Prognostic Meaning of Coronary Microvascular Disease in Type 2 Diabetes Mellitus: A Transthoracic Doppler Echocardiographic Study

Prognostic Meaning of Coronary Microvascular Disease in Type 2 Diabetes Mellitus: A Transthoracic Doppler Echocardiographic Study Lauro Cortigiani, MD, Fausto Rigo, MD, Sonia Gherardi, MD, Maurizio Galderisi, MD, Francesco Bovenzi, MD, and Rosa Sicari, MD, PhD, FESC, Lucca, Mestre, Cesena, Naples, and Pisa, Italy

Background: The prognostic value of Doppler-derived coronary flow velocity reserve (CFVR) of the left anterior descending coronary artery in patients with type 2 diabetes with preserved left ventricular systolic function and without flow-limiting stenoses on angiography remains undetermined. Methods: The study sample consisted of 144 patients with type 2 diabetes (82 men; mean age 62 6 10 years) with chest pain or angina-equivalent symptoms, no histories of coronary artery disease, and echocardiographic ejection fractions $ 50%. All patients underwent dipyridamole stress echocardiography with CFVR assessment of the left anterior descending coronary artery by transthoracic Doppler echocardiography and coronary angiography showing normal coronary arteries or nonobstructive coronary artery disease. Results: Mean CFVR was 2.44 6 0.57. On individual patient analysis, 109 patients (76%) had CFVR > 2, and 35 (24%) had CFVR # 2. During a median follow-up period of 29 months (interquartile range, 14–44 months), 17 hard events (five deaths, 12 nonfatal myocardial infarctions) occurred. The annual hard-event rate was 13.9% in subjects with CFVR # 2 and 2.0% in those with CFVR > 2. The annual event rate associated with CFVR # 2 was significantly higher both in patients with left ventricular hypertrophy (P < .0001) and in those without left ventricular hypertrophy (P = .048). On Cox analysis, CFVR # 2 (hazard ratio, 11.20; 95% confidence interval, 3.07–40.92), and male sex (hazard ratio, 7.80; 95% confidence interval, 1.74–34.97) were independent prognostic indicators, whereas nonobstructive coronary artery disease was not an independent predictor of outcomes. Conclusions: Microvascular dysfunction before the occurrence of coronary artery involvement is a strong and independent predictor of outcomes in patients with type 2 diabetes. Vasodilator stress CFVR is a suitable tool to assess microvascular dysfunction in routine clinical practice. (J Am Soc Echocardiogr 2014;-:---.) Keywords: Diabetes, Vasodilator stress echocardiography, Coronary flow velocity reserve, Prognosis, Microvascular disease

Diabetes mellitus provokes functional and morphologic alterations of the coronary microcirculation even in the absence of epicardial coronary atherosclerosis. In fact, vasomotor function is impaired in patients with type 2 diabetes because of decreased bioavailability of the potent vasodilator endothelium-derived nitric oxide1,2 and increased secretion of vasoconstrictor mediators such as endothelin13 and angiotensin II.4 Diabetic autonomic neuropathy contributes to alter coronary vasoreactivity.5 In addition, hyalinization6 or wall

From the Cardiology Division, Campo di Marte Hospital, Lucca, Italy (L.C., F.B.); Divisione di Cardiologia, Ospedale dell’Angelo, Mestre-Venezia, Italy (F.R.); Cardiology Division, Cesena Hospital, Cesena, Italy (S.G.); Department of Medical Translational Science, Federico II University Hospital, Naples, Italy (M.G.); CNR, Institute of Clinical Physiology, Pisa, Italy (R.S.). The authors were funded by the CNR, Institute of Clinical Physiology, Pisa, Italy. Reprint requests: Rosa Sicari, MD, PhD, FESC, CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.02.010

thickening of intramural arterioles6,7 and reduced density of capillary vessels8 have been reported as structural changes of the diabetic heart. Most patients with type 2 diabetes have associated arterial hypertension,9 dyslipidemia,10 and obesity,11 contributing to coronary microvascular damage.12-15 Previous evidence shows both reduced maximal coronary vasodilation and impairment in the regulation of coronary flow in response to submaximal increases in myocardial demand in patients with diabetes mellitus.16 These microvascular abnormalities may lead to myocardial ischemia in the absence of epicardial coronary atherosclerosis in some circumstances and thus contribute to adverse cardiovascular events in patients with diabetes. Functionally, microvascular disease in patients with diabetes translates into reduced coronary flow reserve, as demonstrated with different techniques such as intracoronary Doppler,16,17 transesophageal Doppler echocardiography,18 and positron emission tomography (PET).19,20 Unfortunately, these techniques do not apply to daily practice. However, coronary flow reserve measurement in patients with diabetes is of potential clinical interest, as invasively detected impaired coronary flow reserve is an established prognostic predictor in unselected cohorts of patients with normal or mildly diseased coronary arteries.21 Moreover, perfusion defects on single-photon emission computed tomography 1

2 Cortigiani et al

were associated with markedly increased risk in asymptomatic CAD = Coronary artery patients with diabetes without disease known coronary artery disease (CAD),22 while the presence of CFVR = Coronary flow coronary vascular dysfunction, as velocity reserve assessed using PET, indepenLAD = Left anterior dently predicted cardiac and descending coronary artery all-cause mortality in patients LV = Left ventricular with and those without diabetes.23 Intriguingly, patients PET = Positron emission with diabetes without known tomography CAD with visually normal results on PET but impaired coronary flow reserve experienced a cardiac mortality rate comparable with that in patients with known CAD23; conversely, patients with diabetes without known CAD and visually normal results on PET who had preserved coronary flow reserve experienced a cardiac mortality rate comparable with that in patients without diabetes free of CAD with normal imaging findings.23 Lately, transthoracic Doppler echocardiography associated with vasodilatory stress has proved to be a highly feasible and effective modality for assessing risk in a general diabetic population,24 as well as in unselected25 and hypertensive26 patients without obstructive CAD. The aim of this prospective, multicenter, observational study was to investigate the prognostic implications of Doppler-derived coronary flow velocity reserve (CFVR) of the left anterior descending coronary artery (LAD) in patients with type 2 diabetes with angiographically normal or near normal coronary arteries and preserved systolic left ventricular (LV) function. Abbreviations

METHODS Patients From January 2006 to December 2009, 144 patients (82 men; mean age, 62 6 10 years) with type 2 diabetes27 were prospectively enrolled at 5 Italian cardiology institutions (in Lucca, Mestre, Cesena, Pisa, and Naples), fulfilling the following inclusion criteria: (1) chest pain or angina-equivalent symptoms, (2) no history of CAD (i.e., acute coronary syndrome, coronary revascularization, and/or angiographic evidence of $50% diameter coronary stenosis), (3) LV ejection fraction on resting echocardiography $ 50%, (4) no significant valvular or congenital heart disease, (5) no prognostically relevant noncardiac diseases (cancer, end-stage renal or liver disease, or severe obstructive pulmonary disease), (6) adequate acoustic window for imaging the left ventricle (for two-dimensional echocardiography) and LAD flow Doppler (for CFVR assessment), (7) dipyridamole stress echocardiography with CFVR assessment of the LAD by transthoracic Doppler echocardiography performed before (within 15 days) coronary angiography, and (8) coronary angiography showing normal coronary arteries or nonobstructive CAD. Follow-up information was available for all patients. Part of this sample (45 patients [31%]) was previously published24 and represents an extension of follow-up. Arterial hypertension,28 hypercholesterolemia,29 overweight or obesity,30 and smoking habit were considered associated cardiac risk factors and defined according to standard definition. According to individual needs and physicians’ choices, 59 patients (41%) were evaluated after antianginal drugs had been discontinued, and 85 patients (59%) were evaluated during antianginal treatment (Table 1). Phylline-containing drugs or beverages were discontinued

Journal of the American Society of Echocardiography - 2014

Table 1 Clinical, echocardiographic, and angiographic findings for patients with CFVR of the LAD > 2 and #2 Variable

Age (y) Men Duration of diabetes (y) Glycated hemoglobin (mg/dL) Insulin therapy Body mass index (kg/m2) Overweight or obesity Arterial hypertension Hypercholesterolemia Smoking habit Number of associated risk factors Left bundle branch block LV ejection fraction (%) LV mass index (g/m2) LV hypertrophy Resting heart rate (beats/min) Resting systolic blood pressure (mm Hg) Resting rate-pressure product Resting wall motion abnormalities Test performed on antianginal therapy b-blocking agents Calcium antagonists Long-acting nitrates Resting velocity in the LAD (cm/sec) Peak velocity in the LAD (cm/sec) CFVR of the LAD Normal coronary arteries Nonobstructive CAD

CFVR > 2 (n = 109)

CFVR # 2 (n = 35)

P

62 6 10 63 (58%) 864 7.8 6 0.8

65 6 12 19 (54%) 10 6 6 7.7 6 1.1

.14 .72 .12 .59

33 (30%) 27.5 6 2.8 96 (88%) 78 (72%) 56 (51%) 37 (34%) 2.4 6 1.0

14 (40%) 27.0 6 2.7 28 (80%) 27 (77%) 30 (86%) 8 (23%) 2.7 6 0.9

.29 .42 .23 .52 .0003 .22 .25

8 (7%) 59 6 6 114 6 25 61 (56%) 69 6 8

3 (9%) 58 6 8 122 6 27 24 (69%) 69 6 10

.81 .69 .11 .19 .95

138 6 16

149 6 17

.001

9,579 6 1,751 10,325 6 2,224

.04

11 (10%)

9 (26%)

.02

62 (57%)

23 (66%)

.36

38 (35%) 34 (31%) 14 (13%) 29 6 9

15 (43%) 15 (43%) 5 (14%) 37 6 15

.39 .21 .83 <.0001

76 6 23

66 6 24

.04

2.64 6 0.49 88 (81%) 21 (19%)

1.80 6 0.18 17 (49%) 18 (51%)

<.0001 .0002 .0002

Data are expressed as mean 6 SD or number (percentage).

$24 hours before testing. The decision to perform coronary angiography in the face of negative results on stress echocardiography was made by the referring physician on the basis of the clinical picture. The study was approved by the institutional review board. All patients gave written informed consent when they underwent stress echocardiography. When patients provided consent, they also authorized physicians to use their clinical data. Stress echocardiographic data were collected and analyzed by stress echocardiographers not involved in patient care.

Resting Echocardiography Two-dimensional targeted M-mode echocardiography was carried out under resting conditions for LV measurements, including interventricular septal thickness at end-diastole, LV internal dimension at end-diastole, and posterior wall thickness at end-diastole. Measurements were made in accordance with recommendations

Cortigiani et al 3

Journal of the American Society of Echocardiography Volume - Number -

from the American Society of Echocardiography.31 LV mass was calculated using the following formula32: LV mass (g) = 0.80  [1.04  (interventricular septal thickness at end-diastole + LV internal dimension at end-diastole + posterior wall thickness at end-diastole)3 (LV internal dimension at end-diastole)3] + 0.6 g. Dividing LV mass by body surface area derived LV mass index. LV mass index > 116 g/m2 in men and >104 g/m2 in women was the criterion for LV hypertrophy.33 Ejection fraction was obtained using Simpson’s rule.31 Stress Echocardiography Transthoracic stress echocardiographic studies were performed using commercially available ultrasound machines (Sonos 7500 or iE33, Philips Medical Systems, Andover, MA; Vivid System 7, GE Medical Systems, Milwaukee, WI; Acuson Sequoia C256, Siemens Medical Solutions USA, Inc, Mountain View, CA) equipped with multifrequency phased-array sector scan probes (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).34 Echocardiographic images were semiquantitatively assessed using a 17-segment, four-point scale model of the left ventricle.35 A wall motion score index was derived by dividing the sum of individual segment scores by the number of interpretable segments. Ischemia was defined as stress-induced new wall motion abnormality. CFVR was assessed during the standard stress echocardiographic examination by intermittent imaging of both wall motion and LAD flow.34 Coronary flow in the mid-distal portion of the LAD was sought in the low parasternal long-axis section under the guidance of color Doppler flow mapping.34 All studies were digitally stored to simplify offline reviewing and measurements. Coronary flow parameters were analyzed offline using the built-in calculation package of the ultrasound unit. Flow velocities were measured at least twice for each study: at baseline and at peak stress (before aminophylline injection). At each time point, three optimal profiles of peak diastolic Doppler flow velocities were measured, and the results were averaged. CFVR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. CFVR # 2 was considered abnormal.24 All observers were trained by the same senior investigator (F.R.), providing consistency in data acquisition, storage, and interpretation, and also through intensive joint reading sessions. All investigators from contributing centers passed quality control criteria for regional wall motion and Doppler interpretation before entering the study, as previously described.36 The previously assessed intraobserver and interobserver variability for measurements of Doppler recordings and regional wall motion analysis assessment were <10%.37 In our previous experience, the assessment of CFVR of the LAD had 94% feasibility.24 Coronary Angiography Coronary angiography in multiple views was performed according to the standard Judkins technique, adopting femoral or radial approach. At least five views (including two orthogonal views) were acquired for the left and at least two orthogonal views for the right coronary artery. Additional appropriate projections were obtained in case of superimposition of side branches or foreshortening of the segment of interest. Obstructive CAD was defined as a quantitatively assessed coronary stenosis of $50%. Normal coronary arteries were defined as 0% stenosis in any major vessel or secondary branch. Nonobstructive CAD was defined as any irregularity between 1% and 9% or vessel stenosis between 10% and 40% stenosis in any coronary artery.

The previously assessed intraobserver and interobserver variability of the method were 7% and 6%, respectively.38 Follow-Up Data Outcomes were determined from patient interviews at the outpatient clinic, hospital chart reviews, and telephone interviews with patients, their close relatives, or referring physician. Death and nonfatal myocardial infarction were registered as clinical events. Coronary revascularization (surgery or percutaneous interventions) was also recorded. To avoid misclassification of the cause of death,39 overall mortality was considered. Myocardial infarction was defined by typical symptoms, electrocardiographic evidence, and cardiac enzyme changes. Follow-up data were analyzed for the prediction of hard events (death or nonfatal myocardial infarction). Statistical Analysis Continuous variables are expressed as mean 6 SD. Differences between groups were compared using Student’s t and c2 tests, as appropriate. Linear regression was used to assess the correlation between CFVR and LV mass index. Hard event rates were estimated using Kaplan-Meier curves and compared using the log-rank test. Only the first event was taken into account. Patients undergoing coronary revascularization (n = 9) were censored at the time of the procedure. Annual event rates were obtained from Kaplan-Meier estimates to take censoring of the data into account. The associations of selected variables with outcomes were assessed using Cox proportional-hazards modeling with univariate and stepwise multivariate procedures. A significance level of .05 was required for a variable to be included into the multivariate model, while a level of .10 was the cutoff for exclusion. Hazard ratios with corresponding 95% confidence intervals were estimated. Statistical significance was set at P < .05. SPSS version 16 (SPSS, Inc, Chicago, IL) was used for analysis.

RESULTS The main clinical, echocardiographic, and angiographic findings in the study group are listed in Table 1. Stress Echocardiographic Findings No complications or limiting side effects occurred. Stress echocardiographic results were negative for ischemia in all patients. Mean CFVR in the entire study group was 2.44 6 0.57. On individual patient analysis, 109 patients (76%) had CFVR > 2, and 35 (24%) had CFVR # 2. Compared with patients with CFVR > 2, those with CFVR # 2 more frequently had hypercholesterolemia, had higher resting and lower peak LAD flow velocities, and had a greater frequency of nonobstructive CAD (Table 1). In the subset with abnormal CFVR, rate-pressure products were significantly higher under resting conditions because of a higher mean systolic blood pressure (see Table 1). CFVR was inversely related with LV mass index (Figure 1), as well as the number of associated cardiac risk factors, 2.54 6 0.61 in the group of 68 patients with two or fewer risk factors and 2.34 6 0.50 in the group of 76 patients with three or more risk factors (P = .03). The number of risk factors was comparable in the 105 patients with normal coronary arteries and 39 patients with nonobstructive CAD (2.4 6 1.0 vs 2.6 6 0.8, P = .27). However, CFVR was markedly lower in the latter group (2.56 6 0.57 vs 2.11 6 0.40, P < .0001).

4 Cortigiani et al

Figure 1 Inverse linear relation between CFVR of the LAD and LV mass index.

Follow-Up Events During a median follow-up period of 29 months (interquartile range, 14–44 months), 17 hard events (five deaths, 12 nonfatal myocardial infarctions) were registered. There were 11 events (31.4%) in patients with CFVR # 2 and six events (5.5%) in those with CFVR > 2. Survival Analysis The annual hard-event rate was 13.9% in subjects with CFVR # 2 and 2.0% in those with CFVR > 2 (P < .0001). When the sample was separated on the basis of LV hypertrophy, the annual event rate associated with CFVR # 2 and with CFVR > 2 were, respectively, 15.4% and 1.6% (P < .0001) in the hypertrophic group and 10.9% and 2.5% (P = .048) in the nonhypertrophic group. Univariate and multivariate prognostic indicators are illustrated in Table 2. Independent predictors of future events were CFVR # 2 (hazard ratio, 11.20; 95% confidence interval, 3.07–40.92; P < .0001), and male sex (hazard ratio, 7.80; 95% confidence interval, 1.74–34.97; P = .007). Nonobstructive CAD provided univariate but not multivariate prognostic contribution. KaplanMeier survival estimates for hard events showed a worse 3-year event rate for patients with CFVR # 2 compared with those with CFVR > 2 (48% vs 7%, P < .0001; Figure 2). DISCUSSION Our results show that Doppler-derived CFVR of the LAD is a useful tool for assessing the presence and prognostic effect of microvascular disease in patients with type 2 diabetes. In particular, we found CFVR to be reduced in one in four patients with diabetes with angiographically normal or near normal coronary arteries and preserved LV ejection fractions, and, most important, CFVR # 2 conferred strong and independent prognostic information, predicting a nearly seven times higher yearly hard-event rate compared with normal CFVR (>2). Male sex was also a multivariate prognostic indicator in these patients, whereas anatomic evaluation demonstrated marginal usefulness in risk stratification. In fact, nonobstructive CAD failed to provide independent prognostic contribution, although it was associated with significantly lower mean CFVR.

Journal of the American Society of Echocardiography - 2014

Comparison with Previous Studies Previous studies using different techniques16-20 have reported abnormal coronary flow reserve in patients with type 2 diabetes with normal coronary arteries, indicating that microcirculation may be affected before the occurrence of coronary atherosclerosis. However, conventional cardiac risk factors are frequently associated to diabetes,9-11 contributing to the progression of microvascular disease.12-15 In a previous experience on unselected patients without significant coronary narrowing, a higher Framingham risk score independently predicted impaired coronary flow reserve.40 Similarly, in the present study of patients with diabetes, mean CFVR was significantly lower in subjects with three or more associated risk factors. Cardiac hypertrophy is another pathophysiologic condition that may negatively affect coronary flow reserve.13 Accordingly, we found an inverse relation between CFVR and indexed LV mass. The association between depressed CFVR and future cardiac events has been extensively documented in unselected patient populations,21,25 as well as in patients with hypertension26 without obstructive CAD. The present results expand to patients with type 2 diabetes the prognostic consequences deriving from microvascular disease. Interestingly, CFVR > 2 was predictive of a benign prognosis, confirming the results of a previous study in patients with diabetes with known or suspected CAD and negative vasodilator stress echocardiographic results.24 In our previous study, we explored the reasons why CFVR may be reduced in the absence of stress-induced wall motion abnormalities: mild to moderate epicardial coronary artery stenosis, severe epicardial coronary artery stenosis in the presence of anti-ischemic therapy, and severe microvascular coronary disease in the presence of patent epicardial coronary arteries. This last item is the focus of the present results, demonstrating that in the face of normal coronary arteries and a lack of wall motion abnormalities at peak stress, the microvascular impairment in patients with diabetes modulates outcomes significantly. Several studies, mainly in patients with type 2 diabetes, have documented reduced coronary flow reserve even in the absence of coronary obstructive disease, using different techniques.41 Microcirculatory dysfunction affects the left ventricle globally as well as regionally,41 and therefore the CFVR assessment of the LAD, which would be inadequate for CAD detection, is an excellent option for evaluating global coronary microcirculation conditions in these patients. Therefore, a conceptually limited approach to a single territory (the LAD) is overcome by the observation that microvascular dysfunction affects the ventricle globally,42 and Doppler becomes a most valuable tool, being an excellent window on both macrovascular and microvascular dysfunction. Moreover, in a study from our group, it was demonstrated that patients with nonischemic dilated cardiomyopathy and normal coronary arteries had significant reductions in CFVR similarly in the LAD and the right coronary artery compared with control subjects. CFVR in the LAD was directly related to CFVR in the right coronary artery in both patients and controls,43 suggesting that coronary microcirculatory damage is diffuse and modulated by similar hemodynamic and functional determinants. Coronary flow reserve may be measured invasively with intracoronary Doppler or noninvasively with PET, myocardial perfusion imaging, magnetic resonance, and transesophageal or transthoracic Doppler echocardiography.44 Compared with other stress imaging techniques, transthoracic Doppler echocardiography offers important advantages, including wider availability, lower cost, and lack of radiation exposure, making it an attractive application for the everyday risk assessment of the diabetic population.

Cortigiani et al 5

Journal of the American Society of Echocardiography Volume - Number -

Table 2 Univariate and multivariate predictors of death and nonfatal myocardial infarction Univariate

Multivariate

Variable

HR (95% CI)

P

Age Male sex Duration of diabetes Glycated hemoglobin Insulin therapy Overweight or obesity Arterial hypertension Hypercholesterolemia Smoking habit Three or more associated risk factors Left bundle branch block LV mass index Resting wall motion abnormalities CFVR of the LAD Nonobstructive CAD

0.96 (0.92–1.00) 4.64 (1.33–16.21) 1.03 (0.97–1.08) 1.25 (0.72–2.15) 0.61 (0.20–1.88) 2.51 (0.33–18.97) 1.94 (0.56–6.77) 1.68 (0.55–5.17) 1.60 (0.61–4.21) 1.56 (0.58–4.23) 1.52 (0.35–6.67) 1.06 (0.89–1.25) 3.10 (1.09–8.80) 7.36 (2.71–19.99) 4.04 (1.56–10.51)

.08 .02 .35 .42 .39 .37 .30 .37 .34 .38 .58 .52 .03 <.0001 .004

HR (95% CI)

P

7.80 (1.74–34.97)

.007

11.20 (3.07–40.92)

<.0001

CI, Confidence interval; HR, hazard ratio.

and original approach to the assessment of microvascular dysfunction: vasodilator stress echocardiography is a sound risk stratifier enabling physicians to identify patients at higher risk for experiencing events; microvascular impairment seems to be an early event in the dysfunction process, leading to macrovascular disease and LV dysfunction. However, the present results cannot provide a definitive answer to what is really needed by clinicians: Would the modulation of CFVR alter outcomes in these patients? Is microvascular dysfunction reversible? Can therapeutic and lifestyle interventions modify the level of microvascular dysfunction? These questions need to be addressed in appropriately designed studies, but this tool is the best trade-off between pathophysiology and a more quantitative approach, as it can be obtained with other imaging and/or invasive techniques. Figure 2 Hard-event rate for patients with diabetes with CFVR of the LAD > 2 and #2. Number of patients per year is shown. Clinical Implications The results of the present study have a potential impact in the management of patients with type 2 diabetes with chest pain or angina–equivalent symptoms. In particular, no further investigation is justified for those with CFVR of the LAD > 2 and negative results on stress echocardiography for ischemia, because of their low risk for future cardiac events. On the contrary, angiographic evaluation should be considered for patients with diabetes with CFVR of the LAD # 2, even in the absence of ischemia. In these higher risk patients, an aggressive strategy, including the achievement of tight metabolic control, adequate intensive pharmacologic therapy, and lifestyle changes seem to represent the logical approach in the case of angiographically normal or mildly diseased arteries. On the basis of the present evidence, it is likely that microvascular dysfunction occurs well before the coronary arteries are affected. Moreover, microvascular impairment may be related to the development of LV dysfunction in the absence of significant CAD.45 The pathogenesis of coronary microcirculatory dysfunction in diabetes is still unsettled, and a uniform therapeutic approach may not be sufficient to prevent its development. The present results are far reaching and offer a novel

Study Limitations In this study, there was no central reading. Stress echocardiography and CFVR measurements were interpreted at the peripheral centers and entered directly into the data bank. This system allowed substantial sparing of human and technological resources, but it was also the logical prerequisite for a large-scale study, designed to represent the realistic performance of the test rather than the results of a single lab, or even a single person, working in a highly dedicated echocardiographic laboratory. Because the assessment of the echocardiograms was qualitative and subjective, variability in their reading might have modulated the results at individual centers. However, all our readers at individual centers had long-term experience in echocardiography, passed quality control in stress echocardiography reading as previously described,36 and had extensive experience in the performance and interpretation of CFVR also through joint reading sessions. CFVR was sampled only in the LAD. There is no doubt that the three-coronary-artery approach would be more fruitful, but at present, it remains too technically challenging for a large-scale assessment. The available technology and echocardiographer expertise would allow the detection of CFVR of the three vascular territories, but this pathophysiologic approach would make the test highly unfeasible

6 Cortigiani et al

on a routine basis. Our main aim was to test not only the efficacy but also the effectiveness of the combined information on wall motion and CFVR in a single test. The average body mass index of the sample under investigation was 27 kg/m2. It is conceivable that a selection bias may have been introduced, because only patients with good acoustic windows were entered into the data bank. Moreover, in Italy, obesity does not have the characteristics of an epidemic, as in the United States, and this may be another reason for the low enrollment rate of obese patients. CONCLUSIONS Microvascular dysfunction before the occurrence of coronary artery involvement is a strong and independent predictor of outcomes in patients with type 2 diabetes. Vasodilator stress CFVR is a suitable tool to assess microvascular dysfunction in routine clinical practice. In particular, CFVR of the LAD # 2 represents a strong and independent predictor of the combined event of death and nonfatal myocardial infarction. REFERENCES 1. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-74. 2. De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol 2000;130:963-74. 3. Park J-Y, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, et al. Induction of endothelin-1 expression by glucose. An effect of protein kinase C activation. Diabetes 2000;49:1239-48. 4. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management. JAMA 2002;287:2570-81. 5. Takahashi T, Nishizawa Y, Emoto M, Kawagishi T, Matsumoto N, Ishimura E, et al. Sympathetic function test of vasoconstrictor changes in foot arteries in diabetic patients. Diabetes Care 1998;21:1495-501. 6. Sutherland CG, Fisher BM, Frier BM, Dargie HJ, Lindop GB. Endomyocardial biopsy pathology in insulin-dependent patients with abnormal ventricular function. Histopathology 1988;14:593-602. 7. Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J 1989;118: 1000-12. 8. Yarom R, Zirkin H, Stammler G, Rose AG. Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material. J Pathol 1992;166:265-70. 9. Geiss LS, Rolka DB, Engelgau MM. Elevated blood pressure among U.S. adults with diabetes 1988-1994. Am J Prev Med 2002;22:42-8. 10. Rubins HB, Robins SJ, Collins D, Iranmanesh A, Wilt TJ, Mann D, et al., Department of Veterans Affairs HDL Intervention Trial Study Group. Distribution of lipids in 8,500 men with CAD. Am J Cardiol 1995;75: 1196-201. 11. Must A, Spadano J, Coakley CH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA 1999; 282:1523-9. 12. Schwartzkopff B, Frenzel H, Dieckerhoff J, Betz P, Flasshove M, Schulte HD, et al. Morphometric investigation of human myocardium in arterial hypertension and valvular aortic stenosis. Eur Heart J 1992; 13(suppl):17-23. 13. Marcus ML. Importance of abnormalities in coronary flow reserve to the pathophysiology of left ventricular hypertrophy secondary to hypertension. Clin Cardiol 1989;12(suppl):IV34-5. 14. Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, et al. Reduction in serum cholesterol with pravastatin improves

Journal of the American Society of Echocardiography - 2014

endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519-24. 15. Granger DN, Rodrigues SF, Yildirim A, Senchenkova EY. Microvascular responses to cardiovascular risk factors. Microcirculation 2010;17:192-205. 16. Nasher PJ Jr., Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995;91:635-40. 17. Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. Impairment of coronary vascular reserve and Ach-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 1993;42:1017-25. 18. Kranidis A, Zamanis N, Mitrakou A, Patsilinakos S, Bouki T, Tountas N, et al. Coronary microcirculation evaluation with transesophageal echocardiography Doppler in type II diabetics. Int J Cardiol 1997;59:119-24. 19. Di Carli F, Janisse J, Grunberger G, Ager J. Role of chronic hyperglicemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol 2003;41:1387-93. 20. Kjaer A, Meyer C, Nielsen FS, Parving HH, Hesse B. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nucl Med 2003;44:19-23. 21. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005;111:363-8. 22. De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Prevalence and prognostic value of perfusion defects detected by stress technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with diabetes mellitus and no known coronary artery disease. Am J Cardiol 2002;90:827-32. 23. Dorbala S, Di Carli MF, Beanlands RS, Merhige ME, Williams BA, Veledar E, et al. Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry. J Am Coll Cardiol 2013;61:176-84. 24. Cortigiani L, Rigo F, Gherardi S, Sicari R, Galderisi M, Bovenzi F, et al. Additional prognostic value of coronary flow reserve in diabetic and nondiabetic patients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol 2007;50:1354-61. 25. 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. 26. Cortigiani L, Rigo F, Galderisi M, Gherardi S, Bovenzi F, Picano E, et al. Diagnostic and prognostic value of Doppler echocardiographic coronary flow reserve in the left anterior descending artery in hypertensive and normotensive patients [published erratum appears in Heart 2012;98:92]. Heart 2011;97:1758-65. 27. Ryd
en L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al, Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88-136. 28. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25: 1105-87. 29. National Cholesterol Education Program Expert Panel. Third report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): full report. Available at: http:// www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed March 3, 2014. 30. Wilson PWF, D’Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk. Arch Int Med 2002;162:1867-72.

Cortigiani et al 7

Journal of the American Society of Echocardiography Volume - Number -

31. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al, Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 32. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 33. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-6. 34. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, et al. Stress echocardiography expert consensus statement from the European Association of Echocardiography. Eur J Echocardiogr 2008;9:415-37. 35. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al., American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42. 36. Picano E, Mathias W, Pingitore A, Bigi R, Previtali M, on behalf of the EDIC Study Group. Safety and tolerability of dobutamine-atropine stress

37.

38.

39. 40.

41. 42. 43.

44.

45.

echocardiography: a prospective, large scale, multicenter trial. Lancet 1994;344:1190-2. 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. Picano E, Parodi O, Lattanzi F, Sambuceti G, Andrade MJ, Marzullo P, et al. Assessment of anatomic and physiological severity of single-vessel coronary artery lesions by dipyridamole echocardiography. Comparison with positron emission tomography and quantitative arteriography. Circulation 1994;89:753-61. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999;34:618-20. Rubinshtein R, Yang EH, Rihal CS, Prasad A, Lennon RJ, Best PJ, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31:936-42. L’Abbate A. Large and micro coronary vascular involvement in diabetes. Pharmacol Rep 2005;57(suppl):3-9. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830-40. Rigo F, Ciampi Q, Ossena G, Grolla E, Picano E, Sicari R. Prognostic value of left and right coronary flow reserve assessment in nonischemic dilated cardiomyopathy by transthoracic Doppler echocardiography. J Card Fail 2011;17:39-46. Pries AR, Habazettl H, Ambrosio G, Hansen PR, Kaski JC, Sch€achinger V, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental setting. Cardiovasc Res 2008;80:165-74. Laakso M. Heart in diabetes: a microvascular disease. Diabetes Care 2011; 34(suppl):145-9.