Risk Stratification of Patients With Chest Pain of Unknown Origin
Risk Stratification of Patients With Chest Pain of Unknown Origin
From 2008 to 2010, 138 chest pain patients were prospectively enrolled at the Cardiology Division, Umberto I Hospital, Mestre, fullfilling the following inclusion criteria: stable chest pain syndrome; 2) no history of CAD (i.e., history of myocardial infarction, coronary revascularization, and/or angiographic evidence of > 50% diameter coronary stenosis); 3) adequate image quality allowing satisfactory wall motion analysis and LAD flow; 4) no significant valvular heart disease; 5) no co-morbidity reducing life expectancy to < 1 year. Of the 138 initially selected patients, 7 were lost to follow-up.
Thus, 131 patients (76 men; age 68 ± 9 years) formed the study group.
The study was approved by the institutional review board of Dell'Angelo Hospital Mestre-Venice Italy. All patients gave their written informed consent before undergoing stress echocardiography. When patients signed the written informed consent they also authorized physicians to use their clinical data according to Italian law. All patients were followed-up for a median of 9 months, with a minimum pre-defined follow-up time of 6 months.
Transthoracic stress echocardiographic studies were performed with a commercially available ultrasound machine (iE 33, Philips Ultrasound, Andover, MA, USA) equipped with multifrequency phased-array sector scan probes (S3 to S8) 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, 4-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 and/or worsening of pre-existing wall motion abnormality. Wall motion abnormality at rest was akinetic or dyskinetic myocardium with no thickening during stress. CFR was assessed during standard stress echocardiographic examination by intermittent imaging of wall motion and LAD flow. Coronary flow in the mid-distal portion of the LAD was searched in the low parasternal long-axis section under the guidance of color Doppler flow mapping. All studies were digitally stored to simplify off-line reviewing and measurements. Coronary flow parameters were analyzed off-line using the built-in calculation package of the ultrasound unit. Flow velocities were measured 2 times for each study, namely 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. CFR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. Images were digitally stored at rest, at peak dipyridamole stress testing, and after aminophylline infusion. A CFR on LAD < 1.9 was taken as abnormal. Quality control of stress echocardiographic performance was previously described in depth. Previously assessed intra- and interobserver variabilities for measurements of Doppler recordings and regional wall motion analysis assessment were < 10%.
Heart rate was controlled by intravenous beta blockers, usually metoprolol, administered before CTCA with a titration dose up to 20 mg in patients with heart rate 65 beats/min. In all patients, CTCA was performed using a 64-slice scanner (64 × 0.625 mm collimation, 330 ms gantry rotation time, VCT, GE Medical Systems, Milwaukee, WI, USA). Dose modulation was attained with "electrocardiographic gating" for a maximum gantry delivery between 40% and 80% during the R-R interval. A bolus of 80 ml of high-concentration contrast (Iomeron 400 mg/ml, Bracco Imaging, Milan, Italy) was administered intravenously at 5 ml/s, followed by 50 ml of saline injected at the same infusion rate. The scan was initiated according to the bolus-tracking technique. The coronary calcium score was assessed with dedicated software (CaScore Package, GE Healthcare, Milwaukee, WI, USA), and Agatston score was recorded.
A calcium score > 100 was considered significant.
Image datasets were analyzed using volume rendering and multiplanar reconstruction on post-processing workstations (CardioQ3 package, Advantage Workstation version 4.2, GE Healthcare). A semiquantitative scale was used by the CCTA readers to grade extent of luminal stenosis as a percentage of the vessel diameter using visual estimations.
A vessel stenosis ≥ 50% in at least one coronary artery was the criterion for CAD at CTCA. CTCA and dipyridamole stress echocardiography data were collected and analyzed by different observers. The imaging data were accessible to the referring physician (FR).
Outcome was determined from patient interviews at outpatient clinics, hospital chart reviews, and telephone interviews with a patient, a patient's close relative, or referring physician. Clinical events recorded during follow-up were death, nonfatal myocardial infarction, early (<6 months) and late (≥6 months) coronary revascularization (surgery or angioplasty). To avoid misclassification of cause of death, overall mortality was considered. The diagnosis of acute myocardial infarction was made on the basis of symptoms, ECG changes, and cardiac enzyme level increases. Late revascularization was considered as clinical end-point, reflecting new or progressive symptoms. The data were analyzed for the prediction of major events (death, infarction, late revascularization).
Data were expressed as mean ± standard deviation for continuous variables and as numbers (percent) for categorical variables. Continuous variables were compared using the Student's unpaired t-test, while differences of categorical variables were assessed by the chi-square test. Linear regression was adopted to assess the correlation between calcium score and peak and rest-stress wall motion score index Kaplan-Meier curves were used for estimation of event rate. Only the first event was taken into account. Patients undergoing coronary revascularization were censored at the time of the procedure. The association of selected variables with outcome was assessed with the Cox proportional hazard model using univariate and stepwise multivariate procedures. A significance of 0.05 was required for a variable to be included in the multivariate model, and 0.1 was the cut-off value for exclusion. Hazard ratios with corresponding 95% confidence intervals were estimated. Statistical significance was set at p < 0.05.
SPSS 16.0 (SPSS, Inc., Chicago, IL, USA) was used for analysis.
Methods
Study Patients
From 2008 to 2010, 138 chest pain patients were prospectively enrolled at the Cardiology Division, Umberto I Hospital, Mestre, fullfilling the following inclusion criteria: stable chest pain syndrome; 2) no history of CAD (i.e., history of myocardial infarction, coronary revascularization, and/or angiographic evidence of > 50% diameter coronary stenosis); 3) adequate image quality allowing satisfactory wall motion analysis and LAD flow; 4) no significant valvular heart disease; 5) no co-morbidity reducing life expectancy to < 1 year. Of the 138 initially selected patients, 7 were lost to follow-up.
Thus, 131 patients (76 men; age 68 ± 9 years) formed the study group.
The study was approved by the institutional review board of Dell'Angelo Hospital Mestre-Venice Italy. All patients gave their written informed consent before undergoing stress echocardiography. When patients signed the written informed consent they also authorized physicians to use their clinical data according to Italian law. All patients were followed-up for a median of 9 months, with a minimum pre-defined follow-up time of 6 months.
Resting and Stress Echocardiography
Transthoracic stress echocardiographic studies were performed with a commercially available ultrasound machine (iE 33, Philips Ultrasound, Andover, MA, USA) equipped with multifrequency phased-array sector scan probes (S3 to S8) 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, 4-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 and/or worsening of pre-existing wall motion abnormality. Wall motion abnormality at rest was akinetic or dyskinetic myocardium with no thickening during stress. CFR was assessed during standard stress echocardiographic examination by intermittent imaging of wall motion and LAD flow. Coronary flow in the mid-distal portion of the LAD was searched in the low parasternal long-axis section under the guidance of color Doppler flow mapping. All studies were digitally stored to simplify off-line reviewing and measurements. Coronary flow parameters were analyzed off-line using the built-in calculation package of the ultrasound unit. Flow velocities were measured 2 times for each study, namely 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. CFR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. Images were digitally stored at rest, at peak dipyridamole stress testing, and after aminophylline infusion. A CFR on LAD < 1.9 was taken as abnormal. Quality control of stress echocardiographic performance was previously described in depth. Previously assessed intra- and interobserver variabilities for measurements of Doppler recordings and regional wall motion analysis assessment were < 10%.
CT Coronary Angiography
Heart rate was controlled by intravenous beta blockers, usually metoprolol, administered before CTCA with a titration dose up to 20 mg in patients with heart rate 65 beats/min. In all patients, CTCA was performed using a 64-slice scanner (64 × 0.625 mm collimation, 330 ms gantry rotation time, VCT, GE Medical Systems, Milwaukee, WI, USA). Dose modulation was attained with "electrocardiographic gating" for a maximum gantry delivery between 40% and 80% during the R-R interval. A bolus of 80 ml of high-concentration contrast (Iomeron 400 mg/ml, Bracco Imaging, Milan, Italy) was administered intravenously at 5 ml/s, followed by 50 ml of saline injected at the same infusion rate. The scan was initiated according to the bolus-tracking technique. The coronary calcium score was assessed with dedicated software (CaScore Package, GE Healthcare, Milwaukee, WI, USA), and Agatston score was recorded.
A calcium score > 100 was considered significant.
Image datasets were analyzed using volume rendering and multiplanar reconstruction on post-processing workstations (CardioQ3 package, Advantage Workstation version 4.2, GE Healthcare). A semiquantitative scale was used by the CCTA readers to grade extent of luminal stenosis as a percentage of the vessel diameter using visual estimations.
A vessel stenosis ≥ 50% in at least one coronary artery was the criterion for CAD at CTCA. CTCA and dipyridamole stress echocardiography data were collected and analyzed by different observers. The imaging data were accessible to the referring physician (FR).
Follow-up Data
Outcome was determined from patient interviews at outpatient clinics, hospital chart reviews, and telephone interviews with a patient, a patient's close relative, or referring physician. Clinical events recorded during follow-up were death, nonfatal myocardial infarction, early (<6 months) and late (≥6 months) coronary revascularization (surgery or angioplasty). To avoid misclassification of cause of death, overall mortality was considered. The diagnosis of acute myocardial infarction was made on the basis of symptoms, ECG changes, and cardiac enzyme level increases. Late revascularization was considered as clinical end-point, reflecting new or progressive symptoms. The data were analyzed for the prediction of major events (death, infarction, late revascularization).
Statistical Analysis
Data were expressed as mean ± standard deviation for continuous variables and as numbers (percent) for categorical variables. Continuous variables were compared using the Student's unpaired t-test, while differences of categorical variables were assessed by the chi-square test. Linear regression was adopted to assess the correlation between calcium score and peak and rest-stress wall motion score index Kaplan-Meier curves were used for estimation of event rate. Only the first event was taken into account. Patients undergoing coronary revascularization were censored at the time of the procedure. The association of selected variables with outcome was assessed with the Cox proportional hazard model using univariate and stepwise multivariate procedures. A significance of 0.05 was required for a variable to be included in the multivariate model, and 0.1 was the cut-off value for exclusion. Hazard ratios with corresponding 95% confidence intervals were estimated. Statistical significance was set at p < 0.05.
SPSS 16.0 (SPSS, Inc., Chicago, IL, USA) was used for analysis.
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