Coronary vasomotion plays an important role in the regulation of coronary perfusion at rest and during exercise. Normal coronary arteries show coronary vasodilation of the proximal (+20%) and distal (+40%) vessel segments during supine bicycle exercise. However, patients with coronary artery disease show exercise-induced vasoconstriction of the stenotic vessel segments. The exact mechanism of exercise-induced stenosis narrowing is not clear but might be related to a passive collapse of the disease-free vessel wall (Venturi mechanism), elevated plasma levels of circulating catecholamines, an insufficient production of the endothelium-derived vesorelaxing factor or increased platelet aggregation due to turbulent blood flow with release of thromboxane A2 and serotonin. Various vasoactive drugs, such as nitroglycerin and calcium antagonists, prevent exercise-induced stenosis vasoconstriction. An additive effect on coronary vasodilation of the stenotic vessel segment was observed after combination of nitroglycerin with diltiazem. Thus, exercise-induced stenosis narrowing plays an important role in the pathophysiology of myocardial ischaemia during dynamic exercise. The antianginal effect of vasoactive substances can be explained—besides the effect on pre- and afterload—by a direct action on coronary stenosis vasomotio

Anliker, M.

Büchi, M.

Gould, K. L.

Hess, O. M.

Kirkeeide, R.

Krayenbühl, H. P.

Niederer, P.

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European Heart Journal (1990) 11, {Supplement B), 58-64Potential role of coronary vasoconstriction inischaemic heart disease: effect of exercise*O. M. HESS, M. BUCHI*, R. KIRKEEIDE**, P. NIEDERERI, M. ANLIKERI, K. L. GOULD**AND H. P. KRAYENBUHL** Department of Internal Medicine, Medical Policlinic, Cardiology, University Hospital andt Institute of Biomedical Engineering, University of Zurich, ** Division of Cardiology,University of Texas, Houston, U.S.A.KEY WORDS: Vasoconstriction, coronary circulation, myocardial ischaemia, exercise.Coronary vasomotion plays an important role in the regulation of coronary perfusion at rest andduring exercise. Normal coronary arteries show coronary vasodUation of the proximal (+20%) anddistal (+40%) vessel segments during supine bicycle exercise. However, patients with coronary arterydisease show exercise-induced vasoconstriction of the stenotic vessel segments. The exact mechanismof exercise-induced stenosis narrowing is not clear but might be related to a passive collapse of thedisease-free vessel wall (Venturi mechanism), elevated plasma levels of circulating catecholamincs, aninsufficient production of the endothelium-derived vasorelaxing factor or increased platelet aggrega-tion due to turbulent blood flow with release of thromboxane A2 and serotonin.Various vasoactive drugs, such as nitroglycerin and calcium antagonists, prevent exercise-inducedstenosis vasoconstriction. An additive effect on coronary vasodUation of the stenotic vessel segmentwas observed after combination of nitroglycerin with diltiazem. Thus, exercise-induced stenosisnarrowing plays an important role in the pathophysiology of myocardial ischaemia during dynamicexercise. The antianginal effect of vasoactive substances can be explained—besides the effect on pre-and afterload—by a direct action on coronary stenosis vasomotion.Introduction vasoactive drugs on coronary vasomotion at rest„ . . . and during exercise.Coronary vasomotion plays an important role inthe pathophysiology of myocardial ischaemia. Exercise protocolStenotic coronary arteries show coronaryvasomotion at the site of the stenosis'1"51 since Simultaneous biplane coronary arteriographyapproximately 70% of all stenoses have a was used for quantitative evaluation of normalnormal musculo-elastic wall segment'6-7'. Coro- and stenotic coronary vessel segments at restnary vasoconstriction of the normal and the and during supine bicycle exercise. Patients werestenotic vessel segment has been reported during selected on a consecutive basis when a history ofisometric handgrip exercise18'. This vasoconstric- stable, effort-related angina pectoris and ation is probably due to reflex activation of the clearly visible coronary stenosis were present,sympathetic nervous system with increased Quantitative biplane analysis was performed inlevels of circulating catecholamines. The pur- the right and left anterior oblique projection butpose of the present study is, therefore, to discuss in some patients cranio-caudal angulation wasthe effect of dynamic exercise on coronary necessary for proper visualization of the stenoticvasomotion in patients with coronary artery segment. Cinefilm was used as a data carrierdisease and to evaluate the effect of various (filming rate 50 frames s"1). Two differentcontrast materials were used: Before January1988 5-8 ml of an ionic contrast materialAddress for correspondence: Otto M. Hess M.D., (amidotrizoate; Urografin-76%) was used forMedical Policlinic, Cardiology, University Hospital, coronary artenogTapn/ '. After January 1988Raemistrasse 100,8091 Zurich, Switzerland. 5-8 ml of a nonionic contrast material0195-668X/90/OB058 + 07 $03.00/0 © 1990 The European Society of CardiologyCoronary vasoconstriction 59(iopamidol-trometamol; Iopamiro 370) was usedfor coronary arteriography to minimize hyper-aemic reactions of the coronary vessels.However, repeated injections with the ioniccontrast material, amidotrizoate, produced onlyminor changes in coronary artery dimensionswhen these measurements were carried out atthe end of the diagnostic coronaryarteriography121. Control biplane arteriographywas performed with the patient's feet in elevatedposition attached to the bicycle ergometer.Exercise was begun at a level of 50-75 W whichwas increased every 2 min in increments of25-50 W. Biplane coronary arteriograms withconcurrent aortic and pulmonary artery pressurerecordings were obtained every 2 min and at theend of exercise. Sublingual nitroglycerin(1-6 mg) was administered immediately at theend of the exercise test and repeat coronaryarteriography was carried out 5 min thereafter.Quantitative coronary arteriographyQuantitative evaluation of biplane coronaryarteriograms was performed with two differentsystems: Before November 1988"-2-*-51 theoutlines of coronary arteries were tracedmanually (4 to 6 times) in a blinded fashion andwere digitized with an electronic digitizer(Numonics Corp.) interfaced to a computer PDP11/34. A portion of the catheter of knowndimension was traced for each cineframe andwas used as a scaling factor. Interobservervariability for this manual system was found tobe small with a standard error of estimate (SEE)for biplane data of 0-30 mm2 (=7-9% of themean vessel area).After November 1988 an automatic systemwas used for quantitative coronaryarteriography*91. The system is based on a 35 mmfilm projector, a slow-scan CCD-camera (imagedigitation) and a computer work-station (ApolloDN 3000; image storage and processing).Calibration is performed by the isocentretechnique, which is based on two fixed referencepoints in the centre of the two image intensifiers.Contour detection is carried out in biplaneprojection using a geometric-densitometric edge-detection algorithm (Fig. 1). Interobservervariability was found to be small with a standarderror of estimate for biplane data of 0-14 mm2( = 4 1 % of the mean vessel area).The methodology for computerized analysis ofcoronary arteriograms has been describedelsewhere'10'. Briefly, a three-dimensional modelof the vessel is constructed by matching centrelines of the individual biplane tracings, assumingthe vessel cross-section to be ellipsoidal. Theproximal and distal as well as the minimalcross-sectional areas of the vessel segment arecalculated and printed out by the computer.Normal coronary vasomorionCoronary vasomotion was studied at rest andduring bicycle exercise in seven normal patientswith no evidence of coronary artery disease andnormal coronary flow reserve as assessed bycoronary sinus thermodilution before and afterintravenous dipyridamole'4'. Coronary luminalarea of the left anterior descending or the leftcircumflex coronary artery were analysed at rest,during exercise and after 1-6 mg nitroglycerinadministered at the end of the exercise test.Coronary luminal area increased by 20% duringexercise and by 45% after sublingual ad-ministration of nitroglycerin. Thus, in normalpatients coronary vasodilation occurs duringdynamic exercise which is, however, notmaximal, since after administration of nitrogly-cerin coronary luminal area is approximatelydouble that during exercise.Coronary artery diseaseCoronary vasomotion of stenotic coronaryarteries represents a significant element in thepathogenesis of myocardial ischaemia'7'. Brownand coworkers"" have reported a decrease incoronary luminal areas of normal and stenoticvessel segments by 14% and 35%, respectively,during isometric handgrip exercise. Coronaryvasoconstriction was prevented after intracoro-nary infusion of nitroglycerin during a secondhandgrip test. Thus, active coronary vasocon-striction during handgrip exercise is probablydue to reflex activation of the sympatheticnervous system and can be suppressed by theuse of intracoronary nitroglycerin. Gage et a/.1'1and Gordon et a/.'3' reported a decrease incoronary luminal area of stenotic coronaryarteries during dynamic exercise, whereasnormal vessel segments showed exercise-inducedvasodilation. This exercise-induced stenosisnarrowing is dependent on the severity ofcoronary stenosis'3', since mild lesions show only60 O. M. Hess et al.Figure 1 Quantitative evaluation of a coronary arteriogram in a patient with a severe stenosis of the leftcircumflex coronary artery. The arteriogram is projected on a 35 mm film projector, digitized on aslow-scan CCD-camera and processed on an Apollo DN 3000 computer work-station. Contour detectionis performed automatically in biplane projection using a geometric-densitometric edge-detectionalgorithm. Luminal areas of the normal and stenotic vessel segment are given in both projections as wellas in biplane projection (top left panel). The patient's data are included in the right hand panel.minimal (—10% area reduction, NS vs rest) butsevere lesions significant (—32% area reduction,P < 0001 vs rest) vasoconstriction during bicycleexercise. The exact mechanism of this exercise-induced stenosis narrowing is not clear but mightinvolve the following: (1) passive collapse of thedisease-free vessel wall within the stenosis dueto an increase in blood flow velocity duringexercise (=Venturi mechanism); (2) activevasoconstriction due to increased levels ofcirculating catecholamines during exercise; (3)insufficient production of the endothelium-derived vasorelaxing factor during exercise dueto the atherosclerotic alterations of the vesselwall1"1; (4) increased platelet aggregation duringexercise due to turbulent blood flow behind thestenosis with release of thromboxane A2 andserotonin'12'. It is likely that more than one ofthese mechanisms combine to produce theobserved stenosis vasoconstriction during bicycleexercise. To examine further this phenomenonwe studied the effect of different vasoactivesubstances on coronary vasomotion of thestenotic vessel segment.Effect of vasoactive drags on coronaryvasomotionThe effect of intracoronary nitroglycerin oncoronary vasomotion of normal and stenoticvessel segments (1) was evaluated in six patientswith coronary artery disease at rest and duringsupine bicycle exercise. Immediately prior to theexercise test, 0-1 mg intracoronary nitroglycerinwas administered which was followed by twolevels of bicycle exercise. A normal (Fig. 3) anda stenotic (Fig. 4) vessel segment were evaluatedquantitatively and compared with a controlgroup of 12 patients with coronary artery diseasebut without intracoronary nitroglycerin beforethe exercise test1". Immediately at the end of theexercise test 1-6 mg sublingual nitroglycerin wasadministered to both groups.The normal vessel segment (Fig. 3) showedCoronary vasoconstriction 6110EV(I nL•nz6 -2 -y = O-997x + -0-001r = 0-999P< 0001SEEa =0-072 mm2 SEErn=21(a )n 1 1 1 1 r2 3 4 5 6 7Vessel area (mme)Measurement 18 9 1010CMEE - 6y = 0-982 x + 00078r =0-998P <0OO1S E E , = 0-137 mm* SEEr. = 4-1*/9 K>Vessel area (mm 2 )Observer 2Figure 2 Intraobserver (a) and interobserver (b) variability for quantitativecoronary arteriography using an automatic contour detection algorithm. Thestandard error of estimate (SEE) was 0-076 mm2 or 2 1 % of the mean (biplane)vessel area (intraobserver variability) and was 0-137 mm2 or 4-1% of the mean(biplane) vessel area (interobserver variability). With the use of an automaticsystem, the standard error (interobserver variability) was reduced from 7-9%(manual system) to 4-1% (automatic system), r: correlation coefficient, P:probability, n: number of measurements.62 O. M. Hess et al.1 5 0125•£ 100o75Normal vessel* * *150 -Rest Ex1 Ex2 NTGFigure 3 % change of the normal vessel area duringbicycle exercise (Exl and Ex2) and after sublingualadministration of 1-6 nig nitroglycerin (NTG). Threegroups of patients were studied: group 1 served as controlgroup and received no pretreatment prior to the exercisetest, group 2 received 0-1 mg intracoronary (i.e.)nitroglycerin prior to exercise and group 3 2-3 mgintracoronary diltiazem. The control group showedcoronary vasodilation during submaximal exercise (Ex2),whereas in the other two groups vasodilation wasobserved after intracoronary injection of the drug;nitroglycerin showed a more pronounced vasodilatoreffect on the normal coronary arteries than diltiazem (forexplanations see text). |—O—| = mean ±1 standard error;• = P < 0 0 5 , •* = /3<0-01, * " = P<0-001 vs rest.= control; O—O=NTG; • • = diltiazem.125 -100 -Rest Ex1 Ex2 NTGFigure 4 % change of the stenotic vessel area duringbicycle exercise (Exl and Ex2) and after sublingualadministration of 1-6 mg nitroglycerin (NTG). The samethree groups as shown in Fig. 3 were studied: group 1served as control group without intracoronary pretreat-ment prior to the exercise test, group 2 received 0-1 mgintracoronary (i.e.) nitroglycerin prior to exercise andgroup 3 2-3 mg intracoronary diltiazem. In contrast tothe normal vessel segment, there is exercise-inducedstenosis narrowing in the control group which is,however, reversible after sublingual administration ofnitroglycerin. Intracoronary administration of nitroglycer-in or diltiazem prevented stenosis narrowing duringexercise when the drug was injected prior to the exercisetest. The combination of intracoronary diltiazem withsublingual nitroglycerin showed an additive effect whichwas significantly (P<0-05) more pronouned after thiscombination than after sublingual nitroglycerin alone (forfurther explanations sec text). Abbreviations and symbolsare as in Fig. 3.coronary vasodilation after intracoronary injec-tion of nitroglycerin (+21%, P<005 vs rest)which persisted during maximum exercise(+29%, P < 0 0 1 vs rest) and after sublingualnitroglycerin (+23%, P < 0 0 5 vs rest). Thestenotic vessel segment (Fig. 4) also showedcoronary vasodilation after intracoronary ad-ministration of nitroglycerin (+22%, P < 005 vsrest) which persisted during the first 2 min ofexercise (+23%, P<0-05 vs rest) but decreasedslightly towards resting levels during maximumexercise (+14%, NS vs rest) and after sublingualadministration of nitroglycerin (+16%, NS vsrest).Thus, intracoronary administration of nit-roglycerin is associated with an increasedCoronary vasoconstriction 63coronary luminal area in normal and stenoticvessel segments. During bicycle exercise nofurther dilation of the coronary arteries wasobserved probably owing to maximal predilationof the coronary arteries after intracoronarynitroglycerin. Thus, exercise-induced stenosisnarrowing is eliminated (Fig. 4) due to thestrong vasodilating effect of nitroglycerin on thesmooth vasculature.The effect of 2-3 mg intracoronary diltiazemon coronary vasomotion of normal and stenoticvessel segments was evaluated in a third groupof nine patients with coronary artery disease'131and compared with the data from 12 patientswith coronary artery disease not given pretreat-ment prior to the exercise test'11.Intracoronary administration of diltiazem wasassociated with coronary vasodilation of thenormal (+14%, P < 0 0 1 vs rest) and stenotic(+15%, NS vs rest) vessel segment which was,however, slightly less than after intracoronarynitroglycerin (Figs 3 and 4). During submaximalbicycle exercise (EX2), luminal area of bothnormal (+19%, P < 0-001 vs rest) and stenotic(+31%, P<0-0l vs rest) vessel segmentsfurther increased. After sublingual administra-tion of nitroglycerin in the patients givenintracoronary diltiazem, there was an additiveeffect on coronary vasodilation of the stenoticvessel segment (+35%, P<0-001 vs rest); the% increase in luminal area was significantly(P < 0-05) more pronounced after diltiazem andnitroglycerin than after sublingual nitroglycerinalone (Fig. 4).Thus, diltiazem exhibits a vasodilatory effecton both normal and stenotic vessel segmentswhich is less pronounced than that after intra-coronary nitroglycerin (Figs 3 and 4). Similarobservations have been made in the chronicallyinstrumented dog1141; it was shown that thecalcium antagonists nifedipine, verapamil anddiltiazem are relatively weak coronary vasodila-tors compared with nitroglycerin. The reasonnitroglycerin appears to be a more potent dilatorof epicardial coronary arteries than calciumantagonists is unclear1141. The additive effect ofdiltiazem and nitroglycerin was observed in thepresent study only in stenotic (Fig. 4) but not innormal (Fig. 3) vessel segments. The mechanismof this additive effect is not clear but might berelated to the different mode of action of thetwo vasodilators: diltiazem reduces the calciuminflux into the smooth muscle cell; nitroglycerinincreases the cyclic guanosine monophosphate inthe vascular musculature. Apparently, thecombined action of these two vasodilatorsenhances the vasodilating properties of eachdrug alone. Both drugs are well established inthe treatment of patients with coronary arterydisease and both have been shown to be highlyefficient in reducing myocardial ischaemia'15161.Calcium antagonists and nitrates are oftencombined in the daily routine for an optimalantiischaemic effect in patients with anginapectoris although clinical trials have not shown abetter result in terms of anginal pain andphysical working capacity for the combinedregimen than for either drug alone1161.References[1] Gage JE, Hess OM, Murakami T, Ritter M, GrimmJ, Krayenbuehl HP. Vasoconstriction of stenoticcoronary arteries during dynamic exercise in patientswith classic angina pectoris: reversibility by nitrogly-cerin. Circulation 1986; 73: 865-76.[2] Gaglione A, Hess OM, Corin WJ, Ritter M, GrimmJ, Krayenbuehl HP. Is there coronary vasoconstric-tion after intracoronary beta-adrenergic blockade inpatients with coronary artery disease? J Am CollCardiol 1987; 10: 299-310.[3] Gordon JB, Zebede J, Wayne RR, Mudge GH,Ganz P, Selwyn AP. Coronary constriction withexercise: possible role for endothelial dysfunctionand alpha tone. Circulation 1986; 74 (Suppl II): II481 (Abstr)[4] Bortone AS, Hess OM, Eberli FR et at. Abnormalcoronary vasomotion during exercise in patients withnormal coronary arteries and reduced coronary flowreserve. Circulation 1989; 79: 516-27.[5] Hess OM, Bortone AS, Eid K el al. Coronaryvasomotor tone during static and dynamic exercise.Eur Heart J 1989; 10: 105-10.[6] Freudenberg H, Lichtlen PR. The normal wallsegment in coronary stenosis—a postmortem study.Z Kardiol 1981; 70: 863-9.[7] Brown BG, Bolson EL, Dodge HT. Dynamicmechanisms in human coronary stenosis. Circulation1984; 42: 917-22.[8] Brown BG, Lee AB, Bolson EL, Dodge HT. Reflexconstriction of significant coronary stenosis as amechanism contributing to ischemic left ventriculardysfunction during isometric exercise. Circulation1984; 70: 18-24.[9] Buchi M, Hess OM, Suter Th et al. Validation of anew automatic system for biplane quantitativecoronary arteriography. Int J Cardiovasc Imaging, inpress.[10] Kirkeeide RL, Gould KL. Cardiovascular imaging:Coronary artery stenosis. Hosp Pract 1984; 19:160-3.[11] Bassenge E, Stewart DJ. Interdependence ofpharmacologically induced and endothelium-64 O. M. Hess et al.mediated coronary vasodilation in antianginaltherapy. Cardiovasc Drugs Ther 1988; 1: 47-55.[12] Folts JD, Gallagher K, Rowe GG. Blood flowreductions in stenosed canine coronary arteries:vasospasm or platelet aggregation? Circulation 1982;65: 248-55.[13] Nonogi H, Hess OM, Ritter M et al. Prevention ofcoronary vasoconstriction by diltiazem duringdynamic exercise in patients with coronary arterydisease. J Am Coll Cardiol 1988; 12: 892-9.[14] Schwartz JS, Bache RJ. Combined effects of calciumantagonists and nitroglycerin on large coronaryartery diameter. Am Heart J 1988; 115: 964-9.[15] Boden WE, Bough EW, Reichmann MJ et al.Beneficial effects of high-dose diltiazem in patientswith persistent effort angina on beta-blockers andnitrates: a randomized, double-blind placebo-controlled cross-over study. Circulation 1985; 71:1197-205.[16] Hossack KF, Eldridge JE, Buckner K. Comparisonof acute hemodynamic effects of nitroglycerin versusdiltiazem and combined acute effects of both drugsin angina pectoris. Am J Cardiol 1986; 58: 722-6.

Potential role of coronary vasoconstriction in ischaemic heart disease: effect of exercise

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