| PART ONE The clinical value of simultaneous assessment of multiplebiomarkers in early diagnosis of acute coronary syndromesBackgroundAcute coronary syndromes (ACS) are a complex array of pathophysiological processes, with artheroscleorotic plaque as the basic pathologic change, and in each process, different and specific biomakers were activated. Although plaque rupture, platelet deposition, and thrombus formation are key components of the underlying pathophysiology, it is increasingly recognized that many episodes of ACS do not follow this standard sequence of events. The increasing circulating levels of these biomarkers, reflecting specific processes occurred, such as plaque rupture, myocardial necrosis, and cardiac neurohormonal activation, can be determined in patients with ACS. Therefore, in the future, multiple cardiac biomarkers measured simultaneously and assessed together, will help clinicians make timely and accurate diagnosis. ObjectivesIn this part of the study, biomarkers of plaque rapture (pregnancy associated plasma protein-A, PAPP-A), myocyte necrosis (heart-type fatty acid-binding protein, H-FABP and cardiac troponin T, cTnT), and neurohormonal activation (N terminal-B type natriuretic peptide, NT-proBNP) were measured simultaneously in the hospitalized patients with suspected ACS. The objective was to evaluate the early diagnostic efficacy of each marker in total suspected ACS patients, as well as in different subgroups divided according to time interval from the onset ofsymptoms to hospitalization, and especially in subgroups of non-ST-elevation and troponin T negative patients. Furthermore, the efficacy of multi-marker strategies in the early diagnosis was also explored in non-ST-elevation and cTnT negative patients. MethodsIn this part, the objects were 791 suspected ACS patients and hospitalized in PLA General Hospital less than 12 hours, since the onset of symptoms during December 2004 and August 2006. The blood samples of these patients were collected at the time of hospitalization and stored at -80 centigrade for later assay of biomarkers H-FABP, PAPP-A, and cTnT. NT-proBNP levels were only measured in 197 random selected samples. ResultsThe receiver operating characteristic cure (ROC) analysis was used to evaluate and compare the efficacy of biomarkers H-FABP, PAPP-A, NT-proBNP and cTnT in early diagnosing ACS, with the clinical final diagnosis as the golden criteria and the non-ACS patients as reference. Comparison of the areas under ROC curves revealed that the sequence from big to small is H-FABP, cTnT, PAPP-A, NT-proBNP, and the threshold levels were 22.41 ug/L, 0.012 ug/L, 11.40 ug/L, and 250.25 ng/L, respectively.In suspicious patients, the respective sensitivities of the four markers in diagnosing ACS were H-FABP > cTnT > PAPP-A > NT-proBNP, and the respective specificities were cTnT > H-FABP > PAPP-A > NT-proBNP. In the subgroup of suspicious patients hospitalized within 3 hours, the respective sensitivities were H-FABP > PAPP-A > NT-proBNP > cTnT, and the respective specificities were cTnT > PAPP-A > H-FABP > NT-proBNP. In 3-6 hours subgroup, the respective sensitivities were H-FABP > cTnT > PAPP-A > NT-proBNP, the respective specificities were cTnT > PAPP-A > H-FABP > NT-proBNP. In 6-12 hours subgroup, the respective sensitivities were H-FABP > NT-proBNP > PAPP-A > cTnT, the respective specificities were cTnT > H-FABP> NT-proBNP > PAPP-A.In suspicious ACS patients with non-ST-elevation, the efficacy of H-FABP, cTnT and PAPP-A in diagnosing ACS were further evaluated. In the subgroup within 3 hours, the respective sensitivities were H-FABP > PAPP-A > cTnT, the respective specificities were cTnT > PAPP-A > H-FABP. In 3-6 hours subgroup, the respective sensitivities were H-FABP > PAPP-A > cTnT, the respective specificities were cTnT > PAPP-A > H-FABP. In 6-12 hours subgroup, the respective sensitivities were H-FABP > PAPP-A > cTnT, the respective specificities were cTnT > H-FABP > PAPP-A. In all of the suspicious ACS patients without ST-segment elevation, the respective efficacy in diagnosing non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) were compared among these three markers. In the subgroup of patients within 6 hours, the respective sensitivities in diagnosing NSTEMI were H-FABP> cTnT > PAPP-A, and the respective specificities were cTnT > PAPP-A > H-FABP, while the respective sensitivities in diagnosing UA were PAPP-A > H-FABP > cTnT, and the respective specificities cTnT > PAPP-A > H-FABP. And the results in 6-12 hours subgroup were, the respective sensitivities H-FABP> cTnT > PAPP-A and specificities cTnT > H-FABP > PAPP-A in diagnosing NSTEMI respectively, the respective sensitivities PAPP-A > H-FABP > cTnT and specificities cTnT > H-FABP > PAPP-A in diagnosing UA, respectively.In patients with negative cTnT and non-ST-elevation but suspected with ACS, separate evaluation and combined assessment of H-FABP and PAPP-A were performed for the early diagnosis of ACS. In the subgroup of patients within 6 hours, PAPP-A sensitivity was better than H-FABP, but its' specificity was less than H-FABP. In 6-12 hours subgroup, H-FABP' sensitivity and specificity were both better than PAPP-A. If the circulating levels of H-FABP and PAPP-A both or either above respective thresholds were all considered positive, and both below considered negative, the sensitivity and specificity of such a combined method in 0-6 hours subgroup were 80.14% and 75.57%, and those in 6-12 hours were71.90% and 62.13%. If the results of H-FABP and PAPP-A were redefined, considering both above as positive and the other condition as negative, the respective sensitivity and specificity of this method in 0-6 hours subgroup were 42.60% and 100.00%, and those in 6-12 hours were 26.89% and 84.83%. Conclusions1. H-FABP, as an early biomarker of myocyte ischemic damage, was superior to cTnT in sensitivity and with relatively high specificity in diagnosing ACS in suspicious patients within 3 hours after symptoms onset. Therefore it seemed to be a promising biomarker in early diagnosis of ACS.2. H-FABP was also useful in the early diagnosis of NSTEMI, and it would make up the inability of cTnT in this field when both measured together.3. PAPP-A was found to be a useful early biomarker in diagnosing UA in patients with suspected ACS because of its high sensitivity in such condition.4. The combined diagnostic efficacy of H-FABP and PAPP-A in assessing suspicious ACS patients with non-ST-elevation and cTnT negative was better than either biomarker alone, and indicated that multi-marker measured simultaneously and assessed together would be useful in clinical.PART TWOThe clinical value of simultaneous assessment of multiple biomarkers in early risk stratification of acute coronarysyndromesBackgroundAcute coronary syndromes (ACS) are a complex array of pathophysiological processes, with artheroscleorotic plaque as the basic pathologic change, and in each process, different and specific biomakers were activated. Although plaque rupture, platelet deposition, and thrombus formation are key components of the underlying pathophysiology, it is increasingly recognized that many episodes of ACS do not follow this standard sequence of events. The increasing circulating levels of these biomarkers, reflecting specific processes occurred, such as plaque rupture, myocardial necrosis, and cardiac neurohormonal activation, can be determined in patients with ACS. Therefore, in the future, multiple cardiac biomarkers measured simultaneously and assessed together, will not only help clinicians make timely and accurate diagnosis, but also be used as useful tools in making detailed risk stratification in ACS, and furthermore, to guide individualized therapy for each patient, especially for patients with non-ST-elevation. Such a multi-marker guided therapy will not only ensure each ACS patient get the maximal benefit from treatment, but also allow appropriate allocation of the medical resources of the whole society.ObjectivesIn this part, the main purpose was to determine whether different combining strategies of multi-markers can better stratify the risks for adverse outcomes in patients with defined diagnosis of ACS. For this purpose, the predictive value of each of these markers was first analyzed both in total ACS patients and in part of these patients with negative cTnT results.MethodsThe objects of this part were 677 patients with final diagnosis of ACS from the above suspected patients. And follow-up were conducted by means of telephone, and outpatient interviews, and reviewing medical records. The study endpoints were cardiac death (CD), non-fatal myocardial infarction (MI), non-fatal heart failure (HF), and non-cardiac death (non-CD). The major adverse cardiovascular events (MACE) were defined as CD, MI and HF, and the combined events of end points included MACE and non-CD.ResultsROC curve analysis over the dynamic range of the biomarkers' assay was used to identify the threshold levels to provide the highest predictive value. The threshold levels were 48.13μg/L, 14.33μg/L, 514.30ng/L, and 0.0185μg/L for H-FABP, PAPP-A, NT-proBNP and cTnT, respectively. The ACS patients were dichotomized into high level and low level groups according to each biomarker's threshold value.During 1-month, 6-month and 12-month of follow-up periods, compared with respective low level patients, patients with high levels of H-FABP, PAPP-A, NT-proBNP, or cTnT, had a relatively significant high risk of combined endpoint events. During 1-month of follow-up, the risk of CD+MI was significantly higher in patients with high levels of one of the four markers than those with respective low marker levels. During 6-month of follow-up, elevated cTnT levels showed no statistically increased risk with relation to CD+MI occurrence, while elevated levels of the other three makers still indicated an increased risk. At the time of 12-month, only patients with elevated PAPP-A levels had a significant high risk of CD+MI.For the endpoint event of HF, only during 1-month of follow-up did elevated PAPP-A levels indicate an increased risk, and during both 1-month and 6-monthof follow-up periods, elevated cTnT levels showed a higher risk, while bothelevated H-FABP and special NT-proBNP levels were associated with anincreased risk during all three follow-up periods.Kaplan-Meier event rate curves showed that cumulative incidence of combinedendpoint events in patients with low levels of H-FABP, PAPP-A, NT-proBNP, orcTnT were significantly less than those with respective low levels of thesemarkers.When the analysis was restricted to cTnT-negative patients, anyone of the otherthree markers still identified a subgroup of patients with high-risk for theincidence of MACE within 6-month follow-up.If the threshold levels of H-FABP and PAPP-A in diagnosing ACS were used as acut-off value to divide the cTnT negative patients into four subgroups, e.g., bothnegative, PAPP-A single positive, H-FABP single positive, and both positivegroups, the risk for the incidence of combined endpoint events in above respectivesubgroups increased rapidly and significantly.The results of Univariate analysis showed that circulating levels of H-FABP,PAPP-A, NT-proBNP and cTnT in patients with adverse events were significantlyhigher than in patients without adverse events. In a multivariable logisticregression model, including biomarkers as well as baseline characteristics,H-FABP, PAPP-A, NT-proBNP and cTnT were independent risk factors.In our study, H-FABP and/or cTnT levels higher than respective threshold value inpredictive analysis were designated with 1 point, while at the same time, PAPP-Aand NT-proBNP were designated with 1 point each. Thus, when H-FABP, cTnT,and PAPP-A were combined in risk stratification, the patients with ACS werecategorized into 0 point, 1 point and 2 point groups according to levels and thenumbers of biomarkers. During all three follow-up periods, the higher of thepoints the group of patients were, significantly more risk the patients for incidenceof combined endpoint events were. When the above method introduced anotherbiomarker, NT-proBNP, the patients were categorized into 0 point, 1 point, 2 pointand 3 point groups. The same risk trend in patients with different score alsoexisted during 6-month follow-up of period.Conclusions1. H-FABP, PAPP-A, NT-proBNP and nt-proBNP were all independent predictors in ACS patients, but with different features as to events and durations with predictive value. Elevated levels of cTnT, H-FABP and NT-proBNP indicated an increased risk for CD+MI in both 1-month and 6-month follow-up of periods, and PAPP-A did so in all three periods. While PAPP-A in 1-month and H-FABP in both 1-month and 6-month of follow-up identified subgroups of patients highly risk for HF, cTnT and NT-proBNP did so in all three periods.2. H-FABP, PAPP-A and NT-proBNP were all of predictive values in patients with ACS but cTnT-negative ACS patients.3. H-FABP and PAPP-A assessed together, with the diagnosing threshold levels as references, would simply identify the high-risk patients in the cTnT-negative ACS.4. The results of Univariate analysis showed that the circulating levels of patients with adverse outcomes were significantly higher than those of patients without adverse outcomes. Such results suggested that they be important risk factors for the adverse outcomes. The results of further multivariable logistic analysis supported that they were all important and independent risk factors.5. According to our scoring method, combination of H-FABP and cTnT reflecting myocyte necrosis, and PAPP-A reflecting artheroscleorotic plaque unstable and ruptured, were able to stratify ACS patients more accurately and earlier. When NT-proBNP was introduced into this combining assessment, the stratification of ACS seemed to be more effective and accurate. Therefore, such a scoring method tended to be a clinically promising utility.
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