OtherClinical Investigations

Influence of Risk Factors on Coronary Flow Reserve in Patients with 1-Vessel Coronary Artery Disease

Maria Lucia Eufrasia Vicario, Lorenzo Cirillo, Giovanni Storto, Teresa Pellegrino, Nicola Ragone, Luca Fontanella, Mario Petretta, Domenico Bonaduce and Alberto Cuocolo
Journal of Nuclear Medicine September 2005, 46 (9) 1438-1443;

Abstract

Coronary artery disease (CAD) risk factors influence the hyperemic response in patients without coronary artery stenosis. The aim of this study was to evaluate the influence of risk factors on coronary flow reserve (CFR) estimated by 99mTc-sestamibi cardiac imaging in patients with 1-vessel CAD. Methods: Forty-eight patients with 1-vessel CAD were enrolled in the study. Systemic hypertension, hypercholesterolemia, diabetes mellitus, and cigarette smoking were considered CAD risk factors. Within 48 h, all patients underwent coronary angiography and regional CFR assessment by 99mTc-sestamibi imaging with dipyridamole (0.74 mg/kg of body weight). Eight patients had no risk factors, 14 had 1 risk factor, 18 had 2 risk factors, and 8 had 3 risk factors. Results: The mean ± SD CFR of the narrowed coronary vessel was 1.28 ± 0.43 in the overall study population (1.52 ± 0.30 in patients with 50%–70% stenosis and 0.94 ± 0.75 in patients with >70% stenosis; P < 0.001). Two-factor ANOVA showed that the number of risk factors significantly affected CFR (P < 0.001) in patients with 50%–70% stenosis, whereas significance was only borderline in patients with >70% stenosis. Finally, a significant interaction among the degree of coronary artery stenosis, the number of risk factors, and the estimated CFR was found (F3 = 14.0; P < 0.001). Conclusion: CFR is inversely related to the number of conventional risk factors in patients with 1-vessel CAD and intermediate coronary artery stenosis, whereas this influence is less evident in patients with more severe stenosis.

Angiographic estimates of coronary artery lesions have been shown to be a poor predictor of their functional significance (1). Gould et al. first demonstrated that coronary vasodilator reserve (defined as the ratio of coronary flow under maximal drug-induced hyperemia to baseline flow) is a useful indicator of the physiologic significance of coronary artery stenosis (2). In laboratories carrying out hemodynamic testing, coronary flow reserve (CFR) measurement is considered important for distinguishing ischemia-producing from non-ischemia-producing coronary lesions (3,4). Different invasive methods have been introduced for the assessment of CFR: Doppler wire-derived measurement of CFR, coronary pressure wire-derived fractional flow reserve measurement, and intravascular ultrasound imaging (5–7). In addition, noninvasive approaches, such as MRI and PET, also have been proposed (8,9). With PET, it has been shown that CFR is reduced in patients with hypertension and hypercholesterolemia, even in the absence of coronary atherosclerosis (10,11). It also has been demonstrated that in young healthy men, the number of conventional coronary artery disease (CAD) risk variables is inversely related to CFR, suggesting that risk factors influence vascular reactivity (12). Sugihara et al. (13) proposed a noninvasive estimation of CFR using 99mTc-labeled myocardial perfusion tracers and the microsphere technique. Recently, Storto et al. (14) demonstrated good agreement between CFR estimated by sestamibi imaging and intracoronary Doppler imaging results in patients with CAD and a lack of intraobserver and interobserver variabilities of this noninvasive approach. The aim of this study was to evaluate the influence of CAD risk factors on CFR estimated by 99mTc-sestamibi cardiac imaging in patients with 1-vessel CAD and different degrees of coronary artery stenosis.

MATERIALS AND METHODS

Study Population

Forty-eight consecutive nonobese patients (body mass index, <27 kg/m2) with 1-vessel CAD (40 men) were enrolled in the study. Patients with anemia, arrhythmia, valvular heart disease, left ventricular dysfunction, history of myocardial infarction, or evidence of left ventricular hypertrophy at echocardiography and patients with other major diseases were excluded. CFR estimation with 99mTc-sestamibi was performed within 48 h before coronary angiography. The ethics committee of University Federico II approved the protocol, and each patient gave informed consent before entry into the study. All patients refrained from smoking and consuming caffeine-containing food or beverages for at least 24 h before the study. For the purposes of the present investigation, we considered as CAD risk factors the following: systemic hypertension, hypercholesterolemia, diabetes mellitus, and cigarette smoking. All patients were receiving treatment with antihypertensive drugs, cholesterol-lowering drugs, oral hypoglycemic agents, or insulin. Finally, CFR also was estimated in 15 control subjects (9 men; mean ± SD age, 56 ± 9 y) with suspected CAD and normal vessels at coronary angiography.

Radionuclide Cardiac Imaging

All patients underwent dipyridamole and rest cardiac imaging as previously described in detail (14). Dipyridamole was infused intravenously at a dose of 0.74 mg/kg of body weight over a period of 6 min with monitoring of symptoms and blood pressure and 12-lead electrocardiography. No patients developed severe angina, hypotension, or other intolerable side effects. 99mTc-sestamibi (555 MBq) was injected intravenously as a bolus 1–2 min before completion of the stress. Dynamic planar images were acquired for 60 s (4 frames per second) in the anterior view to measure the first transit counts in the pulmonary artery. Tomographic imaging was performed 60 min later. Data were acquired with a rotating γ-camera (SP4HR; Elscint) equipped with a low-energy, all-purpose, parallel-hole collimator and connected to a dedicated computer system. No attenuation or scatter correction was applied. Rest imaging was performed on a separate day with the same acquisition protocol.

For first-pass analysis, serial images of the first transit study were evaluated frame by frame, and on the summed image (3- to 5-s duration), a 3 × 2 pixel region of interest (ROI) was assigned at the main right pulmonary artery. After smoothing, the area under the time-activity curve was calculated to obtain the time integral of the first-pass tracer counts for the pulmonary artery: ∫[C(t)dt]. Sestamibi activity was measured on 2 representative short-axis tomograms (at the medial-basal and medial-apical levels). For each tomogram, an epicardial ROI was assigned. In addition, each tomogram was divided into 6 sectors of equal arcs, representing the anterolateral, lateral, inferior, inferoseptal, septal, and anterior myocardium, and an ROI was assigned in the corresponding sector. Tracer activity was expressed as absolute myocardial counts, and mean tracer uptake for each major coronary territory was calculated. Each segment was assigned to 1 of the major vascular territories (15). Briefly, the anterior descending artery territory included the anterior and anterolateral walls and the septum. The right coronary artery was assigned to the inferoseptal and inferior walls. The left circumflex artery was assigned to the lateral wall. Estimated myocardial blood flow (MBF) under stress and rest conditions was measured as myocardial counts divided by ∫[C(t)dt]. Estimated CFR was expressed as the ratio of MBF under stress conditions to MBF under rest conditions.

For the assessment of myocardial perfusion in each patient, 17 segments were automatically scored, and scintigraphic variables incorporating the extent and severity of perfusion defects were calculated: summed stress score, summed rest score, and summed difference score (SDS) (16). Patients with an SDS of between 2 and 7 were considered to have mild ischemia, and patients with an SDS of >7 were considered to have moderate to severe ischemia. Two observers who were unaware of the patient clinical data and angiographic results analyzed the radionuclide studies.

Quantitative Coronary Angiography

Angiographic studies were performed by the conventional femoral approach (Judkins technique) with biplane or single digital acquisition at 30 frames per second. Multiple manual injections of contrast medium were performed, and images were acquired with a 17.78-cm (7-in) image intensifier field size in a 512 × 8 format. Angiographic measurements of coronary artery stenosis were performed with an automated computer-based system by experienced observers not involved in the angiographic procedure. Image calibration was performed with a contrast medium-filled catheter. Coronary end-diastolic frames from matched views obtained on angiograms were analyzed with an automated contour method. The diameter of stenosis (percentage) was calculated as the reference lumen diameter minus the minimal lesion diameter, divided by the reference lumen diameter. Coronary artery stenosis representing 50%–70% luminal narrowing was considered intermediate, whereas stenosis of >70% was considered severe.

Statistical Analysis

Data are presented as the mean ± SD or as a percentage and were analyzed with SPSS version 12.0 statistical software (SPSS Inc.). χ2 analysis for categoric variables and an unpaired Student t test for continuous variables were used to assess differences between groups. Linear regression analysis was used when appropriate. P values of <0.05 were considered statistically significant. One-way ANOVA was used to evaluate the influence of the number of risk factors on CFR separately in patients with coronary artery stenosis of 50%–70% and of >70%. Moreover, 2-factor ANOVA was performed to evaluate the presence of a significant interaction between degree of coronary artery stenosis (intermediate or severe) and the number of risk factors (stenosis × risk factor interaction).

RESULTS

All patients had 1-vessel coronary artery stenosis. The site of coronary artery stenosis and the number of CAD risk factors are reported in Table 1. Intravenous dipyridamole infusion produced an increase in heart rate from 73 ± 10 to 92 ± 15 beats per minute (P < 0.01). Mean ± SD aortic pressure decreased slightly from 105 ± 15 to 98 ± 16 mm Hg (P = not significant [NS]), systolic blood pressure decreased from 139 ± 17 to 128 ± 18 mm Hg (P = NS), and diastolic blood pressure decreased from 78 ± 11 to 72 ± 14 mm Hg (P = NS). The rate × pressure products were 10,524 ± 2,475 mm Hg per minute at rest and 12,524 ± 2,682 mm Hg per minute during maximal vasodilatation. No electrocardiographic changes suggestive of ischemia (ST segment elevation of >0.1 mV) were seen during dipyridamole infusion.

View this table:
TABLE 1

Number of Risk Factors and Site and Degree of Coronary Artery Stenosis in Study Population (n = 48)

CFR in Control Subjects and in Patients

In the 15 control subjects with normal coronary vessels, CFR estimated by sestamibi imaging was 2.49 ± 0.46. In patients with 1-vessel CAD, estimated CFR was 1.28 ± 0.43 in the myocardium subtended by coronary arteries with stenosis of ≥50%; this CFR was significantly lower (both P values were <0.001) than the CFR in the myocardium subtended by normal coronary vessels (1.87 ± 0.38) or by vessels with luminal narrowing of <50% (1.85 ± 0.44). Furthermore, in the territory of coronary vessels with stenosis of ≥50%, CFR in patients with 50%–70% stenosis was 1.52 ± 0.30, and that in patients with >70% stenosis was 0.94 ± 0.75 (P < 0.001).

CFR and CAD Risk Factors

Clinical variables and echocardiographic data for patients according to the degree of coronary artery stenosis are reported in Table 2. No difference was detectable in clinical and echocardiographic data between patients with intermediate coronary artery stenosis and patients with severe coronary artery stenosis. Estimated CFR in the myocardium subtended by a stenosed coronary vessel was always lower in patients with severe stenosis than in patients with intermediate stenosis. One-way ANOVA showed that in patients with intermediate stenosis, the number of risk factors significantly influenced CFR in the territory of the stenosed coronary vessels (P < 0.001), whereas in patients with severe stenosis, the significance was only borderline (P = 0.09) (Fig. 1). When patients with (n = 13) and patients without (n = 35) diabetes mellitus were considered separately, estimated CFR values in the territory of the stenosed coronary arteries were not different between the 2 groups (1.19 ± 0.33 and 1.32 ± 0.46, respectively; P = NS). Finally, 2-factor ANOVA showed a significant interaction among the degree of coronary artery stenosis, the number of CAD risk factors, and the estimated CFR in the territory of the stenosed coronary vessels (stenosis × risk factor interaction: F3 = 14.0; P < 0.001).

FIGURE 1.
FIGURE 1.

Influence of CAD risk factors on CFR in patients with intermediate (50%–70%) (A) or severe (>70%) (B) coronary artery stenosis.

View this table:
TABLE 2

Clinical Variables, Echocardiographic Data, and Estimated CFR According to Degree of Coronary Artery Stenosis

CFR and Stress-Induced Ischemia

Stress-induced myocardial ischemia was present in all patients with 1-vessel CAD, with a mean ± SD SDS of 6.6 ± 3.8. In particular, 36 patients had mild ischemia (SDS of ≤7), and 12 had moderate to severe ischemia (SDS of >7). The estimated CFR in the territory of the stenosed coronary vessels in patients with mild ischemia was 1.44 ± 0.36, and that in patients with moderate to severe ischemia was 0.85 ± 0.39 (P < 0.005). A significant relationship between the estimated CFR in the territory of the stenosed coronary vessels and the SDS was observed (r = −0.60; P < 0.001).

DISCUSSION

The results of this study demonstrate that the presence and the number of CAD risk factors influence the hyperemic response to dipyridamole administration in patients with 1-vessel CAD, in particular, those with intermediate coronary artery stenosis.

Dipyridamole and adenosine administration induces direct vascular smooth muscle relaxation; therefore, measurements of MBF during peak hyperemia seem to reflect primarily endothelium-independent vasodilatation. However, it has been demonstrated that 20%–40% of the maximal vasodilator response induced by dipyridamole is mediated by the release of nitric oxide (NO) from endothelium as a result of the increased shear stress on endothelial cells caused by the hyperemic response. Thus, the vasodilator response to dipyridamole reflects the integrated effects of both vascular smooth muscle and endothelial cell functions (17,18). Therefore, in patients with CAD risk factors, the hyperemic response after dipyridamole infusion may be useful for assessing endothelial cell dysfunction. It is noteworthy that CFR estimated by sestamibi imaging reflects the combined impact of epicardial resistance and microvascular resistance. Therefore, this method seems to be particularly indicated for evaluation of the impact of factors that predominantly influence microvascular properties.

Many studies have focused on CFR assessment by noninvasive methods. Recently, attempts to estimate CFR with single-photon tracers have been made to obtain, with simple noninvasive methods, data for quantitative functional assessment of CAD (13,14,19). CFR measured by sestamibi imaging correlated well with PET data, despite some underestimation at higher flow rates (19). These findings are in agreement with the observation that myocardial retention of 99mTc-labeled agents underestimates CFR at high flow rates, probably because of tracer retention characteristics and kinetics (20). In a recent study, Storto et al. (14) demonstrated good correlation between CFR values estimated by sestamibi imaging and those measured by intravascular Doppler ultrasound in patients undergoing percutaneous coronary intervention. These results demonstrate that sestamibi SPECT is an accurate and simple way to estimate noninvasively CFR. CFR estimated by sestamibi imaging in our patients with CAD was lower than that in subjects with normal coronary vessels. These results are similar to those reported by Gullberg et al. (21) and Sugihara et al. (13). However, the value of this technique in discriminating between significant and not significant coronary artery stenosis remains to be determined.

The procedure used in the present study is based on the microsphere method, which makes use of the fact that sestamibi is taken up by myocardium according to blood flow. We acquired serial planar images to measure the arterial activity of the tracer up to the time of tomographic measurement and acquired tomographic images to measure myocardial counts to estimate the changes in global and regional MBF (13,14,19). In the present study, the accuracy of arterial input function was improved by assigning an ROI at the pulmonary artery, avoiding spillover from bordering cardiac structures that can be observed when the ascending aorta is used (13). In addition, the use of the aorta, which could be less dependent on bolus administration, has some limitations in patients with impaired left ventricular function (19). In the present study, all patients had an adequate time-activity curve without an insufficient bolus (i.e., curve full width at half maximum < 1 s).

In patients with multivessel CAD, the assignment of a perfusion defect to a specific coronary vascular territory by myocardial perfusion scintigraphy has some limitations. Coronary vasodilator reserve is often abnormal, even in territories supplied by vessels with stenosis shown by angiography to be noncritical, reducing the heterogeneity of flow between normal and abnormal zones. The presence of multivessel disease may influence coronary flow during dipyridamole-induced hyperemia and, as a consequence, cardiac tracer uptake during stress. Therefore, in this study, we selected only patients with 1-vessel CAD.

Pitkanen et al. (12), using PET and 15O-labeled water, demonstrated that in lean, young, normotensive, nonsmoking, and nondiabetic subjects, age, family history of CAD, increased cholesterol and triglyceride levels, and insulinemia affected CFR. The same authors found that CFR was impaired in young men with familial hypercholesterolemia (11). Thereafter, Laine et al. (10), using the same method, demonstrated that CFR was reduced in young asymptomatic men with borderline hypertension and no signs of hypertension-induced angina or left ventricular hypertrophy. Fujiwara et al. (22) found that CFR was lower in patients with 1-vessel CAD and with traditional risk factors than in age-matched control subjects (1.62 ± 0.37 vs. 2.58 ± 0.71; P < 0.05), whereas CFR in those without risk factors was not different from that in control subjects (2.54 ± 0.17 vs. 2.58 ± 0.71). These data are not surprising. In fact, it is well know that hypertension, diabetes, smoking, and hypercholesterolemia negatively influence endothelial cell function, 1 of the major determinants of the hyperemic response. In hypertensive patients, a reduction in basal NO synthesis with increased NO inactivation has been demonstrated (23–25). Also, diabetes mellitus appears to cause NO pathway dysfunction by multiple mechanisms. Hyperglycemia and hyperinsulinemia increase the formation of both superoxide and nitrogen peroxide, which can combine directly with NO, reducing the NO half-life and increasing the production of highly reactive peroxynitrite anion (26,27). The impairment of coronary vasodilatation in smokers also has been linked to increased vascular oxidative stress with a reduction in NO production (28,29). The presence of structural abnormalities, such as alteration of intramyocardial arteries, increased perivascular fibrosis, and increased myocardial fibrosis, cannot be excluded. These abnormalities may have contributed to the reduced coronary vasodilatation observed in the present study.

The results of our study demonstrate that the presence and the number of CAD risk factors significantly influence CFR in patients with documented CAD. Interestingly, patients with intermediate lesions and with multiple CAD risk factors exhibited CFR (1.25 ± 0.05) similar to that observed in patients with more severe coronary artery narrowing but without CAD risk factors (1.16 ± 1.18). The influence of CAD risk factors on the hyperemic response to dipyridamole was more evident in patients with intermediate stenosis than in patients with more severe lesions. It should be noted that CFR depends only in part on coronary artery stenosis severity (30). Therefore, it is conceivable that when stenosis is greater than 70%, the influence of other factors is less evident. Tsukamoto et al. (31) evaluated the impact of risk factors and coronary artery stenosis on CFR by using PET and 15O-labeled water. They found that coronary artery stenosis severity was the only independent determinant of CFR in regions with severe stenosis, whereas in regions with less severe stenosis, smoking was the only independent predictor of CFR. However, it should be noted that Tsukamoto et al. (31) also enrolled patients with multivessel CAD.

CONCLUSION

Our results demonstrate a significant influence of CAD risk factors on CFR in patients with 1-vessel CAD and an intermediate degree of stenosis, whereas this influence is less evident in patients with more severe stenosis. Further studies are needed to clarify whether in such patients aggressive risk factor modification, other than reduction of the magnitude of perfusion abnormalities, may improve CFR (32). Finally, our findings support the use of radionuclide imaging for noninvasive estimation of CFR in patients with CAD.

Footnotes

  • Received Feb. 21, 2005; revision accepted May 6, 2005.

    For correspondence or reprints contact: Alberto Cuocolo, MD, Department of Biomorphological and Functional Sciences, University Federico II, Via S. Pansini, 5, I-80131 Napoli, Italy.

    E-mail: cuocolo{at}unina.it

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