Response of Angiographically Normal and Atherosclerotic Left Anterior Descending Coronary Arteries to Acetylcholine Christopher M. Newman, MB, MRCP, Attilio Maseri, MD, David R. Hackett, MD, Hassan M. El-Tamimi, MD, and Graham J. Davies, MD

Acetylcholine-induced constriction of human coronary arteries in vivo is commonly attributed to endothelial dysfunction. To examine the effects of 2 other important determinants of vascular reagonist concentration and the sponses -namely, segment of circulation under study-the diameters of proximal, middle and distal segments of the left anterior descending artery (LAD) and coronary sinus oxygen saturation were measured in 10 patients with angiographically normal coronary arteries (group 1) and in 7 patients with coronary atherosclerosis (group 2) after intracoronary acetylcholine was infused at concentrations from 10e7M tobetween 10m4Mand lo-*M. Ingroup 1, acetylcholine caused minor (16%) but progressive dilatation of the LAD up to 10e4M, but constriction, particularly of the distal segments and tertiary branches, occurred at higher concentrations. Over the same concentration range, coronary sinus oxygen saturation rose progressively from a basal level of 36 f 3% to a maximum of 72 f 3% in the absence of changes in heart rate and blood pressure, suggesting marked progressive dilatation of resistance vessels. Concentrations 1 10e3M caused intense constriction of distal epicardial vessels and, in some cases, angina1 pain and objective signs of ischemia. Conversely, in group 2, acetylcholine (infused only up to 10e4M for ethical reasons) failed to cause significant changes in LAD diameter. These data suggest that the local acetylcholine concentration and coronary vascular segment under study may determine the observed response to at least an equivalent extent as does the presence or

From the Division of Cardiovascular Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom. This study was supported by the British Heart Foundation, and was presented in part at the 60th Scientific Sessions of the American Heart Association, Anaheim, California, November 1987. Dr. Newman holds a Clinician Scientist Fellowship from the Medical Research Council. Manuscript received April 16, 1990; revised manuscript received and accepted June l&1990. Address for reprints: Dr. C. M. Newman, Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W 12 ONN, United Kingdom.

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absence of coronary atherosclerosis, raising the question of whether a constrictor response to intracoronary acetylcholine reliably indicates the presence of coronary atherosclerosis. (Am J Cardiol 1990;66:1070-1076)

he vascular effects of acetylcholine are complex, with agonist-stimulated release of endotheliumderived relaxing factor opposedto a variable extent by direct smooth muscle constriction.’ It has been reported that the net effect of intracoronary acetylcholine is fundamentally different in patients with coronary artery disease,net dilatation being replaced by an overall constrictor effect.2 Acetylcholine-induced constriction has also been observedin angiographically smooth epicardial vesselsof patients with evidenceof coronary artery diseaseelsewhere,leading to the speculation that constriction of angiographically smooth epicardial vessels in responseto intracoronary acetylcholine may predict future coronary artery disease.3 To investigate the importance of 2 further variables-namely agonist concentration and the segment of coronary circulation under study-as determinants of the net observedresponse,we constructeddetailed doseresponsecurves for the effect of intracoronary acetylcholine on successivesegmentsof the coronary circulation of patients with entirely smooth epicardial coronary arteries, and compared them to data obtained in patients with angiographic evidence of coronary atherosclerosis.

T

METHODS Patient characteristics:

Group 1 comprised 10 patients (7 women and 3 men, aged 32 to 60 years [mean 461) with atypical chest pain and no demonstrableevidence of spontaneousor inducible myocardial ischemia, as assessedby treadmill exercisetests,provocation tests for coronary spasmand ambulatory ST-segmentmonitoring. Coronary arteriography was performed for further evaluation of the chest pain syndrome, and all patients had completely smooth and normal coronary arteriograms as assessedby 3 independentobservers. Group 2 comprised 7 patients (6 men and 1 woman, aged 37 to 59 years [mean 491) with a history of chronic stable angina. Four of these patients had had a myo-

(M) and lsosorbide

3

2x10-3

5x10-3

Dinitrate (2 mg/2 ml) on Distal Left Anterior Descending Artery and

lo-2

1O-7

10m6 10-s 10e4 1O-3 2X10m3 5X1O-3

ISDN

1.15 30 1.93 30

29 22

37 25

58 31

75 56

80 72

50 30

2.22 37 2.13 49

33 49

39 52

66 62

76 78

1.39 32

31

35

32

36

ISDN

Basal

1.75 1.20 1.27 1.23*

1.28 1.56

1.33 1.40 1.49 1.32 0.73" 1.84 1.82 1.77 1.74 1.56

1.59

1.05

1.07 1.02 1.06 1.08 1.08

1.13

0.79"

cardial infarction 16 months before this study that had not involved the territory of the left anterior descending (LAD) artery or its branches. Each of these patients was found to have widespreadand diffuse coronary atherosclerosisat diagnostic catheterization, but no critical (250% reduction in luminal diameter) stenoses.Each gave written informed consent, and the study protocol was approved by the Hammersmith Hospital research ethics committee. Procedure: All studies were performed immediately after diagnostic coronary arteriography and after the complete withdrawal of all cardiac medication for 224 hours. Femoral arterial pressure and surface electrocardiographs were monitored throughout each procedure. Coronary sinus oxygen saturation was measuredin 6 of group 1 patients, either by repeated sampling through a Goodale Lubin catheter (3 patients) or by continuous useof a 4Fr fiberoptic oximeter catheter (in vivo combimeter system IVS 4000, Schwarzer) positioned as far up the coronary sinus as possible (3 patients). Left ventricular pressure was measured continuously in 5 of group 1 patients through a micromanometer-tipped 7Fr pigtail catheter (Sentron, Cordis Corporation). Study protocol: All intracoronary infusions were administered through the left Judkins catheter at 1 ml/ min for 2 minutes with a syringe pump (Perfusor, B. Braun Melsungen A.G.). Seven of group 1 patients received 5 consecutiveinfusions of 0.9% saline as a control series;all subsequentpatients received 1 control infusion only. Sequential infusions of acetylcholine in 0.9% saline were then administered, with incremental concentrations in the syringe pump from 1QW7Mup to a maximum of at least 10e3M in group 1 patients (4 received between 2 X 10P3M and 10W2M),and up to a maximum of 10a4M in group 2 patients. An intracoronary bolus of isosorbidedinitrate (2 mg in 2 ml) was administered as the final intervention. Left coronary arteriograms were recorded at the beginning of each study, after each infusion and after the intracoronary injection

80 62'

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84

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70

73

34 70 52

of isosorbide dinitrate; in each casethe samesingle projection that best visualized the entire length of the left anterior descending artery was maintained. Nonionic contrast medium (Omnipaque 350) was used throughout. Dataanalysis:

EPICARDIALVESSELLUMINALDIAMETER:

The single-plane luminal diameters of selected proximal, middle and distal segmentsof the LAD coronary

+20 +lO

L

Proximal

n=7

1

Saline

(control)

infusion

number

FIGURE 1. Plot of percent change in luminal diameter of suecessive segments of the left anterior descending coronary artery (mean f standard error) associated with repeated 2-minute infusions of 0.9% saline in group 1 patients.

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artery were measured by an automated edge-contour detection computer analysis system (Cardiovascular Angiography Analysis [CAA] System, Pie Data Medical). The specific coronary segments were defined by the distances from the side branches. The size of the +30

Proximal

n= 10

+20

/’ Li

1

I

+20

,’ ,’

Middle

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1

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Distal

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-7

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ISDN

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log

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[AChlinfusate

RESULTS

n=6

1

O-’ I Basal 6

I -7

I -6 ‘w

I -5

I

I

-4

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I

ISDN

WhImsate

FIGURE 2. Plots of percent change in (A) luminal diameter of the proximal, middle and distal segments of the left anterior descending coronary artery, and in (R) coronary sinus oxygen saturation associated with P-minute infusions of increasing concentrations of acetykholine (log [ACh]i,,e,=u) and intracoronary injection of 2 mg of imsorbide dinitrate (ISDN) in group 1. Mean values as in Figure 1.

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coronary catheter was used to calibrate the image in millimeters, and correction was made for radiographic pincushion distortion. There was no significant differencein the variances of repeatedanalyses(F coefficient = 0.3, p = 0.6, 95% confidence limits for the difference l 0.15 mm). CHANOESINLE~C~R~NARYBLOODFLOW: The oxygen saturation of venous blood measured as far as possible up the coronary sinus is determined by left coronary artery blood flow and myocardial oxygen demand (Fick’s principle). Because there were no significant changes in arterial pressure, heart rate or indexes of myocardial contractility in any study (see later), any changes in coronary artery sinus saturation were assumed to reflect changesin left coronary blood flow directly.4 Statistical analysis: All values are given as mean f 1 standard error of the mean. Statistical analysesof the effects of intracoronary 0.9% saline and acetylcholine on epicardial vessel luminal diameter, coronary sinus oxygen saturation and hemodynamic parameters were performed using 2-way analysis of variance. Any significant trends in the effects of acetylcholine on epicardial vesselluminal diameter were further assessedby linear, cubic and quadratic contrasts, and on the heart rate/ arterial pressure product after square root transformation of the data. Statistical comparison of epicardial vessel luminal diameter and hemodynamic parameters in the basal state and after intracoronary isosorbidedinitrate was made using the 2-tailed paired t test. The null hypothesis was rejected at p