The implications of serum enzymes and coagulation activities in postinfarction myocardial rupture

Objectives: Associations between cardiovascular diseases and serum enzymes or coagulation activities have been sufficiently documented in patients with myocardial infarction. However, the alterations of these biomarkers in patients with postinfarction myocardial rupture have rarely been reported. The aim of this study is to present the profiles of the markers in patients with postinfarction myocardial rupture. Methods: From 2004 to 2008, 19 consecutive patients were referred to this hospital for surgical repair of postinfarction myocardial rupture. Eight (42.1%) patients had free wall


Abstract
Objectives: Associations between cardiovascular diseases and serum enzymes or coagulation activities have been sufficiently documented in patients with myocardial infarction.However, the alterations of these biomarkers in patients with postinfarction myocardial rupture have rarely been reported.The aim of this study is to present the profiles of the markers in patients with postinfarction myocardial rupture.
Methods: From 2004 to 2008, 19 consecutive patients were referred to this hospital for surgical repair of postinfarction myocardial rupture.Eight (42.1%) patients had free wall

INTRODUCTION
In the event of myocardial damage secondary to acute myocardial ischemia, intracellular cardiac proteins and enzymes are released into the circulation via cardiac cell membranes [1,2].Patients with postinfarction myocardial rupture, a severe complication of acute myocardial infarction, often develop rapid hemodynamic deterioration [3], and are usually associated with more extensive myocardial damage [4], the assessment of which has not been fully conducted in a way similar to that of the myocardial infarction.
The prevalence of myocardial rupture is rare, many patients could not survive longer, and therefore a careful evaluation becomes difficult and impractical.In the evaluation of myocardial rupture, enzymes such as peak serum creatine phosphokinase (CPK) and cardiac troponins seem to be the most commonly utilized biomarkers [5,6].In addition, cytokines and signal transduction proteins have drawn much attention with regard to assessment of myocardial protection efficacy [7].Nevertheless, the myocardial damage of postinfarction myocardial rupture has not been sufficiently elucidated.In this article, it is our purpose to summarize and analyze the pertinent laboratory measurements of our patients with postinfarction myocardial rupture after the onset.

Patient Information
From 2004 to 2008, 19 consecutive patients refering to The Chaim Sheba Medical Center for surgical repair of postinfarction myocardial rupture were enrolled into this retrospective study.A female patient developed myocardial rupture in the Department of Cardiology of our hospital; a male patient had myocardial rupture on the operating table for an elective coronary artery bypass surgery.All other patients were sent to this hospital immediately based on an established diagnosis of myocardial rupture in the local clinics.The interval between the onsets to surgical operation varied from a few minutes to a few hours, usually within 12 hours.Eight (42.1%) patients had free wall rupture, 5 (26.3%) had papillary muscle rupture, 5 (26.3%) had ventricular septal rupture, and one (5.3%)had double structure (ventricular septum + free wall) rupture.Thirteen patients survived the operation, and six died.Heparin was used during the cardiopulmonary bypass, and cryoprecipitates, platelet concentrates and fresh frozen plasma were used after the surgery, in all patients; while fibrinolytics was unnecessarily used.The intramuscular injection was not practiced.

Observations
Laboratory findings of serum enzymes and coagulation activities [aspartate aminotransferase (AST), lactate dehydrogenase (LDH), CPK, creatine phosphokinase fraction MB (CK-MB), international normalized ration (INR), partial thromboplastin time (PTT), D-dimer and fibrinogen], and troponin I were collected and statistically analyzed.Serum AST, LDH, INR and PTT were kinetically presented.Comparisons of the biomarkers and between free wall rupture, 5 (26.3%) had papillary muscle rupture, 5 (26.3%) had ventricular septal rupture, and 1 (5.3%) had double structure (ventricular septum + free wall) rupture.Thirteen patients survived the operation, and 6 died.Laboratory findings including serum enzymes and coagulation activities were collected and analyzed.
Results: The coagulation markers and serum enzymes except for fibrinogen increased significantly after the development of myocardial rupture.Statistical differences in D-dimer, partial thromboplastin time, peak lactate dehydrogenase, peak creatine kinase and creatine kinase fraction MB were found between non-survivors and survivors.Troponin I values were elevated significantly during the early days after the onset or surgical repair of myocardial rupture.Multivariant regression analysis did not show any significant relationship between creatine phosphokinase fraction MB (Y) and D-dimer (X1) or fibrinogen (X2).
Conclusion: Myocardial rupture leads to extremely high serum enzyme and coagulation activities except for fibrinogen after the onset.The evaluation of these biomarkers may help in making diagnostic and treatment decisions and in judging the clinical prognosis of such patients.
rupture, ventricular septal or papillary muscle rupture, and between the survivors and non-survivors were made.Multivariant regression analysis was applied between CK-MB and D-dimer or fibrinogen.

Statistics
All the biomarkers mentioned above including serum AST, LDH, CPK, CK-MB, INR, PTT, D-dimer and tropinin I were expressed as means ± SDs.Unpaired t-tests were used in comparative analyses by using t-test calculator at http://www.graphpad.com/quickcalcs/ttest1.cfm.Twotailed P-values <0.05 were considered to be statistically significant.

Ethics
This retrospective study was approved by the Helsinki Committee of The Chaim Sheba Medical Center with an approval number of SMC-7439-09.

RESULTS
The coagulation and serum enzyme activities increased significantly a few hours after the onset of myocardial rupture except for fibrinogen (Table 1).
Both AST and LDH peaked at day 1 after myocardial rupture, decreased significantly on day 2, and returned to baseline since day 4 (Figures 1 and 2).INR started to rise on day 3, reached a peak value on day 6, and approximated normal value on day 14 (Figure 3).PTT peaked on day 2, and declined gradually since day 3 (Figure 4).
Perioperative troponin I values of eight of these 19 patients were available for evaluation.Two days before the onset of myocardial rupture, the patients troponin was 12.3331 µg/L, from the onset day to the 2 nd day after the onset, troponin increased to 0.769-201 (mean 79 ± 32.25, median 4.59) µg/L, 14-20 days after the onset and surgical repair, troponin values decreased to 0.154-1.2µg/L (Table 2).

CPK = creatine phosphokinase
The coagulation markers did not show any significant difference between free wall rupture and ventricular septal or papillary muscle rupture, with a PTT value of the latter within the normal limit.In addition, a difference was noted in serum CK-MB between free wall rupture and the other two types of ruptures (Table 3).
Statistical differential significances were found in Ddimer, PTT, peak LDH, peak CPK and CK-MB between nonsurvivors and survivors; while no differences were disclosed in fibrinogen and peak AST between patients with different prognosis (Table 4).

DISCUSSION
Serum enzymes, including AST, LDH, CPK, CK-MB, and cardiac troponin, etc., have been sufficiently elucidated as cardiac markers indicative of myocardial damage following acute myocardial infarction [15].However, among these biomarkers, merely peak CPK was commonly reported as an indicator for the evaluation of myocardial rupture secondary to myocardial infarction.
Peak CPK levels were different between postinfarction patients with and without myocardial rupture (4778 ± 3575 vs. 2461 ± 2661 U/L, P = 0.005).A significant elevation of peak CPK have been found in patients with postinfarction myocardial rupture irrespective of the type of the rupture with a maximal reported value of 12199 U/L (Table 5).We noted an analogous peak CPK value which amounted to 11255 U/L the second day in a patient with free wall rupture which developed on the operating table for a scheduled coronary artery bypass.
Feneley et al. [16] did not find significance in peak serum CPK between the survivors and non-survivors of patients with postinfarction ventricular septal rupture (1059 ±173 U/L vs. 1220 ±160 U/L, NS).But we did on the contrary.Besides, we also observed 3-10 folds differences in D-dimer, peak LDH, and CK-MB between the non-survivors and survivors.Our findings disclosed fibrinogen and peak AST were lack of statistical significance.
The biological aspects of troponins have been clarified in detail.Troponins are mostly located in intact myofibers and only very small amount are free in the cytoplasm [20].Of the three isoforms troponins I, T and C, troponin C are lack of cardiac specificity [21].Instead, troponins I and T have shown high specificity and sensitivity for an early diagnosis of coronary artery disease [22], even in patients with minor myocardial injury [23].Troponin I is more sensitive than troponin T in terms of the prediction of myocardial damage [24][25][26].The kinetics of troponins may be mono-or bi-phasic according to a reperfused or a nonreperfused myocardial injury.The typical biphasic pattern may show its first peak in the first few hours after the damage and the second peak may appear in the following days [27].Therefore, it was recommended that troponin could be detectable 2-4 hours after myocardial damage in blood samples and the elevation in the serum may retain for up to two weeks [22].Cardiac troponin levels rely on infarct size [28].When troponin T value is less than 0.01, acute myocardial infarction can be ruled out [29].Nevertheless, implications of troponins were rarely described previously in the patients with postinfarction myocardial rupture.In this regard, Katayama et al. [5] reported an elevated troponin in myocardial infarction patients with no significant differences between myocardial infarction patients with and without myocardial rupture (0.31 ± 0.55 ng/ml vs. 0.50 ± 0.70 ng/ml, NS).Associations between cardiac death and hemostatic factors were found in early stages.If the coronary flow decrease lasts longer, then the hemostatic mechanisms might be enhanced [30].D-dimer has been reported to be significantly higher in acute myocardial infarction patients than in controls [31].D-dimer > 500 ug/L has an independent diagnostic value for myocardial infarction [32].However, some authors [33] claimed its poor early sensitivity.Kinetics of D-dimer increase in plasma following ischemic necrosis substantially reflected that of the troponins, and elevated D-dimer lasted much longer than 24 hours [34].D-dimer was lower in patients with cardiac troponin T < 0.01 ng/ml than those with cardiac troponin T > 0.01 ng/ml.No correlation was found between D-dimer and cardiac troponin T levels in patients with cardiac troponin T > 0.01 ng/ml [1].
Fibrinogen functions as an indicator for the evaluation of fibrinogen responses to thrombolytic therapy.A high concentration of fibrinogen was associated with nonpatency infarct related coronary artery [35].Although it is believed that early postoperative activation of coagulation and fibrinolysis is associated with perioperative myocardial cell damage [36], the findings of our study and of others [37] have led us to believe that fibrinogen has a weak link to the prediction of myocardial damage associated with cardiovascular events.
Schwartz [38] noted that 13% and 10% of the 223 patients with suspected acute coronary syndromes had INR and PTT results beyond the reference ranges, and 70% patients with abnormal coagulation test results had risk factors for coagulation disorder.
Hemodynamic parameters and EuroSCORE appeared to be of prevalent significance in predicting the prognosis, i.e., survival and mortality rate of the patients with myocardial rupture [39].In this study, we tried to disclose the implications of enzyme and coagulation activities as reliable predictors of patients' prognosis.In patients with myocardial rupture, we observed remarkable elevations of coagulation markers and serum enzymes except fibrinogen.The alterations of INR and PTT suggested that myocardial rupture may be associated with less rapid activation of coagulation factors.Troponin can be elevated to a very high level in the first few days after the onset of postinfarction myocardial rupture.Statistical differential significances in D-dimer, PTT, peak LDH, peak CPK and CK-MB between non-survivors and survivors may indicate the prognostic events in such patient setting.These positive markers were 3-10 folds higher in the nonsurvivors than in the survivors.Although these alterations of the biomarkers could be a result of incorporated processes including myocardial infarction, myocardial rupture, cardiac catheterization, heart operation and cardiopulmonary bypass, etc., myocardial rupture may play the key role in the elevations of the biomarkers.
However, the results of the coagulation tests could be influenced somehow by the use of heparin during the operation and the use of blood components after the surgery.To prevent coagulopathy, the use of blood components, which was based on the coagulation screening tests, would predispose better coagulation results.On the other hand, only a small number of patients were enrolled into this retrospective study due to the fact that postinfarction myocardial rupture had a very low incidence, which constituted a major limitation of the study.Thus, a larger patient population with this disorder is necessary for validating the conclusion.

CONCLUSION
In conclusion, myocardial rupture leads to an extreme elevation of sensitive markers including serum enzymes and coagulation indicators soon after the onset.The evaluation of these biomarkers may help in making diagnostic and treatment decisions and in judging the clinical prognosis of such patients.

Table 2 .
Troponin values of the patients with myocardial rupture.
YUAN, SM ET AL -The implications of serum enzymes and coagulation activities in postinfarction myocardial rupture Rev Bras Cir Cardiovasc 2011; 26.1: 7-14

Table 5 .
Peak serum CPK levels of postinfarction myocardial rupture patients reported previously.

Table 4 .
A comparison of the the hemostatic markers and serum enzymes between non-survivors and survivors.