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J Am Coll Cardiol, 2001; 37:1359-1366
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY

Effects of mental stress on coronary epicardial vasomotion and flow velocity in coronary artery disease: relationship with hemodynamic stress responses1

Willem J. Kop, PhD* {dagger}, David S. Krantz, PhD* {dagger}, Robert H. Howell, PhD*, Michael A. Ferguson, MD*, Vasilios Papademetriou, MD, FACC{ddagger}, David Lu, MD{ddagger}, Jeffrey J. Popma, MD, FACC§, John F. Quigley, MA*, Marina Vernalis, DO, FACC* and John S. Gottdiener, MD, FACC||

* Department of Medical and Clinical Psychology, Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USA
{dagger} Division of Cardiology, Department of Medicine, Georgetown University Medical Center, Washington, D.C., USA
{ddagger} Department of Cardiology, Veterans Affairs Medical Center, Washington, D.C., USA
§ Department of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
|| Department of Cardiology?1, St. Francis Hospital, Roslyn, New York, USA

Manuscript received April 7, 2000; revised manuscript received October 25, 2000, accepted December 18, 2000.

Reprint requests and correspondence: Dr. Willem J. Kop, Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda Maryland 20814
wjkop{at}mxb.usuhs.mil


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study examines the prevalence and hemodynamic determinants of mental stress-induced coronary vasoconstriction in patients undergoing diagnostic coronary angiography.

BACKGROUND

Decreased myocardial supply is involved in myocardial ischemia triggered by mental stress, but the determinants of stress-induced coronary constriction and flow velocity responses are not well understood.

METHODS

Coronary vasomotion was assessed in 76 patients (average age 59.9 ± 10.4 years; eight women). Coronary flow velocity responses were assessed in 20 of the 76 patients using intracoronary Doppler flow. Repeated angiograms were obtained after a baseline control period, a 3-min mental arithmetic task and administration of 200 µg intracoronary nitroglycerin. Arterial blood pressure (BP) and heart rate assessments were made throughout the procedure.

RESULTS

Mental stress resulted in significant BP and heart rate increases (p < 0.001). Coronary constriction (>0.15 mm) was observed in 11 of 59 patients with coronary artery disease (CAD) (18.6%). Higher mental stress pressor responses were associated with more constriction in diseased segments (r{Delta}SBP = –0.26, r{Delta}DBP = –0.30, r{Delta}MAP = –0.29; p’s < 0.05) but not with responses in nonstenotic segments. The overall constriction of diseased segments was not significant (p > 0.10), whereas a small but significant constriction occurred in nonstenotic segments (p = 0.04). Coronary flow velocity increased in patients without CAD (32.2%; p = 0.008), but not in patients with CAD (6.4%; p = ns). Cardiovascular risk factors were not predictive of stress-induced vasomotion in patients with CAD.

CONCLUSIONS

Coronary vasoconstriction in angiographically diseased arteries varies with hemodynamic responses to mental arousal. Coronary flow responses are attenuated in CAD patients. Thus, combined increases in cardiac demand and concomitant reduced myocardial blood supply may contribute to myocardial ischemia with mental stress.

Abbreviations and Acronyms
  APV = average peak velocity
  CAD = coronary artery disease
  DBP = diastolic blood pressure
  DSVR = diastolic systolic velocity ratio
  HR = heart rate
  LDL = low density lipoprotein
  QCA = quantitative coronary angiography
  SBP = systolic blood pressure

Mental stress can trigger transient myocardial ischemia in 30% to 60% of patients with coronary artery disease (CAD) (1,2). Mental stress-induced ischemia in the laboratory is predictive of ischemia during ambulatory monitoring (3,4) and of future adverse cardiovascular events (5–7). The pathophysiologic mechanisms of mental stress-included ischemia include activation of the sympathetic nervous system, resulting in hemodynamic changes leading to increased cardiac demand (2). However, because the cardiac demand at which mental stress-induced ischemia occurs is substantially lower than with exercise-induced ischemia (4,8), impaired supply due to coronary constriction (9–11) or impaired responses of the myocardial microcirculation (12) may play important roles in myocardial ischemia elicited by emotional distress.

Prior studies indicate that paradoxical coronary constriction to mental stress is correlated with constrictive responses to intracoronary acetylcholine, suggesting endothelial dysfunction as a pathophysiological mechanism (9). Coronary constriction to mental stress can also occur in the absence of clinically significant coronary disease (10), which is consistent with observations that risk factors such as hypercholesterolemia are associated with acetylcholine-induced coronary constriction in patients free of angiographically determined CAD (13,14). There is also an impairment of the normal increase in microcirculatory coronary flow with mental stress in CAD patients compared with controls (12). Although some studies have not found significant vasomotor responses to mental stress (11,15), others have documented mental stress-induced coronary constriction (9,10) and even complete transient coronary occlusion to mental stress (16). Thus, the extent of coronary vasomotion may vary substantially between patients, and the predictors of these variations are not known. This study assesses the magnitude of potential determinants of coronary vasomotor and microcirculatory responses to mental stress during cardiac catheterization. We also assess whether the blood pressure and heart rate responses to mental stress are related to stress-induced changes in coronary diameter and flow velocity (4,17–19).


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   Seventy-six patients referred for diagnostic coronary angiography were enrolled (average age 59.9 ± 10.4 years; eight women; 17 African American, 56 Caucasian, and three other ethnicity). Inclusion criteria were positive exercise test for inducible myocardial ischemia (n = 63; 83%), known history of CAD (n = 7; 9%) or >80% risk of coronary disease based on risk factors (n = 6; 8%) (20). Exclusion criteria were myocardial infarction within the past month, angioplasty within the past six months, severe valvular disease or congestive heart failure, age ≥80 years, critical left main stenosis, severe three-vessel disease, technically inadequate coronary angiogram and ejection fraction <25%. The study was approved by the Institutional Review Boards of the participating study sites and all patients gave informed consent.

Vasoactive medications were discontinued for >5 half-lives before the study, when clinically safe. Beta-blocking agents were withheld for >48 h, calcium antagonists and angiotensin-converting enzyme inhibitors for 24 h, and long-acting nitrates for 6 h as described previously (8,9,21). Before catheterization, all patients received diphenhydramine (25 mg) for antiemetic purposes. Preprocedural diazepam was withheld when possible (n = 51); midazolam was given (0.5 to 1.0 mg) when necessary to reduce anxiety during the diagnostic procedure (n = 4).

Procedure.   Patients were tested in the morning after an overnight fast. The protocol consisted of a control period (3 min rest), mental stress (2.5 to 3 min), and administration of 200 µg intracoronary nitroglycerin. The duration of the stress task was based on research demonstrating that mental stress-induced ischemia occurs within 2 min following task onset (22). Administration of intracoronary nitroglycerin was used to assess preserved smooth muscle cell function.

Coronary angiography.   Diagnostic catheterization was performed following standard procedures by percutaneous Judkins technique. Angiograms were obtained by injection of a single 5 to 7 cc bolus of nonionic contrast (Isovue-370, Squibb Diagnostics, Princeton, New Jersey) using a cineangiographic system (Bicor, Siemens-Elema, California). At diagnostic angiography 59 of 76 patients revealed significant CAD (>50% lesion). Absence of angiographic CAD was more common among women (63%) than men (18%) but was not more prevalent among the six patients without a positive exercise test.

Angiographic assessments were made at the end of the control, mental stress and nitroglycerin study phases. The optimal angiographic view of the study lesion was chosen on the basis of results of the preceding diagnostic angiography, and camera and patient position were kept constant (9,23).

Mental stress testing.   During the resting period, patients were encouraged to relax, with lights lowered and ambient noise reduced. Task instructions were then given using a tape-recorded standard text (9). Patients subtracted serial sevens from a four-digit number as quickly and accurately as possible and were frequently interrupted. A metronome was played loudly as an additional distractor. Patients rated negative emotions on seven-point Likert scales (anger, frustration, irritation and anxiety) and two control items (interest and tiredness) at the end of the control period and immediately following the mental stress angiogram (total negative emotion score range 1 to 28). Continuous electrocardiograms were recorded and aortic blood pressures were obtained from the catheter tip (Midas system 2000, E for M Corporation, Lenexa, Kansas). Average baseline diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) during the last 2 min of the resting period were compared with the average levels during mental stress. Mean arterial pressure (MAP) was calculated as MAP = [(2 x DBP + SBP)/3] and rate pressure product as SBP x HR.

Risk factors and clinical characteristics.   Risk factors included age, gender, body mass index, hypertension, insulin-dependent diabetes mellitus, current smoking status and lipid profile. Lipid levels were assessed from samples obtained at the time of catheterization. Total cholesterol and triglycerides were assessed by an end point method using a commercially available reagent system and analyzer (Boehringer Mannheim Corporation, Indianapolis, Indiana). High density lipoprotein was determined following precipitation and centrifugation of low density lipoprotein (LDL) and very low density lipoprotein. Fractionation was performed with magnesium/phosphotungstate according to a modification of the Burnstein and Samaille method and LDL was calculated using the Friedwald equation.

Quantitative coronary angiographic analyses.   Quantitative coronary angiography (QCA) was performed at the Washington Hospital Center Angiographic Core Laboratory. Technicians and readers were blinded to patient characteristics and study phase. Two coronary segments per patient were analyzed; the most likely culprit lesion and a nonstenotic control segment. Angiographic frames in the single, most severe, sharpest and unforeshortened projection were selected for assessment. Nonstenotic control segments were obtained from a different artery (left anterior descending and circumflex lesions) or the same artery at the most proximal location possible (right coronary artery lesions). Absolute measurements (in mm) of the reference and minimal luminal diameters (MLD), and mean diameter of the entire segment were obtained using a previously validated edge-detection algorithm (CMS, MEDIS, Tilburg, The Netherlands) as described elsewhere (24,25) (calibration factors ranged from 0.08 mm to 0.10 mm per pixel). Percent stenosis was calculated on the basis of the reference diameter, and plaque area was used as a second indicator of lesion severity. Because MLD and mean obstruction measures revealed essentially the same results (r = 0.87, p < 0.001) and the latter measure appeared less vulnerable to artifact, results for mean diameter of obstruction will be presented here.

Target lesions in the 59 CAD patients revealed a >50% stenosis by QCA in 44 patients and a 25% to 50% narrowing in 15 patients. The 15 patients with intermediate target lesions had more severe distal lesions (>50%) in the same artery not suitable for QCA (n = 2), lesions (>50%) in a different coronary artery (n = 8), or discrepancy between visual inspection and offline QCA (n = 5). In total, 71 diseased and 73 nonstenotic control segments were analyzed.

Diameter variability estimates using the CMS system range from 0.09 mm to 0.16 mm (26). To assess reliability of the present data, 60 images (30 diseased and 30 control segments) of 10 study patients were analyzed twice with a blinded procedure and revealed high test-retest correlations of the diseased (r = 0.90) and normal (r = 0.93) segment diameters. The error range was estimated as 0.15 mm (27), and coronary constriction was therefore defined as a diameter reduction of 0.15 mm or more, a nonresponse as a diameter change between –0.15 and +0.15 mm, and dilation as an increase >0.15 mm.

Doppler flow assessment of coronary flow velocity.   A Doppler flow wire (Cardiometrics Inc., Mountain View, California) was placed in 21 patients after an additional dose of 3,000 to 5,000 U of heparin (28). The wire tip was placed 0.5 mm distal to the lesion (n = 14) or, if no disease was present (n = 6), in the proximal left descending coronary artery (loss of signal occurred in one of 21 patients). Before angiograms were obtained, the flow wire was temporarily pulled back to a proximal position in order to allow QCA without the wire across the lesion. Percent change in average peak velocity (APV; cm/s) and diastolic systolic velocity ratio (DSVR) were assessed to measure coronary flow velocity responses to mental stress (12,28).

Statistical analysis.   Angiographic data are presented as mean ± standard error and all other data as mean ± standard deviation or percentages when appropriate. Stress-induced responses were calculated as change scores and percentage change from baseline control values. Analyses for coronary vasomotion were first conducted on a per-segment basis (71 diseased and 73 nonstenotic segments). Because responses within patients are not statistically independent, further analyses were conducted on a per-patient basis, examining: 1) diseased segments of CAD patients (n = 59); 2) nonstenotic control segments of CAD patients (n = 56); and 3) nonstenotic segments of patients without angiographic CAD (n = 17). Differences between CAD patients versus patients without CAD in stress responses were examined using 2 x 2 mixed-model analysis of variance. Associations of mental stress-induced hemodynamic responses with coronary diameter and flow velocity changes were examined using Pearson correlations. Multiple regression analyses were used to investigate whether stress-induced diameter changes were independently predicted by hemodynamic responses, adjusting for baseline diameter and CAD risk factors. Two-tailed probabilities and a p level of <0.05 were used to indicate statistical significance.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Patient characteristics and task responses.   Table 1 shows patient characteristics; hemodynamic responses to mental stress are shown in Table 2 (p’s < 0.001). The mental stress task induced a significant increase in negative emotion (p < 0.001), whereas no increases in the control items occurred (p > 0.10). Patients who received preprocedural sedation (n = 25/76) experienced less negative emotion during the task than patients without sedation (p = 0.01), but hemodynamic and coronary diameter responses did not differ between these two groups. During mental stress, six patients experienced anginal chest pain and two other patients showed >1 mm downsloping ST-segment depression.


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  		Table 1 Patient Characteristics

 

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  		Table 2 Hemodynamic and Emotional Measures at Baseline and During Mental Stress

 
Epicardial coronary vasomotion.   Coronary responses to mental stress ranged from –15% constriction to 27% dilation in diseased segments. Control segments showed a similar response range (–22% to 12%). No overall constriction was noted in the 71 diseased segments in patients with CAD (–0.4% change; from 2.32 ± 0.07 mm to 2.31 ± 0.07 mm; p > 0.10), whereas a small but significant diameter decrease was observed in the 73 nonstenotic segments (–1.4% change; from 2.91 ± 0.08 mm to 2.87 ± 0.08 mm; p = 0.04). Percent stenosis and plaque area were unrelated to coronary vasomotion with mental stress (r = 0.07 and r = –0.03, respectively, p > 0.10).

Coronary vasomotion responses analyzed on a per-patient basis (Table 3) were consistent with results obtained using coronary segments as unit of analysis. A small but statistically significant constriction to stress was observed in CAD patients’ nonstenotic segments from 2.92 ± 0.10 mm to 2.87 ± 0.10 mm; p = 0.04), where 14 patients (25.5%) evidenced constriction (>0.15 mm) and four (7.3%) dilation (>0.15 mm dilation). Diameter responses of diseased segments were not significant (from 2.31 ± 0.08 mm to 2.30 ± 0.08 mm; p > 0.10); 11 patients (18.6%) constricted and 12 (23.5%) dilated. This lack of response was observed in lesions >50% (n = 44) as well as lesions of 25% to 50% (n = 15). No change in diameter occurred in the 17 patients without angiographic CAD. Nitroglycerin-induced diameter increases were larger in segments from patients without CAD ({Delta} = 0.33 ± 0.07 mm) than in nonstenotic segments of patients with CAD ({Delta} = 0.16 ± 0.03 mm; p = 0.04).


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  		Table 3 Coronary Diameter Change During Mental Stress and Intracoronary Nitroglycerin in Patients With and Without Angiographic CAD

 
Mental stress-induced ST-depression (n = 2) or anginal pain (n = 6) were not related to coronary constriction, hemodynamic stress responses, or CAD risk factors (p’s > 0.1).

Patients who were tested on antianginal medication (n = 21) were not different in measures of coronary diameter or CAD severity from patients titrated off medications (n = 33) or not taking such agents (n = 5). Mean arterial pressure increases were similar in patients in whom medications were withheld versus patients tested on medications (from 123.0 ± 15.4 to 138.1 ± 17.0 mm Hg and from 118.3 ± 19.9 to 130.4 ± 20.1 mm Hg, respectively; pinteraction = 0.31). Similarly, medication withdrawal did not alter coronary responses to mental stress (lesions p = 0.95, control segments p = 0.71).

Coronary flow velocity response to mental stress.   As shown in Figure 1, the average peak velocity increased significantly in patients without CAD during mental stress (32.8%, p = 0.008) but not in patients with angiographic CAD (6.4%; p = >0.10; pinteraction = 0.006). Baseline APV did not differ between patients with CAD (29.7 ± 17.9 cm/s) and without CAD (30.4 ± 17.5 cm/s; p = >0.10). Similar trends were found for the DSVR (baseline CAD 1.6 ± 0.5, non-CAD 2.0 ± 1.3; mental stress CAD 1.5 ± 0.5, non-CAD 2.3 ± 1.5; pinteraction = 0.06).



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  		Figure 1 Coronary flow velocity response to mental stress in patients with coronary artery disease (CAD) compared with patients free of angiographic CAD. Average peak velocity (vertical axis) increased significantly during mental stress in patients without CAD (32.8%, p = 0.008), whereas no such increase occurred in patients with CAD (6.4%; p = >0.10; pgroup x response interaction = 0.006). No group differences (CAD vs. non-CAD) were found in pretask resting velocity measures (29.7 ± 17.9 cm/s vs. 30.4 ± 17.5 cm/s, respectively, p > 0.10).

 
Coronary flow velocity changes during mental stress were significantly related to diameter responses in nonstenotic segments (n = 20, rAPV = 0.51, p = 0.03; rDSVR = 0.46, p = 0.05). Associations between APV change and diameter increase in control segments of patients with CAD (rAPV = 0.52) were comparable to non-CAD (rAPV = 0.49) patients. In contrast, flow velocity measures were not correlated with the percent diameter change of diseased segments.

Hemodynamic responses and coronary vasoconstriction.   Diameter changes in diseased arteries were inversely associated with mental stress-induced changes in SBP (r = –0.26; p = 0.05), DBP (r = –0.30; p = 0.02), MAP (r = –0.29; p = 0.03), and rate pressure product (r = –0.27; p = 0.04). Heart rate responses were not significantly related to vasomotion (r = –0.14; p = >0.10). Diastolic reactivity and coronary vasomotion were correlated in diseased segments, but not in nonstenotic segments of CAD patients (Fig. 2). Similar results were found for severe (>50%) versus moderate (25% to 50%) lesions. Comparing high blood pressure responders with low responders, significantly more constriction (analysis of variance p = 0.024) occurred in the high-DBP responders (Fig. 3).



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  		Figure 2 Associations between diastolic blood pressure reactivity to mental stress and coronary vasomotion in diseased and nonstenotic segments of patients with coronary artery disease. An inverse relationship was found between diastolic blood pressure responses and coronary diameter changes in diseased segments (r{Delta}DBP = –0.30, p = 0.02), whereas no relationship was found between blood pressure responses and coronary constriction in nonstenotic arteries (r{Delta}DBP = –0.02, p > 0.10). This finding was confirmed by multivariate regression analysis.

 


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  		Figure 3 Differential coronary vasomotor response in patients with low, moderate and high diastolic blood pressure (DBP) responses to mental stress. High diastolic blood pressure responders (upper tertile) displayed significantly more coronary constriction compared to low responders (analysis of variance p = 0.02).

 
Cardiovascular risk factors and clinical status.   No associations were observed between coronary diameter changes and risk factors. In patients free of angiographic CAD, triglyceride levels were associated with constriction; r = –0.64; p = 0.02. Indicators of clinical status (number of diseased vessels, ejection fraction, anginal class, peripheral vascular disease, exercise tolerance and maximum heart rate during exercise) were not related to coronary vasomotion.

Multivariate analyses showed that stress-induced DBP responses were significantly associated with coronary vasomotion (ß = –0.28; p = 0.05), after statistically correcting for risk factors and the lesion severity (Table 4). Systolic blood pressure and MAP responses showed similar trends (ß = –0.22, p = 0.11; ß = –0.25, p = 0.076, respectively).


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  		Table 4 Multivariate Analyses Predicting Mental Stress-Induced Coronary Diameter Response From Diastolic Blood Pressure Increases and Control Variables

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study demonstrates that epicardial coronary vasoconstriction in response to mental stress is related to stress-induced blood pressure increases. Coronary flow velocity responses during mental stress were impaired in patients with angiographic CAD. These findings suggest that mental stress-induced myocardial ischemia is produced by both increased cardiac demand and a concomitant decrease in coronary supply.

Stress-induced paradoxical vasoconstriction in coronary artery disease.   Prior research on mental stress-induced coronary vasomotion has revealed mixed results. Yeung et al. (9) documented that mental stress resulted in a 24% diameter constriction in diseased arteries, 9% constriction in irregular segments, and +3% dilation of normal segments. One other small study also reported significant mental stress-induced coronary constriction (10), and we have reported one case of complete coronary occlusion with mental stress (16). However, in the present study, only 18.6% of CAD patients displayed mental stress-induced coronary constriction, and two other studies did not find significant vasomotor responses to mental stress (11,15). The discrepancy between our observations and those of Yeung et al. (9) cannot be explained by differences in duration of the mental challenge task, statistical power, lesion severity or the extent of hemodynamic responses. Potential factors accounting for differences between these mental challenge studies include the QCA techniques, adequacy of blinding and patient characteristics. It is also possible that coronary calcification accounts for the absence of a vasoconstrictive response in the diseased segments in our study.

The observed association of hemodynamic responses to mental stress with constriction in diseased, but not nonstenotic, epicardial arteries is consistent with studies of coronary responses to increased cardiac demand by exercise (29), cold pressor (30,31) and pacing (32). The present study extends these findings in quantifying changes in vasomotion and flow velocity to mental stress.

Mechanisms of coronary vasomotion.   Attenuation of flow-mediated vasodilation via release of endothelial nitric oxide in the presence of endothelial damage (31,33) may be one mechanism explaining the relationship between pressor responses and decreases in coronary diameter with mental stress. Furthermore, the small but statistically significant constriction in nonstenotic segments is consistent with reports of acetylcholine-induced constriction and endothelial dysfunction in angiographically normal segments (34). Other evidence suggests that acetylcholine induces epicardial constriction only in segments with very minor atherosclerosis (35).

Coronary flow velocity increased in patients without CAD, whereas no flow velocity response was observed in CAD patients. These findings support the suggestion (12) that vasomotion of diseased epicardial segments may not play a large role in impaired coronary flow response to mental stress.

Study limitations.   This study assessed a larger sample of patients with mental stress testing than any of the existing studies, but many of the coronary diameter responses were in the error range (±0.15 mm) of QCA analyses. Subtle changes in epicardial diameter may have remained undetected by the angiographic assessment techniques used in this study. However, minimal diameter changes are not likely to result in physiologically important decreases in coronary flow (15). Another limitation concerns the short duration of the pretask rest and the mental challenge task. However, significant hemodynamic and emotional responses were elicited, comparable to other studies in this area. Finally, as a result of assessing catheterization patients, stress-induced ischemia was assessed using ST segment analysis only. ST segment depression and angina are insensitive indicators of mental stress-induced ischemia (4,3,8,17–19). Further studies are needed to validate whether mental stress-induced coronary vasomotion is related to more sensitive measures of ischemia such as ventriculography and perfusion studies.

Clinical implications.   Mental stress-induced myocardial ischemia occurs in a substantial number (30% to 60%) of patients with stable coronary artery disease (2–4,8,22,36–38) and is predictive of future cardiac events (5–7). Research also shows that the magnitude of stress-induced hemodynamic responses is related to the occurrence of ischemia during laboratory mental stress testing (4,17,18). The present study shows that hemodynamic responses to mental arousal are associated with coronary constriction, and that this association is not related to risk factors such as hyperlipidemia and hypertension. Thus, a combined increase in cardiac demand and a parallel impaired increase in myocardial supply may summate in mental stress-induced ischemia.


   Footnotes
 
Preparation of this manuscript was supported by grants from the NIH (HL47337, HL58638), the Dutch Heart Foundation (94-098) and USUHS (RO7233).

1 The opinions and assertions expressed herein are those of the authors and should not be construed as reflecting those of the USUHS or the US Department of Defense. Back


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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