Diagnostic and prognostic utility of heart-type fatty acid binding proteins in cardiovascular diseases and risk factors − an updated review of the literature

Graphical abstract

Overview of the diagnostic and prognostic applications of heart-type fatty acid-binding protein (H-FABP) in cardiovascular diseases, highlighting its early release kinetics and clinical utility across multiple cardiac conditions.

Abstract

Fatty acid-binding proteins (FABPs) are intracellular lipid-binding proteins that significantly contribute to the transport and metabolism of long-chain fatty acids and other hydrophobic ligands. In this review, we focus on the role of heart-type FABP (H-FABPs) as diagnostic and prognostic biomarkers in several cardiovascular diseases. Despite its advantages over troponins and other cardiac biomarkers, H-FABP remains underutilized in clinical practice. The aim of this review is to reassess the role of H-FABPs across various cardiovascular pathologies and promote their adoption into standard clinical practice. Elevated H-FABP levels have been associated with worse outcomes in CAD and serve as sensitive markers for myocardial injury during the early stages of MI and reperfusion. Furthermore, we discuss the potential of H-FABPs in risk stratification for stable CAD and their utility in predicting long-term outcomes post-MI. The prognostic value of H-FABP in cardiac events such as heart failure, pulmonary embolism, and arrhythmias, alongside its application in peripheral arterial disease and non-ischemic dilated cardiomyopathy, highlights its importance in cardiovascular medicine. Given the global burden of cardiovascular diseases, understanding and utilising H-FABPs could enhance patient management through better risk assessment and early diagnosis.

1. Introduction

FABPs are a family of small, intracellular lipid-binding proteins that play a crucial role in the transport and metabolism of long-chain fatty acids and other hydrophobic ligands within cells [1]. FABPs have dual functionality: some are membrane-bound, facilitating cellular uptake of long-chain fatty acids, while others are cytoplasmic, ensuring efficient intracellular transport of these fatty acids for further metabolism [2]..

While there are 12 known FABPs in vertebrates, only 10 isoforms have been identified to exist within the human body [11]. Although all FABPs share a similar tertiary structure, each isoform has distinct tissue distributions, reflecting their specialised roles in fatty acid metabolism and transport within those tissues [12,13]. Furthermore, the level of expression of FABPs varies within different tissues according to the extent of lipid metabolism occurring within them. For instance, the expression of FABPs in hepatocytes and adipocytes, which are cells that are highly involved in lipid metabolism, is much greater compared to in neurons, where lipid metabolism is primarily focused on maintaining cell membrane integrity and function rather than energy storage or mobilization [14].

Heart-type FABP (H-FABP), also known as FABP3, is predominantly expressed in cardiac myocytes and microvessels of the heart. The emergence of H-FABP as a promising marker for myocardial damage can be traced back to the late 1980 s, but despite early enthusiasm in the 1980 s–2000 s, several factors have curtailed the routine clinical use of H-FABP. First, the advent and rapid validation of sensitive and high-sensitivity cardiac troponin (hs-cTn) assays have eclipsed H-FABP for the early diagnosis of myocardial infarction (MI): multicentre trials showed that sensitive troponin markedly improves early MI detection and risk stratification across presentation times. These characteristics have led professional societies to prioritize hs-cTn as the primary biomarker for suspected acute coronary syndrome (ACS), eclipsing earlier candidate markers. H-FABP, despite its early kinetic advantages, has thus been marginalized in guideline algorithms [15]. American Heart Association guidelines identify troponin as the preferred biomarker and state that other markers (e.g., CK-MB, myoglobin) are no longer necessary with modern cTn assays; European Society of Cardiology non-ST-elevation ACS (NSTE-ACS) guidelines explicitly do not recommend routine measurement of additional biomarkers such as H-FABP alongside hs-cTn for initial diagnosis. These positions have reduced clinical demand for H-FABP testing and limited its integration into standardized pathways [16].

Biological and analytical limitations also constrain H-FABP’s standalone specificity. H-FABP is present in extra-cardiac tissues and rises in several non-ischemic states; its rapid renal clearance also makes results difficult to interpret in kidney disease, where baseline levels are frequently elevated independent of acute coronary syndromes. These characteristics increase false-positive risk compared with the cardiac-restricted troponins [17].

Nonetheless, these challenges should not overshadow the ongoing value and potential of H-FABP, as it holds several advantages over troponins and other cardiac biomarkers which will be discussed in this review. For instance, because of its early-release kinetics, H-FABP remains attractive for ultra-early detection, particularly in patients who present very soon after symptom onset. Furthermore, in prognostic settings—heart failure, pulmonary embolism, or risk stratification in ACS—H-FABP may offer complementary information beyond troponin or natriuretic peptides [18]. In spite of these advantages, H-FABPs are yet to gain widespread adoption in clinical practice. Given the global significance of cardiovascular disease as a leading cause of mortality, the identification of new cardiovascular markers remains a key area of research in our efforts to refine risk stratification for patients with cardiovascular disease. In this review, we re-explore the utility of H-FABPs across a range of cardiovascular diseases—including CAD, MI, essential hypertension, insulin resistance, left and right ventricular dysfunction, pulmonary embolism (PE), arrhythmias, cardiac syncope, peripheral arterial disease (PAD), and cardiovascular risk factors—and discuss their roles as both diagnostic and prognostic tools to support their integration into routine clinical practice.

2. Cardiovascular diseases

2.1. Coronary artery disease and myocardial infarction

CAD is the leading cause of mortality in the United States and carries with it a significant risk of adverse events [19]. H-FABP can be used as a prognostic marker in patients with stable CAD. Recently, interest has developed in using H-FABP in cardiac patients and its potential clinical benefits. It may aid, firstly, in identifying patients with stable CAD but also may assist in the risk stratification of these patients, should they require further diagnostic investigations [20].

Studies have shown that elevated H-FABP levels are associated with worse outcomes in patients with CAD and are an independent predictor for adverse cardiovascular events. A study by Ho et al. prospectively investigated patients with stable CAD and analysed the prognostic value of H-FABP in cardiovascular outcomes in such patients [21]. After 24 months, those patients with low levels of H-FABP were half as likely to develop a primary cardiovascular event compared to those patients with high levels of H-FABP (32.36 % vs 15.78 %, p < 0.001). Furthermore, high H-FABP levels were found to be a predictor of acute heart-failure-related hospitalisations (HR 5.16, 95 % CI 1.096–24.324, p = 0.038) and cardiovascular mortality (HR 22.89, 95 % CI 2.16–242.55, p = 0.009). It must be noted that this study lacked significant statistical power, and thus, further studies are required to provide more evidence in this field.

With regards to MI, studies have shown that H-FABP is an incredibly sensitive marker for myocardial injury during the first hours post-insult as well as during reperfusion injury [22,23]. Arguably, H-FABP has been ruled by some academics as the most superior cardiac biomarker to diagnose acute myocardial infarction, especially within three hours of onset of symptoms [24]. One study investigated H-FABP, CK-MB, myoglobin, and cardiac troponin I levels in patients suspected of MI before hospital admission. It was found that compared to the other cardiac biomarkers, H-FABP was significantly superior in sensitivity [22]. Thus, measuring levels during hospital admission may enable healthcare providers to determine which patients may benefit from closer monitoring and more aggressive treatment strategies.

H-FABP is rapidly released into the bloodstream following myocardial injury due to its abundance in cardiomyocytes and its cytosolic localisation. In the context of acute MI, H-FABP levels begin to rise as early as 30 min to 1 h after symptom onset, peak at approximately 6 to 8 h, and return to baseline within 24 to 36 h post-infarction [25,26]. As shown in Fig. 1, this early rise and rapid clearance distinguish H-FABP from cardiac troponins, which typically rise later and remain elevated for several days [27]. Importantly, due to its relatively short half-life, H-FABP may also serve as a valuable biomarker in the detection of reinfarction, particularly within the first 2–3 days following an initial MI, where persistently elevated troponin levels may complicate the diagnostic picture. This kinetic profile is comparable to that of CK-MB and suggests a potential role for H-FABP in similar clinical scenarios.

Fig. 1.

Graph displaying temporal concentration profiles of cardiac biomarkers following myocardial infarction (19).

Even post-MI, H-FABP may still play a valuable role in patient prognosis. A study by Matsumoto et al., which examined 1,283 post-MI patients, showed that H-FABP levels served as an accurate predictor of long-term outcomes, including all-cause mortality and readmission for heart failure [28]. Patients with H-FABP levels above 6.08 ng/ml during the convalescent stage of the disease process may be regarded as high risk for subsequent adverse events such as heart failure and all-cause mortality.

In both CAD and MI, H-FABP has proved to be a valuable biomarker with substantial diagnostic and prognostic utilities. Its early release in response to myocardial insult allows for early diagnosis and, thus, timely management. While cardiac troponins are considered the gold standard biomarkers for MI, H-FABP should be used to complement these biomarkers in both the risk stratification of patients with CAD and the diagnostic workup of acute sequelae.

2.2. Heart failure and ventricular dysfunction

A study by Niizeki et al. determined that compared to troponin T, H-FABP was more precise in detecting ongoing myocardial damage and identifying patients at increased risk [29]. It suggested that heart failure directly corresponds to higher H-FABP release along with the gradual death of cardiomyocytes. The authors established that H-FABP can be considered a biomarker for chronic heart failure. 46 % of patients with CHF demonstrated serum H-FABP (n = 126); in CHF patients, measures of H-FABP were substantially linked to non-fatal cardiac complications as well as cardiac fatalities. Moreover, Arimoto et al. studied that cardiac incidents were greater in patients with higher H-FABP values than those with baseline values [30]. Raised H-FABP signifies underlying cardiomyocyte injury and puts them at a greater risk of subsequent cardiac incidents. Their findings showed that H-FABP release occurs at every stage of heart failure, even though values closely correlate with severity. According to their results, those with moderate heart failure who are more likely to experience cardiac incidents can benefit from more intensive treatment on the basis of increasing H-FABP values.

In addition, a study by Setsuta et al. revealed that in chronic heart failure, H-FABP and troponin T were separate indicators of subsequent cardiac incidents [31]. They observed that individuals with heart failure had higher levels of both cytosolic and myofibril indicators of myocardial injury and that these increases were correlated to a worse prognosis. Similarly, the clinical value of H-FABP in predicting the outcomes of patients with congestive heart failure was investigated by Sugiura et al. [32]. This study revealed that elevated levels of cardiac proteins like H-FABP (50 %) can be related to an increased risk of acute worsening of congestive heart failure patients.

Patients with acute decompensated heart failure have also shown rising H-FABP values when admitted. Baseline H-FABP values are associated with parameters of left ventricular remodelling as well. Not only this, but elevated discharge serum H-FABP values in acute decompensated heart failure patients have been linked to poorer outcomes [33]. H-FABP levels have been shown to increase and stay raised, even when clinical recovery has occurred and there has been a decrease in BNP levels. Hoffmann et al. confirmed that the diagnostic specificity and PPV to rule out acute heart failure are enhanced when H-FABP and NT-proBNP (< 300 ng/l) are combined [34]. Another study revealed that the combined assessment of BNP and H-FABP upon admission may be valuable in risk classification for potential cardiac incidents in patients with CHF [35].

In the paediatric age group, one study has been observed that H-FABP values in patients with stage IV heart failure were 9.744 ± 1.67 ng/ml, which was substantially greater than that of patients in stage III (3.743 ± 1.208 ng/ml) and stage II (2.418 ± 0.07 ng/ml; p < 0.001). As a diagnostic indicator of myocardial damage in congestive heart failure in children, H-FABP has 100 % specificity and 100 % sensitivity. A substantial rise in the H-FABP was linked to unfavourable results, including hospitalisation or death [36]. As per the literature, H-FABP leaks into blood up to three hours after heart failure. Following heart failure, there is an increase in serum H-FABP levels that may last 12 to 14 h [37]. In HFrEF patients, elevated H-FABP values are linked to worse cardiac outcomes and may help clinicians while treating these patients [38].

When it comes to predicting postoperative mortality and ventricular dysfunction following coronary artery bypass graft (CABG) surgery, H-FABP is a more reliable indicator. It rises earlier than established indicators of myocardial damage. Due to its quick rise and fall, H-FABP may help detect persistent or recurrent myocardial damage following heart surgery, which might prompt targeted treatment plan implementation. In this study, postoperative day 1 and peak postoperative H-FABP levels were identified as independent predictors of mortality following CABG surgery, even when adjusting for clinical predictors of mortality [39].

2.3. Pulmonary embolism and associated right-sided myocardial strain

It is widely acknowledged that patients displaying evident signs of shock in PE are prone to experiencing unfavourable clinical outcomes, necessitating more intensive therapeutic approaches beyond anticoagulation [40]. Conversely, certain hemodynamically stable patients with PE initially perceived to have benign prognoses often exhibit poor outcomes, particularly in cases involving right ventricular dysfunction [41]. Therefore, the identification of right ventricular dysfunction holds significant importance, as it can guide risk assessment in individuals with acute PE. This risk stratification could facilitate outpatient care for patients with a low risk of adverse events, while advocating more aggressive interventions for high-risk patients.

Numerous cardiac biomarkers have emerged as indicators of right ventricular dysfunction and predictors of clinical outcomes in acute PE patients. Examples include BNP, troponins, growth differentiation factor 15 (GDF-15), and H-FABP.

In a comprehensive meta-analysis conducted by Liu et al., it was found that out of a total of 119 patients with acute PE who had elevated levels of H-FABP, approximately 28.57 % (95 % CI: 20.42 % to 36.72 %) experienced adverse events including death, cardiopulmonary resuscitation, endotracheal intubation and admission to the intensive care unit during the follow-up period [42]. A subgroup analysis looking at short-term follow-up data for 30 days also revealed similar results. In contrast, among 475 patients with normal H-FABP levels, only 5.05 % (95 % CI: 3.08 % to 7.02 %) encountered adverse events. The pooled odds ratio for this association was calculated at 10.81 (95 % CI: 3.92 to 29.83). The results therefore demonstrate a substantial and clinically relevant link between high H-FABP levels and the likelihood of adverse clinical outcomes.

Another meta-analysis encompassing six distinct studies, involving a collective cohort of 618 patients, established a noteworthy association between heightened levels of H-FABP in patients with acute PE and short-term mortality (occurring within 30 days post-embolism) and complex clinical events (thrombolysis, cardiopulmonary resuscitation, IV vasopressors). Elevated H-FABP levels were linked to complex clinical events with an odds ratio of 32.71 (95 % CI: 11.98 to 89.26). Similarly, the odds ratio for short-term death was 40.78 (95 % CI: 11.87 to 140.09). H-FABP was determined to have a sensitivity of 98 % at predicting both mortality and complex clinical events and a specificity of 86 % for the same [43]. These findings collectively underscore the robust predictive potential of elevated H-FABP levels in relation to adverse clinical outcomes within the acute PE setting.

3. Cardiovascular risk factors

3.1. Essential hypertension

Hypertension is a precursor to heart failure and a key component of cardiovascular and cerebrovascular disease (CCVD) [44]. Although hypertensive myocardial injury has been reported, H-FABP's predictive usefulness has received limited clinical research. A study by Setsuta et al. revealed that in patients with essential hypertension, the H-FABP level represents a distinctive and valuable marker for predicting future CCVDs [45]. Similarly, Gedikli et al. demonstrated an association between elevated levels of H-FABP and arterial rigidity in hypertensive patients [46]. Thus, H-FABP may be a unique predictor of CCVD in essential hypertension patients and reinforce the above evidence suggesting it can be used as a marker for myocardial injury.

3.2. Insulin resistance

Insulin resistance is associated with metabolic disorders such as cardiovascular disease, diabetes, obesity, and hypertension [47,48]. Long-chain fatty acids (LCFA) are necessary for insulin to stimulate glucose metabolism and are the leading cause of insulin resistance as they interfere with insulin signalling [49]. H-FABP is essential for LCFA absorption and utilisation in cardiac and skeletal muscle, thereby preventing LCFA toxicity [50,51]. Recent studies have shown that H-FABP changes how LCFA are burned in the heart's mitochondria and makes the metabolism more flexible when LCFA are scarce. Although H-FABP genetics cannot predict human insulin resistance, several factors including exercise, omega-3-rich foods, and weight loss, affect LCFA flow and H-FABP [52]. However, partial genetic reduction of H-FABP levels in murine models is protective and limits the severity of dietary-induced insulin resistance [53].

4. Arrhythmias

4.1. Ventricular fibrillation in Brugada syndrome

Patients with Brugada syndrome face challenges in risk assessment and implantable cardioverter-defibrillator (ICD) therapy. Furthermore, individuals with Brugada syndrome have a documented high incidence of ICD-related problems [54]. Brugada syndrome was assumed to affect only anatomically normal hearts; however, pathological analysis suggests structural changes such as myocarditis may be present in this condition [55]. Myocardial injury may occur in Brugada syndrome patients, although the incidence and severity of this damage are unclear [56,57]. Nevertheless, biomarkers for cardiac damage like H-FABP and troponin are being explored for the diagnostic work up of patients. H-FABP production peaks 4–6 h after cardiac damage and returns to normal in 20 h due to renal excretions. Conversely, the amounts of troponin T in the heart peak 12 h after myocardial damage [58]. Extensive cohort studies have shown that H-FABP is more sensitive and specific at spotting heart damage than troponin T [59,60]. Myocardial damage is linked to ventricular arrhythmias, and H-FABP’s sensitivity is helpful in predicting cardiac events. A study by Daidoji et al. suggests that monitoring H-FABP levels can aid in selecting ICD candidates and identifying those at higher risk of ventricular arrhythmia in Brugada syndrome patients [61].

5. Atrial fibrillation after cardiac surgery

Atrial fibrillation (AF) affects 60 % of cardiac surgery patients and is clearly linked to poor outcomes [62]. The underlying mechanisms of postoperative AF are unclear, with current medications lacking efficacy [63,64]. A study by Rader et al. found that H-FABP levels in patients undergoing CABG and valve surgeries strongly connected post-surgery H-FABP levels and postoperative AF [65]. The study also suggests that ischaemic injury during open-heart procedures acts as a contributory factor to AF and may actually be a target for therapeutics for reducing AF after cardiac surgery. The ischaemic insults tend to occur during or after surgery, not pre-operatively. Cardiopulmonary bypass duration is linked to post-surgical H-FABP levels; therefore, it might be a potential target to reduce the incidence of postoperative AF [66,67]. Patients with a greater ischemic burden are at higher risk, requiring better monitoring and possibly prophylactic medications [39]. Evidence appears to strongly suggest that higher post-surgery H-FABP levels indicate a more pronounced risk for postoperative AF, implicating ischaemia in arrhythmia development [68,69]. Investigating the capacity of drugs that minimise ischaemic injury and reduce AF post-surgery could be a beneficial avenue for further research.

6. Cardiac Syncope

Syncope, caused by inadequate cerebral blood flow, occurs in 1–3 % of ER visits and 2–6 % of hospitalisations. The causes of cardiac syncope include arrhythmias, anatomical abnormalities of the heart, and acute coronary syndromes [70]. Troponins have historically diagnosed cardiac syncope; however, H-FABP may have identified this issue earlier. Sonmez et al. underline the importance of H-FABP in diagnosing cardiac syncope in emergency care patients [71]. Identifying high-risk patients is crucial to prompt admission following screening. H-FABP may aid in the diagnostic work up of cardiac syncope patients, despite little research. The combination of H-FABP and troponin I improves diagnosis; data supports a causal relationship between these two biomarkers, highlighting H-FABP’s importance in cardiac syncope therapy [72]. H-FABP may be a useful early biomarker for identifying the cardiac cause of syncope or near-syncope and predicting short- and long-term clinical outcomes.

7. Non-ischaemic dilated cardiomyopathy

A study by Komamura et al. found that H-FABP levels on admission independently predicted long-term risk of critical cardiac events like mortality, LVAD placement, and need for cardiac transplantation over four years of follow-up in patients with idiopathic dilated cardiomyopathy [73]. The predictive power was comparable to that of BNP. Patients with both elevated BNP and H-FABP had a statistically significant reduction in prognostic outcome. Although troponin can indicate ongoing myocardial damage, H-FABP outperformed troponin T for prognostication in this cohort. H-FABP outperforms troponin T as a prognostic marker in dilated cardiomyopathy due to its higher detection rate – 93 % of MI cases detected by H-FABP versus 36–46 % cases by cardiac troponin. The study proposed that membrane instability in the dilated ventricles leads to H-FABP release, providing incremental risk information beyond wall-stress-induced natriuretic peptide elevation. Additional large-scale studies are warranted to verify these findings and further define the role of H-FABP for prognostication in non-ischaemic dilated cardiomyopathy.

8. Peripheral arterial disease

Studies have shown preliminary evidence that urine levels of H-FABP may have value as a biomarker for detecting complications and predicting prognosis in PAD. Patients with more severe PAD had a higher ratio of urinary H-FABP levels to creatinine, suggesting utility for detecting disease progression [74]. As a marker of skeletal muscle injury, elevated H-FABP levels may also indicate worsening ischaemia and muscle damage in PAD patients. An acquired form of myopathy can co-exist in patients with PAD due to repetitive ischaemia and reperfusion leading to altered expression of mitochondrial enzymes, dysfunction of mitochondrial respiration, increased mitochondrial oxidative stress, and muscle apoptosis. There is also a described association between elevated blood and urine levels of H-FABP and the presence and severity of PAD, independent of confounders [75]. However, larger, more diverse cohorts are needed to substantiate these findings further before H-FABP can be considered a validated prognostic biomarker in PAD. Broader inclusion of PAD patients, particularly those with various comorbidities, will facilitate analysis of H-FABP utility for tailored PAD risk stratification.

9. Early cardiac effects of diabetic ketoacidosis

Diabetic ketoacidosis is characterised by hyperglycaemia and acidosis, leading to osmotic diuresis, dehydration, electrolyte imbalance, and ischaemia. Acidosis and hyperglycaemia are poor prognostic factors in the setting of cardiac ischaemia [76].

Recent literature has demonstrated the potential utility of H-FABP for the early detection of cellular hypoxia before the onset of myocardial necrosis. The early identification of ischaemia is crucial for preventing the progression of irreversible myocardial damage. As H-FABP is released rapidly from injured cardiomyocytes even before necrosis ensues, it may allow for the detection of early reversible ischaemia before troponin elevation [76]. Studies have revealed an earlier rise (1 h) in the levels of H-FABP compared to troponins (4 h) in an ischaemic event, indicating that it may be helpful as an earlier detector of ischaemia [77,78]. Further research with larger cohorts is warranted to evaluate its ability to identify hypoxia earlier and prevent myocardial injury through prompt initiation of treatment in DKA patients with myocardial ischaemia.

10. Interpretation of H-FABP in the presence of chronic kidney disease

H-FABP is challenging to interpret in the setting of renal insufficiency, with conflicting evidence in the literature regarding its utility. The majority of patients with chronic kidney disease (CKD) have comorbidities, with hypertension and heart failure being among the most common [79]. H-FABP may play a valuable role in monitoring cardiovascular prognosis to guide early intervention.

Renal insufficiency is characterised by inadequate renal perfusion. The renin-angiotensin-aldosterone system consequently increases blood pressure to maintain perfusion, but this leads to hypertension and increased risk of cardiovascular comorbidity over time. In CKD, decreased renal filtration can alter plasma concentrations of molecules that are excreted renally, such as H-FABP. Still, it is unclear how impaired renal clearance alters H-FABP, making interpretation challenging [80,81]. As a result, H-FABP reference ranges have not been established in the setting of renal disease. Patients with CKD but without cardiovascular comorbidity have consistently been reported to have high H-FABP levels that exceed prognostic and diagnostic thresholds for cardiovascular pathology [[82], [83], [84]]. However, this biomarker may still be helpful, as patients with comorbid renal and cardiovascular disease have had even greater levels of H-FABP [85]. H-FABP interpretation requires adjustment in patients with renal insufficiency.

Interpretation of H-FABP in the context of dialysis is complicated. In previous studies, H-FABP concentrations before and after dialysis in patients without CVD have either not changed [84] or decreased but remained above the upper reference limit of normal (> 5.3 ng/ml) [80]. One study found that the post-dialysis H-FABP/myoglobin ratio, but neither biomarker in isolation, was correlated with levels of BNP, cTnT, and other cardiac biomarkers [80]; they suggested measuring the H-FABP/myoglobin ratio would account for changes in H-FABP due to impaired renal filtration as both molecules are excreted via the kidneys, but only H-FABP specifically indicates myocardial damage [84]. However, another study found no change in myoglobin or H-FABP levels before and after dialysis, so it is unclear how much useful information the ratio would truly provide. Furthermore, dialysis itself may increase H-FABP concentration due to subclinical myocardial injury caused by blood pressure variability. Literature is conflicting, with one study reporting a positive correlation between H-FABP and duration of dialysis [83], and another showing no correlation [84].

In the context of MI diagnosis, a study with CKD patients undergoing dialysis reported H-FABP ≥ 12.5 µg/L in all subjects, exceeding the diagnostic threshold despite an absence of MI [18]. To predict the risk of cardiovascular-related and all-cause mortality, a threshold of H-FABP > 4.3 ng/ml has been used alongside other biomarker levels in patients without CKD [35]. However, one study in patients with CKD found that after adjusting for troponin, H-FABP was associated with significant adverse cardiovascular events and non-cardiovascular mortality but not the severity of CHF or cardiovascular mortality [85]. H-FABP concentration alone would likely not be useful in CKD due to high levels at baseline and unclear interpretation of results. Serial measurements to monitor H-FABP levels may be helpful, although further studies are required. To illustrate the variability in diagnostic performance across different clinical settings, Table 1 provides an overview of representative studies examining H-FABP in CKD, MI and PE. The table outlines patient populations, biomarker cut-off values and diagnostic parameters (sensitivity, specificity, positive predictive value and negative predictive value) where available.

Table 1.

Key studies with relevant specificity, sensitivity, PPV and NPV of H-FABP [[3], [4], [5], [6], [7], [8], [9], [10]].

		Case population	Threshold	PPV	NPV	Sensitivity	Specificity
CKD and H-FABP
Furuhashi (2003)	Correlation between H-FABP and other cardiac markers at the end of hemodialysis	21 patients on hemodialysis	Not available	Not available	Not available	Not available	Not available
Al-Hadi (2009)	Correlation between H-FABP and cardiac troponin (cTnT) in renal failure	16 patients with renal failure on dialysis, without ACS	H-FABP: < 5μg/L   cTnT: < 0.01μg/L	50 %	50 %	50 %	50 %
Shirakabe (2019)	Prediction of worsening renal failure in acute heart failure	281 patients with acute heart failure	≥ 22.9 ng/mL	Not available	Not available	73.7 % (94.7 % in non-CKD patients)	76.8 % (72.7 % in non-CKD patients)
Mohammed (2019)	Prediction of cardiac morbidity	20 children with CKD on hemodialysis	> 17.4 pg/mL	44.9 %	99 %	91.7 %	75.0 %
Gorski (1997)	Comparison of H-FABP in chronic renal failure vs. controls	27 patients with renal failure on hemodialysis	Not available	Not available	Not available	Not available	Not available
Schneider (2022)	Association with cardiovascular outcomes	4951 patients with CKD	Not available	Not available	Not available	Not available	Not available
MI and H-FABP
McCann (2008)	Role of novel biomarkers in early detection of acute myocardial infarction	664 patients presenting with chest pain	cTnT ≥ 0.03 microg/L	64 %	74 %	76 %	61 %
Vupputuri (2015)	Role of H-FABP for the evaluation of acute chest pain in patients	54 patients presenting with acute ischemic chest pain	Not available	76.5 %	85.0 %	89.7 %	68.0 %
PE and H-FABP
Boscheri (2010)	H-FABP in patients with intermediate risk PE	101 patients with PE	7 ng/mL	71.4 %	100 %	100 %	95.6 %
Kaczyñska (2006)	H-FABP in patients with PE	77 patients with PE	6 μg/l	Not available	Not available	Not available	Not available
Puls (2007)	H-FABP in patients with PE for predicting a complicated 30-day outcome	77 patients with PE	6 ng/mL	41 %	100 %	100 %	82 %
Dellas (2010)	H-FABP in predicting adverse 30-day outcomes in normotensive patients with acute pulmonary embolism	126 patients with PE	>6 ng/ml	28 %	99 %	89 %	82 %
Gül (2012)	Evaluation of H-FABP positivity and CT metrics as predictors of 30-day mortality	61 patients with PE	7 ng/ml	38.1 %	92.5 %	72.7 %	74.0 %
Vuilleumier (2008)	The prognostic value of H-FABP in patients with non-massive PE specifically for predicting adverse outcomes at 3 months	146 patients with PE	6 ng/ml	33 %	88 %	29 %	90 %
Lankeit (2013)	H-FABP as a diagnostic and prognostic marker for short-term (30-day) adverse outcomes in normotensive acute PE	257 consecutive, normotensive patients with symptomatic PE	≥6 ng/ml	18 %	97 %	65 %	79 %
Arnalich (2013)	H-FABP in predicting 15-day mortality in patients with massive PE	74 consecutive patients with acute PE	6.8 ng/ml	69.5 %	85.7 %	88.9 %	85.7 %

11. Limitations

The value of H-FABP is heavily reliant on its utilisation as a complement to other cardiac biomarkers and diagnostic tests. For myocardial infarction, coronary artery disease, pulmonary embolisms, and right ventricular dysfunction, H-FABP provides diagnostic and prognostic utility. Within insulin resistance, H-FABP genetics cannot predict human insulin resistance but are essential for long-chain fatty acid absorption. H-FABP sensitivity is practical for predicting cardiac events, but there are currently no links to atrial fibrillation after surgery. Larger cohort studies are required to link the rise of H-FABP to gauge its prognostic utility during an ischaemic event. H-FABP is difficult to interpret in the setting of renal insufficiency, and studies have reported conflicting results. H-FABP limitations are most prominent with chronic kidney disease. Patients with CKD but without cardiovascular comorbidity have consistently been reported to have high H-FABP levels that exceed prognostic and diagnostic thresholds for cardiovascular pathology.

12. Future Directions

Despite the growing body of evidence supporting the diagnostic and prognostic value of H-FABP in cardiovascular diseases, several gaps warrant further investigation.

First, large-scale, multicentre randomised controlled trials (RCTs) fail to validate H-FABP as a routine biomarker across diverse cardiovascular conditions. Most available observational studies vary significantly in methodology, population, and outcome measures, limiting generalisability [18,28].

Second, the utility of H-FABP in chronic kidney disease (CKD) remains inconclusive. While elevated levels correlate with adverse cardiovascular outcomes in patients with renal impairment, the biomarker's renal clearance complicates its interpretation, especially in dialysis patients. Future research should establish adjusted reference ranges and clarify whether H-FABP levels represent cardiac damage or reduced renal clearance in this population [81,84].

Integrating H-FABP into multi-marker panels for cardiovascular risk prediction remains underexplored. Combining H-FABP with NT-proBNP, troponins, and other emerging markers such as GDF-15 may improve diagnostic accuracy and risk stratification, especially in acute presentations like myocardial infarction and pulmonary embolism. Prospective studies are needed to compare these combined panels against current clinical standards [35,43].

The prognostic utility of H-FABP in arrhythmogenic syndromes such as Brugada syndrome and postoperative atrial fibrillation has been demonstrated in small cohorts but lacks corroboration in broader patient groups. Further research should aim to define cutoff thresholds and assess whether H-FABP can guide therapeutic decision-making, such as ICD implantation or perioperative antiarrhythmic therapy [61,65].

Lastly, longitudinal studies are essential to evaluate whether serial measurements of H-FABP can track disease progression or predict long-term cardiovascular outcomes, particularly in non-ischaemic dilated cardiomyopathy and peripheral arterial disease. Current evidence is based mainly on cross-sectional or short-term analyses [73,74].

Addressing these evidence gaps will be pivotal for successfully translating H-FABP into clinical practice. Standardisation of assays, establishment of population-specific reference values, and integration into risk algorithms are vital next steps to fully leverage the potential of this biomarker.

The expanding literature surrounding heart-type fatty acid-binding protein (H-FABP) reflects growing enthusiasm for its integration into cardiovascular diagnostics and prognostics. To further unlock the clinical potential of H-FABP, future research should prioritise longitudinal, multicentre cohort studies that track patient outcomes over extended periods. Such studies would enable more nuanced insights into the temporal dynamics of H-FABP levels across various stages of cardiovascular disease. They could define its role in monitoring progression, therapeutic response, and long-term prognosis.

For instance, elevated H-FABP levels are associated with adverse outcomes in conditions such as coronary artery disease and myocardial infarction [18,28]; future studies with serial H-FABP measurements may establish its value in predicting recovery trajectories and recurrent events. Similarly, in non-ischaemic cardiomyopathies, heart failure, and peripheral arterial disease, tracking H-FABP levels over time could offer additional risk stratification layers beyond conventional markers like troponin and BNP [73,74].

Longitudinal studies also aim to address current interpretative challenges, such as chronic kidney disease (CKD). Because renal clearance affects H-FABP levels, time-based trends may be more informative than static thresholds. This approach could help distinguish between persistent elevations due to reduced clearance and those reflecting acute cardiac stress or injury, enhancing clinical reliability in CKD populations [81,84].

Furthermore, future directions should include standardisation of assays, development of population-specific reference ranges, and integration into multi-marker panels alongside NT-proBNP, troponins, and novel markers like GDF-15 to enhance clinical decision-making in acute care and long-term follow-up settings [35,43].

13. Conclusions

H-FABP has proven to be a valuable biomarker in the realm of cardiovascular diseases. This updated review of the literature highlights the diagnostic and prognostic utility of H-FABP across a spectrum of cardiovascular pathologies.

Despite the advances in H-FABP research, the emergence of highly sensitive and specific cardiac troponin assays has somewhat overshadowed its clinical utility. However, the growing recognition of the limitations of troponins, particularly in early MI detection and certain clinical scenarios, has rekindled interest in H-FABP as a complementary biomarker.

H-FABP holds significant promise as both a diagnostic and prognostic tool in cardiovascular medicine. Its early release profile, combined with its prognostic implications, makes it an invaluable addition to the existing biomarker repertoire. Future research and clinical trials will be essential to further refine its application and establish standardised protocols for its use in clinical practice, ultimately enhancing patient outcomes in cardiovascular disease management.

TRANSPARENCY DECLARATION

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted.

ETHICAL APPROVAL

Not required.

CONTRIBUTORSHIP STATEMENT

All other authors drafted the initial version of the manuscript and also provided critical revision of the manuscript.

CRediT authorship contribution statement

Riaz Jiffry: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Ankit Gupta: Writing – review & editing, Writing – original draft. Jeisun Poornaselvan: Writing – review & editing, Writing – original draft. Valerie Mok: Writing – original draft. Arkadeep Dhali: Writing – original draft. Aditi Gupta: Writing – original draft. Tong Liu: Writing – review & editing. Gary Tse: Writing – review & editing. Helen Ye Rim Huang: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.