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Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis
Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis The acute effects of diltiazem on coronary reactive hyperemia were studied in 12 patients with flow-limiting coronary stenosis. Reactive hyperemia was elicited by injection of 8 ml contrast medium into the left coronary artery, while coronary sinus blood flow and left ventricular and aortic pressures were continuously recorded. Relative magnitude of hyperemia was estimated by the ratio of coronary flow at peak hyperemia to baseline flow (hyperemic ratio). Coronary resistance was calculated as the ratio between mean aortic pressure minus left ventricular mean diastolic pressure and coronary sinus blood flow. The 12 patients studied had flow-limiting coronary stenosis since their hyperemic ratio was significantly restrained when compared to that of seven control subjects (1.45 + 0.17 vs 2.02 2 0.24, respectively; p < 0.001). The intravenous infusion of diltiazem (0.30 mg . kg-‘) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p < 0.001). After diltiazem the hyperemic ratio was blunted when compared to the basal state (1.36 i 0.15 vs 1.45 _+ 0.17, respectively; p < 0.05), and hyperemia volume was reduced (-33%; p < 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from -30 -t 8% to -25 i- 8% (p < 0.05). We conclude that diltlarem blunts coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis. This reduction of coronary flow response to a hyperemic stimulus could favorably influence blood flow distribution in patients with significant coronary stenosis. (AM HEART J lg86;112: 1232.)
Jean-Marc Foult, M.D., Alain Nitenberg, M.D., Franqoise Blanchet, and Samir ZouiouGche, M.D. Paris, France
The efficacy of diltiazem as an antianginal agent has been described in detail. Recent data have demonstrated the beneficial effects of this calcium channel blocker in exercise-induced angina,‘-3 while earlier studies had concentrated on the antispastic effect of diltiazem, that is, the action of diltiazem on large epicardial coronary arteries.4-6 Coronary resistance vessels within the myocardiurn are responsible for autoregulation, which allows blood flow to be regulated along with changing myocardial requirements.’ However, in the presence of a coronary proximal stenosis, functional dilation of the microvessels may compromise transmural blood flow distribution by reducing the poststenotic coronary pressure. 8-1o Studies performed in dogs have suggested that a reduction of coronary reactive hyperemia might favorably influence subendocar-
From the Department of Physiology and Hemodynamics, INSERM U 251, University of Paris. Received accepted Reprint Henri
1232
for publication April 1, 1986. requests: Alain Huchard, F-75018
Oct.
17, 1985;
Nitenberg, M.D., Paris, France.
revision CHU
received Xavier
Bichat Feb. Bichat,
Hospital, 24, 1986; 46,
rue
M.D.,
dial perfusion.” Despite this important notion, little attention has been paid to the action of antianginal agents on the coronary distal circulation. The present study was designed to evaluate the effects of diltiazem on coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis.12 Reactive hyperemia induced by the intracoronary injection of contrast medium was used as a model for coronary arteriolar vasodilation,13-15 so that the effects of diltiazem on this transient increase in coronary blood flow could be studied. Left ventricular hemodynamic and myocardial metabolic responses to diltiazem were also examined. METHODS Patient selection. Twelve consecutive patients with angiographically significant (270 % ) obstruction of at least one major vessel were selected for investigation. Informed consent was obtained from all patients. None of the patients had left main coronary artery disease. Angiographic data are listed in Table I. All cardiac drugs were discontinued at least 48 hours before the investigation and no patient was premeditated. Ages ranged from 36 to 62 years (55 f 9 years, mean f SD) and mean body weight was 72 +- 9 kg (mean -t SD). Patients with cardiac
volume Number
112 6
l>iltiazem
1. Coronary arteriography data ___.I__
Table
Patient NO.
AgP iyj 5:
M
100(prox)
3 ‘4 5 ti 7
59 59 5 .-, 63 6” 45
M M M M M M
SO(mid) 90(prox)
8
56
M
9
:%
M
10 11 12
60 6:: 57
M M M
1 ”
95(prox) + N(mid) 95cprox)+ 90(mid) 70(prox) 80(prox)
+ 9O(mid) + 9O(mid) 95(prox) lOO(mid)
+ 70(dist) + 80(dist)
h~s;v?~.c~mia 1233
h’i ‘A
11.4 ____-._I
--_-.-
.
iihlii
SO(prox) 50(prox) 50(prox)
95(dist) 7O(prox) 70(prox) 95(prox) 80(prox)
‘iO(mid) 95(prox)
rewiiw
V~3sd stenosis f (‘f./ LM
CFX
LAD
Sex
and coronary
901 If J !3HI, :0\111 95iIti 4Ol I11
9Uproxl 40fprox)
8Ol[““X)
4O(fl) f 3l~!Illl
50(prox)+ 7Otdist) 95(prox) + 80(dist) lOO(p
1iWl W( II
lOO(prox)
91l(f;
--
_-Abbreviations: CFX = circumflex artery; DA = diagonal artery; LAD = left anterior arteryi; prou = prwimal; dist = distal; 1, II, and I11 are the segments of the RCA.
arrhythmias, systemic hypertension, and valvular dysfunction were excluded from the study. Catheterization procedure. With the use of 1% lidoCaine as a local anesthetic, percutaneous left and right heart catheterization was performed. A 7F high-fidelity, double-tipped micromanometer catheter (PC 770, Millar Instruments, Houston, Texas) was placed into the left ventricle through a femoral artery and positioned for simultaneousrecording of left ventricular and aortic pressures.A 7F Judkins coronary arteriography catheter (Cordis Laboratory, Minneapolis, Minn.) was utilized for left coronary arteriography and was placed into the aorta through the other femoral artery. A 7F Swan-Ganz thermodilution catheter (Edwards Laboratory) was placed into the pulmonary artery via a femoral vein. A 7F thermodilution catheter (Wilton Webster Laboratories, Altadena, Calif.) was inserted via the left subclavian vein and positioned into the coronary sinusin order to measure coronary sinusblood Aow by continuous thermodilutio+; the position of the catheter wasperiodically controlled by fluoroscopy in order to maintain the thermistor proximal to the posterior interventricular vein entry into the coronary sinus. Protocol. After left and right coronary arteriography was performed, a delay of 30 minutes was observed in order to eliminate the effects of contrast material.17Control left ventricular and aortic pressureswere recorded by a catheterization data analysiscomputer system (HewlettPackard 5600 M) which performed on-line analysis on nine beats for averagingout respiratory variations; control cardiac output and coronary sinusblood flow (1 ml + see-’ saline infusion) were measured,and withdrawal of arterial, pulmonary, and coronary sinus blood samples was performed. A hyperemic reaction was then elicited by selective injection of 8 ml contrast material (ioxaglate) into the left coronary artery.‘:‘,‘” Coronary sinus blood flow, aortic and left ventricular pressures,and ECG were continuously recorded during the hyperemia, which was repeated after
descending
artery;
LM = left marginal
arwr\
IK’:\ = right ~~wonow
II. Basal coronary hemodynamics, myocardial metabolism, and hyperemia parameters in the control group (n = 7, mean it SD) -- .--___-._ CSBFc(ml min-‘) 98 I 17 CRC(mmHg. ml-’ . min) 0.99 5 0.15 Table
CSO, (ml lOOml-‘) CSPO, (kPa)
,1.7 rc cl.:\
a-CSO,D(ml lOOml-‘1 MirO, (ml min-‘) Lactate
extraction
CSBFp CSBFpKSBFc AQ (ml) AQKSBFc
( r; )
2.71
t
12.7
+ 0.9
0.40
I::.16 t 1.7” w 62 -t 14
1’97 < r?-.‘35 2.02x 0.24 123 i :1.1 0.18 rr_ 0.02
[(CRp-CRcVCRc]x loo’<> --it9? 6 -..- --- - ~.-. .~._._._.-._---_Abbreviations: a-CSO,D = arterial-coronary sinus hi& oxygen difference: CRc = control coronary resistance: CRp = coronaw resistance at peak reactive hyperemia; CSBFc = control coronar) sinus blood flow: CSBFp = coronary sinus blood flow at peak renctive hyperemia; CSO, = coronary sinus blood oxygen contenf; CSIW, = coron;try sinus blood oxygen pressure; MiiO, = myocardial ~~xv~en consumptirm; A$ = h.vperemia net volume.
coronary flow had returned to control values. The whole procedure was repeated immediately after a l-minute right atrial infusion of diltiazem (0.30 mg . kg-‘). During the same period, contrast medium-induced reactive hyperemia was studied in seven patients with normal coronary angiogramsand normal left ventricular function. Four patients had mild mitral stenosis with normal cardiac index and pulmonary wedge pressures below 15 mm Hg; one had mild pulmonary stenosiswith a 45 mm Hg right ventricular systolic pressure, one had a small left ventricular septal defect, and one had a patent foramen ovale. The latter two patients did not have any detectable left-to-right shunt by oximetry. There was no history of chest pain in any of these patients who were considered to have normal coronary circulation. The effects of diltiazem were not studied in these patients.
1234
Table
Fault
et al.
American
December 1966 Heart &urnaf
III. Coronary hemodynamicsand myocardial metabolism (mean & SD) Lactate CSBFc (ml
Basal Diltiazem P
min-‘)
(mm
154 + 49 148 * 41 NS
CR, Hg ml-’
CSO, . min)
CSPo2 (k Pa)
(ml . 100 ml-‘)
0.69 zk 0.27 0.60 + 0.22 <0.05
5.4 k 0.9 6.8 k 1.7
a-CSOJI (ml 100 ml-‘)
2.70 f 0.32 3.10 f 0.43
MliO, (ml . min-‘)
13.39 * 1.03 11.16 IL 1.83
20.53 +- 6.62 16.85 + 6.32
Abbreviations: a-CSO,D = arterial-coronary sinus bIood oxygen difference; CR< = control coronary resistance; CSBF, = control coronary CSO, = coronary sinus blood oxygen content; CSPoz = coronary sinus blood oxygen pressure; MOO, = myocardial oxygen consumption.
Table
31 + 36 39 f 22 NS sinus blood &xv;
IV. Hyperemia parameters (mean -+ SD) CSBF,
Basal Diltiazem P
extraction (%)
(ml
min-‘j
219 + 63 197 * 45
CSBFJCSBF, 1.45 +- 0.17 1.36 + 0.15 <0.05
AQ (ml) 14.4 & 5.3 9.6 +- 4.8
Abbreviations: CR, = control coronary resistance; CR, = coronary resistance at peak reactive CSBF. = coronary sinus blood flow at peak reactive hyperemia; AQ = hyperemia net volume.
Data analysis and calculations. Cardiac output was measuredby the thermodilution method and was usedto calculate the cardiac index (cardiac output/body surface area, L . min-’ . me*). Heart rate, left ventricular enddiastolic pressure, mean aortic pressure, and systemic vascular resistancewere calculated by the computer system. Mixed venous, arterial, and coronary sinus blood oxygen contents were measuredin duplicate by a galvanic cell method that producesan electric current in proportion to oxygen molecules present (Lex 0, Con K, Waltham Instruments, Waltham, Mass.). Arterial, mixed venous, and coronary sinus blood pH, Pcoz, and PO, were measured in duplicate with an ABL II blood gas analyzer (Radiometer America, Westlake, Ohio). Arterial plasma lactate and coronary sinus lactate concentrations were measuredin duplicate by an enzymatic ultraviolet method (Boehringer Mannheim Laboratories Mannheim, W. Germany). The percentage of lactate extraction was calculated as: (arterial lactate minus coronary sinus lactate/arterial lactate) X 100. Coronary sinusblood flow (ml . min-‘) wascontinuously recorded during contrast medium-induced hyperemia. Coronary resistance was calculated as the ratio between meanaortic pressureminus left ventricular meandiastolic pressureI and coronary sinus blood flow. Total blood volume during reactive hyperemia was calculated by planimetry of the coronary sinusblood temperature curve: hyperemia total blood volume (ml) = mean coronary flow during hyperemia (ml . set-‘) x hyperemia duration (set). Hyperemia net volume was calculated as hyperemia total blood volume (ml) minus control coronary flow (ml . set-I) x hyperemia duration (set). Although coronary sinus thermodilution does not define the mass of myocardium being drained,lg this should not have impaired our results since data analysis was basedon a comparison between flow and resistanceratios. The ratio
AQICSBF,
[(CR,
- CRJICR,]
0.10 ? 0.04 0.07 + 0.03
x 100 (%)
-30 I! 8 -25 + 8 <0.05 CSBF, = control
coronary
sinus blood flow;
between peak and control coronary flow, that is, the hyperemic ratio, and the hyperemia net volume/control coronary flow ratio were used for quantification of the hyperemia relative magnitude. The decreasein coronary resistance during contrast medium-induced hyperemia was expressed as a percentage: (coronary resistance at peak hyperemia minus control coronary resistance/control coronary resistance)x 100. The reproducibility of contrast-induced hyperemia wasdemonstratedsincelessthan 5% variation occurred between two successivehyperemias, both at basal state and after diltiazem. Myocardial oxygen consumption (ml . min-‘) was calculated as arterial-coronary sinus blood oxygen content difference X coronary sinus blood flow. Statistics. Mean values and standard deviation were calculated for each parameter. Differences between basal and diltiazem data were examined by meansof paired t test. Comparisonsbetween normal subjects and patients with coronary artery diseasewere made by means of unpaired t test. Differences were consideredsignificant if p was <0.05. RESULTS Control group. Coronary hemodynamics, myocardial metabolism, and hyperemia parameters of the control group are presented in Table II. Since the effects of diltiaxem were not tested in this group, only baseline results are provided for these seven subjects. Patient hemodynamics. Diltiaxem infusion decreased the heart rate (77 + 15 to 70 +- 13 bpm, p < 0.001) and reduced mean aortic pressure (115 +17 to 98 + 8 mm Hg, p < 0.601). Cardiac index (2.8 + 0.6 to 2.9 k 0.6 L . min-’ . m-Y and left ventricular end-diastolic pressure (19 + 9 to 16 f 6 mm Hg) were not significantly affected by diltiaxem,
Volume Number
112 6
niltiazem
while systemic vascular resistance was reduced in all patients (22.4 t_ 6.7 to 18.1 -t- 4.5 mm Hg - L-l min, p < 0.01). patient
myocardial
blood flow and metabolism
and coronary
reactirlc
hvpewmia
1235
EKG
(Table
III). The intravenous infusion of diltiazem in patients with coronary stenosis did not significantly change coronary blood flow, but coronary sinus oxygen content and pressure increased significantly whereas coronary resistance was reduced. Since the arterialcoronary sinus blood oxygen difference decreased significantly, the calculated myocardial oxygen consumption was reduced. Lactate extraction by the myocardium was not significantly altered. Patient coronary reactive hyperemia (Table IV). At the basal state, the peak/control coronary blood flow ratio was significantly lower in patients with coronary artery disease than in the normal group (1.45 + 0.17 vs 2.02 2 0.24, respectively; p < 0.001). Thus our patients with angiographic coronary artery disease were distinguished as having true flow restriction resulting from coronary stenosis.‘2 In these patients, the intravenous infusion of diltiazem significantly blunted the hyperemia peak flow and net volume, the hyperemic ratio, and the ratio of hyperemia net volume to control flow (Table IV). The decrease in coronary resistance elicited by the injection of contrast medium was also significantly blunted. Fig. 1 provides a representative example of a blunted reactive hyperemia after diltiazem. DISCUSSION
The present study was designed to analyze the acute effects of diltiazem on contrast mediuminduced coronary reactive hyperemia in patients with coronary artery disease. Although the exact mechanism by which hyperosmolar contrast agents result in a transient coronary arteriolar vasodilation remains poorly understood, experimental studies have demonstrated that contrast medium-induced hyperemia was comparable to that obtained after a lo-second coronary occlusion.12 Vasodilation elicited by contrast medium is not maximum, but it provides an estimate of the coronary reserve which is significantly correlated with data obtained after intravenous dipyridamole in doses considered to elicit maximum coronary vasodilation.20s21 Furthermore, the elevation of coronary blood flow after intracoronary injection of contrast medium provides reproducible data both in our laboratory and in others.‘:’ patient selection. One of the difficulties arising from the evaluation of antianginal agents in patients with coronary artery disease stems from the definition of the disease itself: coronary angiography is usually regarded as a “gold standard” for assess-
AOP
LVP cl
j
/
dP/dilWO mmHg.s-I * -1*oo
AoP
LVP
mmllg / il
CSBF ml.min-’
e-
%.-----./-.
Diltiazem
Fig. 1. Typical example of contrast medium-induced reactive hyperemia in a patient at basal state and after diltiazem. Arrow indicates time of contrast medium injection into the left coronary artery. After diltiazem, control coronary sinus blood flow is not different, but peak coronary flow is reduced. AoP = aortic pressure; CSBF = coronary sinus blood flow; EKG = electrocardiogram; LVP = left ventricular pressure.
ment of the severity of coronary stenosis. However, recent studies have emphasized wide discrepancies between angiographic evaluation and true flow restriction resulting from coronary artery disease.2” In our laboratory, the hyperemic ratio in patients with normal coronary circulation is 2.02 + 0.24. The mean value of 1.45 for the hyperemic ratio estab-
1236
Fault et al.
lishes that flow-limiting coronary stenosis was present in our patients. The presence of elevated myocardial oxygen consumption in the patient group vs control subjects (Tables II and III) at basal state should have led to a parallel elevation of the hyperemia peak flow7 and is therefore unlikely to have created an artificially reduced hyperemia flow ratio in the patient group. This authenticates the studied population as a group with coronary lesions defined not only by angiographic evaluation but also by a restricted response to a hyperemic stimulus, that is, reduced coronary flow reserve. Diltiazem and coronary hyperemic response. The major result of this work reveals that diltiazem significantly blunts contrast medium-induced coronary reactive hyperemia in patients with flow-limiting coronary stenosis. Although the observed alteration of the hyperemic ratio after diltiazem is of modest magnitude, it must be stated that the hyperemia net volume decreased by as much as 33% after the infusion of calcium channel blocker (Table IV). We have previously reported a reduction of the hyperemic ratio in patients with coronary artery disease after the administration of bepridil, another calcium channel blocker.15 There are several possible mechanisms by which diltiazem may have reduced reactive hyperemia flow. One of the major determinants of coronary reactive hyperemia is the level of myocardial oxygen consumption: the more elevated the myocardial metabolic activity, the more important the hyperemit response to a given stimulus7 Reduction of the myocardial oxygen consumption1-3 most probably accounted for at least part of the decreased hyperemit response after diltiazem. However, no reduction of hyperemia was observed in dogs after nitrates despite decreased metabolic activity.23 The effects of intravenous nitroglycerin24 were tested in our laboratory in three patients with significant (270 % ) coronary artery disease (2 pg . kg-’ . min-’ x 10 min). There was no alteration of the hyperemic ratio (from 1.44 Jo 0.20 to 1.51 + 0.29), although myocardial oxygen consumption was decreased (from 21.65 + 6.09 to 17.30 ? 3.70 ml . mm-‘). Since the actions of nitrates predominate on large conductance coronary vessels, they do not influence coronary autoregulation which concerns the distal circulation.24 Thus a reduction of the metabolic demand will be followed by a parallel reduction of coronary flow, both in the control state and at peak hyperemia, with no alteration in the relative magnitude of the hyperemia. On the contrary, our findings of a reduced relative intensity of hyperemia after diltiazem or bepridil suggest that some calcium channel blockers may influence the
American
December 1986 Heart journal
vasomotor tone of coronary resistance vessels, especially at elevated flow rates. It may be of interest that although diltiasem blunted coronary reactive hyperemia, it also exhibited significant vasodilator properties in the control state, as demonstrated by decreased coronary resistance (Table II). In contrast with nitrates, diltiasem has little influence on the size of large coronary epicardial vessels. 25Vasodilation as evidenced at the basal state was most likely related to the coronary distal circu1ationz6 Reduction of hyperemia flow could have resulted from a heterogeneous response in myocardial areas supplied by stenotic vs nonstenotic coronary arteries. This could have led to a “steal” phenomenon and thus to some degree of myocardial &hernia. We do not believe that this occurred for several reasons: first, 6 of 12 patients had severe obstructions of the three major vessels; thus reduction of the hyperemia, of necessity, occurred via a stenotic vessel in these patients. In addition, no chest pain, ECG alteration, or elevation of left ventricular enddiastolic pressure occurred in any of the patients, while lactate extraction by the myocardium tended to increase. Regardless of the mechanisms that may account for reduction of hyperemia after diltiaxem, it is possible to question whether this limitation could have deleterious consequences on myocardial perfusion. At first glance, one would speculate that the larger the coronary hyperemic response, the better. There is, however, experimental evidence to support the idea that a reduction of peak hyperemia flow would not have detrimental consequences but instead should be beneficial in the presence of a proximal coronary stenosis. The decrease in the coronary poststenotic pressure that occurs at the time of hyperemiaz7 has been demonstrated to result in a transmural redistribution of blood flow with inability to perfuse the subendocardium.28-31 This detrimental effect of an excessive distal vasodilation downstream from a significant coronary stenosis can be observed regardless of the vasodilator stimulus and has been reported to occur following administration of adenosine or exercise.32f33 According to the hemodynamic behavior of a typical stenosis, the difference between the aortic pressure and the poststenotic pressure, that is, the pressure loss across the stenosis, increases with the second power of the coronary blood flo~.~~ Thus, in the presence of severe stenosis, the subendocardial perfusion can be compromised by a minimal elevation of the coronary flow. By reducing hyperemia, diltiazem should minimize the pressure decrease across the stenosis and thereby contribute to lessening the degree of suben-
Volume Number
112 6
docardial ischemia. This hypothesis is supported by experimental data showing both a restriction of the coronary hyperemia response and an improved subendocardial perfusion after diltiazem.” Although the hyperemic flow response to transient coronary occlusion or intracoronary contrast medium is only a model for coronary arteriolar vasodilation, improved subendocardial perfusion has been demonstrated after diltiazem at exercise in dogs with chronic coronary stenosis. 35This suggests that redistribution of transmural blood flow toward subendocardial layers might represent one of the mechanisms by which diltiazem exerts its protective effect in patients with coronary artery disease. We are indebted to Franqoise Carlier, Anne Borges, and Sylvie Lepape for expert secretarial and technical assistance.
REFERENCES
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L3
4.
5. 6.
7.
Go M Jr, Hollenberg M. Improved efficacy of high-dose versus medium- and low-dose diltiazem therapy for chronic stable angina pectoris. Am J Cardiol 1984,53:669. Koiwaya Y, Nakamura M, Mitsutake A, Tanaka S, Takeshita A. Increased exercise tolerance after oral diltiazem, a calcium antagonist, in angina pectoris. AM HEART J 1981;101:143. Hossack KF, Bruce RA. Improved exercise performance in persons with stable angina pectoris receiving diltiazem. Am J Cardiol 1981;47:95. Rosenthal SJ, Ginsburg R, Lamb IH, Bairn DS, Schroeder JS. Efficacy of diltiazem for control of symptoms of coronarv arterial spasm. Am J Cardiol 1980;46:1027. Schroeder JS, Rosenthal S, Ginsburg R, Lamb IH. Medical therapy of Prinzmetal’s variant angina. Chest 1980;8:231. Pepine CJ, Feldman RL, Whittle J, Curry RC, Conti CR. Effect of diltiazem in patients with variant angina: A randomized double-blind trial. AM HEART J 1981:101:719. Olsson RA. Myocardial reactive hyperemia. Circ Res 1975; 37:263.
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Gewirtz H, Williams DO, Ohley WH, Most AS. Influence of coronary vasodilation on the transmural distribution of myocardial blood flow distal to a severe fixed coronary artery stenosis. AM HEART J 1983;106:674. Rembert JC, Boid LM, Watkinson WP, Greenfield JC Jr. Effect of adenosine on transmural myocardial blood flow distribution in the awake dog. Am J Physiol 1980;239:7. Ball RM, Bathe RJ. Distribution of myocardial blood flow in the exercising dog with restricted coronary artery. Circ Res 1976;18:60. Bathe RJ, Dymek DJ. Effect of diltiazem on myocardial blood flow. Circulation 1982;65(1):19. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87. Mishima M, Inoue M, Hori M, Tsujioka K, Kuzurya T, Kodama K, Nanto S, Abe H. Validity of contrast hyperemia for clinical assessment of coronary flow reserve: The optimal dose of contrast medium and reproducibility of the technique. Cathet Cardiovasc Diagn 1983;9:553. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol 1974; 34:48.
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Foult JM, Nitenberg A, Blanchet F, Zouioueche S, Huyghebaert MF. Alterations in contrast medium-induced coronary
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reactive hyperemia after bepridil in patient.s with coronary artery disease. AM HEART J 1985;109:244. Ganz W, Tamura K, Marcus HS. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181. Cohn PF, Horn HR, Teichholz LE, Kreuien TH, Herman MV, Gorlin R. Effects of angiographic contrast medium on left ventricular function in coronary artery disease. Am J Cardiol 1973;32:21. Nitenberg A, Foult JM, Blanchet F, Zouioueche S. Multifactorial determinants of reduced coronary flow reserve after dipyridamole in dilated cardiomyopathy Am J Cardiol 1985;55:‘748. Webb-Peploe MM. Measurement of coronary sinus blood by continuous infusion thermodilution. In: Mathie RT, ed. Blood flow measurement in man. Tunbridge Wells: Castle House Publications, Ltd, 1982:99. Hoffman JIE. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153. Foult JM, Nitenberg A, Blanchet F, Zouioueche S. Dipyridamole versus intracoronary injection of contrast medium for the evaluation of coronary reserve in man: A comparative study. Circulation 1984;70(11):22. White CW, Wright GB, Doty DB, Hiratza LF, Eastham CL, Harrison DG, Marcus ML. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984;13:819. Bathe RJ, Tockman BA. Effect of nitroglycerin and nifedipine on subendocardial perfusion in the presence of a flowlimiting coronary stenosis in the awake dog. Circ Res 1982;50:678. Winbury MM, Howe BB, Hefner MA. Effect of nitrates and other coronary dilators on large and small coronary vessels: An hypothesis for the mechanism of action of nitrates. .J Pharmacol Exp Ther 1969;168:70. Hossack KF, Brown BG, Stewart DK, Dodge HT: Diltiazeminduced blockade of sympathetically mediated constriction of normal and diseased coronary arteries: I,ack of epicardial coronary dilatory effect in humans. Circulation 1984;70:465. Franklin D, Millard RW, Nagao T. Responses of coronary collateral flow and dependent myocardial mechanical function to the calcium antagonist, dihiazem. Chest 1980;78:200. Ganz P, Abben R, Friedman PI,, Garncc JD, Barry WH, Levin DC. Usefulness of transstenotic coronary pressure gradient measurements during diagnost.ic catheterization. Am J Cardiol 1985;55:910. Gould KL, Lipscomb K, Calvert C. Compensatory changes of the distal coronary vascular bed during progressive coronary constriction. Circulation 1975;51:1085. Bathe RJ, McHale PA, Greenfield JC: Transmural myocardial perfusion during restricted coronary inflow in the awake dog. Am J Physioll1977;232:645. Schwartz JS. Carlvle PF. Cohn JN. Effect of dilation of the distal coronary bed on flow and resistance in severely stenotic coronary arteries in the dog. Am J Cardiol 1979;43:219. Bathe RJ, Schwartz JS. Effect of perfusion pressure distal to a coronary stenosis on transmural myocardial blood flow. Circulation 1982;62:928. Rembert JC, Boyd LM, Watkinson WP. (ireenfield JC Jr. Effect of adenosine on transmural myocardial blood flow distribution in the awake dog. Am ,J Physiol 1980;239:7. Ball RM, Bathe RJ. Distribution of myocardial blood flow in the exercise dog with restricted coronarv artery inflow. Circ Res 1976;38:60. Brown BG, Bolson EL, Dodge HT. Dynamic mechanisms in human coronary stenosis. Circulation 1984;70:917. Matsuzaki M, Gallagher KP, Patritti J. Tajimi T, Kemper WS, White FC, Ross J Jr. Effects of a calcium-entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs. Circulation lq84;69:801.
Jean-Marc Foult, M.D., Alain Nitenberg, M.D., Franqoise Blanchet, and Samir ZouiouGche, M.D. Paris, France
The efficacy of diltiazem as an antianginal agent has been described in detail. Recent data have demonstrated the beneficial effects of this calcium channel blocker in exercise-induced angina,‘-3 while earlier studies had concentrated on the antispastic effect of diltiazem, that is, the action of diltiazem on large epicardial coronary arteries.4-6 Coronary resistance vessels within the myocardiurn are responsible for autoregulation, which allows blood flow to be regulated along with changing myocardial requirements.’ However, in the presence of a coronary proximal stenosis, functional dilation of the microvessels may compromise transmural blood flow distribution by reducing the poststenotic coronary pressure. 8-1o Studies performed in dogs have suggested that a reduction of coronary reactive hyperemia might favorably influence subendocar-
From the Department of Physiology and Hemodynamics, INSERM U 251, University of Paris. Received accepted Reprint Henri
1232
for publication April 1, 1986. requests: Alain Huchard, F-75018
Oct.
17, 1985;
Nitenberg, M.D., Paris, France.
revision CHU
received Xavier
Bichat Feb. Bichat,
Hospital, 24, 1986; 46,
rue
M.D.,
dial perfusion.” Despite this important notion, little attention has been paid to the action of antianginal agents on the coronary distal circulation. The present study was designed to evaluate the effects of diltiazem on coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis.12 Reactive hyperemia induced by the intracoronary injection of contrast medium was used as a model for coronary arteriolar vasodilation,13-15 so that the effects of diltiazem on this transient increase in coronary blood flow could be studied. Left ventricular hemodynamic and myocardial metabolic responses to diltiazem were also examined. METHODS Patient selection. Twelve consecutive patients with angiographically significant (270 % ) obstruction of at least one major vessel were selected for investigation. Informed consent was obtained from all patients. None of the patients had left main coronary artery disease. Angiographic data are listed in Table I. All cardiac drugs were discontinued at least 48 hours before the investigation and no patient was premeditated. Ages ranged from 36 to 62 years (55 f 9 years, mean f SD) and mean body weight was 72 +- 9 kg (mean -t SD). Patients with cardiac
volume Number
112 6
l>iltiazem
1. Coronary arteriography data ___.I__
Table
Patient NO.
AgP iyj 5:
M
100(prox)
3 ‘4 5 ti 7
59 59 5 .-, 63 6” 45
M M M M M M
SO(mid) 90(prox)
8
56
M
9
:%
M
10 11 12
60 6:: 57
M M M
1 ”
95(prox) + N(mid) 95cprox)+ 90(mid) 70(prox) 80(prox)
+ 9O(mid) + 9O(mid) 95(prox) lOO(mid)
+ 70(dist) + 80(dist)
h~s;v?~.c~mia 1233
h’i ‘A
11.4 ____-._I
--_-.-
.
iihlii
SO(prox) 50(prox) 50(prox)
95(dist) 7O(prox) 70(prox) 95(prox) 80(prox)
‘iO(mid) 95(prox)
rewiiw
V~3sd stenosis f (‘f./ LM
CFX
LAD
Sex
and coronary
901 If J !3HI, :0\111 95iIti 4Ol I11
9Uproxl 40fprox)
8Ol[““X)
4O(fl) f 3l~!Illl
50(prox)+ 7Otdist) 95(prox) + 80(dist) lOO(p
1iWl W( II
lOO(prox)
91l(f;
--
_-Abbreviations: CFX = circumflex artery; DA = diagonal artery; LAD = left anterior arteryi; prou = prwimal; dist = distal; 1, II, and I11 are the segments of the RCA.
arrhythmias, systemic hypertension, and valvular dysfunction were excluded from the study. Catheterization procedure. With the use of 1% lidoCaine as a local anesthetic, percutaneous left and right heart catheterization was performed. A 7F high-fidelity, double-tipped micromanometer catheter (PC 770, Millar Instruments, Houston, Texas) was placed into the left ventricle through a femoral artery and positioned for simultaneousrecording of left ventricular and aortic pressures.A 7F Judkins coronary arteriography catheter (Cordis Laboratory, Minneapolis, Minn.) was utilized for left coronary arteriography and was placed into the aorta through the other femoral artery. A 7F Swan-Ganz thermodilution catheter (Edwards Laboratory) was placed into the pulmonary artery via a femoral vein. A 7F thermodilution catheter (Wilton Webster Laboratories, Altadena, Calif.) was inserted via the left subclavian vein and positioned into the coronary sinusin order to measure coronary sinusblood Aow by continuous thermodilutio+; the position of the catheter wasperiodically controlled by fluoroscopy in order to maintain the thermistor proximal to the posterior interventricular vein entry into the coronary sinus. Protocol. After left and right coronary arteriography was performed, a delay of 30 minutes was observed in order to eliminate the effects of contrast material.17Control left ventricular and aortic pressureswere recorded by a catheterization data analysiscomputer system (HewlettPackard 5600 M) which performed on-line analysis on nine beats for averagingout respiratory variations; control cardiac output and coronary sinusblood flow (1 ml + see-’ saline infusion) were measured,and withdrawal of arterial, pulmonary, and coronary sinus blood samples was performed. A hyperemic reaction was then elicited by selective injection of 8 ml contrast material (ioxaglate) into the left coronary artery.‘:‘,‘” Coronary sinus blood flow, aortic and left ventricular pressures,and ECG were continuously recorded during the hyperemia, which was repeated after
descending
artery;
LM = left marginal
arwr\
IK’:\ = right ~~wonow
II. Basal coronary hemodynamics, myocardial metabolism, and hyperemia parameters in the control group (n = 7, mean it SD) -- .--___-._ CSBFc(ml min-‘) 98 I 17 CRC(mmHg. ml-’ . min) 0.99 5 0.15 Table
CSO, (ml lOOml-‘) CSPO, (kPa)
,1.7 rc cl.:\
a-CSO,D(ml lOOml-‘1 MirO, (ml min-‘) Lactate
extraction
CSBFp CSBFpKSBFc AQ (ml) AQKSBFc
( r; )
2.71
t
12.7
+ 0.9
0.40
I::.16 t 1.7” w 62 -t 14
1’97 < r?-.‘35 2.02x 0.24 123 i :1.1 0.18 rr_ 0.02
[(CRp-CRcVCRc]x loo’<> --it9? 6 -..- --- - ~.-. .~._._._.-._---_Abbreviations: a-CSO,D = arterial-coronary sinus hi& oxygen difference: CRc = control coronary resistance: CRp = coronaw resistance at peak reactive hyperemia; CSBFc = control coronar) sinus blood flow: CSBFp = coronary sinus blood flow at peak renctive hyperemia; CSO, = coronary sinus blood oxygen contenf; CSIW, = coron;try sinus blood oxygen pressure; MiiO, = myocardial ~~xv~en consumptirm; A$ = h.vperemia net volume.
coronary flow had returned to control values. The whole procedure was repeated immediately after a l-minute right atrial infusion of diltiazem (0.30 mg . kg-‘). During the same period, contrast medium-induced reactive hyperemia was studied in seven patients with normal coronary angiogramsand normal left ventricular function. Four patients had mild mitral stenosis with normal cardiac index and pulmonary wedge pressures below 15 mm Hg; one had mild pulmonary stenosiswith a 45 mm Hg right ventricular systolic pressure, one had a small left ventricular septal defect, and one had a patent foramen ovale. The latter two patients did not have any detectable left-to-right shunt by oximetry. There was no history of chest pain in any of these patients who were considered to have normal coronary circulation. The effects of diltiazem were not studied in these patients.
1234
Table
Fault
et al.
American
December 1966 Heart &urnaf
III. Coronary hemodynamicsand myocardial metabolism (mean & SD) Lactate CSBFc (ml
Basal Diltiazem P
min-‘)
(mm
154 + 49 148 * 41 NS
CR, Hg ml-’
CSO, . min)
CSPo2 (k Pa)
(ml . 100 ml-‘)
0.69 zk 0.27 0.60 + 0.22 <0.05
5.4 k 0.9 6.8 k 1.7
a-CSOJI (ml 100 ml-‘)
2.70 f 0.32 3.10 f 0.43
MliO, (ml . min-‘)
13.39 * 1.03 11.16 IL 1.83
20.53 +- 6.62 16.85 + 6.32
Abbreviations: a-CSO,D = arterial-coronary sinus bIood oxygen difference; CR< = control coronary resistance; CSBF, = control coronary CSO, = coronary sinus blood oxygen content; CSPoz = coronary sinus blood oxygen pressure; MOO, = myocardial oxygen consumption.
Table
31 + 36 39 f 22 NS sinus blood &xv;
IV. Hyperemia parameters (mean -+ SD) CSBF,
Basal Diltiazem P
extraction (%)
(ml
min-‘j
219 + 63 197 * 45
CSBFJCSBF, 1.45 +- 0.17 1.36 + 0.15 <0.05
AQ (ml) 14.4 & 5.3 9.6 +- 4.8
Abbreviations: CR, = control coronary resistance; CR, = coronary resistance at peak reactive CSBF. = coronary sinus blood flow at peak reactive hyperemia; AQ = hyperemia net volume.
Data analysis and calculations. Cardiac output was measuredby the thermodilution method and was usedto calculate the cardiac index (cardiac output/body surface area, L . min-’ . me*). Heart rate, left ventricular enddiastolic pressure, mean aortic pressure, and systemic vascular resistancewere calculated by the computer system. Mixed venous, arterial, and coronary sinus blood oxygen contents were measuredin duplicate by a galvanic cell method that producesan electric current in proportion to oxygen molecules present (Lex 0, Con K, Waltham Instruments, Waltham, Mass.). Arterial, mixed venous, and coronary sinus blood pH, Pcoz, and PO, were measured in duplicate with an ABL II blood gas analyzer (Radiometer America, Westlake, Ohio). Arterial plasma lactate and coronary sinus lactate concentrations were measuredin duplicate by an enzymatic ultraviolet method (Boehringer Mannheim Laboratories Mannheim, W. Germany). The percentage of lactate extraction was calculated as: (arterial lactate minus coronary sinus lactate/arterial lactate) X 100. Coronary sinusblood flow (ml . min-‘) wascontinuously recorded during contrast medium-induced hyperemia. Coronary resistance was calculated as the ratio between meanaortic pressureminus left ventricular meandiastolic pressureI and coronary sinus blood flow. Total blood volume during reactive hyperemia was calculated by planimetry of the coronary sinusblood temperature curve: hyperemia total blood volume (ml) = mean coronary flow during hyperemia (ml . set-‘) x hyperemia duration (set). Hyperemia net volume was calculated as hyperemia total blood volume (ml) minus control coronary flow (ml . set-I) x hyperemia duration (set). Although coronary sinus thermodilution does not define the mass of myocardium being drained,lg this should not have impaired our results since data analysis was basedon a comparison between flow and resistanceratios. The ratio
AQICSBF,
[(CR,
- CRJICR,]
0.10 ? 0.04 0.07 + 0.03
x 100 (%)
-30 I! 8 -25 + 8 <0.05 CSBF, = control
coronary
sinus blood flow;
between peak and control coronary flow, that is, the hyperemic ratio, and the hyperemia net volume/control coronary flow ratio were used for quantification of the hyperemia relative magnitude. The decreasein coronary resistance during contrast medium-induced hyperemia was expressed as a percentage: (coronary resistance at peak hyperemia minus control coronary resistance/control coronary resistance)x 100. The reproducibility of contrast-induced hyperemia wasdemonstratedsincelessthan 5% variation occurred between two successivehyperemias, both at basal state and after diltiazem. Myocardial oxygen consumption (ml . min-‘) was calculated as arterial-coronary sinus blood oxygen content difference X coronary sinus blood flow. Statistics. Mean values and standard deviation were calculated for each parameter. Differences between basal and diltiazem data were examined by meansof paired t test. Comparisonsbetween normal subjects and patients with coronary artery diseasewere made by means of unpaired t test. Differences were consideredsignificant if p was <0.05. RESULTS Control group. Coronary hemodynamics, myocardial metabolism, and hyperemia parameters of the control group are presented in Table II. Since the effects of diltiaxem were not tested in this group, only baseline results are provided for these seven subjects. Patient hemodynamics. Diltiaxem infusion decreased the heart rate (77 + 15 to 70 +- 13 bpm, p < 0.001) and reduced mean aortic pressure (115 +17 to 98 + 8 mm Hg, p < 0.601). Cardiac index (2.8 + 0.6 to 2.9 k 0.6 L . min-’ . m-Y and left ventricular end-diastolic pressure (19 + 9 to 16 f 6 mm Hg) were not significantly affected by diltiaxem,
Volume Number
112 6
niltiazem
while systemic vascular resistance was reduced in all patients (22.4 t_ 6.7 to 18.1 -t- 4.5 mm Hg - L-l min, p < 0.01). patient
myocardial
blood flow and metabolism
and coronary
reactirlc
hvpewmia
1235
EKG
(Table
III). The intravenous infusion of diltiazem in patients with coronary stenosis did not significantly change coronary blood flow, but coronary sinus oxygen content and pressure increased significantly whereas coronary resistance was reduced. Since the arterialcoronary sinus blood oxygen difference decreased significantly, the calculated myocardial oxygen consumption was reduced. Lactate extraction by the myocardium was not significantly altered. Patient coronary reactive hyperemia (Table IV). At the basal state, the peak/control coronary blood flow ratio was significantly lower in patients with coronary artery disease than in the normal group (1.45 + 0.17 vs 2.02 2 0.24, respectively; p < 0.001). Thus our patients with angiographic coronary artery disease were distinguished as having true flow restriction resulting from coronary stenosis.‘2 In these patients, the intravenous infusion of diltiazem significantly blunted the hyperemia peak flow and net volume, the hyperemic ratio, and the ratio of hyperemia net volume to control flow (Table IV). The decrease in coronary resistance elicited by the injection of contrast medium was also significantly blunted. Fig. 1 provides a representative example of a blunted reactive hyperemia after diltiazem. DISCUSSION
The present study was designed to analyze the acute effects of diltiazem on contrast mediuminduced coronary reactive hyperemia in patients with coronary artery disease. Although the exact mechanism by which hyperosmolar contrast agents result in a transient coronary arteriolar vasodilation remains poorly understood, experimental studies have demonstrated that contrast medium-induced hyperemia was comparable to that obtained after a lo-second coronary occlusion.12 Vasodilation elicited by contrast medium is not maximum, but it provides an estimate of the coronary reserve which is significantly correlated with data obtained after intravenous dipyridamole in doses considered to elicit maximum coronary vasodilation.20s21 Furthermore, the elevation of coronary blood flow after intracoronary injection of contrast medium provides reproducible data both in our laboratory and in others.‘:’ patient selection. One of the difficulties arising from the evaluation of antianginal agents in patients with coronary artery disease stems from the definition of the disease itself: coronary angiography is usually regarded as a “gold standard” for assess-
AOP
LVP cl
j
/
dP/dilWO mmHg.s-I * -1*oo
AoP
LVP
mmllg / il
CSBF ml.min-’
e-
%.-----./-.
Diltiazem
Fig. 1. Typical example of contrast medium-induced reactive hyperemia in a patient at basal state and after diltiazem. Arrow indicates time of contrast medium injection into the left coronary artery. After diltiazem, control coronary sinus blood flow is not different, but peak coronary flow is reduced. AoP = aortic pressure; CSBF = coronary sinus blood flow; EKG = electrocardiogram; LVP = left ventricular pressure.
ment of the severity of coronary stenosis. However, recent studies have emphasized wide discrepancies between angiographic evaluation and true flow restriction resulting from coronary artery disease.2” In our laboratory, the hyperemic ratio in patients with normal coronary circulation is 2.02 + 0.24. The mean value of 1.45 for the hyperemic ratio estab-
1236
Fault et al.
lishes that flow-limiting coronary stenosis was present in our patients. The presence of elevated myocardial oxygen consumption in the patient group vs control subjects (Tables II and III) at basal state should have led to a parallel elevation of the hyperemia peak flow7 and is therefore unlikely to have created an artificially reduced hyperemia flow ratio in the patient group. This authenticates the studied population as a group with coronary lesions defined not only by angiographic evaluation but also by a restricted response to a hyperemic stimulus, that is, reduced coronary flow reserve. Diltiazem and coronary hyperemic response. The major result of this work reveals that diltiazem significantly blunts contrast medium-induced coronary reactive hyperemia in patients with flow-limiting coronary stenosis. Although the observed alteration of the hyperemic ratio after diltiazem is of modest magnitude, it must be stated that the hyperemia net volume decreased by as much as 33% after the infusion of calcium channel blocker (Table IV). We have previously reported a reduction of the hyperemic ratio in patients with coronary artery disease after the administration of bepridil, another calcium channel blocker.15 There are several possible mechanisms by which diltiazem may have reduced reactive hyperemia flow. One of the major determinants of coronary reactive hyperemia is the level of myocardial oxygen consumption: the more elevated the myocardial metabolic activity, the more important the hyperemit response to a given stimulus7 Reduction of the myocardial oxygen consumption1-3 most probably accounted for at least part of the decreased hyperemit response after diltiazem. However, no reduction of hyperemia was observed in dogs after nitrates despite decreased metabolic activity.23 The effects of intravenous nitroglycerin24 were tested in our laboratory in three patients with significant (270 % ) coronary artery disease (2 pg . kg-’ . min-’ x 10 min). There was no alteration of the hyperemic ratio (from 1.44 Jo 0.20 to 1.51 + 0.29), although myocardial oxygen consumption was decreased (from 21.65 + 6.09 to 17.30 ? 3.70 ml . mm-‘). Since the actions of nitrates predominate on large conductance coronary vessels, they do not influence coronary autoregulation which concerns the distal circulation.24 Thus a reduction of the metabolic demand will be followed by a parallel reduction of coronary flow, both in the control state and at peak hyperemia, with no alteration in the relative magnitude of the hyperemia. On the contrary, our findings of a reduced relative intensity of hyperemia after diltiazem or bepridil suggest that some calcium channel blockers may influence the
American
December 1986 Heart journal
vasomotor tone of coronary resistance vessels, especially at elevated flow rates. It may be of interest that although diltiasem blunted coronary reactive hyperemia, it also exhibited significant vasodilator properties in the control state, as demonstrated by decreased coronary resistance (Table II). In contrast with nitrates, diltiasem has little influence on the size of large coronary epicardial vessels. 25Vasodilation as evidenced at the basal state was most likely related to the coronary distal circu1ationz6 Reduction of hyperemia flow could have resulted from a heterogeneous response in myocardial areas supplied by stenotic vs nonstenotic coronary arteries. This could have led to a “steal” phenomenon and thus to some degree of myocardial &hernia. We do not believe that this occurred for several reasons: first, 6 of 12 patients had severe obstructions of the three major vessels; thus reduction of the hyperemia, of necessity, occurred via a stenotic vessel in these patients. In addition, no chest pain, ECG alteration, or elevation of left ventricular enddiastolic pressure occurred in any of the patients, while lactate extraction by the myocardium tended to increase. Regardless of the mechanisms that may account for reduction of hyperemia after diltiaxem, it is possible to question whether this limitation could have deleterious consequences on myocardial perfusion. At first glance, one would speculate that the larger the coronary hyperemic response, the better. There is, however, experimental evidence to support the idea that a reduction of peak hyperemia flow would not have detrimental consequences but instead should be beneficial in the presence of a proximal coronary stenosis. The decrease in the coronary poststenotic pressure that occurs at the time of hyperemiaz7 has been demonstrated to result in a transmural redistribution of blood flow with inability to perfuse the subendocardium.28-31 This detrimental effect of an excessive distal vasodilation downstream from a significant coronary stenosis can be observed regardless of the vasodilator stimulus and has been reported to occur following administration of adenosine or exercise.32f33 According to the hemodynamic behavior of a typical stenosis, the difference between the aortic pressure and the poststenotic pressure, that is, the pressure loss across the stenosis, increases with the second power of the coronary blood flo~.~~ Thus, in the presence of severe stenosis, the subendocardial perfusion can be compromised by a minimal elevation of the coronary flow. By reducing hyperemia, diltiazem should minimize the pressure decrease across the stenosis and thereby contribute to lessening the degree of suben-
Volume Number
112 6
docardial ischemia. This hypothesis is supported by experimental data showing both a restriction of the coronary hyperemia response and an improved subendocardial perfusion after diltiazem.” Although the hyperemic flow response to transient coronary occlusion or intracoronary contrast medium is only a model for coronary arteriolar vasodilation, improved subendocardial perfusion has been demonstrated after diltiazem at exercise in dogs with chronic coronary stenosis. 35This suggests that redistribution of transmural blood flow toward subendocardial layers might represent one of the mechanisms by which diltiazem exerts its protective effect in patients with coronary artery disease. We are indebted to Franqoise Carlier, Anne Borges, and Sylvie Lepape for expert secretarial and technical assistance.
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