Skip to content

Not yet independently audited

This page was written from verified sources but has not yet passed the independent citation audit. Treat its claims as provisional.

Biomarkers and imaging markers in ischemic heart disease

TL;DR — No circulating marker has replaced clinical assessment plus anatomic or functional testing for chronic IHD, and lesion-level prediction remains imprecise. High-sensitivity troponin is indispensable for detecting acute myocardial injury and also predicts risk in chronic coronary disease, but elevation is not specific for type 1 MI (Wereski 2023, PMID 37532417; Park 2017, PMID 29016754). hsCRP identifies inflammatory risk and enriched CANTOS, yet an hsCRP-guided treatment strategy has not been validated (Ridker 2017, PMID 28845751). Lp(a) is a largely inherited causal risk marker; Lp(a)HORIZON completed follow-up in July 2026, but live PubMed searches repeated on 2026-09-02 found no primary outcome report, while OCEAN(a)-Outcomes remains active without recruitment (NCT04023552; NCT05581303). Polygenic scores improve prediction modestly but face ancestry and actionability constraints (Marston 2023, PMID 36576811; Klarin 2022, PMID 34811547). Coronary calcium measures total calcified burden, whereas CCTA provides stenosis and plaque composition; low-attenuation plaque predicted MI in SCOT-HEART (Williams 2020, PMID 32174130). A useful biomarker must improve a decision and outcomes beyond established risk factors—not merely produce a significant association or AUC increment.

Biomarker roles

Role Example Required proof
Diagnosis hs-troponin in suspected MI Sensitivity/specificity in a defined pathway
Prognosis hs-troponin, hsCRP, plaque burden Calibration and incremental discrimination
Treatment selection hsCRP for cytokine trial enrichment Interaction or strategy-trial benefit
Treatment monitoring LDL-C after lipid therapy Change linked to causal exposure and outcome evidence
Mechanistic readout IL-6/hsCRP after ziltivekimab Target engagement, not automatically clinical benefit

Statistical association is the first rung. Clinical utility requires a changed action with net benefit.

High-sensitivity troponin

High-sensitivity cardiac troponin assays detect myocardial injury at low concentrations. Acute MI diagnosis requires a rise/fall plus clinical evidence of ischemia; chronic elevations occur with structural heart disease, CKD, heart failure, and other conditions (Park 2017, PMID 29016754).

In chronic coronary disease, higher hs-troponin concentrations predict cardiovascular events and can improve risk stratification (Wereski 2023, PMID 37532417). The marker may reflect ongoing myocyte injury and total disease burden rather than silent plaque rupture.

Context Valid inference Invalid shortcut
Acute chest symptoms Serial kinetics inform injury One elevated value = type 1 MI
CKD Persistent elevation is common and prognostic Ignore all elevations as “renal”
Stable CAD Higher level indicates higher risk Routine angiography solely from biomarker
Women Sex-specific thresholds alter detection Symptoms are unnecessary once value rises

2026 definition update. Sex-specific 99th-percentile troponin upper reference limits define myocardial injury; accelerated 0/1- and 0/2-hour triage cutoffs serve a different purpose. Section 14.1.5 states that those triage thresholds are “used for risk stratification, rather than to define myocardial injury” (Mills 2026, PMID 42666939, full text). This distinction prevents substituting a rapid-pathway cutoff for the diagnostic injury threshold.

CKD reduces specificity for acute MI but preserves prognostic information; deltas and clinical context are essential (Chuang 2020, PMID 32706208).

Randomized tests of rapid pathways (2026). The diagnostic-accuracy literature behind the ESC 0/1-hour algorithm is observational; three 2026 randomized implementation trials test what it does in practice. They separate safety from throughput:

Trial Design Safety Throughput
0/1 h vs 0/3 h, international (Boeddinghaus 2026, PMID 42667934) Stepped-wedge cluster RCT; 67,624 presentations 30-day death or new type 1 MI 1.1% vs 1.2% (adjusted OR 0.93, 95% CI 0.77–1.13); non-inferior ED length of stay 309 vs 309 min (ratio 1.00, 95% CI 0.97–1.02)
MACROS2, 0/1 h vs 0/3 h, England (Hatherley 2026, PMID 42159533) Pragmatic RCT; 3,543 patients Non-inferior; sensitivity 93.7% vs 89.5% among discharged patients Discharge within 4 h 21.8% vs 19.2% (P=0.07); central-lab turnaround 81 min
ICare-FASTER, point-of-care hs-cTnI (Than 2026, PMID 42895015) Stepped-wedge cluster RCT; 59,980 presentations 30-day MI or cardiac death 0.39% vs 0.39% Length of stay −13% (95% CI 9–16%), −47 min

Shortening the sampling interval did not by itself move patients faster through the department, because laboratory turnaround and system constraints dominated; moving the assay to the point of care did. MACROS2 also found that safety of discharge for both pathways was lower than observational studies had implied (Hatherley 2026, PMID 42159533).

hsCRP and inflammatory markers

hsCRP is a standardized downstream marker of innate immune activity. CANTOS enrolled prior-MI patients with hsCRP ≥2 mg/L and showed IL-1β blockade reduced events without LDL change (Ridker 2017, PMID 28845751).

However:

  • hsCRP is affected by infection, adiposity, smoking, and chronic inflammatory disease.
  • It does not localize coronary inflammation.
  • CIRT was neutral when the intervention did not lower IL-1β/IL-6/CRP (Ridker 2019, PMID 30415610).
  • As of live PubMed and ClinicalTrials.gov searches repeated on 2026-09-02, no completed trial had shown that titrating colchicine to an hsCRP target improves outcomes. RIGHT registered an hsCRP-enriched randomized colchicine strategy (NCT06025071), but its record is stale (status unknown; last known not yet recruiting) and has no posted results.

Thus hsCRP is a risk/enrichment marker, not a stand-alone diagnosis of “residual inflammatory risk requiring therapy.”

Lipoprotein biomarkers

Marker What it approximates Clinical use Limitation
LDL-C Cholesterol mass in LDL particles Treatment target/threshold Discordant with particle number in some states
Non-HDL-C Cholesterol in all apoB particles Secondary target, useful with triglycerides Still cholesterol mass
ApoB Number of atherogenic particles Clarifies discordance Assay/access and guideline variation
Lp(a) Inherited LDL-like particle with apo(a) Once-in-lifetime risk refinement; trial eligibility Units/isoforms; no completed selective outcome proof
Triglycerides Metabolic marker of remnant-rich state Selects REDUCE-IT-like phenotype Variable and not direct particle count

FOURIER and ODYSSEY show event reduction with profound LDL lowering (Sabatine 2017, PMID 28304224; Schwartz 2018, PMID 30403574). Lp(a)HORIZON (NCT04023552) and OCEAN(a)-Outcomes (NCT05581303) test whether selective Lp(a) lowering changes events. HORIZON's September 2026 topline reported Lp(a) lowering without reduction of the primary composite, with full data awaited (Sabouret 2026, PMID 42880684); Lp(a) therefore remains a validated risk marker without a proven treatment target.

Polygenic risk scores

CAD polygenic scores aggregate many common variants. In primary-prevention cohorts, scores improve risk classification beyond conventional variables, but clinical utility depends on ancestry-specific calibration and whether disclosure changes effective treatment (Marston 2023, PMID 36576811; Klarin 2022, PMID 34811547).

Promise Constraint
Stable from birth Does not encode changing environment or treatment
Identifies high lifetime risk early Most derivation cohorts overrepresent European ancestry
May motivate earlier prevention Behavior-change benefit is unproven
Could refine family screening Family history already captures some signal

Healthy lifestyle is associated with lower coronary risk even at high genetic risk, so a high score is not deterministic (Khera 2016, PMID 27959714).

Coronary calcium

CAC is a robust measure of total calcified atherosclerotic burden and refines primary-prevention risk. A CAC score of zero predicts low short-term event risk in many stable chest-pain populations but does not exclude non-calcified plaque or microvascular disease (Wang 2019, PMID 31168373; Koopman 2022, PMID 35081649).

In established IHD, CAC rarely changes the diagnosis that systemic prevention is required; heavy calcification may instead inform procedural complexity and CT interpretability.

CCTA plaque biomarkers

CCTA reports stenosis, total plaque burden, composition, remodeling, and high-risk features. In SCOT-HEART, low-attenuation noncalcified plaque burden strongly predicted subsequent MI, adding information beyond stenosis and CAC (Williams 2020, PMID 32174130).

Semi-quantitative CCTA scores also carry prognostic information (SCOT-HEART analysis, PMID 37673712). AI-enabled plaque/physiology models may improve prediction, but external validation and strategy trials are required before prophylactic PCI or drug escalation is triggered (Koo 2024, PMID 38752951).

Imaging marker Biological interpretation Decision status
Total plaque burden Cumulative atherosclerosis Prognostic; prevention intensity
Low attenuation Lipid-rich component Prognostic, not a routine PCI indication
Positive remodeling Outward plaque expansion High-risk association
Spotty calcification Active mixed plaque phenotype Association; limited specificity
Perivascular fat attenuation Local inflammatory signal Investigational
FFR-CT Modeled lesion physiology Helps select invasive evaluation/PCI

Validation checklist

  1. Define intended use and population before selecting a cutoff.
  2. Compare with a strong clinical base model.
  3. Report calibration, discrimination, reclassification, and decision curves.
  4. Validate externally across sex, ancestry, kidney function, and treatment era.
  5. Show that biomarker-guided action improves outcomes.
  6. Include cost, false positives, incidental findings, and downstream procedures.

Reporting standards for candidate biomarkers

Domain Minimum report
Analytic validity Assay platform, precision, detection limits, batch handling
Population Recruitment, prevalence, treatment and missingness
Base model Established clinical predictors and calibration
Increment ΔC-statistic, calibration, reclassification and decision utility
Threshold Prespecified cutoff and consequences of false results
Replication External cohort and subgroup calibration
Action Exact management change triggered
Outcome Strategy-level benefit, harm and cost

Many biomarker papers stop at discrimination. For chronic IHD, the decisive experiment is whether marker-guided action improves outcomes beyond readily available risk and imaging data (Marston 2023, PMID 36576811; Koo 2024, PMID 38752951).

Quantitative validation landmarks and failure modes

Marker/test Quantified evidence Remaining limitation
ESC hs-cTn 0/1-hour algorithm Meta-analysis supports high diagnostic performance across contemporary hs-cTn assays (Burgos 2021, PMID 32597681); randomized implementation shows non-inferior safety but no throughput gain over 0/3 h (Boeddinghaus 2026, PMID 42667934; Hatherley 2026, PMID 42159533). Performance is assay-, prevalence-, symptom-time-, and subgroup-dependent; “rule-out” is not zero risk.
Presentation hs-cTn rule-out HiSTORIC (31,492 patients, stepped-wedge across hospitals) shortened length of stay and raised direct discharge from 50% to 71%; the 30-day safety outcome did not formally meet noninferiority (upper 1-sided 95% CI 0.70% versus a 0.50% margin; P=0.068) although observed rates favored the early pathway (0.4% versus 0.3%) (Anand 2021, PMID 33752439). Cluster implementation evidence does not validate use before assay-specific minimum symptom duration.
Chronic hs-cTn Detectable concentrations stratify risk in chronic CAD, including values below acute-MI rule-in ranges (Wereski 2023, PMID 37532417). Prognostic association does not specify a new treatment.
CAC added to clinical factors MESA-derived 10-year models improved risk classification when CAC was added and were externally tested in HNR and DHS cohorts (McClelland 2015, PMID 26449133). CAC=0 does not exclude noncalcified plaque (Wang 2019, PMID 31168373).
CCTA low-attenuation plaque In SCOT-HEART, low-attenuation plaque burden predicted subsequent MI beyond conventional measures (Williams 2020, PMID 32174130). Lesion-level positive predictive value limits prophylactic focal treatment (Stone 2011, PMID 21247313; Ahn 2023, PMID 37271356).
Quantitative plaque plus physiology AI-enabled plaque/hemodynamic analysis improves prediction in observational datasets (Koo 2024, PMID 38752951). Calibration drift and prospective decision impact remain unproven.
Lp(a) Participant-level and genetic analyses support risk independent of LDL-C (Bhatia 2025, PMID 39492722; Burgess 2018, PMID 29926099). Association does not prove that a specific drug-induced reduction prevents events.
Polygenic score CAD PRS can add modest prediction (Klarin 2022, PMID 34811547; Marston 2023, PMID 36576811). Ancestry transferability and strategy-level benefit remain inadequate for routine equitable deployment.

The risk-marker philosophy accepts a test if it improves discrimination and motivates established prevention; the strategy-trial philosophy requires evidence that measuring and acting improves outcomes. hs-cTn satisfies the latter for accelerated diagnostic pathways more convincingly than hsCRP, PRS, or plaque-AI currently do (Park 2017, PMID 29016754; Chuang 2020, PMID 32706208). CAC and CCTA sit between the philosophies because downstream testing, incidental findings, radiation/contrast, and treatment changes must be counted with events (Koopman 2022, PMID 35081649; Maclean 2023, PMID 37673712).

CANTOS demonstrated pathway causality after hsCRP enrichment, while CIRT showed that a nominally anti-inflammatory drug that did not lower IL-1β/IL-6/CRP did not reduce events (Ridker 2017, PMID 28845751; Ridker 2019, PMID 30415610). This supports target-engagement measurement but not routine hsCRP-guided treatment. PROSPECT and SCOT-HEART show plaque prognostic signal; PREVENT asks the harder strategy question of whether acting on a non-flow-limiting lesion improves outcomes (Stone 2011, PMID 21247313; Williams 2020, PMID 32174130; Ahn 2023, PMID 37271356).

Chest-pain guidance treats hs-cTn, CAC, and CCTA as components of pathways rather than freestanding answers (Gulati 2021, PMID 34709879). Genetic risk is similarly contextual: healthy lifestyle was associated with lower coronary risk across genetic strata, so PRS should not be framed as destiny (Khera 2016, PMID 27959714). Global LDL-attributable-burden modeling supplies population context but is not a patient-level biomarker validation study (GBD 2023 LDL Collaborators 2026, PMID 42525403).

ESC chronic-coronary guidance consequently positions biomarkers according to the decision they inform rather than recommending indiscriminate multimarker panels (Vrints 2024, PMID 39210710).

A marker can discriminate without improving care

Prospective validation of a 1-hour hs-cTnT algorithm placed 59.5% of 1,320 suspected-MI presentations in rule-out, with sensitivity 99.6% (95% CI 97.6%–99.9%) and NPV 99.9% (95% CI 99.3%–100%); 24.1% remained in an observation zone and therefore still required clinical adjudication (Reichlin 2015, PMID 25869867). High-STEACS then showed why diagnostic yield is not implementation success: sex-specific hs-cTnI thresholds increased detected injury by 42% in women versus 6% in men, yet women still received about half as much coronary treatment and their 1-year MI/CV-death outcome did not improve (adjusted HR 1.11, 95% CI 0.92–1.33) (Lee 2019, PMID 31623760).

Imaging markers similarly mix focal phenotype with total burden. In MESA, CAC ≥100 identified 21% of participants but 55% of cardiovascular events; rates were 22.7–29.5 per 1,000 person-years across lipid-abnormality strata, versus 2.7–5.9 with CAC=0 (Martin 2014, PMID 24141324). In SCOT-HEART, adverse plaque features predicted CHD death/nonfatal MI (4.1% vs 1.4%; HR 3.01, 95% CI 1.61–5.63), but the association was not independent of CAC, warning against treating a visually “vulnerable” plaque as separable from whole-patient plaque burden (Williams 2019, PMID 30678759).

Open questions

  • Does serial hs-troponin-guided intensification improve outcomes in chronic CAD? (Wereski 2023, PMID 37532417)
  • Can hsCRP guide anti-inflammatory therapy rather than merely enrich a trial? (Ridker 2017, PMID 28845751)
  • Will Lp(a) reduction lower events, and what achieved reduction is necessary? (NCT04023552; NCT05581303)
  • Can polygenic scores be recalibrated equitably and tested in treatment-strategy trials? (Klarin 2022, PMID 34811547)
  • Does treatment triggered by low-attenuation plaque improve outcomes beyond intensive systemic prevention? (Williams 2020, PMID 32174130)

References

  1. Wereski R, et al. High-Sensitivity Cardiac Troponin for Risk Assessment in Patients With Chronic Coronary Artery Disease. J Am Coll Cardiol. 2023;82:473-485. PMID 37532417
  2. Park KC, et al. Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc Res. 2017;113:1708-1718. PMID 29016754
  3. Ridker PM, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-1131. PMID 28845751
  4. Marston NA, et al. Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention. JAMA Cardiol. 2023;8:130-137. PMID 36576811
  5. Klarin D, et al. Clinical utility of polygenic risk scores for coronary artery disease. Nat Rev Cardiol. 2022;19:291-301. PMID 34811547
  6. Williams MC, et al. Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction: Results From the Multicenter SCOT-HEART Trial (Scottish Computed Tomography of the HEART). Circulation. 2020;141:1452-1462. PMID 32174130
  7. Chuang AM, et al. High-sensitivity troponin in chronic kidney disease: Considerations in myocardial infarction and beyond. Rev Cardiovasc Med. 2020;21:191-203. PMID 32706208
  8. Ridker PM, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752-762. PMID 30415610
  9. Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-1722. PMID 28304224
  10. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379:2097-2107. PMID 30403574
  11. Khera AV, et al. Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. N Engl J Med. 2016;375:2349-2358. PMID 27959714
  12. Wang X, et al. A zero coronary artery calcium score in patients with stable chest pain is associated with a good prognosis, despite risk of non-calcified plaques. Open Heart. 2019;6:e000945. PMID 31168373
  13. Koopman MY, et al. The Diagnostic and Prognostic Value of Coronary Calcium Scoring in Stable Chest Pain Patients: A Narrative Review. Rofo. 2022;194:257-265. PMID 35081649
  14. Maclean E, et al. Prognostic utility of semi-quantitative coronary computed tomography angiography scores in the SCOT-HEART trial. J Cardiovasc Comput Tomogr. 2023;17:393-400. PMID 37673712
  15. Koo BK, et al. Artificial Intelligence-Enabled Quantitative Coronary Plaque and Hemodynamic Analysis for Predicting Acute Coronary Syndrome. JACC Cardiovasc Imaging. 2024;17:1062-1076. PMID 38752951
  16. Burgos LM, et al. Performance of the European Society of Cardiology 0/1-hour algorithm in the diagnosis of myocardial infarction with high-sensitivity cardiac troponin: Systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care. 2021;10:279–286. PMID 32597681
  17. Anand A, et al. High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial. Circulation. 2021;143:2214-2224. PMID 33752439
  18. McClelland RL, et al. 10-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) With Validation in the HNR (Heinz Nixdorf Recall) Study and the DHS (Dallas Heart Study). J Am Coll Cardiol. 2015;66:1643-53. PMID 26449133
  19. Stone GW, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-35. PMID 21247313
  20. Ahn JM, et al. Preventive PCI or medical therapy alone for vulnerable atherosclerotic coronary plaque: Rationale and design of the randomized, controlled PREVENT trial. Am Heart J. 2023;264:83-96. PMID 37271356
  21. Bhatia HS, et al. Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis. Circulation. 2025;151:312-321. PMID 39492722
  22. Burgess S, et al. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis. JAMA Cardiol. 2018;3:619-627. PMID 29926099
  23. Gulati M, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;144:e368-e454. PMID 34709879
  24. GBD 2023 LDL Cholesterol Collaborators, et al. Global Burden of Elevated LDL-C: Findings From the Global Burden of Disease Study 2023. JAMA. 2026;336:673-698. PMID 42525403
  25. Vrints C, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45:3415-3537. PMID 39210710
  26. Reichlin T, et al. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay. CMAJ. 2015;187:E243-E252. PMID 25869867
  27. Lee KK, et al. Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome. J Am Coll Cardiol. 2019;74:2032-2043. PMID 31623760
  28. Martin SS, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the Multi-Ethnic Study of Atherosclerosis. Circulation. 2014;129:77-86. PMID 24141324
  29. Williams MC, et al. Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study. J Am Coll Cardiol. 2019;73:291-301. PMID 30678759
  30. Boeddinghaus J, et al. Safety and efficacy of the 0/1 h pathway for myocardial infarction in the emergency department: an international, pragmatic, stepped-wedge, cluster-randomised, controlled trial. Lancet. 2026. PMID 42667934
  31. Hatherley J, et al. Accelerated Diagnostic Pathways for Suspected Acute Coronary Syndrome in Practice: A Randomized Trial of 0/1-Hour vs 0/3-Hour Troponin Testing. J Am Coll Cardiol. 2026;88:1211-1221. PMID 42159533
  32. Than M, et al. ICare-FASTER: A Stepped-Wedge Cluster-Randomized Trial of High-Sensitivity Point-of-Care Troponin in the Emergency Department. Circulation. 2026. PMID 42895015

  33. Sabouret P, et al. Pelacarsen and Lp(a)HORIZON: Interpreting the Disconnect Between Lipoprotein(a) Lowering and Cardiovascular Outcomes. Am J Med. 2026. PMID 42880684

  34. Mills NL, et al. Fifth Universal Definition of Myocardial Infarction (2026): On behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS) and the Society of Thoracic Surgeons (STS) Affirmation of Value by the Society for Cardiovascular Angiography and Interventions (SCAI). Glob Heart. 2026;21:64. PMID 42666939