Independent contribution of plaque complexity to myocardial ischemia during dobutamine stress echocardiography

Independent Contribution of Plaque Complexity to Myocardial Ischemia During Dobutamine Stress Echocardiography Robert Fathi, MBBS, Leanne Short, BS, Brian Haluska, RDCS, Paul Garrahy, Vinah Anderson, RN, and Thomas H. Marwick, MBBS, PhD

MBBS,

The influence of complex plaque morphology on the extent of demand-induced ischemia in unselected patients is not well defined. We sought to investigate the functional significance of lesion morphology in patients who underwent coronary angiography and dobutamine stress echocardiography (DSE). Angiography and DSE were performed within a 6-month period (mean 1 ⴞ 1 month) in 196 patients. Angiographic assessments involved quantification of stenosis severity, assessment of the extent of jeopardized myocardium, and categorization of plaque morphology according to the Ambrose classification. DSE was interpreted by separate investigators with respect to wall motion score index (WMSI) and number of coronary territories involved. A general linear model was constructed to assess the independent contribution of patient characteristics and angiographic and DSE results with respect to extent of ischemic myocardium. Complex lesion morphology was seen in 62 patients (32%). Patients with complex lesions were more likely to have had prior myocardial

infarction (p <0.001) and be current smokers (p ⴝ 0.03). During angiography, they exhibited a trend toward a greater number of diseased vessels, had a greater coronary jeopardy score (p <0.001) and more frequent collateral flow (p ⴝ 0.03). During echocardiography, patients had a higher stress WMSI (p <0.001) and were more likely to show ischemia in all 3 arterial territories (p <0.01). On multivariate regression, the coronary artery jeopardy score and the presence of complex plaque morphology were independent predictors of the extent of ischemic myocardium (R2 ⴝ 34%, p <0.001). Thus, patients with complex plaque morphology are older, more likely to smoke, and more likely to have had prior myocardial infarction. They exhibit more extensive disease with higher coronary jeopardy scores and a higher resting and peak stress WMSI. Despite these differences, complex plaque morphology remains an independent predictor of the extent of ischemia during stress. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1026 –1030)

ndothelial injury associated with complex coronary plaques may influence downstream vasodilaE tory capacity. Complex plaque morphology has been

sine responsiveness or whether it has a more general effect on coronary vasodilator function and, hence, on the ischemic threshold. Therefore, we sought to assess the interplay of ischemia (detected as worsening wall motion with DSE) and coronary plaque severity and morphology in a group of unselected patients with varying degrees of left ventricular dysfunction and multivessel disease. This design contrasts with previous studies that used highly selected populations— especially ones with only single-vessel disease.

shown to cause a greater degree of functional ischemia for any given degree of stenosis severity in patients who undergo dipyridamole echocardiography.1,2 However, the weight of evidence with dobutamine stress echocardiography (DSE) suggested that lesion morphology did not influence these results.3 In a study that compared the 2 stressors, Varga et al4 reported an effect of lesion morphology on dipyridamole but not dobutamine results. However, in 1 study of DSE in patients with single-vessel disease, ischemia showed a strong relation with stenosis severity and lesion morphology.5 The determination of whether this phenomenon occurs with dobutamine stress is very important because it would indicate whether the impact of plaque complexity exerts an impact purely on adenoFrom the University of Queensland, Brisbane, Australia. This study was supported in part by a grant-in-aid from the National Heart Foundation of Australia, Melbourne; and a scholarship from the Henkler Foundation, University of Queensland, Queensland, Australia. Manuscript received April 18, 2003; revised manuscript received and accepted June 27, 2003. Address for reprints: Thomas H. Marwick, MD, PhD, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia. E-mail: tmarwick@soms. uq.edu.au.

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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 November 1, 2003

METHODS

Study design: Patients who underwent coronary angiography within 6 months of DSE were eligible. Inclusion criteria included a request for DSE for the investigation of chest pain or assessment of ischemia. Exclusion criteria included significant valvular disease, significant luminal left main stenosis (ⱖ50%), or an acute coronary syndrome between the examinations. DSE was performed using an approved protocol and informed consent was obtained from all patients. Stress echocardiography: Beta blockers and nitrates are routinely withheld for 24 hours before testing. A standard dobutamine stress protocol was used, with atropine if ischemia was not detected at peak dose.6 Standard end points were used, including conclusion of the protocol, development of severe angina or other 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.07.003

intolerable symptoms, development of hypertension (systolic pressure ⬎230 mm Hg), symptomatic hypotension, serious arrhythmia, or extensive ischemia. Standard 2-dimensional echocardiography with harmonic imaging was obtained at baseline, during lowdose dobutamine, and after peak stress using a commercially available system (Vingmed System FiVe; General Electric, Milwaukee, Wisconsin). Studies were analyzed using a 16-segment model by observers blinded to the angiographic findings. A wall motion score index (WMSI) was derived as the sum of the scores divided by the number of visualized segments.7 Ischemia was identified by new or worsening wall motion abnormalities with stress. Segments with severe hypokinesia or akinesia at rest were identified as scared, except when regional function improved with low-dose dobutamine, in which case they were identified as viable. For comparison with angiographic results, segments8 were correlated with arterial supply as proposed by Geleijnse et al.9 The left anterior descending artery was assigned to the basal, mid-anteroseptal and anterior, apical, and mid-septal segments. The right coronary was defined as supplying the basal and mid-inferior as well as the basal septal. The circumflex was assigned to the basal and mid-lateral regions as well as the basal and mid-posterior. Coronary angiography: All patients underwent coronary angiography using the Judkins technique. Angiograms were analyzed by 2 experienced angiographers, independent of the echocardiographic data. Stenosis severity was assessed using quantitative angiography (Philips Medical Imaging, Best, The Netherlands) of the major epicardial arteries and their major branches. Significant coronary disease was defined as a ⱖ50% decrease in luminal diameter in ⱖ1 coronary artery. If 1 artery had more than significant stenosis, we analyzed only the more severe lesion. The techniques of Dash et al10 and Califf et al11 were used for assessing the degree of jeopardized myocardium; they are based on cumulative scoring from the location of luminal stenoses of ⱖ75%. The maximal score for the left anterior descending system is 6 points, left circumflex is 4, and right coronary artery is 2 (maximum score 12 points). Biplane left ventricular ejection fraction was calculated from the difference of the endocardial volume estimation of systole and diastole. Morphologic assessment of significant lesions was based on the Ambrose classification.12 Stenoses were classified into simple (smooth and symmetrical or asymmetric with smooth border and broad neck) and complex (narrow neck, irregular lesion border, sharp edges or intraluminal filling defect suggestive of thrombus). In case of disagreement between the 2 angiographers, the decision of a third angiographer was final. Statistical analysis: All data are expressed as mean ⫾ SD. Baseline characteristics of patients were compared using an independent t test for continuous variables and the chi-square test for categoric variables. Univariate analysis was performed using 1-way analysis of variance, and variables with a univariate p

TABLE 1 Angiographic Results Complex Plaque Variable

⫹ 0 (n ⫽ 62) (n ⫽ 134) p Value

Left anterior descending lesion severity 0% 4 (7%) 44 (33%) — 1–30% 3 (5) 21 (16) — 31–50% 12 (19) 18 (13) — 51–70% 13 (21) 19 (14) — 71–99% 25 (40) 18 (13) — 100% 5 (8) 14 (10) — Circumflex artery lesion severity 0% 10 (16) 65 (49) — 1–30% 7 (11) 18 (13) — 31–50% 9 (15) 14 (10) — 51–70% 13 (21) 13 (10) — 71–99% 19 (31) 18 (13) — 100% 4 (2) 6 (5) — Right coronary artery lesion severity 0% 4 (7) 52 (39) — 1–30% 6 (10) 24 (18) — 31–50% 5 (8) 13 (10) — 51–70% 13 (21) 13 (10) — 71–99% 20 (32) 8 (6) — 100% 14 (23) 24 (18) — Vessel disease 0 0 (0) 47 (35) ⬍0.001 1 17 (27) 47 (35) 2 22 (36) 28 (21) 3 23 (37) 12 (9) Coronary artery jeopardy score 5.2 ⫾ 3.4 2.4 ⫾ 2.8 ⬍0.001 Coronary dominance 56 (90) 106 (79) 0.10 Right 56 (90) 106 (79) 0.10 Left circumflex 6 (10) 23 (17) Co-dominance 9 (0) 5 (4) Collaterals 21 (34) 26 (19) 0.032 Ejection fraction (%) 47 ⫾ 14 53 ⫾ 15 0.056 Values expressed as mean ⫾ SD or number (%).

value ⬍0.05 were selected for multivariate regression analysis. A general linear model was constructed to identify the independent contribution of baseline characteristics, DSE results, and coronary artery disease to the extent of ischemia. Statistical analyses were preformed using SPSS for Windows 11.0 (SPSS Inc., Chicago, Illinois).

RESULTS

Clinical characteristics: The study group comprised 196 consecutive patients (139 men, aged 62 ⫾ 11 years) who underwent DSE and angiography within 6 months. Risk factors for coronary artery disease included diabetes mellitus in 30 patients (15%), hypertension in 103 (53%), hyperlipidemia in 117 (60%), and current smoking in 50 (26%). Prior myocardial infarction was confirmed in 103 patients (53%) in the study group and 22 patients (11%) underwent prior percutaneous coronary angioplasty. Beta blockers were prescribed for 101 patients (52%), calcium channel blockers for 46 (24%), and long-acting nitrates for 73 (37%). Obesity was prevalent, with a mean body mass index of 29 ⫾ 5 kg/m2. Angiographic results: Angiographic results are listed in Table 1. Approximately equal numbers of

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DISCUSSION

TABLE 2 Baseline Clinical Characteristics Complex Plaque Demographics

⫹ (n ⫽ 62)

0 (n ⫽ 134)

p Value

Age (yrs) 66 ⫾ 9 60 ⫾ 12 0.002 Men 49 (79%) 90 (67%) 0.09 28.2 ⫾ 4.4 28.7 ⫾ 4.9 0.6 Body mass index (kg/m2) Heart rate (beats/min) 74 ⫾ 17 73 ⫾ 14 0.59 Systolic blood pressure (mm Hg) 132 ⫾ 24 137 ⫾ 25 0.26 Hyperlipidemia 41 (66%) 76 (57%) 0.21 Hypertension 34 (55%) 69 (52%) 0.66 Diabetes mellitus 9 (15%) 21 (16%) 0.83 Smoker (current) 22 (36%) 28 (21%) 0.03 Previous myocardial infarction 44 (71%) 59 (44%) ⬍0.001 Previous coronary angioplasty 7 (11%) 15 (11%) 0.98 ␤-blocker 35 (57%) 66 (49%) 0.35 Calcium channel blocker 12 (19%) 34 (25%) 0.36 Nitrate 27 (44%) 46 (34%) 0.21

patients had no, single, or multivessel disease; collateral circulation was present in 47 patients (24%). Complex plaques were present in 62 patients (32%); patients with complex disease had a trend for a greater number of diseased vessels, revealed a greater coronary artery jeopardy score, and had more frequent collateral circulation. These patients also demonstrated a strong trend toward a lower ejection fraction (p ⫽ 0.056). Correlates of lesion complexity are listed in Table 2. DSE results: Mean duration between the time of the DSE and coronary angiogram was 1 ⫾ 1 month. The peak systolic blood pressure for the group was 155 ⫾ 32 mm Hg with a peak heart rate of 134 ⫾ 19 beats/min. The WMSI at rest was 1.4 ⫾ 0.5 and increased to 1.5 ⫾ 0.5 with stress. Table 3 lists results of DSE with respect to the presence or absence of complex plaque morphology. Those with complex lesions developed a lower workload, started with a higher WMSI at rest, had a higher peak WMSI, and had a significant change in WMSI. The presence of complex plaque morphology consistently led to a significantly lower proportion of patients with normal segments and higher proportion of patients with ischemic or scarred segments in each arterial distribution. From these scores, the proportion of the left ventricle found to be ischemic or viable was calculated, with the left anterior descending assigned 9 of 16 segments, the left circumflex 4 of 16 segments, and the right coronary artery 3 of 16 segments. Predictors of proportion of ischemic myocardium:

The presence of advanced age, hypertension, hyperlipidemia, previous myocardial infarction, number of diseased vessels, coronary artery jeopardy score, presence of complex plaque morphology, presence of collaterals, lower ejection fraction, and the use of ␤ blockers were all predictors of greater ischemic extent (Table 4). Stepwise forward linear regression was used to define a multivariate model comprising coronary artery jeopardy score and complex plaque morphology (r ⫽ 0.58, p ⬍0.001). This model accounted for 34% (R2 adjusted) of the variability demonstrated in the proportion of ischemic myocardium (Table 4). 1028 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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Patients exhibiting complex plaque morphology are older, more likely to smoke, more commonly have known coronary disease, and have more ischemia. Despite these differences, complex plaque morphology remains an independent predictor of the extent of ischemia during stress. The nature of plaque morphology is known to have clinical implications. Patients with unstable angina have a high rate (up to 70%) of complex plaque morphology12,13 and plaque-associated thrombus.14 These differences in plaque morphology may explain the differing ischemic potential and clinical outcomes of patients with stable and unstable angina pectoris despite similar percent diameter stenosis and number of diseased vessels.15,16 This is important because the extent of jeopardized myocardium is related to outcome. Furthermore, complex lesions are associated with accelerated plaque stenosis progression17,18 and cardiac event rates,19,20 as well as being predictive of future infarction in the same territory.21 Nonetheless, complex plaques also occur in patients with stable angina.22 This study suggests that lesion complexity has consequences for the extent of ischemia in this setting, and several mechanisms are possible. Activated platelets have been shown to adhere to the thrombus collection and cause distal embolization with ensuing infarction.23 Besides platelet embolization, these sites typically are more prone to develop spasm and worsen downstream ischemia due to thrombus-derived mediators.24 Finally, inflammation in complex atherosclerotic plaques may be modified by the anti-inflammatory effects of statins.25,26 In addition to increased myocardial perfusion27 due to the improvement in vasomotor reactivity of epicardial and resistance vessels,28,29 this mechanism may contribute to the anti-ischemic effects of statins. The effect of plaque morphology on functional ischemia with provocative tests has been variable. Lu et al1 performed dipyridamole stress echocardiography within 3 days of coronary arteriography in a cohort of 68 patients (39 stable angina pectoris, 29 unstable angina) who had nonocclusive 1-vessel coronary artery disease with no prior infarction. Patients with complex plaque morphology had a higher sensitivity for ischemia (85% vs 53%, p ⬍0.001). The authors proposed that this may be due to loss of the normal endothelial integrity with complex plaque and resulting alterations in endothelial-associated dilatation. A further study examined the effect of infarctrelated artery plaque morphology on ischemia in patients with single-vessel disease. Patients with complex lesions developed ischemia more readily (59% vs 25%, p ⬍0.01) and more frequently at a low workload (73% vs 22%, p ⬍0.05), possibly due to impaired endothelial function causing reduced vasodilatory capacity.2 Two further studies showed that ischemia provoked by DSE—first in 42 patients with single-vessel coronary artery disease studied with DSE alone3 and then in 68 patients studied with dipyridamole and dobutamine4—was not influenced by plaque morphology. With these results, it appeared NOVEMBER 1, 2003

TABLE 3 Dobutamine Stress Echocardiography (DSE) Results Complex Lesions (n ⫽ 62)

Dobutamine Results Peak systolic blood pressure (mm Hg) Peak diastolic blood pressure (mm Hg) Peak heart rate (beats/min) Peak product (beats/min) ⫻ mm Hg ⫻ 1,000 WMSI at rest Peak WMSI ⌬ WMSI Angina during exam (no. [%]) Left coronary artery Normal Ischemic/viable Scared Circumflex artery Normal Ischemic/viable Scared Right coronary artery Normal Ischemic/viable Scared Proportion of left ventricle Normal Ischemic/viable Scared

No Complex Lesions (n ⫽ 134)

p Value

151 ⫾ 34 73 ⫾ 14 130 ⫾ 17 19.6 ⫾ 4.9 1.5 ⫾ 0.5 1.7 ⫾ 0.5 0.2 ⫾ 0.3 19 (31)

156 ⫾ 32 74 ⫾ 15 136 ⫾ 19 21.2 ⫾ 5.3 1.3 ⫾ 0.5 1.4 ⫾ 0.4 0.1 ⫾ 0.3 34 (25)

0.28 0.71 0.07 0.050 0.02 ⬍0.001 0.04 0.44

6.0 ⫾ 3.1 1.6 ⫾ 2.1 1.3 ⫾ 2.3

8.3 ⫾ 1.8 0.4 ⫾ 1.2 0.3 ⫾ 1.0

⬍0.001 ⬍0.001 0.004

2.2 ⫾ 1.6 1.2 ⫾ 1.5 0.5 ⫾ 1.1

3.4 ⫾ 1.1 0.5 ⫾ 1.0 0.1 ⫾ 0.6

⬍0.001 0.001 0.003

1.1 ⫾ 1.2 1.0 ⫾ 1.1 0.9 ⫾ 1.1

2.3 ⫾ 1.1 0.4 ⫾ 0.8 0.3 ⫾ 0.8

⬍0.001 ⬍0.001 0.001

0.52 ⫾ 0.28 0.31 ⫾ 0.22 0.17 ⫾ 0.19

0.71 ⫾ 0.27 0.17 ⫾ 0.17 0.12 ⫾ 0.18

⬍0.001 ⬍0.001 0.08

TABLE 4 Univariate and Multivariate Predictors of Proportion of Ischemic Left Ventricle Multivariate Analysis

Univariate Analysis Variable Age Gender Hypertension Hyperlipidemia Smoker Previous myocardial infarction Previous coronary angioplasty No. of diseased vessels Complex plaque morphology Coronary jeopardy score Collaterals Ejection fraction Peak product ␤ blocker Calcium channel blocker Nitrate

R2

p Value

0.035 0.006 0.017 0.034 0.014 0.055 0.015 0.25 0.11 0.32 0.07 0.087 0.009 0.03 0.001 0.019

0.01 0.29 0.07 0.01 0.10 0.001 0.09 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 0.22 0.017 0.88 0.06

␤

p Value

investigations. However, we attempted to minimize this possible effect by excluding any patient who developed unstable angina or myocardial infarction after DSE but before angiography. Analysis of lesion morphology remains subjective and no widely accepted quantitative method currently exists. Nonetheless, any error in the attribution of lesions as simple or complex would be evenly shared across the population. Finally, coronary angiography has relatively poor sensitivity for the detection of minor luminal irregularities and the presence of thrombus as opposed to the techniques of angioscopy and intravascular ultrasound; therefore, the role of complex stenoses of “nonsignificant” severity (perhaps as a cause of “false–positive” results) cannot be addressed by this study. The results of this study suggest that complex lesions have greater ischemic potential than simple lesions. Previous work has documented the efficacy of aggressive lipid reduction in the attenuation of ischemia in endstage coronary disease, probably by reversal of resistance vessel function.30 Further studies are justified to determine whether analogous benefits may arise from more aggressive risk-factor management in patients with complex plaques.

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