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

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Prognostic Meaning of Coronary MicrovascularDisease in Type 2 Diabetes Mellitus: A Transthoracic

Doppler Echocardiographic Study

Q2 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 anteriordescending coronary artery in patients with type 2 diabetes with preserved left ventricular systolic function andwithout flow-limiting stenoses on angiography remains undetermined.

Methods: The study sample consisted of 144 patients with type 2 diabetes (82 men; mean age 626 10 years)with chest pain or angina-equivalent symptoms, no histories of coronary artery disease, and echocardio-graphic ejection fractions $ 50%. All patients underwent dipyridamole stress echocardiography with CFVRassessment of the left anterior descending coronary artery by transthoracic Doppler echocardiography andcoronary angiography showing normal coronary arteries or nonobstructive coronary artery disease.

Results:Mean CFVRwas 2.446 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), 17hard 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# 2was significantly higher both in patients with left ventricular hypertrophy (P < .0001) and in those without leftventricular 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 independentprognostic indicators, whereas nonobstructive coronary artery disease was not an independent predictor ofoutcomes.

Conclusions:Microvascular dysfunction before the occurrence of coronary artery involvement is a strong andindependent predictor of outcomes in patients with type 2 diabetes. Vasodilator stress CFVR is a suitable toolto 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 ofthe coronary microcirculation even in the absence of epicardialcoronary atherosclerosis. In fact, vasomotor function is impaired inpatients with type 2 diabetes because of decreased bioavailability ofthe potent vasodilator endothelium-derived nitric oxide1,2 andincreased secretion of vasoconstrictor mediators such as endothelin-13 and angiotensin II.4 Diabetic autonomic neuropathy contributes toalter coronary vasoreactivity.5 In addition, hyalinization6 or wallthickening 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 hyperten-sion,9 dyslipidemia,10 and obesity,11 contributing to coronarymicrovas-cular damage.12-15 Previous evidence shows both reduced maximalcoronary vasodilation and impairment in the regulation of coronaryflow in response to submaximal increases in myocardial demand inpatients with diabetes mellitus.16 These microvascular abnormalitiesmay lead to myocardial ischemia in the absence of epicardial coronaryatherosclerosis in some circumstances and thus contribute to adversecardiovascular events in patients with diabetes. Functionally, microvas-cular disease in patients with diabetes translates into reduced coronaryflow reserve, as demonstrated with different techniques such as intra-coronary Doppler,16,17 transesophageal Doppler echocardiography,18

and positron emission tomography (PET).19,20 Unfortunately, thesetechniques do not apply to daily practice. However, coronary flowreserve measurement in patients with diabetes is of potential clinicalinterest, as invasively detected impaired coronary flow reserve is anestablished prognostic predictor in unselected cohorts of patientswith normal or mildly diseased coronary arteries.21 Moreover,perfusion defects on single-photon emission computed tomographywere associated with markedly increased risk in asymptomatic patients

From the Cardiology Division, Campo di Marte Hospital, Lucca, Italy (L.C., F.B.);

Cardiology Division, Umberto I Hospital, Mestre, Italy (F.R.); Cardiology Division,

Cesena Hospital, Cesena, Italy (S.G.); Department of Clinical and Experimental

Medicine, Federico II University Hospital, Naples, Italy (M.G.); CNR, Institute of

Clinical Physiology, Pisa, Italy (R.S.).

Reprint requests: Rosa Sicari, MD, PhD, FESC, CNR, Institute of Clinical

Physiology, Via G. Moruzzi, 1, 56124 Pisa, ItalyQ1 (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

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with diabetes without knowncoronary artery disease(CAD),22 while the presence ofcoronary vascular dysfunction, asassessed using PET, indepen-dently predicted cardiac andall-cause mortality in patientswith and those without dia-betes.23 Intriguingly, patientswith diabetes without knownCAD with visually normal resultson PET but impaired coronaryflow reserve experienced a car-

diac mortality rate comparable with that in patients with knownCAD23; conversely, patients with diabetes without known CAD andvisually normal results on PET who had preserved coronary flowreserve experienced a cardiac mortality rate comparable with that inpatients without diabetes free of CADwith normal imaging findings.23

Lately, transthoracic Doppler echocardiography associated withvasodilatory stress has proved to be a highly feasible and effectivemodality for assessing risk in a general diabetic population,24 as wellas in unselected25 and hypertensive26 patients without obstructiveCAD. The aim of this prospective, multicenter, observational studywas to investigate the prognostic implications of Doppler-derivedcoronary flow velocity reserve (CFVR) of the left anterior descendingcoronary artery (LAD) in patients with type 2 diabetes withangiographically normal or near normal coronary arteries andpreserved systolic left ventricular (LV) function.

METHODS

Patients

From January 2006 to December 2009, 144 patients (82 men; meanage, 62 6 10 years) with type 2 diabetes27 were prospectivelyenrolled 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 ofCAD (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) nosignificant valvular or congenital heart disease, (5) no prognosticallyrelevant noncardiac diseases (cancer, end-stage renal or liver disease,or severe obstructive pulmonary disease), (6) adequate acousticwindow for imaging the left ventricle (for two-dimensional echocardi-ography) and LAD flowDoppler (for CFVR assessment), (7) dipyrida-mole stress echocardiography with CFVR assessment of the LAD bytransthoracic Doppler echocardiography performed before (within15 days) coronary angiography, and (8) coronary angiographyshowing normal coronary arteries or nonobstructive CAD.Follow-up information was available for all patients. Part of thissample (45 patients [31%]) was previously published24 and repre-sents an extension of follow-up.

Arterial hypertension,28 hypercholesterolemia,29 overweight orobesity,30 and smoking habit were considered associated cardiacrisk factors and defined according to standard definition. Accordingto individual needs and physicians’ choices, 59 patients (41%) wereevaluated after antianginal drugs had been discontinued, and 85patients (59%) were evaluated during antianginal treatment(Table 1). Phylline-containing drugs or beverages were discontinued$24 hours before testing. The decision to perform coronary

angiography in the face of negative results on stress echocardiographywasmade by the referring physician on the basis of the clinical picture.The study was approved by the institutional review board. All patientsgave written informed consent when they underwent stress echocar-diography. When patients provided consent, they also authorizedphysicians to use their clinical data. Stress echocardiographic datawere collected and analyzed by stress echocardiographers notinvolved in patient care.

Resting Echocardiography

Two-dimensional targeted M-mode echocardiography was carriedout under resting conditions for LV measurements, includinginterventricular septal thickness at end-diastole, LV internal dimensionat end-diastole, and posterior wall thickness at end-diastole.Measurements were made in accordance with recommendationsfrom the American Society of Echocardiography.31 LV mass was

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

Variable

CFVR > 2

(n = 109)

CFVR # 2

(n = 35) P

Age (y) 62 6 10 65 6 12 .14Men 63 (58%) 19 (54%) .72

Duration of diabetes (y) 8 6 4 10 6 6 .12Glycated hemoglobin

(mg/dL)

7.8 6 0.8 7.7 6 1.1 .59

Insulin therapy 33 (30%) 14 (40%) .29

Body mass index (kg/m2) 27.5 6 2.8 27.0 6 2.7 .42

Overweight or obesity 96 (88%) 28 (80%) .23

Arterial hypertension 78 (72%) 27 (77%) .52

Hypercholesterolemia 56 (51%) 30 (86%) .0003

Smoking habit 37 (34%) 8 (23%) .22

Number of associated

risk factors

2.4 6 1.0 2.7 6 0.9 .25

Left bundle branch block 8 (7%) 3 (9%) .81

LV ejection fraction (%) 59 6 6 58 6 8 .69

LV mass index (g/m2) 114 6 25 122 6 27 .11

LV hypertrophy 61 (56%) 24 (69%) .19Resting heart rate

(beats/min)

69 6 8 69 6 10 .95

Resting systolic blood

pressure (mm Hg)

138 6 16 149 6 17 .001

Resting rate-pressure

product

9,579 6 1,751 10,325 6 2,224 .04

Resting wall motion

abnormalities

11 (10%) 9 (26%) .02

Test performed on

antianginal therapy

62 (57%) 23 (66%) .36

b-blocking agents 38 (35%) 15 (43%) .39

Calcium antagonists 34 (31%) 15 (43%) .21

Long-acting nitrates 14 (13%) 5 (14%) .83

Resting velocity in the

LAD (cm/sec)

29 6 9 37 6 15 <.0001

Peak velocity in the LAD

(cm/sec)

76 6 23 66 6 24 .04

CFVR of the LAD 2.64 6 0.49 1.80 6 0.18 <.0001

Normal coronary arteries 88 (81%) 17 (49%) .0002Nonobstructive CAD 21 (19%) 18 (51%) .0002

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

Abbreviations

CAD = Coronary arterydisease

CFVR = Coronary flowvelocity reserve

LAD = Left anterior

descending coronary artery

LV = Left ventricular

PET = Positron emissiontomography

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calculated using the following formula32: LV mass (g) = 0.80� [1.04� (interventricular septal thickness at end-diastole +LV internaldimension at end-diastole + posterior wall thickness at end-diastole)3

� (LV internal dimension at end-diastole)3] + 0.6 g. Dividing LV massby body surface area derived LV mass index. LV mass index> 116 g/m2 in men and >104 g/m2 in women was the criterion forLV hypertrophy.33 Ejection fraction was obtained using Simpson’srule.31

Stress Echocardiography

Transthoracic stress echocardiographic studies were performed usingcommercially available ultrasound machines (Sonos 7500 or iE33,Philips Medical Systems, Andover, MA; Vivid System 7, GEMedical Systems, Milwaukee, WI; Acuson Sequoia C256, SiemensMedical Solutions USA, Inc, Mountain View, CA) equipped withmultifrequency phased-array sector scan probes (S3-S8 or V3-V7)and with second-harmonic technology. Two-dimensional echocardi-ography and 12-lead electrocardiographic monitoring wereperformed in combination with high-dose dipyridamole (up to 0.84mg over 6 min).34 Echocardiographic images were semiquantitativelyassessed using a 17-segment, four-point scale model of the leftventricle.35 A wall motion score index was derived by dividing thesum of individual segment scores by the number of interpretablesegments. Ischemia was defined as stress-induced new wall motionabnormality. CFVR was assessed during the standard stress echocar-diographic examination by intermittent imaging of both wall motionand LAD flow.34 Coronary flow in the mid-distal portion of the LADwas sought in the low parasternal long-axis section under the guid-ance of color Doppler flow mapping.34 All studies were digitallystored to simplify offline reviewing and measurements. Coronaryflow parameters were analyzed offline using the built-in calculationpackage of the ultrasound unit. Flow velocities were measured at leasttwice for each study: at baseline and at peak stress (before aminoph-ylline injection). At each time point, three optimal profiles of peakdiastolic Doppler flow velocities were measured, and the resultswere averaged. CFVR was defined as the ratio between hyperemicpeak and basal peak diastolic coronary flow velocities. CFVR # 2was considered abnormal.24 All observers were trained by the samesenior investigator (F.R.), providing consistency in data acquisition,storage, and interpretation, and also through intensive joint readingsessions. All investigators from contributing centers passed qualitycontrol criteria for regional wall motion and Doppler interpretationbefore entering the study, as previously described.36 The previouslyassessed intraobserver and interobserver variability for measurementsof Doppler recordings and regional wall motion analysis assessmentwere <10%.37 In our previous experience, the assessment of CFVRof the LAD had 94% feasibility.24

Coronary Angiography

Coronary angiography in multiple views was performed according tothe standard Judkins technique, adopting femoral or radial approach.At least five views (including two orthogonal views) were acquired forthe left and at least two orthogonal views for the right coronary artery.Additional appropriate projections were obtained in case of superim-position of side branches or foreshortening of the segment of interest.Obstructive CAD was defined as a quantitatively assessed coronarystenosis of $50%. Normal coronary arteries were defined as 0%stenosis in any major vessel or secondary branch. NonobstructiveCAD was defined as any irregularity between 1% and 9% or vesselstenosis between 10% and 40% stenosis in any coronary artery.

The previously assessed intraobserver and interobserver variabilityof the method were 7% and 6%, respectively.38

Follow-Up Data

Outcomes were determined from patient interviews at the outpatientclinic, hospital chart reviews, and telephone interviews with patients,their close relatives, or referring physician. Death and nonfatalmyocardial infarction were registered as clinical events. Coronaryrevascularization (surgery or percutaneous interventions) was alsorecorded. To avoid misclassification of the cause of death,39 overallmortality was considered. Myocardial infarction was defined bytypical symptoms, electrocardiographic evidence, and cardiacenzyme changes. Follow-up data were analyzed for the predictionof hard events (death or nonfatal myocardial infarction).

Statistical Analysis

Continuous variables are expressed as mean 6 SD. Differencesbetween groups were compared using Student’s t and c2 tests, asappropriate. Linear regression was used to assess the correlationbetween CFVR and LV mass index. Hard event rates were estimatedusing Kaplan-Meier curves and compared using the log-rank test.Only the first event was taken into account. Patients undergoingcoronary revascularization (n = 9) were censored at the time of theprocedure. Annual event rates were obtained from Kaplan-Meierestimates to take censoring of the data into account. The associationsof selected variables with outcomes were assessed using Coxproportional-hazards modeling with univariate and stepwise multivar-iate procedures. A significance level of .05 was required for a variableto be included into the multivariate model, while a level of .10 was thecutoff for exclusion. Hazard ratios with corresponding 95% confidenceintervals were estimated. Statistical significance was set at P < .05. SPSSversion 16 (SPSS, Inc, Chicago, IL) was used for analysis.

RESULTS

Themain clinical, echocardiographic, and angiographic findings in thestudy group are listed in Table 1.

Stress Echocardiographic Findings

No complications or limiting side effects occurred. Stress echocardio-graphic results were negative for ischemia in all patients.

Mean CFVR in the entire study group was 2.44 6 0.57. Onindividual patient analysis, 109 patients (76%) had CFVR > 2, and35 (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 agreater frequency of nonobstructive CAD (Table 1). In the subsetwith abnormal CFVR, rate-pressure products were significantly higherunder resting conditions because of a higher mean systolic bloodpressure (see Table 1).

CFVRwas inversely related with LVmass index (Figure 1), as well asthe number of associated cardiac risk factors, 2.546 0.61 in the groupof 68 patients with two or fewer risk factors and 2.34 6 0.50 in thegroup of 76 patients with three or more risk factors (P = .03). Thenumber of risk factors was comparable in the 105 patients with normalcoronary arteries and 39 patients with nonobstructive CAD (2.461.0vs 2.66 0.8, P= .27). However, CFVRwasmarkedly lower in the lattergroup (2.56 6 0.57 vs 2.11 6 0.40, P < .0001).

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Follow-Up Events

During a median follow-up period of 29 months (interquartilerange, 14–44 months), 17 hard events (five deaths, 12 nonfatalmyocardial infarctions) were registered. There were 11 events(31.4%) in patients with CFVR # 2 and six events (5.5%) in thosewith CFVR > 2.

Survival Analysis

The annual hard-event rate was 13.9% in subjects with CFVR # 2and 2.0% in those with CFVR > 2 (P < .0001). When the samplewas separated on the basis of LV hypertrophy, the annual eventrate associated with CFVR # 2 and with CFVR > 2 were, respec-tively, 15.4% and 1.6% (P < .0001) in the hypertrophic group and10.9% and 2.5% (P = .048) in the nonhypertrophic group.Univariate and multivariate prognostic indicators are illustrated inTable 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% confidenceinterval, 1.74–34.97; P = .007). Nonobstructive CAD providedunivariate but not multivariate prognostic contribution. Kaplan-Meier survival estimates for hard events showed a worse 3-yearevent rate for patients with CFVR # 2 compared with those withCFVR > 2 (48% vs 7%, P < .0001; Figure 2).

DISCUSSION

Our results show that Doppler-derived CFVR of the LAD is a usefultool for assessing the presence and prognostic effect of microvasculardisease in patients with type 2 diabetes. In particular, we found CFVRto be reduced in one in four patients with diabetes with angiograph-ically normal or near normal coronary arteries and preserved LVejection fractions, and, most important, CFVR # 2 conferred strongand independent prognostic information, predicting a nearly seventimes higher yearly hard-event rate compared with normal CFVR(>2). Male sex was also a multivariate prognostic indicator in thesepatients, whereas anatomic evaluation demonstrated marginal useful-ness in risk stratification. In fact, nonobstructive CAD failed to provideindependent prognostic contribution, although it was associated withsignificantly lower mean CFVR.

Comparison with Previous Studies

Previous studies using different techniques16-20 have reportedabnormal coronary flow reserve in patients with type 2 diabeteswith normal coronary arteries, indicating that microcirculation maybe affected before the occurrence of coronary atherosclerosis.However, conventional cardiac risk factors are frequently associatedto diabetes,9-11 contributing to the progression of microvasculardisease.12-15 In a previous experience on unselected patientswithout significant coronary narrowing, a higher Framingham riskscore independently predicted impaired coronary flow reserve.40

Similarly, in the present study of patients with diabetes, meanCFVR was significantly lower in subjects with three or more associ-ated risk factors. Cardiac hypertrophy is another pathophysiologiccondition that may negatively affect coronary flow reserve.13

Accordingly, we found an inverse relation between CFVR andindexed LV mass.

The association between depressed CFVR and future cardiac eventshas been extensively documented in unselected patientpopulations,21,25 as well as in patients with hypertension26 withoutobstructive CAD. The present results expand to patients with type 2diabetes the prognostic consequences deriving from microvasculardisease. Interestingly, CFVR > 2 was predictive of a benign prognosis,confirming the results of a previous study in patients with diabetes withknown or suspected CAD and negative vasodilator stressechocardiographic results.24 In our previous study, we explored thereasons why CFVR may be reduced in the absence of stress-inducedwall motion abnormalities: mild to moderate epicardial coronaryartery stenosis, severe epicardial coronary artery stenosis in thepresence of anti-ischemic therapy, and severe microvascular coronarydisease in the presence of patent epicardial coronary arteries. Thislast item is the focus of the present results, demonstrating that in theface of normal coronary arteries and a lack of wall motion abnormal-ities at peak stress, the microvascular impairment in patients withdiabetes modulates outcomes significantly. Several studies, mainly inpatients with type 2 diabetes, have documented reduced coronaryflow reserve even in the absence of coronary obstructive disease, usingdifferent techniques.41 Microcirculatory dysfunction affects the leftventricle globally as well as regionally,41 and therefore the CFVRassessment of the LAD, which would be inadequate for CADdetection, is an excellent option for evaluating global coronarymicrocirculation conditions in these patients. Therefore, a conceptuallylimited approach to a single territory (the LAD) is overcome by theobservation that microvascular dysfunction affects the ventricleglobally,42 and Doppler becomes a most valuable tool, being anexcellent window on both macrovascular and microvascular dysfunc-tion. Moreover, in a study from our group, it was demonstrated thatpatients with nonischemic dilated cardiomyopathy and normal coro-nary arteries had significant reductions in CFVR similarly in the LADand the right coronary artery compared with control subjects. CFVRin the LAD was directly related to CFVR in the right coronary arteryin both patients and controls,43 suggesting that coronary microcircula-tory damage is diffuse and modulated by similar hemodynamic andfunctional determinants. Coronary flow reserve may be measuredinvasively with intracoronary Doppler or noninvasively with PET,myocardial perfusion imaging, magnetic resonance, and transesopha-geal or transthoracic Doppler echocardiography.44 Compared withother stress imaging techniques, transthoracic Doppler echocardiogra-phy offers important advantages, including wider availability, lowercost, and lack of radiation exposure, making it an attractive applicationfor the everyday risk assessment of the diabetic population.

print&web4C=FPO

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

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455456457

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461462463

464465466467

468469470

471472473

474475476477

478479480

481482483

484485486

487488

Clinical Implications

The results of the present study have a potential impact in themanagement of patients with type 2 diabetes with chest pain orangina–equivalent symptoms. In particular, no further investigationis justified for those with CFVR of the LAD > 2 and negative resultson stress echocardiography for ischemia, because of their low risk forfuture cardiac events. On the contrary, angiographic evaluationshould be considered for patients with diabetes with CFVR of theLAD # 2, even in the absence of ischemia. In these higher riskpatients, an aggressive strategy, including the achievement of tightmetabolic control, adequate intensive pharmacologic therapy, andlifestyle changes seem to represent the logical approach in the caseof angiographically normal or mildly diseased arteries. On the basisof the present evidence, it is likely that microvascular dysfunctionoccurs well before the coronary arteries are affected. Moreover,microvascular impairment may be related to the development ofLV dysfunction in the absence of significant CAD.45 The pathogenesisof coronary microcirculatory dysfunction in diabetes is still unsettled,and a uniform therapeutic approach may not be sufficient to preventits development. The present results are far reaching and offer a novel

and original approach to the assessment of microvascular dysfunc-tion: vasodilator stress echocardiography is a sound risk stratifierenabling physicians to identify patients at higher risk for experiencingevents; microvascular impairment seems to be an early event in thedysfunction process, leading to macrovascular disease and LVdysfunction. However, the present results cannot provide a definitiveanswer to what is really needed by clinicians: Would the modulationof CFVR alter outcomes in these patients? Is microvascular dysfunc-tion reversible? Can therapeutic and lifestyle interventions modifythe level of microvascular dysfunction? These questions need to beaddressed in appropriately designed studies, but this tool is thebest trade-off between pathophysiology and a more quantitativeapproach, as it can be obtained with other imaging and/or invasivetechniques.

Study Limitations

In this study, there was no central reading. Stress echocardiographyand CFVR measurements were interpreted at the peripheral centersand entered directly into the data bank. This system allowed substan-tial sparing of human and technological resources, but it was also thelogical prerequisite for a large-scale study, designed to represent therealistic performance of the test rather than the results of a singlelab, or even a single person, working in a highly dedicated echocardio-graphic laboratory.

Because the assessment of the echocardiograms was qualitativeand subjective, variability in their reading might have modulatedthe results at individual centers. However, all our readers at individualcenters had long-term experience in echocardiography, passedquality control in stress echocardiography reading as previouslydescribed,36 and had extensive experience in the performance andinterpretation of CFVR also through joint reading sessions.

CFVR was sampled only in the LAD. There is no doubt that thethree-coronary-artery approach would be more fruitful, but atpresent, it remains too technically challenging for a large-scaleassessment. The available technology and echocardiographer expertisewould allow the detection of CFVR of the three vascular territories, butthis pathophysiologic approach would make the test highly unfeasible

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

Variable

Univariate Multivariate

HR (95% CI) P HR (95% CI) P

Age 0.96 (0.92–1.00) .08Male sex 4.64 (1.33–16.21) .02 7.80 (1.74–34.97) .007

Duration of diabetes 1.03 (0.97–1.08) .35Glycated hemoglobin 1.25 (0.72–2.15) .42

Insulin therapy 0.61 (0.20–1.88) .39Overweight or obesity 2.51 (0.33–18.97) .37

Arterial hypertension 1.94 (0.56–6.77) .30Hypercholesterolemia 1.68 (0.55–5.17) .37

Smoking habit 1.60 (0.61–4.21) .34Three or more associated risk factors 1.56 (0.58–4.23) .38

Left bundle branch block 1.52 (0.35–6.67) .58LV mass index 1.06 (0.89–1.25) .52

Resting wall motion abnormalities 3.10 (1.09–8.80) .03CFVR of the LAD 7.36 (2.71–19.99) <.0001 11.20 (3.07–40.92) <.0001

Nonobstructive CAD 4.04 (1.56–10.51) .004

CI, Confidence interval; HR, hazard ratio.

print&web4C=FPO

Figure 2 Hard-event rate for patients with diabetes with CFVRof the LAD > 2 and #2. Number of patients per year is shown.

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489490491492

493494495

496497498

499500501502

503504505

506507508

509510511

512513514515

516517518

519520521

522523524

525526527528

529530531

532533534

535536537538

539540541

542543544

545546547

548549

550551552553

554555556

557558559

560561562563

564565566

567568569

570571572

573574575576

577578579

580581582

583584585

586587588589

590591592

593594595

596597598599

600601602

603604605

606607608

609610

on a routine basis. Our main aim was to test not only the efficacy butalso the effectiveness of the combined information onwall motion andCFVR in a single test.

The average body mass index of the sample under investigationwas 27 kg/m2. It is conceivable that a selection bias may have beenintroduced, because only patients with good acoustic windowswere entered into the data bank. Moreover, in Italy, obesity doesnot have the characteristics of an epidemic, as in the United States,and this may be another reason for the low enrollment rate of obesepatients.

CONCLUSIONS

Microvascular dysfunction before the occurrence of coronary arteryinvolvement is a strong and independent predictor of outcomes inpatients with type 2 diabetes. Vasodilator stress CFVR is a suitabletool to assess microvascular dysfunction in routine clinical practice.In particular, CFVR of the LAD# 2 represents a strong and indepen-dent predictor of the combined event of death and nonfatal myocar-dial infarction.

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