Coronary Flow Velocity Reserve during Pharmacologic Stress Echocardiography with Normal Contractility Adds Important Prognostic Value in Diabetic and Nondiabetic Patients

CORONARY FLOW VELOCITY RESERVE

Coronary Flow Velocity Reserve during Pharmacologic Stress Echocardiography with Normal Contractility Adds Important Prognostic Value in Diabetic and Nondiabetic Patients Jorge A. Lowenstein, MD, FASE, Cristian Caniggia, MD, Graciela Rousse, MD, Miguel Amor, MD, Marıa E. Sanchez, MD, Diego Alasia, MD, Norberto Casso, MD, Alicia Garcıa, MD, Gustavo Zambrana, MD, Diego M. Lowenstein Haber, MD, and Victor Dar u, MD, Buenos Aires and Santa Rosa, Argentina

Background: Coronary flow velocity reserve (CFVR) increases the diagnostic sensitivity of stress echocardiography. The aim of this study was to evaluate the prognostic value of CFVR in patients without new wall motion abnormalities during pharmacologic stress echocardiography. Methods: The outcomes of 651 patients with normal wall motion response during stress echocardiography with dobutamine up to 50 mg/kg/min (n = 351) or dipyridamole up to 0.84 mg/kg over 4 min (n = 300) were evaluated. CFVR was calculated simultaneously in the distal territory of the left anterior descending coronary artery. CFVR $ 2 was defined as normal. Major events considered during follow-up were cardiovascular death, myocardial infarction, and late myocardial revascularization. Results: Normal CFVR was recorded in 523 patients and reduced CFVR in 128. During a mean follow-up period of 34.6 6 18 months, 48 major events occurred, in 25 patients (4.8%) with normal and 23 patients (18%) with reduced CFVR; event-free survival was significantly different between patients with normal versus abnormal CFVR (P < .0001). Diabetes increased risk only in patients with abnormal CFVR (P = .05). In the multivariate analysis, CFVR and history of smoking were the only independent predictors of combined morbidity and mortality. Abnormal CFVR was associated with a higher event rate, independently of the pharmacologic stress technique used. The event hazard ratio was inversely proportional to CFVR. Conclusions: CFVR was an independent predictor of mortality after pharmacologic stress echocardiography with normal wall motion, and the degree of decrease was associated with increased risk. Diabetes worsened prognosis only with abnormal CFVR. (J Am Soc Echocardiogr 2014;27:1113-9.) Keywords: Stress echocardiography, Stress echocardiographic prognosis, Risk assessment, Coronary flow velocity reserve

It is accepted that a normal contractile response on stress echocardiography has a much better prognosis than in the presence of transient wall motion abnormalities. However, it does not completely rule out the possibility of significant coronary artery disease (CAD), or an event-free prognosis, especially in patients with complete left bundle branch block, in elderly patients or those assessed under anti-ischemic treatment, in patients with left ventricular hypertrophy or single-vessel

From the Investigaciones Me´dicas, Buenos Aires, Argentina (J.A.L., C.C., G.R., M.A., M.E.S., D.A., N.C., G.Z., D.M.L.H., V.D); Polimedic, Santa Rosa, Argentina (A.G.). dicas, Address reprint requests: Jorge A. Lowenstein, MD, Investigaciones Me Department of Echocardiography, Av Coronel Diaz 2149.3 C, CP 1425 Buenos Aires, Argentina (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.05.009

disease, in incomplete studies (e.g., deficient tests with atropine contraindications), and in the diabetic population.1–5 In this last group, there is great concern about the prevention of cardiovascular complications. Hence, it is highly important to identify patients at greater risk for developing coronary disease to adopt special surveillance, treat them more aggressively, and ultimately attempt to reduce morbidity and mortality. In the past 15 years, the potential of stress echocardiography has expanded dramatically, with the possibility of assessing noninvasively coronary flow velocity at rest and its relation with peak pharmacologic stress. The simultaneous recording of wall motion and coronary flow velocity reserve (CFVR) images is today the state of the art for drug-induced stress studies in some laboratories.6–11 It is established that left anterior descending coronary artery (LAD) CFVR < 2 with dobutamine or dipyridamole increases the diagnostic sensitivity of stress echocardiography,11–14 and recent evidence has shown that dipyridamole can also provide additional prognostic information to contractile analysis in patients with known or suspected CAD.15–19 1113

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Abbreviations

AMI = Acute myocardial infarction

CAD = Coronary artery disease

CFVR = Coronary flow velocity reserve CI = Confidence interval HR = Hazard ratio LAD = Left anterior

Journal of the American Society of Echocardiography October 2014

In this observational study, we investigated the mid- and longterm prognostic information derived from the transthoracic Doppler echocardiographic analysis of CFVR and its degree of LAD restriction in patients with and those without diabetes with known or suspected CAD who underwent stress echocardiography with normal wall motion performed with dobutamine or dipyridamole.

descending coronary artery

Wall motion was analyzed under baseline conditions and up to 8 min after ending dipyridamole infusion (hand grip and eventually atropine) and also at each stage of dobutamine. Echocardiographic images were assessed by using a 16-segment model of the left ventricle and a four-point semiqualitative scale.22 The wall motion score was visually calculated by dividing the score obtained from the sum of each individual segment evaluation during stress by the number of interpretable segments. Ischemia was defined as a new abnormality in wall motion or worsening of a preexisting one. Akinesia or dyskinesia was defined as resting wall motion alteration with absence of systolic thickening during stress echocardiography. Studies were digitally stored. Diastolic coronary flow velocities were calculated from the average of 3 baseline recordings and at peak stress (Figure 1). All operators were trained by the same investigator. Follow-Up

MATERIAL AND METHODS Patients The initial population involved 2,455 patients included at two institutions (Investigaciones Medicas, Buenos Aires, Argentina, and Polimedic, Santa Rosa, Argentina) from June 2001 to November 2011. All patients underwent pharmacologic stress echocardiography with dobutamine or dipyridamole (according to the treating physician) with CFVR assessments by transthoracic Doppler echocardiography at the LAD level. Patients with baseline abnormal wall motion in the LAD territory (n = 256), positive transient contractile abnormalities (n = 678), cardiac disease, valve disease or different congenital diseases (n = 357), ejection fraction < 35% (n = 184), suboptimal ultrasound windows (n = 97), impossibility of finding the LAD (n = 90), and no information on poststudy outcomes (n = 142) were excluded from the study. Thus, 651 patients were ultimately analyzed; 329 (50.53%) were men, and the mean age was 66.45 6 11.82 years. Stress echocardiography was indicated for suspected CAD and/or its risk stratification (history of acute myocardial infarction [AMI], myocardial revascularization, and/or angiographic evidence of significant coronary stenoses). All patients provided written informed consent before undergoing stress echocardiography.

Follow-up was provided by the treating physicians on the basis of the information recorded in the medical history at each visit and by telephone interviews with the patients or relatives. Major events were cardiovascular death, AMI, or need for myocardial revascularization (angioplasty or coronary artery bypass grafting) >90 days after study performance. Statistical Analysis Results for continuous variables are expressed as mean 6 SD or median (interquartile range) according to normal or non-normal distribution. Qualitative variables are expressed as frequencies and percentages. Quantitative variables were compared by using Student t tests or nonparametric tests. Categorical variables were compared by using c2 or Fisher’s exact tests. Event-free survival was determined by using the Kaplan-Meier method for patients with normal and reduced CFVR. Survival times were compared by using the log-rank test. A Cox regression model was used to evaluate the association between independent variables and the presence of events, introducing significant variables in univariate analysis and calculating the hazard ratios (HRs) and their 95% confidence intervals (CIs). Statistical significance was set at a value of P < .05. SPSS version 16 (SPSS, Inc, Chicago, IL) was used to perform statistical analyses.

Stress Echocardiography Transthoracic stress echocardiographic studies were performed with commercially available echocardiographs (Vivid 9, Vivid 7, and System 5 [GE Medical Systems, Milwaukee, WI] and, from 2001 to 2006, HDI 5000 [Philips Medical Systems, Andover, MA]), equipped with multifrequency probes and second-harmonic technology. All patients were simultaneously monitored with 12-lead electrocardiography.9 Two-dimensional images were obtained at rest and with doses of up to 50 mg/kg/min dobutamine (n = 351) or 0.84 mg/kg dipyridamole over 4 min (n = 300). Sensitization with atropine was done in patients without contraindications to its use and with handgrip maneuvers. In all patients, distal LAD CFVR was obtained with pulsed Doppler echocardiography under color Doppler guidance. Coronary flow velocity was continuously acquired from baseline until the first minute after ending dipyridamole infusion and intermittently at baseline and at peak maximal dobutamine dose. CFVR was defined as the ratio between maximum diastolic flow velocity at peak stress and baseline flow velocity, considering as abnormal a value <2.7,20,21 It was categorized in 4 groups according to its absolute value: >2, 1.99 to 1.75, 1.74 to 1.5, and <1.49.

RESULTS Stress Echocardiography No major complications were registered during study performance. Baseline Population Characteristics Patients with normal and reduced CFVR had statistically significant differences in age (65.62 6 12.13 vs 69.61 6 9.91 years, P = .001); the rate of patients presenting with mild to moderate left ventricular systolic functional impairment secondary to inferior, lateral, or posterior wall motion abnormal contractility (8.8% vs 21%, P = .01); the presence of previous AMI (12.7% vs 19.5%, P = .047), and histories of diabetes (10.8% vs 24.6%, P = .0001) and active smoking (10.2% vs 17.2%, P = .031) (Table 1). Events during Follow-Up Preserved CFVR was registered in 523 patients and reduced CFVR in 128. The mean follow-up duration was 34.6 6 18 months. During this

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Table 1 Baseline characteristics of the two populations Normal CFVR

Restricted CFVR

Variable

(n = 523)

(n = 128)

Age (y) Male gender Mild to moderate LVEF Unstable angina Prior AMI Prior angina Prior CABG Prior PTCA Hypertension Active smoking Dyslipidemia Diabetes

65.62 6 12.13 259 (48.6%) 41 (8.8%) 15 (2.9%) 66 (12.7%) 136 (26.2%) 46 (8.9) 90 (16.7%) 229 (43.8%) 53 (10.2%) 193 (37%) 53 (10.8%)

69.61 6 9.98 70 (50.8%) 25 (21%) 2 (1.6%) 25 (19.5%) 27 (21%) 12 (9.4%) 25 (17.7%) 67 (52.3%) 22 (17.2%) 44 (34.4%) 29 (24.6%)

P

.001 NS .01 NS .047 NS NS NS NS .031 NS <.0001

Data are expressed as mean 6 SD or number (percentage). CABG, Coronary artery bypass grafting; LVEF, left ventricular ejection fraction; PTCA, percutaneous transluminal coronary angioplasty.

Table 2 Long-term major events, individual and combined analysis

Event

AMI PTCA CABG Cardiovascular death Combined AMI, revascularization, and cardiovascular death

Normal CFVR

Restricted CFVR

(n = 523)

(n = 128)

P

5 (1.1%) 10 (1.9%) 7 (1.3%) 6 (1.1%) 25 (4.8%)

4 (3.5%) 14(10.9%) 6 (4.7%) 9 (7%) 23 (18%)

NS <.001 .026 .001 .001

CABG, Coronary artery bypass graft surgery; PTCA, percutaneous transluminal coronary angioplasty.

period, there were 48 major events (combined end point of cardiovascular death, AMI, or need for revascularization), in 25 patients with normal CFVR and 23 with reduced CFVR (4.8% vs 18%, P < .0001; Table 2). The event rate was 14.6% (n = 82) in the diabetic population and 6.4% (n = 569) in the nondiabetic one (P = .012). In a subgroup analysis, diabetic patients with normal CFVR had 3 events (5.7%) and those with reduced CFVR 9 events (31%) (P = .003) during the course of follow-up. However, the number of events in patients with normal CFVR was not different between those with and those without diabetes (5.7% vs 4.6%, P = NS; Table 3). Univariate Analysis

Figure 1 Two examples of CFVR recordings during pharmacologic stress echocardiography, with dobutamine (A-B) and dipyridamole (C-D). The top recordings are with normal CFVR and the bottom recordings with reduced CFVR (baseline recordings on the left and peak stress on the right), both without abnormal contractility.

The statistically significant events in the univariate analysis of the normal- and reduced-CFVR groups were, respectively, incidence of percutaneous transluminal coronary angioplasty (1.9% vs 10.9%, P = .001), coronary artery bypass grafting (1.3% vs 4.7%, P = .026), and cardiovascular death (1.1% vs 7%, P = .001). The incidence of AMI was 1.1% and 3.5% for the normal- and reduced-CFVR groups, respectively (P = NS), and that of the combined end point (AMI, revascularization, and cardiovascular death) was 4.8% in patients with normal CFVR and 18% in those with reduced CFVR (P = .001; Table 2).

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Table 3 Events in the diabetic population Normal CFVR

Restricted CFVR

Event

(n = 53)

(n = 29)

P

AMI PTCA CABG Cardiovascular death

1(1.9%) 2 (3.8%) 0 (0%) 0 (0%)

1 (3.6%) 6 (20.7%) 1 (3.4%) 3 (10.3%)

NS .021 NS .041

CABG, Coronary artery bypass graft surgery; PTCA, percutaneous transluminal coronary angioplasty.

Figure 2 Kaplan-Meier curve. Event-free survival in 651 patients with normal and reduced CFVR and negative results on stress echocardiography (without abnormal contractility) with dobutamine or dipyridamole. The figure shows that event-free survival at 36 months for the normal CFVR group was significantly higher than that for the reduced CFVR group: 95% (95% CI, 92.6%– 97.3%) versus 79.8% (95% CI, 71%–88.6%) (log-rank test, P < .0001). Multivariate Analysis In the Cox regression multivariate analysis (adjusted for significant variables in the univariate analysis), CFVR (HR, 4.2; 95% CI, 2.4–7.4) and active history of smoking (HR, 2.2; 95% CI, 1.1–4.4) were the only independent predictors of combined morbidity and mortality events. Kaplan-Meier Curves Event-free survival curves showed statistically significant differences between the normal- and reduced-CFVR groups, both overall and for the diabetic and nondiabetic subgroups (P = .001). Estimated event-free survival of 95% (95% CI, 92.6%–97.3%) at 36 months for the normal-CFVR group was significantly higher than that of 79.8% (95% CI, 71%–88.6%) for the reduced-CFVR group (log-rank test, P < .0001; Figure 2). In a subgroup analysis, there were no differences in event-free survival curves between patients with and those without

Figure 3 Kaplan-Meier curves. Event-free survival in patients with normal and reduced CFVR, comparing those with and those without diabetes. The figure shows that event-free survival at 36 months for the normal-CFVR group (left) was 96.2 (95% CI, 91%–99.9%) and 94.9% (95% CI, 92.3%–97.9%) for patients with and those without diabetes, respectively. In the group with decreased CFVR (right), event-free survival at 36 months was 53.3% (95% CI, 32.9%–73.7%) and 84.3% (95% CI, 74.2%–92.4%) for patients with and those without diabetes, respectively. diabetes within the normal-CFVR group, but there were differences in the survival curves of the group with reduced CFVR (P = .05). Eventfree survival at 36 months in the group with normal CFVR was 96.2% (95% CI, 91%–99.9%) and 94.9% (95% CI, 92.3%–97.9%) for the diabetic and nondiabetic groups, respectively. Conversely, in the group with reduced CFVR, survival at 36 months was 53.3% (95% CI, 32.9%–73.7%) and 84.3% (95% CI, 74.2%–92.4%) for the diabetic and nondiabetic groups, respectively (Figure 3).

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Figure 4 Events according to type of stress. The figure shows that on dobutamine stress without abnormal contractility, the event rate with normal CFVR was 5.1%, compared with 21.8% with low CFVR (P < .001), whereas with dipyridamole and normal CFVR the event rate was 4.4% compared with 12% with reduced CFVR (P = .045).

Table 4 Probability of long-term major events according to CFVR value CFVR value

HR

95% CI

1.99–1.75 1.74–1.50 #1.49

2.8 4.7 5.4

(1.2–6.6) (2–11.2) (2.5–11.7)

Individual Analysis of Each Pharmacologic Stress Agent The event rate with dobutamine was 5.1% for patients with normal CFVR and 21.8% for those with reduced CFVR (P < .001), whereas with dipyridamole, the event rate was 4.4% for patients with normal CFVR and 12% for those with decreased CFVR (P = .045) (Figure 4). Analysis According to the Degree of Coronary Flow Reserve Restriction The HRs for long-term major events according to the CFVR value were 2.8 for CFVR of 1.99 to 1.75 (95% CI, 2.2–6.6), 4.7 for CFVR of 1.74 to 1.5 (95% CI, 2–11.2), and 5.4 for CFVR < 1.49 (95% CI, 2.5–11.7) (Table 4).

DISCUSSION Stress echocardiography has long been known as a technique that can stratify risk in patients with CAD. However, its sensitivity is not perfect, being reduced in patients under anti-ischemic treatment and those with poor echocardiographic windows, ventricular hypertrophy, single-vessel disease, diabetes, or left bundle branch block, among other factors.2–5 Another inherent limitation of stress echocardiography is subjectivity in the interpretation of wall contractility by visual analysis, which is still the state of the art according to the latest recommendations of the European Association of Echocardiography and the American Society of Echocardiography guidelines.9,23 In the quest for more objective

techniques, 15 years ago, we were one of the first groups in the world to promote the use of simultaneous CFVR measurement in the LAD territory as a feasible method to increase the sensitivity of stress echocardiography with dipyridamole.7 At present, the possibility of determining mean distal flow in the LAD and its CFVR exceeds 95% of patients evaluated.21,24,25 The CFVR information is additive to the exclusive wall motion result, as confirmed in a meta-analysis performed of five studies by Rigo,10 which included our experience,11 showing an increase in diagnostic sensitivity (from 67 6 9% to 90 6 3%) with scarce loss of specificity (from 93 6 2% to 86 6 12%) and remarkable increase in test accuracy (from 79 6 5% to 89 6 7%). Yet the prognostic value of CFVR has been explored in depth only in recent years.15–19 Rigo and his group were the first to establish that CFVR during dipyridamole stress echocardiography added prognostic value even in the group of patients with normal contractility. In one report from that group,19 reduced CFVR was independently associated with event occurrence or late revascularization in a group of unselected patients with normal contractility during dipyridamole stress echocardiography. Our work showed similar results. Stress echocardiography with reduced CFVR and normal dipyridamole by contractility criteria presented three times more events (mortality, AMI, and late revascularization [percutaneous transluminal coronary angioplasty and coronary artery bypass grafting]) (12% vs 4.4%, P = .045) than in patients with adequate CFVR (Figure 4). Although in the group with low CFVR, there were differences in baseline population characteristics, such as older age, greater incidence of previous AMI, greater proportion of low to moderate left ventricular impairment, and number of smokers and patients with diabetes, CFVR and history of smoking were the only predictors of events in the multivariate analysis. The apparent low prevalence of mid- and long-term events may seem surprising, but this is because all 651 patients included in the study were at low risk because of the inclusion and exclusion criteria we used. All patients had negative test results for myocardial ischemia according to visual analysis and showed no evidence of wall motion abnormalities in the segments perfused by the LAD in baseline conditions. In addition, patients with severely reduced ejection fractions were excluded from the study. Late revascularizations were considered events (>3 months after the study); it should be pointed out that cardiologists in our setting still do not perform revascularizations according to CFVR values and decide interventions only depending on wall motion abnormalities, which were absent in this study. Even with the exclusion of revascularizations, hard events such as death were significantly more prevalent in the group with abnormal CFVR. In a multicenter work from various hospitals in Italy, Cortigiani et al.18 showed that CFVR provides additional prognostic information in patients with and those without diabetes with negative results on stress echocardiography with dipyridamole. They concluded that especially normal CFVR in patients without anti-ischemic treatment was associated with a good prognosis and similar survival in both populations in an average 16-month follow-up of >1,000 patients evaluated. In our study, the diabetic population presented more than twice the number of events as patients without diabetes during follow-up (14.6% vs 6.4%), and event-free survival was significantly lower in patients with diabetes with reduced CFVR. According to a recent publication by the same group,26 LAD and right coronary artery CFVR allowed the identification of different prognostic variables. In particular, preserved CFVR in both vessels was highly predictive of very favorable outcomes, whereas reduced

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CFVR in any of the two arteries, especially the LAD, was a strong predictor of future events. In our study, we analyzed only the value of LAD CFVR, and although in recent years, we have obtained CFVR data from other arteries during dipyridamole stress echocardiography, it must be acknowledged that their feasibility was lower; hence, we decided to include only the results related to values found in the LAD territory. We found that low CFVR and history of smoking were independent risk factors. Coronary flow reserve increased by 4 times the risk for events during follow-up, while smoking doubled the risk. The additional value of measuring CFVR at the LAD level for patient prognosis with pharmacologic stress echocardiography and normal contractile response has been documented in clinical studies using dipyridamole as single stress, but to the best of our knowledge, there is no previous experience on the prognostic value with dobutamine. Dobutamine is one of the main stressors used worldwide in stress echocardiographic studies, so it was highly important to assess the prognostic behavior of CFVR with this agent. In an elegant study, Meimoun et al.24 compared in the same group of patients CFVR during dobutamine stress with CFVR obtained with a vasodilator and found a good correlation and concordance between the two tests in a wide range of LAD diseases. The importance of that study lies in the fact that dobutamine could be a good alternative to adenosine (or dipyridamole) for transthoracic CFVR assessment, particularly in patients with vasodilator contraindications or those scheduled for dobutamine stress echocardiography. It should be noted that in the clinical arena, the feasibility of analyzing LAD CFVR during dobutamine stress is slightly lower (84%–94%) compared with CFVR obtained by using vasodilator agents (about 92%–100%). In one of our studies, the feasibility of determining CFVR in the LAD territory during dobutamine stress echocardiography in ‘‘normal’’ patients was high, at 94%; mean CFVR was 2.67, and it was necessary to achieve a difference of 50 beats/min from the baseline heart rate or $75% of the maximal predicted heart rate to consider that the test for the analysis of CFVR was adequate.21 In the present study, 53.9% of patients were assessed under dobutamine (351 of 651), with a feasibility of 90%, slightly lower than that with dipyridamole. The results showed that dobutamine was as efficient as dipyridamole to predict events, without significant differences between the two stress agents (Figure 4). Analyzing together both types of stress, it was seen that normal CFVR in the LAD had a good prognosis, with a 4.8% event rate during an average follow-up duration of 34.6 6 18 months, while low CFVR was an additional, solid, and independent prognostic indicator, with an 18% hard event rate. Limitations Although the recommendation is to perform stress echocardiography with 48-hour interruption of b-blocker treatment, it is impossible to know whether all patients complied with this requirement, and although CFVR measurement is not largely affected by antiischemic medication,27 the contractile response can be masked.28 In this study, no correlation was performed between baseline blood glucose and/or glycated hemoglobin with CFVR. Although some studies have shown the impact of glucose control on CFVR,29 others have not confirmed this finding.30 In our case, because only outpatients are studied in the echocardiography laboratory, it was difficult to ascertain the actual values of blood parameters.

Journal of the American Society of Echocardiography October 2014

Follow-up of all patients was not accomplished, because of frequent changes of address, telephone number, health insurance provider, and primary care physician. Qualitative and subjective wall motion analysis was performed by highly experienced echocardiographers. The impossibility of an anatomic-functional correlation, which was not the purpose of this study, disallows an unraveling of the intimate mechanism by which low CFVR led to a worse prognosis. The presence of a significant coronary occlusion in the LAD territory was possibly the most common reason, but microvascular involvement or a dysfunctional endothelium cannot be ruled out and should be the subject of future studies. Practical Applications The clinical implications of the present study may have an important impact on the interpretation of stress echocardiographic studies performed with the two pharmacologic stress agents most widely used in daily practice. The most important message of this work is that reduced CFVR, even in the absence of contractile disorders, allows the identification, without other complementary studies, of patients who because of their worse prognosis should be under very special surveillance and be more aggressively treated, especially in the diabetic population, in which stress echocardiography demonstrating normal wall motion and reduced CFVR worsens the prognosis even more. If these results are confirmed in other studies including larger numbers of patients, there will be further grounds to consider the convenience of systematically measuring CFVR, at least in the LAD territory, in all pharmacologic studies.

CONCLUSIONS After stress echocardiography demonstrating normal wall motion, CFVR was an independent predictor of morbidity and mortality, and its degree of restriction was directly associated with greater risk. The presence of diabetes in patients with a normal contractile response on dobutamine or dipyridamole stress echocardiography worsened the prognosis only in patients with low coronary reserve.

REFERENCES 1. Marcowitz P, Armstrong W. Accuracy of dobutamine stress echocardiography in detecting coronary artery disease. Am J Cardiol 1992;69: 1269-73. 2. Sicari R, Cortigiani L, Bigi R, Landi P, Raciti M, Picano E, et al., Echo-Persantine International Cooperative (EPIC) Study Group; Echo-Dobutamine International Cooperative (EDIC) Study Group. Prognostic value of pharmacological stress echocardiography is affected by concomitant antiischemic therapy at the time of testing. Circulation 2004;109:2428-31. 3. Geleijnse ML, Vigna C, Kasprzak JD, Rambaldi R, Salvatori MP, Elhendy A, et al. Usefulness and limitations of dobutamine-atropine stress echocardiography for the diagnosis of coronary artery disease in patients with left bundle branch block. A multicentre study. Eur Heart J 2000; 20:1666-73. 4. Pingitore A, Picano E, Varga A, Gigli G, Cortigiani L, Lowenstein J, et al. Prognostic value of pharmacological stress echocardiography in patients with known or suspected coronary artery disease: a prospective, largescale, multicenter, head-to-head comparison between dipyridamole and dobutamine test. Echo-Persantine International Cooperative (EPIC) and Echo-Dobutamine International Cooperative (EDIC) Study Groups. J Am Coll Cardiol 1999;34:1769-77.

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5. Smart SC, Knickelbine T, Malik F, Sagar KB. Dobutamine-atropine stress echocardiography for the detection of coronary artery disease in patients with left ventricular hypertrophy. Importance of chamber size and systolic wall stress. Circulation 2000;101(3):258-63. 6. Dimitrow PP. Transthoracic Doppler echocardiography-noninvasive diagnostic window for coronary flow reserve assessment. Cardiovasc Ultrasound 2004;1:4. 7. Lowenstein J, Tiano C, Marquez G, Presti C. Increased sensitivity of echodipyridamole stress by simultaneous determination of coronary flow reserve by transthoracic echocardiography. Rev Argent Cardiol 2000; 68:683-96. 8. Pizzuto F, Voci P, Mariano E, Puddu PE, Sardella G, Nigri A. Assessment of flow velocity reserve by transthoracic Doppler echocardiography and venous adenosine infusion before and after left anterior descending coronary artery stenting. J Am Coll Cardiol 2001;38:155-62. 9. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, et al. Stress echocardiography expert consensus statement. Eur J Echocardiogr 2008;9:415-37. 10. Rigo F. Coronary flow reserve in stress-echo lab. From pathophysiologic toy to diagnostic tool. Cardiovasc Ultrasound 2005;25:3-8. 11. Lowenstein J, Tiano C, Marquez G, Presti C, Quiroz C. Simultaneous analysis of wall motion and coronary flow reserve of the left anterior descending coronary artery by transthoracic Doppler echocardiography during dipyridamole stress echocardiography. J Am Soc Echocardiogr 2003;16: 607-13. 12. Rigo F, Richieri M, Pasanisi E, Cutaia V, Zanella C, Della Valentina P, et al. Usefulness of coronary flow reserve over regional wall motion when added to dual-imaging dipyridamole echocardiography. Am J Cardiol 2003;91:269-73. 13. Nohtomi Y, Takeuchi M, Nagasawa K, Arimura K, Miyaka K, Kuwata K, et al. Simultaneous assessment of wall motion and coronary flow velocity in the left anterior descending artery during dipyridamole stress echocardiography. J Am Soc Echocardiogr 2003;16:457-63. 14. Takeuchi M, Miyazaki C, Yoshitani H, Otani S, Sakamoto K, Yoshikawa J. Assessment of coronary flow velocity with transthoracic Doppler echocardiography during dobutamine stress echocardiography. J Am Coll Cardiol 2001;38:117-23. 15. Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am J Cardiol 2009; 103:626-31. 16. Rigo F, Gherardi S, Galderisi M, Pratali L, Cortigiani L, Sicari R, et al. The prognostic impact of coronary flow reserve assessed by Doppler echocardiography in nonischemic dilated cardiomyopathy. Eur Heart J 2006;27: 1319-23. 17. Rigo F, Sicari R, Gherardi S, Djordjevic-Dikic A, Cortigiani L, Picano E. The additive prognostic value of wall motion abnormalities and coronary flow reserve during dipyridamole stress echo. Eur Heart J 2008;29:79-88. 18. Cortigiani L, Rigo F, Gherardi S, Sicari R, Galderisi M, Bovenzi F, et al. Additional prognostic value of coronary flow reserve in diabetic and

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