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Cardiac marker

Cardiac markers, also referred to as cardiac biomarkers, are endogenous substances such as proteins and enzymes released into the bloodstream in response to myocardial injury, stress, or necrosis, serving as key diagnostic and prognostic tools for conditions like acute coronary syndrome (ACS) and acute myocardial infarction (AMI).^[1]^[2] These biomarkers enable rapid assessment of heart damage, guiding clinical decisions in emergency settings where timely intervention can significantly improve patient outcomes.^[1]^[2] The use of cardiac markers dates back to the mid-20th century, with early reliance on less specific enzymes like aspartate aminotransferase (AST) in the 1950s, evolving to more precise indicators such as creatine kinase-MB (CK-MB) in the 1970s and, ultimately, troponins by the late 1990s, which redefined the diagnostic criteria for myocardial infarction.^[1] High-sensitivity troponin assays, approved in the United States in 2017, have further advanced detection, allowing identification of injury within 2-3 hours of onset with near-100% sensitivity.^[1] This progression reflects ongoing refinements in laboratory techniques and international guidelines from bodies like the American College of Cardiology (ACC) and European Society of Cardiology (ESC).^[2] The primary types of cardiac markers include troponins (I and T), which are the gold standard due to their high cardiac specificity and sensitivity, rising within 2-3 hours, peaking at 24 hours, and remaining elevated for up to two weeks; CK-MB, an earlier marker that peaks at 24 hours but normalizes faster, useful for detecting reinfarction; and myoglobin, an early but non-specific indicator detectable within 1-4 hours.^[1]^[2] Additional markers, such as B-type natriuretic peptide (BNP) for heart failure assessment and ischemia-modified albumin for ischemia detection, expand their utility beyond necrosis to include stress and inflammation evaluation.^[2] Interpretation typically involves measuring levels against the 99th percentile upper reference limit of a healthy population, with elevations indicating myocardial injury, though non-ischemic causes like sepsis or renal failure must be considered.^[1]^[2] In clinical practice, cardiac markers are integral to risk stratification in patients presenting with chest pain, with troponin levels at presentation and 3-6 hours later recommended by ACC/AHA guidelines for suspected ACS, enabling differentiation of low-risk cases for safe discharge.^[2] They also support monitoring treatment efficacy and predicting adverse events, such as a four-fold increase in mortality risk with elevated troponins in non-ST-elevation ACS.^[2] Emerging high-sensitivity assays and point-of-care testing facilitate 24/7 availability with rapid turnaround times of 30-60 minutes, enhancing emergency response protocols.^[1]

Definition and Overview

Definition

Cardiac markers, also known as cardiac biomarkers, are endogenous substances released into the bloodstream from cardiac myocytes in response to myocardial damage, stress, ischemia, or inflammation.^[1] These biomarkers serve as objective indicators of underlying pathological processes affecting the heart, providing measurable evidence of cardiac injury or dysfunction through quantitative analysis in blood samples.^[3] The biological basis for their release involves cellular mechanisms such as necrosis, apoptosis, or reversible injury of cardiomyocytes, which disrupt cell membrane integrity and allow intracellular contents—including proteins, enzymes, and peptides—to leak into the circulation.^[4] In necrosis, cell death leads to uncontrolled membrane rupture and biomarker efflux; apoptosis involves programmed cell death with more controlled release; and reversible injury, such as from transient ischemia, can cause temporary membrane permeability changes without full cell demise.^[5] This leakage reflects the heart's response to stressors, enabling detection of subtle or acute cardiac events that may not yet manifest in overt symptoms. Unlike imaging modalities or electrocardiography (ECG), which assess structural abnormalities or electrical activity, cardiac markers function as biochemical sentinels quantifiable via blood tests, thereby complementing but not supplanting other diagnostic tools in evaluating cardiac health.^[4] Key examples include troponins, which signal myocardial injury upon release from damaged contractile apparatus, and B-type natriuretic peptide (BNP), which indicates ventricular wall strain in response to volume or pressure overload.^[1]^[6] These markers collectively aid in the non-invasive assessment of cardiac status across various clinical contexts.

Historical Development

The development of cardiac markers began in the mid-20th century with the identification of enzymes released during myocardial injury. In 1954, aspartate aminotransferase (AST), then known as serum glutamic oxaloacetic transaminase, was the first biomarker recognized for detecting acute myocardial infarction (AMI), following observations of elevated levels in patients post-infarction by LaDue and colleagues using a spectrophotometric assay.^[7] By 1955, lactate dehydrogenase (LDH) was introduced as another early marker, with Wróblewski and LaDue noting its rise 6-12 hours after AMI onset, peaking at 1-3 days, though its low specificity due to expression in multiple tissues limited its utility.^[8] During the 1960s, LDH isoenzymes, particularly LDH-1 predominant in cardiac tissue, were differentiated to enhance specificity, marking an initial shift toward more targeted diagnostics.^[7] The 1970s and 1980s saw the rise of creatine kinase-MB (CK-MB) as a superior enzyme marker for AMI. Discovered in the 1950s, CK-MB gained widespread clinical use after 1972, when Roe et al. developed zone electrophoresis to separate its cardiac-specific isoenzyme, offering better specificity than AST or LDH.^[7] By the late 1970s, radioimmunoassays for CK-MB were established, and in 1985, the first mass immunoassay further improved sensitivity, allowing detection within 6 hours of symptom onset with approximately 91% sensitivity and specificity.^[8] This era represented a pivotal advancement in biochemical diagnostics for myocardial damage, though CK-MB still suffered from some non-cardiac elevations. The 1990s introduced troponins as transformative cardiac markers, supplanting earlier enzymes. Cardiac troponin I (cTnI) was first assayed via radioimmunoassay in 1987 by Cummins et al., followed by cardiac troponin T (cTnT) via ELISA in 1989 by Katus et al., leveraging their high myocardial specificity as regulatory proteins in contraction.^[7] By 2000, the joint European Society of Cardiology (ESC) and American College of Cardiology (ACC) guidelines redefined AMI diagnosis, establishing troponins as the gold standard biomarker based on elevated levels exceeding the 99th percentile in the context of ischemia.^[9] In parallel, natriuretic peptides emerged for broader cardiac assessment. Brain natriuretic peptide (BNP) was discovered in 1988 by Sudoh et al. from porcine brain extracts, with its human cardiac origin and precursor cDNA cloned by 1989, recognizing its role in volume regulation and release during ventricular stress.^[10] N-terminal pro-BNP (NT-proBNP), a stable fragment, followed in clinical development during the 1990s; by the early 2000s, both were integrated into practice, with FDA approval of BNP assays in 2000 and guideline endorsements for heart failure evaluation by 2006.^[10] From the 2000s onward, high-sensitivity troponin (hs-cTn) assays revolutionized early detection. Introduced around 2010 with enhanced analytical sensitivity detecting concentrations 10-fold lower than conventional assays, hs-cTn enabled rule-out of AMI within hours of presentation.^[11] The 2015 ESC guidelines formalized the 0/1-hour algorithm using hs-cTnT or hs-cTnI for rapid triage, balancing high negative predictive value with efficient rule-in capabilities.^[12] Recent advancements since the 2010s emphasize multi-marker strategies for refined diagnostics. Panels combining hs-cTn with natriuretic peptides or other indicators, as explored in studies from 2016 onward, improved prognostic accuracy and risk stratification in acute coronary syndromes, reflecting a shift toward integrated, algorithm-driven approaches in clinical practice.^[13] Subsequent updates to the universal definition of myocardial infarction in 2012 and 2018 further integrated high-sensitivity troponin assays, emphasizing elevations above the 99th percentile with clinical evidence of ischemia for diagnosis, while distinguishing acute myocardial injury from infarction. As of 2025, these criteria remain in use amid discussions on refinements.^[14]

Clinical Applications

Diagnosis of Acute Coronary Syndromes

Cardiac markers play a central role in the diagnosis of acute coronary syndromes (ACS), particularly in confirming myocardial infarction (MI) according to the Fourth Universal Definition of Myocardial Infarction. This definition requires evidence of acute myocardial injury, detected by a rise and/or fall in cardiac troponin (cTn) values with at least one value exceeding the 99th percentile upper reference limit (URL), occurring in the setting of acute myocardial ischemia, such as symptoms of ischemia, new ischemic ECG changes, or imaging evidence of new loss of viable myocardium.^[15] High-sensitivity troponin assays are the primary marker for this purpose due to their superior sensitivity and specificity in detecting even minor myocardial injury in ACS presentations.^[16] Serial measurements of troponin are essential to identify the dynamic rise and/or fall pattern that distinguishes acute injury from chronic elevations. Guidelines recommend protocols such as the 0/1-hour algorithm using high-sensitivity troponin for rapid rule-out or rule-in of non-ST-elevation ACS, where baseline and 1-hour values below specific assay-derived thresholds allow safe discharge of low-risk patients, while changes exceeding delta thresholds indicate likely MI.^[17] Alternatively, a 0/3-hour protocol is endorsed for settings using conventional or high-sensitivity assays, with repeat testing at 3 hours if initial values are inconclusive, enabling efficient triage in emergency departments.^[16] Although troponin elevations are key, cardiac markers alone are insufficient for ACS diagnosis and must be integrated with clinical symptoms (e.g., chest pain), ECG findings (e.g., ST-segment changes), and imaging (e.g., echocardiography for wall motion abnormalities). This multimodal approach is crucial to differentiate type 1 MI, caused by atherothrombotic plaque disruption leading to coronary occlusion, from type 2 MI, resulting from supply-demand mismatch without acute thrombosis, such as in severe anemia or tachyarrhythmias; both show troponin rise/fall above the 99th percentile URL, but clinical context determines the subtype.^[15] Evidence from major trials supports the incorporation of cardiac markers into risk assessment for ACS confirmation. The GRACE risk score, derived from a large international registry, includes elevated cardiac enzymes (e.g., troponin or CK-MB) as a key variable alongside age, vital signs, and Killip class to predict in-hospital and 6-month mortality, aiding in confirming high-risk ACS presentations. Similarly, TIMI trials have demonstrated that troponin-positive patients with unstable angina/non-ST-elevation MI experience higher event rates, validating the use of markers to confirm and stratify ACS risk in therapeutic decision-making.^[18]

Risk Stratification and Prognosis

Cardiac markers play a crucial role in risk stratification by assessing the likelihood of adverse outcomes in patients with cardiovascular disease, enabling clinicians to tailor therapeutic interventions such as intensified antiplatelet therapy or invasive procedures. Higher peak levels of troponin, particularly high-sensitivity cardiac troponin T (hs-cTnT), have been shown to correlate with larger myocardial infarct size and increased short-term mortality risk in patients with ST-elevation myocardial infarction (STEMI), with non-survivors exhibiting mean peak values around 10,000-12,000 ng/L compared to approximately 4,600 ng/L in survivors.^[19] Similarly, delta changes in troponin levels, reflecting dynamic myocardial injury, independently predict early mortality and unfavorable outcomes post-acute coronary syndrome, with rising patterns conferring a substantially elevated risk compared to stable or falling levels.^[20] Multi-marker strategies enhance prognostic accuracy by integrating cardiac markers with clinical scores, providing a more comprehensive assessment of post-myocardial infarction (MI) risk. For instance, combining troponin with B-type natriuretic peptide (BNP) improves prediction of long-term cardiovascular events beyond troponin alone, as elevated BNP levels alongside troponin indicate concurrent myocardial stress and necrosis.^[21] This approach is particularly valuable when incorporated into the Global Registry of Acute Coronary Events (GRACE) score, where multi-biomarker panels including troponin and BNP refine risk categorization for in-hospital and one-year mortality in non-ST-elevation MI patients.^[22] In patients with stable coronary artery disease (CAD), subtle elevations in cardiac markers can signal ongoing subclinical processes, aiding in the identification of high-risk individuals. Detectable high-sensitivity troponin I (hs-cTnI) levels, even below diagnostic thresholds, are associated with an increased risk of major adverse cardiac events (MACE), independent of traditional risk factors, suggesting underlying silent ischemia or vulnerable plaque instability.^[23] Meta-analyses confirm that such troponin elevations predict cardiovascular mortality and MACE with a hazard ratio of approximately 2.6, highlighting their utility in guiding preventive strategies like statin intensification in this population.^[24] Recent advancements as of 2025 emphasize the integration of inflammatory markers into cardiac risk models to address residual inflammatory risk in atherosclerotic cardiovascular disease (ASCVD). High-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels are now recommended for risk prediction in chronic heart failure and ASCVD, with elevated IL-6 associated with increased MACE risk.^[25] Lipoprotein(a) [Lp(a)], particularly when exceeding 50 mg/dL alongside hs-CRP, further stratifies ASCVD risk in updated calculators like the American College of Cardiology's ASCVD Risk Estimator, prompting targeted therapies such as PCSK9 inhibitors.^[26] These 2025 guideline updates from the American College of Cardiology and European Society of Cardiology underscore multi-marker panels incorporating inflammation for personalized prognosis across cardiovascular spectra.^[27]

Monitoring in Heart Failure and Other Conditions

In heart failure (HF) management, B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) serve as primary biomarkers for monitoring disease progression and therapeutic response. Elevated BNP levels exceeding 100 pg/mL or NT-proBNP levels above 125 pg/mL are indicative of HF, particularly in symptomatic patients, and serial measurements help assess the effectiveness of therapies such as diuretics and angiotensin-converting enzyme inhibitors (ACEi).^[28] These peptides reflect ventricular wall stress and fluid overload, allowing clinicians to guide adjustments in medical therapy to optimize hemodynamic status and prevent decompensation.^[28] For decongestion monitoring during acute HF episodes, a relative reduction of at least 30% in NT-proBNP levels from admission to discharge is associated with improved clinical outcomes, including lower rates of readmission and mortality.^[29] This threshold helps evaluate the success of loop diuretics or ultrafiltration in alleviating congestion, with persistent elevations signaling incomplete resolution and higher risk. The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure recommends routine BNP or NT-proBNP assessment at hospital admission for prognosis and during follow-up to track treatment efficacy in both inpatient and outpatient settings.^[28] Beyond HF, cardiac markers aid in monitoring other non-acute coronary syndrome conditions. In myocarditis, serial troponin measurements detect ongoing myocardial injury and inflammation, with elevations correlating to disease severity and guiding immunosuppressive therapy.^[30] For cardiomyopathy, galectin-3 levels indicate fibrotic remodeling and progression, serving as a prognostic tool independent of ejection fraction.^[31] Post-cardiac surgery, creatine kinase-MB (CK-MB) elevations monitor reperfusion injury or perioperative infarction, with trends informing the need for interventions like anti-ischemic support.^[32] Emerging applications include BNP/NT-proBNP in pulmonary hypertension, where rising levels predict hemodynamic deterioration and response to vasodilators.^[33] Clinical trials underscore the value of biomarker trends in therapy optimization. The PARADIGM-HF trial demonstrated that sacubitril/valsartan treatment led to a median 19% increase in BNP levels alongside a 29% decrease in NT-proBNP over 8-10 weeks, reflecting enhanced natriuretic peptide activity and correlating with reduced HF hospitalizations and cardiovascular death.^[34] These dynamic changes highlight how monitoring guides personalized adjustments in angiotensin receptor-neprilysin inhibitors for better long-term outcomes.

Types of Cardiac Markers

Troponins

Troponins are a family of regulatory proteins integral to cardiac muscle contraction, forming a heterotrimeric complex that includes cardiac troponin C (cTnC), cardiac troponin I (cTnI), and cardiac troponin T (cTnT). This complex binds to tropomyosin on the thin filaments of the sarcomere, modulating the interaction between actin and myosin in response to calcium ions. Specifically, cTnC serves as the calcium-binding subunit that initiates contraction upon binding Ca²⁺, while cTnI acts as the inhibitory subunit that prevents actin-myosin binding in the absence of calcium, and cTnT anchors the complex to tropomyosin. The cardiac-specific isoforms of cTnI and cTnT are expressed exclusively in myocardial cells, distinguishing them from skeletal muscle variants and enabling their use as biomarkers of cardiac injury.^[35]^[36] Upon myocardial injury, troponins are released into the bloodstream from damaged cardiomyocytes, with detectable elevations occurring 2-4 hours after the onset of injury. Levels typically peak around 24 hours post-injury and remain elevated for 7-10 days, providing a prolonged diagnostic window compared to earlier markers. High-sensitivity troponin (hs-cTn) assays enhance this detection, allowing identification of injury within less than 1 hour in many cases through rapid algorithms. The release reflects both reversible and irreversible cellular damage, with cytosolic troponin leaking first followed by structural components.^[37]^[38] Two primary subtypes dominate clinical use: cTnI and cTnT. cTnI is generally more stable in circulation and less influenced by non-cardiac factors, making it the preferred isoform in the United States for routine assays. In contrast, cTnT exhibits a slightly earlier rise following injury and is more commonly elevated in chronic conditions, but its interpretation can be confounded by renal disease due to reduced clearance. Both subtypes offer comparable diagnostic accuracy for acute events, though differences in assay availability and stability guide selection.^[39]^[40] Troponins demonstrate high specificity, ranging from 95-100%, for detecting myocardial injury, surpassing older markers by confirming cardiac tissue damage rather than generalized cellular stress. This specificity allows differentiation of myocardial infarction from non-cardiac causes of symptoms, such as pulmonary embolism or sepsis, although elevations alone do not specify the underlying etiology. According to the 2023 European Society of Cardiology (ESC) guidelines, high-sensitivity troponin is recommended as the universal first-line biomarker for diagnosing acute coronary syndromes, emphasizing its central role in initial evaluation and risk assessment.^[41]^[42]

Creatine Kinase-MB and Other Enzymes

Creatine kinase-MB (CK-MB) is a dimeric isoenzyme composed of M (muscle) and B (brain) subunits, forming part of the creatine kinase family that includes CK-MM (predominantly skeletal muscle), CK-BB (brain and smooth muscle), and CK-MB (primarily cardiac muscle). In the myocardium, CK-MB constitutes approximately 15-30% of total creatine kinase activity, catalyzing the reversible transfer of phosphate between ATP and phosphocreatine to maintain energy homeostasis in high-demand tissues like the heart.^[32] Following acute myocardial infarction (MI), CK-MB is released into the bloodstream due to cardiomyocyte necrosis, with levels rising 4-6 hours after symptom onset, peaking at 12-24 hours, and returning to normal within 48-72 hours. This relatively rapid kinetic profile made CK-MB historically valuable for confirming MI diagnosis and detecting reinfarction, particularly when serial measurements showed recurrent elevations. The relative index, calculated as (CK-MB / total CK) × 100, exceeding 5-6% helps distinguish cardiac from skeletal muscle sources.^[32]^[43] Despite its utility, CK-MB has low specificity for cardiac injury, as elevations can occur from skeletal muscle trauma, rhabdomyolysis, strenuous exercise, myocarditis, cardiac surgery, or even renal failure and hypothyroidism. In contemporary practice, CK-MB serves primarily as an adjunct marker for monitoring post-percutaneous coronary intervention complications or assessing infarct timing, having been largely supplanted by more sensitive and specific troponins.^[32]^[44] Other enzymatic cardiac markers include lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), which were among the earliest biomarkers used for MI detection but are now rarely employed due to nonspecificity. LDH, a tetrameric enzyme with five isoenzymes, features LDH-1 (heart-predominant, composed of four H subunits) that flips the LDH-1/LDH-2 ratio above 1 in MI, reflecting myocardial necrosis. LDH levels rise 12-24 hours post-MI, peak at 2-3 days, and persist for 10-14 days, offering utility in late-presenting cases where shorter-acting markers like CK-MB have normalized. However, LDH lacks cardiac specificity, elevating in hemolysis, liver disease, tumors, or skeletal muscle injury, limiting its diagnostic role.^[45]^[43] AST, an enzyme involved in amino acid metabolism, is present in cardiac, hepatic, skeletal, and renal tissues, releasing into circulation upon cell damage. It rises 6-12 hours after MI, peaks at 24-48 hours, and normalizes in 3-5 days, but its broad tissue distribution causes frequent elevations from noncardiac sources like liver injury or muscle strain. Historically pivotal since 1954 for MI confirmation, AST is now obsolete for routine diagnostics due to these limitations.^[46]^[43]

Natriuretic Peptides

Natriuretic peptides serve as key biomarkers of cardiac stress and volume overload, particularly in the context of heart failure (HF), where they reflect hemodynamic strain on the myocardium. These peptides include B-type natriuretic peptide (BNP), which is primarily synthesized in the cardiac ventricles as a response to increased wall tension, and its inactive N-terminal fragment, NT-proBNP. Atrial natriuretic peptide (ANP), produced mainly in the atria, is less commonly measured as a cardiac marker due to its shorter half-life and lower diagnostic utility compared to BNP and NT-proBNP.^[47]^[6]^[48] The synthesis and release of natriuretic peptides are triggered by myocardial wall stretch, a physiological response to ventricular volume expansion or pressure overload. Upon release, BNP binds to particulate guanylyl cyclase receptors (NPR-A) on target cells, activating cyclic guanosine monophosphate (cGMP) production, which promotes natriuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system to counteract fluid retention. BNP has a short plasma half-life of approximately 20 minutes, primarily due to clearance by neutral endopeptidase and receptor-mediated uptake, whereas NT-proBNP, lacking hormonal activity, has a longer half-life of about 120 minutes, making it more stable for measurement in clinical settings.^[47]^[6]^[49] In HF diagnosis, natriuretic peptide levels provide high negative predictive value for ruling out the condition, with thresholds adjusted for age and renal function to enhance accuracy. For NT-proBNP, a level below 300 pg/mL effectively rules out HF in both acute and non-acute settings per ESC guidelines. Age-adjusted cutoffs—such as 450 pg/mL for patients under 50 years, 900 pg/mL for those 50-75 years, and 1800 pg/mL for those over 75—have been proposed (e.g., from the PRIDE study) for ruling out acute HF to improve sensitivity in older patients, while higher levels such as >1250 pg/mL support ruling in acute HF and >2000 pg/mL indicate very high likelihood when combined with clinical evaluation; renal impairment necessitates caution in interpretation, as NT-proBNP clearance is reduced in chronic kidney disease.^[50]^[51] Similarly, BNP levels below 100 pg/mL in acute dyspnea presentations have strong negative predictive value for excluding HF.^[52]^[47] Although highly specific for cardiac stress in HF, natriuretic peptides can be elevated in non-cardiac conditions such as obesity (due to reduced clearance) and renal failure (from impaired excretion), which may confound interpretation. Their utility lies in distinguishing cardiac from pulmonary causes of dyspnea, as levels are markedly higher in HF-related cases compared to primary respiratory disorders. The seminal Breathing Not Properly (BNP) multinational trial, involving 1586 emergency department patients with acute dyspnea, demonstrated that a BNP cutoff of 100 pg/mL achieved 90% sensitivity and 76% specificity for HF diagnosis, outperforming clinical judgment alone and establishing natriuretic peptides as a cornerstone for rapid ED assessment.^[47]^[53]

Emerging Biomarkers

Emerging biomarkers in cardiac diagnostics represent a shift toward more precise, multifaceted approaches to identifying cardiovascular risk and disease progression beyond established markers. These investigational tools, including inflammatory indicators, fibrosis-related proteins, and multi-omics signatures, aim to capture underlying pathological processes such as inflammation, tissue remodeling, and epigenetic alterations, potentially enabling earlier intervention and personalized strategies. Recent advancements, particularly in 2025, have highlighted their promise in refining risk prediction models, though widespread clinical adoption requires further validation through large-scale trials. Inflammatory markers like high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) have gained attention for their role in assessing atherosclerosis risk. Elevated hs-CRP levels are associated with increased incidence of atherosclerotic cardiovascular events, providing prognostic value independent of traditional lipid profiles. Similarly, IL-6, an upstream cytokine driving inflammation, demonstrates a stronger correlation with atherosclerotic outcomes, heart failure, and mortality compared to hs-CRP in asymptomatic populations. Lipoprotein(a [Lp(a)] serves as an independent predictor of coronary heart disease (CHD), with 2025 American Heart Association (AHA) analyses confirming its additive risk beyond conventional factors like smoking and diabetes, enhancing short-term atherosclerotic cardiovascular disease (ASCVD) prediction models. Markers of fibrosis and remodeling, such as galectin-3 and soluble ST2 (sST2), offer insights into myocardial structural changes and heart failure (HF) progression. Galectin-3, a beta-galactoside-binding protein, is linked to cardiac fibrosis and independently predicts incident HF and mortality, with higher levels correlating to adverse remodeling post-myocardial infarction. sST2, a decoy receptor for interleukin-33, reflects myocardial stress and fibrosis, providing independent prognostic value for HF outcomes and cardiovascular death, particularly in chronic settings where it outperforms natriuretic peptides in risk stratification. Epigenetic and multi-omics approaches have unveiled novel biomarkers, including DNA methylation sites and microRNAs, for long-term CVD risk prediction. In 2025 discoveries, over 100 new blood-based epigenetic methylation markers were identified as prospective indicators of cardiovascular health, with 609 sites significantly associated with future events, enabling early risk assessment up to 20 years in advance. Among microRNAs, miR-208 exhibits high specificity for myocardial infarction (MI), with circulating levels rising rapidly post-injury and achieving pooled sensitivity of 83% and specificity of 97% for early diagnosis, distinguishing cardiac damage from other conditions. Multi-marker panels integrating these biomarkers with artificial intelligence (AI) are advancing personalized cardiac risk assessment. AI-driven models combining inflammatory, fibrosis, and epigenetic markers improve prediction accuracy for CVD events, reclassifying risk in diverse populations and incorporating factors like Lp(a) for tailored interventions. Notably, 2025 studies have linked elevated cardiac biomarkers to increased cancer incidence, revealing overlaps in cardio-oncologic pathways and prompting multi-marker strategies to address shared risks in patients with comorbid conditions. Despite their potential, emerging biomarkers face challenges in validation and clinical integration. For instance, soluble urokinase plasminogen activator receptor (suPAR), a marker of endothelial dysfunction, shows promise in predicting cardiovascular mortality and microvascular impairment but requires further prospective studies to confirm its utility across diverse cohorts and rule out confounders like renal function. Ongoing research emphasizes the need for standardized assays and longitudinal data to establish thresholds and cost-effectiveness before routine use.

Measurement and Assays

Laboratory Techniques

Immunoassays represent the primary analytical method for detecting cardiac markers in clinical laboratories, leveraging antigen-antibody interactions to quantify biomarkers such as troponins and natriuretic peptides.^[54] Sandwich enzyme-linked immunosorbent assay (ELISA) is commonly employed for troponin measurement, where capture antibodies bind the target analyte, followed by detection with enzyme-linked secondary antibodies to produce a colorimetric signal proportional to biomarker concentration.^[55] For high-sensitivity cardiac troponin (hs-cTn) assays, chemiluminescent immunoassays predominate, offering enhanced detection limits below 5 ng/L through light-emitting reactions triggered by enzyme-substrate interactions, enabling earlier identification of myocardial injury.^[56] Point-of-care testing (POCT) devices facilitate rapid assessment of cardiac markers like troponin and B-type natriuretic peptide (BNP) directly in emergency departments, providing results within 15-20 minutes to expedite triage.^[57] These portable systems, often based on lateral flow or electrochemical principles, support immediate clinical decision-making; current high-sensitivity POCT assays have limits of detection of 1-5 ng/L, comparable to centralized laboratory immunoassays, though some non-hs systems may exhibit reduced sensitivity and higher LOD, potentially missing low-level elevations.^[58] The evolution toward high-sensitivity troponin assays accelerated in the 2010s, driven by the need for earlier and more precise myocardial infarction diagnosis, with widespread adoption of platforms meeting International Federation of Clinical Chemistry (IFCC) criteria: a coefficient of variation ≤10% at the 99th percentile upper reference limit and the ability to measure troponin in over 50% of a healthy reference population.^[59] This shift, beginning around 2007-2010, transformed hs-cTn into the gold standard biomarker, allowing detection of concentrations 10-fold lower than prior generations and improving risk stratification in low-risk cohorts.^[60] Standardization efforts for cardiac troponin assays have addressed inter-vendor variability, as measurements can differ by 2- to 5-fold across platforms; for instance, Roche Diagnostics and Abbott assays for cardiac troponin I (cTnI) show discrepancies in calibration and epitope recognition, complicating result comparability.^[61] Mass spectrometry serves as the reference method for absolute quantification, providing traceable and isoform-specific measurements without immunoassay biases, and has informed IFCC reference materials to harmonize commercial assays.^[62] By 2025, advances in biosensor technologies have enabled multiplexed panels for simultaneous detection of multiple cardiac markers, integrating electrochemical or surface-enhanced Raman scattering (SERS) platforms with nanomaterials like graphene for sub-picomolar sensitivity and point-of-care compatibility.^[63] These innovations, including AI-enhanced data processing, support comprehensive profiling of troponins, natriuretic peptides, and emerging biomarkers in a single assay, enhancing diagnostic efficiency in resource-limited settings.^[64]

Timing and Sampling Considerations

The timing of sample collection for cardiac markers is crucial to capture peak elevations and enable accurate interpretation, particularly in acute settings. For troponins in suspected acute coronary syndromes (ACS), measurement should occur immediately at patient presentation (0 hours), followed by a serial sample at 1 hour to assess dynamic changes using high-sensitivity assays, as recommended by the European Society of Cardiology (ESC) 2023 guidelines.^[65] This 0/1-hour algorithm facilitates rapid rule-out or rule-in of myocardial infarction by evaluating absolute or relative delta changes in troponin levels. In contrast, B-type natriuretic peptide (BNP) sampling for chronic heart failure can be performed at any time during stable outpatient evaluation, but in acute decompensation, it is best obtained promptly upon presentation to guide diagnosis and therapy initiation.^[66] Venous blood samples are the standard for cardiac marker analysis, with serum or heparinized plasma preferred for troponins and BNP due to compatibility with most commercial assays and stability during transport. For creatine kinase-MB (CK-MB), serum or plasma samples must be handled carefully to prevent hemolysis, as red blood cell rupture can release adenylate kinase, falsely elevating CK-MB activity and interfering with results. Samples should be collected using appropriate anticoagulants like heparin or EDTA where specified, centrifuged promptly, and stored at 2–8°C if not analyzed immediately to maintain integrity.^[1]^[67] Serial sampling frequency varies by clinical context and marker. In ACS, the ESC endorses the 0/1-hour rule for troponins, with an optional third sample at 3 hours if initial results fall in an observe zone, allowing delta calculations to detect rises or falls exceeding assay-specific thresholds (e.g., absolute change >5–10 ng/L). For heart failure monitoring, BNP or NT-proBNP assessments typically include a baseline measurement at admission, a follow-up near discharge, and periodic outpatient checks (e.g., every few weeks to months) to track treatment response and risk of readmission. These intervals help quantify reductions in natriuretic peptides, which correlate with improved outcomes.^[66] External factors can influence marker levels independent of pathology, necessitating consideration of patient context during sampling. BNP exhibits circadian variations, with levels peaking at night and potentially 20–30% higher in evening or nighttime presentations compared to daytime, which may enhance diagnostic accuracy but requires consistent timing for serial comparisons. Post-exercise elevations are common across markers; troponins can rise transiently after strenuous activity due to increased cardiac workload, while CK-MB may increase from skeletal muscle sources, underscoring the need to query recent physical exertion before interpretation. The ESC 2023 guidelines emphasize incorporating delta calculations in serial troponin sampling to distinguish acute ischemic changes from such physiologic influences.^[65]^[68]^[69]

Interpretation and Limitations

Reference Ranges and Cutoffs

Reference ranges and cutoffs for cardiac markers are essential for distinguishing normal physiological variation from pathological elevations, particularly in diagnosing acute coronary syndromes and heart failure. These thresholds are typically established as the 99th percentile upper reference limit (URL) in healthy populations, with adjustments for demographic factors to enhance diagnostic accuracy. For high-sensitivity cardiac troponin I (hs-cTnI), sex-specific 99th percentile URLs are recommended due to differences in cardiac mass between males and females, which influence baseline troponin release. In the Abbott ARCHITECT assay, the 99th percentile URL is less than 16 ng/L for women and less than 34 ng/L for men.^[70] Similarly, for high-sensitivity cardiac troponin T (hs-cTnT), the Roche Elecsys assay uses sex-specific thresholds of 14 ng/L for women and 22 ng/L for men, with an overall cutoff of 14 ng/L in many settings.^[71] In September 2025, Roche introduced a sixth-generation hs-cTnT assay with an overall 99th percentile URL of 27 ng/L, incorporating sex-specific values.^[72] Creatine kinase-MB (CK-MB) cutoffs rely on both absolute levels and relative indices to confirm cardiac origin. Normal absolute CK-MB is typically less than 5 ng/mL, while a relative index exceeding 2.5% of total CK activity indicates myocardial injury rather than skeletal muscle sources.^[73]^[74] Natriuretic peptides, such as NT-proBNP, use cutoffs for ruling out heart failure in ambulatory settings. According to 2021 European Society of Cardiology guidelines, NT-proBNP levels below 125 pg/mL effectively exclude heart failure in non-acute settings. For BNP, a cutoff of less than 100 pg/mL is commonly used for exclusion. Age-stratified cutoffs apply in acute settings, such as NT-proBNP below 300 pg/mL for patients under 50 years, below 450 pg/mL for ages 50-75, and below 900 pg/mL for those over 75.^[50] Adjustments to these cutoffs are necessary for comorbidities affecting marker levels. Reduced renal function, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m², elevates NT-proBNP and BNP concentrations due to decreased clearance, necessitating higher diagnostic thresholds.^[75] Conversely, obesity lowers BNP and NT-proBNP levels, potentially requiring adjusted cutoffs to avoid underdiagnosis of heart failure.^[76] Guideline evolution has refined these parameters for greater precision. The 2017 FDA approval of the first high-sensitivity troponin assay (Roche hs-cTnT) mandated sex-specific 99th percentile URLs in healthy reference populations to improve sensitivity for myocardial injury.^[77] Emerging studies as of 2023 suggest ethnicity-specific variations in troponin URLs, such as lower 99th percentiles in some Asian populations compared to Caucasian cohorts, but international consensus statements have not yet incorporated routine tailored thresholds in diverse settings.^[78]

Sources of Variability and Errors

Cardiac biomarkers such as troponins and natriuretic peptides can exhibit variability due to biological factors unrelated to primary cardiac ischemia, leading to non-specific elevations that complicate interpretation. For instance, troponin levels may rise in pulmonary embolism due to right ventricular strain, in sepsis from systemic inflammation and myocardial stress, and in renal failure owing to reduced clearance and uremic cardiomyopathy.^[79] Similarly, B-type natriuretic peptide (BNP) elevations occur in chronic obstructive pulmonary disease (COPD) as a result of hypoxemia-induced myocardial stretch and cor pulmonale.^[10] These confounders highlight the need to integrate clinical context to distinguish cardiac-specific from extracardiac sources. Analytical errors in biomarker assays further contribute to variability and potential misdiagnosis. Heterophile antibodies can interfere with immunoassays for troponins and BNP, producing false-positive results by cross-linking capture and detection antibodies.^[80] High-sensitivity cardiac troponin (hs-cTn) assays are particularly susceptible to lot-to-lot variability, where differences in reagent batches lead to inconsistent measurements exceeding 10-20% coefficient of variation, affecting serial comparisons.^[81] Pre- and post-analytical phases introduce additional sources of error through handling and patient-related factors. Delayed sample processing can artificially elevate creatine kinase (CK) levels due to ongoing enzymatic activity in vitro, potentially mimicking acute injury.^[82] Exercise or skeletal muscle trauma induces releases of myoglobin and CK-MB, causing transient elevations that overlap with cardiac patterns and necessitate differentiation via isoform analysis or timing.^[83] False-negative results pose risks, particularly in early presentations or chronic conditions. Patients arriving shortly after symptom onset may have undetectable troponin rises, as levels typically peak 6-12 hours post-event, underscoring the value of serial testing.^[84] In individuals with chronic kidney disease or stable heart failure, baseline elevations can mask acute changes, requiring delta assessments over fixed cutoffs for accurate detection.^[85] To mitigate these variabilities, current guidelines stress clinical correlation alongside biomarker results, advising against reliance on isolated values.^[42] A multi-marker approach, combining troponins with BNP or imaging, enhances specificity and reduces error rates by addressing complementary pathophysiological pathways.^[86]

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