Biomarkers in Acute Heart Failure Syndromes: An Update

Abstract

Heart failure is one of the leading healthcare problems in the world. Clinical data lacks sensitivity and specificity in the diagnosis of heart failure. Laboratory biomarkers are a non-invasive method of assessing suspected decompensated heart failure. Biomarkers such as natriuretic peptides have shown promising results in the management of heart failure. The literature does not provide comprehensive guidance in the utilization of biomarkers in the setting of acute heart failure syndrome. Many conditions that manifest with similar pathophysiology as acute heart failure syndrome may demonstrate positive biomarkers. The following is a review of biomarkers in heart failure, enlightening their role in diagnosis, prognosis and management of heart failure.

1. INTRODUCTION

Heart failure (HF) is one of the most prominent healthcare problems throughout the globe due to its high morbidity and mortality rates, as well as an economic and psychosocial burden. About 2.4% of the United States population was diagnosed with HF in 2012, and the prevalence is increasing significantly with age. The American Heart Association (AHA) reported that approximately 12% of the population above 75 years of age carries a diagnosis of HF [1]. The anticipated increase in the total number of HF-labeled patients is 46% by 2030, leading to more than 8 million people with HF in the United States. The most common cause of hospitalization in HF is due to acute exacerbation, and with every exacerbation, the mortality of HF worsens [2]. HF is the leading cause of in-hospital death in the United States.

HF hospitalization has placed a huge financial burden on the health care system in the United States. There is an expected 2.5-fold increase in HF management expenses from $20.9 billion in 2012 to $53.1 billion by 2030. Importantly, approximately 80% of these charges are connected to hospitalizations related to HF exacerbation. During the final 2 years of life in a patient with HF, the predicted mean cost is more than $156,000, and three-quarters of it are connected to HF hospitalizations in the last 6 months of life [3].

An acute HF syndrome (AHFS) is manifested by congestive symptoms along with signs of poor perfusion, which includes fatigue, decreased exercise intolerance, dyspnea, orthopnea, paroxysmal nocturnal dyspnea and lower extremity edema. However, clinical symptoms are considered hetero-geneous, with evident chances of missed diagnosis, which may delay management [4]. Multiple researches implied that delayed management is associated with high morbidities and mortality [5]. Therefore, appropriate treatment at the appropriate timing is crucial for a better outcome.

The assessment of the patient with suspected decompensated HF is largely dependent on clinical evaluation and radiographic findings. Nevertheless, Marantz et al. reported poor sensitivity (50-73%) and specificity (54-78%) in the utilization of clinical data and chest radiography for the diagnosis of HF [6]. Transthoracic echocardiography (TTE) can help to identify abnormal filling pressures and left ventricular function, but many patients with abnormal TTEs are asymptomatic [7]. Thus, rapid, non-invasive and practical methods aiming for timely assessment and optimal outcome of decompensated HF, are essential.

2. BIOMARKERS

The World Health Organization (WHO) defined a biomarker as “Any substance, structure, or process that can be measured in the body or its products and influenced or predicted the incidence of outcome or disease” [8]. The National Academy of Clinical Biochemistry released four principles to appraise the applicability of biomarkers for HF, which are:

● Measurable at a reasonable expense on reasonable notice.

● Add new data to the ongoing evaluation.

● Aid in the management of HF

● Enable the physician to determine the possible underlying pathology causing HF, establish the diagnosis of HF, and assess the severity of HF and the prognosis [9].

It was suggested that a biomarker should be associated with a low coefficient of variation of <10%, which may permit a timely change in the status of the disease [10]. Compared to invasive strategy to assess filling pressures, such as right heart catheterization, a biomarker cannot provide complete guidance, but an efficient biomarker can be utilized as a non-invasive and effective surrogate to guide management in decompensated HF [11].

3. PATHOPHYSIOLOGY OF HEART FAILURE AND BIOMARKERS

There are multiple pathophysiological pathways involved in decompensated HF and, consequently, multiple biomarkers can be associated with it. The basic mechanism involved in AHFS consists of a decrease in arterial filling and peripheral organ blood supply. Subsequently, the renin-angiotensin-aldosterone and sympathetic nervous systems (RAAS and SNS) are stimulated due to disruption of homeostasis. The release of neurohormones triggers sodium and water retention, arterial and venous vasoconstriction; and, in the long run, will lead to cardiac remodeling [12]. Cardiac remodeling involves cardiac myocyte injury and death, inflammatory reactions, and extracellular matrix changes, which progressively creates a vicious circle and hence causing irreversible damage.

Moreover, a decrease in cardiac output and blood pressure causes decreased coronary circulation and cardiac oxygen delivery per cell. The stretch in the ventricular wallowing to elevated filling pressures will lead to a release of biomarkers like natriuretic peptides [13]. With continuous compromise in bloody supply and pressure overload, myocytes will go in either “hibernating” status or apoptosis, which will ultimately lead to the release of intracellular contents like cardiac troponin [14]. Cardiac myocyte injury also stimulates body stress response which initiates inflammatory reaction, oxidative stress and release of multiple markers, such as cytokines, adhesion molecules and chemokines like ST2 and galectin-3. These reactions will lead to myocardial death, tissue fibrosis and reduction of cardiac function. On the other hand, cardiac remodeling gives rise to fibrotic changes in the extracellular matrix, causing alteration in its structures like collagen fibrils and tissue metalloproteinase [15].

4. BIOMARKERS CLASSIFICATION

Despite the complexity of HF pathophysiology and the overlapping mechanisms of production of biomarkers, cardiac biomarkers in acute HF can be classified as mentioned in Table 1. In this discussion, we will elaborate on the most common biomarkers used in routine clinical practice for decompensated HF.

Table 1.

Mechanisms of production of biomarkers.

Cardiac Stretch	BNP, NT-proBNP, MR-proANP
Myocyte Injury	Troponin T, troponin I, myosin light-chain I, heart-type fatty-acid protein, CK-MB
Cell Death and Fibrosis	Metalloproteinases, collagen propeptides, galectin-3, soluble ST2, GDF-15, MicroRNA, VEGFR, epididymis protein 4, Resistin
Neurohormonal Activation	Renin, angiotensin II, aldosterone, vasopressin, copeptin, Norepinephrine, Chromogranin A, MR-proADM, Endothelin-1
Endothelial Dysfunction	CD 146, Neutrophil Gelatinase-Associated Lipocalin
Inflammation	C-reactive protein, TNF-α, soluble TNF receptors, Fas, interleukins (I, 6 and 18), osteoprotegerin, adiponectin, Insulin-like growth factor-binding protein 7
Oxidative Stress	Myeloperoxidase, uric acid, oxidized low-density lipoproteins, urinary biopyrrins, urinary and plasma isoprostanes, plasma malondialdehyde
Renal Biomarkers	Creatinine, BUN, eGFR, cystatin C, β-trace protein
Hepatic Biomarkers	Liver function test
Hematologic Biomarkers	Hemoglobin, RDW, iron, ferritin, transferrin saturation

5. NATRIURETIC PEPTIDES

Natriuretic peptides are produced in response to myocardial stretch through stimulation of B-type natriuretic peptide (BNP) receptors in the ventricles, which lead to an increase in natriuresis and antagonize the effects of the neurohormonal system [16]. It is produced by upregulation of the natriuretic peptide B gene that generates pre-proBNP. Pre-proBNP will be converted to proBNP, which will degrade to BNP and NT-proBNP (N-Terminal B-type natriuretic peptide) [17]. In the plasma, BNP effect is initiated by natriuretic peptide receptors A and B by cyclic guanosine monophosphate (cGMP) mediated cascade. It is cleared from the system by natriuretic peptide receptors C and endopeptidase with a half-life of about 20 minutes, excreted mainly through the kidney [18]. On the other hand, NT-proBNP has a half-life of 70 minutes, and approximately 50% is excreted through the kidneys [19]. Natriuretic peptides have been tested for their relationship with acute HF. BNP can be correlated with pulmonary capillary wedge pressures, LV end-diastolic stress and LV end-diastolic pressure, and New York Heart Association (NYHA) functional class and inversely related to left ventricular ejection fraction [20, 21].

Many studies have investigated the relationship between HF and natriuretic peptides. The first and largest one was the Breathing Not Properly study [22], which studied the role of BNP in diagnosing HF in patients presented with acute dyspnea in the Emergency Department. About 1500 patients were tested and reported that the level of BNP above 100 pg/mL had a positive predictive value of 79%, and the level of BNP below 50 pg/mL had a negative predictive value (NPV) of 96%. On the other hand, the first large NT-proBNP study was the PRIDE study, N-Terminal Pro-BNP Investigation of Dyspnea in the Emergency Department, which studied the role of NT-proBNP in diagnosing HF in patients presenting with acute dyspnea in the Emergency Department [23]. 600 patients were tested for the level of NT-proBNP with the presentation of dyspnea in the Emergency department. The study reported age-related cut-off for the level of NT-proBNP: ≥450 for ages <50 years, ≥900 for 50-75 years and ≥1800 pg/mL for >75 years. Multiple other studies investigate natriuretic peptides and their relation to acute HF in different clinical settings, co-morbidities like chronic kidney disease [24] and age populations; the cutoffs are summarized and modified from Kim et al. [25] in Table 2 [26]. Levels of BNP between a ruling in and exclusion of HF can be interpreted according to the clinical situation and follow-up.

Table 2.

Levels of ProBNP and NT-proBNP in different clinical scenarios.

In Acute Dyspnea: To identify acute HF (multiple cut off point)      • BNP                  < 100 pg/mL to exclude                                  > 400 pg/mL, to rule in      • NT-proBNP     < 450 pg/mL for age <50 years                                 < 900 pg/mL for age 50-75 years                                 < 1800 pg/mL for age > 75 years To identify acute HF from pleural fluids sample [26]      • NT-proBNP     >1500 pg/mL In Renal Failure with glomerular filtration rate (GFR) <60 mL/min/body surface area (BSA)      • BNP                 <200 pg/mL      • NT-proBNP     <1200 pg/mL In Outpatient Setting:      • BNP                  20 pg/mL (asymptomatic)                                  40 pg/mL (symptomatic)      • NT-proBNP      <50 pg/mL for age    <50 years                                  <75 pg/mL for age 50-75 years                                   <250 pg/mL for age > 75 years

Modified from Kim et al. [25].

Natriuretic peptides are considered the most important biomarkers for HF diagnosis and management. They are useful to follow up patients with HF in both inpatient and outpatient settings. It has been reported that a decrease in BNP level by >46% from admission with a BNP level of <300 pg/mL at discharge is associated with a lower rate of recurrent hospitalizations and all-cause mortality [27]. Furthermore, studies reported that an increase in BNP levels by >40% and in NT-proBNP levels by >25% is an indicator for a change in heart function [28]. Canadian Cardiovascular Society Heart Failure Management Guidelines, in their focused update in 2014, recommended measuring BNP level in patients admitted for acute decompensated HF before discharge if they are clinically euvolemic with a goal of >30% reduction from BNP admission level [29]. However, a large randomized controlled trial, the Guiding Evidence-based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) trial, examined the merits of NT-proBNP guided care in patients with HFrEF and reported no difference than a usual care strategy in improving outcomes [30].

Natriuretic peptides are strong indicators for HF prognosis and low levels are associated with preferable outcomes. In the Acute Decompensated Heart Failure National Registry (ADHERE) registry [31], high admission levels of BNP and NT-proBNP were associated with an increase in in-hospital mortality and one-year mortality. However, Miller et al. [32] reported that only large reductions >80% in NT-proBNP or BNP values showed improvement in the outcomes.

Despite extensive use of natriuretic peptides in diagnosis, management, follow-up and outcomes in acute decompensated HF, it should be interpreted in appropriate clinical settings. There are multiple cardiac and systemic conditions affecting the level of natriuretic peptides, which can affect their interpretations. Common conditions are summarized in Table 3 [22]. On the contrary to HFrEF, HF with preserved ejection fraction (HFpEF) was associated with lower levels of BNP and NT-proBNP and lower sensitivity, however, the same cutoff points for BNP or NT-proBNP can be utilized [33]. Moreover, the use of Neprilysin inhibitors (such as LCZ696 in Entresto) leads to higher BNP values but has minimal effect on NT-proBNP levels [34].

Table 3.

Conditions associated with high and low levels of BNP and NT-proBNP.

Conditions Associated with Lower levels of BNP or NT-proBNP

• Obesity      • Flash pulmonary edema      • Pericardial tamponade

Conditions Associated with higher levels of BNP or NT-proBNP

• Age      • Right heart failure      • Renal failure      • Valvular disorders      • Arrhythmias      • Coronary artery diseases      • Cardiomyopathies      • Liver disease      • Sepsis      • Subarachnoid Hemorrhage      • Trauma      • Stroke      • Anemia      • Adult respiratory distress syndrome

Natriuretic peptides can be applicable for HF management, but they should be sought in the presence of clinical evidence as a supportive marker. Given all the data, the European Society of Cardiology, AHA (American Heart Association), and HFSA (Heart Failure Society of America) has recommended the use of natriuretic peptides for HF management [35-37].

Another natriuretic peptide studied in the literature, is Atrial Natriuretic Peptide (ANP). It is secreted from the atria as a response to cardiac stretch. Similar to BNP, it is metabolized to NT-pro-ANP, but unlike BNP, it is unstable and difficult to measure. Mid-regional pro-atrial natriuretic peptide (MR-proANP) is more stable and can be measured [38]. MR-proANP showed high sensitivity in the diagnosis of HF in acute dyspnea and was non-inferior to BNP at a 100 pg/mL cutoff [39, 19]. Moreover, MR-proANP showed an advantage in the assessment of acute decompensated HF in cases where BNP has limitations such as chronic kidney disease and obesity. The suggested cutoffs are: < 104 pmol/L for age < 65 years and 214 pmol/L for age ≥ 65 years [19]. However, atrial conditions like atrial arrhythmias can affect its level [39].

6. TROPONIN

Cardiac troponin is a product from the metabolism of troponin-tropomyosin complex and released secondary to myocardial injury [40]. The most commonly used type of troponin in clinical settings are cardiac troponin T (cTnT), troponin I, and highly-sensitive cardiac troponin-T (HS-cTnT), which detects cardiac troponin T at a lower threshold level [41]. High levels of cTnT have been reported with low cardiac output state, high left ventricular end-diastolic pressure and pulmonary pressure [42].

• The primary clinical use of troponin is to diagnose ischemic heart, especially in the case of myocardial infarction type I. However, it is recommended to measure troponin, mainly HS-cTnT, in decompensated heart failure for various reasons that include:

• To diagnose concomitant myocardial infarction type I as precipitating factor for HF decompensation and the extent of cardiac myocyte injury [43].

• High level of HS-cTnT (above20 pg/mL) in acute heart failure syndrome without acute myocardial infarction was associated with higher mortality and HF hospitalization [44].

• HS-cTnT can also be used to monitor HF exacerbation improvement with down-trending levels of HS-cTnT signifies clinical improvement.

Nonetheless, multiple conditions can cause elevated hs-cTnT levels, such as ventricular enlargement, arrhythmias, thyroid diseases, stroke, pulmonary embolism, sepsis, and shock [45].

7. HEART FATTY ACID-BINDING PROTEIN

Heart fatty acid-binding protein (H-FABP), like troponin, is released from cardiac myocytes in case of injury. It was reported in myocardial infarction and in cases of suspected myocardial infarction with negative troponin. High levels of H-FABP are associated with worse outcomes in myocardial infarction and HF [46].

8. SOLUBLE ST2

Soluble ST2 (sST2, suppression of tumorigenicity 2, growth stimulation expressed gene 2) is an interleukin-1 receptor-like 1 (IL1RL1) protein produced as one of the isoforms of IL1RL1 gene that binds to interleukin-33 (IL-33) competitively to prevent its protective effect and promotes myocardial fibrosis [47]. sST2 was found to be increased in myocardial infarction, cardiac remodeling and myocyte strain [48]. Studies failed to prove the significance of measuring sST2 in diagnosing acute HF [49]. However, a decrease in sST2 in patients with acute HF was found to be associated with reduced mortality as it is not affected by age, renal dysfunction, obesity, or atrial arrhythmias [50]. sST2 has been included in the ACC/AHA guidelines in the management of HF as a biomarker for its prognostic value [51].

9. GALECTIN-3

Galectin-3 (Gal-3) is a β-galactosidase binding protein produced by macrophages to stimulate fibrosis; it was found to be elevated in cardiac remodeling and fibrosis, and renal impairment [52]. Gal-3 was studied in the diagnosis of acute HF and found to be inferior compared to NT-proBNP according to PRIDE study [53] and non-inferior without added benefits in other studies [54]. High levels of Gal-3 were found to be associated with a worse prognosis in HF [55]. Gal-3 has been included in the ACC/AHA guidelines in the management of HF as a biomarker for its prognostic value.

10. GROWTH DIFFERENTIATION FACTOR (GDF)-15

GDF-15 expression is increased in inflammation, tissue injury and certain cancers; and is found to be high in HF and myocardial infarction. High levels of GDF-15 concentration were associated with more severe HF symptoms and associated with higher mortality [56]. Bettencourt et al. reported that higher GDF-15 levels in acute HF, independently of BNP levels, are associated with worse outcomes, and when both are elevated, it is associated with higher mortality [57].

11. MICRORNAS

MicroRNAs are post-transcriptional regulators of gene expression and were connected with embryonic development. Lower levels of MicroRNAs were found in acute HF and, to less extent, chronic HF likely due to hemodilution [58].

12. HUMAN EPIDIDYMIS PROTEIN 4 (HE4)

Studies suggested the role of HE4 in fibrosis due to the relation to extracellular proteinase inhibitors. High levels of HE4 were found in fibrosis, renal impairment and certain cancers [59]. HE4 levels were directly correlated with HF severity and worse outcomes [60]. Liu et al. utilized HE4 as a part of a multi-marker model to investigate the response to treatment in patients with acute HF and reported that multi- marker tools have the potential to improve clinical testing of drugs [61].

13. RESISTIN

Resistin is a cysteine-rich peptide secreted by macrophages and associated with atherosclerosis and diabetes [62]. High resistin level is inversely related to left ventricular systolic function [63]. Multiple studies reported that elevated resistin levels were found to be associated with a high risk of coronary disease, development and worsening heart failure, more cardiac events in patients with HF, and worse prognosis [64].

14. MID-REGIONAL PRO ADRENOMEDULLIN (MR-PROADM)

Adrenomedullin is a vasodilatory peptide synthesized in cardiac myocytes and fibroblasts and released in response to an increased wall stretch and neurohormonal activation [65]. Mid-regional pro-adrenomedullin (MR-proADM) is produced during the production of adrenomedullin, however, adrenomedullin has a short half-life and is difficult to be measured in contrary to MR-proADM [66]. MR-proADM was found to be elevated with many conditions as age, hypertension, renal failure, coronary artery disease, and diabetes mellitus. However, MR-proADM was found superior to natriuretic peptides in predicting mortality in patients with acute HF [67]. Moreover, MR-proADM was reported to improve the accuracy of acute decompensated HF diagnosis in >70 years old population when combined with natriuretic peptides [68].

15. ENDOTHELIN-1 (ET-1)

ET-1 is a vasoconstrictor produced by endothelial cells in response to neurohormonal activation. Elevated ET-1 was found to be independent of natriuretic peptides, and is associated with worsened inpatient and long-term mortality in HF [69].

16. COPEPTIN

Antidiuretic hormone (arginine vasopressin) is produced from the posterior pituitary as a response to a reduction in the plasma volume and increase in serum osmolality, causing salt and water retention. Copeptin is produced from an arginine vasopressin precursor molecule and can be measured in serum. The use of copeptin to diagnose acute HF was studied, and the results showed no advantages over natriuretic peptides [70]. Nonetheless, elevated copeptin levels were found to be associated with a higher risk of readmissions, need for transplant and mortality, especially if it is associated with hyponatremia and high natriuretic peptides [71]. Moreover, Copeptin prognostication was proven accurate in cases of HF with renal dysfunction [72].

17. NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL)

NGAL, a glycoprotein expressed by neutrophils, kidney and liver. High levels of NGAL were associated with acute tubular injury and HF [73]. Increased levels of NGAL were reported to be associated with higher mortality, readmission risk and to predict acute kidney injury during acute HF hospitalization [21].

18. SOLUBLE CLUSTER OF DIFFERENTIATION 146 (SCD146)

CD146 is part of the receptor at the junction between endothelial cells and is responsible for tissue integrity. It is released in the circulation as soluble CD146 (sCD146) in cases of endothelial injury to promote angiogenesis in myocardial injury, heart failure, liver disease and atherosclerosis [74]. High levels of sCD146 levels aid with the diagnosis of acute HF in cases of equivocal natriuretic peptides level [75].

19. PROCALCITONIN

One of the commonest presentations for acute decompensated HF is dyspnea. Dyspnea is a common presentation for many pulmonary diseases, which makes the differentiation from acute HF challenging. Moreover, pulmonary conditions like pneumonia can precipitates HF exacerbation or can coexist with it. Procalcitonin is a protein increased in inflammatory states, especially due to bacterial etiology [76]. Elevated procalcitonin level has improved the accuracy in diagnosing bacterial pneumonia in patients hospitalized with acute HF with its role to guide antibiotic therapy [77]. HF can also have increased procalcitonin levels without bacterial infection and it is directly related to the severity of HF [78]. Moreover, elevated procalcitonin level was associated with poorer outcome in HF patients [79]. Given all the data, interpreting the procalcitonin level should be individualized according to the presence and severity of HF. The suggested cutoff for procalcitonin level to exclude bacterial infection is >0.21 ng/mL [77]. The role of procalcitonin in acute HF will be better understood with the results of the Improve Management of Heart Failure with Procalcitonin (IMPACT-EU) study.

20. INTERLEUKIN-6 (IL-6)

IL-6 is an inflammatory marker increased in stress, stroke, surgery, and myocardial infarction and serves as an anti-apoptotic agent. On the other hand, long exposure of IL-6 was found to be associated with cardiac function depression and hypertrophy [80]. An elevated level of IL-6 in combination with another cardiac biomarker has shown to be associated with worse HF outcomes [81].

21. INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN 7 (IGFBP-7)

IGFBP-7 binds to insulin-like growth factor 1 (IGF-1) to regulate growth hormone and insulin-like growth factor-1 activities that promote growth in different tissues, including cardiac tissue [82]. Elevated IGFBP-7 was found in myocardial hypertrophy, HF, cancers, metabolic syndrome, and lung diseases [83]. High levels of IGFBP-7 have been studied in HF prognosis, especially HF with preserved ejection fraction (HFpEF) due to its relation with diastolic dysfunction and metabolic syndrome [84]. Moreover, IGFBP-7 levels in urine and tissue inhibitor of metalloproteinase 2 (TIMP-2) were predictive for acute renal injury in acute HF [85].

22. PARATHYROID HORMONE (PTH)

PTH was studied for its relation with HF and its related outcomes. Altay et al. reported that PTH was correlated to natriuretic peptide levels in acute HF patients; and was more accurate to anticipate the diagnosis of HFpEF and severe HFrEF [86]. Elevated PTH level was associated with more HF risk in the general population [87].

23. PENTRAXIN 3

Pentraxin 3 is an inflammatory biomarker, which can be present in HFpEF, and its increased level can predict worse outcomes in HF [88].

24. MYELOPEROXIDASE (MPO)

MPO is an enzyme released by leukocytes for the formation of reactive oxidants that leads to tissue damage. Elevated levels of MPO (> 99 pmol/L) in patients with acute HF have been associated with increased 1-year mortality. Another study reported the feasibility of MPO to predict HF in 65-75-year-old population [89].

25. EXTRACELLULAR MATRIX MODELING

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are parts of extracellular matrix remodeling during HF remodeling. MMPs concentration was associated with poor outcomes in HFrEF [90]. TIMP1 levels were reported to predict all-cause mortality in HF [91]. TIMP-2 and IGFBP-7 levels in urine were predictive for acute renal injury in acute HF [85].

26. ANGIOGENIN

Angiogenin is a biomarker that stimulates blood vessel formation. It can be increased in cancers, inflammation and HF. High levels of angiogenin were reported in HF population [92]. Jiang et al. reported that high angiogenin concentration was associated with poor outcomes [93].

27. CARDIO-RENAL BIOMARKERS

Derangement of renal function is a common variable in acute HF and is associated with adverse outcomes in this population [94]. Cystatin C and protein traza beta (BTP) were studied for their relationship with acute HF outcomes and risk for rehospitalization. It is observed to have a better correlation than blood urea nitrogen and creatinine in predicting outcome and readmission, and to predict mild renal dysfunction [95]. Hence, the combined CKD-EPI creatinine-cystatin equation to calculate eGFR was superior to an equation based on serum creatinine or cystatin C alone as a prognostic marker in ADHF [96].

28. CARDIO-HEMATOLOGIC BIOMARKERS

Anemia, specifically iron deficiency anemia is an associated comorbid condition observed with HF and its presence can lead to frequent HF exacerbations [97]. Elevated red blood cell distribution width (RDW) was found to have a prognostic relation with acute HF regardless of ejection fraction [98]. It is recommended to treat iron deficiency anemia in HF patients if ferritin <100 ng/ml or 100-300 ng/ml if transferrin saturation <20% [99].

29. BIOMARKERS IN HFREF AND HFPEF

Although the disease progression and symptomatology in Heart failure with reduced ejection fraction (HFrEF) and Heart failure with preserved ejection fraction (HFpEF) is similar, its pathophysiology differs in hemodynamic effects on the cardiovascular system. According to Tromp et al., HFrEF interacts more with contractile reserves of cardiac tissue and thus has more impact on the stretch mechanism of the heart [100]. On the contrary, HFpEF is proposed to interact with angiogenic and inflammatory mechanisms and has an impact on the remodeling of the heart leading to diastolic dysfunction. The same authors supported the hypothesis by a differential increase of stretch markers (pro-BNP, ANP), angiogenic and inflammatory markers such as Neurolipin, Osteopontin and hs-CRP in cohorts of HFrEF and HfpEF, respectively. In many studies, it has been hypothesized that an increase in Pro-BNP is more pronounced and can be sought with more reliability in HFrEF patients compared to HFpEF patients [101]. The difference in stretch biomarker release in HFpEF is explained by the hypertrophied heart (with fibrosis) in this group neutralizing the effect of stretch by shear forces. Owing to multiple comorbidities associated with HFpEF, the role of biomarkers, especially pro-BNP, is not validated, and hence disease course cannot be predicted solely by its elevation. Since studies have been conducted in populations carrying the diagnosis of HF irrespective of type, more data is required to elucidate the importance of biomarkers in disease progression and outcomes of the two separate HF groups. The role of various biomarkers in HFrEF and HFpEF patients is highlighted in Table 4.

Table 4.

Biomarkers in HFrEF and HFpEF.

-	HFrEF	-		HFpEF
-	Diagnosis	Exacerbation	Prognosis	Diagnosis	Exacerbation	Prognosis
NT-proBNP	High	High	High mortality	High to normal	High	Unknown
Galectin-3	High	High	High mortality	High	High	High mortality
ST2	High	High	High mortality	High	High	High mortality (compered to Pro-BNP)
HS-Troponin	High	High	High mortality	High	High	Unknown
Hs-CRP	High	High	Unknown	High (compered to Pro-BNP)	High (compered to Pro-BNP)	Unknown
Neurolipin	High	High	Unknown	High (compered to Pro-BNP)	High (compered to Pro-BNP)	Unknown

Abbreviations: HFrEF -Heart failure with reduced ejection fraction, HFpEF—Heart failure with preserved ejection fraction.

CONCLUSION

Decompensated HF is associated with a huge financial burden on the health economics of US. Incorporating biomarkers along with clinical assessment for acute HF diagnosis and prognostication is suggested to lessen the hospitalization rates and ultimately morbidity. Natriuretic peptides are still the primary biomarkers to aid acute decompensated HF diagnosis. On the other hand, MR-proANP, MR-proADM, sST2, copeptin, and Gal-3 have shown encouraging results in the diagnosis of acute HF. Although with a multisystem disorder such as acute kidney injury and uncontrolled hypertension, the results can be misleading, but in the proper clinical setting, the implication can still be considered. Compared to invasive methods of volume assessment, biomarkers are inferior, but their importance as a non-invasive modality for prediction in HF management cannot be entirely negated. Further data will be required to validate the use of new biomarkers in the setting of HFrEF and HFpEF, their role in exacerbations and prognosis. Ongoing trials, such as IMPACT-EU, will help to guide our practice in managing acute HF.

LIST OF ABBREVIATIONS

CK-MB

Creatine kinase MB

GDF-15

Growth Differentiation Factor-15

VEGFR

Vascular Endothelial Growth Factor Receptor

MicroRNA

Ribonucleic Acid

MR-proADM

Mid-Regional Pro-Adrenomedullin

TNF-α

Tumor Necrosis Factor-Alpha

BUN

Blood Urea Nitrogen

RDW

Red Cell Distribution Width

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.