Clinical significance of abrupt vasodepression during dobutamine stress echocardiography

havebeenreported in the presenceof painful versussilent ischemia in the setting of unstable angina,7but whether this reflected greater severity or extent of ischemia is unclear. Exercise echocardiography offers both good resolution of regional wall motion (not available with gated nuclear imaging), and multiplane imaging (not available with first-pass nuclear studies). The results of this study indicate that exertional angina is unrelated to the occurrence of electrocardiographic changesof ischemia, the degree of deterioration of regional function, or to the number of ischemicsegmentsinvolved. Thus, angina appearsto be unrelated to the extent or severityof ischemia, defined by exercise echocardiography. These findings Somepreviousreportshavefailed to showany relation suggestthat characteristicsof the ischemic event are not betweenthe occurrence of angina1pain and the severity major determinants of the presenceor absenceof exerof exercise-inducedleft ventricular dysfunction.4y5These tional angina. studies, however, may be criticized on a methcdologic basis;the useof gated nuclear ventriculography may have 1. Draste C, Roskamm H. Experimental pain measurementin patients with precluded accurate analysis of the severity of regional asymptomatic myocardial ischemia.J Am Coil Cardiol 1983;2:940-945. dysfunction, with attention being paid to global ejection 2. Bleske BE, Shea MJ. Current conceptsof silent myocardial &hernia. Clin Pharm 1990;9:339-351. fraction. In contrast, other reports have demonstrateda 3. lskandrian AS, Hakki AH. Left ventricular function in patientswith coronary correlation between symptoms and the severity of isch- heart diseasein the presenceor absenceof angina pectorisduring exerciseradi+ nuclide ventriculography. Am J Cardiol 1984;53:1239-1243. emia. The use of first-pass nuclear ventriculography fa- 4. Cohn RF. Brown EJ.._ Wvnne J. Holman L. Atkins HA. Global and renional left cilitates better appreciation of regional function; Iskan- ventricular ejection fraction abnormalities during exercisein patients with silent drian and Hakki3 found angina to correlate with more myocardial &hernia. J Am CON Cardiol 1983;1:931-933. Vassiliadis IV, Machac J, O’Hara M, Sezhiyan T, Horowitz SF. Exerciseseveredeterioration of regional function, using the first- 5. inducedmyocardial dysfunction in patientswith coronary artery diseasewith and passmethodology.Unfortunately, this techniquedoesnot without angina. Am Hearf J 1991;121:1403-1408. permit the examination of all myocardial regions,so that 6. FeigenbaumH. Exerciseechocardiography.J Am Sot Echo 1988;1:161-166. Chierchia S, Lazzari M, FreedmanB, Brunelli C, Maseri A. Impairment of a correlation betweenangina and the extent of ischemia 7. myocardial perfusion and function during painlessmyocardial ischemia.J Am was not possible. Greater hemodynamic disturbances CON Cardiol 1983;1:924-930. was 1.4 f 0.8 in the silent &hernia and 1.7 f 0.9 in the angina1 group (p = not significant). Infarct regions accountedfor 2.5 f 2.8 and 1.6 f 1.8 segments, respectively (p = not significant). Moreover, the “ischemic index” (conceived in order to compensate for the presence and extent of infarction) also showed no significant dtfference in the proportion of noninfarcted myocardium showing evidence for ischemia in the groups with and without angina. Even with the exclusion ofpatients without ST-segment changes, patients with silent ischemia (n = 19) and those with angina (n = 14) did not differ with respect to the number of ischemic segments (4.3 f 2.1 us 3.5 f 1.7) or the number of severely ischemic segments (1.5 f 1.9 us 1.5 f 1.6).

Clinical Siecnificance of Abruut Vasodepression Stress E&&cardiography -

During Dobutamine

Peter K. Mazeika, MRCP, Aleksander Nadazdin, MD, and Celia M. Oakley, MD marker for severecoronary diseaseand poor prognosis, which is seenin patients with a dilated, poorly functioning left ventricle due to extensive new regional asynergy on method of detecting coronary artery disease.l In a differ- post-treadmill exerciseechocardiography. We describe ent clinical setting, exogenous catecholamine infusion instancesof paradoxical hypotension-bradycardiain paduring upright tilt testing has been used to elicit symp- tients undergoing dobutamine stress echocardiography tomatic hypotension and bradycardia in patients with for suspectedcoronary disease,comment on its clinical recurrent syncopeof unknown origin.2 This followed the significance and recommend precautions to maximize observationthat increasesin heart rate and arterial pres- test safety. We studied 50 patients (44 men and 6 women, aged sure,3and elevatedcirculating catecholaminelevels4frequently precedevasovagalreactionsimplicating transient 54 f 9 years) awaiting cardiac catheterization for susheightened sympathoadrenal activity before vasodepres- pected coronary disease after pharmacologic washout of sion. Hypotension during exercise is recognized as a cardioactive treatment. Dobutamine stress echocardiogobutamine stresstogether with 2-dimensional echocardiography for identification of ischemia-induced D wall motion abnormalities is emerging as an accurate

From the Department of Medicine (Clinical Cardiology), Hammersmith Hospital and RPMS, 150 Du Cane Road, London, W 12 ONN, United Kingdom. This study was funded by Grant 3/90 from the Coronary Artery DiseaseResearchAssociation,London, United Ringdom. Additional support was obtained from Eli Lilly and Company Limited, Basingstoke,Hampshire, United Kingdom. Dr. Mazeika is a Coronary Artery DiseaseResearchAssociationResearchFellow. Manuscript received October 8, 1991;revisedmanuscript receivedJanuary 31.1992, and accepted February 2.1992. 1484

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69

raphy was performed with patients semirecumbent, using an 8-minute stepwise infusion of 5, 10, 15 and 20 pg/kdmin during 2-dimensional echocardiographic imaging of the parasternal long-axis, short-axis and apical 4- and 2-chamber views (Toshiba SSH-16OA, 3.75 MHz transducer). Heart rate and electrocardiographic monitoring was continuous, and blood pressure was measured every 1 to 2 minutes using a Critikon, Dinamap vital signs monitor. Previously reported end points were JUNE 1, 1992

used,’ and the induction of transient regional asynergy defined an abnormal study. Presyncopewas defined aspremonitory symptoms of imminent syncope,and a hypotensive responseas a >20 mm Hg decreasein systolic pressure or a lesserreduction associatedwith presyncope.After documentation of vasodepression,we reviewed the clinical, investigative and stress echocardiographic data in all patients and followed up those with hypotension to establish the clinical signijkance of this reaction. All patients also underwent a modified Bruce exercise electrocardiogram without antianginal medication using conventional end points. Coronary angiography wasperformed by thefemoral approach; a 2 70%diame-

ter stenosisin I I major epicardial vesselwasconsidered signijkant . Continuous data are expressedas mean f SD. Parametric statistics and the Yates’ correctedchi-square test were used, as appropriate. A p value KO.05was considered statistically significant. The protocol was approved by the hospital ethics committee, and all patients gave informed consent. Sevenpatients (14%) had a hypotensiveresponsethat occurred after a mean infusion duration of 27 f 3 minutes (Table I and Figure I). The mean maximum decreasesin systolic arterial pressure and heart rate were 49 f 23 mm Hg and 21 f I1 beatslmin, respectively,and followed mean increasesof 29 f 22 mm Hg and 45 f IO

TABLE I Clinical Data, Hemodynamic Changes and Echocardiographic Hypotensive Response to Dobutamine Stress Case NO.

Age (yr) &Sex

1

55F 50M 63M 53M 59M 58M 66~

2 3 4 5 6 7

Findings in Seven Patients Who Manifested an Abrupt

Maximum SAP Decrease (mm l-k)*

Maximum HR Decrease (beats/min)*

Preceding SAP Increase (mm Hg)*

Preceding HR Increase (beats/min)*

28

30 23 16

5 65 23 36 2 39 36

48 47 55 31 36 58 41

19

41 78 39 61 77

1

16 26 33

Transient Regional

Presyncope

Junctional Rhythm

Coronary Artery Disease (vessel)

+ + + + + 0 +

+ 0 0 0 0 + +

0 0 0 1 VD (LAD) 2 VD U-AD, LC)

Anterior

1 VD U-AD)

Anterior

1 VD (right)

Inferior

Asynergyt

0 0 0 0

l Vasodepression

occurred at peak infustion rate in 6 patients and at 15 &kg/mm in case 7. tWall motion pretest was normal in all patients, except case 5 who had localizad lateral akines&. Heart rate and systolic arterial pressure at baseline were 70 + 10 beats/min and 141 2 8 mm Hg, respectively. HR = heart rate; LAD = laft antenor descending coronary artery; LC = left circumflex coronary artery; SAP = systolic arterial absent.

@I

dobutamine

I presyncope H junctional rhythm H

Go - 160

140-

-150

120-

-130

80-

pressura;

VD = vassal disease; + = present; IJ =

dobutamine I

I presyncope

H

160 150 32 %E 140 5z. .c?lJ 130 -0,' !Lw 120 c/IF

gn ,

0

dobutamine

’

120

60

I

,

I

I

I

dobutamine

I

@

presynoope cI

180

'

I

I

I anterior WMA-

120

r200 3s

160 140

110

-180

100

-160 $ r g

;

100

80

90

12' 100

80')

80

60

0

5

10 15 20 25 Time (minutes)

30

35

-140

'SE CE ;; s; "xm c/J?

ga -r-120 0

5

10 15 20 25 Time(minutes)

30

35

BRIEF REPORTS

1485

beats/min, respectively. Minor reductions in bloodpressure preceded the main reaction in cases1,4,5,6 and 7 (Figure I). Peak heart rate, systolic blood pressure and double product during dobutamine were similar in patients with and without vasodepression(p = not sign@cant [NS’]). Symptoms resolved, and hemodynamics normalized rapidly on test termination that was necessary in all except case 2, although the patient with the worst reaction (case 7) also neededsupine positioning and intravenous atropine (0.6 mg). There wereno significant differencesin age(58 f 6 us 54 f 9 years) or gender ratio betweenpatients with and without vasodepression.Two of 50 patients gave a current (case 7) or remote (case 1) history of unexplained syncope.A similar proportion of patients with normal coronaries (3 of 14; 21W) and coronary artery disease(4 of 36; 1I To)had a hypotensiverespome(p = NS) . Echocardiography revealedtransient regional asynergyin 3 of 7 patients (43%, all had coronary disease) with vasedepressioncompared with 21 of 43 (49%) of the others (p = NS). Global left ventricular function was good or vigorous in all 7 casesbefore and during the reaction. Furthermore, 3 (43%; casesI, 2 and 7) of thesepatients had a vasovagal episode needing atropine at cardiac catheterization compared with I of 43 (2%) of the others (p = 0.004). One of 50 patients (case 7) manifested a hypotensiveresponseto exercise;angina and electrocardiographic evidenceof inferior ischemia during exercise werefollowed by severe hypotemion-bradycardia with syncope in the recwery phase. No patient with vasodepression experienced cardiovascular morbidity or mortality over a total follow-up period of 121 months (range 15 to 20), although case 6 subsequently underwent coronary angioplasty, and case5 had coronary artery bypass surgery. The inotropic, chronotropic and pressoreffectsof dobutamine are mediated by stimulation of /3i, & and (~1 adrenoceptors6In the peripheral vasculature, /32and qmediated vasomotoreffectscancelout, and systemicvascular resistancedecreaseslargely by a reflex withdrawal of sympathetic tone in responseto an increasing cardiac output. We observedhypotension in the setting of good global left ventricular function implicating abrupt systemic vasodilation and cardiac slowing. Patients with coronary disease or inducible asynergy were as likely to develop hypotension as were the other subjects,and follow-up suggesteda good prognosis.This reaction appears to represent a ceiling to the myocardial stressoreffects attainable with dobutamine. The features describedsuggestthat a cardiovascular vasodepressorreflex is operative. Neurally mediated hypotension-bradycardia is believed to be a frequent cause of syncopethat on the basisof work in animal modelshas beenascribed to the activation of cardiac vagal afferents innervating mechanoreceptorsin the inferoposterior wall of the left ventricle.7*8Vigorous myocardial contraction around a small chamber (conditions presentduring dobutamine stress) is thought to trigger sympathoinhibition and increasedparasympatheticdischarge.Patients prone to vasodepressionmay have exaggerated cardiac mechanoreflex activity perhapsdue to mechanoreceptorhypersensitivity, or altered @receptoraffinity or numbers8 1486

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69

Whether p-blockade or atropine co-administration prevents dobutamine-induced hypotension is unknown and warrants further study, although the former maneuver would probably have the disadvantageof reducing test sensitivity.1 The associatedvasovagalepisodesat cardiac catheterization may be similarly mediated, perhapstriggered directly after arteriography of the dominant vesselor provoked by increased endogenouscatecholaminesdue to pain or fear.7*9,10 Postexercischypotension (as in case7) has also been considered to be a vasovagal reaction,” although ischemia-inducedbradycardia is a possiblealternative explanation in our patient. Interestingly, hype tension is seenin patients with pheochromocytomaand is now no longer attributed to intravascular volume depletion.i2 Tan et ali3 did not observevasodepressionin patients with heart failure undergoing assessmentof pump function using dobutamine, a finding consistentwith evidence indicating impaired cardiac vagal afferent nerves in this condition.8 None of our patients had poor left ventricular function. In conclusion we found that vasodepressionduring dobutamine stressechocardiographyis not a marker for coronary artery disease,transient asynergy or global left ventricular dysfunction. The association with hypotension-bradycardia at cardiac catheterization suggestsit may identify patients with a latent or manifest susceptibility to vasovagalepisodes.We recommendthat atropine should be available and that test termination should be consideredif systolic arterial pressuredecreasesby >30 or to < 100 mm Hg. Thesefindings needconfirmation in larger studies. AWe are grateful to the Coronary Artery DiseaseResearch Association, London, and Eli Lilly and Company Limited, Basingstoke, Hampshire, United Kingdom, for financial support. We also thank Senka Dinarevic, MD, Mohammed Khan, MD, and Jo Joshi, BSc (Hon), for expert technical assistance. 1. Cohen JL, Greene TO, Ottenweller J, Binenbaum SZ, Wilchfort SD, Kim CS, Alston JR. Dobutamine digital echocardiography for detecting coronary artery disease. Am J Cardiol 1991;67:1311-1318. 2. Almquist A, Goldenberg IF, Milstein S, Chen MY, Chen X, Hansen R, Gomick CC, Benditt DG. Provocation of bradycardia and hypotension by isopre terenol and upright posture in patients with unexplained syncope. N Engl J Med 1989;320:346-351. 3. Click G, Yu PN. Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 1963;34:42-51. 4. Chosy JJ, Graham DT. Catecholamines in vasovagal fainting. J Psychosom Res 1965;9:189-194. 5. Sanmarco ME, Pontius S, .%&ester RH. Abnormal blood pressure response and marked ischemic ST-segment depression as predictors of severe coronary artery disease. Circulation 1980;61:572-518. 6. L&r CV, Unverferth DV. Dobutamine. Ann Into-rn Med 1983;99:490-496. 7. Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coil Cardiol 1983;1:90-102. 8. Abboud FM. Ventricular syncope. Is the heart a sensory organ? N Engl J Med 1989;320:390-392. 9. Eckberg DL, White CW, Kioschos JM, Abboud FM. Mechanisms mediating bradycardia during coronary arteriography. J C/in Inwst 1974;54: 1455- 1461. 10. Sharpey-Schafer EP, Hayter CJ. Barlow ED. Mechanisms of acute hyotension from fear or nausea. Br Med J 1958;2:878-880. 11. Fleg JL, Lakatta EG. Prevalence and significance of p&exercise hypotension in apparently healthy subjects. Am J Cardiol 1986;57:1380-1384. 12. Gangoly A, Grim CE, Weinberger MH, Henry DP. Rapid cyclic fluctuations of blood pressure associated with an adrenal pheochromocytoma. Hypertemion 1984;6:281-284. 13. Tan LB, Bain RJI, Littler WA. Assessing cardiac pumping capability by exercise testing and inotropic stimulation. Br Heart J 1989;62:20-25.

JUNE 1, 1992