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Original article
Diagnostic and prognostic value of Doppler echocardiographic coronary flow reserve in the left anterior descending artery
  1. Lauro Cortigiani1,
  2. Fausto Rigo2,
  3. Maurizio Galderisi3,
  4. Sonia Gherardi4,
  5. Francesco Bovenzi1,
  6. Eugenio Picano5,
  7. Rosa Sicari5
  1. 1Cardiology Division, Campo di Marte Hospital, Lucca, Italy
  2. 2Cardiology Division, Umberto I Hospital, Mestre-Venice, Italy
  3. 3Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
  4. 4Cardiology Division, Cesena Hospital, Italy
  5. 5CNR, Institute of Clinical Physiology, Pisa, Italy
  1. Correspondence to Dr Rosa Sicari, CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy; rosas{at}


Background Vasodilator stress echocardiography allows dual imaging of regional wall motion and coronary flow reserve (CFR) on left anterior descending (LAD) artery. Hypertension may affect CFR independently of obstructive coronary artery disease (CAD) through coronary microcirculatory damage.

Aims The authors sought to determine the best value of Doppler-echocardiography-derived coronary flow reserve (CFR) for detecting ≥75% stenosis of the left anterior descending artery (LAD) and assessing the risk in patients with and without hypertension.

Participants The study group was formed by 2089 patients (1411 hypertensive patients and 678 normotensive patients) with known or suspected coronary artery disease who underwent dipyridamole (up to 0.84 mg/kg over 6 min) stress echo with CFR assessment of LAD by Doppler and coronary angiography.

Results Mean CFR was 2.20±0.62 in hypertensive patients and 2.36±0.70 in normotensive patients (p<0.0001). A significant LAD stenosis was present in 376 (18%) cases. With a receiver operating characteristic analysis, a CFR ≤1.91 was the best value for diagnosing LAD stenosis in both hypertensive patients (area under curve 0.86 (95% CI 0.84 to 0.88), sensitivity 87% (95% CI 82% to 91%), specificity 76% (95% CI 73% to 78%)) and normotensive patients (area under curve 0.90 (95% CI 0.88 to 0.92), sensitivity 89% (95% CI 81% to 95%), specificity 80% (95% CI 77% to 83%)). During a median follow-up of 15 months, there were 348 events (58 deaths, 79 ST elevation myocardial infarctions and 211 non-ST elevation myocardial infarctions). Multivariable prognostic indicators were age (HR=1.0; 95% CI 1.0 to 1.04), test positivity for wall motion criteria (HR=5.9; 95% CI 3.6 to 9.6) and CFR on LAD ≤1.91 (HR=3.4; CI 95% 2.0 to 5.6) in normotensive patients and previous myocardial infarction (HR=1.3; 95% CI 1.0 to 1.7), test positivity for wall motion criteria (HR=5.0; 95% CI 3.8 to 6.6) and CFR on LAD ≤1.91 (HR=3.1; CI 95% 2.4 to 4.1) in hypertensive patients.

Conclusions CFR on LAD provides useful information for vessel stenosis and prognostic assessment in both hypertensive and normotensive patients. However, diagnostic specificity is reduced in hypertensive.

Statistics from

Risk stratification of hypertensive patients is a major objective for the clinical cardiologist, given their increased risk for coronary artery disease (CAD).1 2 The non-invasive diagnosis of CAD in hypertensive individuals is particularly challenging for the cardiologist, because the coexistence of hypertension dramatically lowers the specificity of exercise electrocardiography and perfusion scintigraphy.3–6 Stress echocardiography has been proven to have a higher specificity than ECG7 8 or perfusion stress testing9 10 and has demonstrated its usefulness in stratification in hypertensive individuals.11 12 The combined evaluation of wall motion and coronary flow reserve (CFR) in the left anterior descending artery (LAD) during dipyridamole stress echocardiography has been recently proposed as a feasible13 and accurate method for the diagnosis of CAD, increasing test sensitivity with modest loss in specificity.13–16 Previous studies have shown that abnormal CFR correlates with unfavourable outcome in several subsets of patients such as those with known or suspected CAD,17 diabetes,18 normal or near-normal coronary arteries and negative stress echo by wall motion criteria.19 However, the relative diagnostic and prognostic importance of CFR over wall motion analysis remains to be established in the hypertensive population. In fact, several studies have documented a reduced CFR even in the absence of coronary obstructive disease20 using different techniques.21 Coronary microcirculatory dysfunction affects the left ventricle globally22 as well as regionally,23 24 and therefore, the CFR assessment on LAD—which would be inadequate for CAD detection—is an excellent option for evaluating global coronary microcirculation conditions in these patients. This prospective, multicentre, observational study aimed to compare the diagnostic and prognostic value of CFR in the LAD in hypertensive and normotensive patients with known or suspected CAD undergoing vasodilator stress echocardiography.



The initial population comprised 3987 patients prospectively enrolled at five Italian cardiology institutions (Lucca, Mestre, Cesena, Pisa and Napoli) from August 2003 to June 2009. The study design is observational, not randomised, and the analysis was retrospective, although the data were acquired in a prospective fashion and entered the databank at the time of initial assessment. The selection criteria included all patients referred for stress echo with subsequent documentation of coronary anatomy. All patients underwent stress echocardiography with wall motion and CFR assessment of LAD by transthoracic Doppler ultrasound, and the indications for stress echocardiography were as follows: suspicion of CAD (chest pain and/or positive or non-diagnostic exercise electrocardiogram) in 1238 (59%) patients and risk stratification of known CAD (ie, history of myocardial infarction, percutaneous coronary interventions and/or angiographic evidence of >50% diameter coronary stenosis) in 851 (41%) patients. Of the 3987 patients initially selected for the study, the following were excluded for varying reasons: 218 (5%) had undergone a previous surgical revascularisation (coronary artery bypass graft), 1445 (36%) did not undergo coronary angiography, 153 (4%) had inadequate echocardiographic image quality precluding satisfactory imaging of LAD flow, 77 (1.9%) had inadequate wall motion analysis and 5 had contraindications to dipyridamole (3 patients with asthma in treatment and 2 patients with severe chronic obstructive pulmonary disease). No patient had contraindication to aminophylline infusion. Thus, 2089 (1250 men; mean (±SD) age 64±11 years) patients formed the study group; of these, 1411 were hypertensive. Hypertensive patients were defined as those who have systolic pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg and/or who have undergone antihypertensive treatment. The diagnosis of hypertension was based on at least two blood pressure measurements per visit and at least two visits, although in particularly severe cases, the diagnosis was based on measurements taken during a single visit.1 All patients underwent coronary angiography within 3 months of the index test. According to individual needs and physician's choices, 1038 (50%) patients were evaluated after antianginal drugs had been discontinued, and 1051 (50%) patients were evaluated during antianginal treatment (table 1). All patients gave their written informed consent when they underwent stress echocardiography. When patients signed the written informed consent, they also authorised physicians to use their clinical data. Stress echo data were collected and analysed by stress echocardiographers not involved in patient care.

Table 1

Characteristics of hypertensive and normotensive patients

Stress echocardiography

Transthoracic stress echocardiographic studies were performed using commercially available ultrasound machinery (Sonos 7500 or iE 33, Philips Ultrasound, Andover, Massachusetts; Sequoia C256, Acuson Siemens, Mountain View, California; Vivid System 7, GE/Vingmed, Milwaukee, Wisconsin) equipped with a multifrequency phased-array sector scan probe (S3–S8 or V3–V7) and with second harmonic technology. Two-dimensional echocardiography and 12-lead electrocardiographic monitoring were performed in combination with high-dose dipyridamole (up to 0.84 mg over 6 min).25 Echocardiographic images were semiquantitatively assessed using a 17-segment, four-point scale model of the left ventricle.26 A wall motion score index was derived by dividing the sum of individual segment scores by the number of interpretable segments. Ischaemia was defined as stress-induced new and/or worsening of pre-existing wall motion abnormality. Rest wall motion abnormality was akinetic or dyskinetic myocardium with no thickening during stress. CFR was assessed during the standard stress echo examination by an intermittent imaging of both wall motion and LAD flow.25 Coronary flow in the mid-distal portion of LAD was searched in the low parasternal long-axis section under the guidance of colour Doppler flow mapping25 according to previously published protocols. Quality control of stress echo performance and reading in enrolled centres was previously described in depth.27 Briefly, the reader from each recruiting centre met the predefined criteria for stress echo reading. At that point, the centre could start recruiting patients.

The previously assessed intraobserver and interobserver variability for measurements of Doppler recordings and regional wall motion analysis assessment were <10%.16

Coronary angiography

Coronary angiography in multiple views was performed according to the standard Judkins or Sones technique. Obstructive CAD was defined by a quantitatively assessed coronary stenosis ≥75%. A vessel stenosis between 50% and 70% was taken as intermediate. The previously assessed intraobserver and interobserver variability of the method were 7% and 6%, respectively.28

Follow-up data

Events were defined as death or non-fatal acute coronary syndromes. In order to avoid misclassification of the cause of death,29 we considered overall mortality. The definition of non-fatal acute coronary syndromes included ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI). STEMI was defined by typical symptoms, ST elevation on electrocardiogram and cardiac enzyme changes. NSTEMI was an acute coronary syndrome causing typical chest pain, cardiac enzyme elevation and/or electrocardiographic modifications consistent with acute ischaemia requiring hospitalisation. Follow-up data were analysed for the prediction of hard events (death, STEMI or NSTEMI). When more than one of these events occurred, the patient was censored at the time of the most severe event.

Statistical analysis

The statistical analyses included descriptive statistics (frequency and percentage of categorical variables and mean and SD of continuous variables) and Kaplan–Meier survival curves. The individual effect of certain variables on event-free survival was evaluated with the use of the Cox regression model. To adjust for several risk factors, we performed multivariable Cox analysis with all the variables found to be significant at the univariable analysis entering in a single step. The proportional hazards assumptions of the Cox model was verified with the linear correlation test. A significance of 0.05 was required for a variable to be included in the multivariable model, while 0.1 was the cut-off value for exclusion. HRs with the corresponding 95% CI were estimated. Annual event rates were obtained from Kaplan–Meier estimates to take censoring of the data into account. Differences in survival rates between groups were tested by the log-rank test. A receiver operating characteristic analysis was used to assess the best value of CFR for diagnosing LAD stenosis in the hypertensive and normotensive populations. Calculations of sensitivity, specificity and accuracy were performed according to standard definitions. The 95% CIs were calculated, and the individual intervals were compared. Differences were considered significant at the 0.05 level when 95% CI did not overlap. All analyses were performed using SPSS statistical software (SPSS V.16.0, SPSS Inc.); all tests were two sided, and p values <0.05 were considered to be statistically significant.


The main clinical and echocardiographic findings in the study population are reported in table 1.

Stress echocardiographic findings

Mean CFR was 2.20±0.62 in hypertensive patients (1st quartile ≤1.77, 2nd quartile 1.78–2.10, 3rd quartile 2.11–2.52, 4th quartile ≥2.53) and 2.36±0.70 in normotensive patients (1st quartile ≤1.87, 2nd quartile 1.88–2.30, 3rd quartile 2.31–2.70, 4th quartile ≥2.71) (p<0.0001). Stress echo was positive for ischaemia in 603 (29%) cases. Wall motion score index was 1.17±0.3 at rest and 1.23±0.3 at peak stress (p<0.0001). Ejection fraction was significantly lower in the previous myocardial infarction group of patients than in those with no history of myocardial infarction (50±8 vs 57±8, p=0.02). Left bundle branch block was more frequently present in subjects with no history of myocardial infarction than in those with a previous myocardial infarction (7% vs 4%, p=0.002). Patients with diabetes had a significantly lower CFR in the hypertensive subset (2.08±0.61 vs 2.25±0.62, p<0.0001), whereas no interaction was observed in normotensive patients (2.26±0.80 vs 2.37±0.67, p=0.11). Coronary angiography showed obstructive CAD in 839 (40%) patients, of whom 376 (18%) had LAD stenosis, 263 (13%) had intermediate stenosis of at least one coronary artery and 987 (47%) had normal or near-normal coronary arteries. Of these 987 patients, 265 had known CAD (previous myocardial infarction and/or previous percutaneous coronary intervention) and 722 had suspected CAD. Twenty-one (1%) patients had a total LAD occlusion at angiography. CFR on the LAD territory was significantly reduced in the presence of a significant (≥75%) LAD stenosis (1.65±0.44 vs 2.39±0.61, p<0.0001); when a significant coronary stenosis was in a vascular bed different from LAD, CFR was above the normal value in hypertensive (2.32±0.52 vs 2.42±0.63, p<0.0001) and normotensive (2.28±0.51 vs 2.51±0.67, p=0.004) patients.

With a receiver operating characteristic analysis, a CFR ≤1.91 was the best value for diagnosing significant LAD stenosis in both hypertensive patients (area under curve 0.86 (95% CI 0.84 to 0.88), sensitivity 87% (95% CI 82% to 91%), specificity 76% (95% CI 73% to 78%)) and normotensive patients (area under curve 0.90 (95% CI 0.88 to 0.92), sensitivity 89% (95% CI 81% to 95%), specificity 80% (95% CI 77% to 83%)) (figure 1). While sensitivity was similar (p=0.53) in the two patient groups, specificity was lower (p=0.046) in patients with hypertension. At individual patient analysis, 711 (34%) patients had a CFR ≤1.91: 513 (36%) hypertensive patients and 198 (29%) normotensive patients (p=0.001). Diagnostic sensitivity was comparable between patients tested on and off β-blocking treatment (87% (95% CI 81% to 92%) vs 88% (95% CI 82% to 92%)). However, CFR was significantly lower in subjects on β-blocking treatment than in those off β-blocking treatment: 2.13±0.57 vs 2.26±0.65 (p<0.0001) in hypertensive patients and 2.17±0.59 vs 2.42±0.72 (p<0.0001) in normotensive patients. The same also applies to patients on calcium channel blockers: 2.10±0.56 vs 2.24±0.64 (p<0.0001) in hypertensive patients and 2.00±0.47 vs 2.41±0.71 (p<0.0001) in normotensive patients.

Figure 1

Receiver operating characteristic analysis showing a value of CFR ≤1.91 as the best cut-off for diagnosing significant (≥75%) LAD artery stenosis in hypertensive as well as normotensive patients.

Follow-up events

During a median follow-up of 15 months (IQR 5–38 months), there were 348 hard events (58 deaths, 79 STEMIs and 211 NSTEMIs). Two hundred and seven events occurred in patients with a positive test and 141 events occurred in those with a negative test for wall motion criteria (34% vs 9%, p<0.0001). Two hundred and sixty-eight events occurred in hypertensive patients and 80 events occurred in normotensive patients (19% vs 12%, p<0.0001). Patients on β-blocking agents at the time of testing had a similar incidence of events when compared to those off β-blocking treatment (16% vs 17%, p=NS). Additionally, 526 patients underwent revascularisation (135 surgery and 391 angioplasty) after a median of 102 days (1st quartile 31, 3rd quartile 210) from stress echo: 393 hypertensive patients and 133 normotensive patients (28 vs 20%, p<0.0001).

Survival analysis

Annual event rate was 12.7% in hypertensive patients and 9.7% in normotensive patients (p=0.04) with known CAD and 9.2% in hypertensive patients and 3.8% in normotensive patients (p<0.0001) with suspected CAD. Survival estimates in hypertensive and normotensive patients with suspected CAD are reported in figure 2.

Figure 2

Event rate for hypertensive and normotensive patients with suspected CAD. Number of patients per year is shown.

Using the Kaplan–Meier method, low CFR as expressed by the lowest quartile was predictive of a significantly (p<0.0001) worse outcome than other quartiles in hypertensive and normotensive patients (figure 3). This dynamic of stratification also applied to the subset of patients with negative stress echo for wall motion criteria: low CFR as expressed by lowest quartile identified the subset at higher risk for hard events (figure 4). In the subset of patients with normal or near-normal coronary arteries, low CFR identified by the lowest quartile was associated with markedly increased risk (p<0.0005) than other quartiles in hypertensive and normotensive patients (figure 5). Finally, from the interaction of two prognostically important echocardiographic parameters, such as positivity for wall motion criteria and low CFR, an effective risk stratification was obtained in both hypertensive and normotensive patients (figure 6). In figure 7, the hard survival rates are reported in hypertensive and normotensive patients separated on the basis of gender. Univariate and multivariate prognostic indicators are reported in tables 2–5.

Figure 3

Event rate for hypertensive and normotensive patients according to quartiles of CFR in the whole study population. Number of patients per year is shown.

Figure 4

Event rate for hypertensive and normotensive patients according to quartiles of CFR in the group with no wall motion abnormalities at stress echo. Number of patients per year is shown.

Figure 5

Event rate for hypertensive and normotensive patients according to quartiles of CFR in the group with normal or near-normal coronary arteries. Number of patients per year is shown.

Figure 6

Annual event rate for hypertensive and normotensive patients according to the presence (Positive SE) or absence (Negative SE) of ischaemia at stress echocardiography and normal (CFR>2) or abnormal (CFR≤2) CFR.

Figure 7

Event rate for women and men with CFR >2.0 or <2.0 in hypertensive and normotensive patients. Number of patients per year is shown.

Table 2

Univariable predictors of hard events (death, STEMI, NSTEMI) in hypertensive and normotensive patients

Table 3

Multivariable predictors of hard events (death, STEMI, NSTEMI) in hypertensive and normotensive patients

Table 4

Univariable predictors of hard events (death, STEMI, NSTEMI) in hypertensive and normotensive patients with negative test for wall motion criteria

Table 5

Multivariable predictors of hard events (death, STEMI, NSTEMI) in hypertensive and normotensive patients with negative test for wall motion criteria


In patients with arterial hypertension, wall motion changes and Doppler-derived CFR on LAD during dipyridamole stress echocardiography are additive and complementary for the identification of patients at higher risk of experiencing hard events. A reduced CFR is an additional parameter to be considered in the risk stratification of the stress echocardiographic response, whereas patients with a negative test and normal CFR have a favourable outcome. Interestingly, the cut-off value of CFR for risk stratification is different between hypertensive and normotensive patients, with the value being lower in the hypertension subset.

Comparison with previous studies

Several studies have shown that in hypertensive patients, pharmacological stress echocardiography shows an accuracy at least comparable to that of myocardial scintigraphy, with superior specificity and a similar sensitivity.6–10 In addition, pharmacological stresses have a significantly higher feasibility than exercise stress testing, especially with vasodilator testing, which does not evoke the often limiting hypertensive response30 that can be associated with dobutamine stress and which induces false-positive results.31 Our results add information regarding the diagnostic accuracy of abnormal CFR in normotensive and hypertensive patients: sensitivities are comparable between the two groups, but the specificity is lower in the hypertensive group. Moreover, the dual-imaging approach assessing both wall motion and CFR has the ability to stratify patients, identifying those at risk of experiencing hard events. The prognostic value of stress-induced wall motion abnormalities is strong and extensively documented in hypertensive patients.11 12 32 In fact, hypertensive patients with inducible wall motion abnormalities are at higher risk than those without. These results confirm and expand previous studies showing an additive value of CFR assessment. In keeping with our previous results, we did not use a dichotomised value of CFR; rather, we used a continuous scale.33 The wide spectra of risk, as obtained by the combination of wall motion and CFR, are further dissected by the range of CFR values. Arterial hypertension can provoke a reduction in CFR through several mechanisms, which may overlap in the individual patient: CAD, left ventricular hypertrophy and microvascular disease.23 34 Abnormal CFR has been demonstrated in patients with essential hypertension, despite the presence of angiographically normal arteries and the absence of left ventricular hypertrophy20 by using different techniques.21 Noteworthy, coronary microvascular dysfunction in patients with hypertension is not necessarily related to the presence or degree of left ventricular hypertrophy and its onset is often early, as it is associated with changes in left ventricular geometry (concentric remodelling) when left ventricular mass is still normal.35 However, hypertension is only one of the many factors that may significantly affect the microcirculation with a significant reduction in CFR. In fact, it has been recently demonstrated that in a large cohort of patients without obstructive CAD undergoing invasive coronary angiography and comprehensive assessment of coronary vasomotion, the conventional Framingham risk factors were independently associated with coronary microcirculatory vasodilator function, specifically with the direct measurement of CFR.36 From a pathophysiological standpoint, it is conceivable that coronary atherosclerosis involves the microcirculation at the very early stages of disease.37 Our study, in line with these reports, adds an important piece of information by showing that the more significant is the impairment of CFR, the worse is the outcome. All these pathophysiological conditions may contribute to impairment of CFR and may adversely affect prognosis. When compared to other stress imaging techniques with comparable prognostic value, such as myocardial perfusion scintigraphy, stress echocardiography has three clear advantages: lower cost, higher specificity (no need for coronary angiography) and lack of radiation exposure. Contrast stress echocardiography may be a suitable tool in this setting,38 but still safety concerns, costs and reimbursement policy in different countries do not allow its widespread use. The potential role of CT scanning in this set of patients has yet to be established, and its cost and limited availability do not allow its routine use in the clinical practice.

Clinical implications

The clinical implications of this study are far reaching and have a powerful impact on the interpretation of the stress echocardiographic response in hypertensive and normotensive patients, able to identify several classes of patients with different levels of risk. Not all tests are created equal, and a spectrum of stratification is possible inside both positive and negative test results. A large extent of inducible myocardial ischaemia expressed by the delta variation of wall motion score index between rest and peak stress at a low workload will identify patients with an underlying severe CAD. This is consistent with our previous results showing that stress echo result allows an effective prognostication in hypertensive and normotensive patients. However, a non-ischaemic test predicts better survival in normotensive patients than in hypertensive patients with no regional wall motion abnormalities.39 Wall motion and CFR are additive and complementary in both hypertensive and normotensive patients. The annual event rate is as low as 1.5% in normotensive patients with negative test and normal CFR; however, the risk is doubled in hypertensive patients. In all the several subgroups (figure 4), hypertensive patients have a higher annual event rate. In the subset of patients with normal or near-normal coronary arteries, abnormal CFR on LAD can identify a subgroup of patients with a less benign prognosis; however, hypertensive patients have a worse prognosis than normotensive patients. It is conceivable that these higher-risk patients should be treated more aggressively in terms of lifestyle changes and risk factor modifications. Strict surveillance is strongly recommended for those with a negative test under medical treatment and abnormal CFR.40 If wall motion analysis is heavily influenced by concomitant medical treatment, CFR is not. The possibility of obtaining in the same test a piece of information that is totally independent of the anti-ischaemic effect of medical treatment may add value to risk stratification and overcome the limits of the interpretation of tests performed under medical treatment. The number of false-negative tests by wall motion criteria can be reduced according to normal/abnormal CFR, when discontinuation of treatment is not possible or feasible. On the other hand, medical treatment efficacy provided by test negativity will allow further risk stratification if CFR is not above the value of 2.

Study limitations

The CFR was sampled only on LAD. There is no doubt that a three-coronary approach would be more fruitful, but at present, it remains too technically challenging for a large-scale assessment. However, as demonstrated in one of our previous reports,41 the CFR impairment on one single territory is more relevant when it occurs on the anterior one; therefore, from a practical viewpoint, the assessment of CFR only on LAD is more feasible and less technically demanding, and its prognostic value remains unchanged even after RCA assessment. It has been observed, using several techniques, that microcirculatory dysfunction affects the left ventricle globally as well as regionally.23 24 The study was not designed to address the effect of antihypertensive treatment; therefore, enrolling centres evaluate each patient according to the referring physician's prescriptions. Also, we cannot exclude that during the follow-up period, medical treatment may have been changed to obtain optimal hypertension control. Still, this population represents the wide variety of patients referred for high-volume stress echo laboratories with a recommendation to undergo a second-line imaging technique for diagnostic and prognostic purposes. A further limitation is the non-inclusion of left ventricular mass and hypertrophy—recognised independent hallmarks of cardiovascular risk in arterial hypertension—in the multivariate models.42 These data were not available in the majority of patients in our databank, which comprised a very large population sample; however, it must be taken into account that the impairment of CFR occurs early in the clinical history of hypertensive patients, even before the onset of clear-cut left ventricular hypertrophy.


In hypertensive patients, stress echocardiography with dual-imaging assessment of wall motion and CFR provides effective risk stratification, especially in patients with negative tests and markedly reduced CFR, identifying the subset with a severe form of microvascular impairment. Hypertensive patients with inducible wall motion abnormalities (with or without underlying CAD) are at higher risk than those without. Within the subset with no wall motion abnormalities, patients with reduced CFR are at intermediate risk and patients with neither wall motion abnormalities nor abnormal CFR are at lowest risk.


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  • The preliminary data were presented at the European Society of Cardiology Meeting, Barcelona, Spain, 30 August–3 September, 2009.

  • Funding Financial support for the present study was received from institutional funding of the CNR, Institute of Clinical Physiology, Pisa, Italy.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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