The Effect Of Ischemia Modified Albumin (IMA) And N-terminal Pro-brain Natriuretic Peptide(NT-proBNP) In The Diagnosis Of Myocardial Ischemia

BackgroundMyocardial ischemia is the main pathophysiology characteristic of coronary heart disease (CHD),detection of which is very important for diagnosis,treatment and prognosis of CHD. However,unfortunately,the early diagnosis of CHD is one of the weakest parts in the modern cardiology.In large heart centers of the United States,only 25%of the patients with suspected acute coronary syndrome(ACS) had the same diagnosis when discharged,thus cost huge wastes of clinical resourses.On the other hand,there were 2%ACS patients missed annually which resulted in serious outcomes.The most important reason of the phenomenon is that at present there is no effective and convenient measurement of early detecting myocardial ischemia at hand. The usual biomarkers of myocardial ischemia damage such as MB isoenzyme of creatine kinase (CK-MB),cardiac troponin T(cTnT) are sensitive for myocardial necrosis,but have limited ability to identify acute ischemia of coronary artery.Further,these highly specific markers are frequently negative in quite a few chest pain patients present to hospital,which will not show positive until a couple of hours later of continuous survey.During that time,more cadiocytes die, missing the best chance of treatment.So it will be desirable to have a biochemistry marker which can identify myocardial ischemia before the onset of irreparable myocardial cell damage,and will bring tremendous benefits for the clinical diagnosis and treatment of coronary heart disease and some related cardiovascular events.Searching and developing such a rapidly and easily detectable, highly sensitive and specific marker for myocardial ischemia has great importance in screening potential high-risk ischemic chest pain patients,ruling out low-risk ones,and thus helping clinicians decrease expences of clinical resourses as well as diagnose with high efficiency without malpractice.A few biochemical markers have already aroused people's attention such as ischemia modified albumin(IMA) and brain natriuretic peptide(BNP),which are the main objectives of this article.Bar-Or initially found that the N-terminus of human serum albumin(HAS) could change its structure and thus reduce the in vivo transitional metal binding capacity by the oxidative stress effect of myocardial ischemia,forming the so-called "ischemia modified albumin(IMA)".Basing on that they also created the albumin cobalt binding(ACB) test method to determine the level of IMA.Thereafter,quite a few studies were committed abroad to estimate its diagnostic value for myocardial ischemia.In February 2003,the Food and Drug Administration(FDA) of the United States approved the assay for detecting myocardial ischemia and assisting in the diagnosis of low-risk ACS patients,including the early diagnosis of acute myocardial ischemia, the ruling out and risk stratification of ACS.Brain natriuretic peptide(BNP) is a neuroendocrine hormone secreted by cardiac ventricular cells.It has the effects of promoting natriuresis,diuresis,vasodilation and suppression of the sympathetic nervous system and renin-angiotensin-aldosterone system.Its synthesis and secretion enhances when the ventricular load and ventricular wall tension increases.N-terminal pro-brain natriuretic peptide(NT-proBNP) is a coproduct in the generation of BNP and equimolarly secreted as the latter.For its longer biological half-life and higer concentrations in the plasma,it is easier to be detected in the peripheral circulation.Both of them have been approved by the FDA in November 2000 as the diagnostic biomarker of congestive heart failure,which has been widely accepted.Later,however,through more and more studies people have found that cardiac ischemia is another important stimulating factor of their secretion,and their level correlates well with the degree of ischemia and changes regularly in ACS patients.So the application of BNP in this aspect arises people's attention increasingly.PartⅠObjectiveSubmit the suspected or definite low-risk stable CHD patients to treadmill exercise to create ischemic status in their coronary arteries,then observe the serum level changes of IMA and NT-proBNP in positive and negative stress test patients.At the same time detect the "classic" biomarker of cardiac ischemic damage such as cTnT and CK-MB,to find out compared with which,whether IMA,NT-proBNP are more sensitive to identify myocardial ischemia.The ultimate cardioangiography result is used to ascertain the severity of coronary arteries and taken as the "golden standerd" to check whether IMA and NT-proBNP can inhance the accuracy of CHD diagnosis when combined with treadmill load test.MethodsI collected 80 cases who were admitted as "chest pain or distress of unknown" and "recheck after PCI(percutaneous coronary artery intervention) procedure" and meaning to undergo cardioangiography during March to November of 2007 in Zhongshan Hospital.All the subjects were excluded of contraindications for treadmill test,definite peripheral artery disease,myopathy and renal function insufficiency.Maximal or sub- maximal amount of Bruce protocol exercise was adopted to enhance cardiac load and provocate myocardial ischemia.Venous blood was drewn before(on the second morning of admission routinely )and two hours after the exercise,for the detection ofNT-proBNP,cTnT,CK-MB,CK-MM and IMA.The patients' general information, case history,chemical analysis,treadmill and cardioangiography results were documented.To observe whether there were significant differences of IMA and NT-proBNP level between the stress test positive and negative patients before and after the exercise,and check whether IMA and NT-proBNP can inhance the accuracy of CHD diagnosis when combined with treadmill load test according to the result of cardioangiography as a "golden standard".Results1.General statistics and diagnoses of the patients:In the 80 cases,there were 57 males and 23 females,who aged 38～76(59.6±8.3) years.The treadmill test results:27(33.75%) were positive,17(21.25%) were "follow up" and 36(45.00%) were negative.The result of cardioangiography(in which "positive" was defined as existing at least one coronary artery branch(diameter＞2mm) which had stenosis more than 70%or the left main stem had stenosis more than 50%):35(43.75%) were positive while 45(56.25%) were negative.2.The results of each biomarker subgrouped by treadmill test result:(1) IMA(U/ml):None significant differences existed between pro- and post-exercise values in all the positive, follow-up and negative groups(p＞0.05);(2) NT-proBNP(pg/ml):None significant differences existed between pro- and post-exercise values in all the positive, follow-up and negative groups(p＞0.05);(3) cTnT(ng/ml):All patients had less than 0.01ng/ml values both before and after exercise.(4) CK-MB(U/L):None significant differences existed between pro- and post-exercise values in all the positive, follow-up and negative groups(p＞0.05);(5) CK-MM(U/L):Significant differences existed between pro- and post-exercise values in the positive and negative groups(p=0.044,p=0.027) but not in the follow-up group(p＞0.05).3.The results of each biomarker subgrouped by cardioangiography result:(1) IMA(U/ml):None significant differences existed between pro- and post-exercise values in both the positive,and negative groups(p=0.162,p=0.634);Further substratify the positive group into mono-,di- and tri-branch affection subgroups,and there were no significant differences of△IMA or post-exercise IMA existed among them(p=0.546,p=0.798);Divide△IMA and post-exercise IMA into four groups by quartering,and there were no significant differences about the cardioangiography result existed among them(p=0.813, p=0.984).(2) NT-proBNP(pg/ml):Significant differences existed between pro- and post-exercise values in the negative group(p=0.034) but not the positive group(p=0.416);Further substratify the positive group into mono-,di- and tri-branch affection subgroups,and there were no significant differences of△NT-proBNP existed among them(p=0.345);Divided△NT-proBNP into four groups by quartering,and there were no significant differences about the cardioangiography result existed among them(p=0.984).(3) cTnT(ng/ml):All patients had less than 0.01 ng/ml values both before and after exercise.(4) CK-MB(U/L):None significant differences existed between pro- and post-exercise values in both the positive,and negative groups(p=0.172,p=0.165).(5) CK-MM(U/L):Significant differences existed between pro- and post-exercise values in the positive group(p=0.009) but not in the negative group(p=0.955).For according to the receiver operating characteristic(ROC) curve and calculation and test result of the area under the curve(AUC),there were no statistic significance of△IMA,△NT-proBNP for the diagnosis of myocardial ischemia(p＞0.05) when the result of cardioangiography was taken as a "surrogate standard",so it was impossible to select one cut-off value for each index to calculate their diagnosis characteristics,and to further estimate whether they can increase the sensitivity of CHD diagnosis when combined with treadmill exercise test.ConclusionIn low-risk stable CHD patients,IMA and NT-proBNP didn't show diagnostic meaning of myocardial ischemia evoked by treadmill exercise test,also when combined with which they cann't inhance the sensitivity of CHD diagnosis. PartⅡObjectiveTo observe in the patients who visited the emergency department because of "chest pain or distress",the diversity of IMA values among the different clinical caterory groups.And to find out if IMA has the capability of identifying the cardiogenic chest pain induced by acute cardiac ischemia as well as reflecting the serious degree of the event,and when combined with ECG and /or cTnT,if IMA can inhance the sensitivity of ACS diagnosis.MethodsI collected the continuous 43 patients who suffered from "chest pain or distress" and presented to the emergency room of our hospital during 5th to 20th of April in 2008,excluding those who had chronic heart failure or renal function insufficiency.Their serum of different time points sent for chemical examination was taken to determine the IMA value.Before that,based on the comprehensive estimation of the CHD risk factors,characteristics of chest discomfort symptom, serial detection of myocardial injury biomarkers(cTnT mainly),electrocardiogram examination and some patients' cardioangiography results,they were put into either non-ischemic chest pain (NICP) group or acute coronary syndrome(ACS) group.For the patients in the latter one,they were further devided into three subgroups according to the ACC/AHA guidelines:unstable angina (UA) group,non-ST elevated myocardial infarction(NSTEMI) group and ST elevated myocardial infarction(STEMI) group.The diversity of IMA values among the defferent clinical groups was surveyed,and also other examination results were combinded to analyze if IMA could reflect the serious degree of acute cardiac ischemia,and when combined with ECG and/or cTnT, whether IMA can inhance the sensitivity of ACS diagnosis.Results1.General statistics and diagnoses of the patients:There were 43 cases and 85 serum samples collected totally,30 cases were males and 13 were females,who aged 38～88(66.56±16.05) years. The category results were:NICP group 23 cases(53.49%) and 39 samples,UA group 8 cases(18.60%) and 14 samples,NSTEMI group 5 cases(11.63%) and 13 samples,STEMI group 7 cases(16.28%) and 19 samples,ACS group 20 cases(46.51%) and 46 samples totally.2.Taken ABSU/ml as the measurement unit(which was defined as 0.1 of absorbance unit(ABSU) from every milliliter serum),the IMA values in each group were as follows: NICP group 55.9±13.9,ACS group 68.7±14.4,between which significant difference existed (p＜0.001).In subgroups of the latter,UA group 63.4±9.7,NSTEMI group 65.5±10.0, STEMI group 74.7±17.8,when compared with the NICP group as four groups,the mean value were not identical statistically.Among them,there were significant differences between STEMI group and UA group,STEMI group and NICP group,NSTEMI group and NICP group(p＜0.05).3.Taken the ultimate discharging diagnosis as the standard,the several indexes of IMA for diagnosing ACS were:cutoff value 65.6 ABSU/ml,which was established from ROC curve; area under the curve(AUC) 0.736(0.629～0.842);sensitivity 65.2%,specificity 79.5%,given the 46.51%(20/43) prevalence of ACS in this group,the positive and negative predict values were 79.0%and 66.0%respectively;positive likelihood ratio 3.18,negative likelihood ratio 0.44. When combined with cTnT,ECG and both,it increased the sensitivity of diagnosing ACS to 84.78%,86.96%and 95.65%respectively.Compared with NICP group,the ratio of above cutoff value samples was higher in ACS group,and the difference was statistically significant(p＜0.05).4.The correlation of IMA and other clinical measurements:The increasing level of IMA was correlated positively with the degree and extent of ST-T changes in the electrocardiogram (p＜0.05).However,no similar relationship was found between IMA and cTnT concentrations (p＞0.05).Conclusion1.Among patients who visited the emergency department because of "chest pain or distress",the IMA level in ACS group was higher than that in NICP group,and for the former,the more serious the category of disease was,the more obviously IMA increased.2.IMA had some value in differentiating ACS and NICP patients,and when combined with ECG and/or cTnT,it can inhance the sensitivity of ACS diagnosis.3.The increasing level of IMA was correlated with the degree and extent of ST-T changes in the electrocardiogram,thus reflecting the serious degree of cardiac ischemia.