Ischemia in collateral-dependent myocardium: Effects of nifedipine and diltiazem in man

It has recently been shown that Ischemia in collateral-dependent myocardium may develop at a very variable threshold in anginal patients; accordingly, the aim of this study was to assess whether nifedipine and diltiazem can increase blood flow to collateralized myocardium in man. Nine patients with complete coronary occlusion filled by collaterals, with no other coronary stenosis, normal left ventricular function, and reproducibly positive exercise tests were studied. They underwent exercise tests off therapy and after acute randomized administration of nifedipine (10 mg sublingually), diltiazem (120 mg orally), and nitroglycerin (0.5 mg sublingually), the latter a drug known to increase blood flow to collateralized myocardium. Following nifedipine, time to 1 mm ST segment depression increased significantly (from 430 + 176 to 576 ± 205 seconds, p < 0.01), while heart rate and rate-pressure product remained unchanged (115 ± 16 vs 121 ± 17 beats/min and 199 ± 29 vs 204 ± 44 beats/min • mm Hg • 10^, respectively, p = NS for both). Similarly, diltiazem significantly increased time to ischemic threshold from baseline to 638 ± 125 seconds (p < 0.01), but did not change heart rate and rate-pressure product at 1 mm ST segment depression. Submaximal rate-pressure products were significantly lowered by both nifedipine and diltiazem. Nitroglycerin not only significantly improved time to ischemic threshold (from baseline to 666 ± 76 seconds, p < 0.01), but also increased heart rate (from baseline to 137 ± 16 beats/min, p < 0.01) and rate-pressure product (from baseline to 242 ± 48 beats/min mm Hg - 10^ p < 0.05); submaximal rate pressure products were unchanged after nitroglycerin. Thus it is concluded that in patients with chronic coronary occlusion and collateral circulation, nifedipine and diltiazem increase exercise duration; this effect is achieved through a reduction of myocardial oxygen consumption rather than by increasing blood flow to collateral-dependent myocardium. (AM HEART J 1993;126:86-94.)

Giuseppe Pupita, MD, Domenico Mazzara, MD, Maurizio Centanni, MD,

Carla Rimatori, MD, Gino Fabrizio Ferretti, MD, Paolo Dessi-Fulgheri, MD,

Paolo Russo, MD, and Alessandro Rappelli, MD Ancona, Italy

Several lines of evidence suggest that changes in cor­onary collateral resistances can play an important role in determining the presence and severity of my­ocardial ischemia. Animal studies have demonstrated that blood flow to collateralized myocardium may be influenced by several physiologically present sub­stances by inducing changes of collateral resis­tances^"^; furthermore, it has been recently shown that ischemia in collateral-dependent myocardium may develop at a very variable threshold in patients with stable angina and complete coronary occlusion.* Nifedipine and diltiazem are widely used in the treatment of chronic stable angina; they can exert

From Institute of Patologia Medica, University of Ancona.

Received for publication Aug. 14, 1992; accepted Jan. 4, 1993.

Reprint requests: Giuseppe Pupita, MD, Istituto di Patologia Medica,

Servizio di Cardiologia, Ospedale Regionale di Torrette, 60020, Ancona, It­

aly.

Copyright ® 1993 by Mosby-Year Book, Inc. 0002-8703/93/$1.00 + .10 4 / 1 / 4 6 2 9 1

antiischemic effects through coronary stenosis dila­tation,^'^ prevention of stenosis constriction,^"^^ and reduction of myocardial oxygen consumption.^' ' ^^'^'^ It is still controversial, however, if they can also act to increase collateral blood flow.

In the present study we selected a highly homoge­neous group of patients with isolated coronary artery occlusion and normal ventricular function, so that ischemia would be present in only a noninfarcted, entirely collateral-dependent myocardial region. In these patients we evaluated the effects of short-term nifedipine and diltiazem administration; the effects of these substances were also compared with those of nitroglycerin, a substance known to increase blood flow to collateralized myocardium.^^"^"

METHODS Patients. Nine consecutive patients, all males aged

60 ± 5 years (range 52 to 69), participated in the study. Their clinical, electrocardiographic, and angiographic char­acteristics are summarized in Table I. They were selected

86

Volume 126, Number 1 American Heart Journal Pupita et al. 87

Table I. Clinical, electrocardiographic, and angiographic data of the study patients

Patient No.

1 2 3 4 5 6 7 8 9

Age (yr)

69 64 55 63 60 61 54 60 52

Occluded vessel

RCA LAD RCA RCA LAD LAD LAD RCA + OMi RCA + Cx

EF (%)

72 70 71 62 70 62 70 68 65

12-lead ECG

Normal Normal Flat Tw V4-Normal Neg Tw Vr Normal Normal Normal Normal

•Ve

•V2

Symptom onset (yr)

2 13 3 3 3 2 0.9

14 1

Angina

Occ Occ E/VT E/VT Occ E E B/VT/R EA^T

Angina

class*

— — II III

— Ill II II III

Cx, Circumflex coronary artery; E, exertional; EF, ejection fraction; LAD, left anterior descending artery; Neg, negative; Occ, only occasional effort angina; OM,, first obtuse marginal branch; R, rest; RCA, right coronary artery; Tw, T waves; VT, variable threshold effort angina. 'According to the classification of the Canadian Cardiovascular Association.^'

on the basis of the following criteria: (1) chronic stable an­gina without changes in symptoms in the last 3 months; (2) presence of >1 completely blocked coronary arteries filled by collateral circulation arising from angiographically nor­mal coronary arteries; (3) no stenoses in the remaining cor­onary vessels; (4) normal global and segmental left ven­tricular wall motion; and (5) positive exercise tests off therapy. All patients were in sinus rhythm and none had evidence of heart failure, cardiomyopathy, or valvular dis­ease. All patients had a normal resting ST segment level and none were taking digitalis. The blocked artery was the right coronary artery in three cases and the left anterior descending in four patients. One patient had a complete occlusion of both circumflex and right coronary arteries and one had a complete occlusion of the right coronary ar­tery and of the first obtuse marginal branch. Collateral filling, assessed according to the criteria of Rentrop et al., ^ was grade 3 in all patients. Mean left ventricular ejection fraction at rest was 68 + 4% (range 62% to 72%).

Study protocol. Written informed consent was obtained from all patients. After pharmacologic washout (>2 days for calcium channel blockers and oral nitrates and >4 days for /^-blockers), patients underwent a baseline exercise test. They then performed (at 2-day intervals) exercise tests: (1) 5 minutes after 10 mg of sublingual nifedipine; (2) 1 hour after 120 mg of oral diltiazem; and (3) 5 minutes after 0.5 mg of sublingual nitroglycerin. The order of drug admin­istration was randomized. Finally, within 2 weeks, a second exercise test with patients off therapy was repeated; its re­sults were used for comparison with drug treatments.

Exercise testing. Exercise tests were performed be­tween 9:00 A.M. and noon, with the room temperature kept at 20° to 24° C. Patients were requested to abstain from smoking for >3 hours and from xanthine-containing food and drinks for >I2 hours before the tests. A modified Bruce protocol was used^ ; end points were fatigue, pro­gressive angina, and ST segment depression >2 mm (1 mm = 0.1 mV). Twelve-lead electrocardiograms and blood pressure monitoring (cuff sphygmomanometer) were re­corded at baseline, after drug administration just before starting the exercise, at 1-minute intervals during exercise,

and for >:6 minutes during recovery. The level of the ST segment, 60 msec after the J point, was calculated after signal averaging by a computer-assisted system (ExTol 700, Burdick Corp., Milton, Wise.) in all 12 leads. The electrocardiographic lead showing the greatest ST segment depression was selected for analysis. For each test time to 1 mm ST segment depression, heart rate and heart rate-systolic blood pressure product (rate-pressure product) at 1 mm ST segment depression and at peak exercise were measured. Maximal ST segment depression was also re­corded. In addition, the rate-pressure product was also measured at submaximal levels—that is, at exercise times corresponding to 20%, 40%, 60%, 80%, and 100% of the time at which the ischemic threshold (1 mm ST segment depression) was reached with patients off treatment.

Statistical analysis. Data are presented as mean ± 1 standard deviation. Statistical analysis was performed by repeated measurements analysis of variance; the Scheffe test was used for comparisons between treatments. A value of p < 0.05 was considered statistically significant.

RESULTS Reproducibility during exercise testing off therapy.

All tests were positive for ST segment depression on both occasions. None of the exercise parameters showed statistically significant differences when the two tests with patients off therapy were compared. Mean absolute differences between the two tests were 39 ± 12 seconds (9%), 9 ± 7 beats/min (7%), and 17 ± 14 (8%) beats/min -mm Hg • 10^ for time, heart rate, and rate-pressure product at 1 mm ST segment depression; similar values were obtained for the same parameters at peak exercise (9 %, 6 %, and 9%, respectively). The mean difference in peak ST segment depression was 0.15 ± 0.09 mm (9%).

Effects of nifedipine. Nifedipine significantly in­creased resting heart rate and decreased systolic blood pressure, whereas resting rate-pressure prod­uct was unchanged (Table II). After nifedipine, the

88 Pupita et al. July 1993

American Heart Journal

1000

0)^ 800

o p ^600

• y ^ 01400

^ ^ 200

p<0.01 p<0.01 p<0.01

Off N Off D Off NTG

o 3

v •• 9

5i CO * -0 ) ' -9-ni 0) (0 GC

400

o o 6)300 l E

g200 ^

p=NS

Off N

p=A/S

Off D

p<0.05

Off NTG

Fig. 1. Exercise time and rate-pressure product at the ischemic threshold (1 mm ST segment depression [STl]) off treatment (Off) and following short-term administration of nifedipine (N), diltiazem (D), and nitroglycerin (NTG).

Table II. Hemodynamic parameters before and after short-term administration of nifedipine, diltiazem, and nitroglycerin

HR (beats/min)

SBP (mm Hg)

RPP (beats/min • mm

Hg • m

Baseline Nifedipine

Baseline Diltiazem

Baseline Nitroglycerin

71 ± 19 79 ± 16t

80 ± 20 71 ± U t

75 ± 18 99 + 19*

136 ± 12 125 ± 17*

127 ± 16 121 + 7

130 + 20 113 + 23t

96 + 29 98 + 20

102 ± 31 86 + 18t

98 + 28 110 ± 18

HR, Heart rate; RPP, rate-pressure product; SBP, systolic blood pressure. *p < 0.01 versus off therapy, fp < 0.05 versus off therapy.

exercise test remained positive in all patients. Time to 1 mm ST segment depression significantly in­creased from 430 ± 176 to 576 ± 205 seconds (p < 0.01) (Fig. 1), while heart rate, systolic blood pressure, and rate-pressure product at 1 mm ST seg­ment depression did not show significant changes (115 ± 16 vs 121 ± 17 beats/min, 173 + 19 vs 168 ± 20 mm Hg, and 199 ± 29 vs 204 ± 44 beats/ min • mm Hg • 10^, respectively). No significant changes in exercise time, heart rate, rate-pressure

product, or ST segment depression at peak exercise were observed (Table III) (Fig. 2). Submaximal rate-pressure products were lower following nife­dipine than during exercise testing with patients off treatment; these differences achieved statistical sig­nificance (p < 0.01, <0.01, and <0.05, respectively), at times corresponding to 60%, 80%, and 100% of the time at which the ischemic threshold was reached with patients ofi treatment (Fig. 3).

Effects of diltiazem. Diltiazem significantly de­creased resting heart rate and rate-pressure product; systolic blood pressure did not change significantly (Table II). After diltiazem, the exercise test became negative in one patient (patient No. 6) in whom the test had to be stopped because of progressive angina; at that time there was 0.8 mm ST segment depres­sion. On average, time to 1 mm ST segment depres­sion significantly increased to 638 ± 125 seconds (p < 0.01). Heart rate, systolic blood pressure, and rate-pressure product at 1 mm ST segment depres­sion were not significantly different (116 ± 16 beats/ min, 165 ± 16 mm Hg, and 192 ± 37 beats/min • mm Hg • 10^, respectively) (Fig. 1). A significant increase of exercise time was also observed at peak exercise (from 500 ± 170 to 648 ± 141 seconds, p < 0.05). Heart rate, systolic blood pressure, rate-pressure product, and maximal ST segment depression at

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American Heart Journal Pupita et al. 89

E

03

<D X 0) 4-* O

1000

^ 8 0 0

§ 600

"« 400

200

p=A/S p<0.05 p<0.01

Off N Off D Off NTG

o 3 "D 0) O «

^9

400

I 300 E

S 0) E CL a o 200

(0 cc

^- X 3 03 to >-.

0) ™

p=A/S p=WS p<0.01

Off N Off D Off NTG

Fig. 2. Total exercise time and rate-pressure product at peak exercise off treatment (Off) and following short-term administration of nifedipine (N), diltiazem (D), and nitroglycerin (NTG).

Table III. Exercise parameters off therapy and after short-term administration of nifedipine, diltiazem, and nitroglycerin

1 mm T (sec) 1 mm HR (beats/min) 1 mm SBP (mm Hg) 1 mm RPP (beats/min • mm Hg • 10^) pk T (sec) pk HR (beats/min) pk SBP (mm Hg) pk RPP (beats/min • mm Hg • 10^) pk STi (mm)

Off therapy

430 ± 176 115 ± 16 173 ± 19 199 ± 29 500 ± 170 120 ± 15 182 ± 18 217 + 26 1.39 ± 0.30

Nifedipine

576 ± 205* 121 ± 17$ 168 ± 20 204 ± 44§ 612 + 181 123 ± 16$ 170 ± 22 211 ± 44$ 1.37 ± 0.44

Diltiazem

638 ± 125* 116 + 16$ 166 ± 17 192 ± 37§ 648 ± 141$ 119 ± 15$ 168 + 16 201 ± 3 6 $ 1.40 ± 0.53

Nitroglycerin

666 ± 76* 137 ± 16* 176 ± 23 242 ± 48$ 744 ± 136* 137 ± 14* 182 ± 21 249 ± 38* 1.13 ± 0.27

I mm HR, Heart rate at 1 mm ST segment depression; 1 mm RPP, rate-pressure product at 1 mm ST segment depression; 1mm SBP, systolic blood pressure at 1 mm ST segment depression; 1 mm T, exercise time at 1 mm ST segment depression; pk HR, heart rate at peak exercise; pk RPP, rate-pressure product at peak exercise; pk SBP, systolic blood pressure at peak exercise; pk STI, ST segment depression at peak exercise; pk T, time to peak exercise. *p < 0.01 versus off therapy. fp < 0.05 versus off therapy. $p < 0.01 versus nitroglycerin. §p < 0.05 versus nitroglycerin.

peak exercise did not change significantly (Table III) (Fig. 2). Submaximal rate-pressure products were significantly (p < 0.01) lower following diltiazem than when patients were off treatment at each submaximal level (Fig. 3).

Effects of nitroglycerin. Nitroglycerin administra­tion resulted in a significant increase in resting heart rate. Systolic blood pressure significantly decreased,

while resting rate-pressure product did not change significantly (Table II). After nitroglycerin, the exer­cise test became negative for ischemic ECG changes in two patients: in one of them (patient No. 6), the test was stopped because of progressive angina when there was 0.8 mm ST segment depression. The other patient (patient No. 5) exercised till fatigue with no ST segment depression. Time to 1 mm ST segment

90 Pupita et al. July 1993

American Heart Journal

300

250 o

2 2

CO E w p Q.

200

150 ^

100

• Off therapy

H Nifedipine

A Diltiazem

n Nitroglycerin

Rest 20 40 60 80 100 Exercise time

(% of time to ischemic thresliold off therapy)

Fig. 3. Comparison of submaximal rate-pressure prod­ucts oil therapy and after short-term administration of nifedipine, diltiazem, and nitroglycerin. Exercise rate-pressure products have been measured (off therapy and after drug administration) at exercise times corresponding to 20 %, 40 %, 60 %, 80 % and 100 % of the time at which the ischemic threshold was reached off treatment. **,* p < 0.01 and <0.05 off therapy vs nifedipine; foff therapy vs diltiazem; ? p < 0.01 nitroglycerin vs nifedipine; § p < 0.01 nitroglycerin vs diltiazem.

depression significantly increased from 430 ± 176 to 666 ± 76 seconds {p < 0.01), together with an in­crease in heart rate (from 115 ± 16 to 137 + 16 beats/min, p < 0.01). Rate-pressure product in­creased (from 199 ± 29 to 242 ± 48 beats/min • mm Hg • 10^, p < 0.05) at 1 mm ST segment depression (Fig. 1). Systolic blood pressure at 1 mm ST segment depression was unchanged (173 ± 19 vs 176 ± 23 mm Hg) (Table III). Similarly, at peak exercise sig­nificant increases of time (from 500 ± 170 to 744 ± 136 seconds, p < 0.01), heart rate (from 120 ± 15 to 137 ± 14 beats/min, p < 0.01), and ra te-pressure product (from 217 ± 26 to 249 ± 38 beats/ min • mm Hg • 10^, p < 0.01) were observed (Fig. 2). Peak systolic blood pressure was unchanged (182 ± 18 vs 182 ± 21 mm Hg). Maximal ST seg­ment depression decreased from 1.39 ± 0.30 to 1.13 ± 0.27 mm, but the difference was not statisti­cally significant (Table III). At each submaximal level, the rate-pressure products following nitro­glycerin were not significantly different from those observed when patients were off treatment (Fig. 3).

Comparison between nitroglycerin, nifedipine, and

diltiazem. After nitroglycerin, exercise time was higher than after nifedipine and diltiazem, both at 1 mm ST segment depression (666 ± 76 vs 576 ± 205 and 638 ± 125 seconds) and at peak exercise (744 ± 136 vs 612 ± 181 vs 648 ± 141 seconds); these differ­ences, however, were not statistically significant (Table III). Compared to both nifedipine and dilt­iazem, heart rate and rate-pressure product at 1 mm ST segment depression were significantly higher with nitroglycerin (p < 0.01 and p < 0.05, respectively); heart rate and rate-pressure product at peak exercise were also significantly higher (p < 0.01 for both) (Table III). Submaximal rate-pressure products were significantly higher following nitroglycerin than after nifedipine and diltiazem. The differences between nitroglycerin and nifedipine were statistically signif­icant (p < 0.01) at times corresponding to 60 %, 80 %, and 100 % of the time at which the ischemic thresh­old was reached with patients off treatment, while the differences between nitroglycerin and diltiazem were significant (p < 0.01) at each submaximal level (Fig. 3).

DISCUSSION

In patients with stable coronary artery disease, angiographically visible collateral circulation plays an important role in protecting from stress-induced myocardial ischemia.^"^'^^ In addition, recruitable collateral vessels—although not visible during stan­dard coronary angiography—are present in the majority of patients with severe coronary ste-noses.^^'^^"^^ Following the demonstration that is­chemia in collateral-dependent myocardium may develop at a very variable threshold in angina pa­tients,* we designed this study to evaluate (in man) whether nifedipine and diltiazem can improve ische­mia arising in collateralized myocardium. To obtain meaningful data, we adopted very restrictive selec­tion criteria: none of our patients had evidence of previous myocardial necrosis; the only potentially is­chemic region was entirely collateral-dependent and collateral vessels supplying that region originated from angiographically normal coronary arteries. These patients therefore represent an optimal setting in which to study collateralized myocardium in man.^^

Our study shows that diltiazem and (to a lesser ex­tent) nifedipine increases exercise tolerance in pa­tients with chronic coronary occlusion and collateral circulation; however, these agents do not increase the ischemic threshold, indicating that blood flow to col­lateral-dependent myocardium is not significantly influenced. This observation is supported by the fact that neither drug improved heart rate or rate-pres-

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American Heart Journal Pupita et al. 91

sure product (a reliable index of myocardial oxygen consumption^^'^^) at 1 mm ST segment depression; furthermore, submaximal rate-pressure products were significantly lower following nifedipine and dil-tiazem than when patients were off therapy (Fig. 3). These data strongly indicate that in these patients the improvement in exercise time obtained with these substances has to be ascribed to the already-documented^' 8,12,13 effect of reduction of myocardial oxygen consumption and not to an improved blood supply to collateralized myocardium.

Comparing the results obtained with nifedipine and diltiazem to those obtained with nitroglycerin, this point of view is further strengthened: nitroglyc­erin did not change submaximal rate-pressure prod­ucts and improved not only exercise time but also in­creased heart rate and rate-pressure product. This indicates, in agreement with the findings of previous clinical and experimental studies,^^"^" that in these patients it was possible to improve blood supply to collateralized myocardium, but that neither nife­dipine nor diltiazem achieved this.

Previous studies on nifedipine. Animal studies have given conflicting results. Zyvoloski et al.^^ found in dogs that nifedipine increases blood flow to collater­alized myocardium, but directs it preferentially to the subepicardial layers. On the contrary, White et al. ® did not observe any increase of collateral blood flow in swines. The use of different animal species might account for this discordance, although Bache et al.^^ also could not observe (30 minutes after nife­dipine administration) any effect on collateral blood flow during exercise in dogs with chronic coronary occlusion.

Studies in patients with coronary artery disease have often been limited by patient selection. Feld-man et al.*" did not observe improvement of pacing-induced angina and ST segment depression following short-term nifedipine administration. As the authors point out, the study was limited by being performed on patients with multivessel disease (>;2 coronary stenoses in 8 of 13 patients), evidence of myocardial damage (12 patients had > 1 area of hypokinesia/ak­inesia), a variable degree of collateralization (only eight patients had "good" collateral filling), and of­ten assuming other antianginal medications (propra­nolol in 11 patients). On the other hand, Carboni et al.*^ found that patients with a good ergometric response to short-term nifedipine administration had a higher "collateral score" compared with non-responders; in this study, however, only 11 of 28 pa­tients had single-vessel disease and 15 patients had evidence of previous myocardial infarction.

More stringent selection criteria were used by

Schulz et al.,*^ who failed to detect beneficial effects of steady-state administration of nifedipine in pa­tients with single coronary occlusion and collaterals, and by Barilla et al.,*^ who studied nine patients with isolated coronary occlusion and collaterals, observing significantly higher exercise time, maximal work load, and rate-pressure product after nifedipine than after isosorbide dinitrate. In this study, however,*^ it is not reported if the drugs were administered orally or sublingually; since the patients were exercised 30 minutes after the administration of 10 mg of sus­tained-release nifedipine and of 5 mg of isosorbide dinitrate, one of the possible explanations for the differences between that and our study is that either the dose of isosorbide dinitrate or its timing were in­adequate to produce full collateral dilatation.

Previous studies on diltiazem. Animal studies per­formed on mature canine collateral vessels found that diltiazem increases collateral blood flow, especially to the subendocardium,^'' ^^ * and improves stress-in­duced contractile dysfunction,''^ although to a lesser extent than nitroglycerin.*^ The discordance be­tween these studies and ours might depend on the different anatomic structure of the collateral circula­tion of dogs and humans. In fact, while collateral cir­culation is almost exclusively intramyocardial in hu­mans,*^ collateral blood flow in dogs derives from in­tramyocardial and epicardial collateral vessels*^"^^ having different origins and different reactivities.^^ To our knowledge, no study has been published ex­amining the effects of diltiazem in patients with chronically collateralized myocardium.

Potential limitations of the study. No direct measure­ment of collateral blood flow was obtained and therefore no definite statements can be made. Al­though direct estimates of blood flow would be desir­able, no currently available method of measuring the perfusion of collateralized myocardium is free of limitations. Thallium imaging provides additional information on relative rather than absolute myo­cardial perfusion, and it is practically difficult and ethically unacceptable to perform four scintigraphies in a week in the same patient. Methods employing coronary sinus catheterization (thermodilution, oxy­gen saturation) can only be used in left anterior de­scending disease and are affected by both the unpre­dictability of the source of venous drainage into the coronary sinus^* and by the collection of blood from other territories.^^ Cine computed tomography and magnetic resonance imaging are still in the develop­mental stages (as far as measurement of coronary blood flow is concerned), and so is contrast echocar­diography,^^' 5' although attempts at measuring col­lateral perfusion have been reported.^®"^^ Positron

92 Pupita et al. July 1993

American Heart Journal

emission tomography would appear to be the best method to measure collateral blood flow^^'^^; how­ever, coronary flow reserve can only be measured us­ing pharmacologic coronary vasodilation (usually with dipyridamole), a stimulus quite different from exercise. Besides, positron emission tomography can­not evaluate flow distribution in subendocardial and subepicardial layers, an aspect the importance of which has been recently emphasized in patients with stable angina.®* Finally, collateral blood flow has been evaluated by measuring retrograde flow with a Doppler-tipped guide wire during PTCA^^; this tech­nology, however, evaluates "recruitable" rather than angiographically visible collaterals and does not pro­vide any index of flow distribution. Furthermore, no correlation between retrograde flow and protection from myocardial ischemia has been presented so far. The index used in our study, the rate-pressure prod­uct, has been extensively validated as a reliable indi­cator of myocardial oxygen consumption. *"^® Since in our patients the only potentially ischemic region was entirely dependent on collateral circulation, it is reasonable to assume that the rate-pressure product properly predicted collateral perfusion.

Left ventricular volumes were not measured and myocardial oxygen consumption might be lower than the rate-pressure product would estimate. Indeed, nitroglycerin reduces resting left ventricular end-di-astolic volume,®®'®^ while diltiazem''°'''^^ and nife­dipine®®"® ' ' ' ' ^ have not been shown to do so (with some exceptions^*). However, it has been demon­strated®® that the response to short-term nitrates administration is not necessarily related to changes of left ventricular volume. Volume changes of similar magnitude can be observed in patients responding or not responding to nitrates, and similar increases in rate-pressure product can be observed in the same patients with nitrates and with other drugs not affecting left ventricular volume but capable of reducing coronary tone. Besides, similar end-dias-tolic volumes have been shown at maximal exercise following nitroglycerin and nifedipine administra­tion.®^ Furthermore, it must be emphasized that the behavior of the rate-pressure product following nife­dipine and diltiazem indicates per se an effect on myocardial oxygen consumption rather than on blood supply; nitroglycerin has only been used to better prove that these patients had the potential for improvement in perfusion of collateral-dependent myocardium. This study examined the short-term effects of nifedipine and diltiazem, which might not be predictive of the long-term effects during chronic therapy.

Conclusions. In patients with longstanding coro­

nary occlusion and collateral circulation, nifedipine and diltiazem increase exercise duration. This effect is achieved through a reduction of myocardial oxygen consumption rather than by increasing blood flow to collateral-dependent myocardium.

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