Pranas Šerpytis1,2,3, Justina Alunderytė2,3, Aleksandras Briedis2,3, Stanislovas Ambrasas2
1 Clinic of Emergency Medicine, Vilnius University, Vilnius, Lithuania
2 Vilnius University, Faculty of Medicine, Vilnius, Lithuania
3 Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
Introduction: H-FABP is a novel biomarker for early diagnosis of acute coronary events with no practical application yet.
The aim: Evaluate H-FABP as a diagnostic biomarker in acute myocardial infarction (AMI).
Material and Methods: The trial was performed in emergency care unit and coronary unit of Vilnius University Santaros Klinikos. 122 patients (78 males [64%] and 44 females [36%]) were chosen who present with typical acute chest pain that lasted more than 30 minutes and with changes in ECG. The average age of the patients was 54.3 (±10,1). All the patients were divided to 3 groups. 1 group: 46 patients who presented in ICU with chest pain after 0-6 hours from the onset of symptoms. 2 group: 42 patients who presented in ICU with chest pain after 6-12 hours from the onset of symptoms. 3 group: 34 patients who presented in ICU with chest pain after 12-24 hours from the onset of syptoms. Blood tests were made to determinate the concentration of H-FABP (the method of CardioDetect was used), CK-MB and Troponin I.
Results: 56 patients (45,9%) presented with ST elavation in ECG, non-ST elavation 66 patients (54,1%).
1 group: H-FABP was positive for 42 patients (91,3%), CK-MB elavated for 20 patients (43,4%), Troponin I was elevated for 2 patients (0,43%).
2 group: H-FABP was positive for 39 patients (92,8%), CK-MB elavated for 24 patients (57,11%), Troponin I was elevated for 8 patients (1,9%).
3 group: H-FABP was positive for 31 patients (91,1%), CK-MB elavated for 32 patients (94,1%), Troponin I was elevated for 32 patients (94,1%).
Conclusions: H-FABP included in a risk evaluating model could be valuable in the first hours after the onset of cardiac ischemia symptoms as a rule out method.
To reduce mortality from CHD, a very important role plays fast and accurate diagnosis of myocardial infarction. MI typically diagnosed with myocardial necrosis marker in the bloodstream and at least one of the following: myocardial ischemic symptoms or characteristic ECG changes. While there is unquestionable advantage of MI biochemical markers as troponin T, troponin I and CKMB in diagnosing MI, however all these biomarkers have weaknesses, therefore researchers still looking for the perfect biomarker which is characterized by:
1. a sufficient amount in the heart muscle and homogeneous distribution;
2. are not found in other tissues (both in normal or pathological conditions);
3. rapidly and completely secreted into the bloodstream after myocardial injury;
4. released biochemical marker content should be proportional to the area of myocardial necrosis
5. must maintain long enough in the bloodstream, to produce convenient diagnostic window, but not too long, in order to determine re-infraction;
6. Must be ensured fast, reliable and non-expensive method to detect the biomarker. At this moment new biochemical markers are found, which could fasten diagnosis of the myocardial infarction. One of them – H-FABP – heart fatty acid binding protein. The purpose of this study was to compare H-FABP with other biomarkers, often used in diagnosing the MI.
MATERIAL AND METHODS
The trial was performed in emergency care unit and coronary unit of Vilnius University Santaros Klinikos. 122 patients (78 males [64%] and 44 females [36%]) were chosen who present with typical acute chest pain that lasted more than 30 minutes and with changes in ECG. The average age of the patients was 54.3 (±10.1).
All the patients were divided in 3 groups. 1 group: 46 patients who presented in ICU with chest pain after 0-6 hours from the onset of symptoms. 2 group: 42 patients who presented in ICU with chest pain after 6−12 hours from the onset of symptoms. 3 group: 34 patients who presented in ICU with chest pain after 12−24 hours from the onset of syptoms.
Blood tests were made to determinate the concentration of H-FABP (the method of CardioDetect was used), CK-MB and Troponin I.
56 patients (45,9%) presented with ST elavation in ECG, non-ST elavation 66 patients (54.1%).
1 group: H-FABP was positive for 42 patients (91.3%), CK-MB elavated for 20 patients (43.4%), Troponin I was elevated for 2 patients (0.43%). No statistically significant association between ST elevation and positive H-FABP was observed (p=0.8772).
2 group: H-FABP was positive for 39 patients (92.8%), CK- MB elavated for 24 patients (57.11%), Troponin I was elevated for 8 patients (1.9%). No statistically significant association between ST elevation and positive H-FABP was observed (p=0.8809).
3 group: H-FABP was positive for 31 patients (91.1%), CK- MB elavated for 32 patients (94.1%), Troponin I was elevated for 32 patients (94.1%). No statistically significant association between ST elevation and positive H-FABP was observed (p=0.1221) (Fig. 1).
H-FABP is a low molecular weight (15 kDa) cytoplasmic protein that is produced in tissues with active fatty acid metabolism, for example – heart, liver and intestines. Each protein consists of 126−137 amino acids linked with reversible non covalent junctions. The main role of H-FABP is the transport of hydrophobic long-chain fatty acids from the cell membrane to their intracellular sites of metabolism in the mitochondria . Currently known 9 fatty acid-binding protein types, of which the most studied is the cardiac form. In 1988 it has been proved that H-FABP released from the damaged myocardium. Since then began active H-FABP research.
Because of its small size, H-FABP is released quickly into the circulation. Levels of H-FABP are detectable 30 min after the onset of AMI, reaching a peak value at 6−8 h. It returns to baseline levels typically within 12−24 hours after injury. Due to its characteristics such H-FABP quick appearance in the blood, may allow not only to identify MI, but also to detect ischemic processes. Early detection of the H-FABP and early treatment would help to avoid a potential MI.
In our study, we have demonstrated that H-FABP assay is more sensitive method to identify early myocardial infarction. Similar study have been done in 2003 in Tokyo . It was concluded that the sensitivity of MI at 2 h was significantly higher with serum H-FABP compared with cardiac troponin T or myoglobin (89 vs. 22 and 38%, respectively). However, cardiac troponin T had a significantly higher specificity (94 vs. 52%).
The aim of another study done in 2013−2014 was to compare H-FABP with hs-cTnT . The latter outperformed H-FABP in sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy. Also it was concluded that H-FABP cannot be used as a single biomarker for AMI diagnosis.
Adding H-FABP to other cardiac biomarkers could increase diagnostic value. Combination of troponin and H-FABP looked promising. A meta-analysis was performed in 2012 to summarize existing knowledge about H-FABP as an additional biomarker near troponins in diagnosing AMI . 4 studies were included. The time from symptom onset to sampling varied from 3.5 to 5.3 (median) hours. The addition of H-FABP to troponin increased sensitivity from 42-75% to 76-97% but decreased specificity from 94−100% to 65−93%. Due to loss in specificity there is still uncertainty regarding the role of H-FABP in early diagnosis of MI.
As a rule-out method for patients with symptoms suggestive of AMI combination of H-FABP and hs-cTn was assessed . In this study, H-FABP in combination with hs-cTn and ECG without ischemic changes improved the rule-out of AMI compared to hs-cTn alone and ECG. 40.9% patients can be identified as low-risk for AMI on the basis of blood test performed at presentation whilst maintaining 99% sensitivity. If implemented this method could accelerate early patients discharge from the ED.
More accurate methods are in search to rule-out and rule-in patients with suspected acute coronary syndromes. The study done in 2016 compared original Manchester Acute Coronary Syndromes model (MACS) with Troponin-only Manchester Acute Coronary Syndromes model (T-MACS) . The aim of these models is to categorize patients to certain risk groups (from very low to high risk). MACS model include hs-cTnT, H-FABP, ECG and 5 clinical symptoms. T-MACS model does not include H-FABP. The original MACS have ruled-out ACS in 18% patients (with sensitivity of 100% and specificity of 20.9%) while T-MACS ruled-out ACS in 40.5% patients (with sensitivity of 98.4% and specificity of 46.8%). As a rule-in tool MACS categorized 5.5% of patients as high risk (83.3% of them had ACS) while T-MACS ruled-in 4.4% of patients (91.4% of them had ACS). Having similar diagnostic value T-MACS can be used more widely than MACS because it requires only hs-cTnT and not less accessible H-FABP biomarker.
Value of adding H-FABP to other models remained unclear. A prospective observational study published in 2017 compared TIMI score with combinations of H-FABP, hs-cTnT and a modified HEART (history, electrocardiogram, age, risk factors and troponin) score for early rule-out of 30-day major adverse cardiac events . The strategy yielding the largest number of patients for safe discharge is combined modified TIMI/HEART assessment including hs-cTnT. H-FABP provided no additional prognostic value to the scores as a rule-out tool. However we do have any studies comparing modified TIMI/HEART model including hs-cTnT with T-MACS model.
There are some limitations of H-FABP assays. The human skeletal muscle FABP has been reported to be identical to that of H-FABP . H-FABP content of skeletal muscle is variable to range between 0.05 and 0.2 mg/g and depends on muscle type . Skeletal muscle damaged by a variety of procedures using first aid in MI, intramuscular injections, electric cardioversion or cardiopulmonary resuscitation . It can cause the leakage of H-FABP and this could interfere with the results of the assays. Surgery (cardiac and non-cardiac) is another reason for causing increased levels of H-FABP in the blood because damaged tissues and muscles relaxes this enzyme. H–FABP is excreted by the kidney, therefore the results of H–FABP concentration in patients with renal insufficiency should be carefully considering. Because of decreased clearance of H–FABP, elevated concentration of enzyme lasts longer than usual and in this situation of AMI and renal failure, the H–FABP test results could lead overestimation of myocardial infarct size . In early diagnosis of MI the test results of biochemical marker should be carefully considered.
In order to confirm MI diagnosis we need to find cardiac ischemia biomarkers with typical ECG changes or clinical symptoms. Troponin may not rise till 12h after the onset of symptoms and may have to be repeated several times in order to confirm or negate the diagnosis. Troponin is not very valuable biomarker in early diagnostics. However reperfusion therapy is most effective in the first hours of AMI. H-FABP being a small molecule and found in high concentrations in cardiac muscle is a more sensitive biomarker in the first 12 hours of AMI. Unfortunately H-FABP can not be used as a single biomarker in diagnosing AMI due to lack of specificity. The role of H-FABP in combination with hs-cTn and ECG changes is to evaluate risk of acute coronary syndromes. Low risk patients could be early discharged from emergency department. However inclusion of H-FABP in other rule-out models (MACS, TIMI and HEART in combination with H-FABP) provides no additional prognostic value.
H-FABP included in a risk evaluating model could be valuable in the first hours after the onset of cardiac ischemia symptoms as a rule out method, but the optimal model is still unknown.
The study was supported by grants from Lithuania Heart Association.
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Conflict of interest
All authors state that there is no conflict of interest.
Address for correspondence
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Fig. 1. Results in different groups.