Biomarkers involved in cardiac surgery are unique and diverse tools that enable the surgeon to manage the treatment process. Over the last years, diagnostic biomarkers for myocardial function evolved. However, there is no report indicating all potential biomarkers in cardiac surgery. This review summarizes new discovered beside conventional markers that could be predictive in cardiac surgery.
The National Institute of Health defines the biomarker as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic intervention.”. Biomarkers involved in cardiac surgery are unique and diverse tools that enable the surgeon to manage the treatment process. They also facilitate the follow up process after surgery and give insight regarding myocardial function. Over the last decades, diagnostic markers for myocardial function evolved. Hence, until 1970s lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) were used widely. Afterward, cardiac creatine kinase (CK-MB) was accepted by surgeons. After that, during 2000s cardiac troponin T (cTnT) was the specific biomarker for myocardial function.
However, recently new markers have been presented that could be novel potential tools for the surgeons. To date, there is no report to introduce all potential biomarkers involved in cardiac surgery. In this review, new discovered biomarkers beside conventional markers are summarized to facilitate the comparative approach toward existing markers for analyzing myocardial function and patient’s improvement.
The troponin complex (troponin I, T and C) along with tropomyosin is located on the actin filament and is crucial for the calcium-mediated regulation of skeletal and cardiac muscle contraction . There is one cardiac troponin I (cTnI) isoform in myocardial tissue . Human cardiac muscle contains 4 troponin T isoforms, but only one is distinctive of the normal adult heart . Therefore, the measurement of cTnT levels has cardiac specificity correspondent to that of cTnI. Troponin assays are not only more sensitive but are also more specific assays . Recently, cTnT is measured by fourth generation and high-sensitivity assays. Cardiac troponin provides diagnostic and prognostic information in coronary syndromes and after cardiac surgery .
Creatine phosphokinase (CPK)
It has been found that CPK levels could be used for analyzing cardiac recovery after myocardial injury . Also, CPK analysis can help to monitor patients’ recovery that underwent coronary artery bypass grafting (CABG) [8,9]. Additionally, it has been established that release of cardiac CPK after percutaneous and catheter-based coronary intervention could be predictive [10-13].
Cardiac creatine kinase (CK-MB)
CK-MB beside cTnI are widely used as indicators of myocardial stability after cardiac surgery. Although it has been reported that release pattern of CK-MB after heart surgery depends on the type of procedure. But highest and longest elevation of postoperative CK-MB concentration has been illustrated .
The specificity of CK-MB can be enhanced by the calculation of the CK-MB/CK ratio. However, the use of this ratio markedly reduces sensitivity in patients with concurrent cardiac and skeletal muscle injury [15,16].
However, it should be considered that expression of CK-MB is not unique to the heart. CK-MB is found in skeletal muscle and the gastrointestinal tract as well as in the uterus of pregnant women [17-19].
Lactate dehydrogenase (LDH)
Lactate dehydrogenase (LDH), one of the routine laboratory tests, was significantly elevated than normal value in patients who underwent coronary surgery [8, 20]. Nevertheless, it has been observed that LDH level might increase in the absence of any myocardial injury. This false positive laboratory result may be due to other conditions . It should be noted that even though LDH is used by cardiac surgeons, but it does not provide sensitive and specific data for interpretation.
Neutrophil gelatinase-associated lipocalin (NGAL)
Human NGAL is generally expressed at very low concentrations in several human tissues, including kidney, trachea, lungs, stomach, and colon . NGAL has crucial role in the area of acute renal failure research, not only as a novel biomarker but also as an innovative therapeutic method. NGAL is the only biomarker that has been investigated in both serum and urine for the early diagnosis of ischemic renal injury. After cardiopulmonary bypass concentrations of NGAL in urine and serum denote sensitive, specific, and highly predictive early biomarkers for acute renal injury after cardiac surgery .
N-terminal pro–B-type natriuretic peptide (NTproBNP)
Ventricular cardiomyocytes secrete brain natriuretic peptide (BNP), that is a pro-hormone, and its inactive cleavage product N-terminal fragment (N-terminal-pro–B-type natriuretic peptide [NT-proBNP]) into the blood in response to atrial or ventricular wall stretch or myocardial ischemia [24,25]. Plasma BNP is a powerful predictor of death in patients with adverse cardiovascular events [26-28]. Furthermore, another meta-analysis study suggests that pre-operative BNP or NT-proBNP concentration is a powerful, independent predictor of cardiovascular events in the first 30 days after non-cardiac surgery .
Growth differentiation factor 15 (GDF-15)
Growth differentiation factor (GDF)-15, previously entitled macrophage-inhibitory cytokine, is a member of the transforming growth factor family . Low quantities of GDF-15 are expressed in most tissues, including myocardium, lung, kidney, brain, liver, and the intestine. Increased expression of this cytokine can be induced by myocardial stretch, volume overload, and experimental cardiomyopathy as well as oxidative stress, inflammatory cytokines, and ischemia/reperfusion . Recent data revealed that the plasma concentrations of this peptide may be used for predicting short- and long- term mortality in patients with coronary artery disease, myocardial infarction, and chronic heart failure [32-34]. Most recently, analysis of a large population has shown that the pre-operative plasma level of GDF-15 is an independent predictor of post-operative mortality and morbidity in cardiac surgery patients .
Heart type fatty acid binding protein (h-FABP)
Heart-type fatty acid-binding protein (h-FABP), binds long-chained fatty acids reversibly and is abundant in the cytoplasm of myocardial cells and also is found in skeletal muscle [36,37]. h-FABP is a new biochemical marker of sarcolemmal injury due to acute myocardial ischemia. High h-FABP levels, is an early diagnostic parameter that indicate the presence of more severe myocardial damage in cardiac surgery. Quantitative h-FABP analysis could predict the severity of myocardial ischemia and injury early during cardiac surgery . It has been found that within 6h of acute coronary syndrome the sensitivity of quantitative h-FABP is significantly higher than TnT in the detection of myocardial necrosis . And also it has been reported that in comparison to conventional markers of myocardial injury after CABG surgery, h-FABP increases earlier and is an independent predictor of postoperative mortality and ventricular dysfunction .
Serum level of myoglobin has been found to increase somewhat after prolonged muscular activity, or even more in acute myocardial infarction (AMI) [41-43]. Additionally, myoglobin as a marker of myocardial damage has been reported to be of prognostic value in patients with cardiovascular events [44,45]. It has been established that the myoglobin level as a marker of organ failure has been described in vascular surgical patients .
Myoglobin has been suggested as a postoperative marker of graft failure in cardiac bypass operations . Serum myoglobin is associated with outcome in patients after cardiac surgery, as non-survivors had a considerably elevated serum myoglobin than survivors .
Inflammatory and vascular markers have proved to be predictors of outcome in myocardial infarction and heart failure. Two main classes of cytokines have been recognized in heart failure (HF): vasoconstrictor cytokines, such as endothelin; and vasodepressor pro-inflammatory cytokines, such as TNF, interleukin (IL)-6, and IL-1 . Peripheral-circulating in addition to intra-cardiac levels of these cytokines are elevated in patients with HF . The inflammatory markers: INF-gamma, IL-10, IL-13, IL-2, IL-5, IL-8, TNF-alpha, and IL-6 could increase significantly after surgery in comparison to the preoperative levels .
Pentraxin 3 (PTX3) is a called as 'brand-new protein in traditional family' because it belongs with pentraxin family included C-reactive protein(CRP) . PTX3, is a biomarker of vascular inflammation and cardiovascular damage, and could be predictor of short-term functional recovery and 1-year MACE in patients undergoing rehabilitation after cardiac surgery . Unlike CRP, PTX3 is expressed in atherosclerotic lesions which involve macrophages, neutrophils, dendritic cells, or smooth muscle cells, predominantly. It has been proven that coronary stenting enhanced circulating PTX3 levels in association with an inflammatory response . Also it has been demonstrated that operations performed with the use of cardiopulmonary bypass are associated with a more noticeable release of PTX3 immediately after operation .
C-reactive protein (hsCRP)
C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein that contributes in the systemic response to inflammation . It is exclusively produced in the liver and its plasma concentration increases during inflammation. CRP is a powerful independent predictor of cardiovascular events in patients with coronary artery disease and studies have shown that they are elevated in patients with postoperative and non-postoperative atrial fibrillation [56,57]. Postsurgical activation of the complement system after CABG involves CRP. This response is associated with postoperative arrhythmia, and is related to baseline CRP levels . Another study has shown that hsCRP is sensitive to identify vascular risk patients, but not suited to monitor progression of the disease [59,60].
Several diagnostic markers help cardiovascular surgeon to monitor continuous healthcare and improvement of the patient. Even though there are various markers in the clinic that facilitate the treatment process, but care must be taken in the interpretation of data by surgeons. Because in some clinics the conventional and non-specific markers like CPK and LDH are still analyzed. Each marker has its own advantages and disadvantages. It should never be underestimated that myoglobin, CK, and troponin are intracellular components with their origin in muscle, but they are not specific to the myocardial muscle. However, by analyzing various and specific markers at the same time points, the findings could confirm and validate each other. Furthermore, contributing factor of differences in myocardial injury biomarkers and their prognostic value after heart surgery should be accurately assessed.
- Vasan RS (2006) Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113: 2335-2362. [Crossref]
- Takeda S, Yamashita A, Maeda K, Maéda Y (2003) Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature 424: 35-41. [Crossref]
- Cummins P, Perry SV (1978) Troponin I from human skeletal and cardiac muscles. Biochem J 171: 251-259. [Crossref]
- Anderson PA, Malouf NN, Oakeley AE, Pagani ED, Allen PD (1991) Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ Res 69: 1226-1233. [Crossref]
- Babuin L, Jaffe AS (2005) Troponin: the biomarker of choice for the detection of cardiac injury. CMAJ 173: 1191-1202. [Crossref]
- Peacock WF 4th, De Marco T, Fonarow GC, Diercks D, Wynne J, et al. (2008) Cardiac troponin and outcome in acute heart failure. N Engl J Med 358: 2117-2126. [Crossref]
- George I, Xydas S, Mancini DM, Lamanca J, DiTullio M, et al. (2006) Effect of clenbuterol on cardiac and skeletal muscle function during left ventricular assist device support. J Heart Lung Transplant 25: 1084-1090.
- Mohammadzadeh A, Jafari N, Hasanpour M, Sahandifar S, Ghafari M, et al. (2013) Effects of pulsatile perfusion during cardiopulmonary bypass on biochemical markers and kidney function in patients undergoing cardiac surgeries. Am J Cardiovasc Dis 3: 158-162.
- Mohammadzadeh A, Jafari N, Babapoursaatlou B, Doustkami H, Hosseinian A, et al. (2012) Effect of staged preconditioning on biochemical markers in the patients undergoing coronary artery bypass grafting. ISRN Cardiol 204624. [Crossref]
- Matthews MA, Kunselman SJ, Gascho JA, Gilchrist IC (2005) Differential release of cardiac enzymes after percutaneous coronary intervention. Catheter Cardiovasc Interv 65: 19-24. [Crossref]
- Lim R, Zawacki K, Laskey WK (1997) Creatine kinase release after catheter-based coronary intervention. Cathet Cardiovasc Diagn 41: 117-119. [Crossref]
- Ghazzal Z, Ashfaq S, Morris DC, Douglas JS, Marshall JJ, et al. (2003) Prognostic implication of creatine kinase release after elective percutaneous coronary intervention in the pre-IIb/IIIa antagonist era. Am Heart J 145: 1006-1012.
- Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, et al. (1997) Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 277: 461-466.
- Mastro F, Guida P, Scrascia G, Rotunno C, Amorese L, et al. (2015) Cardiac troponin I and creatine kinase-MB release after different cardiac surgeries. J Cardiovasc Med (Hagerstown) 16: 456-464. [Crossref]
- Adams JE 3rd, Sicard GA, Allen BT, Bridwell KH, Lenke LG, et al. (1994) Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 330: 670-674. [Crossref]
- Adams JE 3rd, Dávila-Román VG, Bessey PQ, Blake DP, Ladenson JH, et al. (1996) Improved detection of cardiac contusion with cardiac troponin I. Am Heart J 131: 308-312. [Crossref]
- Tsung JS, Tsung SS (1986) Creatine kinase isoenzymes in extracts of various human skeletal muscles. Clin Chem 32: 1568-1570. [Crossref]
- Genser N, Mair J, Talasz H, Puschendorf B, Calzolari C, et al. (1997) Cardiac troponin I to diagnose percutaneous transluminal coronary angioplasty-related myocardial injury. Clin Chim Acta 265: 207-217.
- Mair J (1997) Cardiac troponin I and troponin T: are enzymes still relevant as cardiac markers? Clin Chim Acta 257: 99-115. [Crossref]
- Kim JJ, Kim CK, Park HJ, Park JK, Moon SW, et al. (2014) Elevation of serum lactate dehydrogenase in patients with pectus excavatum. J Cardiothorac Surg 9: 75. [Crossref]
- Maghamiour N, Safaie N (2014) High Creatine Kinase (CK)-MB and Lactate Dehydrogenase in the Absence of Myocardial Injury or Infarction: A Case Report. J Cardiovasc Thorac Res 6: 69-70. [Crossref]
- Cowland JB and Borregaard N (1997) Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 45: 17-23.
- Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, et al. (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365: 1231-1238.
- Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med 339: 321-328. [Crossref]
- Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, et al. (2003) Increased cardiac BNP expression associated with myocardial ischemia. FASEB J 17: 1105-1107. [Crossref]
- Kragelund C, Grønning B, Køber L, Hildebrandt P, Steffensen R (2005) N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 352: 666-675. [Crossref]
- de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, et al. (2001) The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 345: 1014-1021. [Crossref]
- Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, et al. (2004) N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 110: 2168-2174.
- Karthikeyan G, Moncur RA, Levine O, Heels-Ansdell D, Chan MT, et al. (2009) Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies. J Am Coll Cardiol 54: 1599-1606. [Crossref]
- Wollert KC (2007) Growth-differentiation factor-15 in cardiovascular disease: from bench to bedside, and back. Basic Res Cardiol 102: 412-415. [Crossref]
- Kempf T, Wollert KC (2009) Growth-differentiation factor-15 in heart failure. Heart Fail Clin 5: 537-547. [Crossref]
- Kempf T, Sinning JM, Quint A, Bickel C, et al. (2009). Growth-differentiation factor-15 for risk stratification in patients with stable and unstable coronary heart disease: results from the AtheroGene study. Circ Cardiovasc Genet 2: 286-292.
- Kempf T, Björklund E, Olofsson S, Lindahl B, Allhoff T, et al. (2007) Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 28: 2858-2865. [Crossref]
- Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, et al. (2007) Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 116: 1540-1548.
- Heringlake M, Charitos EI, Gatz N, Käbler JH, Beilharz A, et al. (2013) Growth differentiation factor 15: a novel risk marker adjunct to the EuroSCORE for risk stratification in cardiac surgery patients. J Am Coll Cardiol 61: 672-681. [Crossref]
- Storch J, Thumser AE (2000) The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta 1486: 28-44. [Crossref]
- Glatz JF, Storch J (2001) Unravelling the significance of cellular fatty acid-binding proteins. Curr Opin Lipidol 12: 267-274. [Crossref]
- Liu YH, Zhou YW, Tu ZG, Ji SY, Chen M, et al. (2010) [Predictive value of human fatty acid binding protein for myocardial ischemia and injury in perioperative period of cardiac surgery]. Zhonghua Xin Xue Guan Bing Za Zhi 38: 514-517. [Crossref]
- Ruzgar O, Bilge AK, Bugra Z, Umman S, Yilmaz E, et al (2006) The use of human heart-type fatty acid-binding protein as an early diagnostic biochemical marker of myocardial necrosis in patients with acute coronary syndrome, and its comparison with troponin-T and creatine kinase-myocardial band. Heart Vessels 21: 309-314.
- Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Collard CD, et al (2010) Heart-type fatty acid binding protein is an independent predictor of death and ventricular dysfunction after coronary artery bypass graft surgery. Anesth Analg 111: 1101-1109.
- Laurence AS (2000) Serum myoglobin and creatine kinase following surgery. Br J Anaesth 84: 763-766. [Crossref]
- Koz M, Erbas D, Bilgihan A and Aricioglu A (1992) Effects of acute swimming exercise on muscle and erythrocyte malondialdehyde, serum myoglobin, and plasma ascorbic acid concentrations. Can J Physiol Pharmacol 70: 1392-1395.
- Stone MJ, Waterman MR, Harimoto D, Murray G, Willson N, et al. (1977) Serum myoglobin level as diagnostic test in patients with acute myocardial infarction. Br Heart J 39: 375-380. [Crossref]
- Pruszczyk P, Bochowicz A, Kostrubiec M, Torbicki A, Szulc M, et al. (2003) Myoglobin stratifies short-term risk in acute major pulmonary embolism. Clin Chim Acta 338: 53-56. [Crossref]
- Iqbal MP, Kazmi KA, Mehboobali N, Rahbar A (2004) Myoglobin--a marker of reperfusion and a prognostic indicator in patients with acute myocardial infarction. Clin Cardiol 27: 144-150. [Crossref]
- Hofmann D, Buettner M, Rissner F, Wahl M, Sakka SG (2007) Prognostic value of serum myoglobin in patients after cardiac surgery. J Anesth 21: 304-310. [Crossref]
- Thielmann M, Massoudy P, Marggraf G, Knipp S, Schmermund A, et al. (2004) Role of troponin I, myoglobin, and creatine kinase for the detection of early graft failure following coronary artery bypass grafting. Eur J Cardiothorac Surg 26: 102-109. [Crossref]
- Mann DL (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 91: 988-998. [Crossref]
- Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S (1994) Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 72: 561-566. [Crossref]
- Mahle WT, Matthews E, Kanter KR, Kogon BE, Hamrick SE, et al. (2014) Inflammatory response after neonatal cardiac surgery and its relationship to clinical outcomes. Ann Thorac Surg 97: 950-956.
- Inoue K (2011) [Pentraxin 3]. Rinsho Byori 59: 694-701. [Crossref]
- Ferratini M, Ripamonti V, Masson S, Grati P, Racca V, et al.(2012) Pentraxin-3 predicts functional recovery and 1-year major adverse cardiovascular events after rehabilitation of cardiac surgery patients. J Cardiopulm Rehabil Prev 32: 17-24.
- Kotooka N, Inoue T, Fujimatsu D, Morooka T, Hashimoto S, et al. (2008) Pentraxin3 is a novel marker for stent-induced inflammation and neointimal thickening. Atherosclerosis 197: 368-374. [Crossref]
- Kunes P, Lonsky V, Mandak J, Kolackova M, Andrys C, et al. (2007) The long pentraxin 3 in cardiac surgery: distinct responses in "on-pump" and "off-pump" patients. Scand Cardiovasc J 41: 171-179. [Crossref]
- Black S, Kushner I, Samols D (2004) C-reactive Protein. J Biol Chem 279: 48487-48490. [Crossref]
- Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, et al. (2001) C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 104: 2886-2891.
- Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, et al. (2003) Inflammation as a risk factor for atrial fibrillation. Circulation 108: 3006-3010. [Crossref]
- Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardevelt FW, et al. (1997) Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 96: 3542-3548.
- Schulze Horn C, Ilg R, Sander K, Bickel H, Briesenick C, et al. (2009) High-sensitivity C-reactive protein at different stages of atherosclerosis: results of the INVADE study. J Neurol 256: 783-791. [Crossref]
- Moura LM, Rocha-Goncalves F, Zamorano JL, Barros I, Bettencourt P, et al. (2008) New cardiovascular biomarkers: clinical implications in patients with valvular heart disease. Expert Rev Cardiovasc Ther 6: 945-954.