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Cardiac marker
Kinetics of cardiac markers Troponin and CK-MB in myocardial infarction with or without reperfusion treatment.
LOINC58260-1

Cardiac markers are biomarkers measured to evaluate heart function. They can be useful in the early prediction or diagnosis of disease.[1] Although they are often discussed in the context of myocardial infarction, other conditions can lead to an elevation in cardiac marker level.[2][3]

Cardiac markers are used for the diagnosis and risk stratification of patients with chest pain and suspected acute coronary syndrome and for management and prognosis in patients with diseases like acute heart failure.

Most of the early markers identified were enzymes, and as a result, the term "cardiac enzymes" is sometimes used. However, not all of the markers currently used are enzymes. For example, in formal usage, troponin would not be listed as a cardiac enzyme.[4]

Applications of measurement

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Measuring cardiac biomarkers can be a step toward making a diagnosis for a condition. Whereas cardiac imaging often confirms a diagnosis, simpler and less expensive cardiac biomarker measurements can advise a physician whether more complicated or invasive procedures are warranted. In many cases medical societies advise doctors to make biomarker measurements an initial testing strategy especially for patients at low risk of cardiac death.[5][6]

Many acute cardiac marker IVD products are targeted at nontraditional markets, e.g., the hospital ER instead of traditional hospital or clinical laboratory environments. Competition in the development of cardiac marker diagnostic products and their expansion into new markets is intense.[7]

Recently, the intentional destruction of myocardium by alcohol septal ablation has led to the identification of additional potential markers.[8]

Types

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Types of cardiac markers include the following:

Test Sensitivity and specificity Approximate peak Description
Troponin test The most sensitive and specific test for myocardial damage. Because it has increased specificity compared with CK-MB, troponin is composed of 3 proteins- Troponin C, Cardic troponin I, and Cardiac troponin T. Troponin I especially has a high affinity for myocardial injury. 12 hours Troponin is released during MI from the cytosolic pool of the myocytes. Its subsequent release is prolonged with degradation of actin and myosin filaments. Isoforms of the protein, T and I, are specific to myocardium. Differential diagnosis of troponin elevation includes acute infarction, severe pulmonary embolism causing acute right heart overload, heart failure, myocarditis. Troponins can also calculate infarct size but the peak must be measured in the 3rd day. After myocyte injury, troponin is released in 2–4 hours and persists for up to 7 days.

Normal value are - Troponin I <0.3 ng/ml and Troponin T <0.2 ng/ml. In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).[2]

Creatine Kinase (CK-MB) test It is relatively specific when skeletal muscle damage is not present. 10–24 hours The CK-MB isoform of creatine kinase is expressed in heart muscle. It resides in the cytosol and facilitates movement of high energy phosphates into and out of mitochondria. Since it has a short duration, it cannot be used for late diagnosis of acute MI but can be used to suggest infarct extension if levels rise again. This is usually back to normal within 2–3 days. Normal range - 2-6 ng/ml
Lactate dehydrogenase (LDH) LDH is not as specific as troponin. 72 hours Lactate dehydrogenase catalyses the conversion of pyruvate to lactate. LDH-1 isozyme is normally found in the heart muscle and LDH-2 is found predominantly in blood serum. A high LDH-1 level to LDH-2 suggest MI. LDH levels are also high in tissue breakdown or hemolysis. It can mean cancer, meningitis, encephalitis, or HIV. This is usually back to normal 10–14 days.
Aspartate transaminase (AST) This was the first used.[9] It is not specific for heart damage, and it is also one of the liver transaminases.
Myoglobin (Mb) low specificity for myocardial infarction 2 hours Myoglobin is used less than the other markers. Myoglobin is the primary oxygen-carrying pigment of muscle tissue. It is high when muscle tissue is damaged but it lacks specificity. It has the advantage of responding very rapidly,[10] rising and falling earlier than CK-MB or troponin. It also has been used in assessing reperfusion after thrombolysis.[11]
Ischemia-modified albumin (IMA) low specificity IMA can be detected via the albumin cobalt binding (ACB) test, a limited available FDA approved assay. Myocardial ischemia alters the N-terminus of albumin reducing the ability of cobalt to bind to albumin. IMA measures ischemia in the blood vessels and thus returns results in minutes rather than traditional markers of necrosis that take hours. ACB test has low specificity therefore generating high number of false positives and must be used in conjunction with typical acute approaches such as ECG and physical exam. Additional studies are required.
Pro-brain natriuretic peptide This is increased in patients with heart failure. It has been approved as a marker for acute congestive heart failure. Patients with < 80 have a much higher rate of symptom-free survival within a year. Generally, pt with CHF will have > 100. In patients with non-severe asymptomatic aortic valve stenosis, increased age- and sex-adjusted N-terminal pro-brain natriuretic peptide (NT-proBNP) levels alone and combined with a 50% or greater increase from baseline had been found associated with increased event rates of aortic valve stenosis related events (cardiovascular death, hospitalization with heart failure due to progression of aortic valve stenosis, or aortic valve replacement surgery).[3]
Glycogen phosphorylase isoenzyme BB 0.854 and 0.767[12] 7 hours

Glycogen phosphorylase isoenzyme BB (abbreviation: GPBB) is one of the three isoforms of glycogen phosphorylase. This isoform of the enzyme exists in cardiac (heart) and brain tissue. Because of the blood–brain barrier, GP-BB can be seen as being specific to heart muscle. GP-BB is one of the "new cardiac markers" which are considered to improve early diagnosis in acute coronary syndrome. During the process of ischemia, GP-BB is converted into a soluble form and is released into the blood. A rapid rise in blood levels can be seen in myocardial infarction and unstable angina. GP-BB is elevated 1–3 hours after process of ischemia.

Limitations

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Reference ranges for blood tests, measured in units, including several cardiac markers.

Depending on the marker, it can take between 2 and 24 hours for the level to increase in the blood. Additionally, determining the levels of cardiac markers in the laboratory - like many other lab measurements - takes substantial time. Cardiac markers are therefore not useful in diagnosing a myocardial infarction in the acute phase. The clinical presentation and results from an ECG are more appropriate in the acute situation.[citation needed]

However, in 2010, research at the Baylor College of Medicine revealed that, using diagnostic nanochips and a swab of the cheek, cardiac biomarker readings from saliva can, with the ECG readings, determine within minutes whether someone is likely to have had a heart attack[citation needed].

Comparison of cardiac markers over time
  • Comparison of cardiac marker in the first hours after chestpain onset and the relative concentration.
    Comparison of cardiac marker in the first hours after chestpain onset and the relative concentration.
  • Comparison of cardiac marker in the first hours after chestpain onset and the multiples of the cutoff.
    Comparison of cardiac marker in the first hours after chestpain onset and the multiples of the cutoff.
  • Kinetics of cardiac markers in myocardial infarction with or without reperfusion treatment.
    Kinetics of cardiac markers in myocardial infarction with or without reperfusion treatment.

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cardiac marker

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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 , serving as key diagnostic and prognostic tools for conditions like (ACS) and acute (AMI). These biomarkers enable rapid assessment of heart damage, guiding clinical decisions in emergency settings where timely intervention can significantly improve patient outcomes. 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, by the late 1990s, which redefined the diagnostic criteria for . High-sensitivity assays, approved in 2017, have further advanced detection, allowing identification of injury within 2-3 hours of onset with near-100% sensitivity. This progression reflects ongoing refinements in techniques and international guidelines from bodies like the (ACC) and (ESC). 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 , an early but non-specific indicator detectable within 1-4 hours. 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 evaluation. Interpretation typically involves measuring levels against the 99th percentile upper reference limit of a healthy , with elevations indicating myocardial , though non-ischemic causes like or renal failure must be considered. In , cardiac markers are integral to risk stratification in patients presenting with , with 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. 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. Emerging high-sensitivity assays and facilitate 24/7 availability with rapid turnaround times of 30-60 minutes, enhancing emergency response protocols.

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 . 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. The biological basis for their release involves cellular mechanisms such as , , or reversible injury of cardiomyocytes, which disrupt integrity and allow intracellular contents—including proteins, enzymes, and peptides—to leak into the circulation. In , cell death leads to uncontrolled membrane rupture and efflux; involves with more controlled release; and reversible injury, such as from transient ischemia, can cause temporary membrane permeability changes without full cell demise. 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 (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. 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. 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 recognized for detecting acute (AMI), following observations of elevated levels in patients post-infarction by LaDue and colleagues using a spectrophotometric . By 1955, (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. During the , LDH isoenzymes, particularly LDH-1 predominant in cardiac tissue, were differentiated to enhance specificity, marking an initial shift toward more targeted diagnostics. 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. 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. 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 in by Cummins et al., followed by cardiac (cTnT) via in 1989 by Katus et al., leveraging their high myocardial specificity as regulatory proteins in contraction. By 2000, the joint (ESC) and (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. 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. 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. From the 2000s onward, high-sensitivity (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. The 2015 ESC guidelines formalized the 0/1-hour algorithm using hs-cTnT or hs-cTnI for rapid , balancing high negative predictive value with efficient rule-in capabilities. Recent advancements since the 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. Subsequent updates to the universal definition of in 2012 and 2018 further integrated high-sensitivity assays, emphasizing elevations above the 99th percentile with clinical evidence of ischemia for diagnosis, while distinguishing acute myocardial injury from . As of 2025, these criteria remain in use amid discussions on refinements.

Clinical Applications

Diagnosis of Acute Coronary Syndromes

Cardiac markers play a central role in the of acute coronary syndromes (ACS), particularly in confirming (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 (cTn) values with at least one value exceeding the 99th percentile upper reference limit (), 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. High-sensitivity assays are the primary marker for this purpose due to their superior in detecting even minor myocardial injury in ACS presentations. Serial measurements of 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 using high-sensitivity 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. 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 in departments. Although elevations are key, cardiac markers alone are insufficient for ACS diagnosis and must be integrated with clinical symptoms (e.g., ), ECG findings (e.g., ST-segment changes), and (e.g., for wall motion abnormalities). This multimodal approach is crucial to differentiate type 1 MI, caused by atherothrombotic plaque disruption leading to , from type 2 MI, resulting from supply-demand mismatch without acute , such as in severe or tachyarrhythmias; both show rise/fall above the 99th percentile URL, but clinical context determines the subtype. Evidence from major trials supports the incorporation of cardiac markers into for ACS confirmation. The GRACE risk score, derived from a large international registry, includes elevated cardiac enzymes (e.g., or CK-MB) as a key variable alongside age, vital signs, and to predict in-hospital and 6-month mortality, aiding in confirming high-risk ACS presentations. Similarly, trials have demonstrated that -positive patients with /non-ST-elevation MI experience higher event rates, validating the use of markers to confirm and stratify ACS risk in therapeutic decision-making.

Risk Stratification and Prognosis

Cardiac markers play a crucial role in risk stratification by assessing the likelihood of adverse outcomes in patients with , enabling clinicians to tailor therapeutic interventions such as intensified antiplatelet therapy or invasive procedures. Higher peak levels of , particularly high-sensitivity cardiac (hs-cTnT), have been shown to correlate with larger myocardial infarct size and increased short-term mortality in patients with ST-elevation (STEMI), with non-survivors exhibiting mean peak values around 10,000-12,000 ng/L compared to approximately 4,600 ng/L in survivors. Similarly, delta changes in levels, reflecting dynamic myocardial injury, independently predict early mortality and unfavorable outcomes post-acute coronary syndrome, with rising patterns conferring a substantially elevated compared to stable or falling levels. Multi-marker strategies enhance prognostic accuracy by integrating cardiac markers with clinical scores, providing a more comprehensive assessment of post-myocardial (MI) risk. For instance, combining 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 . 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. In patients with stable (CAD), subtle elevations in cardiac markers can signal ongoing subclinical processes, aiding in the identification of high-risk individuals. Detectable high-sensitivity (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 instability. Meta-analyses confirm that such elevations predict cardiovascular mortality and MACE with a of approximately 2.6, highlighting their utility in guiding preventive strategies like intensification in this population. Recent advancements as of 2025 emphasize the integration of inflammatory markers into cardiac risk models to address residual inflammatory risk in atherosclerotic (ASCVD). High-sensitivity (hs-CRP) and interleukin-6 (IL-6) levels are now recommended for risk prediction in chronic and ASCVD, with elevated IL-6 associated with increased MACE risk. Lipoprotein(a) [Lp(a)], particularly when exceeding 50 mg/dL alongside hs-CRP, further stratifies ASCVD risk in updated calculators like the 's ASCVD Risk Estimator, prompting targeted therapies such as inhibitors. These 2025 guideline updates from the and underscore multi-marker panels incorporating for personalized prognosis across cardiovascular spectra.

Monitoring in Heart Failure and Other Conditions

In (HF) management, B-type (BNP) and N-terminal pro-B-type (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 inhibitors (ACEi). These peptides reflect ventricular wall stress and fluid overload, allowing clinicians to guide adjustments in medical therapy to optimize hemodynamic status and prevent . 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. This threshold helps evaluate the success of or in alleviating congestion, with persistent elevations signaling incomplete resolution and higher risk. The 2022 AHA/ACC/HFSA Guideline for the Management of recommends routine BNP or NT-proBNP assessment at hospital admission for and during follow-up to track treatment in both inpatient and outpatient settings. Beyond HF, cardiac markers aid in monitoring other non-acute coronary syndrome conditions. In , serial measurements detect ongoing myocardial injury and , with elevations correlating to disease severity and guiding immunosuppressive . For , galectin-3 levels indicate fibrotic remodeling and progression, serving as a prognostic tool independent of . Post-cardiac , creatine kinase-MB (CK-MB) elevations monitor or perioperative , with trends informing the need for interventions like anti-ischemic support. Emerging applications include BNP/NT-proBNP in , where rising levels predict hemodynamic deterioration and response to vasodilators. Clinical trials underscore the value of biomarker trends in therapy optimization. The PARADIGM-HF trial demonstrated that treatment led to a median 19% increase in BNP levels alongside a 29% decrease in NT-proBNP over 8-10 weeks, reflecting enhanced activity and correlating with reduced HF hospitalizations and cardiovascular death. 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 contraction, forming a heterotrimeric complex that includes cardiac (cTnC), cardiac (cTnI), and cardiac (cTnT). This complex binds to on the thin filaments of the , modulating the interaction between and 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 variants and enabling their use as biomarkers of cardiac . Upon myocardial injury, s 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 (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 leaking first followed by structural components. 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. 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.

Creatine Kinase-MB and Other Enzymes

Creatine kinase-MB (CK-MB) is a dimeric isoenzyme composed of M (muscle) and B () subunits, forming part of the family that includes CK-MM (predominantly ), CK-BB ( and ), and CK-MB (primarily ). In the myocardium, CK-MB constitutes approximately 15-30% of total activity, catalyzing the reversible transfer of phosphate between ATP and to maintain in high-demand tissues like the heart. Following acute (MI), CK-MB is released into the bloodstream due to cardiomyocyte , 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 sources. Despite its utility, CK-MB has low specificity for cardiac injury, as elevations can occur from trauma, , strenuous exercise, , , or even renal failure and . 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. 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. AST, an involved in , is present in cardiac, hepatic, skeletal, and renal tissues, releasing into circulation upon . 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 or muscle strain. Historically pivotal since 1954 for MI confirmation, AST is now obsolete for routine diagnostics due to these limitations.

Natriuretic Peptides

Natriuretic peptides serve as key biomarkers of cardiac stress and , particularly in the context of (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 and lower diagnostic utility compared to BNP and NT-proBNP. 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 (cGMP) production, which promotes , , 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 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. In HF diagnosis, 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 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 . Similarly, BNP levels below 100 pg/mL in acute dyspnea presentations have strong negative predictive value for excluding HF. Although highly specific for cardiac stress in HF, natriuretic peptides can be elevated in non-cardiac conditions such as (due to reduced clearance) and renal failure (from impaired ), 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 , outperforming clinical judgment alone and establishing natriuretic peptides as a cornerstone for rapid ED assessment.

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 , 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 (hs-CRP) and interleukin-6 (IL-6) have gained attention for their role in assessing 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, , and mortality compared to hs-CRP in populations. [Lp(a)] serves as an independent predictor of coronary heart disease (CHD), with 2025 American (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 and soluble ST2 (sST2), offer insights into myocardial structural changes and (HF) progression. , a beta-galactoside-binding protein, is linked to cardiac 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 , 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 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 up to 20 years in advance. Among microRNAs, miR-208 exhibits high specificity for (MI), with circulating levels rising rapidly post-injury and achieving pooled sensitivity of 83% and specificity of 97% for early , distinguishing cardiac damage from other conditions. Multi-marker panels integrating these biomarkers with (AI) are advancing personalized cardiac . AI-driven models combining inflammatory, , 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 plasminogen activator receptor (suPAR), a marker of , 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 s and natriuretic peptides. Sandwich is commonly employed for 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. For high-sensitivity cardiac (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. Point-of-care testing (POCT) devices facilitate rapid assessment of cardiac markers like and B-type natriuretic peptide (BNP) directly in emergency departments, providing results within 15-20 minutes to expedite . 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 immunoassays, though some non-hs systems may exhibit reduced sensitivity and higher LOD, potentially missing low-level elevations. 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 (IFCC) criteria: a ≤10% at the 99th upper reference limit and the ability to measure in over 50% of a healthy reference population. This shift, beginning around 2007-2010, transformed hs-cTn into the gold standard , allowing detection of concentrations 10-fold lower than prior generations and improving stratification in low-risk cohorts. Standardization efforts for cardiac assays have addressed inter-vendor variability, as measurements can differ by 2- to 5-fold across platforms; for instance, Diagnostics and Abbott assays for cardiac (cTnI) show discrepancies in calibration and recognition, complicating result comparability. serves as the reference method for absolute quantification, providing traceable and isoform-specific measurements without biases, and has informed IFCC reference materials to harmonize commercial assays. By 2025, advances in technologies have enabled multiplexed panels for simultaneous detection of multiple cardiac markers, integrating electrochemical or surface-enhanced (SERS) platforms with like for sub-picomolar sensitivity and point-of-care compatibility. These innovations, including AI-enhanced data processing, support comprehensive profiling of troponins, natriuretic peptides, and emerging biomarkers in a single , enhancing diagnostic efficiency in resource-limited settings.

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 2023 guidelines. This 0/1-hour algorithm facilitates rapid rule-out or rule-in of by evaluating absolute or relative delta changes in 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 , it is best obtained promptly upon presentation to guide diagnosis and therapy initiation. 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 , as red blood cell rupture can release , falsely elevating CK-MB activity and interfering with results. Samples should be collected using appropriate anticoagulants like or EDTA where specified, centrifuged promptly, and stored at 2–8°C if not analyzed immediately to maintain integrity. 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 monitoring, BNP or NT-proBNP assessments typically include a baseline 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. 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 sources, underscoring the need to query recent physical exertion before interpretation. The ESC 2023 guidelines emphasize incorporating delta calculations in serial sampling to distinguish acute ischemic changes from such physiologic influences.

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 . These thresholds are typically established as the 99th upper reference limit () in healthy populations, with adjustments for demographic factors to enhance diagnostic accuracy. For high-sensitivity cardiac (hs-cTnI), sex-specific 99th are recommended due to differences in cardiac mass between males and females, which influence baseline troponin release. In the Abbott , the 99th is less than 16 ng/L for women and less than 34 ng/L for men. Similarly, for high-sensitivity cardiac (hs-cTnT), the Elecsys uses sex-specific thresholds of 14 ng/L for women and 22 ng/L for men, with an overall of 14 ng/L in many settings. In September 2025, introduced a sixth-generation hs-cTnT with an overall 99th of 27 ng/L, incorporating sex-specific values. 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 sources. Natriuretic peptides, such as NT-proBNP, use cutoffs for ruling out in ambulatory settings. According to 2021 guidelines, NT-proBNP levels below 125 pg/mL effectively exclude 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. Adjustments to these cutoffs are necessary for comorbidities affecting marker levels. Reduced renal function, defined as estimated (eGFR) below 60 mL/min/1.73 m², elevates NT-proBNP and BNP concentrations due to decreased clearance, necessitating higher diagnostic thresholds. Conversely, lowers BNP and NT-proBNP levels, potentially requiring adjusted cutoffs to avoid underdiagnosis of . 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 . Emerging studies as of 2023 suggest ethnicity-specific variations in 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.

Sources of Variability and Errors

Cardiac biomarkers such as and can exhibit variability due to biological factors unrelated to primary cardiac ischemia, leading to non-specific elevations that complicate interpretation. For instance, levels may rise in due to right ventricular strain, in from and myocardial stress, and in renal failure owing to reduced clearance and uremic . Similarly, B-type (BNP) elevations occur in (COPD) as a result of hypoxemia-induced myocardial stretch and cor pulmonale. 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 and BNP, producing false-positive results by cross-linking capture and detection antibodies. High-sensitivity cardiac (hs-cTn) assays are particularly susceptible to lot-to-lot variability, where differences in batches lead to inconsistent measurements exceeding 10-20% , affecting serial comparisons. Pre- and post-analytical phases introduce additional sources of error through handling and patient-related factors. Delayed sample processing can artificially elevate (CK) levels due to ongoing enzymatic activity , potentially mimicking acute injury. Exercise or trauma induces releases of and CK-MB, causing transient elevations that overlap with cardiac patterns and necessitate differentiation via isoform analysis or timing. 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. In individuals with or stable , baseline elevations can mask acute changes, requiring delta assessments over fixed cutoffs for accurate detection. To mitigate these variabilities, current guidelines stress clinical alongside biomarker results, advising against reliance on isolated values. A multi-marker approach, combining troponins with BNP or imaging, enhances specificity and reduces error rates by addressing complementary pathophysiological pathways.

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