Metabolic Syndrome Is the Main Predictor of Myocardial Ischemia in SPECT

Background: Data show that metabolic syndrome (MS) increases the risk of cardiovascular disease. Objectives: To describe and compare the scintigraphic abnormalities and the predictive value of myocardial ischemia in individuals with and without MS referred for single photon emission computed tomography (SPECT) in a University Hospital using three diagnostic criteria. Methods: Prospective observational study of patients referred for SPECT from June to December 2010. Height, weight and waist circumference were measured. Risk factors were assessed and medical records were reviewed to look for parameters for laboratory diagnosis of MS and complete SPECT reports. Results: The study included 203 patients; 138 women (68.0%); mean age 63.6±11.5 years. Metabolic syndrome was found in 135 patients (66.5%). Of the 99 abnormal tests, 91.9% (n=91) occurred in patients with MS and 8.1% (n=8) in patients without MS. There was a significant association between MS and abnormal scintigraphy (67.0% vs. 11.8%; p<0.001) and patients with MS had abnormalities of greater extent and severity (summed stress score (SSS)=7.3±6.5 vs. 3.0±0.9; p<0.001 and summed difference score (SDS)=3.4±4.3 vs. 0.9±2.5; p<0.001). MS was an independent predictor of myocardial ischemia in the three definitions studied (OR=10.07, 6.25 and 4.26 for modified NCEP-ATP III, NCEP-ATP III and IDF, respectively). Conclusions: Patients with MS had more perfusion defects on SPECT (both fixed and reversible); and MS defined by the modified NCEP-ATP III was the best independent predictor of myocardial ischemia on scintigraphy.


Introduction
Cardiovascular (CV) disease is the leading cause of death worldwide.Patients with MS are at increased risk of myocardial infarction and have higher total and cardiovascular mortality [1][2][3] .
MS is a constellation of interrelated risk factors whose central mechanism is insulin resistance.Patients present hyperglycemia, central obesity, hypertension and an a t h e r o g e n i c l i p i d p h e n o t y p e c o m p o s e d o f hypertriglyceridemia, reduced HDL-cholesterol and increased low-density LDL which favors coronary atherosclerosis 4,5 .
Prevalence is high: 23.7% in the United States 6 , 30% in Brazil 7 and 56.9% in elderly populations 8 .Studies in cardiologic outpatient clinics show prevalence of 61.5% 9 .This high prevalence of MS in patients who seek medical assistance indicate the relevance of an appropriate diagnosis.
It is easy to diagnose MS in clinical practice, but it remains underdiagnosed.There are several definitions [10][11][12] , but there are controversies over which one is more useful.The present study sought to clarify this question by evaluating three simple, easy-to-use classic definitions.
Few research studies addressed scintigraphic abnormalities in patients with MS.Studies conducted by Wong et al. 13 and Shaw et al. 14 showed an association between MS and perfusion defects, but they did not study the classical definitions of MS, replacing the criterion of abdominal obesity for obesity.
This study aims to: 1) To describe and compare the scintigraphic abnormalities in patients with and without MS referred for single photon emission computed tomography (SPECT) in tertiary hospitals; 2) To determine the main predictors of myocardial ischemia; 3) To compare the ischemic predictive value of MS using three definitions.

Methods
This is an observational study of consecutive adult patients who underwent clinically indicated SPECT from June to December 2010.
The exclusion criteria were: patients who did not sign the informed consent; severe valvular or pericardial disease; presence of chronic liver disease, ascites or abdominal tumor; severely ill patients; mental illness; and insufficient laboratory data in the medical records to confirm diagnosis of MS.
From 218 eligible patients, 15 were excluded: 4 with ascites, 5 with serious illness, 2 with severe valve disease and 4 who did not agree to participate.No patient was excluded because of incomplete data for the diagnosis of MS.
This study conforms to the ethical guidelines of the 1975 Declaration of Helsinki, was approved by the Ethics Committee of Hospital Universitário Clementino Fraga Filho under No. 051/10-CEP and all participants have signed an informed consent.
MS was defined by three diagnostic criteria (Chart 1): 1) The NCEP-ATPIII definition (National Cholesterol Education Program Adult Treatment Panel III) requires at least three of the following five criteria: high waist circumference (WC) (>88 cm in women and >102 cm in men), high triglyceride levels (TG) (≥150 mg/dL), reduced HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), high blood pressure (BP) (≥130/85 mmHg) and high fasting glucose (≥ 110 mg/dL).Drug treatment for hypertension or for high triglyceride levels (TG) (fibrates or nicotinic acid) and diabetes were also accepted as specific criteria as recommended by the Brazilian guidelines for MS 15 .
2) The NCEP-ATP III definition modified by AHA/ NHLBI (American Heart Association/National Heart Lung and Blood Institute) is very similar to the previous one 11 .It requires at least three of the same five criteria including drug treatment and diabetes.The only difference is a lower cutoff point for fasting glucose (100 mg/dL).
3) The IDF definition (International Diabetes Federation ), which main difference is the previous requirement of abdominal obesity for diagnosis plus two of the other four criteria including high fasting glucose levels ≥ 100 mg/dL 12 .
Hypertension and Diabetes Mellitus were classified for those patients previously diagnosed or receiving treatment.The variables are presented in Tables 1 and 2 and were defined according to the World Health Organization (WHO) criteria 16 .
Abdominal obesity was defined for waist circumference (WC) >88 cm in women and >102 cm in men according to the NCEP-ATP III criteria 10 ; and IDF criteria using stricter cutoff points of 80 cm in women and 94 cm in men according to the WHO criteria and because these measures are being used in Brazilian studies 12 .
Laboratory parameters, body mass index and WC were analyzed as continuous variables.
The variable hyperglycemia ≥100 mg/dL, according to the American Diabetes Association (ADA) criteria included all patients with fasting glucose ≥100 mg/dL on two occasions.The pharmacological stress agent used was dipyridamole in 184 patients (90.6%) or dobutamine in 5 (2.5%) due to the patients' physical limitations.Exercise stress test was performed using Bruce protocol in 14 patients (6.9%).
During the test, the patients were continuously monitored with 3-lead electrocardiographic monitors.
Imaging was performed using a Millennium MG gamma camera (General Electric Healthcare, Milwaukee, USA) with two detectors for image acquisition, low-energy high-resolution, parallel beams, using a circular 180° acquisition (45° right anterior oblique, 45° left anterior oblique) for 64 projections with a duration of 20 seconds per projection.Two energy windows were used for images with 201 Tl (70KeV 30%, 167 keV 20%).
Images were acquired using a 64x64 matrix with pixel width and depth of 0.6 cm.No attenuation, motion or scatter correction was used.
Reconstruction of transaxial tomographic images was performed.To be interpreted, the images were reoriented in pairs (rest and after stress) on a video display screen.

Interpretation of images
A semiquantitative visual interpretation of perfusion defects was performed using a 17-segment model according to the recommendations of the American Society of Nuclear Cardiology and the American Heart Association 18 .Each myocardial segment was graded using a five-point scoring system: 0=normal perfusion, 1=mild defect, 2=moderate defect, 3=severe defect, 4=no detectable radioactive tracer in a segment.Summed scores were obtained by adding the scores for the 17 segments.Summed stress score (SSS) represents the extent and magnitude of perfusion defect in stress related to ischemia and fibrosis.SSS <4 was considered normal.Summed Rest Score (SRS) was obtained by means of adding the scores for the 17 segments of the rest thallium images and represents the extension of nonreversible perfusion defects determined by myocardial infarction.
The Summed Difference Score (SDS) is the sum of the differences between the stress and rest scores and represents the level of ischemia.An SDS of 0 to 1 is considered normal, 2 to 4 is mild ischemia and >4, moderate to severe ischemia.
Perfusion defect territories were classified as abnormalities in the left anterior descending (LAD) territory or in another territory.Mammary attenuation was registered when present.
All images were evaluated by a second blinded experienced observer.A recent study analyzed the agreement between observers of this team and the kappa coefficient was 0.637 19 .
Outcomes: Percentages of abnormal scintigraphy (both ischemic and/or fixed defects); of ischemic tests, of fixed defects and quantification scores and abnormalities in GATED SPECT (global and segmental left ventricular function and ventricular volumes) were assessed.

Phase 3: Medical records and classification of patients with MS
All data questioned in clinical query were confirmed in medical records.The three last records of complete laboratory tests (glucose and lipid profile) were registered.In treated patients with normal lipid profile, records were collected before laboratory data to determine the type of previous dyslipidemia.

Statistical analysis
The continuous variables were expressed as mean±standard deviation and the categorical variables were expressed in proportions.Categorical variables were compared using the chi-square test.Mean differences for continuous variables were compared by Student's t test.Multivariate logistic regression was used to assess myocardial ischemia predictors.A p value <0.05 was considered statistically significant.For statistical analysis, the statistical software SPSS 17.0, Chicago Illinois, was used.

Results
Demographic data and clinical characteristics are presented in Table 1.
Of the 203 patients included, 68.0% were women.Patients' age ranged from 36 to 89 years and the mean age was 63.6±11.5 years.
SPECT was requested from 143 (70.4%) patients for diagnostic purposes, and from 60 (29.6%) for the control of previous coronary artery disease (CAD) (myocardial infarction or revascularization surgery).There was a tendency to obesity, with body mass index (BMI) ranging from 17 to 46.5 kg/m 2 (28.4±5.6 kg/m 2 ).Table 3 shows the scintigraphic findings in patients with and without MS.Patients with MS classified by the modified NCEP-ATPIII definition had higher percentage of abnormal scintigraphy tests, more ischemic and fixed perfusion defects, greater number of ischemic segments, greater extension and severity of abnormalities with higher scores.The GATED SPECT test showed more abnormalities in contractility and myocardial thickening (hypokinesia and decreased thickening) and differences were significant in both genders.
Patients classified by the NCEP-ATPIII definition had significant differences in most variables studied but there were no abnormalities in the myocardial contractility nor any significant association with ischemia in males.
Patients with MS, according to the IDF definition, had higher percentages of abnormal and ischemic scintigraphy, but these were not associated with fixed perfusion defects.There were no differences in SSS and SRS scores, in segmental motility and no association with ischemia was found in males.
No association with mammary attenuation artifacts and no differences in function or ventricular volumes were found in any of the definitions studied.
Perfusion defects territories were analyzed by the number of criteria for MS.Patients with 5 criteria had more perfusion defects in the left anterior descending artery territory [(n=10) 52.6% vs. 15.8%(n=3)].
Univariate analysis was performed to determine predictors of myocardial ischemia.All risk factors, independent criteria for MS, diabetic subgroups (with and without MS) and MS by three definitions were analyzed.
The main predictors of myocardial ischemia were the MS in the three definitions, high fasting glucose ≥100 mg/dL, hypertension, diabetics with MS, high triglyceride levels and reduced HDL-colesterol.Abdominal obesity was not an independent predictor (Table 4).
Multivariate logistic regression analysis was performed independently for the three definitions studied with adjustments for age, gender and smoking and the three definitions were independent predictors of myocardial ischemia.

Discussion
Several studies show increased cardiovascular risk in patients with SM [1][2][3] .SPECT provides incremental prognostic information toward the identification of cardiac death in the general population and has good relation with angiographic lesions 20 .Few studies, however, have evaluated scintigraphic abnormalities in MS.
Previous studies demonstrated an association of MS with myocardial ischemia on scintigraphy, but the predictive value of ischemia according to different definitions of MS was not analyzed [13][14] .
This study demonstrated that there is a significant association between MS and scintigraphic abnormalities.
Patients with MS had also higher number of ischemic segments, more alterations in contractility and thickening in GATED SPECT and greater extent and severity of perfusion defects evidenced by higher SSS, SRS and SDS (p<0,001).
In the multivariate analysis, the presence of MS maintained its predictive power of detecting myocardial ischemia after adjustments for age, gender and smoking in all definitions used.
This study proved that the best definition to be used is the modified NCEP-ATPIII definition.Such definition was a better predictor of myocardial ischemia (OR=10.07),showed significant differences in all outcome variables studied (fixed perfusion defects and ischemia), in all scores, and was associated with ischemia in both genders.
The NCEP-ATPIII definition was intermediate in its predictive power of ischemia detection (OR=6.25),but proved to be a good definition as it presented differences in most parameters evaluated.
The IDF definition showed a lower predictive power (OR=4.26)and showed differences only in some of the studied outcomes.The event-free survival for two years ranged from 96% to 48% in patients with 0 to 5 criteria for MS, respectively (p<0.001).The authors concluded that SPECT provides adequate information for risk stratification in the short term in patients with MS.
Wong et al. 13 used the NCEP-ATPIII criteria and Shaw et al. 14 used the IDF criteria, but none of them measured WC.In this study, the abdominal obesity criterion was important in the diagnosis of MS in 47 patients (35%).

Study limitations
Like previous studies on MS and scintigraphy, this study had the limitation of being performed in patients referred for clinically indicated SPECT, being a population from a university hospital, with mean age of 63,6 years, with higher prevalence of risk factors than in the general population.However, the results of this research can be applied to populations with similar characteristics as the studied one.
Studies in outpatient clinics show the prevalence of MS and risk factors similar and even higher than those of this study 9  Another limitation is the absence of a gold standard for comparison of the existence of CAD, which could determine that some patients interpreted as having perfusion defects could be false positives.

Clinical application
MS proved to be a main predictor of myocardial ischemia.Regardless of controversies, MS is an effective tool that can help the clinician in the early detection of patients at risk.The definition is simple: five risk factors are used in a dichotomous way, compared with risk scores that are more complicated to use.In patients older than 74 years who are out of risk assessment by the Framingham score, MS also proved to be a main predictor (OR=12.69).
Diagnosing MS is relevant in deciding the appropriate request of a SPECT.Of the 143 scintigraphy tests, requested for suspected CAD, only 51 (35.7%) had abnormal results.However, 67.4% (n=91) of patients with MS had abnormal scintigraphy (positive predictive value of 67.4%) and of the 68 patients without MS, 88.2% (60) had normal results (negative predictive value of 88.2%).

Table 1 Characteristics of the patients studied Values
BMI -body mass index; CAD -coronary artery disease; HDL -high density lipoprotein; IDF -International Diabetes Federation; NCEP-ATP III -National Cholesterol Education Program -Adult Treatment Panel III; SD -standard deviation *The continuous variables are expressed as mean±standard deviation.† Categorical variables are expressed as frequencies.

Table 2 Clinical data of patients with and without MS (modified NCEP-ATP III definition)
BMI -body mass index; CAD -coronary artery disease; NCEP-ATP III -National Cholesterol Education Program -Adult Treatment Panel III; BMI -body mass index; HDL -high density lipoprotein; LDL -low-density lipoprotein; VLDL -very low-density lipoprotein; SD -standard deviation * Continuous data are expressed as mean±SD.† Categorical data are expressed as frequencies.

Table 2
shows the clinical data of patients with and without MS.Groups did not present any significant differences in terms of age, gender and symptoms, differing only in the criteria for MS and obesity.
Of the 99 abnormal scintigraphy tests, 91.9% (91 tests) were patients with MS and only 8.1% (8 tests) occurred in patients without MS.

Table 3 Scintigraphic findings in patients with and without MS
NCEP-ATP III -National Cholesterol Education Program -Adult Treatment Panel III; IDF -International Diabetes Federation; EDV -end-diastolic volume; ESV -end-systolic volume; EF -ejection fraction; SSS -summed resting score; SRS -summed rest score; SDS -summed difference score; MS -metabolic syndrome; SD -standard deviation Continuous data are expressed as mean±SD.Categorical data are expressed as frequencies.

Table 4 Univariate and multivariate analyses for predictors of myocardial ischemia
We conducted multivariate logistic regression analysis independently for the three studied definitions: NCEP-ATP III, NCEP-ATP III and IDF modified definition adjusted for age, sex and smoking.NCEP-ATP III -National Cholesterol Education Program -Adult Treatment Panel III; IDF -International Diabetes Federation; Ӿ MS -metabolic syndrome; CI -confidence interval; OR -odds ratio 8 80.1%; reduced HDL cholesterol: 86.7%.A population-based study conducted in southern Brazil also reported high prevalence of MS and risk factors in the elderly population (68.0±6.0 years) (MS: 56.9%; hypertension: 84.0%; reduced HDL cholesterol: 56.0%)8.