Biomarkers & Cardiac Enzymes | Cardiac Injury Markers

Cardiac Troponin (cTnI / cTnT)

Gold standard biomarker for myocardial injury

📌 What It Is

Structural proteins (Troponin I & T) of the cardiac sarcomere. Released into blood when cardiomyocytes are damaged/necrosed. High-sensitivity assays (hs-cTn) detect levels at nanogram/Liter (ng/L) concentrations.

⏱️ Kinetics

• Rise: 2–4 hrs post-injury (hs-cTn: 1–3 hrs)
• Peak: 12–24 hrs (cTnI), 12–48 hrs (cTnT)
• Duration: cTnI: 5–10 days; cTnT: 10–14 days
• Serial testing: 0/1hr or 0/3hr protocol (ESC)

🔬 When to Order

Absolute Indications:

Suspected ACS (chest pain, dyspnea, diaphoresis)
ECG changes — ST elevation/depression, new LBBB, T-wave inversions
Hemodynamic instability with suspected cardiac etiology
Post-cardiac arrest / ROSC
Acute heart failure (to differentiate ACS from decompensation)
Post-PCI or CABG (periprocedural MI detection)
Pulmonary embolism (risk stratification)
Myocarditis / Takotsubo suspicion

ICU Indications:

Type 2 MI (demand ischemia in sepsis, anemia, tachycardia)
Septic cardiomyopathy assessment
Prognostication in critically ill patients
Cardiotoxicity monitoring (chemotherapy)

📊 Interpretation & Reference Values

Level (hs-cTnI)	Interpretation	Clinical Action
<5 ng/L	Normal — MI essentially ruled out	NPV >99%. Consider discharge (if low HEART score)
5–99th %ile	Mildly elevated — observe trend	Repeat at 1–3 hrs. Rising/falling pattern key
>99th %ile	Elevated — myocardial injury confirmed	Determine Type 1 vs Type 2 MI vs non-ischemic
>5× ULN + Δ>20%	Acute MI (with rise/fall pattern)	Urgent cardiology consult, cath lab activation

⚠️ Critical Points:

• Delta (Δ) change is more important than absolute value — a rise/fall pattern >20% suggests acute injury
• 99th percentile URL is sex-specific (Female: ~16 ng/L, Male: ~34 ng/L for hs-cTnI)
• CKD patients have chronically elevated troponin — look for delta change
• hs-cTnT may be falsely elevated in skeletal myopathy, CKD (cross-reactivity)

⚡ Non-ACS Causes of Elevated Troponin

Cardiac:

Heart failure (acute/chronic)
Myocarditis, Pericarditis
Takotsubo cardiomyopathy
Cardiac contusion
Cardioversion / Ablation
Aortic dissection
Hypertrophic cardiomyopathy

Non-Cardiac:

Pulmonary embolism
Sepsis / Septic shock
Renal failure (CKD Stage 4–5)
Stroke (SAH, ischemic)
Burns (>30% BSA)
Rhabdomyolysis (cross-reactivity)
Extreme exertion (marathon runners)
Cardiotoxic drugs (doxorubicin, 5-FU)

💎 Clinical Pearls — ICU/ED

• 0/1hr Algorithm (ESC 2020): hs-cTnI <5 at 0hr → Rule-out. ≥52 at 0hr or Δ≥6 at 1hr → Rule-in. Others = Observe zone.
• Type 1 vs Type 2 MI: Type 1 = plaque rupture. Type 2 = supply/demand mismatch (tachycardia, hypotension, anemia). Treatment differs drastically.
• Chronic elevation: Stable elevated troponin (no delta) in CKD/HF = chronic myocardial injury, NOT indication for catheterization.
• Prognostic value: Any detectable hs-cTn predicts higher mortality in ICU patients even without ACS.

BNP / NT-proBNP

Natriuretic peptides — Heart failure biomarkers

📌 Physiology

BNP (32 aa) & NT-proBNP (76 aa) are released from ventricular cardiomyocytes in response to myocardial wall stress (volume/pressure overload). proBNP (108 aa) is cleaved into active BNP + inactive NT-proBNP.

• BNP half-life: ~20 min (cleared by NPR-C receptors & neprilysin)
• NT-proBNP half-life: ~120 min (renally cleared)
• NT-proBNP NOT affected by sacubitril (neprilysin inhibitor)

🔬 When to Order

• Acute dyspnea — cardiac vs pulmonary etiology
• Suspected acute decompensated heart failure
• Monitoring HF treatment response (target >30% reduction)
• Prognostication in ACS & PE
• Pre-op risk stratification (non-cardiac surgery)
• Screening in high-risk populations (Stage B HF)

📊 Interpretation

Marker	HF Unlikely	Grey Zone	HF Likely
BNP	<100 pg/mL	100–400 pg/mL	>400 pg/mL
NT-proBNP	<300 pg/mL	300–age cutoff	Age-based (see below)

NT-proBNP Age-Stratified Cut-offs (Rule-In):

• Age <50: >450 pg/mL
• Age 50–75: >900 pg/mL
• Age >75: >1800 pg/mL

⚠️ Confounders & Pitfalls

↑ False Elevations:

Renal failure (especially NT-proBNP)
Atrial fibrillation
Pulmonary embolism / PHT
Sepsis
Advanced age
Anemia

↓ Falsely Low (Caution!):

Obesity (BMI >35 — use lower thresholds)
Flash pulmonary edema (<2hr onset)
Constrictive pericarditis
Mitral stenosis (no ventricular stretch)
Sacubitril affects BNP (NOT NT-proBNP)

💎 Clinical Pearls

• Negative predictive value >98% — A normal BNP essentially rules out HF
• In obese patients: use cut-off of BNP >54 pg/mL or NT-proBNP at 50% of age-adjusted cut-off
• On ARNI (sacubitril/valsartan): Monitor NT-proBNP, NOT BNP (sacubitril inhibits BNP degradation)
• >30% decline from admission = adequate treatment response (target-guided therapy)
• Persistently elevated despite treatment = poor prognosis, consider advanced HF therapies

D-Dimer

Fibrin degradation product — Exclusion marker for VTE

📌 Physiology

D-dimer is a cross-linked fibrin degradation product released when plasmin cleaves fibrin clot. Indicates activation of both coagulation and fibrinolysis.

Half-life: ~8 hrs. Normal: <500 ng/mL (FEU).

🔬 When to Order

• Suspected PE (after Wells/Geneva score)
• Suspected DVT (after Wells criteria)
• DIC screening (with PT, aPTT, fibrinogen, platelets)
• Aortic dissection (high sensitivity)
• Age-adjusted in elderly patients

📊 Interpretation

D-Dimer Value	Interpretation	Action
<500 ng/mL (FEU)	Negative — VTE excluded if low/moderate PTP	No imaging needed. Sensitivity ~97%
Age-adjusted: Age × 10	For patients >50 yrs	Use cut-off = age × 10 ng/mL (e.g., 70yo → 700)
>500 ng/mL	Positive — does NOT confirm VTE	Requires imaging (CTPA for PE, US for DVT)

🚨 NEVER use D-dimer to rule out PE/DVT in HIGH pre-test probability patients. Go directly to imaging.

⚡ Causes of Elevated D-Dimer (Non-VTE)

Post-surgery Pregnancy Malignancy Sepsis/Infection Trauma DIC Liver disease Atrial fibrillation Age >50 Hospitalization Aortic dissection COVID-19

💎 Clinical Pearls

• Rule-out only: High sensitivity (~97%), low specificity (~40%). A negative D-dimer rules OUT VTE; a positive one does NOT rule IN.
• Age-adjusted cut-off (>50 yrs): Age × 10 ng/mL FEU — reduces unnecessary CT scans by ~30%
• YEARS algorithm: If no YEARS items + D-dimer <1000 → PE excluded (even more conservative approach)
• DIC score (ISTH): D-dimer is one of 4 components (with platelets, PT, fibrinogen). Moderate increase = 2 points, strong increase = 3 points.
• Aortic dissection: D-dimer >500 has 97% sensitivity for acute dissection — useful as a rule-out tool (ADD-RS score)

Procalcitonin (PCT)

Bacterial infection biomarker — Antibiotic stewardship tool

📌 Physiology

Precursor of calcitonin, normally produced by thyroid C-cells. In bacterial infection, extra-thyroidal production (liver, lung, kidney, fat, muscle) is induced by TNF-α, IL-6, and bacterial endotoxins (LPS).

• Rise: 2–4 hrs after infection onset
• Peak: 12–24 hrs
• Half-life: 24–30 hrs
• Normal: <0.05 ng/mL

🔬 When to Order

• Differentiating bacterial vs viral infection
• Sepsis diagnosis & severity assessment
• Guiding antibiotic initiation (LRTI)
• Antibiotic de-escalation/discontinuation in ICU
• Monitoring treatment response in sepsis
• CAP — initiate vs withhold antibiotics

📊 Interpretation & Antibiotic Guidance

PCT Level	Interpretation	Antibiotic Decision
<0.1 ng/mL	Bacterial infection very unlikely	Strongly discourage antibiotics
0.1–0.25 ng/mL	Bacterial infection unlikely	Discourage antibiotics (re-evaluate)
0.25–0.5 ng/mL	Possible bacterial infection	Consider antibiotics (clinical correlation)
0.5–2.0 ng/mL	Likely bacterial — possible sepsis	Strongly encourage antibiotics
>2.0 ng/mL	Severe bacterial infection / sepsis	Mandatory antibiotics + source control
>10 ng/mL	Septic shock / overwhelming infection	Aggressive resuscitation + broad-spectrum

📉 De-escalation Rule (ICU):

Stop antibiotics when PCT drops >80% from peak OR falls below 0.25–0.5 ng/mL + clinical improvement. This reduces antibiotic duration by 2–3 days without increasing mortality (ProRATA, SAPS trials).

⚠️ Limitations & False Elevations

Non-infectious causes of elevated PCT:

Major surgery / Trauma / Burns (transient, peaks day 1–2)
Cardiogenic shock / Post-cardiac arrest
Medullary thyroid carcinoma
Severe pancreatitis
Neonates (first 48 hrs of life — physiologically elevated)
Medications: OKT3, anti-thymocyte globulin, IL-2

PCT may be LOW despite true infection:

Localized infections (abscess, empyema) — no systemic response
Early infection (<6 hrs from onset)
Atypical/intracellular organisms (Mycoplasma, Chlamydia, TB)
Subacute bacterial endocarditis

💎 Clinical Pearls

• PCT > CRP for bacterial vs viral differentiation (viral infections rarely elevate PCT above 0.5)
• Serial monitoring q48–72h in ICU is more valuable than single measurement
• PCT-guided antibiotic therapy in ICU reduces antibiotic exposure by ~2 days with no mortality difference
• In neutropenic fever: PCT >0.5 suggests bacteremia with 80% sensitivity
• NOT reliable for fungal infections — PCT typically stays low in invasive candidiasis/aspergillosis

CK / CK-MB

Creatine Kinase — Muscle damage & reinfarction marker

📌 Isoforms

• CK-MM (~95%): Skeletal muscle
• CK-MB (~5%): Cardiac muscle (also some in skeletal)
• CK-BB: Brain, smooth muscle

CK-MB rises 3–8 hrs, peaks 12–24 hrs, normalizes 48–72 hrs. Shorter window than troponin makes it useful for detecting reinfarction.

🔬 Clinical Use Today

• Reinfarction detection (within 2 weeks of first MI, when troponin still elevated)
• Periprocedural MI (post-PCI/CABG)
• Rhabdomyolysis (total CK)
• Myositis / Muscular dystrophies
• Malignant hyperthermia
• Statin-induced myopathy monitoring

📊 Reference Values

Marker	Normal	Significance
Total CK	M: 39–308 U/L; F: 26–192 U/L	Non-specific muscle damage
CK-MB	<25 U/L (or <5% of total CK)	Cardiac specificity if CK-MB/CK ratio >5%
CK-MB index	(CK-MB/Total CK) × 100	>5% suggests cardiac origin; <5% = skeletal
Rhabdomyolysis	CK >5× ULN (~1000 U/L)	AKI risk if CK >5000; dialysis risk >15000

💎 Clinical Pearls

• CK-MB is largely obsolete for primary MI diagnosis — hs-Troponin is superior. But CK-MB retains value for reinfarction timing.
• Rhabdomyolysis: Aggressive IVF (200–300 mL/hr NS) targeting UOP 200–300 mL/hr. Monitor CK q6–12h until trending down.
• Post-PCI: CK-MB >3× ULN = Type 4a MI; Post-CABG: >10× ULN = Type 5 MI
• Hypothyroidism can chronically elevate CK (up to 10× normal)

Lactate

Tissue hypoperfusion marker — Sepsis severity & resuscitation endpoint

📌 Physiology

Product of anaerobic glycolysis. Produced when oxygen delivery is inadequate (Type A) or due to metabolic dysfunction (Type B). Cleared primarily by liver (60%) and kidneys (30%).

🔬 When to Order

• Sepsis / Septic shock (SSC guidelines q2–4h)
• Any shock state assessment
• Mesenteric ischemia
• Resuscitation adequacy monitoring
• DKA (metformin-associated lactic acidosis)
• Post-cardiac arrest prognostication

📊 Interpretation

Lactate	Interpretation	Action
<2 mmol/L	Normal	Adequate perfusion
2–4 mmol/L	Mild hyperlactatemia — occult hypoperfusion	Initiate fluid resuscitation. Re-check q2–4h.
>4 mmol/L	Severe — defines septic shock (with vasopressors)	Aggressive resuscitation. Target clearance >20%/2h
>10 mmol/L	Critical — very high mortality (~80%)	ICU, consider mesenteric ischemia, ECMO evaluation

⚡ Type A vs Type B Lactic Acidosis

Type A (Tissue Hypoxia):

Cardiogenic shock
Septic shock
Hemorrhagic shock
Mesenteric ischemia
Severe anemia / CO poisoning
Cardiac arrest

Type B (No Hypoxia):

Metformin toxicity
Liver failure (impaired clearance)
Seizures / Extreme exertion
Malignancy (Warburg effect)
Thiamine deficiency
Epinephrine infusion / β2 agonists
Linezolid, NRTIs

💎 Clinical Pearls

• Lactate clearance >20% in 2 hrs = adequate resuscitation (equal to ScvO2 targeting per ANDROMEDA-SHOCK)
• Sepsis-3 definition: Septic shock = sepsis + vasopressor need + lactate >2 mmol/L despite adequate fluid resuscitation
• Venous vs Arterial: Venous lactate is acceptable for screening/trending (±0.2–0.3 mmol/L difference)
• Tourniquet/fist-clenching during blood draw can falsely elevate lactate — use free-flowing sample
• Lactate-to-albumin ratio >2.96 predicts 28-day mortality in sepsis better than lactate alone

CRP / hs-CRP

Acute phase reactant — Inflammation & Cardiovascular risk

📌 Physiology

Pentraxin produced by hepatocytes in response to IL-6. Non-specific marker of inflammation. Half-life ~19 hrs. Rises within 6–8 hrs of stimulus, peaks at 48 hrs.

📊 Levels

<3 mg/L	Normal (hs-CRP: CV risk low)
3–10 mg/L	Mild inflammation / moderate CV risk
10–100 mg/L	Active inflammation / infection
>100 mg/L	Severe bacterial infection / Sepsis
>200 mg/L	Burns, severe sepsis, major trauma

💎 Clinical Pearls

• hs-CRP <1 / 1–3 / >3 mg/L = low/moderate/high cardiovascular risk (JUPITER trial)
• CRP >100 mg/L in bacterial infection has ~80% PPV for bacteremia
• CRP rises slower than PCT but stays elevated longer — useful for monitoring treatment response over days
• CRP doesn't rise in SLE flares (unless serositis/infection) — a rising CRP in SLE patient suggests infection
• Obesity, smoking, and HRT chronically elevate hs-CRP by 1–2 mg/L

LDH (Lactate Dehydrogenase)

Non-specific tissue damage marker — hemolysis, malignancy, PCP

📌 Isoenzymes

LDH-1
Heart, RBC

LDH-2
RES

LDH-3
Lung

LDH-4
Kidney, Pancreas

LDH-5
Liver, Muscle

Normal: 140–280 U/L. Non-specific — found in virtually all tissues.

🔬 Key Clinical Uses

• Hemolysis: Elevated LDH + low haptoglobin + elevated indirect bilirubin + reticulocytosis = hemolytic anemia
• TTP/HUS: LDH markedly elevated (often >1000) + schistocytes + thrombocytopenia
• PJP (Pneumocystis pneumonia): LDH >500 with bilateral GGO in immunocompromised → suspect PJP
• Lymphoma: Elevated LDH = high tumor burden, poor prognosis (IPI score component)
• Pleural fluid: LDH >2/3 upper normal serum = exudate (Light's criteria)
• Testicular cancer: Tumor marker (with AFP, β-hCG)

💎 Clinical Pearls

• COVID-19: LDH >365 U/L associated with 6× higher odds of severe disease and death
• "Flipped" LDH ratio (LDH-1 > LDH-2): Seen in acute MI and hemolysis
• In PJP: LDH elevation correlates with disease severity and predicts treatment response
• Hemolyzed blood sample will falsely elevate LDH — always check specimen quality

Ferritin

Iron storage protein & acute phase reactant — HLH, Still's, iron overload

📊 Reference & Thresholds

<12 ng/mL	Iron deficiency (absolute)
<30 ng/mL	Iron deficiency likely (esp. if CKD/HF)
30–300 ng/mL	Normal range
>500 ng/mL	Elevated — iron overload or inflammation
>1000 ng/mL	Consider HLH, Still's, severe sepsis
>10,000 ng/mL	HLH highly likely (H-score)

🔬 Key Uses

• Iron deficiency anemia diagnosis
• HLH / Macrophage activation syndrome
• Adult-onset Still's disease (>10,000)
• Hemochromatosis monitoring
• COVID-19 cytokine storm marker
• Iron overload in transfusion-dependent patients

💎 Clinical Pearls

• Ferritin is an acute phase reactant — can be normal/elevated even in iron deficiency if inflammation is present. Check TSAT (transferrin saturation) and reticulocyte Hb.
• HLH diagnosis: Ferritin >10,000 has 90% sensitivity & 96% specificity for HLH in febrile patients
• Iron deficiency in HF: Ferritin <100 OR Ferritin 100–299 + TSAT <20% = IV iron indicated (FAIR-HF, AFFIRM-AHF)
• Glycosylated ferritin <20% = pathognomonic for Adult-onset Still's disease

Myoglobin

Earliest muscle damage marker — Rhabdomyolysis & early MI (historical)

📌 Characteristics

• Small heme protein (17 kDa) — rapidly released
• Found in skeletal AND cardiac muscle
• Rise: 1–3 hrs post-injury (earliest cardiac marker)
• Peak: 6–9 hrs
• Normalized: 24–36 hrs (rapid renal clearance)
• Normal: <85 ng/mL

🔬 Clinical Relevance

• Rhabdomyolysis: Causes dark brown urine, nephrotoxic (myoglobin cast nephropathy)
• Myoglobin >1000 ng/mL → significant AKI risk
• Historical early MI rule-out (replaced by hs-Troponin)
• Poor cardiac specificity limits modern use for ACS

💎 Clinical Pearls

• Largely obsolete for cardiac diagnosis — hs-Troponin now detects MI within 1 hr
• Main use today: Rhabdomyolysis monitoring — correlates with AKI risk better than CK for renal toxicity
• Urine myoglobin: Positive urine "blood" on dipstick with NO RBCs on microscopy = myoglobinuria
• Alkalinize urine (target pH >6.5) when myoglobin >1000 to prevent cast formation (controversial but still practiced)

Marker	Rise	Peak	Normal	Best For
hs-Troponin	1–3 hr	12–24 hr	5–14 days	MI diagnosis (gold standard)
CK-MB	3–8 hr	12–24 hr	48–72 hr	Reinfarction detection
Myoglobin	1–3 hr	6–9 hr	24–36 hr	Rhabdomyolysis
BNP	Hours	Variable	With treatment	Heart failure diagnosis
D-Dimer	Immediate	Variable	Days	VTE exclusion
Procalcitonin	2–4 hr	12–24 hr	T½ 24–30h	Bacterial sepsis / ABx guidance
Lactate	Minutes	Variable	With perfusion	Shock / Resuscitation

Cardiac Troponin (cTnI / cTnT)

📌 What It Is

⏱️ Kinetics

💎 Clinical Pearls — ICU/ED

BNP / NT-proBNP

📌 Physiology

🔬 When to Order

💎 Clinical Pearls

D-Dimer

📌 Physiology

🔬 When to Order

💎 Clinical Pearls

Procalcitonin (PCT)

📌 Physiology

🔬 When to Order

💎 Clinical Pearls

CK / CK-MB

📌 Isoforms

🔬 Clinical Use Today

💎 Clinical Pearls

Lactate

📌 Physiology

🔬 When to Order

💎 Clinical Pearls

CRP / hs-CRP

📌 Physiology

📊 Levels

💎 Clinical Pearls

LDH (Lactate Dehydrogenase)

📌 Isoenzymes

🔬 Key Clinical Uses

💎 Clinical Pearls

Ferritin

📊 Reference & Thresholds

🔬 Key Uses

💎 Clinical Pearls

Myoglobin

📌 Characteristics

🔬 Clinical Relevance

💎 Clinical Pearls

📋 Quick Comparison — Cardiac Biomarker Kinetics