Myocardial protection by intracoronary nicardipine administration during percutaneous transluminal coronary angioplasty

Myocardial Protection by lntracoronary Nicardipine Administration During PercutaneousTransluminal Coronary Angioplasty CLAUDE HANET, MD, MICHEL F. ROUSSEAU, MD, MARIE-FRANCOISE VINCENT, MD, EDITH LAVENNE-PARDONGE, MD, and HUBERT POULEUR, MD

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. lntracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 f 61 vs 159 f 72 ml/min); lactate (-9 f 21% vs - 17 f 21 O/O,p <0.025) and hypoxanthine production (-107 f 65% vs -216 f 153%, p <0.05) were less severe after nicardipine pretreat-

T

1 he anti-ischemic action of calcium antagonist drugs in patients with angina pectoris is usually explained by 2 mechanisms: a reduction in myocardial oxygen demand related to the afterload reduction or to the negative inotropic effect of some of these compounds* and an increase in myocardial oxygen supply, related to the coronary vasodilating properties.2-5 Recent observations,6-10however, suggest that some calcium antagonists may protect the myocardial cell by a direct mechanism that is independent of the oxygen supply/ demand balance and of the slow-channel blockade. From the Departments of Physiology and Cardiology and International Institute of Cellular and Molecular Pathology, University of Louvain, Brussels, Belgium. This work was supported in part by Grants FRSM 3.454685, FNRS 1.5.106.85f and SPPS 83/ 88-51. Dr. Vincent was “Charge de Recherches” from the Fonds National de la Recherche Scientifique. Manuscript received September 23, 1986; revised manuscript received December 22, 1986, accepted December 24.1986. Address for reprints: Claude Hanet, MD, University of Louvain, School of Medicine, Avenue Hippocrate 55, Box 5560, B1200 Brussels, Belgium.

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ment than afler control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No slgnlficant changes in thromboxane B2 or prostacyclln levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 76 pg/ml, p <0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine. (Am J Cardiol 1987;59:1035-1040)

The existence of such additional beneficial effects has never been shown in patients with angina pectoris, mainly because in vivo this hypothetical action cannot be dissociated from the effects of these agents on the myocardial oxygen supply and demand. To determine if such a protective action could also be relevant in man, we studied changes in myocardial metabolism after intracoronary administration of nicardipine, 0.2 mg, in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Intracoronary administration of nicardipine has negligible systemic or direct myocardial depressant effects,ll and PTCA is a unique clinical model to study the effects of brief episodes of severe regional ischemia.

Methods The study was performed in 12 consecutive patients undergoing PTCA of the left anterior descending or of the left circumflex coronary artery. All had incapacitating angina pectoris refractory to medical therapy. Their clinical characteristics are listed in Table I. Use of antiplatelet drugs (including aspirin, taken by only 2 patients) and all other cardioactive medications except

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METABOLIC

TABLE I

EFFECTS

Clinical

Data No.

Pt

OF NICARDIPINE

of

% Diameter

CAs

Age (~0 6 Sex

Stenosis

Dilated

Narrowed

Before

CA

After

1 2

42M

2

LAD

80

49M

1

LAD

95

10

3

51M

2

LAD

90

20

4

55M

1

LC

80

30

5

56M

1

LAD

90

20

6

58M

2

LAD

90

50

10

7

59M

2

LAD

85

30

8

59M

2

LC

80

40

9

61F 63M

1

LAD

2

LAD

80 95

50

10

10

11

64F

1

LAD

85

20

12

89F

1

LAD

90

20

CA = coronary circumflex artery.

artery;

LAD

=

left

anterior

descending

artery;

LC =

left

short-acting nitrates was discontinued at least 3 days before PTCA in all but 1 patient, who had severe angina. In this patient, propranolol treatment had to be maintained. No premeditation and no drug except heparin was given before the end of data acquisition. A thermodilution catheter (Webster Laboratories] was introduced through an antecubital vein in the coronary sinus and its position was confirmed by injection of contrast medium. A guiding catheter was introduced percutaneously and was advanced to the aortic root through the right femoral artery. The diseased coronary artery was visualized by injection of contrast material and the balloon dilation catheter was positioned across the stenosis. Then, before the first balloon inflation, coronary sinus and arterial blood samples were taken simultaneously to determine lactate, STUDY *

12

PATIENTS

PTCA

BALLOON

PROTOCOL

OF

LACTATE,

1

THE

CATHETER

CORONARY

TXB2.

I

LACTATE.

TXBP.

LACTATE,

CBF

(+2

DURING CX)

STENOSIS

PO12

SINUS

INFLATION

LACTATE,

LAD

THROUGH

1 INFLATION t

STUDIED

FLOW

(45 PGl2.

II (45

(THERMOOIL.)

s) CBF

s)

CBF

FIGURE 1. Experlmental protocol. lntracoronary InJectIon of nlcardlplne was made randomly before Inflation I or Inflation II. CBF = coronary blood flow; CX = circumflex artery; LAD = left anterior descending artery; PG12 = prostacyclln; TXBP = thromboxane Bz.

hypoxanthine, thromboxane B2 and 6-keto PGF1, content [Fig. 1). Coronary sinus blood flow was measured by the thermodilution methodI immediately after blood sampling. After data collection, the balloon catheter was inflated at a pressure of 8 atm for 45 seconds. Coronary sinus and arterial blood samples were again simultaneously taken immediately after measurement of coronary sinus flow, i.e., 60 seconds after deflation. The second balloon inflation was performed 5 minutes after the first and the same data as during the first inflation (except blood samples for prostaglandins determinations) were obtained. During each coronary sinus flow measurement, aortic pressure and the electrocardiographic signal were recorded on magnetic tape (Honeywell 101). In each patient, 1 inflation was performed with the patient in the basal state and 1 was performed after intracoronary injection of 0.2 mg of nicardipine diluted in 1 ml of blood.” The nicardipine injection was made 30 seconds before balloon inflation and distal to the stenosis. The sequence of control and nicardipine inflations was randomly assigned so that in half of the patients the first inflation was made in basal state and in the other half after intracoronary nicardipine. Then, PTCA was performed. All patients gave informed consent before the study and no complication related to the research protocol was observed in any patient. Data analysis: The values of coronary sinus blood flow were determined before inflation with the balloon catheter placed across the stenosis, during the last seconds of balloon inflation and 50 seconds after deflation, when myocardial blood flow was stabilized. The myocardial lactate and hypoxanthine extraction ratios were calculated as A-V/A X 100, where A and V = arterial and coronary sinus concentrations, respectively. Lactate was measured by an enzymatic method.13 Plasma concentrations of 6-keto-PGF1,, the inactive metabolite of prostacyclin, and the concentrations of thromboxane Bz were determined by radioimmunoassay (Amersham Kit). Variation within and between assays was less than 15%. Abnormally high values were observed in 2 samples (1,195 and 609 pg/ml, respectively], suggesting platelet activation within the catheters-l4 Hypoxanthine concentrations were determined by high-pressure liquid chromatography (Hewlett-Packard 1090; column p-Bondapak-Cl*, Waters Associates). Samples from the first 3 patients, analyzed using standard procedures, yielded inadequate separation between hypoxanthine and the contrast medium (meglumine amidotrizoate)used to locate coronary lesions. In the last 9 patients, reliable hypoxanthine separation was achieved by using a very diluted buffer (NaH2P04 10 mM; pH 5.5); the data from these patients only are presented. Statistical analysis: Differences between groups were determined using a Mann-Whitney U test. Comparisons between values before and after PTCA or with and without nicardipine in the same patients were performed using a Wilcoxon test. Values are expressed as mean f standard deviation, except for the

May 1, 1987

TABLE II Coronary Sinus Blood (ml/mln) and After Balloon Inflation

Flow Before, Durlng

Control Inflation Pt

Nicardipine

JOURNAL

50 s After

Before

During

50 s After

133 98 113 211 171 77 153 83 59 316 149 152 143 f70

127 123 121 127 105 85 158 55 84 295 192 124 130 f65

143 138 127 192 184 78 208 88 64 295 268 148 159 f72

112 107 117 173 150 78 128 75 65 278 180 140 133 f58

117 115 121 121 137 88 145 140 66 272 184 114 133 f54

128 138 128 218 181 85 192 188 66 289 209 146 181 f81

s = second: pn = standard deviation.

thromboxane B2 data, which were not normally distributed; in this case, individual values and their median are presented.

Results Hemodynamic data: Before and during inflations, levels of coronary sinus flow were comparable in the absence of pretreatment with nicardipine and after nicardipine infusion (Table II). One minute after balloon deflation, no statistically significant hyperhemia was seen, and flow levels remained similar in both groups. No significant difference in heart rate or systolic blood pressure was observed between control and nicardipine procedure before, during and after balloon inflation (Table III), although systolic pressure tended to be lower after nicardipine infusion. Transcardiac lactate and hypoxanthine extraction: Individual values of transcardiac lactate extraction fraction 1 and 4 minutes after balloon deflation are shown in Figure 2. When the whole group was considered, average lactate extraction fraction before

Before HR (beats/min) SAP (mm Hg) During HR (beats/min) SAP (mm Hg) 50 set after HR (beatslmin) SAP (mm Hg)

4 rnin

1 min

1 Ink

30

CONTR.

NFL.

4 min

lNFL

NIC. INFL.

t

Nicardipine Inflation

Before,

p Value

66f 143 f

11 21

67 f 151 f

10 20

NS NS

68f 138 f

12 29

69f 130 f

12 19

NS NS

65 f 145 f

12 26

67 f 131 f

12 16

NS NS

inflation but with the catheter across the stenosis was -11 f 36% (n = 12) in control and -12 f 29% (n = 12) before nicardipine injection. In the absence of nicardipine pretreatment, lactate production averaged -17 f 21% [n = 12) 1 minute after deflation and lactate production continued 4 minutes after deflation in the 6 patients not pretreated with nicardipine at the first inflation (Fig. 2). In contrast, after nicardipine pretreatment, lactate production was already slightly improved 1 minute after deflation, to -9 f 21% (p <0.025 vs control, n = 12), and all 6 patients pretreated with nicardipine had shifted back toward lactate extraction at the 4th minute. Consequently, 1 and 4 minutes after balloon deflation, mean lactate production was significantly less severe for procedures preceded by intracoronary nicardipine infusion than for control procedures. Figure 3 shows individual values of hypoxanthine release 1 minute after balloon deflation. Hypoxanthine release was markedly reduced in the 5 patients in whom nicardipine had been administered before the second inflation. When nicardipine had been in-

PTCA NICARDIPINE

PTCA NICARDIPINE

PTCA CONTROL

1 min -

AFTER NC.

Pressure

The p value refers to comparison between control and nicardipine inflations HR = heart rate; NS = not significant; SAP = systolic arterial pressure.

PTCA CONTROL AFTER

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Control Inflation

During

1 min

OF CARDIOLOGY

TABLE Ill Heart Rate and Systolic During and After Balloon lnflatlon

Inflation

Before

1 2 3 4 5 8 7 8 9 10 11 12 Mean f SD

THE AMERICAN

CONTR.

01

NFL.

A

0

-30

1 d

K -60

/

p
&

p
FIGURE 2. Leff, lndlvldual values of myocardlal lactate extraction fraction (EF) 1 and 4 minutes after control Inflation (Contr. Infl.) wlthout nlcardlplne pretreatment and 1 minute after the second inflation, performed during nlcardipine lnfuslon (Nlc. Infl.). Rlghf, the 6 patients In whom the sequence of Inflation was reversed.

p-co.05

l p.SEQUENCE

CONTROL

.,....

NIC

*SEQUENCE

- - ->

--->

NIC

CONTROL

FIGURE 3. Transcardiac hypoxanthine extractlon fraction 1 minute after balloon deflation In patients undergolng percutaneous translumlnal coronary angioplasty (PTCA). Less hypoxanthlne was released when intracoronary nicardipine was administered before Inflation.

METABOLIC

1038

EFFECTS OF NICARDIPINE

fused before the first inflation, an increase in hypoxanthine release compared with that during nicardipine inflation was still observed in 2 patients; another patient showed only minor improvement during the second inflation. For the 9 patients, average hypoxanthine release after nicardipine pretreatment was therefore significantly less than after control inflation (-107 f 85% vs -218 f 153~6, p <0.05].

Changes in prostacyclin and thromboxane B2: Transcardiac uptake of prostacyclin and thromboxane AZ metabolites were studied before and after the first balloon inflation in the 12 patients. In 2 patients, measurements were repeated before and after the first inflation of a second balloon catheter of greater diameter. Thus, a inflations performed without medication were compared with a procedures preceded by intracoronary infusion of nicardipine. Before inflation, arterial levels of thromboxane B2 and prostacyclin were comparable in both groups (Fig. 4 and 5). In 5 patients of the control group, balloon deflation was followed by an increase in arterial thromboxane B2 concentration (Fig. 4); no significant change was observed in the coronary sinus. After balloon deflation in patients receiving intracoronary ni-

cardipine, thromboxane B2 continued to increase in 5 patients, The median values of arterial thromboxane B2 concentrations were, however, significantly lower after nicardipine inflation than after control inflation (76 vs 169 pg/ml; p <0.05), even when the abnormally high value of 1,095 pg/ml was included in the statistical analysis. The arterial prostacyclin concentration significantly increased after deflation in the control group (mean 35 f 22 to 47 f 13 pg/ml, p <0.05), but did not change in the nicardipine group (52 f 19 to 40 f 19 pg/ml, difference not significant]. No consistent change was observed in the coronary sinus concentration of prostacyclin (Fig. 5).

Discussion Our data indicate that 1 minute after a brief coronary occlusion in humans, a smaller amount of lactate was produced and less hypoxanthine was released when coronary occlusion had been preceded by an intracoronary injection of 0.2 mg of nicardipine. Lactate production by the ventricle indicates use of the anaerobic glycolysis by the myocardium15J6 and the presence of hypoxanthine in cardiac venous

t :@ i&iii A0

CONTROL

A0

NIC

A0

CONTROL

A0

NIC

1195

200 z ‘g ; :!

150

p
NS

200

.

100

150

F x

; r

.

01Before-

100

l

.

01

After

PTCA

/

01

Before

PTCA

After

CS

CONTROL

CS

PTCA

NIC CS

After

Before

PTCA

CS

CONTROL

NIC

-609

F

100

\ I s

\

Do 9

x

Before

After PTCA

Before

After PTCA

FIGURE 4. lndlvldual values and their median of aortlc (AO) and coronary sinus (CS) concentration of thromboxane Bz (TXBP) before and 1 minute alter balloon deflation In patients undergoing percutaneous translumlnal coronary angloplasty (PTCA). The medlan values of thromboxane B2 were comparable In the 2 groups before PTCA but were lower (p <0.05) when PTCA was performed after lntracoronary nlcardlpine (NIC) pretreatment than after control PTCA.

NS

150

NS

150

50

0I Before

After PTCA

Before

After PTCA

FIGURE 5. lndlvldual values of aorllc (AO) and coronary slnus (CS) concentration of prostacyclln (PG12, estimated from Its stable metabollte) before and 1 minute after balloon deflation In patients undergoing percutaneous transluminal coronary angloplasty (PTCA). The Increase In arterial levels of prostacyclln was reduced when PTCA was performed after lntracoronary nlcardlplne (NIC) pretreatment.

May 1,1987

blood reflects depletion of the high-energy phosphate stores.lT.18Our observations are therefore consistent with the hypothesis that nicardipine protects the myocardium during regional ischemia, allowing a faster recovery of aerobic metabolism after reperfusion. Different interpretations of this protective effect of nicardipine may be considered based on the general properties of calcium antagonists. Serruys et all9 showed that the amount of lactate released by the myocardium during PTCA appeared to be constant during the first 2 inflations. Care was taken in our study to randomize the inflations with or without nicardipine pretreatment, so that an artifact related to the sequence of inflation can be ruled out as an explanation for our findings. From the data of hypoxanthine and lactate release, one may suspect that if nicardipine was given during the first inflation, some protection may have persisted during the second inflation. Although indexes of contractility were not measured, a decrease in oxygen cost of contraction resulting from a negative inotropic or chronotropic effect or from a peripheral vasodilating effect seems unlikely. In a previous study,‘l,“” intracoronary injection of 0.2 mg of nicardipine increased coronary sinus flow but had no effects on heart rate, peak positive dP/dt or the rate of isovolumic relaxation. Visser et al”l confirmed these observations. These results indicate that in contrast to other calcium antagonists such as nifedipine, Il.21 nicardipine at the dose used in this study had negligible effects on myocardial contractility. Moreover, no significant change in blood pressure was observed with nicardipine during or after coronary occlusion, indicating that this dose was insufficient to elicit a significant afterload reduction. Intracoronary or intravenous administration of nicardipine may increase coronary blood flow,“,7 but it did not do so under our experimental conditions. The presence of the dilatation catheter, even deflated, across the coronary stenosis markedly impedes flow. This flow reduction was sufficient to induce ischemia, as indicated by the lactate and hypoxanthine productions noted in most patients before balloon inflation. Thus, because of the coronary autoregulation,lg vasodilation occurred distal to the stenosis before inflation. This may explain the absence of coronary flow increase with nicardipine and the lack of significant hyperhemia. One cannot exclude the possibility, however, that redistribution in coronary flow may have occurred during inflations. Feldman et alZ2 reported an increase in collateral flow in the ischemic region during PTCA after treatment with nicardipine. Such an increase in regional perfusion may explain the beneficial myocardial effect of nicardipine observed in this study. Another explanation for our observation, however, is that nicardipine protects the myocardium in the territory distal to the balloon occlusion by acting directly on the myocardial cells, This conclusion is compatible with findings in experimental studies,6,8m10 particularly that of Berland et al,“” who showed in anesthetized dogs that intracoronary nicardipine prevented lactate

THE AMERICAN

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1039

production and accelerated recovery of function after coronary occlusion. Moreover, in this latter study, no appreciable change in great cardiac vein flow was seen during the protective effect of nicardipine. The mechanism of action at the cellular level is beyond the scope of this study. Changes in the transcardiac handling of thromboxane B2 and of prostacyclin were also observed after nicardipine pretreatment. The largest changes in prostaglandins 1 minute after control coronary occlusion were seen on the arterial side and not in the coronary venous blood. Changes in thromboxane B2and prostacyclin during cardiac catheterization should, however, be interpreted with caution because platelet activation within catheters and contrast material may influence the results.14.24,25 Two very high thromboxane B2 values were observed, suggesting platelet activation, and this phenomenon may have occurred to a lesser degree in other patients. Nevertheless, to minimize the delay between catheter insertion and blood sampling, prostanoid concentrations were considered mainly for the first balloon inflation, and the sequence of blood sampling was identical for both procedures. This suggests that sampling-related artifacts cannot entirely account for the differences in thromboxane Bz and prostacyclin concentrations observed after control or nicardipine inflation. Opposite results were recently reportedz6 during PTCA in patients pretreated with aspirin, but only a few patients in our series received aspirin within 1 week before study. Mehta et alz7 reported abnormalities similar to those reported here for thromboxane B2 in some patients with stable angina pectoris at rest. They explained this finding by transcardiac abnormalities in platelet agregation function, such as a reduced activity of platelets in atherosclerotic coronary vasculature.27 Independent of the origin of these changes in arterial thromboxane B2 and prostacyclin levels, on which we can only speculate, these observations suggest that nicardipine also affects platelet function. In addition, the hypothesis that these effects on platelet function could be a cause rather than a consequence of the regional metabolic protection observed cannot be excluded. Acknowledgment: We thank Dr. Bryan J. Harlow, from Syntex Research, Europe, for his help and criticisms during the course of the study. The secretarial help of Veronique Heirman and Sylvie Ahn is also gratefully acknowledged.

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OF NICARDIPINE

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mia. JACC 1985;5:1138-1146. 17. Remme WJ, de Jong JW. Verdouw PD. Effects of pacing-induced myocardial ischemia on hypoxanthine efflux from the human heart. Am r Cardiol 1977;40:55-62. 18. Berne RM, Rubio R. Coronary circulation. In: Berne, RM, Sperelokis N. Handbook of Physiology. Section II. The Cardiovascular System. Vol. I. The Heart. Baltimore: Williams 6 Williams 1979:873-952. 19. Serruys PW, Wyns W, van den Brand M. Meij S, Slager C, Schuurbiers ]CH. Hugenholtz PG, Brewer RW. Left ventricular performance. regional blood flow, wall motion, and lactate metobolism during tronsluminal ongiopJasty. Circulation 1984;70:25-36. 20. Rousseau MF, Veriter C, Detry JMR, Brasseur LA, Pouleur H. Impaired early left ventricular relaxation in coronary artery disease. Effects of introcoronary nifedipine. Circulation 1980;62:764-772. 21. Visser CA, Koolen JJ,Van Wezen H, Jonges R. Hoedemaker G. Effects of introcoronary nifedipine and nicardipine on left ventricular inotropy and relaxation (abstr). fACC 1987;9:163A. 22. Feldman RL, Macdonald RG, Pepine CJ. Do calcium antagonists improve collateral flow during acute coronary occlusion in man? (abstr]. Circulation 1986;74:suppl rr-190. 23. Berland J, Kar S. Rajagopalan R, Tokioka H, Meerbaum S, Drury JK, Corday E. rntracoronary nicardipine is more effective than nifedipine for myocardial protection during brief coronary occlusion (obstr). Circulation 1986.74:suppl rr:rr-170. 24. FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67:1174-1177. 25. Roy L, Knapp HR, Robertson RM, FitzGerald GA. Endogenous biosynthesis of prostacyclin during cardiac cotheterizotion and ongiography in man. Circulation 1985;71:434-440, 26. Mehta J, Feldman RL, Macdonald RG, Letts G. Effect of human coronary occlusion on thromboxane A2 and leukotriene C4 release (obstr). [ACC 1986;7:106A. 27. Mehta J. Mehta P, Feldman RL, Horalek C. Thromboxane release in coronary artery disease: spontaneous versus pacing-induced angina. Am Heart J 1984;107:286-292.