Risk stratification in patients with acute coronary syndromes (ACS) is achieved today by clinical models, “blind” to the prognostic support of imaging methods. To assess the value of simple at rest cardiac chest sonography in predicting the intra- and extrahospital risk of death or myocardial infarction, we enrolled 470 consecutive in-patients (312 men, age 71 ± 12 years) who had been admitted for ACS. On admission, all had received a clinical score using the Global Registry in Acute Coronary Events and Thrombolysis in Myocardial Infarction systems and, within 1 to 12 hours, a comprehensive cardiac-chest ultrasound scan. Each of the 16 echocardiographic parameters evaluating left and right, systolic and diastolic, ventricular function and structure, was scored from 0 (normal) to 3 (severely abnormal). The median follow-up was 5 months (interquartile range 1 to 10). Patients with hard events (n = 102) could be separated from patients without events (n = 368) using the Global Registry in Acute Coronary Events score, Thrombolysis in Myocardial Infarction score, and several echocardiographic parameters. On multivariate Cox analysis, ejection fraction (hazard ratio 1.45, 95% confidence interval 1.02 to 2.08, p = 0.040), tricuspid annular plane systolic excursion (hazard ratio 1.66, 95% confidence interval 1.13 to 2.45, p = 0.010) and ultrasound lung comets (hazard ratio 1.69, 95% confidence interval 1.25 to 2.27, p = 0.001) were independent predictors of cardiac events. The 3-variable echocardiographic score (from 0, normal to 9, severe abnormalities in ejection fraction, ultrasound lung comets, and tricuspid annular plane systolic excursion) effectively stratified patients and added value (hazard ratio 2.52, 95% confidence interval 1.89 to 3.37, p <0.0001) to the Global Registry in Acute Coronary Events score (hazard ratio 1.60, 95% confidence interval 1.07 to 2.39, p = 0.003). In conclusion, for patients with ACS, effective risk stratification can be achieved with cardiac and chest ultrasound imaging parameters, adding prognostic value to the clinical risk scores.
Acute coronary syndromes (ACS) encompass a spectrum of clinical conditions, ranging from ST-segment elevation myocardial infarction (STEMI) to non-STEMI (NSTEMI) and unstable angina. Although these conditions share common underlying pathophysiologic mechanisms, patients with ischemic discomfort at rest are heterogeneous in terms of the diagnosis, treatment, and prognosis. The American College of Cardiology/American Heart Association and the European Society of Cardiology Guidelines for ACS have recommended early risk stratification using several clinical risk scores to identify high-risk patients. All risk scores available, such as the Global Registry in Acute Coronary Events (GRACE) and the Thrombolysis in Myocardial Infarction (TIMI), have a relatively high predictive value for in-hospital and 1 and 12-month mortality but are “blind” to the support of imaging methods. The aim of the present study was to assess the relative value of simple at rest cardiac chest ultrasound parameters for risk stratification of patients with ACS compared to the GRACE and TIMI risk scores.
Methods
Initially, we prospectively considered 487 consecutive patients, who had been admitted for ACS. The patients were enrolled from September 2006 to September 2008 from the Coronary Care Unit of Clinical Physiology Institute (National Council of Research, Pisa, Italy). Eligible patients were adults (≥18 years old) who had met the following inclusion criteria: (1) symptoms consistent with ACS and objective signs of myocardial ischemia, such as electrocardiographic changes and/or serial increases in levels of biochemical markers of cardiac necrosis (creatine kinase myocardial subforms and/or troponins); (2) a transthoracic echocardiogram adequate to assess the at rest regional wall function (the echocardiogram was considered adequate if ≥13 of the maximum of 17 segments were visualized); and (3) enrollment in a follow-up program. The exclusion criteria were (1) technically poor acoustic window precluding satisfactory imaging of the left ventricle (for 2-dimensional echocardiography); (2) patients with noncoronary causes of chest pain (i.e., trauma, aortic aneurysm, pulmonary embolism, or pericarditis); (3) significant co-morbidity reducing life expectancy to <1 year; (4) cardiac chest sonography performed >12 hours after admission; and (5) an unwillingness to give informed consent.
All cases were assigned to one of the following categories: STEMI, NSTEMI, or unstable angina, according to standard definitions. Myocardial infarction was defined as the detection of an increase and decrease of troponin I with at least one value greater than the ninety-ninth percentile of the upper reference limit (coefficient of variation ≥10%) and one of the following: (1) acute onset of prolonged (>20 minutes) typical ischemic chest pain; (2) ischemic electrocardiographic changes at presentation (persistent or transient ST-segment depression of ≥0.1 mV in ≥2 contiguous leads or T-wave inversion, flat T waves, pseudonormalization of T waves for NSTEMI; or persistent [>20 minutes] ST-segment elevation of ≥0.1 mV in ≥2 contiguous leads or new left bundle branch block or the development of pathologic Q waves for STEMI). Unstable angina was defined as new-onset class III or IV anginal chest pain or equivalents of the Canadian Cardiovascular Society classification with diagnostic ischemic electrocardiographic changes (ST-segment changes or T-wave inversion) and negative cardiac enzymes and/or troponin levels.
Of the 487 patients initially selected for the study, 6 (1%) were excluded because of inadequate echocardiographic image quality, and 11 additional patients (2%) were lost to follow-up. Thus, 470 patients (312 men; age 71 ± 12 years) who had been admitted for ACS (137 [29%] with STEMI, 231 [49%] with NSTEMI, and 102 [22%] with unstable angina) represented the final study group. When the patients provided written informed consent, they also authorized the physicians to use their clinical data. The institutional review board approved the present study.
On admission, all enrolled patients received a clinical score using GRACE and TIMI for NSTEMI/unstable angina or TIMI for STEMI according to the admission diagnosis and, within 1 to 12 hours, underwent a comprehensive cardiac chest ultrasound scan, including evaluation of ultrasound lung comets (an echographic index of extravascular lung water). A total of 356 patients (76%) underwent coronary angiography, 241 (51%) percutaneous coronary angioplasty, and 42 (9%) coronary artery bypass grafting. All patients were followed up for a median of 5 months (interquartile range 1 to 10).
All patients underwent transthoracic echocardiographic examinations at rest, using conventional methods with commercially available ultrasound machines (Sonos 7500 and IE33, Philips Medical Systems, Andover, Massachusetts; Sequoia C256 Acuson, Siemens, Mountain View, California; Famiglia Mylab25, Esaote, Genoa, Italy; Vivid System 7, GE/Vingmed, Milwaukee, Wisconsin) equipped with a 2.5 to 3.5-MHz phased-array sector scan probe and second harmonic technology. The left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left atrium, and right ventricle end-diastolic diameter were measured from the internal dimensions obtained from 2-dimensional images on the parasternal long-axis view. The left ventricular end-diastolic diameter was indexed to the body surface area. The left ventricular end-diastolic and end-systolic volumes were measured, and the ejection fraction was obtained from the 2- and 4-chamber views using the biplane disks’ summation method (Simpson’s rule), according to the recommendations of the European Association of Echocardiography. The wall motion score index was measured using a 17-segment model in multiple views. The left ventricular mass was calculated using the Devereux formula and then indexed to the body surface area. To determine the tricuspid annular plane systolic excursion, the monodimensional cursor was oriented to the junction of the tricuspid valve plane with the right ventricle free wall, using the 2-dimensional apical 4-chamber view. The tricuspid annular plane systolic excursion was measured as the total excursion of the tricuspid annulus from end-diastole to end-systole, with values representing the average tricuspid annular plane systolic excursion of 3 to 5 beats. A value >20 mm suggested normal right ventricular systolic function. The mitral annular plane systolic excursion was measured with the same method, with the monodimensional cursor oriented to the junction of the mitral valve plane with the left ventricle free wall. Mitral regurgitation was assessed semiquantitatively (0, absent or trivial; 1, mild; 2, moderate; and 3, severe), according to the European Society of Cardiology recommendations. Left ventricular diastolic function was determined from the pattern of mitral and pulmonary venous flow velocity by pulsed Doppler echocardiography, complemented by mitral annular velocity using tissue Doppler imaging, when needed. Diastolic dysfunction was graded as absent (grade 0), mild (grade 1, impaired relaxation), moderate (grade 2, pseudonormalized filling pattern), and severe (grade 3, restrictive filling pattern). The pulmonary artery systolic pressure was derived from the maximal velocity of the tricuspid Doppler tracing according to the modified Bernoulli equation and adding the value of the right atrial pressure, which was estimated on the basis of the inspiratory collapse index of the inferior vena cava.
The chest ultrasound examinations were performed at the end of the standard 2-dimensional echocardiographic examination, with the same probe and the same setting used for the echocardiographic study, as previously described. A lung comet was defined as a hyperechogenic, coherent bundle with a narrow basis, spreading from the transducer to the further border of the screen and arising only from the pleural line. In brief, the ultrasound scanning of the anterior and lateral chest was obtained on the right and left hemithoraxes, from the second to the fourth (on the right side to the fifth) intercostal space, along the parasternal, midclavicular, anterior axillary, and midaxillary lines, as previously described. The sum of the ultrasound lung comets found at each scanning site yielded a score denoting the extent of the extravascular fluid of the lung. Zero was defined as a complete absence of ultrasound lung comets on the investigated area. The presence of ultrasound lung comets was staged in 3 grades: mild (6 to 15 comets), moderate (16 to 30 comets), and severe (>30 comets). A score of ≤5 ultrasound lung comets was defined as a normal echographic chest pattern, because it has been reported that healthy patients could have a small number of ultrasound lung comets, especially confined laterally to the last intercostal spaces above the diaphragm.
The full details of the design and methods of the GRACE and TIMI risk scores have been previously published (available at www.outcomes-umassmed.org/grace and www.timi.org , respectively). The GRACE risk score is calculated from 8 individual variables: patient age, admission systolic blood pressure, heart rate, Killip score, baseline creatinine level, cardiac arrest on admission, ST-segment deviation on the initial electrocardiogram, and elevation of cardiac biomarkers. The estimated 6-month risk of death or myocardial infarction was calculated using the GRACE ACS risk model 0.36. The 7 predictor variables for unstable angina/NSTEMI TIMI risk score calculation are patient age, ≥3 cardiovascular risk factors, previous coronary artery disease, severe anginal symptoms (≥2 episodes in the previous 24 hours), use of aspirin in the previous 7 days, ST-segment deviation, and elevated serum troponin level. The TIMI risk score for STEMI includes 8 predictor variables: age, systolic blood pressure <100 mm Hg, heart rate >100 beats/min, Killip’s classification 2 to 4, anterior STEMI or left branch bundle block, diabetes mellitus, hypertension or angina pectoris, weight <67 kg, and interval to treatment >4 hours. For the TIMI risk score, we calculated the 1-month risk of death for patients with STEMI and the 14-day risk of death or myocardial infarction for patients with NSTEMI/unstable angina. From these risk scores, the patients were divided into tertiles of risk.
In-hospital mortality or recurrent myocardial infarction were recorded. Nonfatal myocardial infarction included STEMI and NSTEMI, according to standard definitions. Out-hospital follow-up was obtained every 3 months by questionnaire or telephone interview with the patient, the patient’s family, or the physician to assess survival and recurrent myocardial infarction. All reported events were confirmed by a review of the medical records or death certificate. To avoid misclassification of the cause of death, overall mortality was considered. Therefore, the outcome events were all-cause death and nonfatal myocardial infarction. When one of these events occurred, the patient was censored.
The statistical analyses included descriptive statistics: the frequency and percentage for categorical variables and the mean and standard deviation or median (interquartile range), as appropriate, for continuous variables. The comparison of continuous variables was performed using an independent sample t test. For categorical variables, the chi-square test was used. The individual effect of certain variables on event-free survival was evaluated using the Cox regression model. To adjust for several risk factors, multivariate Cox analysis was performed, including all variables significant on univariate analysis, entered sequentially (forward). The proportional hazards assumptions of the Cox model was verified with the linear correlation test. A significance of p <0.05 was required for a variable to be included in the multivariate model. Significance of p <0.1 was the cutoff value for exclusion. Hazard ratios with the corresponding 95% confidence intervals were estimated. The following covariates from the history and clinical data were analyzed: gender, New York Heart Association class on admission, Canadian Cardiovascular Society angina classification in the previous 6 weeks, previous heart failure and peripheral arterial disease, hemoglobin, glucose, and GRACE and TIMI risk scores. The variables incorporated into the GRACE and TIMI risk scores were excluded from the multivariate analysis. For the cardiac chest ultrasound data, the 16 parameters analyzed, evaluating left and right, systolic and diastolic, ventricular function and structure, were scored in quartiles of risk from 0 to 3 (grade 0, normal pattern; grade 1, mild; grade 2, moderate; and grade 3, severe, abnormal features). Of the echocardiographic variables significant on Cox univariate analysis, multivariate Cox analysis selected the variables that were independent predictors of hard events: ejection fraction, tricuspid annular plane systolic excursion, and ultrasound lung comet score. The echocardiographic score was the sum of the scores of the 3 variables selected. According to this modeling, a score of 0 would indicate a totally normal cardiac chest ultrasound study, and a total score of 9 would indicate a severely abnormal cardiac chest ultrasound study. All the intermediate patterns were scored from 0 to 9, as appropriate. Finally, the echocardiographic score was entered into the clinical model. Kaplan-Meier analysis was used to calculate the overall event-free survival rates, and differences in survival rates between groups were tested using the log-rank test for the scores analyzed. All tests were 2-sided, and p values <0.05 were considered statistically significant. All analyses were performed using Statistical Package for Social Sciences statistical software, version 13.0 (SPSS, Chicago, Illinois).
Results
The main clinical characteristics and the cardiac chest ultrasound data of the patient population are summarized in Tables 1 and 2 , respectively.
| Variable | Events | p Value | ||
|---|---|---|---|---|
| Total | No | Yes | ||
| Men | 312 (66%) | 248 (67%) | 64 (63%) | 0.379 |
| Age (years) | 71 ± 12 | 69 ± 12 | 78 ± 10 | <0.0001 |
| New York Heart Association class on admission | 1 (1–2) | 1 (1–2) | 2 (1–4) | <0.0001 |
| Killip class on admission | 1 (1–1) | 1 (1–1) | 1 (1–2) | <0.0001 |
| Risk factors ≥3 | 161 (34%) | 129 (35%) | 32 (31%) | 0.488 |
| Canadian Cardiovascular Society angina class in previous 6 weeks | 0 (1–3.5) | 0 (1–3) | 0 (1–4) | 0.603 |
| Previous myocardial infarction | 130 (28%) | 88 (24%) | 42 (41%) | 0.001 |
| Previous percutaneous transluminal coronary angioplasty | 107 (22%) | 80 (22%) | 27 (26%) | 0.350 |
| Previous coronary artery bypass grafting | 55 (12%) | 42 (11%) | 13 (13%) | 0.727 |
| Previous heart failure | 25 (5%) | 18 (4%) | 7 (7%) | 0.068 |
| Peripheral arterial disease | 65 (14%) | 50 (14%) | 15 (15%) | 0.441 |
| ST-segment deviation | 249 (53%) | 193 (52%) | 56 (55%) | 0.660 |
| Troponin I peak (ng/ml) | 2.0 (0.2–10.9) | 1.5 (0.2–9.0) | 4.8 (0.7–14.6) | 0.001 |
| Creatinine (mg/dl) | 1.0 (0.9–1.3) | 1.0 (0.9–1.2) | 1.3 (1.1–1.8) | <0.0001 |
| Hemoglobin (g/dl) | 13.5 (12.1–14.8) | 13.8 (12.4–15) | 12.3 (10.9–13.7) | <0.0001 |
| Glucose (mg/dl) | 117 (98–156) | 113 (96–146) | 136 (107–199) | <0.0001 |
| Global Registry in Acute Coronary Events ⁎ | 28 (19–40) | 25 (18–36) | 39 (28–50) | <0.0001 |
| Thrombolysis In Myocardial Infarction † | 5 (3–12) | 5 (3–12) | 7 (5–19) | <0.0001 |
⁎ Six-month risk % of death or myocardial infarction.
† One-month risk % of death for ST-segment elevation myocardial infarction or 14-day risk % of death or myocardial infarction for non–ST-segment elevation myocardial infarction/unstable angina.
| Variable | Events | p Value | ||
|---|---|---|---|---|
| Total | No | Yes | ||
| Ejection fraction (%) | 50 (40–58) | 53 (45–60) | 40 (30–50) | <0.0001 |
| Wall motion score index | 1.4 (1.12–1.8) | 1.35 (1.15–1.76) | 1.7 (1.3–1.9) | <0.0001 |
| Mitral annular plane systolic excursion (mm) | 12 (10–15) | 13 (11–15) | 10 (8–13) | <0.0001 |
| Left ventricular end-diastolic diameter (mm) | 50 (46–55) | 50 (46–55) | 51 (47–55) | 0.151 |
| Left ventricular end-systolic diameter (mm) | 34 (28–39) | 33 (28–38) | 38 (31–42) | <0.0001 |
| Left ventricular end-diastolic diameter/body surface area (mm/m 2 ) | 27.4 (24.8–30.3) | 27 (24.6–29.8) | 29 (26.4–32) | <0.0001 |
| Left ventricular end-diastolic volume (ml) | 102 (83–135) | 102 (83–129) | 113 (90–141) | 0.021 |
| Left ventricular end-systolic volume (ml) | 44 (32–64) | 41 (32–58) | 60 (40–79) | <0.0001 |
| Left atrium (mm) | 40 (36–45) | 40 (36–44) | 42 (38–48) | 0.001 |
| Mitral regurgitation | 1 (0-2) | 1 (0-2) | 2 (1–2) | <0.0001 |
| Left ventricular mass index (g/m 2 ) | 128 (103–163) | 123 (99–159) | 140 (118–187) | 0.001 |
| Diastolic dysfunction | 1 (1–2) | 1 (1–1) | 1 (1–3) | <0.0001 |
| Tricuspid annular plane systolic excursion (mm) | 20 (17–23) | 21 (17–23) | 17 (13–20) | <0.0001 |
| Right ventricular end-diastolic diameter (mm) | 26 (23–28) | 26 (23–28) | 27 (24–29) | 0.103 |
| Pulmonary artery systolic pressure (mm Hg) | 37 (31–46) | 35 (30–43) | 44 (37–50) | <0.0001 |
| Ultrasound lung comets (n) | 7 (0–31) | 4 (0–19) | 43 (11–92) | <0.0001 |
During a median follow-up of 5 months, a total of 102 events (22%) occurred (56 deaths and 46 nonfatal myocardial infarctions). Using the Cox proportional hazards model, the New York Heart Association class, hemoglobin, and GRACE and TIMI risk scores were independent predictors of death or myocardial infarction ( Table 3 ). When the cardiac chest ultrasound parameters were entered into the model, the ultrasound lung comets, tricuspid annular plane systolic excursion, and ejection fraction scores were independent predictors of hard events ( Table 4 ). The Kaplan-Meier survival estimates for death or myocardial infarction showed a better outcome for patients with a low- to intermediate-risk GRACE score than for those with a high-risk GRACE score (log-rank 53.15, p <0.0001; Figure 1 ). The survival estimates for hard events showed a better outcome for patients with a low-risk TIMI score than for those with an intermediate- or high-risk TIMI score (log-rank 26.45, p <0.0001; Figure 2 ).
| Variable | HR (95% CI) | p Value | HR (95% CI) | p Value |
|---|---|---|---|---|
| Men ⁎ | 0.8 (0.5–1.2) | 0.214 | ||
| New York Heart Association class on admission † | 1.7 (1.4–1.9) | <0.0001 | 1.36 (1.15–1.61) | <0.0001 |
| Canadian Cardiovascular Society angina class in previous 6 weeks † | 0.964 (0.853–1.1) | 0.558 | ||
| Previous heart failure ⁎ | 1.78 (0.9–3.5) | 0.099 | ||
| Peripheral arterial disease ⁎ | 1.0 (0.57–1.76) | 0.992 | ||
| Hemoglobin (g/dl) † | 0.8 (0.7–0.8) | <0.0001 | 0.87 (0.79–0.95) | 0.003 |
| Glucose (mg/dl) † | 1.0 (1.0–1.0) | <0.0001 | ||
| Global Registry in Acute Coronary Events ‡ | 2.84 (1.97–4.09) | <0.0001 | 1.72 (1.15–2.57) | 0.001 |
| Thrombolysis In Myocardial Infarction ‡ | 1.99 (1.54–2.59) | <0.0001 | 1.39 (1.04–1.86) | 0.026 |
| Variable | HR (95% CI) | p Value | HR (95% CI) | p Value |
|---|---|---|---|---|
| Ejection fraction | 1.86 (1.58–2.19) | <0.0001 | 1.45 (1.02–2.08) | 0.040 |
| Wall motion score index | 1.75 (1.39–2.20) | <0.0001 | ||
| Mitral annular plane systolic excursion | 2.09 (1.60–2.73) | <0.0001 | ||
| Left ventricular end-diastolic diameter | 1.14 (0.88–1.49) | 0.312 | ||
| Left ventricular end-systolic diameter | 1.36 (1.13–1.65) | 0.001 | ||
| Left ventricular end-diastolic diameter/body surface area | 1.26 (1.00–1.58) | 0.048 | ||
| Left ventricular end-diastolic volume | 1.22 (1.02–1.47) | 0.033 | ||
| Left ventricular end-systolic volume | 1.33 (1.15–1.54) | <0.0001 | ||
| Left atrium | 1.37 (1.14–1.65) | 0.001 | ||
| Mitral regurgitation | 1.96 (1.59–2.41) | <0.0001 | ||
| Left ventricular mass index | 1.40 (1.19–1.66) | <0.0001 | ||
| Diastolic dysfunction | 2.03 (1.65–2.50) | <0.0001 | ||
| Tricuspid annular plane systolic excursion | 2.54 (2.01–3.22) | <0.0001 | 1.66 (1.13–2.45) | 0.010 |
| Right ventricular end-diastolic diameter | 1.37 (0.96–1.95) | 0.085 | ||
| Pulmonary artery systolic pressure | 1.60 (1.30–1.96) | <0.0001 | ||
| Ultrasound lung comets | 1.97 (1.66–2.33) | <0.0001 | 1.69 (1.25–2.27) | 0.001 |
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