Effect of nicardipine on determinants of myocardial ischemia occurring during acute coronary occlusion produced by percutaneous transluminal coronary angioplasty

Effect of Nicardipine on Determinant of Myocardial Ischemia Occurring During Acute Coronary Occlusion Produced by Percutaneous Transluminal Coronary Angioplas ROBERT L. FELDMAN,

MD, ROBERT G. MacDONALD, MD, JAMES and CARL d. PEPINE, MD

In 10 patients undergoing percutaneous transluminal coronary angioplasty of the left anterior descending coronary artery (LAD), the clinical, electrocardiographic and hemodynamic effects of acute intravenous calcium channel antagonism with nicardipine (2 mg over 1 minute, followed by a constant infusion of 25 to 50 pg/min) were assessed during temporary LAD occlusion. Onset of myocardial ischemia during coronary occlusion was prevented or delayed after administration of nicardipine in 7 of the 10 patients. During infusion of nicardipine and during LAD occlusion, residual great cardiac vein

blood flow increased in 9 of 10 patients compared with residual flow during occlusion before nicardipine (IO%, p <0.05). Nicardipine also decreased mean aortic pressure, but was associated with a reflex-mediated increase in heart rate. Overall, the double product, an index of global myocardial oxygen demand, decreased 7% (p KO.05). Thus, nicardipine usually diminished &hernia induced by acute transient coronary occlusion by increasing collateral flow while oxygen demand decreased. (Am J Cardiol

W

e have demonstrated the feasibility of using balloon coronary occlusion of the left anterior descending coronary artery (LAD) to estimate pressure and flow determinants of coronary collateral function in unsedated patients undergoing percutaneous transluminal coronary angioplasty (PTCA).Q The angioplasty setting of acute coronary occlusion has also been used to assess clinical, electrocardiographic (ECG] and left ventricular (LV) functional responses to regional or systemic administration of vasoactive medications and regional perfusion with oxygenated blood or fluoso13-I2 This study uses this balloon occlusion model to determine whether acute calcium channel antagonism induced by intravenous administration of the dihydropyridine calcium antagonist, nicardipine, diminished myocardial ischemia during brief periods of acute LAD occlusion.

Methods Patient group: We studied 10 patients, aged 46 to 68 years (Table I]. Each had severe stenosis of the proximal LAD and was undergoing clinically indicated From the Division of Cardiology, Department of Medicine, University of Florida, and the Veterans Administration Medical Center, Gainesville, Florida 32610. Manuscript received February 19,1987; revised manuscript received and accepted April 10, 1987. Address for reprints: Robert L. Feldman, MD, Box J-277, Division of Cardiology, Department of Medicine, JHM Health Center, Liniversity of Florida, Gainesville, Florida 32610. 267

1987;60:267-270

PTCA. In every patient LV wall motion was preserved [ejection fraction at least 45%) and anterior wall motion was normal or only minimally hypokinetic. In no patient was LAD filling by way of the collateral vessels visualized before PTCA. Calcium antagonist drugs were discontinued at least 5 half-lives before the study. No patient took long-acting nitrates, but use of sublingual nitroglycerin was permitted until 6 hours before the study. All patients received 325 mg of aspirin orally the night before the study and 10,000 LJ of heparin intraarterially at the beginning of the procedure. No intravenous or intracoronary nitroglycerin was administered before the study. All patients gave written informed consent. The study was approved by the appropriate institutional review committees. Angioplasty procedure: Angioplasty of the LAD was performed as described previously.1-4 From the right femoral vein a catheter was positioned in the pulmonary artery wedge position to measure LV filling pressure. From the right or left antecubital vein, a multithermistor catheter was positioned in the coronary sinus to measure regional coronary venous flow (thermodilution). The distal thermistor was positioned in the great cardiac vein close to its juncture with the anterior interventricular vein. The balloon dilation catheter usually initially obstructed the LAD at an amount sufficient to lead to signs or symptoms of myocardial ischemia. In all cases, several brief balloon inflations were performed to decrease the magnitude of obstruction. The balloon was then deflated, and pressures and EGG and clinical

NICARDIPINE

266

AND

TABLE

MYOCARDIAL

I

Clinical

ISCHEMIA

Profile Left

Age W

EF W)

61 68 63 64

47 83 79 50

6 7

63 46 55

60 74 63

a

63

50

9 10

59

84 65

Pt

5

48

*Distal. EF = ejection

fraction:

LAD

Ventriculography

Coronary LAD

Wall

Motion

= left anterior

descending

:

0

10

20

30 FIRST OCCULUSION

/

40

50

60

diameter

>60

(SW)

FIGURE 1. Time to onset of transient myocardial ischemia (defined by changes in the ST segment and T wave) during repeated control period, anterior descending occlusions and during the nicardipine period. Time to ischemia during the first control period was compared with values during subsequent occlusions. Time to ischemia was remarkably reproducible during the control period and usually considerably longer during the nicardipine period.

Right reduction)

70 90 90 90

40 20 0 0

60’

90

Time Ischemia, Occlusion

18 20

0 0

0 0

29 30

20

20

31

70

10

0

32

90

30 20

0 0

33 45

coronary

artery;

LC

= left coronary

to First (set)

16 17

10 0 0

70 95

80

signs were monitored. In addition to ECG leads I and II, precordial lead VZ or V5 was monitored continuously. The precordial lead showing the largest amount of ST-segment deviation was chosen. Control period: When all evidence (electrocardiographic, hemodynamic or clinical) for transient myocardial ischemia was absent for at least 5 minutes, control period recordings of aortic, distal coronary and LV filling pressures; leads I, II and VZ or Vs; and coronary sinus, great cardiac vein and indicator temperature signals were obtained. When these values stabi>6Or

LC (%

Normal Normal Normal Anterior hypokinesia Normal Normal Anterior hypokinesia Anterior hypokinesia Normal Anterior hypokinesia

Angiography

artery

lized (& 5%) the balloon was inflated, “totally” OCeluding the LAD and thereby preventing anterograde flow to the anterior LV region. Balloon inflation was continued until important ischemic ECG changes occurred. If no ECG change occurred after 70 seconds of inflation, the balloon was deflated and ischemia was considered to have been absent. To assess reproducibility, at least 2 control period recordings, separated by an ischemia-free interval of at least 5 minutes, were obtained in each patient. Nicardipine period: Nicardipine was administered intravenously as a 2-mg bolus given over 1 minute and followed by an infusion (25 to 50 pg/min) titrated to maintain a lo- to 20-mm Hg decrease in systolic pressure. Five and 15 minutes after the infusion was started, the same recordings obtained during the control period were repeated. After these measurements were made, nicardipine was discontinued and PTCA completed. Definitions and calculations: Clinical evidence for myocardial &hernia was defined as the presence of chest discomfort typical of the patient’s usual exertionally provoked symptom. Important ECG evidence of myocardial ischemia was defined as new ST-segment depression or elevation of at least l-mm 0.08 second after the J point, T-wave inversion and normalization of previously inverted T wave. Change in time to onset of ischemia was assessed by matching the magnitude of ECG change during the first control period LAD occlusion to subsequent control or nicardipine period recordings. Great cardiac vein blood flow was calculated as described elsewhere.13 An index of coronary collateral resistance was calculated as the ratio of the difference between mean aortic and distal coronary pressures (e.g., pressure gradient across collateral bed] and great cardiac vein blood fl0w.1,‘~ The product of heart rate and systolic aortic pressure was used as an index of LV myocardial oxygen demand. Statistics: Hemodynamic parameters were compared before LAD occlusion and during ischemia produced by LAD occlusion. Comparisons of values be-

August

TABLE

II

Individual

Hemodynamic

Heart Rate (beats/min) Pt

1 2 3 4 5 6 7 8 9 10 Mean &SD

Values

Mean

AoP

(mm

W

During

Mean

Left

Anterior

CorP

3, 7987

THE AMERICAN

Descending

Occlusion

Mean

(mm Hg)

(mm Hg)

N

C

N

C

N

C

N

C

84 54 72 63 60 84 84 78 60 78 72

96 66 78 81 66 102 90 84 72 90 83

105 102 120 112 85 110 110 85 100 97 103

80 93 100 87 70 95 102 65 77 90 86

16 25 32 33 16 16 45 50 27 22 25

19 25 23 25 15 20 42 17 37 38 26

18 18 20 44 15 10 21 8 22 15 19

20 19 17 25 12 14 20 8 22 20 18

17 44 27 8 72 39 59 31 55 60 41

rtll

f13

f9

f9

rt12

AoP = aortic pressure; C = control; CorP = distal coronary pressure; LAD = left anterior descending coronary artery; LVFP = left ventricular

f10

f5

CR = collateral filling pressure;

fore and after nicardipine were made using t tests for paired samples. A p value
Results Data collection during control period LAD occlusions was repeated once in 6 patients and twice in 4 patients. These repeated LAD occlusions before nicardipine administration showed that ECG evidence of transient myocardial ischemia (Fig. 1) and hemodynamic data were reproducible in each patient. The difference in the time interval between similar ECG changes during repeated control period occlusions was never longer than 5 seconds. Hemodynamic values during the repeated control period occlusions were similar (& 5%), and reported data were obtained from the occlusion immediately preceding nicardipine administration. Hemodynamic responses at 5 and 15 minutes after initiating the nicardipine infusion were also very similar. Accordingly, to simplify the presentation only values after 5 minutes were reported. Clinical response to left anterior descending occlusion: Evidence for myocardial ischemia did not occur earlier, and in no patient were ischemia-related ECG changes more severe during LAD occlusion with nicardipine infusion (Fig. I]. Although evidence for myocardial ischemia recurred after nicardipine, in all but 1 patient (no. 91, the time to onset of ischemia was consistently delayed in 7 of the 10 patients. In 3 patients (nos. 1, 2 and 8), ischemia was neither delayed nor prevented by nicardipine. Time to onset was very brief in patients 1 and 2 (16 and 17 seconds during the first control period occlusion]. No other clinical feature separated patients who did or did not have a beneficial response. Coronary and systemic hemodynamic values during left anterior descending occlusion (Table II): During nicardipine infusion mean aortic pressure decreased (16%, p <0.05), accompanied by an increase in heart rate (15%, p <0.05]. The double product was usually slightly decreased (7%, p <0.05). Mean distal coronarv oressure (4%. difference not significant1 and

OF CARDIOLOGY

Residual GCVF (ml/min)

LVFP

C

f12

JOURNAL

421

CR (mm Hg/ mllmin)

Volume

60

ass

DP (mm Hg beats/ (min X lo*)

N

C

N

C

N

20 62 33 12 81 48 61 22 67 65 47 f24

5.12 1.75 3.26 9.88 0.96 2.41 1.10 2.10 1.33 1.25 2.92 f2.75

3.05 1.10 2.33 5.17 0.68 1.56 0.98 2.18 0.60 0.085 1.85 f1.42

118 70 115 101 78 118 118 90 84 90 98 fl8

106 79 98 85 69 117 117 71 72 95 9? fl8

resistance; DP = double product: N = nicardipine; SD = standard

GCVF = great deviation.

cardiac

vein

flow;

LV filling pressure (-5%, difference not significant) were not consistently altered. The pressure gradient across the collateral bed was consistently less during nicardipine administration (average 18 mm Hg, p <0.05]. Residual great cardiac vein flow increased in 9 of 10 patients (15%, p KO.05) and the estimated collateral resistance declined in the same 9 (37%, p
Discussion In most patients studied, calcium antagonism with nicardipine resulted in prevention or delayed onset of myocardial ischemia during balloon occlusion of the proximal LAD. The clinical and coronary hemodynamic responses before and during nicardipine infusion were examined in an attempt to explain the basis for this beneficial response. Nicardipine consistently altered 2 major determinants of myocardial oxygen demand. Aortic pressure decreased but heart rate reflexly increased. Thus, the double product, an index of global myocardial oxygen demand, was only slightly reduced. Furthermore, another major determinant of myocardial oxygen demand, LV filling pressure, was usually unchanged. These acute nicardipine-induced alterations in systemic hemodynamic changes would not likely account for an important reduction in myocardial oxygen demand during LAD occlusion. We have previously shown that nicardipine causes large increases in total LV caironary flow in patients with generally patent LAD coronary arteriesJ5J6 In this study during acute, complete LAD occlusion, residual great cardiac vein flow represents an index of the collateral blood flow to the anterior region. This index increased in 9 of 10 patients during nicardipine infusion. This important Icoronary hemodynamic change was accomnanied bv a large decrease in collat-

270

NICARDIPINE

AND

MYOCARDIAL

ISCHEMIA

era1 resistance. This increase in anterior LV myocardial perfusion correlated with the observed clinical benefit in 7 of the patients. Acute proximal LAD occlusion is a potent method to promptly produce myocardial ischemia. Each of the patients studied here had angina accompanied by ischemia-related ST and T changes within 60 seconds of the onset of occlusion. In 7 of the 10 patients, nicardipine consistently prolonged the time to a similar degree of ECG change. The 3 patients who did not benefit differed from the others in that ischemia developed fastest in 2 (16 and 17 seconds after control LAD occlusion) and residual great cardiac vein flow decreased and collateral resistance increased during nicardipine infusion only in the third patient. Thus, coronary steal may occur occasionally with this potent coronary vasodilator. Review of the effects of other calcium antagonists on global and regional myocardial blood flow in patients shows variable responses have been observed. Diltiazem, nifedipine and verapamil have been shotin to induce only slight increases of no change in global estimates of coronary blood flow as blood pressure declines.17-23 Hence, estimates of global coronary resistance are usually decreased. Some newer dihydropyridines may be more potent coronary vasodilators. In patients with chronic total proximal LAD occlusion, nifedipine did not increase residual great cardiac vein flow, but did decrease anterior region collateral resistance.lg Although nicardipine is a dihydropyridine like nifedipine, it possesses the ancillary properties of phosphodiesterase inhibition and possible facilitation of calcium influx.24 Perhaps these properties lead to greater coronary vasodilation with nicardipine. Because of differences found comparing coronary responses to nicardipine and other calcium antagonists, these data with nicardipine should not be extrapolated to other calcium antagonists. Our patients represented a relatively homogeneous group, predominantly with l-vessel disease and preserved LV function. Our technique for estimating coronary collateral function during balloon occlusion of the LAD coronary artery requires several hemodynamic assumptions, which have been discussed in detail previously;1-4 These pressure and flow measuremetits should be taken only as estimates of coronary collateral hemodynamic function. Other studies show that these pressure and flow measurements do separate patients with chronic angiographically visible collateral vessels from those without visible collateral vessels,l and also patients who during LAD occlusion evolve transient ST elevation from others with transient ST depression.2 In our experience, repeated brief coronary occlusions lead to similar clinical, ECG and hemodynamic changes as long as duration of occlusion is constant and no medication is administered. Presence or absence of specific easily identifiable reversible ST- and T-wave changes were used as an indicator of myocardial ischemia. The specificity and sensitivity of this index as a severity of transient myocardial ischemia is debatable. Additional techniques have also been used

to complement chest pain responses and the surface electrocardiogram.5*6J5J6

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