International Journal of Cardiology, 11 (1986) 25-36

Elsevier

25

IJC 00374

The response of the coronary collateral circulation to acute administration of nifedipine: an angiographic

and ergometric study

Gian Piero Carboni, Marino D’Ermo, Mark Mattioli, Ernest0 Lioy and Giorgio Biffani

Cardiology Department, San Camille Hospitul, Rome, Italy

(Received 2 April 1985; revision accepted 29 October 1985)

Carboni GP, D’Ermo M, Mattioli M, Lioy E, Biffani G. The response of the coronary collateral circulation to acute administration of nifedipine: an angiographic

and ergometric study. Int J Cardiol 1986;11:25-36.

To evaluate the role of collaterals in patients with effort angina we retrospectively compared the coronary cineangiograms of 14 subjects (“responders”) who improved their exercise tolerance after acute nifedipine therapy with 14 subjects (“non-re- sponders”) with the same symptomatology who did not respond to the same treatment. The status of collaterals was graded with a score from a minimum of 0 to a maximum of 5. The responders showed a greater score than the non-responders (3 f 1 vs. 1 f 1, P < O.OOl), whereas there was no difference in the number of steno& vessels between the two groups (1.8 f 0.9 vs. 2 f 0.8). Thus, in patients with effort angina and critical coronary stenosis, the presence of an efficient coronary collateral circulation can favour the increase in coronary flow reserve after vasodilator therapy. Our results suggest that the grading of collaterals may add useful information to the simple classification of one-, two- or three-vessel coronary artery disease.

(Key words: coronary collateral circulation; coronary flow reserve; effort angina; exercise testing; nifedipine)

Introduction

The normal human heart has an extensive network of anastomotic channels which is present at birth and increases with age along with development of the rest of the

Reprint requests to: G.P. Carboni, M.D., Division of Cardiology “A”. San Camillo Hospital.

Circonvallazione Gianicolense. Rome. Italy.

0167-5273/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

26

coronary circulation. The three most important stimuli to the opening of these

channels are thought to be severe obstructive coronary artery disease, chronic

hypoxia, and left ventricular hypertrophy [l]. It has been suggested that local

vasodilators are responsible for the collateral circulation which may be observed in

obstructive coronary artery disease [2]. If this is true, then vasodilating drugs may

play a part in opening up anastomotic channels, and thus may partly account for their favourable influence on coronary flow. We have examined this proposition by

means of a detailed analysis of the coronary arteriograms of a group of patients who responded to the slow calcium channel blocking agent nifedipine, compared with a

group who did not respond.

Patients and Methods

All patients undergoing coronary angiography with a history of angina pectoris of

at least 1 year duration were considered for entry into the study. All had a history of classical angina1 pain precipitated by exertion and relieved by rest and by sublingual

nitroglycerine. Patients were excluded with a history of recent infarction (3 months), hypertension ( > 160/90), electrocardiographic conduction defects, and if they had

taken drugs (e.g. digitalis) likely to influence ST segment duration on exercise.

All cardio-active drugs (apart from sublingual nitrates) were gradually withdrawn over a l-week period. At the end of this time. each patient underwent a symptom- limited maximal treadmill exercise test. A Bruce protocol was employed and each

test was terminated at the onset of angina or 3 mm of ST depression at J + 80 msec. Leads 1, 2, and 3 were continuously monitored and the test was considered positive if the ST segment was depressed by 1 mm at J + 80 msec with a slope of < 0.1 mV.

The electrocardiogram was recorded at rest and every minute during the exercise.

peak exercise, and at 1, 3, and 6 min during the recovery period. The exercise test was repeated the following day at the same time and under

identical conditions with the exception of a single 70 mg dose of nifedipine taken

orally 2 hours beforehand. The patients were then divided into two groups. “Responders” were those

patients who satisfied the following arbitrary criteria [3]. First, they were required to

show an improvement in exercise time by at least 1 min into the next stage of the Bruce protocol, plus either 2 or 3. Second, they needed to evidence the same or increased myocardial oxygen consumption as indicated by increased peak “double

product” with a lesser degree of “ischaemia” as indicated by a decreased peak ST

depression. Finally, they showed the same degree of “ischaemia” at a higher peak

double product. “Non-responders” were those who failed to satisfy the above

criteria. All patients who entered the study underwent coronary arteriograms performed

by the Judkins technique. The angiograms were interpreted independently by two experienced observers who had no knowledge of the exercise results. They each scored the coronary collateral circulation as follows:

Score 0 - no collaterals (Fig. 1). Score 1 - collaterals served by one stenotic vessel (Fig. 2).

Fig. 1. A. Left coronary angiogram in the 30” right anterior oblique projection: 90% stenosis (arrow) in

the left anterior descending artery (lad): no collateral circulation. The circumflex artery is not visualized

and has a separate origin. B. Right coronary angiogram in the 60” left anterior oblique projection: 70%

stenosis (arrow) in the right coronary artery (rca): no collateral circulation. Score 0.

Fig 2. A. Left coronary angiogram in the 60” left anterior oblique projection with 15” cranial angulation:

85% stenosis (black arrow) in the left anterior descending artery (lad) and 90% stenosis (black arrow) in

the circumflex (cx). Patent left main (mica). Collateral circulation from the cx (white arrows) to the rca. B.

Right coronary angiogram in the 30” right anterior oblique projection: complete obstruction (black

arrow) in the right coronary artery (rca). Score 1.

Fig. 3. A. Left coronary angiogram in the 30” right anterior oblique projection: 85% stenosts (black

arrows) in the left anterior descending artery (lad). Complete obstruction (black arrow) in the circumflex

(cx). Patent left main (r&a). Collaterals from cx and lad (white arrows) to the right coronary artery (rca)

and from lad (white arrows) to the obtuse marginal of cx. B. Right coronary angiogram in the 60° left

anterior oblique projection: subtotal stenosis (black arrow) in the right coronary artery (rca). Collaterals

(white arrows) from rca to lad. Score 2.

Fig. 4. A. Left coronary angiogram in the 30” right anterior oblique projection: complete obstruction

(black arrow) in the circumflex (cx). Patent left main (mica). Collaterals (white arrows) from a patent left

anterior descending artery (lad) to cx. B. Right coronary angiogram in the 30” right anterior oblique

projection: right coronary artery (rca) without significant narrowings. Score 3.

Fig. 5. For legend see next page

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Fig. 5. A. Left coronary angiogram in the lateral projection: 95% stenosis (black arrow) in the left anterior

descending artery (lad). Collaterals (white arrows) from a patent circumflex (cx) to lad. Patent left main

(mica). B. Left coronary angiogram in the 30” right anterior oblique projection: collaterals (white arrows)

from the circumflex (cx) and left anterior descending artery (lad) to the right coronary artery (rca). C.

Right coronary angiogram in the lateral projection: 95% stenosis (black arrow) in the right coronary

artery (rca). Score 4.

Score 2 - collaterals served by two or more stenotic vessels (Fig. 3). Score 3 - collaterals served by one patent vessel (Fig. 4). Score 4 - collaterals served by one patent vessel and one stenotic vessel (Fig. 5).

Score 5 - collaterals served by two patent vessels (Fig. 6).

Statistical analysis was performed using paired and unpaired Student’s t-tests.

Results

Twenty-eight patients entered the study: 14 Responders and 14 Non-responders.

Angiograms

There were 11 males and three females with a mean age of 52 ( + 8) in the group of Responders. Eight (57%) had a history’ and electrocardiographic evidence of infarction at least 2 years previously. The angiograms showed 2 70% stenosis in all three vessels in 5, two vessels in 2, and one vessel in 7. There was & 90% stenosis of at least one vessel in 11.

Fig. 6. A. Left coronary angiogram in the 60” left anterior oblique proJection with 15’ cranial angulation:

95% stenosis (black arrows) in the left anterior descending artery (lad). Patent left main (mica). Collaterals

(white arrows) from a patent circumflex (cx) to the lad. 9. Right coronary angiogram in the 30” right

anterior oblique projection. Collaterals (white arrows) from a patent right coronary artery (rca) to lad.

Score 5.

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TABLE 1

Exercise test results of 14 patients (Responders) with effort angina who improved their exercise capacity

after nifedipine acute therapy and of another 14 patients (Non-responders) with the same symptomatol-

ogy but who did not respond to the same treatment.

Responders

1 st exercise

test

(basal)

Non-responders

2nd exercise 1st exercise

test (after test

nifedipine (basal)

therapy)

2nd exercise

test (after

nifedipine

therapy)

Exercise time

(min) 4*2 P < 0.001 8+2 5*4 NS 5i_4 ST depression

(mm) 1.6 F 0.7 P < 0.05 1+1 1.710.7 NS 1.5*1

Double

product/100 188+49 NS 194+44 211+58 NS 184*48

Angina (1% patients) 100% P i 0.001 28% 100% P i 0.01 42%

The Non-responders group consisted of 12 males and two females with a mean age of 53 (t-8). Seven (50%) had a history and electrocardiographic evidence of

infarction at least 18 months previously. The angiograms showed 2 70% stenosis of all three vessels in 5, two vessels in 5, and one vessel in 4. There was 3 90% stenosis

of at least one vessel in 12.

Exercise Testing (Tables 1 and 2)

There was no significant difference between the groups for age or for exercise capacity at the first test. Similarly, there was no significant difference in the number

of stenosed vessels, the ejection fraction, and the left ventricular end-diastolic pressure between the two groups. By definition, the exercise tolerance increased in

all the Responders (9 with a lesser degree of ischaemia, and 5 with the same degree). Similarly, there was a significantly more extensive coronary collateral circulation

in the group of Responders (see Table 2).

TABLE 2

Coronary cineangiogram data of 14 patients (Responders) with effort angina who improved their exercise

tolerance after acute nifedipine therapy and the data of another 14 patients (Non-responders) with the

same symptomatology but who did not respond to the same therapy.

Responders Non-responders

Number of stenosed vessels Collaterals score

Ejection fraction(%)

Left ventricular end-diastolic pressure (mm Hg)

1.8k 0.9 NS 2+ 0.8

3 +1 P i 0.001 la! 1

66 +18 NS 64k15

18 + 5 NS 19+ 5

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Discussion

The resting coronary perfusion pressure distal to a 50% stenosis may be as much

as 40-60 mm Hg, which is adequate to perfuse the myocardium [4]. During exercise-induced ischaemia, however, there is a fall in perfusion pressure and the left

ventricular end-diastolic pressure may rise to 30-40 mm Hg [4]. A single dose of nifedipine produces a transitory fall in blood pressure with an associated reduction

in left-ventricular end-diastolic volume and pressure. This leads to reduction in

myocardial oxygen demand and a redistribution of blood flow across the existing

collateral vessels [5]. When these are served by patent coronary arteries. the increase

in collateral flow should be even greater. The improved exercise tolerance at the

same level of double product in the group of Responders was associated with a significantly greater collateral circulation, suggesting that at least some of the

beneficial effects of the drug are due to its effects in increasing collateral flow. The

double product is by no means an accurate measure of myocardial oxygen consump- tion, but it is easily measured and its validity has been thoroughly established [6].

The importance of an effective collateral circulation in patients with obstructive

coronary artery disease has been disputed [7.8]. The method of scanning the collateral circulation described here gives a better and more complete picture than a simple classification into one-, two-, or three-vessel disease. Ttie improvement in

exercise tolerance in these patients correlated better with the collateral score than with the number of stenosed vessels.

This cannot be considered as anything other than a pilot study but the results are

such as to suggest that a larger prospective randomised study to investigate the functional significance of the collateral coronary circulation and its responses to

vasodilator therapy would be worth undertaking. Such a study might produce new and valuable information on the patho-physiology of intermittent myocardial ischaemia and its therapeutic management.

Acknowledgement

We are grateful to Dr. E.B. Raftery for assistance in the preparation of the

manuscript.

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