- Email: [email protected]
Mental stress–induced myocardial ischemia in coronary artery disease patients with left ventricular dysfunction
Mental stress–induced myocardial ischemia in coronary artery disease patients with left ventricular dysfunction Mustafa Hassan, MD,a,b Kaki M. York, PhD,a,b Haihong Li, PhD,c Qin Li, MS,c and David S. Sheps, MD, MSPHa,b Background. Reduced left ventricular ejection fraction (LVEF) is a risk factor for poor outcomes in patients with coronary artery disease (CAD). Mental stress–induced myocardial ischemia (MSIMI) also identifies a subset of CAD patients at increased risk for future cardiovascular events. Susceptibility to MSIMI in patients with CAD and reduced LVEF is unknown. Methods and Results. We enrolled 182 patients (67 women) with a mean age of 64 years and a documented history of CAD in this study. Baseline resting ejection fraction was determined by use of technetium 99m sestamibi gated single photon emission computed tomography. Abnormal LVEF was defined as less than 45% for men and less than 50% for women (based on published norms for our software [Cedars-Sinai Medical Center]). All participants underwent mental stress testing with a public speaking task. Rest/stress myocardial perfusion single photon emission computed tomography was performed via conventional methodology. Images were visually compared for number and severity of perfusion defects by use of a scoring method from 0 to 4. A summed difference score was calculated as the difference between summed stress and rest scores. A score of greater than 3 was considered abnormal. MSIMI developed in 19% of patients with normal LVEF and 31% of those with reduced LVEF. There is no statistically significant difference between the two groups (P ⴝ .11). Conclusions. CAD patients with left ventricular dysfunction are equally susceptible to MSIMI as those with normal LVEF. (J Nucl Cardiol 2007;14:308-13.) Key Words: Mental stress • myocardial ischemia • coronary artery disease • left ventricular ejection fraction
See related article, p. 269 Patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF) have increased rates of mortality and adverse cardiovascular events.1-4 Mental stress–induced myocardial ischemia (MSIMI) also defines a subset of CAD patients at increased risk for poor outcomes.5-8 One of the mechaFrom Cardiovascular Research, Division of Cardiology, Department of Medicine,a and Department of Biostatistics,c University of Florida, and North Florida/South Georgia VA Healthcare System,b Gainesville, Fla. This study was supported by grants HL 070265 and HL 072059 from the National Heart, Lung, and Blood Institute. This material is also the result of work supported by resources and with the use of facilities at the Department of Veterans Affairs Medical Center, Gainesville, Fla. Received for publication Oct 9, 2006; final revision accepted Jan 17, 2007. Reprint requests: Mustafa Hassan, MD, Cardiology Research (151), VAMC, 1601 SW Archer Rd, Gainesville, FL 32608; mustafa. [email protected]fl.edu. 1071-3581/$32.00 Copyright © 2007 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2007.01.040 308
nisms by which mental stress induces myocardial ischemia is by epicardial coronary artery vasoconstriction.9-12 It is plausible that patients with reduced LVEF might have increased susceptibility to MSIMI, given the associated increase in left ventricular (LV) end-diastolic pressure, which consequently could increase the coronary artery resistance and decrease the myocardial perfusion pressure. This mechanism could be further exacerbated by vasoconstriction. The prevalence and significance of MSIMI in patients with reduced ejection fraction are unknown. Most studies evaluating the susceptibility of CAD patients to this phenomenon did not report LVEF. Furthermore, many of these studies included only patients with normal LVEF. In this study we sought to compare the susceptibility to MSIMI in a cohort of CAD patients with normal versus reduced LVEF. METHODS Subjects Participants in this study were recruited from outpatient cardiology clinics affiliated with a regional Veterans Affairs
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hospital and a university-based medical center. To be included in the study, patients had to be aged at least 18 years with a documented clinical diagnosis of CAD supported by angiographic evidence, previous coronary artery bypass graft (CABG) surgery, previous myocardial infarction (MI) (documented by an elevated troponin level in the range typical of MI, Q-wave abnormalities on an electrocardiogram, or fixed wall motion abnormalities on a nuclear scan), or a positive radionuclide dobutamine or exercise stress test. Patients were excluded if they had unstable angina or acute MI within the 2 months before enrollment, a severe comorbid medical problem restricting life expectancy to less than 5 years, body weight over 400 lb, or if they were pregnant.
Study Design The study protocol was approved by the University of Florida Institutional Review Board (Gainesville, Fla). Informed consent was obtained from all participants. Demographic and psychosocial characteristics were obtained before study procedures. Baseline resting ejection fraction was determined with technetium 99m sestamibi gated single photon emission computed tomography by use of a semiautomated volumetric algorithm (ADAC Laboratories/Philips Medical Systems, Milpitas, Calif).13-17 Abnormal LVEF was defined as less than 45% for men and less than 50% for women (Auto Quant 6.0; ADAC Laboratories/Philips Medical Systems).17-21 Mental stress tests were conducted after an overnight fast. -Blockers, calcium channel blockers, and long-acting nitrates were withheld for 24 hours before testing.
Mental Stress Procedure Patients were initially placed in a cool, dark, and quiet room. They rested in a reclined position for 30 minutes while their heart rate (HR) and blood pressure were obtained every 5 minutes by use of an electrocardiographic monitor and automatic oscillometric device (Dinamap; Critikon Inc, Tampa, Fla), respectively. Mental stress was then induced via a public speaking task. Participants were given a scenario describing a real-life stressful event (such as a family member with a serious illness, an automobile accident, a dog bite, or an inconsiderate houseguest) and asked to make up a realistic story around it. Participants were given 2 minutes to prepare their speech and 3 minutes to speak. They were told that their speech would be videotaped and the laboratory staff would replay the tape to rate it for content, quality, and duration of the speech. Hemodynamic measurements were obtained every minute during the speech and at 1, 3, 5, and 10 minutes into the recovery period. Systolic blood pressure (SBP) and HR were used to calculate the double product (DP) value (DP ⫽ SBP ⫻ HR). Peak stress and rest values were compared.
Myocardial Perfusion Imaging Imaging with Tc-99m sestamibi was used. At 1 minute into the speech, a total dose of 20 to 30 mCi (based on the patient’s body weight) was injected. The time of the injection
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Table 1. Clinical and demographic characteristics for normal versus reduced LVEF group
Variable Mean age (y) Gender (male) Ethnicity White Black Previous MI Mean number of diseased coronary arteries (⬎50% stenosis) Abnormal exercise or pharmacologic stress test Previous CABG Previous PTCA Past or current smoker Hypertension Diabetes Angina symptoms Hyperlipidemia Cerebrovascular disease -Blockers ACE inhibitors Calcium channel blockers Mean LVEF (%) Body mass index (kg/m2)
Normal Reduced LVEF LVEF group group (n ⴝ 150) (n ⴝ 32)
P value
63 ⫾ 9 91 (61%)
64 ⫾ 8 24 (75%)
NS NS
129 (86%) 14 (9%) 27 (18%) 1.9 ⫾ 1
28 (88%) 3 (9%) 13 (41%) 2.1 ⫾ 1
NS NS P ⫽ .005 NS
81 (53%)
13 (41%)
NS
53 (35%) 54 (36%) 99 (66%)
11 (34%) 14 (44%) 23 (72%)
NS NS NS
119 (79%) 47 (31%) 103 (69%)
24 (75%) 14 (44%) 20 (63%)
NS NS NS
133 (89%) 22 (15%)
29 (91%) 5 (16%)
NS NS
117 (78%) 82 (55%) 31 (21%)
26 (81%) 23 (72%) 6 (16%)
NS NS NS
61 ⫾ 9 30 ⫾ 6
32 ⫾ 10 30 ⫾ 5
P ⬍ .05 NS
Values are expressed as mean ⫾ SD or number (%). Statistical significance considered as P ⱕ .05. NS, Not significant; PTCA, percutaneous transluminal coronary angioplasty; ACE, angiotensin-converting enzyme.
was decided based on the published evidence that adrenergic sympathetic nervous system response to mental stress usually occurs very quickly, within the first minute of starting the stressful task.12,22,23 Stress perfusion images were acquired 30 to 60 minutes later by use of conventional single photon emission computed tomography methodology (64 projections over a circular 180° orbit, with the gamma camera set at a 140-keV energy peak with a 20% window).17 A high-resolution collimator and 2-dimensional Butterworth filter were used, and transaxial tomograms were recon-
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Table 2. Hemodynamic variables during rest and stress in patients with normal versus reduced LVEF
Variable Mean SBP (mm Hg) Rest Stress Difference Mean DBP (mm Hg) Rest Stress Difference Mean HR (beats/min) Rest Stress Difference Mean DP Rest Stress Difference
Normal LVEF group (n ⴝ 150)
Reduced LVEF group (n ⴝ 32)
P value
119 ⫾ 18 163 ⫾ 24 44 ⫾ 19
119 ⫾ 22 158 ⫾ 32 39 ⫾ 18
NS NS NS
65 ⫾ 9 93 ⫾ 13 28 ⫾ 10
65 ⫾ 12 98 ⫾ 18 33 ⫾ 13
NS NS NS
60 ⫾ 9 78 ⫾ 15 19 ⫾ 11
62 ⫾ 13 84 ⫾ 18 21 ⫾ 13
NS NS NS
7,092 ⫾ 1,472 12,834 ⫾ 3,560 5,742 ⫾ 2,994
7,486 ⫾ 2,181 13,338 ⫾ 4,357 5,852 ⫾ 3,387
NS NS NS
Values are expressed as mean ⫾ SD. Statistical significance considered as P ⱕ .05. NS, Not significant.
90 80 70 60 %
structed via backprojection with a ramp filter. Resting images were obtained within 1 week of the stress test. The studies were interpreted by experienced nuclear cardiologists blinded to the condition (rest vs stress) and LVEF status. Rest and stress images were visually compared for number and severity of perfusion defects by use of a scoring method from 0 to 4, with 0 indicating normal uptake and 4 indicating no uptake. A summed difference score was calculated as the difference between summed stress and rest scores; a score of greater than 3 was considered abnormal.
50
Negative ischemia
40
Positive ischemia
30 20 10 0 Normal LVEF
Statistical Analysis Results were expressed as means and SDs for continuous variables and frequencies and percentages for categoric variables. Stress hemodynamic response variables were calculated as the difference between stress and rest measurements. Statistical differences between groups were determined by use of the Student t test for continuous variables and 2 analyses for categoric variables. The ␣ value was set at P ⫽ .05. To determine the relationship between LVEF status and the development of MSIMI, we used logistic regression analysis to control for possible confounding factors, including age, gender, severity of CAD by number of diseased vessels on coronary angiogram and results of stress test, history of CABG, history of MI, history of hypertension, diabetes, smoking status, and antianginal medication use (-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors).
Reduced LVEF
Figure 1. MSIMI in patients with normal versus reduced LVEF.
RESULTS Demographic Characteristics There were 182 individuals who participated in this study, 67 (37%) of whom were women. The mean age was 64 years. The majority of participants were white (86%), with black participants comprising 9%. Most participants (82%) had normal LVEF; mean LVEF was 61% ⫾ 9% in the normal LVEF group and 32% ⫾ 10% in the reduced LVEF group. All patients had documented CAD (78% had abnormal coronary angiograms, 22% had a history of MI, 68% had a history of anginal symptoms,
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Figure 2. Short-axis and horizontal long-axis tomograms displaying severe inferior perfusion defect during mental stress with partial reversibility on rest images.
and 33% had previous CABG). Cardiac catheterization data were available for 118 patients (65%) (92 [61%] in the normal LVEF group and 16 (50%) in the reduced LVEF group). The mean number of diseased coronary arteries with greater than 50% stenosis was 1.9 ⫾ 1. The participants also had a number of comorbid conditions: 79% had a history of hypertension, 89% had a history of hyperlipidemia, 34% had diabetes, and 67% were current or past smokers. Patients with reduced LVEF were more likely to have a history of MI (41%) compared with those with normal LVEF (18%) (P ⫽ .005); however, there was no significant difference in the number of diseased coronary arteries between the two groups (mean number of diseased vessels, 2.1 ⫾ 1 and 1.9 ⫾ 1, respectively; P ⫽ .45). There were no other significant differences in other measures of CAD disease severity (by angina
symptoms or exercise and pharmacologic stress test results), frequency of comorbid conditions, or antianginal medication use between the two groups. Demographic and clinical characteristics of the two groups are reported in Table 1. Hemodynamic Variables Mental stress induced a significant increase in SBP, diastolic blood pressure (DBP), HR, and DP measurements from the resting state. The mean increase in SBP, DBP, and HR from rest to stress was 43 ⫾ 19 mm Hg, 29 ⫾ 11 mm Hg, and 19 ⫾ 12 beats/min, respectively. All patients exhibited a significant hemodynamic response at the time of the isotope injection. At 1 minute into the speech, the mean percent increase in SBP, DBP, and HR was 26%, 32%, and
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Table 3. Methodologic differences between previously published study and current study
Methodologic differences No. of patients LVEF determination
Mental stress protocol Isotope injection time -Blocker withheld?
Study of Akinboboye et al24
Current study
58 Past cardiac catheterization data used in 59% of patients (mean time lapse of 32 mo between LVEF estimation and mental stress procedure); single photon emission computed tomography in 41% of patients Combination of anger recall and 4-min math task Only after HR had risen to at least 110% of baseline Withheld for ⬎36 h in 11/42 patients
182 Resting single photon emission computed tomography used in all patients
Calcium channel blocker withheld? ACE inhibitor withheld?
Withheld for ⬎20 h in 3/9 patients
Nitrate withheld?
Withheld for ⬎36 h in 1/9 patients
Withheld for ⬎20 h in 2/32 patients
Public speech At 1 min into speech Withheld for about 24 patients Withheld for about 24 patients Withheld for about 24 patients Withheld for about 24 patients
h in all h in all h in all h in all
ACE, Angiotensin-converting enzyme.
23%, respectively, relative to the resting values. There were no significant differences in hemodynamic responses to mental stress between the patients with reduced versus normal LVEF; the mean SBP, DBP, and HR increased by 44 ⫾ 19 mm Hg, 28 ⫾ 10 mm Hg, and 19 ⫾ 11 beats/min, respectively, from rest to stress in the normal LVEF group and 39 ⫾ 18 mm Hg, 33 ⫾ 13 mm Hg, and 21 ⫾ 13 beats/min, respectively, in the abnormal LVEF group (P ⬎ .05). This information is shown in Table 2. MSIMI Mental stress induced myocardial ischemia in 10 of 32 patients (31%) with reduced LVEF compared with 28 of 150 patients (19%) with normal systolic function, with no statistically significant difference (P ⫽ .11) (Figure 1). By use of logistic regression analysis to control for possible confounding factors, LVEF status did not predict susceptibility to MSIMI (P ⫽ .36). Figure 2 shows an example of a severe perfusion defect during mental stress with partial reversibility on the rest images. DISCUSSION Our study demonstrates that CAD patients with abnormal LVEF (defined as ⬍45% for men and ⬍50% for women) are equally susceptible to MSIMI compared with those with normal LVEF. This finding remained true after controlling for possible confounding factors including measures of CAD severity, other comorbid medical conditions, and antianginal medications used. In
our protocol we took into account the current evidence that a gender difference exists in the normal limits for LVEF, with the cutoff for women being higher than that for men.18-21 Both MSIMI and reduced LVEF are established risk factors for adverse cardiovascular events in patients with CAD.1,5-8 It is important to study any interactions between these two risk factors, as it is possible that their effect is additive, putting patients who have both characteristics at increased risk for adverse cardiac events. Only one published study to date has examined the susceptibility to MSIMI in CAD patients with reduced LVEF.24 In that study patients were classified according to their LVEF into 3 groups: normal LV function (ⱖ50%), mild to moderate LV dysfunction (30%-50%), and severe LV dysfunction (ⱕ30%). The percentage of MSIMI in patients with normal LV function, those with mild to moderate LV dysfunction, and those with severe LV dysfunction was 9%, 31%, and 50%, respectively. No significant difference was found between the group with mild to moderate LV dysfunction and the group with severe LV dysfunction. However, several methodologic differences exist between our study and that study (Table 3), the most obvious of which are the sample size, method of determining LVEF, timing of the isotope injection during mental stress, the mental stress protocol used, and the use of cardiac medication in the studied cohort. These methodologic differences could account for the different findings between the two studies. Our findings are consistent with the previously mentioned data in showing that CAD patients with LV dysfunction are susceptible to MSIMI; however, we found that they
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are not at increased susceptibility when compared with those with normal LVEF. Further research should define whether MSIMI confers increased risk to that of depressed LV function alone in this patient subset. One possible limitation in our protocol should be noted. The timing of the isotope injection during mental stress was chosen to be at 1 minute into the speech in all patients. This is because of the short nature of the mental stress procedure used. Although we documented that all patients had a significant hemodynamic response at 1 minute, we acknowledge that the detection of MSIMI could have been missed in some patients as a result of this approach. Acknowledgment The authors have indicated they have no financial conflicts of interest.
References 1. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Available from: URL: http://content.onlinejacc.org/cgi/reprint/46/ 6/e1. Accessed October 4, 2006. 2. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998;97:282-9. 3. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:1948-55. 4. Carson P, Johnson G, Fletcher R, Cohn J. Mild systolic dysfunction in heart failure (left ventricular ejection fraction ⬎35%): baseline characteristics, prognosis and response to therapy in the Vasodilator in Heart Failure Trials (V-HeFT). J Am Coll Cardiol 1996;27:642-9. 5. Krantz DS, Sheps DS, Carney RM, Natelson BH. Effects of mental stress in patients with coronary artery disease: evidence and clinical implications. JAMA 2000;283:1800-2. 6. Sheps DS, McMahon RP, Becker L, Carney RM, Freedland KE, Cohen JD, et al. Mental stress-induced ischemia and all cause mortality in patients with coronary artery disease: results of the psychological investigations of myocardial ischemia study. Circulation 2002;105:1780-4. 7. Krantz DS, Santiago HT, Kop JW, Bairey Merz CN, Rozanski A, Gottdiener JS. Prognostic value of mental stress testing in coronary artery disease. Am J Cardiol 1999;84:1292-7. 8. Gottdiener JS, Krantz DS, Howell RH, Hecht GM, Klein J, Falconer JJ, et al. Induction of silent myocardial ischemia with mental stress testing: relation to the triggers of ischemia during daily life activities and to ischemic functional severity. J Am Coll Cardiol 1994;24:1645-51. 9. Papademetriou V, Gottdiener JS, Kop WJ, Howell RH, Kranz DS. Transient coronary occlusion with mental stress. Am Heart J 1996;132:1299-301.
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10. Kop WJ, Krantz DS, Howell RH, Ferguson MA, Papademetriou V, Lu D, Popma JJ, et al. Effects of mental stress on coronary epicardial vasomotion and flow velocity in coronary artery disease: relationship with hemodynamic stress responses. J Am Coll Cardiol 2001;37:1359-66. 11. Goldberg AD, Becker LC, Bonsall R, Cohen JD, Ketterer MW, Kaufman PG, et al. Ischemic, hemodynamic and neurohormonal response to mental stress and exercise stress: experience from the Psychophysiological Investigations of Myocardial Ischemia study (PIMI). Circulation 1996;94:2402-9. 12. Becker LC, Pepine CJ, Bonsall R, Cohen JD, Goldberg AD, Coghlan C, et al. Left ventricular, peripheral vascular, and neurohumoral responses to mental stress in normal middle-aged men and women: reference group for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study. Circulation 1996;94:2768-77. 13. Germano G, Kiat H, Kavanagh PB, Moriel M, Mazzanti M, Su HT. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138-47. 14. Iskandrian AE, Germano G, VanDecker W, Ogilby JD, Wolf N, Mintz R. Validation of left ventricular volume measurements by gated SPECT 99mTc-labeled sestamibi imaging. J Nucl Cardiol 1998;5:574-8. 15. Williams KA, Taillon LA. Left ventricular function in patients with coronary artery disease assessed by gated tomographic myocardial perfusion images: comparison with assessment by contrast ventriculography and first-pass radionuclide angiography. J Am Coll Cardiol 1996;27:173-81. 16. He ZX, Cwajg E, Preslar JS, Mahmarian JJ, Verani MS. Accuracy of left ventricular ejection fraction determined by gated myocardial perfusion SPECT with Tl-201 and Tc-99m sestamibi: comparison with first-pass radionuclide angiography. J Nucl Cardiol 1999;6: 412-7. 17. Auto Quant Release 6.0 [instructions for use]. Milpitas (CA): ADAC Laboratories/Philips Medical Systems; 2004. 18. Sharir T, Kang X, Germano G, Bax JJ, Shaw LJ, Gransar H, et al. Prognostic value of post-stress left ventricular volume and ejection fraction by gated myocardial perfusion SPECT in women and men: gender-related differences in normal limits and outcomes. J Nucl Cardiol 2006;13:495-506. 19. Ababneh AA, Sciacca RR, Kim B, Bergmann SR. Normal limits for left ventricular ejection fraction and volumes estimated with gated myocardial perfusion imaging in patients with normal exercise test results influence of tracer, gender, and acquisition camera. J Nucl Cardiol 2000;7:661-8. 20. Rozanski A, Nichols K, Yao SS, Malholtra S, Cohen R, DePuey EG. Development and application of normal limits for left ventricular ejection fraction and volume measurements from 99mTc-sestamibi myocardial perfusion gates SPECT. J Nucl Med 2000;41:1445-50. 21. Bondt PD, Van de Wiele C, De Sutter J, De Winter F, De Backer G, Dierckx RA. Age and gender specific differences in left ventricular cardiac function and volumes determined by gated SPECT. Eur J Nucl Med 2001;28:620-4. 22. Goldberg AD, Becker LC, Bonsall R, et al. Ischemic, hemodynamic, and neurohormonal responses to mental and exercise stress. Experience from the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI). Circulation 1996;94:2402-9. 23. Jain D, Shaker SM, Burg M, et al. Effects of mental stress on left ventricular and peripheral vascular performance in patients with coronary artery disease. J Am Coll Cardiol 1998;31:1314-22. 24. Akinboboye O, Krantz DS, Kop WJ, Schwartz SD, Levine J, Negro AD, et al. Comparison of mental stress-induced myocardial ischemia in coronary artery disease patients with versus without left ventricular dysfunction. Am J Cardiol 2005;95:322-6.
See related article, p. 269 Patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF) have increased rates of mortality and adverse cardiovascular events.1-4 Mental stress–induced myocardial ischemia (MSIMI) also defines a subset of CAD patients at increased risk for poor outcomes.5-8 One of the mechaFrom Cardiovascular Research, Division of Cardiology, Department of Medicine,a and Department of Biostatistics,c University of Florida, and North Florida/South Georgia VA Healthcare System,b Gainesville, Fla. This study was supported by grants HL 070265 and HL 072059 from the National Heart, Lung, and Blood Institute. This material is also the result of work supported by resources and with the use of facilities at the Department of Veterans Affairs Medical Center, Gainesville, Fla. Received for publication Oct 9, 2006; final revision accepted Jan 17, 2007. Reprint requests: Mustafa Hassan, MD, Cardiology Research (151), VAMC, 1601 SW Archer Rd, Gainesville, FL 32608; mustafa. [email protected]fl.edu. 1071-3581/$32.00 Copyright © 2007 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2007.01.040 308
nisms by which mental stress induces myocardial ischemia is by epicardial coronary artery vasoconstriction.9-12 It is plausible that patients with reduced LVEF might have increased susceptibility to MSIMI, given the associated increase in left ventricular (LV) end-diastolic pressure, which consequently could increase the coronary artery resistance and decrease the myocardial perfusion pressure. This mechanism could be further exacerbated by vasoconstriction. The prevalence and significance of MSIMI in patients with reduced ejection fraction are unknown. Most studies evaluating the susceptibility of CAD patients to this phenomenon did not report LVEF. Furthermore, many of these studies included only patients with normal LVEF. In this study we sought to compare the susceptibility to MSIMI in a cohort of CAD patients with normal versus reduced LVEF. METHODS Subjects Participants in this study were recruited from outpatient cardiology clinics affiliated with a regional Veterans Affairs
Journal of Nuclear Cardiology Volume 14, Number 3;308-13
hospital and a university-based medical center. To be included in the study, patients had to be aged at least 18 years with a documented clinical diagnosis of CAD supported by angiographic evidence, previous coronary artery bypass graft (CABG) surgery, previous myocardial infarction (MI) (documented by an elevated troponin level in the range typical of MI, Q-wave abnormalities on an electrocardiogram, or fixed wall motion abnormalities on a nuclear scan), or a positive radionuclide dobutamine or exercise stress test. Patients were excluded if they had unstable angina or acute MI within the 2 months before enrollment, a severe comorbid medical problem restricting life expectancy to less than 5 years, body weight over 400 lb, or if they were pregnant.
Study Design The study protocol was approved by the University of Florida Institutional Review Board (Gainesville, Fla). Informed consent was obtained from all participants. Demographic and psychosocial characteristics were obtained before study procedures. Baseline resting ejection fraction was determined with technetium 99m sestamibi gated single photon emission computed tomography by use of a semiautomated volumetric algorithm (ADAC Laboratories/Philips Medical Systems, Milpitas, Calif).13-17 Abnormal LVEF was defined as less than 45% for men and less than 50% for women (Auto Quant 6.0; ADAC Laboratories/Philips Medical Systems).17-21 Mental stress tests were conducted after an overnight fast. -Blockers, calcium channel blockers, and long-acting nitrates were withheld for 24 hours before testing.
Mental Stress Procedure Patients were initially placed in a cool, dark, and quiet room. They rested in a reclined position for 30 minutes while their heart rate (HR) and blood pressure were obtained every 5 minutes by use of an electrocardiographic monitor and automatic oscillometric device (Dinamap; Critikon Inc, Tampa, Fla), respectively. Mental stress was then induced via a public speaking task. Participants were given a scenario describing a real-life stressful event (such as a family member with a serious illness, an automobile accident, a dog bite, or an inconsiderate houseguest) and asked to make up a realistic story around it. Participants were given 2 minutes to prepare their speech and 3 minutes to speak. They were told that their speech would be videotaped and the laboratory staff would replay the tape to rate it for content, quality, and duration of the speech. Hemodynamic measurements were obtained every minute during the speech and at 1, 3, 5, and 10 minutes into the recovery period. Systolic blood pressure (SBP) and HR were used to calculate the double product (DP) value (DP ⫽ SBP ⫻ HR). Peak stress and rest values were compared.
Myocardial Perfusion Imaging Imaging with Tc-99m sestamibi was used. At 1 minute into the speech, a total dose of 20 to 30 mCi (based on the patient’s body weight) was injected. The time of the injection
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Table 1. Clinical and demographic characteristics for normal versus reduced LVEF group
Variable Mean age (y) Gender (male) Ethnicity White Black Previous MI Mean number of diseased coronary arteries (⬎50% stenosis) Abnormal exercise or pharmacologic stress test Previous CABG Previous PTCA Past or current smoker Hypertension Diabetes Angina symptoms Hyperlipidemia Cerebrovascular disease -Blockers ACE inhibitors Calcium channel blockers Mean LVEF (%) Body mass index (kg/m2)
Normal Reduced LVEF LVEF group group (n ⴝ 150) (n ⴝ 32)
P value
63 ⫾ 9 91 (61%)
64 ⫾ 8 24 (75%)
NS NS
129 (86%) 14 (9%) 27 (18%) 1.9 ⫾ 1
28 (88%) 3 (9%) 13 (41%) 2.1 ⫾ 1
NS NS P ⫽ .005 NS
81 (53%)
13 (41%)
NS
53 (35%) 54 (36%) 99 (66%)
11 (34%) 14 (44%) 23 (72%)
NS NS NS
119 (79%) 47 (31%) 103 (69%)
24 (75%) 14 (44%) 20 (63%)
NS NS NS
133 (89%) 22 (15%)
29 (91%) 5 (16%)
NS NS
117 (78%) 82 (55%) 31 (21%)
26 (81%) 23 (72%) 6 (16%)
NS NS NS
61 ⫾ 9 30 ⫾ 6
32 ⫾ 10 30 ⫾ 5
P ⬍ .05 NS
Values are expressed as mean ⫾ SD or number (%). Statistical significance considered as P ⱕ .05. NS, Not significant; PTCA, percutaneous transluminal coronary angioplasty; ACE, angiotensin-converting enzyme.
was decided based on the published evidence that adrenergic sympathetic nervous system response to mental stress usually occurs very quickly, within the first minute of starting the stressful task.12,22,23 Stress perfusion images were acquired 30 to 60 minutes later by use of conventional single photon emission computed tomography methodology (64 projections over a circular 180° orbit, with the gamma camera set at a 140-keV energy peak with a 20% window).17 A high-resolution collimator and 2-dimensional Butterworth filter were used, and transaxial tomograms were recon-
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Table 2. Hemodynamic variables during rest and stress in patients with normal versus reduced LVEF
Variable Mean SBP (mm Hg) Rest Stress Difference Mean DBP (mm Hg) Rest Stress Difference Mean HR (beats/min) Rest Stress Difference Mean DP Rest Stress Difference
Normal LVEF group (n ⴝ 150)
Reduced LVEF group (n ⴝ 32)
P value
119 ⫾ 18 163 ⫾ 24 44 ⫾ 19
119 ⫾ 22 158 ⫾ 32 39 ⫾ 18
NS NS NS
65 ⫾ 9 93 ⫾ 13 28 ⫾ 10
65 ⫾ 12 98 ⫾ 18 33 ⫾ 13
NS NS NS
60 ⫾ 9 78 ⫾ 15 19 ⫾ 11
62 ⫾ 13 84 ⫾ 18 21 ⫾ 13
NS NS NS
7,092 ⫾ 1,472 12,834 ⫾ 3,560 5,742 ⫾ 2,994
7,486 ⫾ 2,181 13,338 ⫾ 4,357 5,852 ⫾ 3,387
NS NS NS
Values are expressed as mean ⫾ SD. Statistical significance considered as P ⱕ .05. NS, Not significant.
90 80 70 60 %
structed via backprojection with a ramp filter. Resting images were obtained within 1 week of the stress test. The studies were interpreted by experienced nuclear cardiologists blinded to the condition (rest vs stress) and LVEF status. Rest and stress images were visually compared for number and severity of perfusion defects by use of a scoring method from 0 to 4, with 0 indicating normal uptake and 4 indicating no uptake. A summed difference score was calculated as the difference between summed stress and rest scores; a score of greater than 3 was considered abnormal.
50
Negative ischemia
40
Positive ischemia
30 20 10 0 Normal LVEF
Statistical Analysis Results were expressed as means and SDs for continuous variables and frequencies and percentages for categoric variables. Stress hemodynamic response variables were calculated as the difference between stress and rest measurements. Statistical differences between groups were determined by use of the Student t test for continuous variables and 2 analyses for categoric variables. The ␣ value was set at P ⫽ .05. To determine the relationship between LVEF status and the development of MSIMI, we used logistic regression analysis to control for possible confounding factors, including age, gender, severity of CAD by number of diseased vessels on coronary angiogram and results of stress test, history of CABG, history of MI, history of hypertension, diabetes, smoking status, and antianginal medication use (-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors).
Reduced LVEF
Figure 1. MSIMI in patients with normal versus reduced LVEF.
RESULTS Demographic Characteristics There were 182 individuals who participated in this study, 67 (37%) of whom were women. The mean age was 64 years. The majority of participants were white (86%), with black participants comprising 9%. Most participants (82%) had normal LVEF; mean LVEF was 61% ⫾ 9% in the normal LVEF group and 32% ⫾ 10% in the reduced LVEF group. All patients had documented CAD (78% had abnormal coronary angiograms, 22% had a history of MI, 68% had a history of anginal symptoms,
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Figure 2. Short-axis and horizontal long-axis tomograms displaying severe inferior perfusion defect during mental stress with partial reversibility on rest images.
and 33% had previous CABG). Cardiac catheterization data were available for 118 patients (65%) (92 [61%] in the normal LVEF group and 16 (50%) in the reduced LVEF group). The mean number of diseased coronary arteries with greater than 50% stenosis was 1.9 ⫾ 1. The participants also had a number of comorbid conditions: 79% had a history of hypertension, 89% had a history of hyperlipidemia, 34% had diabetes, and 67% were current or past smokers. Patients with reduced LVEF were more likely to have a history of MI (41%) compared with those with normal LVEF (18%) (P ⫽ .005); however, there was no significant difference in the number of diseased coronary arteries between the two groups (mean number of diseased vessels, 2.1 ⫾ 1 and 1.9 ⫾ 1, respectively; P ⫽ .45). There were no other significant differences in other measures of CAD disease severity (by angina
symptoms or exercise and pharmacologic stress test results), frequency of comorbid conditions, or antianginal medication use between the two groups. Demographic and clinical characteristics of the two groups are reported in Table 1. Hemodynamic Variables Mental stress induced a significant increase in SBP, diastolic blood pressure (DBP), HR, and DP measurements from the resting state. The mean increase in SBP, DBP, and HR from rest to stress was 43 ⫾ 19 mm Hg, 29 ⫾ 11 mm Hg, and 19 ⫾ 12 beats/min, respectively. All patients exhibited a significant hemodynamic response at the time of the isotope injection. At 1 minute into the speech, the mean percent increase in SBP, DBP, and HR was 26%, 32%, and
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Table 3. Methodologic differences between previously published study and current study
Methodologic differences No. of patients LVEF determination
Mental stress protocol Isotope injection time -Blocker withheld?
Study of Akinboboye et al24
Current study
58 Past cardiac catheterization data used in 59% of patients (mean time lapse of 32 mo between LVEF estimation and mental stress procedure); single photon emission computed tomography in 41% of patients Combination of anger recall and 4-min math task Only after HR had risen to at least 110% of baseline Withheld for ⬎36 h in 11/42 patients
182 Resting single photon emission computed tomography used in all patients
Calcium channel blocker withheld? ACE inhibitor withheld?
Withheld for ⬎20 h in 3/9 patients
Nitrate withheld?
Withheld for ⬎36 h in 1/9 patients
Withheld for ⬎20 h in 2/32 patients
Public speech At 1 min into speech Withheld for about 24 patients Withheld for about 24 patients Withheld for about 24 patients Withheld for about 24 patients
h in all h in all h in all h in all
ACE, Angiotensin-converting enzyme.
23%, respectively, relative to the resting values. There were no significant differences in hemodynamic responses to mental stress between the patients with reduced versus normal LVEF; the mean SBP, DBP, and HR increased by 44 ⫾ 19 mm Hg, 28 ⫾ 10 mm Hg, and 19 ⫾ 11 beats/min, respectively, from rest to stress in the normal LVEF group and 39 ⫾ 18 mm Hg, 33 ⫾ 13 mm Hg, and 21 ⫾ 13 beats/min, respectively, in the abnormal LVEF group (P ⬎ .05). This information is shown in Table 2. MSIMI Mental stress induced myocardial ischemia in 10 of 32 patients (31%) with reduced LVEF compared with 28 of 150 patients (19%) with normal systolic function, with no statistically significant difference (P ⫽ .11) (Figure 1). By use of logistic regression analysis to control for possible confounding factors, LVEF status did not predict susceptibility to MSIMI (P ⫽ .36). Figure 2 shows an example of a severe perfusion defect during mental stress with partial reversibility on the rest images. DISCUSSION Our study demonstrates that CAD patients with abnormal LVEF (defined as ⬍45% for men and ⬍50% for women) are equally susceptible to MSIMI compared with those with normal LVEF. This finding remained true after controlling for possible confounding factors including measures of CAD severity, other comorbid medical conditions, and antianginal medications used. In
our protocol we took into account the current evidence that a gender difference exists in the normal limits for LVEF, with the cutoff for women being higher than that for men.18-21 Both MSIMI and reduced LVEF are established risk factors for adverse cardiovascular events in patients with CAD.1,5-8 It is important to study any interactions between these two risk factors, as it is possible that their effect is additive, putting patients who have both characteristics at increased risk for adverse cardiac events. Only one published study to date has examined the susceptibility to MSIMI in CAD patients with reduced LVEF.24 In that study patients were classified according to their LVEF into 3 groups: normal LV function (ⱖ50%), mild to moderate LV dysfunction (30%-50%), and severe LV dysfunction (ⱕ30%). The percentage of MSIMI in patients with normal LV function, those with mild to moderate LV dysfunction, and those with severe LV dysfunction was 9%, 31%, and 50%, respectively. No significant difference was found between the group with mild to moderate LV dysfunction and the group with severe LV dysfunction. However, several methodologic differences exist between our study and that study (Table 3), the most obvious of which are the sample size, method of determining LVEF, timing of the isotope injection during mental stress, the mental stress protocol used, and the use of cardiac medication in the studied cohort. These methodologic differences could account for the different findings between the two studies. Our findings are consistent with the previously mentioned data in showing that CAD patients with LV dysfunction are susceptible to MSIMI; however, we found that they
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are not at increased susceptibility when compared with those with normal LVEF. Further research should define whether MSIMI confers increased risk to that of depressed LV function alone in this patient subset. One possible limitation in our protocol should be noted. The timing of the isotope injection during mental stress was chosen to be at 1 minute into the speech in all patients. This is because of the short nature of the mental stress procedure used. Although we documented that all patients had a significant hemodynamic response at 1 minute, we acknowledge that the detection of MSIMI could have been missed in some patients as a result of this approach. Acknowledgment The authors have indicated they have no financial conflicts of interest.
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