Effect of Mental Stress on Myocardial Blood Flow and Vasomotion in Patients with Coronary Artery Disease

Heiko Schoder, Daniel H. Silverman, Roxana Campisi, Harold Karpman, Michael E. Phelps, Heinrich R. Schelbert, and Johannes Czernin

Department ofMolecular and Medical Pharmacology, Division ofNuclear Medicine, School ofMedicine, University of California, Los Angeles; and Laboratory ofStructural Biology and Molecular Medicine, University ofCalifornia, Los Angeles, California

dial oxygen demand is physiologically accommodated by an In patients with coronary artery disease (CAD), mental stress increase in myocardial blood flow (MBF). Therefore, in may provoke ischemic electrocardiographchanges and abnor healthy individuals mental stress induces coronary artery malities in regionaland global left ventricularfunction. However, vasodilatation (3,4). In patients with coronary artery disease little is known about the underlyingmyocardialblood flow (CAD), however, mental stress modeled in a laboratory or response(MBF)inthesepatients.Methods: We investigatedthe experienced in daily life can induce myocardial ischemia as hemodynamic, neurohumoral, and myocardial blood flow re sponses to mental stress in 17 patients with CAD and 17 healthy evidenced by ischemic changes on electrocardiography volunteers of similar age. Mental stress was induced by asking (ECG) (5), left ventricular wall motion abnormalities, and a individualsto solve mathematicsubtractionsin a progressively decline in left ventricular ejection fraction (6, 7). Such challenging sequence; MBF was quantified at rest and during abnormal responses to mental stress may also predict mentalstressusing13NammoniaPET.Results:Mentalstress ischemic events, such as unstable angina pectoris or myocar induced significant (P < 0.01) and comparable increases in dial infarction, in daily life (8,9). rate—pressureproduct, measured in beats per minute x mm Hg, The mechanisms underlying these mental stress—induced in bothpatients(from7826 ±2006to 10586±2800)and healthy volunteers (from 8227 ±1272 to 10618 ±2468). Comparable alterations in cardiac function are poorly understood. Yeung increases also occurred in serum epinephrine(58% in patients et al. (4) observed a significant association between the versus 52% in healthy volunteers) and norepinephrine (22% in endothelium-dependent coronary vasomotor response to patients versus 27% in healthy volunteers). Although MBF intracoronary acetylcholine and that to mental stress in increasedin patients(from0.67 ±0.15to 0.77 ±0.18 mL/min/g, patients with CAD. This association suggested that endothe P < 0.05) and healthy volunteers (from 0.73 ±0.13 to 0.95 ± hal dysfunction may account for the inadequate MBF 0.22 mL/min/g,P < 0.001),the magnitudeof flow increasewas response to mental stress. However, the MBF response to smaller in patients (14% ± 17%) than in healthy volunteers (29% ±14%) (P = 0.01). The increase in MBF during mental mental stress has not, to our knowledge, been studied stress correlated significantly with changes in cardiac work in systematically. Therefore, our aim was to quantify noninva healthy volunteers (r = 0.77; P < 0.001) but not in patients. sively, with dynamic PET, the MBF response to mental Conclusion:Despitesimilarincreasesin cardiacworkand stress in patients with CAD. comparablesympatheticstimulationin CADpatientsand healthy volunteers, CAD patients exhibit an attenuated blood flow re sponse to mental stress that may contribute to mental stress MATERIALS AND METHODS inducedischemicepisodesindailylife. StudyPopulation KeyWords:mentalstress;myocardialbloodflow;PET The study population comprised 17 patients with documented J NucIMed2000;41:11—16 CAD (11 men, 6 women; age range, 45—76y; mean age [±SD], 63 ±11y) and17healthyvolunteerswith a low probabilityfor CAD (8 men, 9 women; age range, 40—74y; mean age, 57 ±11y). The age difference between the two groups was not statistically he normal cardiovascular response to mental stress significant (NS). All patients had stable CAD, and none had involves increases in heart rate, blood pressure and cardiac undergone coronary artery bypass surgery. CAD was documented contractility (1,2). The corresponding increase in myocar by coronary angiography in 14 patients, a myocardial stress or rest perfusion test in 5, and a history of a previous myocardial infarction in 6. Nine patients had a history of hypercholesterolemia (but ReceivedJan. 4, 1999; revision accepted May 4, 1999. cholesterol levels were normal on the day of the test), 6 had For correspondenceor reprintscontact:JohannesCzemin,MD, UCLA hypertension, 2 had a remote history of cigarette smoking, and 1 School of MedicineICHS, DepartmentofMolecularand Medical Pharmacology, Ahmanson Biological Imaging Clinic, 10833 Le Conte Ave., Los Angeles, CA had type II diabetes mellitus. Three patients were treated with 90095-6942. angiotensin-converting enzyme (ACE) inhibitors; 9, with f3-block

Ewr@cr OF [email protected]@ss ON MBF IN CAD PATIENTS •SchOder et al. 11 ers; 2, with calcium antagonists; 6, with @3-3-hydroxy-3-methylglu distribution. Normal resting perfusion was defined as a ‘3N taryl coenzyme A reductase inhibitors; 1, with oral antidiabetic ammonia uptake within 2 SDs of the mean of a normal database agents; and I, with diuretics. All @3-blockersand calcium channel previously established at our institution (13). Polar maps of the blockers were discontinued 24 h before PET was performed. mental stress findings were normalized to the peak 5% of activity A low probability for CAD in the healthy volunteers was based within each map because a normal database for the MBF response on absence of anginal symptoms, normal findings on resting ECG, to mental stress had not been established. and absence of cardiovascular risk factors (10); all healthy Quantificationof MBF volunteers were nonsmokers, and none had a history of hyperten Regional MBF at rest and during mental stress was quantified in sion, diabetes mellitus, or familial hyperlipidemia. In addition, all the vascular territories of the left anterior descending, left circum participants more than 50 y old underwent a treadmill test that flex, and right coronary arteries. Sectors of interest ranging from revealed no evidence of CAD. 700 to 900 were placed in one basal, one midventricular, and one Each participant signed an informed consent form approved by apical short-axis slice of the left ventricle. A small region of interest the Human Subject Protection Committee. (25 mm2) was centered in the left ventricular blood pool to derive Study Protocol the arterial input function (14). These regions were then copied to MBF was quantified at baseline and during mental stress with the serially acquired images, and regional myocardial time—activity ‘3Nammonia and PET. For baseline measurements, 555—740MBq curves were obtained. For each vascular territory, a single time (15—20mCi)13Nammoniawereinjectedintravenouslyandtrans activity curve was derived by averaging the time activity data from axial images were acquired in a sequence consisting of 12 image three short-axis images. frames of 10 5 each, 2 frames of 30 s each, and 1 frame of 900 s. Partial-volume effects were corrected for using a recovery During and after this baseline study, the room lights were dimmed, coefficient of 0.73 that assumes a uniform left ventricular wall background noise was minimized, and participants were encour thickness of 1 cm. Both the blood pool and the myocardial aged to relax. Forty-five minutes afterward (to allow for radioactive time—activitycurves were corrected for physical decay of ‘3N decay of ‘3Nammonia), mental stress was induced for 7 mm using ammonia and were fitted with a previously validated two a standardized mental stress protocol (2). In brief, each participant compartment tracer kinetic model that corrects for activity spill was asked to serially subtract a 1- or 2-digit number from a 4-digit over from the blood pool into the left ventricular myocardium number. Every 2 mm, the problem was made more difficult and the (15,16). time to solve it was shortened. After an initial increase in heart rate Serum Lipid and CatecholamineMeasurements and blood pressure, a stable plateau in hemodynamic response was Total serum cholesterol and high-density lipoprotein cholesterol consistently observed at minute 2 or 3 of the mental stress protocol. were measured using standard enzymatic methods. Low-density At that time, a second dose of ‘3Nammonia (555—740MBq) was lipoprotein cholesterol was calculated using the formula of Friede injected and the mental stress protocol was continued for another wald et al. (17). Serum epinephrine and norepinephrine were 4—5mm, i.e., 7 mm total. Heart rate, arterial blood pressure measured using high-performance liquid chromatography (18). (measured by an automated blood pressure cuff), and I2-lead ECG findings were recorded at 1-mm intervals throughout the test; Statistical Analysis during application of mental stress the ECG findings were recorded Data are presented as mean values with SD. Comparisons within continuously. The rate—pressureproduct was calculated to obtain groups were performed using a Student t test for paired data; an index ofcardiac work (11). comparisons between groups used t testing for unpaired data. Venous blood samples for determination of plasma glucose, Correlations were sought using the least squares method. Possible serum cholesterol, and triglyceride levels were taken before the differences in the magnitude of blood flow and hemodynamic study. In addition, venous blood samples for serum epinephrine and response to mental stress between groups were evaluated using a norepinephrine were drawn at rest (10 mm before stress) and two-sample Mann-Whitney test. P < 0.05 was considered statisti during mental stress to evaluate the neurohumoral response. cally significant.

PET RESULTS A whole-body ECAT/EXACT positron emission tomograph Hemodynamic and Clinical Findings (CTI/Siemens, Knoxville, TN), which acquires 63 image planes Table 1 summarizes hemodynamic findings. The resting simultaneously, was used. The tomograph has a 15-cmaxial field of rate—pressureproduct, measured in beats per minute X mm view and an intrinsic in-plane resolution of 3.6 mm full width at Hg, was similar (P = NS) in healthy volunteers (8227 ± half maximum (12). The images were reconstructed using a 1272) and patients (7826 ±2006). During mental stress, the Hanning filter with a cutoff frequency of 0.4 cycles per pixel, product increased by 27% ±11% in healthy volunteers and resulting in an effective in-plane resolution of 10 mm. A 20-mm transmission scan was obtained first for correction of photon 33% ± 16% in patients (P = NS between groups and P < attenuation, followed by measurement of MBF as described above. 0.01 versus baseline in each group). In 1 patient, slight chest pain and horizontal 0.10-mV ST segment depression devel VisualandSemiquantitativePETImageAnalysis oped immediately after stress testing. The remaining pa The transaxially acquired image sets were reoriented into tients did not exhibit ECG changes or clinical signs sugges horizontal and vertical long-axis and short-axis views of the left tive of myocardial ischemia. ventricle. Images were analyzed visually for presence (reversible or fixed) or absence of perfusion defects by 2 physicians unaware of SemiquantitativeAnalysis clinical and PET data. The short-axis images were composed and The vascular territories numbered 102—51 each (17 X 3) displayed as polar maps of the relative myocardial ‘3Nammonia in healthy volunteers and patients. In healthy volunteers,

12 THE JOURNALOF NUCLEARMEDICINE •Vol. 41 •No. 1 •January 2000 TABLE1 Hemodynamic Parameters at Rest and During Mental Stress volunteersParameter PatientsHealthy stressHeart RestMental stressRestMental 10*Systolicrate(beats/mm) 61±1168 ±13*69 ±977 ± 25*Diastolicbloodpressure(mmHg) 127±18155 ±23*123 ±20138 ± 9*Mean blood pressure (mm Hg) 70 ±782 ±8*74 ±781 ± 14*Ratearterialbloodpressure(mmHg) 89±10106 ±11@90 ±10100 ± 2468**Ppressureproduct 7826±20061 0586 ±2800*8227 ±12721 0618 ±

rest.Data< 0.001 for measurements dunng mental stress versus during mental stress and rest are not different between patients and healthyvolunteers.

visual and polar map analysis showed that tracer uptake in mL'min/g before stress versus 0.61 ±0.15 mL/min/g after all 5 1 vascular territories was normal and homogeneous. In stress). patients, 43 vascular territories showed normal tracer up Changes in MBF from baseline with mental stress corre take, 2 showed stress-induced perfusion defects, and 6 lated significantly with changes in the rate—pressureproduct showed fixed (rest and stress) perfusion defects. Fixed in healthy volunteers (r = 0.77; P = 0.0003) but not in defects corresponded to areas of clinically documented patients (r = 0.40; P 0.10). myocardial infarction, and blood flow in these areas was Coronary Vascular Resistance analyzed separately. Coronary vascular resistance was calculated as the ratio of MBF at Rest and During Mental Stress mean arterial blood pressure to mean MBF (19). At baseline, The following data pertain to 51 vascular territories in coronary vascular resistance was similar in patients (territo healthy volunteers and 45 territories in patients (i.e., 43 ries with normal polar map and reversible perfusion defects: territories with a normal polar map and two with reversible 138 ±28 mm Hg/mLlmin/g) and healthy volunteers (127 ± perfusion defects). At baseline, MBF was similar (P = NS) 21 mm Hg/mLlmin/g). During mental stress the resistance in patients (0.67 ±0.15 mL/min/g) and healthy volunteers declined significantly in healthy volunteers (to 109 ± 18 (0.73 ±0.13mL/min/g). In bothgroups,MBF did not differ mm Hg/mL/min/g, P < 0.001) but remained unchanged in (P = NS) between vascular territories of the left anterior patients (145 ± 35 mm Hg/mL/min/g, P = NS versus descending artery, left circumflex artery, and right coronary baseline and P = 0.002 versus healthy volunteers during artery (in patients, 0.67 ±0.21, 0.78 ±0.19, and 0.60 ± stress). In the 6 territories with a fixed perfusion defect, 0.16 mL/min/g, respectively; in healthy volunteers, 0.70 ± 0.13, 0.80 ±0.15, and 0.68 ±0.13 mL'minlg, respectively). Mental stress induced an increase in MBF in both patients (from 0.67 ±0.15 to 0.77 ±0.18 mL/min/g, P < 0.05) and healthy volunteers (from 0.73 ± 0.13 to 0.95 ± 0.22 mL/min/g, P < 0.001). However, the magnitude of flow increase was significantly greater (P = 0.01) in healthy volunteers (29% ±14%) than in patients (14% ± 17%) despite similar increases in the rate—pressureproduct (29% ± 11% in healthy volunteers and 33% ±16% in patients, P = NS; Fig. 1). In patients the blood flow increase during mental stress was similarly attenuated in the territories of the left anterior descending, left circumflex, and right coronary arteries. To correct for individual differences in the hemody namic response to mental stress, MBF was normalized to the rate—pressure product. At baseline, the normalized blood flow was similar in patients and healthy volunteers. With Patients Controls mental stress it declined from 0.86 ±0.17 to 0.73 ±0.18 in patients (P < 0.001) but remained unchanged in healthy FIGURE1. Magnitudeof increasein cardiacwork(rate volunteers (0.87 ±0.13 before stress versus 0.90 ±0.14 pressure product, white bars) and MBF (shaded bars) during mentalstressinpatientsandhealthyvolunteers.Despitesimilar after stress; Fig. 2). mentalstress—inducedincreasesincardiacwork,MBFincreased @ In the six vascular territories with fixed perfusion defects, significantly less in patients than in healthy volunteers. MBF did not increase during mental stress (0.59 ±0.18 probabilityvalueof 0.01versuscontrols.

EFFECT OF MErsrru. Si'iu@ss ON MBF IN CAD PATIENTS •Schoder et al. 13 1.5 , p = NS

1.25 0.86 0.87 0.90 ±0.17 073 ±0.13 ±0.14 @ ±0.18 0.75 -@ u.a. @cr0.5 FIGURE 2. Mental stress—induced changes in myocardial blood flow (MBF) 0.25 normalized to cardiac work. During mental stress (MS) normalizedblood flow declined 1@ in patients but remainedunchangedin Rest MS Rest MS healthy volunteers. NS = not statistically Patients Controls significant; APP = rate pressure product.

which were again analyzed separately, coronary resistance stress-induced wall motion abnormalities and a decline in remained unchanged (154 ±41 versus 170 ±41 mL/min/ the left ventricular ejection fraction (6, 7). However, changes g/mmHg;P= NS). in left ventricular function are influenced by several factors, including catecholamine stimulation, MBF, and loading Serum Measurements conditions. Some studies reported mental stress—induced Table 2 lists serum concentrations for epinephrine and perfusion defects (20,22), but the blood flow response to norepinephrine. Patients and healthy volunteers showed a mental stress has never, to our knowledge, been quantified. similar increase (P = NS) in epinephrine and norepineph In this study, mental stress induced a comparable neurohu tine in response to mental stress. Serum lipid levels did not moral and hemodynamic response in CAD patients and differ (P = NS) between patients and healthy volunteers healthy volunteers. However, the mental stress—induced (180 ±33 versus 192 ±26 mg/dL for total cholesterol, increase in cardiac work was accommodated by a propor 107 ±31 versus 125 ±36 mg/dL for low-density lipopro tional increase in MBF only in healthy volunteers; patients tein cholesterol, and 37 ±10 versus 44 ±10 mg/dL for exhibited an attenuated flow response. These findings might high-density lipoprotein cholesterol for patients and healthy contribute to the understanding of pathophysiologic mecha volunteers, respectively) and were unrelated to the MBF nisms involved in the development of mental stress—induced response to mental stress. ischemia, because they indicate an uncoupling between stress-induced increases in cardiac work (and, therefore, DISCUSSION oxygen demand) and changes in MBF. Mental stress, although producing smaller increases in heart rate and blood pressure than does physical exercise, PathophysiologicMechanisms can induce myocardial ischemia in susceptible patients with Mental stress, like other sympathetic stimuli or physical CAD (9,20,21). The pathophysiologic mechanisms underly exercise, induces a release of catecholamines from terminal ing this abnormal response to mental stress are still being cardiac nerve endings and from the adrenal medulla (23). In investigated. Previous studies using mental stress testing in the coronary as well as the peripheral circulation, the CAD patients have mainly focused on the left ventricular vasomotor response to mental stress and to acetyicholine functional response to mental stress and have reported correlate closely, suggesting that the abnormal vasomotor response to mental stress is related to endothelial dysfunc TABLE 2 tion and a reduced availability of endothelium-derived Serum Epinephrine and Norepinephrine at Rest relaxing factor (nitric oxide) (4,24,25). For instance, in and During Mental Stress angiographically smooth coronary segments, mental stress HealthySerum was associated with vasodilatation or no change in the epicardial artery diameter, whereas any degree of angio componentPatientsvolunteersMentalMental(pg/mL)Rest graphically detectable atherosclerosis was associated with stressReststress coronary vasoconstriction (4). In addition, administration of the nitric oxide synthetase inhibitor N-monomethyl-L Epinephrine 36±12 57±21* 29±17 44±16 Norepinephnne289±111352±140k258±124 327±167* arginine significantly blunted the normal blood flow increase in response to mental stress (24,25). Thus, nitric oxide release from intact endothelium contributes to the physi *P < 0.01 for measurements during mental stress versus rest. ologic rise in blood flow during mental stress. In contrast,

14 Ti@mJOURNALOFNUCLEARMEDICINE•Vol. 41 •No. 1 •January 2000 damaged endothelium responds to stress-induced increases changes in MBF were modest, but differences were signifi in circulating catecholamines with an increase in coronary cant between patients and healthy volunteers despite similar vasomotor tone (3,26). increases in the rate—pressureproduct. Chest pain developed The attenuated blood flow response to mental stress in only 1 patient, and 2 patients exhibited reversible observed in this study might therefore be related to an perfusion defects. These findings are not surprising: Blunted unopposed, and thus relatively enhanced, vasoconstrictor blood flow increase during mental stress occurred in all three response to circulating catecholamines (26). Accordingly, vascular territories, and the resulting balanced reductions despite comparable increases in cardiac work, only healthy could not be detected by relative perfusion imaging. The volunteers showed proportional increases in cardiac work lack of clinical evidence for myocardial ischemia, in turn, and MBF during mental stress, whereas in patients the might be accounted for by two factors. First, previous stress-induced increase in blood flow was significantly studies observed an average oxygen extraction of only 66% blunted. However, although the MBF response to mental at rest in normal myocardium of patients with cardiac stress was blunted, it was not completely abolished. This disease (35). Thus, an increase in oxygen extraction might finding suggests that other, endothelium-independent vasodi suffice to compensate for the attenuated flow increase during lators, such as adenosine, may contribute to the regulation of mental stress. Second, mental stress induces only a moderate coronary flow during mental stress (27). increase in cardiac work. The increase is smaller than that The attenuated blood flow response to sympathetic stimu caused by, for instance, treadmill testing (23,36). However, lation (mental stress or cold pressor test) or intracoronary mental stress or other sympathetic stimuli are not designed administration of acetylcholine can be attributed largely to or used for the detection of CAD. Rather, these tests provide abnormal vasomotion at the level of the coronary resistance an alternative, noninvasive means to probe coronary vasomo vessels (4,28,29). In this study, coronary vascular resistance tion (4,30). Finally, the observation that clinical or ECG decreased during mental stress in healthy volunteers but not signs of myocardial ischemia during mental stress develop in patients, despite similar increases in cardiac work, in only a subset of patients also agrees with findings from a indicating increased coronary vasomotor tone in patients. recent multicenter study (36). Similar findings were reported by Dakak et al. (3), who assessed coronary blood flow velocity during mental stress Study Limitations in patients with mild CAD. In their study, as in this study, This study has some limitations. First, 3 patients were coronary resistance declined in healthy volunteers but not in treated with ACE inhibitors, which have been shown to patients. However, resistance did decrease in patients when improve coronary endothelial dysfunction (37). Therefore, mental stress testing was repeated after intracoronary admin the true degree of coronary endotheial dysfunction in these istration ofphentolamine, indicating an unopposed a-adreno patients may have been underestimated. However, no differ receptor activation in microvascular smooth muscle cells ences were observed in the blood flow response to mental (3). Other sympathetic stimuli, such as the cold pressor test, stress between patients receiving and not receiving medica also induce coronary vasoconstriction in patients with risk tion. Thus, a significant effect ofACE inhibition on coronary factors for or clinically manifest CAD (30), and this vasomotion was not apparent. paradoxic vasoconstriction can be attenuated by a1-receptor Although all 17 patients had documented CAD, the blockade (31). angiographic extent of the disease was assessed in only 14 Alternatively, the abnormal MBF response to mental patients (3—24mo before PET). The actual extent and degree stress may be related to alterations in the sympathetic of atherosclerosis in most patients at the time of PET were innervation of the coronary vasculature. Abnormal coronary therefore unknown, and the effects of stenosis severity on sympathetic innervation has been shown after cardiac trans the MBF response to mental stress could not be addressed. plantation, after myocardial infarction, and in patients with Finally, CAD could have been ruled out with certainty in cardiomyopathy (32,33). However, in this study all patients the healthy volunteers only by coronary angiography. Per had stable CAD and normal left ventricular function. In forming such an invasive study was considered ethically addition, territories with previous myocardial infarction unacceptable. However, all healthy volunteers had a pretest were analyzed separately. Thus, inhomogeneities in cardiac probability for CAD ofless than 5% based on the established innervation are unlikely to explain the abnormal MBF criteria of Diamond and Forrester (10). In addition, normal response to mental stress in CAD patients. findings from treadmill ECG were required in all healthy volunteers more than 50 y old. MethodologicConsiderations Mental stress may induce coronary vasoconstriction in patients with CAD (4,34). Thus, ischemic episodes during CONCLUSION mental stress could be accounted for by both moderate Patients with CAD show an attenuated MBF increase increases in myocardial oxygen demand (increased cardiac during mental stress. Their abnormal vasomotor response work) and reductions in myocardial oxygen supply (vasocon may contribute to the previously reported induction of striction or lack of vasodilatation). In this study, the absolute ischemic events from mental stress in daily life.

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