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 ± 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 ± 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.
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 oxide and increased secretion of vasoconstrictor mediators such as endothelin-1 and angiotensin II. Diabetic autonomic neuropathy contributes to alter coronary vasoreactivity. In addition, hyalinization or wall thickening of intramural arterioles and reduced density of capillary vessels have been reported as structural changes of the diabetic heart. Most patients with type 2 diabetes have associated arterial hypertension, dyslipidemia, and obesity, contributing to coronary microvascular damage. 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. 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, transesophageal Doppler echocardiography, and positron emission tomography (PET). 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. Moreover, perfusion defects on single-photon emission computed tomography were associated with markedly increased risk in asymptomatic patients with diabetes without known coronary artery disease (CAD), while the presence of coronary vascular dysfunction, as assessed using PET, independently predicted cardiac and all-cause mortality in patients with and those without diabetes. Intriguingly, patients with diabetes without known CAD with visually normal results on PET but impaired coronary flow reserve experienced a cardiac mortality rate comparable with that in patients with known CAD ; 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. 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, as well as in unselected and hypertensive 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.
Methods
Patients
From January 2006 to December 2009, 144 patients (82 men; mean age, 62 ± 10 years) with type 2 diabetes 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 published and represents an extension of follow-up.
Arterial hypertension, hypercholesterolemia, overweight or obesity, 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 ≥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.
| Variable | CFVR > 2 ( n = 109) | CFVR ≤ 2 ( n = 35) | P |
|---|---|---|---|
| Age (y) | 62 ± 10 | 65 ± 12 | .14 |
| Men | 63 (58%) | 19 (54%) | .72 |
| Duration of diabetes (y) | 8 ± 4 | 10 ± 6 | .12 |
| Glycated hemoglobin (mg/dL) | 7.8 ± 0.8 | 7.7 ± 1.1 | .59 |
| Insulin therapy | 33 (30%) | 14 (40%) | .29 |
| Body mass index (kg/m 2 ) | 27.5 ± 2.8 | 27.0 ± 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 ± 1.0 | 2.7 ± 0.9 | .25 |
| Left bundle branch block | 8 (7%) | 3 (9%) | .81 |
| LV ejection fraction (%) | 59 ± 6 | 58 ± 8 | .69 |
| LV mass index (g/m 2 ) | 114 ± 25 | 122 ± 27 | .11 |
| LV hypertrophy | 61 (56%) | 24 (69%) | .19 |
| Resting heart rate (beats/min) | 69 ± 8 | 69 ± 10 | .95 |
| Resting systolic blood pressure (mm Hg) | 138 ± 16 | 149 ± 17 | .001 |
| Resting rate-pressure product | 9,579 ± 1,751 | 10,325 ± 2,224 | .04 |
| Resting wall motion abnormalities | 11 (10%) | 9 (26%) | .02 |
| Test performed on antianginal therapy | 62 (57%) | 23 (66%) | .36 |
| β-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 ± 9 | 37 ± 15 | <.0001 |
| Peak velocity in the LAD (cm/sec) | 76 ± 23 | 66 ± 24 | .04 |
| CFVR of the LAD | 2.64 ± 0.49 | 1.80 ± 0.18 | <.0001 |
| Normal coronary arteries | 88 (81%) | 17 (49%) | .0002 |
| Nonobstructive CAD | 21 (19%) | 18 (51%) | .0002 |
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 from the American Society of Echocardiography. LV mass was calculated using the following formula : 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/m 2 in men and >104 g/m 2 in women was the criterion for LV hypertrophy. Ejection fraction was obtained using Simpson’s rule.
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). Echocardiographic images were semiquantitatively assessed using a 17-segment, four-point scale model of the left ventricle. 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. 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. 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. 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. The previously assessed intraobserver and interobserver variability for measurements of Doppler recordings and regional wall motion analysis assessment were <10%. In our previous experience, the assessment of CFVR of the LAD had 94% feasibility.
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.
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, 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 ± SD. Differences between groups were compared using Student’s t and χ 2 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 ± 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 ± 0.61 in the group of 68 patients with two or fewer risk factors and 2.34 ± 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 ± 1.0 vs 2.6 ± 0.8, P = .27). However, CFVR was markedly lower in the latter group (2.56 ± 0.57 vs 2.11 ± 0.40, P < .0001).
