Myocardial Ischemia and Angiotensin-Converting Enzyme Inhibition: Comparison of Ischemia During Mental and Physical Stress RONNIE RAMADAN, MD, ARSHED A. QUYYUMI, MD, A. MAZIAR ZAFARI, MD, PHD, JOSE N. BINONGO, PHD, AND DAVID S. SHEPS, MD, MSPH Objective: Mental stress provokes myocardial ischemia in many patients with stable coronary artery disease (CAD). Mental stressY induced myocardial ischemia (MSIMI) portends a worse prognosis, independent of standard cardiac risk factors or outcome of traditional physical stress testing. Angiotensin II plays a significant role in the physiological response to stress, but its role in MSIMI remains unknown. Our aim was to evaluate whether the use of angiotensin-converting enzyme inhibitors (ACEIs) is associated with a differential effect on the incidence of MSIMI compared with ischemia during physical stress. Methods: Retrospective analysis of 218 patients with stable CAD, including 110 on ACEI, was performed. 99m-Tc-sestamibi myocardial perfusion imaging was used to define ischemia during mental stress, induced by a standardized public speaking task, and during physical stress, induced by either exercise or adenosine. Results: Overall, 40 patients (18%) developed MSIMI and 80 patients (37%) developed ischemia during physical stress. MSIMI occurred less frequently in patients receiving ACEIs (13%) compared with those not on ACEIs (24%; p = .030, adjusted odds ratio = 0.42, 95% confidence interval = 0.19Y0.91). In contrast, the frequency of myocardial ischemia during physical stress testing was similar in both groups (39% versus 35% in those on and not on ACEIs, respectively); adjusted odds ratio = 0.91, 95% confidence interval = 0.48Y1.73). Conclusion: In this retrospective study, patients using ACEI therapy displayed less than half the risk of developing ischemia during mental stress but not physical stress. This possible beneficial effect of ACEIs on MSIMI may be contributing to their salutary effects in CAD. Key words: angiotensin-converting enzyme inhibitors, coronary artery disease, myocardial perfusion imaging, stress ischemia, mental stress, stress test.

ACEI = angiotensin-converting enzyme inhibitor; BP = blood pressure; CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; CI = confidence intervals; DBP = diastolic blood pressure; HR = heart rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MPI = myocardial perfusion imaging; MS = mental stress; MSIMI = mental stressYinduced myocardial ischemia; OR = odds ratio; PSIMI = physical stressYinduced myocardial ischemia; PTCA = percutaneous transluminal coronary angioplasty; RPP = rate-pressure product; SBP = systolic blood pressure; SDS = summed difference score; SRS = summed rest score.

INTRODUCTION pproximately 20% to 60% of patients with coronary artery disease (CAD) develop myocardial ischemia during mental stress (MSIMI), irrespective of ischemia during physical (exercise or pharmacologic) stress testing (PSIMI) (1Y10). The observation that areas of myocardium affected might differ between mental and physical stress in the same individual suggests that there are differences in the mechanisms involved in precipitation of ischemia with these stimuli (11,12). Importantly, MSIMI has been associated with a 2.5- to 3-fold higher rate of fatal and nonfatal cardiac events, independent of the risk related to PSIMI (1Y5,7,13). Thus, treatment of this phenomenon could potentially reduce morbidity and mortality in patients with CAD (14,15). Although studies have attempted to explore the mechanisms underlying MSIMI (6,14Y16), few have addressed potential therapeutic approaches (6,17Y20).

A

From the Department of Medicine (R.R., A.A.Q., A.M.Z.), Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Administration Medical Center GA (A.M.Z.), Decatur, Georgia; Department of Biostatistics & Bioinformatics (J.N.B.), Rollins School of Public Health, Emory University, Atlanta, Georgia; Department of Epidemiology (D.S.S.), School of Public Health, University of Florida, Gainesville, Florida. Address correspondence and reprint requests to Ronnie Ramadan, MD, Emory Clinical Cardiovascular Research Institute, 1462 Clifton Road N.E. Suite 507, Atlanta GA 30322. E-mail: [email protected] Received for publication October 17, 2012; revision received October 2, 2013. DOI: 10.1097/PSY.0000000000000015

The importance of angiotensin II in the physiological response to stress is well established (21). Angiotensin II plays a key role in the central nervous system stress pathways as well as contributing to endothelial function, both of which have been implicated as potential mechanisms of MSIMI. However, its role in the pathogenesis or treatment of MSIMI has not been investigated. Angiotensin II blockade reduces stress and improves endothelial dysfunction (22). Importantly, angiotensinconverting enzyme inhibitor (ACEI) therapy is known to reduce mortality and morbidity in patients with CAD (23,24). Whether this protective effect is partly caused by a reduction in MSIMI and whether ACEI therapy modifies responses to mental stress remain unknown. The purpose of this study was to conduct a retrospective comparison of the frequency of MSIMI in patients with stable CAD treated with or without an ACEI, with the hypothesis that ACEIs might reduce the occurrence of MSIMI. METHODS Patient Population We performed a retrospective analysis of 218 participants with clinically stable CAD who were recruited directly from cardiology clinics to participate in the ‘‘Psychological Stress and Risk of Cardiac Events’’ study at the University of Florida, Gainesville, between 2004 and 2008 (Table 1) (8,12,25). Presence of CAD was defined by abnormal coronary angiogram, previous coronary revascularization, documented myocardial infarction (MI), or a positive nuclear stress test result. Patients with unstable angina, decompensated heart failure, or MI in prior 2 months, or unstable psychiatric conditions were excluded. Clinical information including, previous CAD events, CAD risk factors, and current medications was assessed by using standardized questionnaires and chart reviews. Particularly, ACEI therapy during the week before testing was confirmed and documented by interviewing the patients directly on the day of enrollment. The research protocol was approved by the institutional review board, and all participants provided informed consent.

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R. RAMADAN et al. TABLE 1. Clinical Characteristics of Study Population ACEI

pa

Total (n = 218) Yes (n = 110) Age (SD), y

No (n = 108)

64 (9)

64 (9)

65 (8)

.31

149 (68)

81 (74)

68 (63)

.090

39 (18)

23 (21)

16 (15)

.24

Previous PTCA, n (%)

100 (46)

52 (47)

48 (44)

.68

Previous CABG, n (%) Angina in the past 4 wk, n (%)

73 (34) 102 (47)

41 (37) 59 (54)

32 (30) 43 (40)

.23 .039

55 (13)

54 (13)

56 (13)

.20

Male sex, n (%) Previous MI, n (%)

LVEF (SD), % Cardiovascular risk factors Diabetes, n (%)

67 (31)

31 (28)

36 (33)

.33

Hypertension, n (%)

173 (80)

93 (85)

80 (74)

.095

Current or ex-smokers, n (%)

156 (72)

81 (74)

75 (69)

.56

58 (27)

23 (21)

35 (32)

.055

Depression, n (%) Treatment A-Blocker, n (%)

163 (75)

92 (84)

71 (66)

.002

Calcium-channel blocker, n (%)

46 (21)

26 (24)

20 (19)

.35

Antidepressant, n (%)

33 (15)

13 (12)

20 (19)

.17

168 (77)

96 (87)

72 (67)

G.001

4.3 (7.6)

3.2 (5.9)

.27

Statin, n (%) Perfusion imaging SRS, mean (SD)

3.8 (6.8)

SDS, mean (SD) MSIMI PSIMI

5.6 (1.6) 6.2 (2.2)

5.4 (1.4) 6.3 (2.3)

5.7 (1.7) 6.1 (2.1)

.48 .64

ACEI = angiotensin-converting enzyme inhibitor; SD = standard deviation; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft surgery; LVEF = left ventricular ejection fraction; SRS = summed rest score; SDS = summed difference score; MSIMI = mental stressYinduced myocardial ischemia; PSIMI = physical stressYinduced myocardial ischemia. a Two-tailed unpaired Student’s t test or W2 test was used for comparison, as appropriate.

Study Protocol All patients were tested, in the morning after an overnight fast, while on their usual medications except for antianginal medications (A-blockers, calcium-channel blockers, and longacting nitrates), which were withheld for 24 to 48 hours, depending on the half-life of these medications, before stress testing. Mental Stress Procedure In a quiet dimly lit, temperature-controlled (21-CY23-C) room, after a 30-minute rest period, vital signs were measured and mental stress was induced by a standardized public-speaking task as previously described (26). Patients were asked to imagine a situation in which a close relative had been mistreated in a nursing home. Patients were given 2 minutes to prepare their speech and 3minutes to deliver their speech in front of an evaluative audience. Blood pressure (BP) and heart rate (HR) were recorded at 5-minute intervals during the resting phase and at 1-minute intervals during and after the mental stress task by the use of an automatic oscillometric device (Dynamap Critikon Inc, Tampa, FL). Rate-pressure product (RPP) was calculated as peak systolic BP  peak HR. To ensure adequacy of the mental stress testing, the procedure was administered by trained and experienced staff. Close 816

attention was paid to the psychophysiological stress-provoking elements of the test. All personnel participating in administering the test were wearing white coats and made sure not to give the patients any information about the specific contents of the test before they receive it. Myocardial Perfusion Imaging for Stress Testing Myocardial perfusion imaging (MPI) with 99m-Tcsestamibi was performed on two separate days up to 1 week apart, at rest and during mental and exercise/pharmacologic stresses, according to standard protocols (27). The sequence of the stressor (mental or physical) was done at random. During mental stress testing, the radioisotope injection was given at 1 minute into the speech based on previous reports demonstrating that the maximal hemodynamic, neurohormonal, and ischemic responses to mental stress usually occur at the near onset of the stressful task (15). Exercise stress testing was performed using the Bruce Protocol, and when contraindicated, pharmacologic testing with a standard 6-minute adenosine stress test was performed. Xanthine derivatives and caffeinecontaining products were discontinued 48 and 12 hours before testing, respectively. The radioisotope injection was given at peak exertion during the exercise test and at 3 minutes during the adenosine protocol. Exercise was continued for at least Psychosomatic Medicine 75:815Y821 (2013)

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EFFECT OF ACEIS ON STRESS-INDUCED ISCHEMIA 1 minute after the injection. Stress images were acquired 30 to 60 minutes later using conventional methodology with singlephoton emission computed tomography (27). Studies were interpreted by two experienced nuclear cardiologists blinded to the stressor (mental or exercise/pharmacologic). Rest and stress images were visually compared for number and severity of perfusion defects using a 20-segment model (28). Each segment was scored from 0 to 4, with 0 being normal uptake and 4 being no uptake. A summed difference score (SDS) was calculated as the difference between summed stress and summed rest scores (SRS). Ischemia was defined as new or worsening perfusion defects during mental, exercise, or adenosine stress as compared with the resting baseline images with an SDS of 4 or greater. For the purpose of comparison in this study, the same ischemia definition was used for all testing protocols. The severity of baseline myocardial perfusion was quantified based on SRS as normal (0Y3), mild (4Y8), moderate (9Y13), or severe (913). Similarly, the same criteria were used to quantify the severity of inducible ischemia using SDS.

Statistical Methods Patient characteristics were summarized as means (standard deviation) for continuous variables or as proportions for categorical variables. We compared mean changes in hemodynamic measures between groups using a two-tailed unpaired Student’s t test. The W2 test was used for comparison of categorical variables. Correlations between continuous variables were assessed with Pearson or Spearman correlation tests, as appropriate. Logistic regression was used to examine the effect of ACEI therapy on prediction of the binary outcome of ischemia. Covariates included in the multivariate analysis were age, sex, diabetes mellitus, hypertension, MI, depression, left ventricular ejection fraction (calculated by single-photon emission computed tomography), and A-blocker and statin therapy. Statistical significance was based on two-tailed tests, and p values less than or equal to 0.05 were considered significant. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were reported. Analyses were performed with SPSS (version 19.0; SPSS, Inc, Chicago, IL).

underwent pharmacologic stress testing. Of those who underwent exercise testing, 14 (14%) had significant ST-segment depression consistent with ischemia and 33 (33%) had ischemia diagnosed by MPI. Of those who underwent pharmacologic stress testing, 11 (9%) displayed significant ST-segment changes and 47 (40%) developed ischemia measured with MPI. During mental stress testing, only 2% had significant ST-segment changes suggestive of ischemia. ACEI Therapy and Frequency of Myocardial Ischemia The frequency of MSIMI was lower in patients receiving compared with those not receiving ACEI therapy (13% versus 24%, respectively; p = .030). The unadjusted OR of developing MSIMI, comparing patients receiving versus those not receiving ACEIs, was 0.46 (95% CI = 0.23Y0.94). The adjusted OR for relevant covariates mentioned previously was 0.42 (95% CI = 0.19Y0.91). In contrast, the frequency of PSIMI during physical stress was similar in both groups (39% in those receiving ACEI therapy versus 35% in those not on therapy, p = .65); the unadjusted OR was 1.1 (95% CI = 0.64Y1.92), and the adjusted OR was 0.91 (95% CI = 0.48Y1.73) (Fig. 1). Notably, the frequency of PSIMI in relationship to ACEI therapy was similar in those undergoing either exercise ( p = .12) or pharmacologic ( p = .34) stress testing. Overall, 80 patients had a positive physical stress test result, and of these patients, 24 (30%) developed MSIMI. Even among these patients with PSIMI, the frequency of MSIMI was

RESULTS Table 1 summarizes the demographics and risk factor profile of the 218 participants stratified by treatment with ACEIs. Patients taking ACEIs had more reported angina and higher rates of A-blocker and statin use. Stress Testing and Myocardial Ischemia The extent and severity of the resting perfusion defect, measured as SRS, were similar in those with or without MSIMI, indicating that the severity of previous MI was similar (Table 1). In the 218 participants, the frequency was 18% (n = 40) for MSIMI and was 37% (n = 80) for PSIMI. For detection of PSIMI, 101 (46%) patients underwent exercise and 117 (54%)

Figure 1. Percentage of patients with mental stressYinduced myocardial ischemia and physical stress-induced myocardial ischemia treated with or without ACEI. The frequency of mental stressYinduced myocardial ischemia in those on ACEIs (n = 110) was significantly lower than those not on ACEIs (n = 108). However, the frequency of physical stressYinduced myocardial ischemia was similar in those receiving or not receiving ACEIs. ACEI = angiotensin-converting enzyme inhibitor.

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817

R. RAMADAN et al. higher in those not on as compared with those who were on ACEIs (42% versus 19%, respectively; p = .025). Most patients with MSIMI (93%) and PSIMI (85%) had mild ischemia. The mean SDS in those with MSIMI and PSIMI was similar in patients with or without ACEI therapy, indicating that the severity of ischemia during mental or physical stress was similar in the presence or absence of ACEI therapy (Table 1). Hemodynamic Responses to Stress Testing We also examined HR and BP responses during mental stress to investigate whether the difference in frequency of MSIMI was caused by a blunted hemodynamic response to mental stress in patients receiving ACEIs. Table 2 shows baseline hemodynamic measures and reactivity to mental stress in all participants according to ACEI intake and MSIMI status. Only the diastolic BP change was significantly higher in those on ACEIs. Notably, there was no significant difference in mean peak RPP during mental stress for those with MSIMI (12,870 [3143]) compared with those without (12,697 [3610]; p = .78). Moreover, there was no significant difference in the mean peak RPP during mental stress for those treated with ACEIs (12,575 [3403]) versus those who were not (12,889 [3650]; p = .51). The peak HR and RPP in those with MSIMI was similar in participants with or without ACEI therapy (HR = 80 [8] versus 83 [18] beats/min [ p = .41] and RPP = 12,341 [1782] versus 13,156 [3678; p = .44], respectively). Moreover, the SDS during mental stress did not correlate with the change in HR, systolic BP, or RPP, but positively correlated with the degree of diastolic BP reactivity in response to mental stress in the total cohort and, more importantly, in those with MSIMI (Fig. 2A and B). Notably, only patients not taking ACEIs demonstrated this positive correlation between the SDS and the degree of diastolic BP reactivity (Fig. 2C and D). Even among those with MSIMI (n = 40), those on ACEIs (n = 14) did not have a significant correlation between SDS and diastolic BP reactivity (r = 0.42, p = .13), as opposed to those not on ACEIs (n = 26, r = 0.45, p = .022).

Similarly, there was no significant difference in mean peak RPP achieved during exercise stress for those with PSIMI (21,879 [3440]) versus those without (21,556 [4225]; p = .71). Finally, of the 101 patients undergoing exercise stress, 47 (47%) were on ACEI therapy, and no difference in the mean peak RPP achieved during exercise stress was found between those treated with ACEIs (21,171 [4665]) versus those who were not (21,359 [4972]; p = .84). Notably, the threshold for inducibility of exercise-induced ischemia, defined as 85% of age-predicted maximal HR, was similar in those with or without ACEI therapy (133 [7] versus 132 [7]; p = .39). Moreover, the mean peak RPR in those undergoing pharmacologic stress testing was similar between those who developed PSIMI (11,003 [3774]) and those who did not (10,786 [2857]; p = .74). Similarly, no difference in the mean peak RPP measured during pharmacologic stress was found with respect to ACEI treatment ( p = .25). DISCUSSION The major finding of this study is that patients with stable CAD who were treated with ACEIs had a significantly lower risk of developing MSIMI compared with those who were not treated with ACEIs. However, ACEI therapy was not associated with a lower frequency of PSIMI in the same participants. Furthermore, even in the subset of patients with PSIMI, the frequency of MSIMI was significantly lower in those treated with ACEIs. This suggests that the differences observed during mental stress are not caused by a lower risk of all-cause ischemia in patients receiving ACEIs but are likely caused by a specific effect of ACEIs on the mechanisms responsible for MSIMI. Angiotensin II and the Stress Response Stress enhances peripheral and central angiotensin II generation and activity, which, in turn, stimulate stress pathways in the brain and the synthesis of stress hormones including, adrenocorticotrophic hormone, corticosterone, aldosterone, and

TABLE 2. Hemodynamic Measurements During Mental Stress in Patients With and Without ACEI Therapy and Patients With and Without MSIMI

Resting SBP (SD), mm Hg Resting DBP ((SD), mm Hg

ACEI

No ACEI

pb

MSIMI

No MSIMI

119 (17) 65 (9)

118 (18) 63 (8)

.62 .22

115 (15) 62 (7)

119 (18) 64 (9)

pb .15 .11

Resting HR (SD), BPM

64 (10)

66 (11)

.077

67 (12)

65 (10)

.35

MS SBPa (SD), mm Hg

164 (26)

160 (26)

.33

156 (20)

163 (27)

.086

MS DBPa (SD), mm Hg

95 (15)

89 (12)

.004

92 (9)

92 (15)

.99

MS HRa (SD), BPM

77 (14)

80 (17)

.13

82 (15)

77 (16)

.087

SBP change (SD), mm Hg

45 (20)

43 (19)

.41

42 (16)

44 (20)

.53

DBP change (SD), mm Hg

30 (12)

26 (10)

.008

30 (9)

28 (12)

.24

HR change (SD), BPM

13 (11)

13 (12)

.64

15 (13)

12 (11)

.14

ACEI = angiotensin-converting enzyme inhibitor; MSIMI = mental stressYinduced myocardial ischemia; SBP = systolic blood pressure; SD = standard deviation; DBP = diastolic blood pressure; HR = heart rate; BPM = beats per minute; MS = mental stress. a Peak value during speaking task. b Two-tailed unpaired Student’s t test was used for comparison. 818

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EFFECT OF ACEIS ON STRESS-INDUCED ISCHEMIA

Figure 2. Relationship between number of reversible perfusion defects (SDS) and diastolic blood pressure reactivity during mental stress. The degree of diastolic blood pressure reactivity during mental stress correlated positively with the number of reversible perfusion defects (SDS) in the entire cohort (A) and in those with MSIMI (B). In the entire cohort, those not on ACEIs (C) demonstrated a significant correlation between diastolic blood pressure reactivity and SDS, but not those on ACEIs (D). Diastolic blood pressure responses greater than 70 mm Hg (n = 2) are not shown. Results from analyses including these two cases are essentially the same as those reported. SDS = summed difference score; MSIMI = mental stressYinduced myocardial ischemia; ACEI = angiotensin-converting enzyme inhibitor.

catecholamines (21,29,30). Increased ACE activity is also associated with depression, hypothalamic-pituitary-adrenal axis hyperactivity, and anxiety (31Y33). Moreover, blocking the angiotensin II pathways in the brain reduces stress and anxiety (34Y36). Our finding of reduced frequency of MSIMI in participants treated with ACEIs suggests that their beneficial effects may extend to improving coronary blood flow during mental stress. The preferential protective effect of ACEIs on MSIMI versus PSIMI also indicates that the underlying mechanisms inducing ischemia with these stimuli differ. Whereas RAS activation contributes importantly to the mechanisms underlying MSIMI, PSIMI is largely caused by increased workload exceeding coronary blood supply. Furthermore, the effects of angiotensin II antagonism on the central pathways involved in

the stress response may be more specific to the mechanisms underlying MSIMI. Potential Mechanistic Role of Angiotensin-Converting Enzyme Inhibition in Reducing MSIMI Several vascular mechanisms may contribute to MSIMI including endothelial dysfunction (37), epicardial coronary vasospasm (38), and increased microvascular tone in response to mental stress (39). ACEI therapy may protect against MSIMI by modulating one or all of these processes. First, ACEIs improve endothelial function (22,40) by reducing oxidative stress and elevating bradykinin levels (22). Because paradoxical vasoconstriction (11) or inappropriate vasodilation during stress is associated with endothelial dysfunction, improvement in mental

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R. RAMADAN et al. stressYmediated coronary vasoconstriction by ACEIs could be a potential mechanism of benefit of ACEI therapy. Second, angiotensin II enhances sympathetic nervous systemYmediated vasoconstriction in the coronary circulation, whereas ACEI therapy attenuates coronary sympathetic vasoconstriction (41,42). Hemodynamic Reactivity, MSIMI, and Angiotensin-Converting Enzyme Inhibition Mental stress elicits a heightened hemodynamic response characterized by a rapid increase in catecholamines that cause peripheral vasoconstriction and an increase in myocardial oxygen demand (15). Angiotensin II contributes to this by stimulating both the central and peripheral sympathetic nervous system (29). One possible explanation underlying the favorable effect of ACEIs on MSIMI is blunting of the increase in the hemodynamic response to mental stress (9,15). However, we found that the RPP increase, a measure of myocardial oxygen demand, was similar in those with and without MSIMI and in those with and without ACEI therapy. Moreover, patients treated with ACEIs had a significantly higher diastolic BP increase with mental stress, a finding that has been shown to be associated with ischemia in this setting (9,38). The lack of association between hemodynamic reactivity to mental stress and MSIMI, in our study, has also been demonstrated by other investigators (43). Interestingly, the degree of diastolic BP reactivity to mental stress in those with MSIMI was positively correlated with the number of reversible perfusion defects only in those not on ACEIs, suggesting that ACEI therapy may improve the deleterious impact associated with diastolic BP reactivity on the mechanisms of MSIMI. Overall, our data suggest that the protective effect of ACEIs on MSIMI is independent of the drug’s effect on the hemodynamic responses to mental stress, pointing to improvement in myocardial blood flow delivery during ACEI therapy as a potential mechanism of benefit (22,44). Limitations Our study is a retrospective analysis of patients, and therefore, the dose and specific type of ACEI therapy could not be standardized, nor could the exact indication be ascertained. Thus, we cannot infer a causal effect of ACEI therapy on MSIMI. Our conclusions are intended to be hypothesis generating and will need to be verified in a randomized clinical trial. The frequency of MSIMI in this study was lower than previously reported, partly because most previous studies only investigated patients with exercise-induced ischemia, whereas we included participants with a broad definition of CAD, and partly because of differing methodologies and sensitivity of criteria used for diagnosing ischemia (1,15,45,46). In fact, the rate of MSIMI in our study in those with PSIMI was 30%, a rate similar to previous reports. Moreover, we used MPI, a diagnostically more specific modality that may have also contributed to the comparatively lower rate of ischemia observed. CONCLUSIONS MSIMI is an important pathophysiological phenomenon in that it is associated with a significantly worse prognosis in 820

patients with CAD (1Y5,7,13). However, therapeutic approaches to this phenomenon are unclear, and research in this arena has been scarce. We found a possible protective association between ACEI therapy and the risk of developing MSIMI that may constitute one of the benefits of ACEI therapy in patients with CAD. These observations need confirmation in randomized studies with longer-term follow-up. Source of Funding and Conflicts of Interest: This study was supported by the National Institutes of Health (Grant No. 5R01HL70265-5). The authors declared no conflict of interest.

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EFFECT OF ACEIS ON STRESS-INDUCED ISCHEMIA

15.

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