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Cold pressor test during two-dimensional echocardiography: Usefulness in detection of patients with coronary disease
Cold pressor test during two-dimensional echocardiography: Usefulness in detection patients with coronary disease
of
We assessed the feasibility and value of the cold pressor test (CPT) during real-time two-dimensional echocardiography (2DE) in patients with suspected coronary artery disease and normal resting left ventricular wall motion. Twenty patients were studied without knowledge of angiographic findings that demonstrated no significant coronary artery disease in seven (group 1) and significant coronary lesions in 13 (group 2). The increments In physiologic parameters (heart rate, systolic blood pressure, and double PrOdUCt) Where not significantly different in both groups. CPT-induced wall motion abnormalltles were identified echocardlographically in nine patients in group 2 and in one patient in group 1 (sensitivity 69% and specificity 66%). None of the patients in our study developed chest pain, ST changes, or ectopy during the test. It is concluded that 2DE combined wtth the CPT is valuable in Identifying patients with coronary artery disease who show no left ventricular asynergy at rest. (AM HEART J 107:276, 1964.)
Bapineedu Gondi, M.D., and Navin C. Nanda, M.D. Rochester,
Identification of ventricular wall motion abnormalities (WMA) is one of the principal means of detecting ischemic heart disease. However, many patients with severe coronary artery disease (CAD) have normal wall motion at rest but develop ventricular WMA and/or reduced ejection fraction during increased myocardial oxygen demand resulting from dynamic exercise. Recently, WMA induced by dynamic exercise (bicycle and treadmill) have been detected by two-dimensional echocardiography @DE) performed in conjunction with or immediately after exercise. l-4 However, some patients are unable to perform dynamic exercise and echocardiography may be difficult during exercise, since the patient is actively moving and is breathing rapidly. An alternative simple intervention that can increase myocardial oxygen consumption and unmask latent WMA during echocardiographic examination would be valuable. The cold pressor test (CPT), first described by Hines et al.,5-7 increases myocardial oxygen conFrom the Cardiology Unit, Department ester School of Medicine and Dentistry.
of Medicine,
Supported Training
by National Heart, Lung, and Grant in Cardiology No. HL07220.
Received accepted
for publication Nov. 15, 1982.
Reprint requests: Memorial Hospital, NY 14642.
278
June
1’7, 1982;
Navin C. Nanda, M.D., University of Rochester
Blood revision
University Institute received
Box 679-Cardiology, Medical Center,
of RochPostgraduate
Oct.
16, 1982;
Strong Rochester,
N. Y.
sumption by acutely increasing blood pressure and heart rate. It has also been shown to increase coronary vascular resistance (CVR) and reduce coronary blood flow in patients with CAD.s This report represents the first study describing the usefulness of CPT in conjunction with real-time 2DE in evaluating patients with suspected CAD.g METHODS Patients. The study population consistedof 20 patients, 13 men and ‘7 women. Their agesranged from 34 to 72
years (mean52years, Table I). All patients included in the study were admitted to the hospital for evaluation of CAD by cardiac catheterization and coronary angiography. It is a common practice at our institution to perform echocardiography prior to cardiac catheterization. The criterion for inclusion in the study wasnormal left ventricular wall motion by 2DE in patients who were subsequentlyundergoing cardiac catheterization. Patients with unstable angina pectoris, prior myocardial infarction, Rayuaud’s phenomena, peripheral vascular disease, previous cardiac surgery, or valvular or congenital heart diseasewere not studied. Informed consentwas obtained from all patients and the study protocol was approved by the Human Investigations Committee of the University of Rochester Medical Center. For practical and safety reasons,and also for the purpose of conducting the study in a realistic setting, no attempt wasmadeto withhold cardiac medicaThus, 18of the 20 patients were tions from any patient. 12-16 on either one or more cardiac medications at the time of the study (18 on beta blockers and 10 on long-acting nitrates) (Table I). The CPT was performed in conjunc-
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Table
2DE cold pressor
1. Clinical
Patient NO. Group
Age (yr)l Sex
test
for
279
CAD detection
data
Symptoms
Cardiac medications
ETT
Thalliuminduced scintigraphy*
CPT-induced WMA
Catheterization angiography
and
1
Normal
Not done
None
Nitrates Propranoloi Propranolol
Not done
Not done
None
Positive
Not done
None
Propranolol Nitrates Propranolol
Not done
Not done
None
Negative
Not done
None
Positive
Not done
None
Propranolol
Positive
Not done
Chest pain
Nitrates Propranolol
Positive
Not done
None
No WMA, EF 63 % , LAD 9O%,CX80%, RCA
M/54
Chest pain
Negative
Not done
None
10
M/50
Chest pain
Positive
Not done
None
No WMA, EF 70 % , LAD lOO%, cx 50% No WMA, EF 56 % , LAD
11
M/48
Chest pain
Nitrates Propranolol Nitrates Propranolol None
Negative
Not done
None
12
M/51
Chest pain
Nitrates Propranolol
Positive
Not done
Akinesis-distal 2/3 of left ventricle
13
F/40
Chest pain
Not done
Not done
LV apical hypokinesis
14
M/46
Chest pain
Propranoiol
Negative
Positive
LV apical hypokinesis
15
M/62
Chest pain
Positive
Not done
LV apical hypokinesis
16
F/59
Chest pain
Nitrates Propranolol Propranolol
Positive
Not done
LV apical hypokinesis
17
F/72
Chest pain
Nitrates Propranolol
Positive
Not done
LV apical akinesia
18
F/39
Chest pain
Propranolol
Positive
Positive
LV apical dyskinesis
19
Ml60
Chest pain
Positive
Not done
20
F/57
Chest pain
Nitrates Propranolol Nitrates Propranolol
Not done
Not done
Proximal inferior akinesis Diffuse LV hypocontractility
1
Ml34
Chest pain
2
Ml66
Chest pain
3
M/63
Chest pain
4
Ml53
Chest pain
5
F/61
Chest pain
6
F/44
Chest pain
7
M/36
Chest pain
M/61
9
Group 8
No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD
Diffuse LV hypocontractility
EF 65 % , no EF 67 % , no EF 71%, no EF 65 % , no EF 72 % , no EF 62 % , no EF 55 % , no
2
70%
5o%,cxloo%
No WMA, EF 60 % , LAD 9O%,CX70%, RCA 90% No WMA, EF 65 % , LAD 80%, CX lOO%, RCA 100% No WMA, EF 65%) LAD 60%, RCA 60% No WMA, EF 62%, LAD 8O%,CX70%
No WMA, EF 70%, LAD 50%, RCA 50% No WMA, EF 66%) LAD 8O%,CX90%, RCA 90% No WMA, EF 58 % , CX 70%) RCA 90 % , LAD 70 % No WMA, EF 51%) LAD 70%, RCA 90%, CX 50%
Abbreviations: E’IT = treadmill exercise test (graded positive or negative according to American Heart Association LV = left ventricular; WMA = left ventricular wall motion abnormalities; EF = left ventricular ejection fraction; CAD CX = circumflex artery; LAD - left anterior descending artery; RCA = right coronary artery. *Graded positive according to criteria used by Wackers et al.”
tion with 2DE within 24 hours of cardiac catheterization by an examiner who was completely blinded from clinical and angiographic data of the patient. Echo during-CPT. The patient was positioned in the 60-degree left lateral decubitus position and baseline
No WMA, EF 75 % , LAD 50%, RCA 70% No WMA, EF 64 % , CX 80%, RCA 100% criteria’O); = significant
CPT = cold pressor test; coronary artery disease;
blood pressure was obtained from the left arm with the use of a cuffed anerobic sphygmomanometer. The heart rate was noted. Real-time 2DE examination was performed by using a wide-angle (go-degree) mechanical sector scanner (ATL Mark III) and a 3 MHz transducer. Images were
280
February,
Gondi and Nanda
American
1984
Heart Journal
/
Fig. 1. Schematic diagram of various echocardiographicplanes studied. The left ventricular walls were subdivided into segmentsas shown. 1 = parasternal long-axis plane; 2 = apical four-chamber plane; 3 = apical two-chamber plane; 4 = subcostalfour-chamber plane. Abbreviations: A = anterior; A0 = aorta; AP = apical (distal) segment;A W = anterior wall; D W = diaphragmatic (inferior) wall; I = inferior; L = left or liver; LA = left atrium; LV = left ventricle; M = midsegment;P = proximal segment;PO= posterior; PW = posterior wall; RA = right atrium; RV = right ventricle; S = superior; VS = ventricular septum.
obtained from the standard parasternal, apical, and subcostal transducer positions.17Particular attention was paid to apical four- and two-chamber views and the parasternal long-axis plane. All imageswere recorded on videotape for later analysisin real-time, slow motion, and stop-frame fashion. The initial echocardiographicexamination was performed to record baseline images, to explore the cardiac window, and to establishthe transducer positionsfrom which optimal imagescould be obtained. The patient was then asked to slowly immersethe right hand up to the wrist into a plastic bucket containing ice-cold water (lo to 4’ C). The position of the patient was not altered and the echocardiographic examination was continued without interruption. The transducer positions and echocardiographicplanesestablishedduring the baseline examination facilitated rapid and optimal examination. The CPT wascontinued aslong asthe patient could tolerate the test. The duration of the test was 3 to 5 minutes in all except three patients (2 minutes in two and
1 minute in one patient). The lead I of the ECG was monitored with the echocardiogram. Heart rate, blood pressure, and rate-pressure product were measured 30 secondsand 1 minute after commencementof the CPT and thereafter at l-minute intervals. After termination of the CPT, echocardiographic examination was continued until the blood pressure came down to baseline (1 to 2 minutes). Left ventricular walls were evaluated for development of wall motion abnormalities. The echocardiogramat rest, during the CPT, and after the CPT were graded independently in a blinded fashion without knowledge of angiographic data. For the purposeof the study, left ventricular walls weredivided into three equal segmentsand eachwas analyzed for WMA (Fig. 1). In all planes studied, wall motion wasclassifiedasnormal or abnormal (hypokinetic, akinetic, or dyskinetic)1-4in comparison with baseline echocardiograms. Cardiac catheterization. Cardiac catheterization was
Volume
107
Number
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2DE cold pressor test for CAD detection
N=IJ P
IOO-
NORMAL
(GROUP
PRE
I,
CPT
CAD
IGROuP
PRE
N=13 PCO.01 21
c10
(GROUPP,
CPT
PRE
PCO.05 40
NORMAL
(GROUP
P~cJ.01
P
CA0
281
(GROUPZJ
5000-
NORMAL
(GROOP
CPT
P
Cd0
,GRO”PZ,
2. Systolic and diastolic blood pressures,heart rate, and rate-pressureproduct before and during the CPT in patients without (group 1) and with significant coronary artery disease(group 2). In one patient, heart rate changeswere not available since an adequatequality ECG wasnot obtained and rate-pressure product could not be calculated. Fig.
performed in all patients by meansof the Judkin technique. All patients had left ventriculography performed in the SO-degreeright anterior oblique position. Subsequently, selective angiography of the left and right coronary systemswaxperformed in multiple projections. The angiographic and hemodynamic data were analyzed in the standard fashion by the angiographerwithout knowledge of the results of echocardiographic examination. Significant CAD was defined angiographically asa decreaseof at least 50% in luminal diameter of one or more of the major coronary arteries.L3 Patients were further classified as having one-, two-, or three-vessel involvement. Seven patients had no significant coronary artery lesions(group 1) and 13 patients had significant coronary artery lesions (one-vesseldiseasein none, 2-vesseldiseasein seven,and 3-vesseldiseasein six patients). None of the patients in our study had significant involvement of the left main coronary artery. Statistical analysis. The sensitivity and specificity of the echocardiographic results were calculated as follows: sensitivity (% ) = (true positives)/(true positives + false negatives) x 100 and sensitivity (%) = (true negatives)/ (true negatives + false positives) X 100.
RESULTS Blood pressure, heart rate, and rate-pressure product. The CPT resulted in a significant increase in
systolic pressure, heart rate, and rate-pressure product (heart rate X maximum systolic pressure) in almost all patients in our study compared to measurements at rest (Fig. 2). The systolic pressure increased by an average of 36 mm Hg in group 1 and 34 mm Hg in group 2. All patients showed an increase in heart rate that averaged 6 bpm in group 1 and 13 bpm in group 2. The rate-pressure product increased from baseline value by an average of 4030 (49% ) in group 1 and 3000 (37% ) in group 2. The change in diastolic blood pressure was significant in group 2 (p < 0.05) but not in group 1 (p = NS). In one patient heart rate changes were not available since an adequate quality ECG was not obtained and rate-pressure product could not be calculated. The increments in these parameters were not significantly different when both groups were compared. The blood pressure returned to baseline 1 to 2
282
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February, 1984 Heart Journal
Fig. 3. 2DEs before (A) and during (B) the CPT in a patient with CAD. The echocardiographic images on the left represent diastolic frames and systolic frames are on right side. Notice the uniform contractility of left ventricular (LV) walls prior to the intervention. Dyskinesia involving posteroapical wall and distal ventricular septum (KS) is seen during intervention. Abbreviations: Z = inferior; L = left; LA = left atrium; MV = mitral valve; PW = posterior wall; R = right; RA = right atrium; RV = right ventricle; S = superior; TA = tricuspid anulus.
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minutes after the hand was taken out of the ice cold water in all patients. Left ventricular wall motion (Tables I and II). None of the seven patients without significant CAD (group 1) showed left ventricular segmental WMA in any echocardiographic planes during CPT. In one patient, however, diffuse left ventricular hypocontractility was observed in response to the test. Of the 13 patients with significant CAD (group 2), CPTinduced WMA were detected in nine patients (Fig. 3). In seven patients the asynergy was confined to the apical segments of the left ventricle, seen in all echocardiographic planes (hypokinesis in four, akinesis in two, dyskinesis in one). In one patient proximal inferior wall akinesis was seen. The remaining patient showed diffuse left ventricular hypocontractility without segmental WMA. Of the nine patients in whom WMA developed during the CPT, five had two-vessel and four had three-vessel CAD. There was no correlation between WMA observed in our patients with the location and severity of coronary stenosis. Four patients did not show WMA and the alterations in blood pressure, heart rate, rate-pressure product, and doses of beta blockers in this group did not differ significantly from those who developed WMA. In all patients, WMA reverted back to normal when the physiologic parameters returned to baseline. Neither chest pain nor specific ST changes suggestive of myocardial ischemia developed in any patient in either group during the intervention. One patient in group 1 complained of transient nausea after completion of the test unassociated with changes in ST segment, heart rate, or blood pressure. The sensitivity of CPT-induced wall motion abnormalities in detecting CAD was 69 % and the specificity was 86 % . DISCUSSION CPT-induced physiologic changes. It is well known that exposure to cold produces angina in both natural and controlled investigational settings.18-23 The CPT, first described by Hines and Brown in 1932, produces an acute increase in both heart rate and blood pressure, and the product of these two parameters has been shown to be proportional to myocardial oxygen consumption.= It has been shown that patients with CAD develop an inappropriate increase in CVB through alpha-adrenergic stimulation with consequent decrease in coronary blood flow.% Studies by Mudge et al.* showed a mean increase of 27 % in CVB in patients with CAD but no changes in patients with normal coronary arteries8 Thus, CPT has the potential of producing myocardial ischemia by two mechanisms: increasing myocar-
2DE cold pressor
Table
II. CPT-induced
test for cm
detection
283
left ventricular asynergy CPT-induced left ventricular asynergy
CAD No CAD, 7 patients (group 1) CAD, 13 patients (group 2)
Absent
Present
6
1 (diffuse)
4
9 (8 segmental) (1 diffuse)
dial oxygen consumption as well as decreasing coronary blood flow through increased CVFL In contrast, dynamic and pacing-induced myocardial ischemia is mostly due to increased myocardial oxygen consumption. The concomitant increase in the CVR explains the induction of myocardial ischemia by CPT at a lower rate-pressure product as compared to exercise testing. 2DE during CPT. Our study demonstrates the utility of combining the CPT with real-time 2DE in the evaluation of patients with suspected CAD, who have normal left ventricular wall motion on the resting echocardiogram. This method was useful in inducing wall motion abnormalities in the majority of the patients with CAD disease and in all cases induced left ventricular motion abnormalities reverted back to normal shortly after termination of the test. No untoward effects were noted in any patient. Failure to identify WMA during the CPT in some patients with CAD may be due to the inability of the test to induce myocardial ischemia. It is also possible that asynergy may have developed during the CPT in myocardial segments that were not visualized in the standard echocardiographic planes studied by us. The reason for marked diffuse hypocontractility in one patient with normal coronary arteries is not clear. During cardiac catheterization, intracardiac pressures were normal with no evidence of congestive cardiomyopathy in which the left ventricular ejection fraction has been shown to decrease during the CPT.26 In this patient, the coronary arteries may be unduly sensitive to cold, producing marked vasoconstriction resulting in myocardial ischemia. However, he did not develop any chest pain or ST changes. False positive tests may occur in patients with valvular heart disease and normal coronary arteries. WMA without ST changes. None of our patients with CPT-induced WMA developed chest pain or ST changes. Similar experience has been reported previously during this intervention and isometric exercise.26s27 It has been shown in experimental animals that lactate production and regional
284
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and Nanda
mechanical or global dysfunction precede surface or epicardial EGG changes. 28-32This observation was supported by a recent radionuclide angiocdiographic study during exercise.3” Significant abnormalities in left ventricular function were detected in the majority of patients before development of clinical symptoms or ECG evidence of myocardial ischemia. The observation of WMA during CPT without concomitant ST changes in our patients might be due to the development of low level myocardial ischemia enough to cause mechanical but not ECG changes. CPT with cardiac scintigraphy. Wainwright et al.,26 with the use of CPT and technetium-99m gated blood pool imaging, reported development of WMA in patients with significant CAD and no WMA in patients without CAD.26 Subsequently, two independent studies using similar technique have also shown the test to be highly specific in detecting patients with CAD. 34,35However, the sensitivity was considerably low (33 % and 38 % ). CPT has also been performed in conjunction with thallium-201 myocardial scintigraphy and demonstrated transient perfusion defects that normalized 4 hours later in 23 of 25 patients with CAD and normal scintigrams in all patients without significant CAD.36 Recently, CPT during M-mode echocardiography has been described to be a useful technique for detecting latent wall motion abnormalities in patients with CAD.37 Our report represents the first 2DE study during this intervention. Normal resting wall motion. We deliberately chose patients with only normal resting wall motion for this study, since patients with resting asynergy can be easily identified by real-time 2DE without inducing any stress on the myocardium. Unlike a previous radionuclide study, no special attempt was made to withdraw or withhold any cardiac medications in an attempt to simulate a realistic clinical setting and to make the test simple and less time consuming. WMA could be reliably diagnosed since comparison was made with the baseline echocardiogram that was obtained just prior to the intervention. Ideally, changes in wall thickness should also be evaluated during the CPT. However, this finding is difficult to evaluate when changes predominantly involve the apical region (as in most of our patients) where myocardium is relatively thin. Comparison of echocardiograms before, during, and after the test permits accurate evaluation of alterations in segmental wall motion and is less subjective and more reliable than interpreting a single echocardiographic study, as resting segmental asynergy may occur in the absence of significant CAD and beta blockers
American
February, 1984 Heart Journal
may also result in resting diffuse hypocontractility.’ Limitations. In contrast to dynamic exercise, the CPT is a less time-consuming and less cumbersome procedure. It does not significantly increase the respiratory rate; thus technically adequate echocardiographic examination (baseline, during CPT, and after CPT) is feasible without any change in position of the patient during intervention. Static stress will be clearly useful in patients who are unable to perform dynamic exercise. However, this intervention is not without problems. Some patients are very sensitive to cold and may not tolerate the test well. Three of 20 patients in our study could tolerate the cold for only up to 1 to 2 minutes. This intervention may not provide adequate stress to unmask WMA and this may explain the absence of WMA in 4 of 13 patients with CAD. Although so far none has been reported, the potential exists for the development of myocardial infarction in patients with extensive CAD. The CPT also produces coronary spasm, which may give a false positive response for athersclerotic CAD. However, we encountered only one false positive response in our series. This aspect requires further evaluation. Conclusions. Real-time 2DE performed during the CPT has a high specificity in the identification of patients with significant CAD. Further studies are needed to confirm the clinical validity of this intervention in the assessment of patients with CAD. The ated.
secretarial
assistance
of Lisa
Gaynier
is greatly
appreci-
REFERENCES 1. Maurer
2.
3.
4.
5.
6.
7. 8.
9.
G, Nanda NC: Two-dimensional echocardiographic evaluation of exercise-induced left and right ventricular asynergy: Correlation with thallium scanning. Am J Cardiol 48:720, 1981. Wann SL, Faris JV, Childress RS, Dillon JC, Weyman AE, Feigenbaum H: Exercise cross-sectional echocardiography in ischemic heart disease. Circulation 60:1300, 1979. Morganroth J, Chen C, David X, et al: Exercise crosssectional echocardiographic diagnosis of coronary artery disease. Am J Cardiol 47:20, 1981. Mason SJ, Weiss JL, Weisfeldt ML, Garrison JB, Fortuin NJ: Exercise echocardiography: Detection of wall motion abnormalities during ischemia. Circulation 59:50, 1979. Hines EA, Brown GE: The cold pressor test for measuring the reactibility of the blood pressure: Data concerning 571 normal and hypertensive subjects. AM HEART J 1 l:l, 1936. Godden JO, Roth GM, Hines EA: The changes in the intra-arterial pressure during immersion of the hand in ice cold water. Circulation 12:936, 1955. Hines GA: Technic of the cold pressor test: Sta@ meetings of the Mayo Clinic, 1939, pp 185-189. Mudae GH. Grossman W, Mills RM, Lesch M, Braunwald E: Reflei increase in coronky vascular resistance in patients with ischemic heart disease. N Engl J Med 295:1333, 1976. Gondi B, Nanda NC: Evaluation ofcoronary artery disease by cold pressor two-dimensional echocardiography (abstr). Circulation 64:IV-14, 1981.
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10. A Reporting System on Patients Evaluated for Coronary Artery Disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease. Council on Cardiovascular Surgery, American Heart Association, Circulation 51:5, 1975. 11. Wackers F, Becker A, Samson G, et al: Location and size of acute transmural myocardial infarction estimated from thallium scintiscans-a cliniconatholoaical studv. Circulation 56~72, 1977. 12. Alderman EL, Coltart DJ, Wettach GE, Harrison DC: Coronary artery syndromes after sudden propranolol withdrawal. Ann Intern Med 81:625, 1974. 13. Miller RR, Olson HG, Amsterdam EA, Mason DT: Propran0101withdrawal rebound phenomenon: Exacerbation of coronary events after abrupt cessation of antianginai therapy. N Engl J Med 293:416, 1975. 14. Boudoulas H, Lewis RP, Kates RE, Dalamangas G: Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects. Ann Intern Med 87:433, 1977. 15. Myers JH, Horowitz LD: Hemodynamic and metabolic response after abrupt withdrawal of long-term propranolol. Circulation 58:196, 19xX. 16. Nattel S, Rangno RE, Van Loon G: Mechanism of proprano101withdrawal phenomena. Circulation 59:1158, 1979. 17. Nanda NC, Gramiak R: Clinical echocardiography. St. Louis, 1978, The CV Mosby Company, p 379. 18. Neil WA, Duncan DA, Kloster F, Mahler DJ: Response of coronary circulation to cutaneous cold. Am J Med 56:471. 1974. 19. Greene MA, Boltax AJ, Lustig GA, Rogow E: Circulatory dynamics during the cold pressor test. Am J Cardiol 16:54, 1965. 20. Hattenhauer M, Neil WA: The effect of cold air inhalation on angina pectoris and myocardial oxygen supply. Circulation 51:1053, 1975. 21. Lassvik CT, Areskog N: Angina in cold environment. Reactions to exercise. Br Heart J 42:396, 1979. 22. Lassvik CT, Areskog N. Angina pectoris during inhalation of cold air. Reactions to exercise. Br Heart J 43:661, 1980. 23. Alexander S: Effect of cold on the cardiovascular system. Practitioner 213:785, 1974. 24. Gobel FL, Nordstrom LA, Nelson RR, Jorgensen CR, Wang Y: The rate pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation 57:549, 1978. 25. Mudge GH, Goldberg S, Gunther S, Mann T, Grossman W: Comparison of metabolic and vasoconstrictor stimuli on coronary vascular resistance in man. Circulation 59:544, 1979.
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Wainwright RJ, Brennand-Roper DA, Cueni TA, Sowton E, Hilson AJW, Maisey MN: Cold pressor test in detection of coronary heart-disease and cardiomyopathy using technetium-99m gated blood-pool imaging. Lancet: 320, 1979. 27. Mitamura H, Ogawa S, Hori S, Yamazaki H, Handa S, Nakamura Y: Two dimensional echocardiographic analysis of wall motion abormalities during hand grip exercise in patients with coronary artery disease. Am J Cardiol 48:711, 1981. 28. Waters DD, DA Luz P, Wyatt HL, Swan HJC, Forrester JS: Early changes in regional and global left ventricular function induced by reduction in regional coronary perfusion. Am J Cardiol s&537, 1977. 29. Scheur J, Brachfeld N: Coronary insufficiency: Relation between hemodynamic electrical and biochemical parameters. Circulation 28:178, 1966. 30. Sayen JJ, Sheldon WF, Peirce G, Kuo PT: Polarographic oxygen, the epicardial electrocardiogram and muscle contraction in experimental acute regional ischemia of the left ventricle. Circ Res 6:779, 1958. 31. Sayen JJ, Sheldon WF, Peirce G, Kuo PT: Motion picture studies of ventricular muscle dynamics in experimental localized ischemia, correlated with myocardial oxygen lesion and electrocardiograms. J Clin Invest 33:962, 1954. 32. Lekven J, Mj$ OD, Kjekshus JK: Compensatory mechanisms during graded myocardial ischemia. Am J Cardiol 31:467, 1973. 33. Upton MT, Rerych SK, Newman GE, Ports, Cobb FR, Jones RH: Detecting abnormalites in left ventricular function during exercise before angina and ST-segment depression. Circulation 62:341, 1980. 34. Manyari DE, Nolewajka AJ, Purves P, Kostuk WJ: Ineffectiveness of quantitative radionuclide angiography during the cold-pressor test to detect patients with coronary artery disease. Comparison with rest-exercise studies (abstr). Circulation 3:229, -1980. 35. Wynne J, Holman L, Mudge GH, Borow KM: Clinical utility .. . .. . . of cold pressor radionuclide ventriculography in coronary artery disease (abstr)Am J Cardiol. 47:444, 1981. 36. Ahmad M, Dubiel JP, Haibach H, Goldberg SH, Sanfelippo JF, Martin RH: Cold pressor thallium-201 myocardial scintigraphy in detection of coronary artery disease: An alternative to exercise scintigraphy (abstr). Am J Cardiol 47:444, 1981. 37. Kurtz RG, Lemire MS, Chene R, Stacewicz M, Pitt B: Cold pressor echocardiography (abstr). Am J Cardiol 47:453, 1981. 26.
of
We assessed the feasibility and value of the cold pressor test (CPT) during real-time two-dimensional echocardiography (2DE) in patients with suspected coronary artery disease and normal resting left ventricular wall motion. Twenty patients were studied without knowledge of angiographic findings that demonstrated no significant coronary artery disease in seven (group 1) and significant coronary lesions in 13 (group 2). The increments In physiologic parameters (heart rate, systolic blood pressure, and double PrOdUCt) Where not significantly different in both groups. CPT-induced wall motion abnormalltles were identified echocardlographically in nine patients in group 2 and in one patient in group 1 (sensitivity 69% and specificity 66%). None of the patients in our study developed chest pain, ST changes, or ectopy during the test. It is concluded that 2DE combined wtth the CPT is valuable in Identifying patients with coronary artery disease who show no left ventricular asynergy at rest. (AM HEART J 107:276, 1964.)
Bapineedu Gondi, M.D., and Navin C. Nanda, M.D. Rochester,
Identification of ventricular wall motion abnormalities (WMA) is one of the principal means of detecting ischemic heart disease. However, many patients with severe coronary artery disease (CAD) have normal wall motion at rest but develop ventricular WMA and/or reduced ejection fraction during increased myocardial oxygen demand resulting from dynamic exercise. Recently, WMA induced by dynamic exercise (bicycle and treadmill) have been detected by two-dimensional echocardiography @DE) performed in conjunction with or immediately after exercise. l-4 However, some patients are unable to perform dynamic exercise and echocardiography may be difficult during exercise, since the patient is actively moving and is breathing rapidly. An alternative simple intervention that can increase myocardial oxygen consumption and unmask latent WMA during echocardiographic examination would be valuable. The cold pressor test (CPT), first described by Hines et al.,5-7 increases myocardial oxygen conFrom the Cardiology Unit, Department ester School of Medicine and Dentistry.
of Medicine,
Supported Training
by National Heart, Lung, and Grant in Cardiology No. HL07220.
Received accepted
for publication Nov. 15, 1982.
Reprint requests: Memorial Hospital, NY 14642.
278
June
1’7, 1982;
Navin C. Nanda, M.D., University of Rochester
Blood revision
University Institute received
Box 679-Cardiology, Medical Center,
of RochPostgraduate
Oct.
16, 1982;
Strong Rochester,
N. Y.
sumption by acutely increasing blood pressure and heart rate. It has also been shown to increase coronary vascular resistance (CVR) and reduce coronary blood flow in patients with CAD.s This report represents the first study describing the usefulness of CPT in conjunction with real-time 2DE in evaluating patients with suspected CAD.g METHODS Patients. The study population consistedof 20 patients, 13 men and ‘7 women. Their agesranged from 34 to 72
years (mean52years, Table I). All patients included in the study were admitted to the hospital for evaluation of CAD by cardiac catheterization and coronary angiography. It is a common practice at our institution to perform echocardiography prior to cardiac catheterization. The criterion for inclusion in the study wasnormal left ventricular wall motion by 2DE in patients who were subsequentlyundergoing cardiac catheterization. Patients with unstable angina pectoris, prior myocardial infarction, Rayuaud’s phenomena, peripheral vascular disease, previous cardiac surgery, or valvular or congenital heart diseasewere not studied. Informed consentwas obtained from all patients and the study protocol was approved by the Human Investigations Committee of the University of Rochester Medical Center. For practical and safety reasons,and also for the purpose of conducting the study in a realistic setting, no attempt wasmadeto withhold cardiac medicaThus, 18of the 20 patients were tions from any patient. 12-16 on either one or more cardiac medications at the time of the study (18 on beta blockers and 10 on long-acting nitrates) (Table I). The CPT was performed in conjunc-
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Table
2DE cold pressor
1. Clinical
Patient NO. Group
Age (yr)l Sex
test
for
279
CAD detection
data
Symptoms
Cardiac medications
ETT
Thalliuminduced scintigraphy*
CPT-induced WMA
Catheterization angiography
and
1
Normal
Not done
None
Nitrates Propranoloi Propranolol
Not done
Not done
None
Positive
Not done
None
Propranolol Nitrates Propranolol
Not done
Not done
None
Negative
Not done
None
Positive
Not done
None
Propranolol
Positive
Not done
Chest pain
Nitrates Propranolol
Positive
Not done
None
No WMA, EF 63 % , LAD 9O%,CX80%, RCA
M/54
Chest pain
Negative
Not done
None
10
M/50
Chest pain
Positive
Not done
None
No WMA, EF 70 % , LAD lOO%, cx 50% No WMA, EF 56 % , LAD
11
M/48
Chest pain
Nitrates Propranolol Nitrates Propranolol None
Negative
Not done
None
12
M/51
Chest pain
Nitrates Propranolol
Positive
Not done
Akinesis-distal 2/3 of left ventricle
13
F/40
Chest pain
Not done
Not done
LV apical hypokinesis
14
M/46
Chest pain
Propranoiol
Negative
Positive
LV apical hypokinesis
15
M/62
Chest pain
Positive
Not done
LV apical hypokinesis
16
F/59
Chest pain
Nitrates Propranolol Propranolol
Positive
Not done
LV apical hypokinesis
17
F/72
Chest pain
Nitrates Propranolol
Positive
Not done
LV apical akinesia
18
F/39
Chest pain
Propranolol
Positive
Positive
LV apical dyskinesis
19
Ml60
Chest pain
Positive
Not done
20
F/57
Chest pain
Nitrates Propranolol Nitrates Propranolol
Not done
Not done
Proximal inferior akinesis Diffuse LV hypocontractility
1
Ml34
Chest pain
2
Ml66
Chest pain
3
M/63
Chest pain
4
Ml53
Chest pain
5
F/61
Chest pain
6
F/44
Chest pain
7
M/36
Chest pain
M/61
9
Group 8
No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD No WMA, CAD
Diffuse LV hypocontractility
EF 65 % , no EF 67 % , no EF 71%, no EF 65 % , no EF 72 % , no EF 62 % , no EF 55 % , no
2
70%
5o%,cxloo%
No WMA, EF 60 % , LAD 9O%,CX70%, RCA 90% No WMA, EF 65 % , LAD 80%, CX lOO%, RCA 100% No WMA, EF 65%) LAD 60%, RCA 60% No WMA, EF 62%, LAD 8O%,CX70%
No WMA, EF 70%, LAD 50%, RCA 50% No WMA, EF 66%) LAD 8O%,CX90%, RCA 90% No WMA, EF 58 % , CX 70%) RCA 90 % , LAD 70 % No WMA, EF 51%) LAD 70%, RCA 90%, CX 50%
Abbreviations: E’IT = treadmill exercise test (graded positive or negative according to American Heart Association LV = left ventricular; WMA = left ventricular wall motion abnormalities; EF = left ventricular ejection fraction; CAD CX = circumflex artery; LAD - left anterior descending artery; RCA = right coronary artery. *Graded positive according to criteria used by Wackers et al.”
tion with 2DE within 24 hours of cardiac catheterization by an examiner who was completely blinded from clinical and angiographic data of the patient. Echo during-CPT. The patient was positioned in the 60-degree left lateral decubitus position and baseline
No WMA, EF 75 % , LAD 50%, RCA 70% No WMA, EF 64 % , CX 80%, RCA 100% criteria’O); = significant
CPT = cold pressor test; coronary artery disease;
blood pressure was obtained from the left arm with the use of a cuffed anerobic sphygmomanometer. The heart rate was noted. Real-time 2DE examination was performed by using a wide-angle (go-degree) mechanical sector scanner (ATL Mark III) and a 3 MHz transducer. Images were
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1984
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/
Fig. 1. Schematic diagram of various echocardiographicplanes studied. The left ventricular walls were subdivided into segmentsas shown. 1 = parasternal long-axis plane; 2 = apical four-chamber plane; 3 = apical two-chamber plane; 4 = subcostalfour-chamber plane. Abbreviations: A = anterior; A0 = aorta; AP = apical (distal) segment;A W = anterior wall; D W = diaphragmatic (inferior) wall; I = inferior; L = left or liver; LA = left atrium; LV = left ventricle; M = midsegment;P = proximal segment;PO= posterior; PW = posterior wall; RA = right atrium; RV = right ventricle; S = superior; VS = ventricular septum.
obtained from the standard parasternal, apical, and subcostal transducer positions.17Particular attention was paid to apical four- and two-chamber views and the parasternal long-axis plane. All imageswere recorded on videotape for later analysisin real-time, slow motion, and stop-frame fashion. The initial echocardiographicexamination was performed to record baseline images, to explore the cardiac window, and to establishthe transducer positionsfrom which optimal imagescould be obtained. The patient was then asked to slowly immersethe right hand up to the wrist into a plastic bucket containing ice-cold water (lo to 4’ C). The position of the patient was not altered and the echocardiographic examination was continued without interruption. The transducer positions and echocardiographicplanesestablishedduring the baseline examination facilitated rapid and optimal examination. The CPT wascontinued aslong asthe patient could tolerate the test. The duration of the test was 3 to 5 minutes in all except three patients (2 minutes in two and
1 minute in one patient). The lead I of the ECG was monitored with the echocardiogram. Heart rate, blood pressure, and rate-pressure product were measured 30 secondsand 1 minute after commencementof the CPT and thereafter at l-minute intervals. After termination of the CPT, echocardiographic examination was continued until the blood pressure came down to baseline (1 to 2 minutes). Left ventricular walls were evaluated for development of wall motion abnormalities. The echocardiogramat rest, during the CPT, and after the CPT were graded independently in a blinded fashion without knowledge of angiographic data. For the purposeof the study, left ventricular walls weredivided into three equal segmentsand eachwas analyzed for WMA (Fig. 1). In all planes studied, wall motion wasclassifiedasnormal or abnormal (hypokinetic, akinetic, or dyskinetic)1-4in comparison with baseline echocardiograms. Cardiac catheterization. Cardiac catheterization was
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107
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2DE cold pressor test for CAD detection
N=IJ P
IOO-
NORMAL
(GROUP
PRE
I,
CPT
CAD
IGROuP
PRE
N=13 PCO.01 21
c10
(GROUPP,
CPT
PRE
PCO.05 40
NORMAL
(GROUP
P~cJ.01
P
CA0
281
(GROUPZJ
5000-
NORMAL
(GROOP
CPT
P
Cd0
,GRO”PZ,
2. Systolic and diastolic blood pressures,heart rate, and rate-pressureproduct before and during the CPT in patients without (group 1) and with significant coronary artery disease(group 2). In one patient, heart rate changeswere not available since an adequatequality ECG wasnot obtained and rate-pressure product could not be calculated. Fig.
performed in all patients by meansof the Judkin technique. All patients had left ventriculography performed in the SO-degreeright anterior oblique position. Subsequently, selective angiography of the left and right coronary systemswaxperformed in multiple projections. The angiographic and hemodynamic data were analyzed in the standard fashion by the angiographerwithout knowledge of the results of echocardiographic examination. Significant CAD was defined angiographically asa decreaseof at least 50% in luminal diameter of one or more of the major coronary arteries.L3 Patients were further classified as having one-, two-, or three-vessel involvement. Seven patients had no significant coronary artery lesions(group 1) and 13 patients had significant coronary artery lesions (one-vesseldiseasein none, 2-vesseldiseasein seven,and 3-vesseldiseasein six patients). None of the patients in our study had significant involvement of the left main coronary artery. Statistical analysis. The sensitivity and specificity of the echocardiographic results were calculated as follows: sensitivity (% ) = (true positives)/(true positives + false negatives) x 100 and sensitivity (%) = (true negatives)/ (true negatives + false positives) X 100.
RESULTS Blood pressure, heart rate, and rate-pressure product. The CPT resulted in a significant increase in
systolic pressure, heart rate, and rate-pressure product (heart rate X maximum systolic pressure) in almost all patients in our study compared to measurements at rest (Fig. 2). The systolic pressure increased by an average of 36 mm Hg in group 1 and 34 mm Hg in group 2. All patients showed an increase in heart rate that averaged 6 bpm in group 1 and 13 bpm in group 2. The rate-pressure product increased from baseline value by an average of 4030 (49% ) in group 1 and 3000 (37% ) in group 2. The change in diastolic blood pressure was significant in group 2 (p < 0.05) but not in group 1 (p = NS). In one patient heart rate changes were not available since an adequate quality ECG was not obtained and rate-pressure product could not be calculated. The increments in these parameters were not significantly different when both groups were compared. The blood pressure returned to baseline 1 to 2
282
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Fig. 3. 2DEs before (A) and during (B) the CPT in a patient with CAD. The echocardiographic images on the left represent diastolic frames and systolic frames are on right side. Notice the uniform contractility of left ventricular (LV) walls prior to the intervention. Dyskinesia involving posteroapical wall and distal ventricular septum (KS) is seen during intervention. Abbreviations: Z = inferior; L = left; LA = left atrium; MV = mitral valve; PW = posterior wall; R = right; RA = right atrium; RV = right ventricle; S = superior; TA = tricuspid anulus.
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minutes after the hand was taken out of the ice cold water in all patients. Left ventricular wall motion (Tables I and II). None of the seven patients without significant CAD (group 1) showed left ventricular segmental WMA in any echocardiographic planes during CPT. In one patient, however, diffuse left ventricular hypocontractility was observed in response to the test. Of the 13 patients with significant CAD (group 2), CPTinduced WMA were detected in nine patients (Fig. 3). In seven patients the asynergy was confined to the apical segments of the left ventricle, seen in all echocardiographic planes (hypokinesis in four, akinesis in two, dyskinesis in one). In one patient proximal inferior wall akinesis was seen. The remaining patient showed diffuse left ventricular hypocontractility without segmental WMA. Of the nine patients in whom WMA developed during the CPT, five had two-vessel and four had three-vessel CAD. There was no correlation between WMA observed in our patients with the location and severity of coronary stenosis. Four patients did not show WMA and the alterations in blood pressure, heart rate, rate-pressure product, and doses of beta blockers in this group did not differ significantly from those who developed WMA. In all patients, WMA reverted back to normal when the physiologic parameters returned to baseline. Neither chest pain nor specific ST changes suggestive of myocardial ischemia developed in any patient in either group during the intervention. One patient in group 1 complained of transient nausea after completion of the test unassociated with changes in ST segment, heart rate, or blood pressure. The sensitivity of CPT-induced wall motion abnormalities in detecting CAD was 69 % and the specificity was 86 % . DISCUSSION CPT-induced physiologic changes. It is well known that exposure to cold produces angina in both natural and controlled investigational settings.18-23 The CPT, first described by Hines and Brown in 1932, produces an acute increase in both heart rate and blood pressure, and the product of these two parameters has been shown to be proportional to myocardial oxygen consumption.= It has been shown that patients with CAD develop an inappropriate increase in CVB through alpha-adrenergic stimulation with consequent decrease in coronary blood flow.% Studies by Mudge et al.* showed a mean increase of 27 % in CVB in patients with CAD but no changes in patients with normal coronary arteries8 Thus, CPT has the potential of producing myocardial ischemia by two mechanisms: increasing myocar-
2DE cold pressor
Table
II. CPT-induced
test for cm
detection
283
left ventricular asynergy CPT-induced left ventricular asynergy
CAD No CAD, 7 patients (group 1) CAD, 13 patients (group 2)
Absent
Present
6
1 (diffuse)
4
9 (8 segmental) (1 diffuse)
dial oxygen consumption as well as decreasing coronary blood flow through increased CVFL In contrast, dynamic and pacing-induced myocardial ischemia is mostly due to increased myocardial oxygen consumption. The concomitant increase in the CVR explains the induction of myocardial ischemia by CPT at a lower rate-pressure product as compared to exercise testing. 2DE during CPT. Our study demonstrates the utility of combining the CPT with real-time 2DE in the evaluation of patients with suspected CAD, who have normal left ventricular wall motion on the resting echocardiogram. This method was useful in inducing wall motion abnormalities in the majority of the patients with CAD disease and in all cases induced left ventricular motion abnormalities reverted back to normal shortly after termination of the test. No untoward effects were noted in any patient. Failure to identify WMA during the CPT in some patients with CAD may be due to the inability of the test to induce myocardial ischemia. It is also possible that asynergy may have developed during the CPT in myocardial segments that were not visualized in the standard echocardiographic planes studied by us. The reason for marked diffuse hypocontractility in one patient with normal coronary arteries is not clear. During cardiac catheterization, intracardiac pressures were normal with no evidence of congestive cardiomyopathy in which the left ventricular ejection fraction has been shown to decrease during the CPT.26 In this patient, the coronary arteries may be unduly sensitive to cold, producing marked vasoconstriction resulting in myocardial ischemia. However, he did not develop any chest pain or ST changes. False positive tests may occur in patients with valvular heart disease and normal coronary arteries. WMA without ST changes. None of our patients with CPT-induced WMA developed chest pain or ST changes. Similar experience has been reported previously during this intervention and isometric exercise.26s27 It has been shown in experimental animals that lactate production and regional
284
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and Nanda
mechanical or global dysfunction precede surface or epicardial EGG changes. 28-32This observation was supported by a recent radionuclide angiocdiographic study during exercise.3” Significant abnormalities in left ventricular function were detected in the majority of patients before development of clinical symptoms or ECG evidence of myocardial ischemia. The observation of WMA during CPT without concomitant ST changes in our patients might be due to the development of low level myocardial ischemia enough to cause mechanical but not ECG changes. CPT with cardiac scintigraphy. Wainwright et al.,26 with the use of CPT and technetium-99m gated blood pool imaging, reported development of WMA in patients with significant CAD and no WMA in patients without CAD.26 Subsequently, two independent studies using similar technique have also shown the test to be highly specific in detecting patients with CAD. 34,35However, the sensitivity was considerably low (33 % and 38 % ). CPT has also been performed in conjunction with thallium-201 myocardial scintigraphy and demonstrated transient perfusion defects that normalized 4 hours later in 23 of 25 patients with CAD and normal scintigrams in all patients without significant CAD.36 Recently, CPT during M-mode echocardiography has been described to be a useful technique for detecting latent wall motion abnormalities in patients with CAD.37 Our report represents the first 2DE study during this intervention. Normal resting wall motion. We deliberately chose patients with only normal resting wall motion for this study, since patients with resting asynergy can be easily identified by real-time 2DE without inducing any stress on the myocardium. Unlike a previous radionuclide study, no special attempt was made to withdraw or withhold any cardiac medications in an attempt to simulate a realistic clinical setting and to make the test simple and less time consuming. WMA could be reliably diagnosed since comparison was made with the baseline echocardiogram that was obtained just prior to the intervention. Ideally, changes in wall thickness should also be evaluated during the CPT. However, this finding is difficult to evaluate when changes predominantly involve the apical region (as in most of our patients) where myocardium is relatively thin. Comparison of echocardiograms before, during, and after the test permits accurate evaluation of alterations in segmental wall motion and is less subjective and more reliable than interpreting a single echocardiographic study, as resting segmental asynergy may occur in the absence of significant CAD and beta blockers
American
February, 1984 Heart Journal
may also result in resting diffuse hypocontractility.’ Limitations. In contrast to dynamic exercise, the CPT is a less time-consuming and less cumbersome procedure. It does not significantly increase the respiratory rate; thus technically adequate echocardiographic examination (baseline, during CPT, and after CPT) is feasible without any change in position of the patient during intervention. Static stress will be clearly useful in patients who are unable to perform dynamic exercise. However, this intervention is not without problems. Some patients are very sensitive to cold and may not tolerate the test well. Three of 20 patients in our study could tolerate the cold for only up to 1 to 2 minutes. This intervention may not provide adequate stress to unmask WMA and this may explain the absence of WMA in 4 of 13 patients with CAD. Although so far none has been reported, the potential exists for the development of myocardial infarction in patients with extensive CAD. The CPT also produces coronary spasm, which may give a false positive response for athersclerotic CAD. However, we encountered only one false positive response in our series. This aspect requires further evaluation. Conclusions. Real-time 2DE performed during the CPT has a high specificity in the identification of patients with significant CAD. Further studies are needed to confirm the clinical validity of this intervention in the assessment of patients with CAD. The ated.
secretarial
assistance
of Lisa
Gaynier
is greatly
appreci-
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2.
3.
4.
5.
6.
7. 8.
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