- Email: [email protected]
Abnormal Coronary Vasomotion in Hypertension: Role of Coronary Artery Disease1
JACC vol. 28, No. 4 October 1996:935-41
935
Abnormal CoronaryVasomotion in Hypertension:Role of Coronary ArteryDisease JURGEN FRIELINGSDORF, MD, PHILIPP KAUFMANN, MD, CHRISTIAN SEILER, MD, GIUSEPPE VASSALLI, MD, THOMAS SUTER, MD, OTTO M. HESS, MD Zurich,Switzerland
(Mjectives. Thisstudysoughtto evaluatetheeffectofdynamic exerciseon coronaryvasomotion in hypertensive patientsin the presenceand absenceofcoronaryarterydisease. Background. Endothelialdysfunction withabnormalcoronary vasodilationin responseto acetylcholine has beenreportedin patientswitharterialhypertension. Methodr.Coronaryarterydimensions ofa norrmdand stenotic vesselsegmentweredetermined in 64patientsbybiplanequantitativecoronaryarteriography at restandduringsupinebieyeleexercise.Patientswereclassifiedintotwogroups:20 patientswithout evidence ofcoronaryarterydisease(10normotensive, 10hypertensive[group1]) and 44 patientswithcoronaryarterydisease(26 normotensive, 18hypertensive [group2]).Bothgroupswerecomparablewithregardtoclinicalcharacteristics, serumcholesterol levels, bodymassinde%exercise capacityandhemodynamic data. Results. Mean aortic pressurewas significantlyhigher in hypertensive than normotensive patients,Exercise-induced vasodilationofthenormalvesselsegmentwassimilarinnormotensive andhypertensive patientswithoutcoronaryarterydisease(group 1),namely,+19%0 versus+20%,However, inhypertensive patients withcoronaryarterydisease,exercise-induced vasodilationwas
significantly lessinbothnormalandstenoticvessel segmentsthan in normotensive subjects(+1%vs. +20%o fornormal[p c 0.003] and -20%0vs. -5% forstenoticvessels[p c 0.025]).Administrationof1,6mgofsublingualnitroglycerin at theendofexereiseled toa normalization ofthevasodilatorresponsein normotensive as wellas hypertensivepatients.However,this responsebecame progressively abnormalin group2 whencoronaryarterydisease waspresent, Conclusions. In the absenceof coronaryartery disease,the vasomotorresponseto exerciseis normalin bothnormotensive andhypertensive patients.However, in hypertensive patientswith coronaryarterydisease,an abnormalresponseof the coronary vesselscan be observed,witha reducedvasodilatorresponseto exereisein normalarteries but an enhancedvasoconstrictor responsein stenoticarteries.This behaviorof the epicardial vesselsduringexereisesuggeststhe occurrenceof endothelial dystimction(i.e.,tkmctionaldefect)that is not evidentin the absenceof coronaryartery disease.Nitroglycerin reversesimpairedcoronaryvasodilation,but this effectis bluntedin the presenceofcoronaryarterydisease(i.e.,structuraldefeet).
The endotheliumplaysan importantrole in the regulationof vascularsmoothmuscletone by the releaseof relaxingand constrictingfactors.Endothelium-derived relaxingfactor (l), whichhasbeenrecentlyidentifiedasnitricoxide(2),is a major determinantofvascularrelaxation.However,the endothelium also releasesvasoconstricting factors(3), but its exactrole is stillnotyetclearlydefinedin humans.Arterialhypertensionis associatedwithmorphologicand functionalalterationsof the endothelium,suchas increasesin endothelialcellvolume(4), extracellularmatrix(5) and vascularresponsivenessto vasoconstrictorstimuli(6). In hypertensiveanimals,there is evidence that endothelium-dependentrelaxationis impaired, probablydue to a reduced release of endothelin-derived relaxingfactoror nitricoxide(7–12).In humanstudies,various
pharmacologic agents,mainlyacetylcholine, havebeenusedto evaluatethe responseof the endotheliumin hypertensive patients(13-26). Dependingon the presenceor absenceof atherosclerosis, the resultsof thesestudieshavebeen somewhatcontroversial; somehavereportedthe occurrenceof endothelialdysfunction, othershavenot.Thus,the purposeof the presentstudywasto evaluatecoronaryvasomotionin patientswithessentialhypertensionand normalor diseasedcoronaryarteriesusingexercise as a physiologicvasodilatorstimulus.This studyshould helpto definethe roleof the endotheliumin the regulationof coronaryvasomotortone in normotensiveand hypertensive patientsduringexercise.
(JAnrCoilCardiol1996;28:935-41)
Methods Fromthe Departmentof Cardiology, UniversityHospital,Zurich,Switzerland.ThisstudywassupportedbytheSwissNationalScienceFoundation,Bern, Switzerland. ManuscriptreceivedFebruary12,1996;revisedmanuscriptreceivedMay10, 1996,acceptedMay14,1996. Addressfor correspondence: Dr. Otto M. Hess,Divisionof Cardiology, UniversityHospital,Ramistrasse100,8091Zurich,Switzerland. 01996 by the AmericanCollegeof Cardiology Publishedby ElsevierScienceInc.
Study patients. Sixty-fourpatients (61 men, 3 women) assignedto coronaryarteriographywere classifiedinto two groupsaccordingto thepresenceor absenceofcoronaryartery disease.The twogroupswerefurtherclassitledintonormotensiveandhypertensivesubjects.Group1 included17menand 3 0735-1097/96/$15.00 PII SO735-1097(96)OO26O-4
936
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
women(mean[~SD] age50 ~ 8 years)withnormalcoronaq arteriographicfindings.Ten patientsin this groupwere normotensive,with a mean aortic pressure at rest of 90 * 12 mm Hg, and 10 were hypertensive,with a significantly increasedmeanaorticpressureof 106* 16mmHg (p < 0.02). Group 2 included44 men (mean age 53 ~ 8 years) with angiographicevidenceofcoronaryarterydisease.In thisgroup a normal vessel (group 2a) and a stenoticvesselsegment (group2b) were evaluated.Onlypatientswith one- or twovesseldiseasewereincludedingroup2;an averageof 1.8~ 0.8 vessels/patient wereinvolved.Twenty-six patientswerenormotensive,witha meanaorticpressureat restof 92 f 12mmHg, and 18werehypertensive,witha significantly increasedmean aorticpressureof 103t 15 mm Hg (p < 0.01).All patients performeduprightbicycleexercisetestingon the daybefore coronaryarteriography. Inclusioncriteria. Study patients were selectedfrom a cohortevaluatedby quantitativecoronaryangiographyon the basis of followingcriteria: 1) written informedconsentto undergo the exercisestudy; 2) qualitativelygood biplane angiogramfor quantitativeevaluation;3) angiographically smoothcoronaryarteries in group 1 (lumenalirregularities wereexcluded)and patientswithcoronaryarte~ diseasewith a normalaswellas a stenoticvesselsegmenton the angiogram (group2); 4) the normalvesselsegmentwas chosenfrom a nonstenosedartery and the stenoticvesselsegmentfrom a diseasedvesselsegmentwith a localizedstenosisof >50% (quantitativelyassessed).The stenosedvesselsegments(culprit lesion)were chosenonlyfromthe proximaltwothirdsof the respectiveartery. Exclusioncriteria. Patients were excludedif they had severeor unstableanginapectoris,ditfusethree-vesseldisease, a recent myocardialinfarction(<1 month),infarctionwith hypokineticor akineticmyocardialregions,renal or hepatic diseaseor a historyof diabetesmellitus. Definitionof arterial hypertension.Hypertensionwas defined as a historyof highblood pressure(diastolicpressure =95 mm Hg or systolicpressure =160 mm Hg, or both) requiring long-termtherapy and sustainedblood pressure elevationdocumentedduringthehospitalstayovera drug-free period (drugsdiscontinued24 h before cardiaccatheterization).Patientswereconsideredto havenormalbloodpressure if continuousbloodpressurereadingsshoweddiastolicvalues <90 mm Hg and systolicvalues<140 mm Hg. Patientswith secondarycausesof hypertensionand evidenceof damageto end-organswereexcluded. Definitionof coronaryrisk factors. Coronaryriskfactors, such as hypercholesterolemia (>200 mg/100ml), cigarette smoking,familyhistory(coronaryarterydiseasein one of the patient’sparentsor sibling<60 yearsold) and obesity(body massindex228 kg/m2),wereevaluatedin thepresentanalysis. Cardiaccatheterization.Medicationwas stoppedat least 24h beforecardiaccatheterization.Aorticpressurewasmeasuredwithan 8FJudkinscatheterinsertedfromthe groin,and pulmonaryartery pressurewas determinedwith a 6F pacing catheterwitha sideholefor pressuremeasurements.Biplane
JACC Vol. 28, No. 4 October 1996:935-41
left ventricularangiographywas performed in all patients, followedby diagnosticcoronaryarteriography. Studyprotocol.Simultaneousbiplanecoronaryarteriographywascarriedoutin twoorthogonalprojectionsto guarantee optimalvisualizationof the stenoticlesions.A controlarteriogram was acquiredwith the patient’sfeet attached to the bicycleergometer(model380 B, SiemensAlbisAG, Zurich, Switzerland).Exercisewas begun at 50 to 75 W and was increasedeve~ 2 minin incrementsof 25 to 50 W. Coronary arteriographywascarriedout at the end of eachexerciselevel withthe patientholdinghis or her breath duringinjectionof the contrastmedium.Arteriogramsat maximalexerciselevel were used for analysisof coronaryvasomotion.The exercise test wasterminatedbecauseof anginapectoris,fatigueor ST segmentdepression>0,2 mV.At the end of the exercisetest, 1.6mgof nitroglycerin wasadministeredsublingually. Biplane coronaryarteriographywasrepeated5 min thereafter.There wereno complicationsrelatedto the studyprotocol. Quantitativecoronaryarteriography.Quantitativeevaluation of biplanecoronaryarteriogramswas performedwith a semiautomaticcomputersystemthat has been describedpreviously(27-29).Interobservervariabilityfor this systemis 4.1%and intraobservervariability2.1%. Quantitativeanalysiswas performedin a proximalvessel segmentof a normal coronaryartery (group 1) or in an unaffectedcoronaryarterywithoutlumenchangesaswellasin a stenoticvesselsegment(group2). Measurementsiteswere selectedon the basis of the followingcriteria: 1) sufficient tillingofthevesselwithradiographiccontrastmedium;2) high qualitylate diastolicor end-diastoliccineframewithoutmotion artifacts;3) straightnessof the vessel segmentto be analyzed;and 4) biplaneX-rayviews.Angiogramswere measuredinblindedmannerwithregardto thevariablesofinterest as well as the actualstudysequence(rest, exerciseor nitroglycerin).Lumenarea changeswere determinedduringexercise (percentchangeversusrest = 100%)as well as after administrationof sublingualnitroglycerin. Statisticalanalysis.Between-groupcomparisonswith regard to clinical,hemodynamicand angiographicdata were performedby one-wayanalysisof variancefor continuous variables,followedby the Scheff6test if the probabilityvalue wassignificant(p < 0.05).The Fisherexacttest wasusedfor categoricvariables.Resultsin textand tablesare expressedas meanvaluet SD and in figuresas meanvalue* SEM.
Results Patient characteristics.Gender distribution,body mass index,New York Heart Associationfunctionalclassification and frequencyof anginapectoriswerecomparablein the two groups (Table 1). However,normotensivepatientswithout coronaryarterydiseasewereyounger(p < 0,02)than normotensivesubjectswithcoronaryarterydisease.In patientswith
JACC Vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
937
Table1. Patient Characteristics, Risk Factors and Medical Treatment Before Angiographyin Normotensive and HypertensiveSubjects With and Without Coronary Artery Disease* Group1 (withoutcwronary arterydisease) Norrnotensive Subjects (n= 10) WF Age(yr) BMI(kgjm2) NYHAclass Patienthistory Anginapectoris Myocardialinfarction
9/1 48~ 7 I 26&2 1.5~ 07
p<0.02 25~ 2 1.6? 0.5
9
9
0
o
I Riskfactors Totalcholesterol(mg/100ml) Cholesterol>200mg/100ml Familyhistory Obesity Smoking Anti-ischemic drugs Beta-blocker Ca antagonist Nitrates Tripletherapy
8/2 52~ 9
o I
No.ofvesselsdiseased
Hypertensive Subjects (n= 10)
Group2 (withcoronaryarterydisease) Normotensive Subjects (n= 26)
Hypertensive Subjects (n= 18)
26/0 54~ I I 25? 3 1.8? 0.6
26? 2 1.8~ 0.5
21 12
16 6
18/0 52~ 9
p
0
p<0.001
2.1? 0.8 II
1.4t
0.7
p <0.03 J
232? 33 8 2 4 5
I 220*37 6 4 4 7
p < o.ol~ 240? 64 20 7 8 22
245? 35 16 6 9 16
4 3 3 1
8 6 5 3
17 17 16 8
14 12 12 7
*p= NSforallcomparisons unlessotherwiseindicated.Datapresentedaremeanvahret SD or numberof subjects. BMI = bodymassindex;F = female;M = male;NYHA= NewYorkHeartAssociation.
coronaryartery disease,norrnotensivesubjectshad a larger numberof diseasedcoronaryarteriesthan hypertensivesubjects (p < 0.03).Coronaryrisk factorsfor coronaryartery disease,especiallycholesterol,wereevenlydistributedamong thetwogroups.Therewasa trend(p < 0.06)to a slightlylesser use of anti-ischemicdrugsin normotensivepatientswithout than withcoronaryheart disease(Table1). Exerciseand hemodynamicdata. Exerciseworkload (absolutevaluesas wellas data in percentof age-,gender-and height-correctednormalvalues)in the uprightpositionwas similarin both groups,namely,147 * 39 W (96Y0of the normalvalue)in group1 and 139~ 27W (9170of the normal value)in group2. STsegmentdepressionwas0.12t 0.09mV in group1 and 0.12* 0.13mV in group2. The frequencyof anginapectorisduringexercisedid not differbetweenthe tsvo groups.Exerciseworkloadwas lowerin the supinethan the uprightpositionbutwassimilarinbothstudygroups(Table2), exceptfor normotensivepatientswithcoronaryarterydisease who performed less exercisethan those without coronary artery disease(p < 0.03).Changesin heart rate and mean pulmonaryartery pressureat rest, duringexerciseand after sublingualnitroglycerinadministrationwere alsocomparable in the twogroups.Heart rate,meanpulmonaryarterypressure andmeanaorticpressureincreasedsignificantly duringbicycle exercise(p <0.001 in both groups).Thesevariablesreturned
—..
to baselinevaluesafteradministrationof sublingualnitroglycerin.Meanaorticpressureat restdifferedsignificantly between normotensiveandhypertensive patientswithout(p < 0.02)and withcoronaryheartdisease(p < 0.01).Exercise-induced mean aorticpressurewashigherin hypertensivepatientswithcoronaryheart diseasethan in normotensivesubjects(p < 0.01). Thisdifferencewasnot significantbetweennormotensiveand hypertensive patientswithoutcoronaryheartdisease,probably due to the higherwork load in normotensivesubjects,Left ventricularfunction (end-diastolicvolume, left ventricular ejection fraction) and left ventricularmass did not differ betweenthe twogroupsand subgroups(Table3). Coronaryangiographicdata. In patientswithoutcoronary arterydisease(group1), normalvesselswere similarin size, andtheincreaseinlumenareawascomparableduringexercise (percentchangeduringexercisein percentof controlvalue)in normotensive(+19 t 970) and hypertensive(+20 ~ 870) patients(p = NS) (Fig.1, left panel).When thesedata were comparedwithnormalvesselsin patientswithcoronaryartery disease(group2a),therewasa significantdifferenceinpercent changeof the coronaryarteriesduringexercise(p < 0.003) betweennormotensive(+20 f 25%)andhypertensivesubjects (+1 ~ 9%) (Fig. 1, middlepanel). In contrast to normal segments, stenotic vessel segments (group 2b) showed exercise-induced vasoconstriction, witha significantdifference
938
FRIELINGSDORF ET AL,. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
JACC Vol. 28, No. 4 October 1996:935-41
Table2. Exercise and HemodynamicData During Angiographyin Normotensive and Hypertensive Subjects With and Without Coronary Artery Disease* Group1 (withoutcoronmyarterydisease) Normotensive Subjects (n= 10) Supinebicycleexercise Workload(W) Workload(% of normal) Heartrate (beats/rein) Rest Exercise Nitroglycerin MPAP(mmHg) Rest Exercise Nitroglycerin MAP(mmHg) Rest Exercise Nitroglycerin
9(J~ 12 Lp 111? 12
Hypertensive Subjects (n= 10)
106? 16 K0.02J
89~ 14
118* 10 93~ 8
Group2 (withcoronaryarterydisease) Nocmotensive Subjects (n= 26)
92~ 12 LP 105t 16 Lp 84~ 12
Hypertensive Subjects (n= 18)
103t 15 <0.01J 119? 16 <0.01J 93~ 16
*p = NS forallcomparisons [email protected] SD.MAP= mean aortic pressure;MPAP= meanpulmonaryarterypressure.
(p< 0.025)betweennormotensive(-5 f 21%)andhypertensive(–20 ~ 19%)patients(Fig.1, rightpanel).Lumenarea stenosisingroup2brangedbetween58?4and7790(mean63k 19%). Sublingualadministrationof 1.6mg of nitroglycerinafter exercisewas associatedwith an increasein lumen area in normotensiveaswellas hypertensivepatients(Fig.1): +49 ~ 24% and +38 t 11%, respectively,in group 1 (p = NS); +30 ? 24% and +23 ? 14%,respectively,in group2a (p = NS);and +16 * 17%and +15 t 21%,respectively, in group 2b (p = NS). Comparedwith the changesobservedduring exercise,vasodilationof allvesselswasfurtherenhancedafter treatmentwith nitroglycerin,but the increasein lumenarea was graduallysmallerwhen the extent of coronaryartery diseaseincreased(Fig.2);thus,vasodilationwaslessin group 2a than group1 (p <0.05 for normotensivesubjects,p <0.02 for hypertensivesubjects)and lessin group2b than group2a
(p< 0.01for normotensivesubjects,p = NSfor hypertensive subjects).
Discussion To our knowledge,the presentstudyis the firstto assess coronaryvasomotionin normal subjectsand patientswith coronaryarterydiseasein responseto exerciseandto evaluate the effectof hypertensionon coronaryvasomotorresponse. Therewerefour importantfindings:1) Coronaryvasodilation was preserved in normotensiveand hypertensivepatients withoutanyangiographicevidenceof coronaryarterydisease. 2) Hypertensivepatientswith angiographically documented coronaryarterydiseaseshowa bluntedvasodilatoryresponse of the “normal”vesselcomparedwith that in normotensive controlsubjects.3) Hypertensivepatientselicitedenhanced vasoconstriction ofthe stenoticvesselsegmentduringexercise.
Table3. LeftVentricular Angiographic Data in Normotensiveand Hypertensive SubjectsWith and Without Coronary Artery Disease* Group1 (withoutcoronaryarterydisease)
End-diastolic volume(rnf/m2) LVejeetionfraction(%) LVwallthickness(mm) LVmusclemass(g/mz)
Normotensive (n= 10)
Hypertensive (n= 10)
74~ 21 67~ 6 0.84~ 0.12 82* 25
82~ 25 67~ 11 0.84t 0.29 87~ 32
Group2 (withcoronaryarterydisease) Norrnotensive (n= 26) 74~ 16 62~ 8 0.86t 0.17 81~ 17
*P = NS for ~] ~mpmisons.Data presented are mean value t SD. LV = left ventricular,
Hypertensive (n= 18) 81~ 22 65~ 6 0.84t 0.12 84~ 15
JACC Vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
Figure1. Lumenareachange(ACSA[in percentofrestcross-sectional area])during exercise(Ex)as wellas aftersublingual nitroglycerin (Ntg)innormotensive andhypertensive controlsubjectswithout(group 1) and in patientswithcoronaryartery disease(group2).In theabsenceof coronaryarterydisease,lumenareachangein responseto exerciseis normalin all pzl~ tients.However, in hypertensive patients [:
with coronary artery disease, an abnormal lumen area change can be observed,with a reduced vasodilator response in normal arteries but an enhanced vasoconstrictor de-
controls (Group Normal
Coronary 1)
Vessel
Normal
--/’:-
-’o-20.
sponsein stenoticarteries.Nitroglycerin -304 administered at theendofexercise showed an increase inlumenareachangeinnormotensiveaswellasinhypertensive patients.
Artery Disease (Group 2)
Vessel
Stenosis
-&:-
$t4EAt.J+l
Rest
■
Nornrotensive
A Hypertensive
❑
Hypertensive
4) Maximalvasodilationafternitroglycerintendedto decrease in proportionto severityof disease,suggestinga structural abnormalityof the vessel wall. Thus, abnormal coronary vasomotionwasfoundduringexercisein patientswithhypertensionandatherosclerosis. Thisfindingimpliesthathypertension in conjunctionwith atherosclerosishas a detrimental effeeton the functionof the endothelium. Previousstudies. In hypertensiveanimals,endothelialdysfunctionhasbeensuggestedto beresponsiblefortheabnormal vasomotorresponseto pharmacologicstimuli.The underlying pathogeneticmechanismhas been thoughtto be the diminishedreleaseof the endothelium-derived relaxingfactorwhich hasbeenidentifiedasnitricoxide(7-12,30,31). In theseanimal models,hypertensionwas found to be associatedwith an impairedrelaxationto acetylcholine,adenosinediphosphate and thrombinin the largeconductancearteries(8,9,12,31,32) and smallresistancevessels(30,33).However,a more recent study(34)couldnot confirmthesefindings. In the forearmvasculatureof patientswithhypertension,a normal (13) and an impairedvasodilatorresponseof the resistancevesselsto acetylcholine wasreported(14–19)comparedwiththat in normotensivesubjects.The largecoronary arteriesof hypertensivepatientsexhibitedvasoconstriction of epicardialcoronaryarteriesmainlyin responseto intracoronary acetylcholine(20,21).However,another investigation
I
Ntg
Rest
Ex
r
025 ● N~r~~ten~ive
.
I
Ntg
Rest
... ...........
O Hvc+rten,lve
Ex
J
Ntg
(22)showedthat hypertensionwas not associatedwith coronary vasoconstrictionafter intraeoronaryacetylcholine.Although previousstudies (23,24)have found endotheliumdependentvasodilationto be impaired in microvesselsof patientswithhypertension,thisfindinghasnot been observed in otherreports(25,26).A recentinvestigation(26)described impairedendothelium-dependent relaxationin elderlypatients withhypercholesterolemia but not in thosewitharterialhypertension.Hence,endothelialdysfunctionis not uniformlydistributedin the coronaryandforearmvasculatureand dtiers in differentmodelsand vascularbeds. Somecoexistingfactorsmayhaveinfluencedthoseresults: 1) Smallvariationsin the dose and rate of acetylcholine infusionmayinfluenceintraluminalconcentration,whichcan convertvasodilationto vasoconstriction(35).Furthermore,a heterogenotisvasomotorresponseto acetylcholinein different segmentsof the same vessel has been described (36). A differentapproachto inducecoronaryvasodilationwasusedin our studyprotocol,namely,dynamicexercise.Althoughthe physiologiceffectsof exerciseon vasomotionare probably more complexthan that of pharmacologiccompounds,this stimulusforcoronaryvasomotionreflectsthe dailyactivitiesof the studypatientsbetter than pharmacologicinterventions.2) Recenthumandata indicatethat endothelialdysfunctionoccursveryearlyin the developmentof atherosclerosis(35,37–
** -4$
Hypertensive
Normotensive
Figure2. Lumenareachange(ACSA[inpercentof rest cross-sectional area])duringexercise@x)as wellas after sublingual nitroglycerin (Ntg)innormotensive andhypertensivepatientswithout(triangles)andwithcoronaryartery disease(squares= normalvessel;circles= stenosis).In normotensive patientswithcoronaryarterydisease,onlythe stenoticvesselsshowedan abnormalresponseto exercise.In hypertensive patients,theresponseofthecoronaryarteriesto exercisewasabnormalnotonlyinstenotic,but alsoinnormal vesselsegmentsin the presenceof coronaryarterydisease. Impairedcoronaryvasomotionwasreversedafteradministrationof nitroglycerinin allpatientsbut wasattenuatedas the extentof coronaryarterydiseaseincreased.
--+!,
S.EM ANonnoterrsive
Ex
939
1 *:pd 1
**
pc.05
1 pc.021
*+
~.ol
*J
Wool
—
———
——
6 MEAN+ 1 SEM ‘* p<.01 versusEx * p<.ool versusEx
Rest
Ex
A GrOUD1 ❑ Group2a O Group2b Ntg
*
1
——
—
pdol 1
T
————.
F.03 1
@
Rest
Ex
Ntg
~,ol
J
940
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
43).However,angiographyis not a verysensitivemethodfor detectionof earlyatherosclerosis.Undetectedatherosclerotic changesin angiographically smoothvesselsmay accountfor insufficient vasodilatorresponse(29).The presentstudycompared “normal”with stenosedvesselsin patientswith angiographicallydocumentedcoronaryarterydiseaseand in vessels of patientswithentirelysmoothcoronaryarteriesand showed a completelydifferentvasomotorresponsein relationto the extentof corona~ arterydisease.3) Cardiachypertrophymay influencethe reactionof coronaryarteriesto differentvasoactivestimulibecauseofanatomicalterationsinseveralsegments of thecoronaryvasculature.It hasbeenshownthatthearterial media becomes thicker with left ventricularhypertrophy (5,44),which probablyaugmentsvasoconstrictoreffectsin thesearteries(45).In the presentstudy,patientswithsignificantventricularhypertrophywere excludedto avoidanybias resultingfromtheseinfluences.4) There has been increasing emphasisin publishedreports on the functionalimpact of hypercholesterolemia on the vasculature(22,26,46).Studiesin humanshave shown(22,26)that hypercholesterolemia and other risk factorscauseabnormalvasodilatorresponses,not onlyin patientswith angiographically provedatherosclerosis but alsoin thosewithangiographically normalvessels.In the presentstudythere were no majordifferencesin cholesterol levelsor in coronaryriskfactorsotherthan arterialhypertensionbetweenthe tsiogroups. Pathophysiologic mechanisms.Coronaryvasodilationwas foundto be reducedin responseto exercisein patientswith hypertensionandthe presenceof coronaryarterydisease(Fig. 1). However,endothelium-independent vasodilatorcapacity after nitroglycerinwas maintainedin hypertensivepatients comparedwith that in normotensivesubjects.This finding suggestsa preservedfunctionof the vascularsmoothmuscle but a prima~ defectofthe endothelium-dependent regulation ofthe epicardialcoronaryarteries.Thediminishedresponseto sublingual nitroglycerin in patients with atherosclerotic changessupportsthe presenceof structuralabnormalitiesthat are responsiblefor abnormalvasodilation,even in “normal” coronaryarteries (Fig. 2). Intraoperativeechocardiographic studiesand intravascularultrasoundhavedemonstrated(47) thatin vivocoronaryatherosclerosis isfar moreextensivethan predictedby coronaryarteriography.An enhancedvasoconstrictoryeffectto exercisewas observedin the stenoticcoronaryarteriesofpatientswithhypertensionthatwasnot seenin normalarteries.The exactmechanismof thisparadoxicvasoconstrictionhasnotyetbeenelucidated(48-51)but appearsto be either relatedto the aforementionedendothelialdysfunction with attenuationof endothelium-dependent relaxation (52), an enhancedvasoconstrictionduring exercisedue to circulatingcatecholamines, a Venturimechanismwithcollapse of the atherosclerosis-free vesselwallwithinthe stenosis(53) or enhancedplateletaggregationwithreleaseof thromboxane A2and serotonin(54),aloneor in combination.Theimpactof each of thesemechanismson abnormalcoronaryvasomotion of the stenoticvesselsegmentsis not clearand awaitsfurther elucidation.These resultsraise the intriguingpossibilitythat
JACC Vol. 28, No. 4 October 1996:935–41
nitric oxide dysfunctionmay be mechanistically linked to the development of coronary artery disease. Patients with hypertension but a normal epicardial vasomotor response to the physiologicstress of dynamicexercise may not be at increased risk of coronary disease despite their hypertension, but this is purely hypothetical.
Study limitations.Because no histologicproof for the presenceor absenceof an atheroscleroticlesionof the normal vesselswas availablein our study,the interpretationof an exclusivechangein endothelialfunctionremainsspeculativein patientswith normalepicardialcorona~ arteries.However, thesepatientshad evidenceof atherosclerosis elsewherein the coronarysystem,suggestingthat these normal vesselsmay represent the normal part of an otherwiseatherosclerotic artery. Normotensivepatientsin group 2 performedless in the supineexercisetest (Table2) thanhypertensivepatientsin the samegroupaswellas normotensiveand hypertensivepatients in the controlgroup.This findingmay be due to the more pronouncedcoronaryartery disease in this subgroup(2.1 vesselsdiseasedvs.1,4in the hypertensivesubjectsin group2), whichmayleadto differencesin the extentof exercise-induced vasodilation.However,this was not the case, as shownin Figure2 (leftpanel). Another limitationis the lack of coronary blood flow measurementsin the presentstudy;thus,no firmconclusionas to the significanceof coronaryvasoconstriction can be made. However,in a previousstudy(55),coronarybloodflowreserve wasfoundto decreaseduringbicycleexercisebut to increase after pharmacologicvasodilationwith papaverine,,suggesting that exercise-induced coronaryvasoconstriction playsan importantrole duringconditionsof physiologicstress. Conclusions,Exercisehas a differenteffecton corona~ dynamicsin patientswith coronaryartery diseasewho also havehypertension.The impairedvasomotorresponseto exercise in hypertensionsuggeststhe occurrenceof endothelial dysfunction witha reducedreleaseofnitricoxide.Ourfindings of normalcoronaryvasomotionin hypertensivehumanswithout coronaryatherosclerosis do not argueagainstthe presence ofendothelialdysfunctionbut suggesta normalresponsiveness of the coronaryvascularbed to a physiologicstimulussuchas bicycleexercise.
References 1. FurchgottRF,Zawadzki~. Theobligato~roleof endothelialcellsin the relaxationof arterial smoothmuscleby acetylcholine. Nature 1980;299: 373-6. 2. PalmerRMI,FerrigeAG,MoncadaS.Nitricoxidereleaseaccountsforthe biologicalactivityof endothelium-derived relaxingfactor.Nature1987;327: 524-6. 3. Yanagisawa M,KuriharaH,KimuraS,et al.A novelpotentvasoeonstrictor peptideproducedbyvascularendothelialcells.Nature1988;332:411-5. 4. Haudenschild CC,PrescottMF,ChobanianAV.Effectsofhypertension and itsreversalon aorticintimrdlesionsof the rat. Hypertension1980;2:33-44. 5. TomanekRJ, PalmerPJ, PiefferGW,Schrieber& EasthamCL,Marcus ML.Morphometry of caninecoronaryarteries,arterioles,and capillaries duringhypertension andleftventricularhypertrophy. CircRes 1986;58:3846.
JACC vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
6. BrushJE, CannonRO, SchenkeWH, et al. Anginadue to coronary microvaserdar diseasein hypertensive patientswithoutleft ventricularhypertrophy.N En@J Med1988; 319:1302-7. 7. CarvalhoMHC,Scivoletto R,FortesZB,NigroD,CordeMrriS. Reactivity of aorta and mesentericrnicrovessekto drugsin spontaneously hypertensive rats:roleof the endothelium. J Hypertens1987;5:377–82. 8. KonishiM,SuC.Roleofendothelium indicatorresponsesofspontaneously hypertensive rat arteries.Hypertension1983;5:881-6. 9. LocketteW, OtsukaY, CarreteroO. Tirelossof endothelium-dependent va.mdarrelaxationin hypertension. Hypertension1986;8Suppl11:11-61–6. 10.LiischerTF, VanhouttePM.Endothelirrm-dependent contractionsto acetylcholinein the aortaof the spontaneously hypertensive rat. Hypertension 1986;8:344-8. 11.ShirasakiY,KolmP,NickelsGA,LeeTJF.Endothelialregrdationofcyclic GMP and vascularresponsesin hypertension.J PharrnacolExp Ther 1988;245:53-8. 12.Van de VoordeJ, Larsen I. Endothelium-dependent and independent relaxationof aorticringsformhypertensive rats. Am J Physiol1986;250: H711-7. 13. CockcroftJR, ChowiencrykPJ, BenjaminN, Ritter JM. Preserved endothelium-dependent vasodilatationin patientswithessentialhypertension.N EnglJ Med1994;330:1036–40. 14. PanzaJA, QuyyumiAA, BmshJE, EpsteinSE.Abnorrnrdendotheliumdependentvaserrlarrelaxationinpatientswhhessentialhypertension. NEngl J Med1990;323:22-7. 15. Panza J~ CasinoPR, Badar DM, QuyyumiAA. Effectof increased availability of endothelium-derived nitricoxideprecursoron endotheliumdependentvascularrelaxationin normalsubjectsand in patientswith essentirdhypertension. Cirerrlation 1993;87:1475–81. 16. ParrzaJA, CasinoPR, KilcoyneCM,QuyyumiAA.Roleof endothelimnderivednitricoxidein the abnormalendotheliurn-dependent vascularrelaxationofpatientswithessentialhypertension. Cireufation1993;87:1468-74. ofincreased 17. EganB,PanisR,HinderliterA,SchorkN,JuliusS.Mechanism alphaadrenergicvasoeonstrietion in humanessentialhypertension. J Clin Invest1987; 80:812-7. 18. LinderL,KiowskiW,BiihlerFR,LiischerTF.Indirectevidenceforrelease ofendothelium-derived relaxingfactorinhumanforearmcirculationinvivo. Circulation1990; 81:1762-7. in 19. TaddeiS, VirdisA, MatteiP, SalvettiA. Vasodilationto aectylcholine primaryand secondaryformsof humanhypertension. Hypertension1993; 21:929-33. 20. TreasureCB,ManorrkianSV,KleinJL, et al. Epicardialcoronaryartery responsesto acetylcholine are impairedin hypertensive patients.CircRes 1992;71:776-81. 21. Brush JE, Faxon DP, Salmon S, Jacobs AK, Ryan TJ. Abnormal endothelium-dependent coronaryvaaomotion inhypertensive patients.JAM Co]]Cardiol1992; 19:809-15. 22. VitaJA, TreasureCB,NabelEG, et al. Coronaryvasomotorresponseto acetylcholine relatesto riskfactorsfor coronaryarterydisease.Cirerrlation 1990;81:491-7. 23. EgashiraL InouT,HirookaY,et al.Impairedcoronarybloodflowresponse to actetylcholine inpatientswithcoronaryriskfactorsandproximalatheroscleroticlesions.J ClinInvest1993;91:29-37. 24. TreasureCB,KleinJL, Vita JA, et al. Hypertensionand left ventricular hypertrophy are aasoeiatedwithimpairedendothelirnn-mediated relaxation in humancoronaryresistancevessels.Circulation1993;87:86–93. AA,CannonRO,PanzaJA,DiodatiJG,EpsteinSE.Endothelial 25. Quyyrrmi dysfunctionin patientswith chest pain and normalcoronaryarteries. Circulation1992;86:1864-71. coronary 26. ZeiherAM,DrexlerH,SaurbierB,JustH.Endothelium-mediated bloodflowmodulationin humans:effectsof age,atherosclerosis, hyperchoIesterolemia, andhypertension. J ClinInvest1993;92:652-62. 27. BuechiM, HessOM,KirkeeideRL,et al. Validationof a newautomatic systemfor biplanequantitativecoronaryarteriography. Int J CardImaging 1990;5:93-103. 28. KirkeeideRI+ GouldKL,ParselL. Assessmentof coronarystenosesby myocardial imagingduringeoronaryvaaodifation, VII:validationofcoronary flowreserveasa singfeintegratedmeasureofstenosisseverityaecorrntingfor allitsgeometricdimensions. J AmCo]]Cardiol1986;7:103-13. relationsofthe 29. SeilerC,KirkeeideRL,GouldKL.Basicstructure-function epicardialcoronaryvasculartree:baaisof quantitativecoronaryarteriographyfor ditlusecoronaryarterydisease.Circrdation1992; 85:1987-2003.
941
30. Dohi Y, Thiel MA, BiihlerFR, LiischerTF. Activationof endothelial l-arginirrepathwayin pressurizedmesentericresistancearteriesof the rat: effectof ageandhypertension. Hypertension1990; 15:170-9. 31. LiiseherTF,Raij~ VanhouttePM.Endothelimn-dependent vaaeularresponse innorrnotenaive andhypertensive Drddrats.Hypertension 1987;9:157–63. 32. WinquistRJ,BuntingPB,BaafdnEP,WallaceAA.DecreasedendotheliumdependentrelaxationinNewZealandgenetichypertensive rats.J Hypertens 1984;2:541-5. 33. WrightCE,AngusJA.Effectsofhypertension andhypercholesterolemia on vasodilatation in the rabbit.Hypertension 1986; 8:361–71. 34. LiJ, BukoskiRD.Endothelium-dependent relaxationof hypertensive resistancearteriesisnotimpairedunderallconditions.CircRes1993;72:290-6. 35. NewmanCM,Maseri~ HackettDR,E1-Tamimi HM,DaviesGJ.Response of angiographically normaland atheroscleroticleft anterior descending coronaryarteriesto aeetylcholine. AmJ Cardiol1990;66:1070-6. 36. PennyWF,RockrnanH,LongJ, et al.Heterogeneity ofvasomotorresponse to acetylcholinealongthe humancoronaryarte~, J Am CoffCardiol 1995;25:1046-55. 37. LopezJAG,ArmstrongML,PiegorsDJ, HeistadDD.Effectof earlyand advancedatherosclerosis on vaserdarresponseto serotonin,thromboxane A2,andADP.Circulation1989;79:698-705. H, Just H. Modulationof coronary 38. ZeiherAM,DrexlerH, WoOschfaeger vasomotortonein humans:progressiveendothelirddysfunction withdifferent earlystagesof coronaryatherosclerosis. Circulation1991; 83:391–401. 39. NabelEG, GanzP, GordonJB, AlexanderRW,SelwynAP. Dilationof normalandconstrictionof atheroscleroticcoronaryarteriescausedbythe coldpressuretest.Circulation1988;77:43–52. 40. WemsSW,WaltonJA,HsiaHH,NabelEG,SanrML,PittB.Evidenceof endothelialdysfunctionin angiographically normalcoronaryarteries of patientswithcoronaryarterydisease.Circulation1989;79:287-91. of 41. McLenachanJM, WifliamsJ~ Fish RD, Ganz P, SelwynAP. LQSS flow-mediated endotheliumdependentdilationoccursearlyin the developmentof atherosclerosis. Circulation1991;84:1273–8. 42. COXDA, VitaJ& TreasureCB,et al.Atherosclerosis impairsflow-mediated dilationof coronaryarteriesin humans.Circulation1989;80:458-65. 43. LudmerPL, SelwynAP, ShookTL, et al. Paradoxicalvasoeonstriction inducedbyacetylcholine in atherosclerotic coronaryarteries.N EnglJ Med 1986; 315:1046-51. 44. TanakaM,FujiwaraH,OnoderaT,et al.Quantitativeanalysisofnarrowings ofintrarnyoeardial smallarteriesin normalhearts,hypertensive hearts,and heartswithhypertrophic cardiomyopathy. Circulation1987; 75:1130 -9. 45. DzauVJ, GibbonsGH. Cellbiologyof vascularhypertrophyin systemic hypertension. AmJ Cardiol1988;62:30G-35G. 46. SeiferC, HessOM,BuechiM, SuterTM,KrayenbuehlHP. Influenceof semmcholesterolandothercoronaryriskfactorsonvasomotionof angiographically normalcoronaryarteries.Circulation1993;88:2139-48. DD,HiratzkaLF,LamberthWC,et al.Delineationoftheextent 47. McPherson ofcoronaryatherosclerosis byhigh-frequeney epicardialechocardiography. N En@J Med1987;316:304-9. ofsignificant 48. BrownBG,LeeAB,BolsonEL,DodgeHT.Reflexconstriction eoronmystenosisas a mechanismcontributingto ischemicleftve&icrrlar dysfunction duringisometricexercise.Circrrlation 1984;70:18-24. 49. GageJE, HessOM,MurakamiT, Ritter M, GrimmJ, KrayenbuehlHP. Vasoemrstrietion of stenoticcoronaryarteriesduringexereisein patientswith classicanginapeetoris:rmersibility~nitroglycerin. Cirerdation 1986;73:865-76. 50. GordonJB, Ganz P, Nabel EG, et al. Atherosclerosisinfluencesthe vasomotorresponseofepicardialcoronaryarteriesto exercise.J ClinInvest 1989;83:1946-52. 51. SuterTM,BuechiM,HessOM,Haemmerli-Saner C, GaglioneA, KrayenbuehfHP.Normalization of coronaryvasomotionafter transluminalcoronaryarrgioplasty? Circulation1992;85:86-92. 52. ForstermannU, MiiggeA, AlheidU, HaverichA, FrolichJC. Seleetive attenuationofendothelium-mediated vasodilation inatherosclerotic human coronaryarteries.CircRes 1988; 62:185-90. 53. BrownBG,BolsonEL,DodgeHT.Dynamicmechanisms inhumancoronary stenosis.Circulation1984;70:917–22. 54. ZeiherAM,Schachinger V,WeitzelSH,Wollschlager H,JustH.Intracoronarythrombusformationcausesfocalvasoconstriction ofepicardirdarteries in patientswithcoronaryarterydisease.Circulation1991;83:1519-25. 55. FelderL,VassalliG, VassalliF, et al.Clinicalsignificance of coronaryflow reserve:effeetofpapaverine andexercise.CoronaryArteryDia1994;5:347-58.
935
Abnormal CoronaryVasomotion in Hypertension:Role of Coronary ArteryDisease JURGEN FRIELINGSDORF, MD, PHILIPP KAUFMANN, MD, CHRISTIAN SEILER, MD, GIUSEPPE VASSALLI, MD, THOMAS SUTER, MD, OTTO M. HESS, MD Zurich,Switzerland
(Mjectives. Thisstudysoughtto evaluatetheeffectofdynamic exerciseon coronaryvasomotion in hypertensive patientsin the presenceand absenceofcoronaryarterydisease. Background. Endothelialdysfunction withabnormalcoronary vasodilationin responseto acetylcholine has beenreportedin patientswitharterialhypertension. Methodr.Coronaryarterydimensions ofa norrmdand stenotic vesselsegmentweredetermined in 64patientsbybiplanequantitativecoronaryarteriography at restandduringsupinebieyeleexercise.Patientswereclassifiedintotwogroups:20 patientswithout evidence ofcoronaryarterydisease(10normotensive, 10hypertensive[group1]) and 44 patientswithcoronaryarterydisease(26 normotensive, 18hypertensive [group2]).Bothgroupswerecomparablewithregardtoclinicalcharacteristics, serumcholesterol levels, bodymassinde%exercise capacityandhemodynamic data. Results. Mean aortic pressurewas significantlyhigher in hypertensive than normotensive patients,Exercise-induced vasodilationofthenormalvesselsegmentwassimilarinnormotensive andhypertensive patientswithoutcoronaryarterydisease(group 1),namely,+19%0 versus+20%,However, inhypertensive patients withcoronaryarterydisease,exercise-induced vasodilationwas
significantly lessinbothnormalandstenoticvessel segmentsthan in normotensive subjects(+1%vs. +20%o fornormal[p c 0.003] and -20%0vs. -5% forstenoticvessels[p c 0.025]).Administrationof1,6mgofsublingualnitroglycerin at theendofexereiseled toa normalization ofthevasodilatorresponsein normotensive as wellas hypertensivepatients.However,this responsebecame progressively abnormalin group2 whencoronaryarterydisease waspresent, Conclusions. In the absenceof coronaryartery disease,the vasomotorresponseto exerciseis normalin bothnormotensive andhypertensive patients.However, in hypertensive patientswith coronaryarterydisease,an abnormalresponseof the coronary vesselscan be observed,witha reducedvasodilatorresponseto exereisein normalarteries but an enhancedvasoconstrictor responsein stenoticarteries.This behaviorof the epicardial vesselsduringexereisesuggeststhe occurrenceof endothelial dystimction(i.e.,tkmctionaldefect)that is not evidentin the absenceof coronaryartery disease.Nitroglycerin reversesimpairedcoronaryvasodilation,but this effectis bluntedin the presenceofcoronaryarterydisease(i.e.,structuraldefeet).
The endotheliumplaysan importantrole in the regulationof vascularsmoothmuscletone by the releaseof relaxingand constrictingfactors.Endothelium-derived relaxingfactor (l), whichhasbeenrecentlyidentifiedasnitricoxide(2),is a major determinantofvascularrelaxation.However,the endothelium also releasesvasoconstricting factors(3), but its exactrole is stillnotyetclearlydefinedin humans.Arterialhypertensionis associatedwithmorphologicand functionalalterationsof the endothelium,suchas increasesin endothelialcellvolume(4), extracellularmatrix(5) and vascularresponsivenessto vasoconstrictorstimuli(6). In hypertensiveanimals,there is evidence that endothelium-dependentrelaxationis impaired, probablydue to a reduced release of endothelin-derived relaxingfactoror nitricoxide(7–12).In humanstudies,various
pharmacologic agents,mainlyacetylcholine, havebeenusedto evaluatethe responseof the endotheliumin hypertensive patients(13-26). Dependingon the presenceor absenceof atherosclerosis, the resultsof thesestudieshavebeen somewhatcontroversial; somehavereportedthe occurrenceof endothelialdysfunction, othershavenot.Thus,the purposeof the presentstudywasto evaluatecoronaryvasomotionin patientswithessentialhypertensionand normalor diseasedcoronaryarteriesusingexercise as a physiologicvasodilatorstimulus.This studyshould helpto definethe roleof the endotheliumin the regulationof coronaryvasomotortone in normotensiveand hypertensive patientsduringexercise.
(JAnrCoilCardiol1996;28:935-41)
Methods Fromthe Departmentof Cardiology, UniversityHospital,Zurich,Switzerland.ThisstudywassupportedbytheSwissNationalScienceFoundation,Bern, Switzerland. ManuscriptreceivedFebruary12,1996;revisedmanuscriptreceivedMay10, 1996,acceptedMay14,1996. Addressfor correspondence: Dr. Otto M. Hess,Divisionof Cardiology, UniversityHospital,Ramistrasse100,8091Zurich,Switzerland. 01996 by the AmericanCollegeof Cardiology Publishedby ElsevierScienceInc.
Study patients. Sixty-fourpatients (61 men, 3 women) assignedto coronaryarteriographywere classifiedinto two groupsaccordingto thepresenceor absenceofcoronaryartery disease.The twogroupswerefurtherclassitledintonormotensiveandhypertensivesubjects.Group1 included17menand 3 0735-1097/96/$15.00 PII SO735-1097(96)OO26O-4
936
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
women(mean[~SD] age50 ~ 8 years)withnormalcoronaq arteriographicfindings.Ten patientsin this groupwere normotensive,with a mean aortic pressure at rest of 90 * 12 mm Hg, and 10 were hypertensive,with a significantly increasedmeanaorticpressureof 106* 16mmHg (p < 0.02). Group 2 included44 men (mean age 53 ~ 8 years) with angiographicevidenceofcoronaryarterydisease.In thisgroup a normal vessel (group 2a) and a stenoticvesselsegment (group2b) were evaluated.Onlypatientswith one- or twovesseldiseasewereincludedingroup2;an averageof 1.8~ 0.8 vessels/patient wereinvolved.Twenty-six patientswerenormotensive,witha meanaorticpressureat restof 92 f 12mmHg, and 18werehypertensive,witha significantly increasedmean aorticpressureof 103t 15 mm Hg (p < 0.01).All patients performeduprightbicycleexercisetestingon the daybefore coronaryarteriography. Inclusioncriteria. Study patients were selectedfrom a cohortevaluatedby quantitativecoronaryangiographyon the basis of followingcriteria: 1) written informedconsentto undergo the exercisestudy; 2) qualitativelygood biplane angiogramfor quantitativeevaluation;3) angiographically smoothcoronaryarteries in group 1 (lumenalirregularities wereexcluded)and patientswithcoronaryarte~ diseasewith a normalaswellas a stenoticvesselsegmenton the angiogram (group2); 4) the normalvesselsegmentwas chosenfrom a nonstenosedartery and the stenoticvesselsegmentfrom a diseasedvesselsegmentwith a localizedstenosisof >50% (quantitativelyassessed).The stenosedvesselsegments(culprit lesion)were chosenonlyfromthe proximaltwothirdsof the respectiveartery. Exclusioncriteria. Patients were excludedif they had severeor unstableanginapectoris,ditfusethree-vesseldisease, a recent myocardialinfarction(<1 month),infarctionwith hypokineticor akineticmyocardialregions,renal or hepatic diseaseor a historyof diabetesmellitus. Definitionof arterial hypertension.Hypertensionwas defined as a historyof highblood pressure(diastolicpressure =95 mm Hg or systolicpressure =160 mm Hg, or both) requiring long-termtherapy and sustainedblood pressure elevationdocumentedduringthehospitalstayovera drug-free period (drugsdiscontinued24 h before cardiaccatheterization).Patientswereconsideredto havenormalbloodpressure if continuousbloodpressurereadingsshoweddiastolicvalues <90 mm Hg and systolicvalues<140 mm Hg. Patientswith secondarycausesof hypertensionand evidenceof damageto end-organswereexcluded. Definitionof coronaryrisk factors. Coronaryriskfactors, such as hypercholesterolemia (>200 mg/100ml), cigarette smoking,familyhistory(coronaryarterydiseasein one of the patient’sparentsor sibling<60 yearsold) and obesity(body massindex228 kg/m2),wereevaluatedin thepresentanalysis. Cardiaccatheterization.Medicationwas stoppedat least 24h beforecardiaccatheterization.Aorticpressurewasmeasuredwithan 8FJudkinscatheterinsertedfromthe groin,and pulmonaryartery pressurewas determinedwith a 6F pacing catheterwitha sideholefor pressuremeasurements.Biplane
JACC Vol. 28, No. 4 October 1996:935-41
left ventricularangiographywas performed in all patients, followedby diagnosticcoronaryarteriography. Studyprotocol.Simultaneousbiplanecoronaryarteriographywascarriedoutin twoorthogonalprojectionsto guarantee optimalvisualizationof the stenoticlesions.A controlarteriogram was acquiredwith the patient’sfeet attached to the bicycleergometer(model380 B, SiemensAlbisAG, Zurich, Switzerland).Exercisewas begun at 50 to 75 W and was increasedeve~ 2 minin incrementsof 25 to 50 W. Coronary arteriographywascarriedout at the end of eachexerciselevel withthe patientholdinghis or her breath duringinjectionof the contrastmedium.Arteriogramsat maximalexerciselevel were used for analysisof coronaryvasomotion.The exercise test wasterminatedbecauseof anginapectoris,fatigueor ST segmentdepression>0,2 mV.At the end of the exercisetest, 1.6mgof nitroglycerin wasadministeredsublingually. Biplane coronaryarteriographywasrepeated5 min thereafter.There wereno complicationsrelatedto the studyprotocol. Quantitativecoronaryarteriography.Quantitativeevaluation of biplanecoronaryarteriogramswas performedwith a semiautomaticcomputersystemthat has been describedpreviously(27-29).Interobservervariabilityfor this systemis 4.1%and intraobservervariability2.1%. Quantitativeanalysiswas performedin a proximalvessel segmentof a normal coronaryartery (group 1) or in an unaffectedcoronaryarterywithoutlumenchangesaswellasin a stenoticvesselsegment(group2). Measurementsiteswere selectedon the basis of the followingcriteria: 1) sufficient tillingofthevesselwithradiographiccontrastmedium;2) high qualitylate diastolicor end-diastoliccineframewithoutmotion artifacts;3) straightnessof the vessel segmentto be analyzed;and 4) biplaneX-rayviews.Angiogramswere measuredinblindedmannerwithregardto thevariablesofinterest as well as the actualstudysequence(rest, exerciseor nitroglycerin).Lumenarea changeswere determinedduringexercise (percentchangeversusrest = 100%)as well as after administrationof sublingualnitroglycerin. Statisticalanalysis.Between-groupcomparisonswith regard to clinical,hemodynamicand angiographicdata were performedby one-wayanalysisof variancefor continuous variables,followedby the Scheff6test if the probabilityvalue wassignificant(p < 0.05).The Fisherexacttest wasusedfor categoricvariables.Resultsin textand tablesare expressedas meanvaluet SD and in figuresas meanvalue* SEM.
Results Patient characteristics.Gender distribution,body mass index,New York Heart Associationfunctionalclassification and frequencyof anginapectoriswerecomparablein the two groups (Table 1). However,normotensivepatientswithout coronaryarterydiseasewereyounger(p < 0,02)than normotensivesubjectswithcoronaryarterydisease.In patientswith
JACC Vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
937
Table1. Patient Characteristics, Risk Factors and Medical Treatment Before Angiographyin Normotensive and HypertensiveSubjects With and Without Coronary Artery Disease* Group1 (withoutcwronary arterydisease) Norrnotensive Subjects (n= 10) WF Age(yr) BMI(kgjm2) NYHAclass Patienthistory Anginapectoris Myocardialinfarction
9/1 48~ 7 I 26&2 1.5~ 07
p<0.02 25~ 2 1.6? 0.5
9
9
0
o
I Riskfactors Totalcholesterol(mg/100ml) Cholesterol>200mg/100ml Familyhistory Obesity Smoking Anti-ischemic drugs Beta-blocker Ca antagonist Nitrates Tripletherapy
8/2 52~ 9
o I
No.ofvesselsdiseased
Hypertensive Subjects (n= 10)
Group2 (withcoronaryarterydisease) Normotensive Subjects (n= 26)
Hypertensive Subjects (n= 18)
26/0 54~ I I 25? 3 1.8? 0.6
26? 2 1.8~ 0.5
21 12
16 6
18/0 52~ 9
p
0
p<0.001
2.1? 0.8 II
1.4t
0.7
p <0.03 J
232? 33 8 2 4 5
I 220*37 6 4 4 7
p < o.ol~ 240? 64 20 7 8 22
245? 35 16 6 9 16
4 3 3 1
8 6 5 3
17 17 16 8
14 12 12 7
*p= NSforallcomparisons unlessotherwiseindicated.Datapresentedaremeanvahret SD or numberof subjects. BMI = bodymassindex;F = female;M = male;NYHA= NewYorkHeartAssociation.
coronaryartery disease,norrnotensivesubjectshad a larger numberof diseasedcoronaryarteriesthan hypertensivesubjects (p < 0.03).Coronaryrisk factorsfor coronaryartery disease,especiallycholesterol,wereevenlydistributedamong thetwogroups.Therewasa trend(p < 0.06)to a slightlylesser use of anti-ischemicdrugsin normotensivepatientswithout than withcoronaryheart disease(Table1). Exerciseand hemodynamicdata. Exerciseworkload (absolutevaluesas wellas data in percentof age-,gender-and height-correctednormalvalues)in the uprightpositionwas similarin both groups,namely,147 * 39 W (96Y0of the normalvalue)in group1 and 139~ 27W (9170of the normal value)in group2. STsegmentdepressionwas0.12t 0.09mV in group1 and 0.12* 0.13mV in group2. The frequencyof anginapectorisduringexercisedid not differbetweenthe tsvo groups.Exerciseworkloadwas lowerin the supinethan the uprightpositionbutwassimilarinbothstudygroups(Table2), exceptfor normotensivepatientswithcoronaryarterydisease who performed less exercisethan those without coronary artery disease(p < 0.03).Changesin heart rate and mean pulmonaryartery pressureat rest, duringexerciseand after sublingualnitroglycerinadministrationwere alsocomparable in the twogroups.Heart rate,meanpulmonaryarterypressure andmeanaorticpressureincreasedsignificantly duringbicycle exercise(p <0.001 in both groups).Thesevariablesreturned
—..
to baselinevaluesafteradministrationof sublingualnitroglycerin.Meanaorticpressureat restdifferedsignificantly between normotensiveandhypertensive patientswithout(p < 0.02)and withcoronaryheartdisease(p < 0.01).Exercise-induced mean aorticpressurewashigherin hypertensivepatientswithcoronaryheart diseasethan in normotensivesubjects(p < 0.01). Thisdifferencewasnot significantbetweennormotensiveand hypertensive patientswithoutcoronaryheartdisease,probably due to the higherwork load in normotensivesubjects,Left ventricularfunction (end-diastolicvolume, left ventricular ejection fraction) and left ventricularmass did not differ betweenthe twogroupsand subgroups(Table3). Coronaryangiographicdata. In patientswithoutcoronary arterydisease(group1), normalvesselswere similarin size, andtheincreaseinlumenareawascomparableduringexercise (percentchangeduringexercisein percentof controlvalue)in normotensive(+19 t 970) and hypertensive(+20 ~ 870) patients(p = NS) (Fig.1, left panel).When thesedata were comparedwithnormalvesselsin patientswithcoronaryartery disease(group2a),therewasa significantdifferenceinpercent changeof the coronaryarteriesduringexercise(p < 0.003) betweennormotensive(+20 f 25%)andhypertensivesubjects (+1 ~ 9%) (Fig. 1, middlepanel). In contrast to normal segments, stenotic vessel segments (group 2b) showed exercise-induced vasoconstriction, witha significantdifference
938
FRIELINGSDORF ET AL,. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
JACC Vol. 28, No. 4 October 1996:935-41
Table2. Exercise and HemodynamicData During Angiographyin Normotensive and Hypertensive Subjects With and Without Coronary Artery Disease* Group1 (withoutcoronmyarterydisease) Normotensive Subjects (n= 10) Supinebicycleexercise Workload(W) Workload(% of normal) Heartrate (beats/rein) Rest Exercise Nitroglycerin MPAP(mmHg) Rest Exercise Nitroglycerin MAP(mmHg) Rest Exercise Nitroglycerin
9(J~ 12 Lp 111? 12
Hypertensive Subjects (n= 10)
106? 16 K0.02J
89~ 14
118* 10 93~ 8
Group2 (withcoronaryarterydisease) Nocmotensive Subjects (n= 26)
92~ 12 LP 105t 16 Lp 84~ 12
Hypertensive Subjects (n= 18)
103t 15 <0.01J 119? 16 <0.01J 93~ 16
*p = NS forallcomparisons [email protected] SD.MAP= mean aortic pressure;MPAP= meanpulmonaryarterypressure.
(p< 0.025)betweennormotensive(-5 f 21%)andhypertensive(–20 ~ 19%)patients(Fig.1, rightpanel).Lumenarea stenosisingroup2brangedbetween58?4and7790(mean63k 19%). Sublingualadministrationof 1.6mg of nitroglycerinafter exercisewas associatedwith an increasein lumen area in normotensiveaswellas hypertensivepatients(Fig.1): +49 ~ 24% and +38 t 11%, respectively,in group 1 (p = NS); +30 ? 24% and +23 ? 14%,respectively,in group2a (p = NS);and +16 * 17%and +15 t 21%,respectively, in group 2b (p = NS). Comparedwith the changesobservedduring exercise,vasodilationof allvesselswasfurtherenhancedafter treatmentwith nitroglycerin,but the increasein lumenarea was graduallysmallerwhen the extent of coronaryartery diseaseincreased(Fig.2);thus,vasodilationwaslessin group 2a than group1 (p <0.05 for normotensivesubjects,p <0.02 for hypertensivesubjects)and lessin group2b than group2a
(p< 0.01for normotensivesubjects,p = NSfor hypertensive subjects).
Discussion To our knowledge,the presentstudyis the firstto assess coronaryvasomotionin normal subjectsand patientswith coronaryarterydiseasein responseto exerciseandto evaluate the effectof hypertensionon coronaryvasomotorresponse. Therewerefour importantfindings:1) Coronaryvasodilation was preserved in normotensiveand hypertensivepatients withoutanyangiographicevidenceof coronaryarterydisease. 2) Hypertensivepatientswith angiographically documented coronaryarterydiseaseshowa bluntedvasodilatoryresponse of the “normal”vesselcomparedwith that in normotensive controlsubjects.3) Hypertensivepatientselicitedenhanced vasoconstriction ofthe stenoticvesselsegmentduringexercise.
Table3. LeftVentricular Angiographic Data in Normotensiveand Hypertensive SubjectsWith and Without Coronary Artery Disease* Group1 (withoutcoronaryarterydisease)
End-diastolic volume(rnf/m2) LVejeetionfraction(%) LVwallthickness(mm) LVmusclemass(g/mz)
Normotensive (n= 10)
Hypertensive (n= 10)
74~ 21 67~ 6 0.84~ 0.12 82* 25
82~ 25 67~ 11 0.84t 0.29 87~ 32
Group2 (withcoronaryarterydisease) Norrnotensive (n= 26) 74~ 16 62~ 8 0.86t 0.17 81~ 17
*P = NS for ~] ~mpmisons.Data presented are mean value t SD. LV = left ventricular,
Hypertensive (n= 18) 81~ 22 65~ 6 0.84t 0.12 84~ 15
JACC Vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
Figure1. Lumenareachange(ACSA[in percentofrestcross-sectional area])during exercise(Ex)as wellas aftersublingual nitroglycerin (Ntg)innormotensive andhypertensive controlsubjectswithout(group 1) and in patientswithcoronaryartery disease(group2).In theabsenceof coronaryarterydisease,lumenareachangein responseto exerciseis normalin all pzl~ tients.However, in hypertensive patients [:
with coronary artery disease, an abnormal lumen area change can be observed,with a reduced vasodilator response in normal arteries but an enhanced vasoconstrictor de-
controls (Group Normal
Coronary 1)
Vessel
Normal
--/’:-
-’o-20.
sponsein stenoticarteries.Nitroglycerin -304 administered at theendofexercise showed an increase inlumenareachangeinnormotensiveaswellasinhypertensive patients.
Artery Disease (Group 2)
Vessel
Stenosis
-&:-
$t4EAt.J+l
Rest
■
Nornrotensive
A Hypertensive
❑
Hypertensive
4) Maximalvasodilationafternitroglycerintendedto decrease in proportionto severityof disease,suggestinga structural abnormalityof the vessel wall. Thus, abnormal coronary vasomotionwasfoundduringexercisein patientswithhypertensionandatherosclerosis. Thisfindingimpliesthathypertension in conjunctionwith atherosclerosishas a detrimental effeeton the functionof the endothelium. Previousstudies. In hypertensiveanimals,endothelialdysfunctionhasbeensuggestedto beresponsiblefortheabnormal vasomotorresponseto pharmacologicstimuli.The underlying pathogeneticmechanismhas been thoughtto be the diminishedreleaseof the endothelium-derived relaxingfactorwhich hasbeenidentifiedasnitricoxide(7-12,30,31). In theseanimal models,hypertensionwas found to be associatedwith an impairedrelaxationto acetylcholine,adenosinediphosphate and thrombinin the largeconductancearteries(8,9,12,31,32) and smallresistancevessels(30,33).However,a more recent study(34)couldnot confirmthesefindings. In the forearmvasculatureof patientswithhypertension,a normal (13) and an impairedvasodilatorresponseof the resistancevesselsto acetylcholine wasreported(14–19)comparedwiththat in normotensivesubjects.The largecoronary arteriesof hypertensivepatientsexhibitedvasoconstriction of epicardialcoronaryarteriesmainlyin responseto intracoronary acetylcholine(20,21).However,another investigation
I
Ntg
Rest
Ex
r
025 ● N~r~~ten~ive
.
I
Ntg
Rest
... ...........
O Hvc+rten,lve
Ex
J
Ntg
(22)showedthat hypertensionwas not associatedwith coronary vasoconstrictionafter intraeoronaryacetylcholine.Although previousstudies (23,24)have found endotheliumdependentvasodilationto be impaired in microvesselsof patientswithhypertension,thisfindinghasnot been observed in otherreports(25,26).A recentinvestigation(26)described impairedendothelium-dependent relaxationin elderlypatients withhypercholesterolemia but not in thosewitharterialhypertension.Hence,endothelialdysfunctionis not uniformlydistributedin the coronaryandforearmvasculatureand dtiers in differentmodelsand vascularbeds. Somecoexistingfactorsmayhaveinfluencedthoseresults: 1) Smallvariationsin the dose and rate of acetylcholine infusionmayinfluenceintraluminalconcentration,whichcan convertvasodilationto vasoconstriction(35).Furthermore,a heterogenotisvasomotorresponseto acetylcholinein different segmentsof the same vessel has been described (36). A differentapproachto inducecoronaryvasodilationwasusedin our studyprotocol,namely,dynamicexercise.Althoughthe physiologiceffectsof exerciseon vasomotionare probably more complexthan that of pharmacologiccompounds,this stimulusforcoronaryvasomotionreflectsthe dailyactivitiesof the studypatientsbetter than pharmacologicinterventions.2) Recenthumandata indicatethat endothelialdysfunctionoccursveryearlyin the developmentof atherosclerosis(35,37–
** -4$
Hypertensive
Normotensive
Figure2. Lumenareachange(ACSA[inpercentof rest cross-sectional area])duringexercise@x)as wellas after sublingual nitroglycerin (Ntg)innormotensive andhypertensivepatientswithout(triangles)andwithcoronaryartery disease(squares= normalvessel;circles= stenosis).In normotensive patientswithcoronaryarterydisease,onlythe stenoticvesselsshowedan abnormalresponseto exercise.In hypertensive patients,theresponseofthecoronaryarteriesto exercisewasabnormalnotonlyinstenotic,but alsoinnormal vesselsegmentsin the presenceof coronaryarterydisease. Impairedcoronaryvasomotionwasreversedafteradministrationof nitroglycerinin allpatientsbut wasattenuatedas the extentof coronaryarterydiseaseincreased.
--+!,
S.EM ANonnoterrsive
Ex
939
1 *:pd 1
**
pc.05
1 pc.021
*+
~.ol
*J
Wool
—
———
——
6 MEAN+ 1 SEM ‘* p<.01 versusEx * p<.ool versusEx
Rest
Ex
A GrOUD1 ❑ Group2a O Group2b Ntg
*
1
——
—
pdol 1
T
————.
F.03 1
@
Rest
Ex
Ntg
~,ol
J
940
FRIELINGSDORF ET AL. ABNORMALCORONARY VASOMOTIONIN HYPERTENSION
43).However,angiographyis not a verysensitivemethodfor detectionof earlyatherosclerosis.Undetectedatherosclerotic changesin angiographically smoothvesselsmay accountfor insufficient vasodilatorresponse(29).The presentstudycompared “normal”with stenosedvesselsin patientswith angiographicallydocumentedcoronaryarterydiseaseand in vessels of patientswithentirelysmoothcoronaryarteriesand showed a completelydifferentvasomotorresponsein relationto the extentof corona~ arterydisease.3) Cardiachypertrophymay influencethe reactionof coronaryarteriesto differentvasoactivestimulibecauseofanatomicalterationsinseveralsegments of thecoronaryvasculature.It hasbeenshownthatthearterial media becomes thicker with left ventricularhypertrophy (5,44),which probablyaugmentsvasoconstrictoreffectsin thesearteries(45).In the presentstudy,patientswithsignificantventricularhypertrophywere excludedto avoidanybias resultingfromtheseinfluences.4) There has been increasing emphasisin publishedreports on the functionalimpact of hypercholesterolemia on the vasculature(22,26,46).Studiesin humanshave shown(22,26)that hypercholesterolemia and other risk factorscauseabnormalvasodilatorresponses,not onlyin patientswith angiographically provedatherosclerosis but alsoin thosewithangiographically normalvessels.In the presentstudythere were no majordifferencesin cholesterol levelsor in coronaryriskfactorsotherthan arterialhypertensionbetweenthe tsiogroups. Pathophysiologic mechanisms.Coronaryvasodilationwas foundto be reducedin responseto exercisein patientswith hypertensionandthe presenceof coronaryarterydisease(Fig. 1). However,endothelium-independent vasodilatorcapacity after nitroglycerinwas maintainedin hypertensivepatients comparedwith that in normotensivesubjects.This finding suggestsa preservedfunctionof the vascularsmoothmuscle but a prima~ defectofthe endothelium-dependent regulation ofthe epicardialcoronaryarteries.Thediminishedresponseto sublingual nitroglycerin in patients with atherosclerotic changessupportsthe presenceof structuralabnormalitiesthat are responsiblefor abnormalvasodilation,even in “normal” coronaryarteries (Fig. 2). Intraoperativeechocardiographic studiesand intravascularultrasoundhavedemonstrated(47) thatin vivocoronaryatherosclerosis isfar moreextensivethan predictedby coronaryarteriography.An enhancedvasoconstrictoryeffectto exercisewas observedin the stenoticcoronaryarteriesofpatientswithhypertensionthatwasnot seenin normalarteries.The exactmechanismof thisparadoxicvasoconstrictionhasnotyetbeenelucidated(48-51)but appearsto be either relatedto the aforementionedendothelialdysfunction with attenuationof endothelium-dependent relaxation (52), an enhancedvasoconstrictionduring exercisedue to circulatingcatecholamines, a Venturimechanismwithcollapse of the atherosclerosis-free vesselwallwithinthe stenosis(53) or enhancedplateletaggregationwithreleaseof thromboxane A2and serotonin(54),aloneor in combination.Theimpactof each of thesemechanismson abnormalcoronaryvasomotion of the stenoticvesselsegmentsis not clearand awaitsfurther elucidation.These resultsraise the intriguingpossibilitythat
JACC Vol. 28, No. 4 October 1996:935–41
nitric oxide dysfunctionmay be mechanistically linked to the development of coronary artery disease. Patients with hypertension but a normal epicardial vasomotor response to the physiologicstress of dynamicexercise may not be at increased risk of coronary disease despite their hypertension, but this is purely hypothetical.
Study limitations.Because no histologicproof for the presenceor absenceof an atheroscleroticlesionof the normal vesselswas availablein our study,the interpretationof an exclusivechangein endothelialfunctionremainsspeculativein patientswith normalepicardialcorona~ arteries.However, thesepatientshad evidenceof atherosclerosis elsewherein the coronarysystem,suggestingthat these normal vesselsmay represent the normal part of an otherwiseatherosclerotic artery. Normotensivepatientsin group 2 performedless in the supineexercisetest (Table2) thanhypertensivepatientsin the samegroupaswellas normotensiveand hypertensivepatients in the controlgroup.This findingmay be due to the more pronouncedcoronaryartery disease in this subgroup(2.1 vesselsdiseasedvs.1,4in the hypertensivesubjectsin group2), whichmayleadto differencesin the extentof exercise-induced vasodilation.However,this was not the case, as shownin Figure2 (leftpanel). Another limitationis the lack of coronary blood flow measurementsin the presentstudy;thus,no firmconclusionas to the significanceof coronaryvasoconstriction can be made. However,in a previousstudy(55),coronarybloodflowreserve wasfoundto decreaseduringbicycleexercisebut to increase after pharmacologicvasodilationwith papaverine,,suggesting that exercise-induced coronaryvasoconstriction playsan importantrole duringconditionsof physiologicstress. Conclusions,Exercisehas a differenteffecton corona~ dynamicsin patientswith coronaryartery diseasewho also havehypertension.The impairedvasomotorresponseto exercise in hypertensionsuggeststhe occurrenceof endothelial dysfunction witha reducedreleaseofnitricoxide.Ourfindings of normalcoronaryvasomotionin hypertensivehumanswithout coronaryatherosclerosis do not argueagainstthe presence ofendothelialdysfunctionbut suggesta normalresponsiveness of the coronaryvascularbed to a physiologicstimulussuchas bicycleexercise.
References 1. FurchgottRF,Zawadzki~. Theobligato~roleof endothelialcellsin the relaxationof arterial smoothmuscleby acetylcholine. Nature 1980;299: 373-6. 2. PalmerRMI,FerrigeAG,MoncadaS.Nitricoxidereleaseaccountsforthe biologicalactivityof endothelium-derived relaxingfactor.Nature1987;327: 524-6. 3. Yanagisawa M,KuriharaH,KimuraS,et al.A novelpotentvasoeonstrictor peptideproducedbyvascularendothelialcells.Nature1988;332:411-5. 4. Haudenschild CC,PrescottMF,ChobanianAV.Effectsofhypertension and itsreversalon aorticintimrdlesionsof the rat. Hypertension1980;2:33-44. 5. TomanekRJ, PalmerPJ, PiefferGW,Schrieber& EasthamCL,Marcus ML.Morphometry of caninecoronaryarteries,arterioles,and capillaries duringhypertension andleftventricularhypertrophy. CircRes 1986;58:3846.
JACC vol. 28, No. 4 October 1996:935-41
FRIELINGSDORF ET AL. ABNORMALCORONARYVASOMOTIONIN HYPERTENSION
6. BrushJE, CannonRO, SchenkeWH, et al. Anginadue to coronary microvaserdar diseasein hypertensive patientswithoutleft ventricularhypertrophy.N En@J Med1988; 319:1302-7. 7. CarvalhoMHC,Scivoletto R,FortesZB,NigroD,CordeMrriS. Reactivity of aorta and mesentericrnicrovessekto drugsin spontaneously hypertensive rats:roleof the endothelium. J Hypertens1987;5:377–82. 8. KonishiM,SuC.Roleofendothelium indicatorresponsesofspontaneously hypertensive rat arteries.Hypertension1983;5:881-6. 9. LocketteW, OtsukaY, CarreteroO. Tirelossof endothelium-dependent va.mdarrelaxationin hypertension. Hypertension1986;8Suppl11:11-61–6. 10.LiischerTF, VanhouttePM.Endothelirrm-dependent contractionsto acetylcholinein the aortaof the spontaneously hypertensive rat. Hypertension 1986;8:344-8. 11.ShirasakiY,KolmP,NickelsGA,LeeTJF.Endothelialregrdationofcyclic GMP and vascularresponsesin hypertension.J PharrnacolExp Ther 1988;245:53-8. 12.Van de VoordeJ, Larsen I. Endothelium-dependent and independent relaxationof aorticringsformhypertensive rats. Am J Physiol1986;250: H711-7. 13. CockcroftJR, ChowiencrykPJ, BenjaminN, Ritter JM. Preserved endothelium-dependent vasodilatationin patientswithessentialhypertension.N EnglJ Med1994;330:1036–40. 14. PanzaJA, QuyyumiAA, BmshJE, EpsteinSE.Abnorrnrdendotheliumdependentvaserrlarrelaxationinpatientswhhessentialhypertension. NEngl J Med1990;323:22-7. 15. Panza J~ CasinoPR, Badar DM, QuyyumiAA. Effectof increased availability of endothelium-derived nitricoxideprecursoron endotheliumdependentvascularrelaxationin normalsubjectsand in patientswith essentirdhypertension. Cirerrlation 1993;87:1475–81. 16. ParrzaJA, CasinoPR, KilcoyneCM,QuyyumiAA.Roleof endothelimnderivednitricoxidein the abnormalendotheliurn-dependent vascularrelaxationofpatientswithessentialhypertension. Cireufation1993;87:1468-74. ofincreased 17. EganB,PanisR,HinderliterA,SchorkN,JuliusS.Mechanism alphaadrenergicvasoeonstrietion in humanessentialhypertension. J Clin Invest1987; 80:812-7. 18. LinderL,KiowskiW,BiihlerFR,LiischerTF.Indirectevidenceforrelease ofendothelium-derived relaxingfactorinhumanforearmcirculationinvivo. Circulation1990; 81:1762-7. in 19. TaddeiS, VirdisA, MatteiP, SalvettiA. Vasodilationto aectylcholine primaryand secondaryformsof humanhypertension. Hypertension1993; 21:929-33. 20. TreasureCB,ManorrkianSV,KleinJL, et al. Epicardialcoronaryartery responsesto acetylcholine are impairedin hypertensive patients.CircRes 1992;71:776-81. 21. Brush JE, Faxon DP, Salmon S, Jacobs AK, Ryan TJ. Abnormal endothelium-dependent coronaryvaaomotion inhypertensive patients.JAM Co]]Cardiol1992; 19:809-15. 22. VitaJA, TreasureCB,NabelEG, et al. Coronaryvasomotorresponseto acetylcholine relatesto riskfactorsfor coronaryarterydisease.Cirerrlation 1990;81:491-7. 23. EgashiraL InouT,HirookaY,et al.Impairedcoronarybloodflowresponse to actetylcholine inpatientswithcoronaryriskfactorsandproximalatheroscleroticlesions.J ClinInvest1993;91:29-37. 24. TreasureCB,KleinJL, Vita JA, et al. Hypertensionand left ventricular hypertrophy are aasoeiatedwithimpairedendothelirnn-mediated relaxation in humancoronaryresistancevessels.Circulation1993;87:86–93. AA,CannonRO,PanzaJA,DiodatiJG,EpsteinSE.Endothelial 25. Quyyrrmi dysfunctionin patientswith chest pain and normalcoronaryarteries. Circulation1992;86:1864-71. coronary 26. ZeiherAM,DrexlerH,SaurbierB,JustH.Endothelium-mediated bloodflowmodulationin humans:effectsof age,atherosclerosis, hyperchoIesterolemia, andhypertension. J ClinInvest1993;92:652-62. 27. BuechiM, HessOM,KirkeeideRL,et al. Validationof a newautomatic systemfor biplanequantitativecoronaryarteriography. Int J CardImaging 1990;5:93-103. 28. KirkeeideRI+ GouldKL,ParselL. Assessmentof coronarystenosesby myocardial imagingduringeoronaryvaaodifation, VII:validationofcoronary flowreserveasa singfeintegratedmeasureofstenosisseverityaecorrntingfor allitsgeometricdimensions. J AmCo]]Cardiol1986;7:103-13. relationsofthe 29. SeilerC,KirkeeideRL,GouldKL.Basicstructure-function epicardialcoronaryvasculartree:baaisof quantitativecoronaryarteriographyfor ditlusecoronaryarterydisease.Circrdation1992; 85:1987-2003.
941
30. Dohi Y, Thiel MA, BiihlerFR, LiischerTF. Activationof endothelial l-arginirrepathwayin pressurizedmesentericresistancearteriesof the rat: effectof ageandhypertension. Hypertension1990; 15:170-9. 31. LiiseherTF,Raij~ VanhouttePM.Endothelimn-dependent vaaeularresponse innorrnotenaive andhypertensive Drddrats.Hypertension 1987;9:157–63. 32. WinquistRJ,BuntingPB,BaafdnEP,WallaceAA.DecreasedendotheliumdependentrelaxationinNewZealandgenetichypertensive rats.J Hypertens 1984;2:541-5. 33. WrightCE,AngusJA.Effectsofhypertension andhypercholesterolemia on vasodilatation in the rabbit.Hypertension 1986; 8:361–71. 34. LiJ, BukoskiRD.Endothelium-dependent relaxationof hypertensive resistancearteriesisnotimpairedunderallconditions.CircRes1993;72:290-6. 35. NewmanCM,Maseri~ HackettDR,E1-Tamimi HM,DaviesGJ.Response of angiographically normaland atheroscleroticleft anterior descending coronaryarteriesto aeetylcholine. AmJ Cardiol1990;66:1070-6. 36. PennyWF,RockrnanH,LongJ, et al.Heterogeneity ofvasomotorresponse to acetylcholinealongthe humancoronaryarte~, J Am CoffCardiol 1995;25:1046-55. 37. LopezJAG,ArmstrongML,PiegorsDJ, HeistadDD.Effectof earlyand advancedatherosclerosis on vaserdarresponseto serotonin,thromboxane A2,andADP.Circulation1989;79:698-705. H, Just H. Modulationof coronary 38. ZeiherAM,DrexlerH, WoOschfaeger vasomotortonein humans:progressiveendothelirddysfunction withdifferent earlystagesof coronaryatherosclerosis. Circulation1991; 83:391–401. 39. NabelEG, GanzP, GordonJB, AlexanderRW,SelwynAP. Dilationof normalandconstrictionof atheroscleroticcoronaryarteriescausedbythe coldpressuretest.Circulation1988;77:43–52. 40. WemsSW,WaltonJA,HsiaHH,NabelEG,SanrML,PittB.Evidenceof endothelialdysfunctionin angiographically normalcoronaryarteries of patientswithcoronaryarterydisease.Circulation1989;79:287-91. of 41. McLenachanJM, WifliamsJ~ Fish RD, Ganz P, SelwynAP. LQSS flow-mediated endotheliumdependentdilationoccursearlyin the developmentof atherosclerosis. Circulation1991;84:1273–8. 42. COXDA, VitaJ& TreasureCB,et al.Atherosclerosis impairsflow-mediated dilationof coronaryarteriesin humans.Circulation1989;80:458-65. 43. LudmerPL, SelwynAP, ShookTL, et al. Paradoxicalvasoeonstriction inducedbyacetylcholine in atherosclerotic coronaryarteries.N EnglJ Med 1986; 315:1046-51. 44. TanakaM,FujiwaraH,OnoderaT,et al.Quantitativeanalysisofnarrowings ofintrarnyoeardial smallarteriesin normalhearts,hypertensive hearts,and heartswithhypertrophic cardiomyopathy. Circulation1987; 75:1130 -9. 45. DzauVJ, GibbonsGH. Cellbiologyof vascularhypertrophyin systemic hypertension. AmJ Cardiol1988;62:30G-35G. 46. SeiferC, HessOM,BuechiM, SuterTM,KrayenbuehlHP. Influenceof semmcholesterolandothercoronaryriskfactorsonvasomotionof angiographically normalcoronaryarteries.Circulation1993;88:2139-48. DD,HiratzkaLF,LamberthWC,et al.Delineationoftheextent 47. McPherson ofcoronaryatherosclerosis byhigh-frequeney epicardialechocardiography. N En@J Med1987;316:304-9. ofsignificant 48. BrownBG,LeeAB,BolsonEL,DodgeHT.Reflexconstriction eoronmystenosisas a mechanismcontributingto ischemicleftve&icrrlar dysfunction duringisometricexercise.Circrrlation 1984;70:18-24. 49. GageJE, HessOM,MurakamiT, Ritter M, GrimmJ, KrayenbuehlHP. Vasoemrstrietion of stenoticcoronaryarteriesduringexereisein patientswith classicanginapeetoris:rmersibility~nitroglycerin. Cirerdation 1986;73:865-76. 50. GordonJB, Ganz P, Nabel EG, et al. Atherosclerosisinfluencesthe vasomotorresponseofepicardialcoronaryarteriesto exercise.J ClinInvest 1989;83:1946-52. 51. SuterTM,BuechiM,HessOM,Haemmerli-Saner C, GaglioneA, KrayenbuehfHP.Normalization of coronaryvasomotionafter transluminalcoronaryarrgioplasty? Circulation1992;85:86-92. 52. ForstermannU, MiiggeA, AlheidU, HaverichA, FrolichJC. Seleetive attenuationofendothelium-mediated vasodilation inatherosclerotic human coronaryarteries.CircRes 1988; 62:185-90. 53. BrownBG,BolsonEL,DodgeHT.Dynamicmechanisms inhumancoronary stenosis.Circulation1984;70:917–22. 54. ZeiherAM,Schachinger V,WeitzelSH,Wollschlager H,JustH.Intracoronarythrombusformationcausesfocalvasoconstriction ofepicardirdarteries in patientswithcoronaryarterydisease.Circulation1991;83:1519-25. 55. FelderL,VassalliG, VassalliF, et al.Clinicalsignificance of coronaryflow reserve:effeetofpapaverine andexercise.CoronaryArteryDia1994;5:347-58.