Dobutamine thallium myocardial perfusion tomography

JACC ““I Noiemkr

18. Nio 6 I(. IWI IAil-9

METHODS

Dobutamine Thallium DUDtXY

1. PENNELL.

R. HOWARD

MA.

S’WANTON.

PETER

J. ELL,

Londu,,,

D,aloml

FRCP.

MRCF.

MD,

S. RICHARD

FKCP.

J

,MALCOLM

UVDEKWOOD. D’AI.KER.

MA. MD.

MKCP.

MRCP.

FRCR

Dobulamine has fawrabte properties for the pbarmacelogic mantputation of mywardiat oxygen dc;nxxl in !bc prurwlion ilT tscbemia during the inresdgalinn ol romnaq artery diar*. Tbc vstw of dahutalnine inlusion Lr thallium woeardia. wnagnphy

was aswed

prrturian

in SOpatients with ewrtional chest pain

undergoing rwmwy uteriography. Dabutamins was infuxd in S.mia stager “t incremootat rates from 3 to 20 pgkg per min (II uatittimited by symptoms. The myacardiila segment5 br sndyris al perfusion. Tbktyaint al 40 patients with raronor) rewlblc pwfurion d&t demonstrated bj tomognphy tsmsitivity 97%) and 8 ol 10

artery disease bad a dubutamine lballiwn patients nith n~rm~t

coronnry art&es

perkion

80961. Thee wtug

P&m

with

bad nmmst

mywardiot

were sinnifirsnttv

known

may undergo B variety

or suspected

wx divided ink nine

,rpeciiicity

hater than the sznsitivit%

coronary

of investigation>.

artery

A hiWry

dwu! oftypwl

angina confirmed by an abnormal electrocardiugaphx (ECG) response to exercise is otlen wffic~en! to make the diagnosis. but in sebcting appropriate treatment. II I\ atw important to assess the r;ak of future cacdnc evcnr\. .Tbrlhum myccardial perfusion imaging is eqecx~lly valuable for the assessment of prograis

II)and

ib wpcnor

to coronx)

angiography and exercise electrocardiograph) both before (21 and after (3) myocardral mbrc~~on. Becsux cornnary arwiograpby doa not pruwde a c

m!ocardiat

is~bemid. particularly

when wxcire

potential k tii-

ited. Buth the whet) of dobutamine in asthmatic patiwi\ and the retrtiun ktautn arhiewd dose and excise time represent adran. ,B~R mrr the USC “f adenminc DC dipyrtdam&.

Methods Stud! palienls. Fifty patients who were scheduled 10 undergo coronmy anglography because of known or 5”s. rated coronary arlery discdsc were studied. r‘ony-two were male and ;he mean age was 54 years ::ange 36 IO ?5) All pewnts had a history of exertional chest pein. I5 00%;) had had 8 prevmur myoiardial infarction and 36 (72%) had ST segment depression on Ihe exercise ECG. Excluded from the -study &re patienls with chebl pain at rest. adverrs red&n during convendonal exercise lesfing. rysmbc ‘jlood pressure ,200 mm Hg or diarrvlic blood pressure >IDil mm Hg. known vemricular arrhythmias, second or i;nird degree atrioventrular hean block. implanted pacemaker. hypenmphic cardiomyopathy. valvular heart disease or hean failure of New York Heart Association class III or IV. Normal medication was contmued except for betaadrenergic blockers. which were discontinued 48 h hefore the study. The study was approved by the local Ethical Committee and mcoormed consent was obtained from each p&em. The estimated radiation exposure fo the patient from 80 MBq of thallium is 25 mSv 17). Dobulamine stress test. The patiems were supine and dobutamine was infused by an lVAC 711 syringe pump (WAC Corp.) imo a peripheral vein. starting at a rate of 5 &kg per min and increasing by 5 &kg per min each 5 min 10 a maximum of 20 &kg per min or until the occurrence of rignificanf symptoms or signs. These were defined es chest pain of a severity that would normally require the use of sublingual nilroglycerin. any other intolerable symptom. suslained arrhylhmia or hypertension (syslolic pressure >220 mm Hg. diastolic pres&e > I IO mm t&j. Lead CM, of the ECG was monivxcd and blood preswe was measured at each stage of the infusion. AI the peak dobulamine infusion rate, 80 MBq of thallium was injected through a wand intravenous cannula and the dobummine was conlinued for a further minute Imaging technique. Emission tomographic imaging was beeun within 5 min of stoooine the dabutamine infusion and redistribution imaging was performed 4 h later in an idenlical manner. A General Electric 4OOAZS gamma camera and a Star computer system were used. Thirty-Iwo planar images (64 x 64 pixel mafnx. 400.mm field of view. 30 s/image) were acquired over a 180” arc from Ihe righl anlrrioroblique to left posLerior oblique posilion. The planar images were REL)Ostructrd into transaxial nomograms of I-pixel depth using back projection and a RampHanning filter with a 0.75. pixel-’ cutoff frequency. From these. cblique tomogramt were reoriemcd in the vertical long-axis. horironlal long-axis and short&a planea. Duct anal& The thallium tomograms were assessed by two experienced operators without knowledge of the core. nary anatomy. The heart was divided into nme segmcms corresponding 10 the basal and apical portions. respee~ively. of the anterior. inferior and lawal ~11s and scpwm. with a smgle segmen: I Ihe apex (Fig. 0, Thallium uptake was

t

..

I

Figure 1. The myoeardium was divided ,nlo nine segments for analysisof the apical and basalponions of the inferior. lateral and anterior walls and septum with a single apical segmenf. HLA = horizonlal Ion&r plane: SA = ,honaris plane: VLA = venical long-axir plane.

classified in each segment as normal, mildly. moderately or severely reduced or absent. A reversible defect WE one that improved by at leas1 one category after redistribution and a fixed defect was one that was unchanged in both images. DiKerences in interpretation were resolved by consensus. Coronary angiograms in multiple projections were interpreted visually by the clinician in charge of the palient’s care without knowledee of the thallium images. Siinificant dis ease was defined& a reduction of nodal l&al diameter by ~50% in a maim vessel or its principal branches. An e&se ECG war~erformed with uie of Ihe Bruce protocol and an abnormal ST segment response was defined as > I-mm planar or downsloping ST segmem depression 80 ms after the J point. Slatiatiral analysis. McNemar’s test for comparison of two proportions was used to analyze the difference between thallium tomography and rhe exercise KG in the deteclion of coronary &&disease. One-way analysis of variance with repwed measures was used m con.bare the hemodynamic data for Ihe groups. Linear regression analysis was

used to analyze the relauon between ;he treadmill ewrcw times and the tolerated dobutamine dosage. The dirlnbutwn of the “umber of ischemic iballium regmsnl~ ~cordmg to Ihe number ol diseased coronary onerie& aa> andl)rcd hy using the Sprarman ranh correlation coefficient. Proh;Mil) values ~0.05 were considered signiiic;mt Results ttemodynamic etfects of dobutamine ITable 1). Each increment in dobutamine mfuslon rate war aswxad ui~h a” increase in systolic blood pre~rc. heart rate dnd double (rate-pressure) product WI p < 0.1X31). bul dia>Iolnc blood presrure did not change significanlly. Ar the mammal mfusion rate of 20 &kg per min. @he rate-prrwrs product approximately doubled. Sensitivity of thallium tomography (Tables ? 10 5). Significant coronary artery disease was present in JO pmienis tBO%) with one-. WO- and thrce.verrel involvement in 14, 16 and IO parients. respectively. The left main stem was involved in two patients. The stress thallium tomograms showed reversible ischcmia in 39 of these pabents ITable 2. Fig. 2). yielding an overall srnsitivlty of 97% for Ihe dew lion of coronary anery disease. The on< paticnl wilh coronary artery disease who bad a normal dobulimdne lhallium tonwgram had relalively minor disease WJ an occluded nondominant left circumflex artery and i’ lesion of the diagonal branch of the lefl anterior descendi’lg artery. There was a significant r&lion berween the numoer of dnedred coronary ancries and the r,,ean number of abnorms, myocardial segmenu (Spearman rank corrcI..+~o” coeffic~ea lr.1

dobulamino

isolated n$ht coronary awry lesion. If aher rhe inferior or Idleral udll II considered to be Ihe tsrrnory of the left circumile\ arler!, then sensitivity for Ihc delecuon of left urcumflsx srter) disease in ihese pauems was 83%.

Figure 2. Thallium myocardiai perfusion iomography uring dobw iaminr stress in a patient with rbrce-vessel coronary artery disease. A, B and C. images. D, E and F, Redislribulion images. A ad D, Vertical long-axis plane. 3 and E, Horizontal lw@axis plane. C and F, Shanw.ir plane. There is reversible irchemia uf the distal

Stress

anrcrior wdl. sepmm and apex and lateral wall. There is a fixed perfusion defect of Ihe inferior wall. The patient had mferior Q waves on lhe electrocnrdic@m, with a blocked Primal right coronary anery and proaimal enoses ofthe left circumflex alid left anterior descending corcmary arleries.

I

thallium optake and had a reversible defect. In four patients with a non-Q wne iniarclion. one had a fixed defect. two had a reversible defect and no defect WM present in one p&n! oho had had an anrcrio, non-Q rra*e mfarcrolurored 411 pa ienh are shown. but lhore who renmnared lion but only hemodynamically insignificacr atheromatous ewrcw for reasons other than angma are disrmgutshed from disease ofrhe left anreriordescending artery.No fixed defect was found in patients without a history of mvocardxd infarction. Specificity ofdobutnmine thallium tomcwapby (Tables 1 to la0 pamnt~ r = 0 32. p < 0.05:pattents mawnal 6). &ht oithe 10 patienls wh angiognphlcally normal e’icrcw r - O.ih. o < 0.001). .Alrhoueh ihe number of coronary arteries had a normal thallium fomogram (specificpatrrw aho ml&d only low do&of dobutamine IS ity BCPA)(Table 21. Both patients with an rbnormdl dmlb~rn rnxdl. rhc rriaiion to exercise time suggests [ha rhe dobu,am,ne dote could he used in the ,ame say as exercise ume tomognm were subsequently classified hy Ihr ,uperviGng clinician as having syndrome X. One \\a a 58.ye;tr old IO claaaif) Ihe spnea anh Side erects of dobulamine. -\ dose of 5. IO. I5 and 2.mm ST depression m the I’aWteral ECG leads after only 3 min of a standard Bruce orotocol exercise wt. Dobutamine thallium tomography showedanteroseptal reversible ischemia (Fig. 3). The other patient. a 42.year old man. had a-~ exercise time of 7 min tha! was limi!vi h? chest pain and dwmea with 3 mm of inferolateml ST depresaon. DohuIamine thallium tomography showed revertible anteroseplal eHcc,s d‘u,& rhe infusion. Some iorm’of arrhythmia ocischcmia. curred ,,I IV oat~rnls 138%l: ,,I 16 of Ihew, ven,ncular Five of 23 patients wilhout significant s,enosi< of the left anletio, descending coronary artery had an abnormal tomopremaure huti were seen hut were infrequem and not gram suggesting revenibk ischemia in rhc anterior wall. asocialed *lth bcmodgnamx dwurbance. ittiiai premalure septum or apex (specificity for left anwrto, descendmg beats uere been in six parirms. and sinus pauses. acc~lcranew disease 78%) (Table 6). Two of the R\c had a stenoJis aled nodal rhythm and left bundle branch biock occurred m thal&asjudged to he40%. one had aleft anteriordescendmg one patient each The most cowman norxdiac s,de effeus were &in imglmg and Rurhmg. Overall. Ihe dohulahdne arlerv mvocardial bridze and two had P diaenosis of syndrome XI Because of the difficuky in assigning an exclusive mfurnon 1131 nell tolerated and -“any patients preferred I, to dynamic cwrcw tetitow to the left circumRea anery, thn artery was considered~toSether wuh the right coronary aner& Three of 13 patients wilhou, significant sLewsi\ ofe0hw the right or left Discus&n circumflex coronaw artery had an abnormal lomogram weDohutammr has been used previously for lhe detectloo of geating reversible iichemia of rit!>e, :!:e infenor or Fbe la~cnl coronary artery disease in combinauon with electrocardbw&II (specificity for both right and leh cwcumfler arrery graphy IO. echocudiognphy (18) and radionuclide ventricdireax 76%,) (Table 61. Two of iln: pauents had sewre rcaia ofthe right coronary anrry: !hc .h,,d p:Wot had an ulogrdphy (19). II has also been performed in combination occiudcd large left an,eriar dcvzwdinp at iury that supplied with thalhum mymardial perfusion imaging with use of a piana, Iechnique (20,. !mprovemenls m imaging hardware Ihe inferior wall. and software hare ted 10 a greater senssivlrp and specificity Comparison of dobulsmirw thallium tomograph> aud exfor the deleclwn of ischemm with romagraphic ~magmg 121) e&e electrotsnliography. Thirty-one of the 40 palienls and Ihl$ 15 Ihe first study IO our knowledge to combine with coronxv aneiv direa% had an ahnormal ST %e~.ment dohutamine \t,e% with lhallium myocardd perfusion tomoewhy

achieving

Fi&wr 3. Thallium myocardial perfurian tomogramr af a patient with syndrome X (normal epicardial coronary w.ries) displayed in the same format ar that in Figure 2. There is rcvcrsible ischemla of the anlcrior wall. septum and apex.

~e,~n,.i,~vc

of coronary artcry dice& with dobulsmmc thaibum myocardial perfusion tomography. This lcwl of %nsmvily i\ high, but such results mtgh, be exprckd I” i~ goup of pa,ien,s who had exlenhive coronary arwy ei::arc and aho were sufficiently symptomatic 10 be ddmnwd for coronary ar,eriograpby. I, is likely tba, ,he IWO parwn,? n t,h normal

,fth; e&se ECG I” the %cneral QvQ”,aU”” ,Isble sngma Becaurc a” abnormal or

r.f Qdriemi ailh

ddful, c\err,x ECO ma” lead ,o r&rral Lx coronary arretqraph!, ,hcrc I\ a \tro”g Qrelesr bias iowvnrd Qauentr r”h

J fid\e nowiye

ECG and hence a low soeciQci,v

Patients ~;i,b disparity between Iballium lknogmphh aild euronary angiograpbir dota. I, i> relevant 10 consider ,be rive other pa,~en,\ I” %hom there wils diipaniy be!ween the resulti of thidl~m~ lomography and coronary angiography. Two psuc”,*

had a revernble

a lei, ,%“,erwr dcrccndinp diameter \,e”osis.

anlerior

perfuwm

defec, wi,h

le~m” lha, iwah judged 1” he 40%

In hgh, of ,he vanabili,y

of v,s~al assew

me”, of coronai! ar,eriograms. I, IS likely ,hnr the lessons in rhrcc Qaue”,i itere indeed hemodynamically significant. In nne Q?,,,e,,,. a m)ocardwl ridge constricled ,he lef, anrerior dcscendang drrerg in ~y~,ole bur no, in diaslole and the pnlx”, na\ therefore clarsiF.cd as no, having rignifica”, di~~c. in fact. the associa,io” of myocardial bridging w,,h a correrpondmp ,hallium defect has been reponcd previouzly 127281 T\\o patienls wi,h a” inferior wall defect in the absence of wmhca”, nab, coronary or left circumflex artery \,e”ou( had a xvercly -&ic right corxxq anery that may have lmusd coronary flow. These ca% a&u” emphasize the prohlemr of comparing functional and anatomy ,es,s. Re,a,inn belween dobutamine dose and exercise lime. 1” ,hlb wdy

ae demons,rared

for the fin,

time a relation

hewren the mnximal tolerated dobulamine dose and treadmdl exercise pc&rma”ce in pa,ie”,s being assessed for caronary art& disease. allhoogh a relatm” was previously rcporied (!9, hctwee” the maximal cardiac outpu, achieved P tlh dohutaminc and dynamic ehercise in pnfienrs W,th hea, Mure The rei.mo” was burly cowse because the palirnts rho ,olera,ed ,he two highest doses of dobutamine achlevsd A Inrge iangc oicxercise

times. The Qane”,s might have been

further s,r”,iFwd by uqe of higher loses. ho, we decided 1” bm~t our init experience ,o more convenlional doses. I” addmo”. I, wa\ clear tha, it WRI possible to increase the

dox IO :I ~mmum an patmts whose exercise tmle hai1 heen limited hy noncardiac problems or hy techniuan mtcrvcntion for sIgnific;mt ST segment changes wthout clInica rymplonn 7,x w,n,i,,i ,>c~rwrr,i ‘,,,h ,,,,, winr d0.w ,‘.d ~.w~cir~ Ibnu I, Ihe severity of symptoms and IP also an mdlcatol of prognow Other agenta such as dipyridamole and adcno,wc produce incquahtics of perfusion and myocardial nchemla by a mechamsm dlffcrcnt from that v;hich occun durine dvnamic cxcrciic and a r&lion bclwccn dose and aevcrify of symptoms has not been demonstrated. Although wc do not have sufficient experience to suggest that dohutamme sba~~ldbe ured instead ofdynamic exercise in all patient,. the reldtion \trcngthens the tax that it could be ucd in thi, way. Choice of hea-adrenergie sgmdrt. The beta-sympathetic agonists increase mynwdial oxygen demand by virtue of their inotropic and chronotropic actions. Epinephrine, no;eoineohrine. isooroterenol. dooamine and dobutamine are t6c mbst commordy used agents. hut they differ in a number of ways. includmg hemodynamic effect, anhythmogenicity and route of adminwration. Epinephrine-induced myocardial ischemia ha been detected by echocardiography (301. hut the drug i\ unnuivahle for routine itreEs testing because I& alpha-adrcnergic agoonismleads to venoconstriction and makes ii unsuitable for administration into a wioheral vein. The same is true of norcpinephrine and do&one. although the latter produces less intenv venoconstriction. Isoprotercool has pure beta-sympathetic effects, but 0 is maintained in a solution of pH 2 and is highly irritant. Only dobutamine can he given safely into small peripheral veins. lsapmterenol has been used successfully for the echocardiographic imaging of irchemia (31 I. hut it increases hean rate with no aclion on blood pressure and therefore has less effect 0” the rale ~re~iure product than does dobmnmine. Dobutamine k less ‘arrhythr&geaie than the other beta-agonists in the ischemic heart (32-341 and is more effective than dopaminc in causmg wall motion abnormalities (351. It IS therefore the beta-agonist of choice for the pharmacologic manipulation of myocardial oxygen demand. Dobutamtne e&et% The plasma half-life of dobutamine is 120 s. giving. it B rapid onset and cessation of action that allow easy control of hlaod levels during imaging. The main &Lion of dobutamtnc IS to increase myocardtal oxygen demand and. in the settme of acute ischemia. II has been dohutmine

<,f,ric,~,,) ,rrr;rorm~r becawe excrcilc lime isoften urdas a mcawe d _

I

myocardial ischemia in patients with eorwary artery disease. It dilates the distal coronary vessels, which leads to an increase in coronary Row (37.38) and a decrease m perfusion pressure distal to a coronary stenosn. Flow therefore bemm% heterogeneous (39) and may be redirected to the subepicardium (40). In this respect. it IS simdar to adenosine and dipyridamole. It may also increase Row resistance at the site of a stenosis (401.

Tlr mosr impormm limirnrion of dobnramine is rhar irs action is ronrpedriwlv inkibired by befo-adrenergic blockers. Atenolol wes the most commonly prescribed beta-blocker in our group of patients and this has a long plasma haWife of 6 to 9 h. Because of the confounding et+eectsof beta-blockers. our padents discontinued treatment 48 h before the ~a (approhimately 5 half-livesl. No clinical complications resulted. but a worsening of angina or rest pain IS a rheoretic possibility. One patient inadvertently continued beta-blocker therapy despite instructions. At 20 @kg per min of dobutamine. very little cbanae m bean rate or blood pressure had occurred and thall~m tomography revealed no kvidence of myocardial ischemia. After consenting to a repeat study in the absence of beta-blocker therapy, there was the expected change in ratepressure product with stress, and reversible ischemia was detected. It is possible that higher doses of dobutamine would compete with beta-blockade. but the safety of such a manewer has not been established. Clinial role of dobutamino. 8% demonstrated the value of dobutamine dutine: thallium mvocardial perfusion tomography. but its role in relation tb that of-dipyridamok or adenorine (6.7) remains to be established. Dobutamine was well tolerated by six patients with asthma in this study and thus would certainly be the agent of first choice in patients with a history oihronchoconstriction. in whom dipytidamok and adenosine are contraindicated. It is also likely to be suuerior when combined with imaging t.?chnisues such as e&cardiography. radionuclide v&&uiqr$hy and nuclear magnetic resonance imaging (41) that require significant myocardial ischemia to pmduce an abnormality of regional ventricular function. This advantage occurs because the main action of dipyridamole and adenosine is to increase coronaryflow rather than oxygen demand so that thallium defects may occur as a result of flow heterogeneity alone without accompanying isehemia (7.42). In addition, dobufamine causes hypcrkinesia gf normal areas, an effect thar accentuates the contrast with the hypokinesia or akin&a of abnormal areas (43). making it particularly suitable for wall motion studies. An advantage shared by dobtttamitte and adenosine is the short plasma half-life of each, which allows p%w. levels to be maintained by constant infusion for operator-defined duration of stres% This ability is essential for radionuclide ventriculography and nuclear magnetic resonance imaging, although it may be less important for echocardiography.

tn~bluteoftiuetenrMedrine for theircoanbsionr.

References

coldpresro, and Pold.195m. Br Heart J 1984.53 Sihbl.