probably acts peripherally to decrease the myo- cardial oxygen demands during exercise. I ts effec- tiveness in both areas of the supply-demand relation- ship justifies its use in effort angina.

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914 Br~mll i , Spattarossa, Ghigliotti, Ca~dulto, Iamtetti a~d Caponnetto

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