Demystifying NT-proBNP as a Screening Marker for Underwriting Purposes
September  2017


Introduction
Since the early 2000s cardiac biomarkers have become the cornerstone for diagnosis, risk stratification and therapeutic decision in cardiovascular diseases, specifically NT-proBNP (congestive heart failure) and cardiac troponins1 (acute coronary syndromes).

NT-proBNP is widely used in the emergency clinical setting (diagnosis and triage) in the U.S., much less in Canada, to differentiate acute shortness of breath or other non-specific symptoms and signs potentially caused by cardiovascular disease versus pulmonary or other causes. It is also a clinical predictor of short-term mortality for patients with acute heart failure. Given the longer biological half-life of NT-proBNP (better stability with less fluctuation compared to BNP), this makes an ideal marker for insurance screening, given the longer transportation from the collection site to the insurance laboratory. As well, the NT-proBNP assays have stricter licensing requirements, including the use of the same antibodies making the results more comparable.

Relative mortality varies not only by values but also by gender and age (specifically at age 50 and older), whereby higher values (e.g. falsely elevated) may classically be normal in women and the elderly population. Therefore, abnormal results must be interpreted in the appropriate context.

Natriuretic peptides (NP) can be elevated in individual with asymptomatic or symptomatic left ventricular dysfunction and is associated with coronary artery disease and myocardial ischemia, thus gaining popularity as a less expensive replacement for the traditional routine resting ECG in presumably healthy applicants.

Clinical indications and applications
Natriuretic peptides, brain-type (BNP) or N-terminal (NT-proBNP) are produced primarily by the heart and released in response to increased wall tension. Their main use is to help establish the diagnosis of heart failure in emergency care patients when the diagnosis is uncertain and to exclude (rule out) a pulmonary cause for the patient’s symptoms of shortness of breath and edema. Generally, the higher the value the more likely the presence (rule in) and severity of the heart dysfunction. However, the test is sensitive to other biological factors such as: age, gender, renal function and diastolic dysfunction. There are numerous heart failure conditions, other than chronic, related to elevated natriuretic peptides (NP):

  • Coronary heart disease
  • Atrial fibrillation
  • Diastolic dysfunction
  • HTN
  • Valvular heart diseases
  • Myocarditis
  • Renal failure, acute or chronic
  • Pulmonary diseases, such as pulmonary hypertension, severe COPD, etc.
  • Liver cirrhosis
  • Hyperthyroidism

Interestingly, falsely lower than expected or lack of NP values have been reported in moderate to morbid obesity, flash pulmonary edema, pericardial constriction, acute (within the 1st hour) congestive heart failure or ventricular inflow obstruction (e.g. hypertrophic obstructive cardiomyopathy, mitral stenosis, atrial myxoma).

Biochemistry and action
NP are cardiac neurohormones (protein molecules) that are secreted by the ventricular muscle in response to volume or pressure overload. The natural action of the NP is to help the heart regulate vasodilatation, natriuresis (urinary sodium excretion) and diuresis (increased urinary excretion) by regulating blood pressure, fluid homeostasis (sodium and water balance) and glomerular filtration. They are markers for atrial and ventricular distension resulting from an increased intracardiac pressure. Several studies have demonstrated that the concentration of circulating natriuretic peptides (BNP or NT-proBNP) increases with the severity of heart dysfunction based on the NYHA classification2. NT-proBNP is the terminal fragment of BNP.

Conclusion
Originally thought to only be a diagnostic tool to rule out (exclude) heart failure in patients with shortness of breath in the emergency department, NT-proBNP has emerged as an adjunct diagnostic and prognostic biomarker for various cardiovascular diseases as it reflects the hemodynamic myocardial stress of the underlying pathology. Studies have shown the correlation between increased NT-proBNP values and all-cause mortality. Findings show that NP values typically increase with progressing age or decreasing left ventricular function, coronary artery disease and even valvular heart disease.

Left ventricular (LV) dysfunction can occur as part of coronary heart disease, arterial hypertension, valvular heart disease and primary myocardial disease. If the LV dysfunction remains untreated, it will progress and the potential for sudden cardiac death is high. Chronic cardiac insufficiency is a clinical syndrome caused by the impairment of the cardiac pumping ability. NT-proBNP increases with the increasing level of heart dysfunction, reflecting the severity of the underlying disease.

Because NT-proBNP is very sensitive, it can also allow the detection of milder forms of cardiac dysfunction in asymptomatic applicants with silent ischemic or structural heart diseases3.  This explains its growing popularity as an independent underwriting screening tool in lieu of  resting and exercise ECG’s. As well, NT-proBNP has the potential to be used as a reflex for applicants with uncontrolled HTN, Diabetes mellitus, COPD, chronic kidney disease and rheumatic arthritis to assess the disease burden on the individual’s prognosis related to premature cardiovascular or renal mortality.

For underwriting purposes, abnormal NT-proBNP values in the absence of admitted cardiovascular history should be adequately investigated to rule out any underlying, silent or asymptomatic, left ventricular dysfunction.

Notes

  1. http://www.cmaj.ca/content/173/10/1191.full
  2. https://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp
  3. http://www.rochecanada.com/content/dam/roche_canada/en_CA/documents/package_inserts/ProBNPII-04842464190-EN-V9-CAN.pdf

Further reading

  • Bay M., Kirk V., Parner J, Hassager C., Nielsen H., Krogsgaard K., Trawinski J., Boesgard S., Aldershvile J.; NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function; Heart 2003;89:150-154
  • Braun R.; NT ProBNP – Serum marker for ventricular dysfunction and CAD; On-The-Risk vol.23, n.2 (2007) p.48
  • Clark M., Kaufman V., Fulks M., Stout R.L., Dolan V.F.; NT-proBNO as a predictor of all-causse mortality in a population of insurance applicants; J Insur Med (2014) 44:7-16 and On-The-Risk vol.30 n.2 (2014) p.64
  • Fulks M. & Stout R.L.; Using NT-proBNP to improve risk assessment for applicants with heart disease; On The Risk vol.33 n.2 (2017) p.75
  • Illango R.K.; Utilizing NT-proBNP in the selection of risks for Life insurance; J Insur Med 2007;39:182-191
  • Januzzi J.L., von Kimmenade R., Lainchbury J., Bayes-Genis A., Ordonez-Llanos J., Santalo-Bel M., Pinto Y.M., Richards M.; NT-proNBP testing for diagnosis and short-term prognosis in acute destabilized heart fairlure: an international pooled analysis of 1256 patients; European Heart Journal (2006);27:330-337
  • MacKenzie R.; NT-proBNP and Life insurance revisited; J Insur Med 2014; 44:3-6
    Weber M., Hamm C.; Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine; Heart 2006;92:8.43-8.49