Cardiac Biomarkers for Diagnosis, Prognosis, and Therapy Guidance

Cardiac Biomarkers for Diagnosis, Prognosis, and Therapy Guidance

Reduction of circulating cardiac biomarkers is often associated with improved prognosis, making them potentially useful in therapy guidance

April16th,2020
Michelle Dotzert, PhD

Cardiac biomarkers are enzymes, hormones, and proteins released into circulation as a result of cardiac stress or damage. ­They are valuable adjuncts to current diagnostic methods, especially for diagnosis among patients presenting with breathlessness for the first time, as chest x-rays do not offer high sensitivity and specificity, and echocardiograms are not always feasible in an acute setting. Several cardiac biomarkers have been identified for their diagnostic and prognostic value, and others are being explored for their potential to guide therapy. ­These include proteins associated with myocardial injury, neurohormonal activation, and remodeling processes.

Biomarkers for Diagnosis

  • BNP (B-type natriuretic peptide)
  • NT-proBNP (N-terminal pro B-type natriuretic peptide)
  • ANP (atrial natriuretic peptide)
  • MR-proANP (mid-regional pro atrial natriuretic peptide) 

­The natriuretic peptides are considered the gold standard biomarkers. BNP and NT-proBNP assays are widely used, and are useful to support the diagnosis of heart failure (HF). ANP is also produced in patients with HF, however its shorter half-life (< 5 minutes) poses challenges for detection. Novel assays are designed to detect its stable midregional sequence (MR-proANP).

Biomarkers for Prognosis

  • BNP (B-type natriuretic peptide)
  • NT-proBNP (N-terminal pro B-type natriuretic peptide)
  • MR-proANP (mid-regional pro atrial natriuretic peptide)
  • cTnT (cardiac troponin T) and cTnI (cardiac troponin I)
  • ADM (adrenomedullin)           
  • MR-proADM (mid-regional segment of pre-proADM)
  • ST2 (suppression of tumorigenicity 2; interleukin-1 receptor-like 1)
     Galectin-3

In addition to the natriuretic peptides, cardiac troponins (cTnT, cTnI) are released in response to myocardial infarction, inflammation, apoptosis, and cytotoxicity. Cardiac troponins are the core biomarker for myocardial infarction diagnosis. Abnormal circulating cardiac troponins are also found in patients with HF, and are associated with increased mortality rates. ADM is mediated by vasoactive hormones, and is elevated as a result of increased volume overload. Th­e mid-regional segment of its precursor (MR-proADM) is released in equimolar concentrations, but has a longer half-life making it a superior marker. ST2 has been shown to be associated with adverse outcomes and mortality risk, and has prognostic value in both acute and chronic heart failure. Galectin-3 is a surrogate marker of cardiac remodeling and fibrosis, and is correlated with the development of HF.

Biomarkers for therapy guidance

Reduction of circulating cardiac biomarkers is often associated with improved prognosis. As such, their use for therapy guidance has been proposed. According to the American College of Cardiology Foundation and American Heart Association, “BNP- or NT-proBNP-guided HF therapy can be useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a well-structured HF disease management program” (Class IIa, Level of Evidence: B). The following are details on studies that are currently investigating biomarkers for use in therapy guidance:

STARS-BNP (Systolic Heart Failure Treatment Supported by BNP)

Patients: New York Heart Association functional class II to III patients considered optimally treated with angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics.  

BNP group: Therapy increased with the aim of lowering plasma BNP levels (target <100 pg/ml).

Clinical group: Therapy adjusted according to the opinion of the investigator on the basis of physical examination and paraclinical and biological parameters.

Primary endpoint: Unplanned hospital stays for heart failure or death related to heart failure. 

Results: In optimally treated CHF patients, the BNP-guided strategy reduced the risk of CHF-related death or hospital stay.

PROTECT (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting)

Patients: Patients with HF due to left ventricular systolic dysfunction.

NT-proBNP group: Standard HF management with a goal of minimizing HF symptoms and achieving maximal dosages of therapies with proven mortality benefit in HF, with treatment adjustments to reduce NT-proBNP concentrations ≤1000 pg/ml.

Standard of care group: Standard HF management with a goal of minimizing HF symptoms and achieving maximal dosages of therapies with proven mortality benefit in HF.

Primary endpoint: Total cardiovascular events for a 1-year period.

Results: NT-proBNP-guided therapy was superior to standard of care, with reduced event rates, improved quality of life, and favorable effects on cardiac remodeling.

BATTLE-SCARRED (NT-proBNP-Assisted Treatment Lessen Serial Cardiac Readmissions and Death)

Patients: Patients admitted to a single hospital with heart failure.

NT-proBNP-guided group: Titration of medication aimed at reducing plasma levels of NT-proBNP to <150 pmol/l.

Clinically-guided group: Intensive standardized clinical assessment, with trial-based drug doses. Heart failure scores ≥ 2.0 triggered escalation of drug therapy according to a pre-set algorithm.

Usual care group: Management undertaken by primary care with or without additional attendance of hospital cardiology or specialist heart failure clinics as requested by their primary care physician.

Primary outcomes: All-cause mortality and the composite of death plus hospitalization for heart failure.

Results: NT-proBNP-guided and clinically-guided groups demonstrated lower 1-year mortality compared to usual care group. 3-year mortality reduced in patients ≤75 years of age receiving NT-proBNP-guided treatment compared to clinically-guided and usual care groups.

TIME-CHF (Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure)

Patients: Patients aged 60 years or older with systolic heart failure (ejection fraction ≤ 45%, New York Heart Association class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal.

NT-proBNP-guided group: Therapy prescribed according to European Society of Cardiology and American College of Cardiology/American Heart Association guidelines with predefined escalation rules simulating clinical practice to reduce N-terminal BNP levels to less than 400 pg/ml (<75 years) and <800 pg/ml (>75 years) and NYHA class of II or less.

Symptom-guided group: Therapy prescribed according to European Society of Cardiology and American College of Cardiology/American Heart Association guidelines with predefined escalation rules simulating clinical practice to reduce symptoms to dyspnea NYHA class of II or less.

Primary outcomes: 18-month survival free of all-cause hospitalizations and quality of life assessed by structured validated questionnaires.

Results: NT-proBNP-guided therapy did not improve overall clinical outcomes or quality of life compared to symptom-guided treatment.

PRIMA (Can Pro-brain-natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?)

Patients: Patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission.

NT-proBNP-guided group: Treatment guided by individually set NT-proBNP defined by the lowest level at discharge or 2 weeks thereafter.

Clinically-guided group: Treatment determined by clinical assessment. A therapy advisor was designed to give individual treatment advice depending on several individual variables (cause of HF, left ventricular ejection fraction, clinical signs of heart failure, and creatinine clearance).

Primary endpoint: Number of days alive outside the hospital after index admission.

Results: NT-proBNP-guided therapy resulted in advanced detection of HF-related events and influenced therapy, but did not provide significant clinical improvement in terms of morbidity and mortality.


Michelle Dotzert, PhD

Michelle obtained her PhD in Kinesiology from the University of Western Ontario. Her research examined the effects of exercise training on skeletal muscle lipid metabolism and insulin resistance in the context of Type 1 Diabetes.