Editor's Note: This article is based on Patton KK, Heckbert SR, Alonso A, Bahrami H, Lima JA, Burke G, Kronmal RA. N-terminal pro-B-type natriuretic peptide as a predictor of incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis: the effects of age, sex and ethnicity. Heart 2013 Dec; 99(24):1832-6.

Synopsis of the Study

Since atrial fibrillation (AF) remains the most common sustained arrhythmia in clinical practice, there is a constant need to identify risk factors and biomarkers that can predict its development and propagation. N terminal pro-brain natriuretic peptide (NT-proBNP) is a peptide neurohormone that is secreted by cardiac myocytes in response to ventricular wall stress and overload and is an established biomarker for ventricular dysfunction.^1,2 Previous studies have identified the association of NT-proBNP with incident AF.^3,4; however, these studies were in mostly homogeneous populations.

Patton and colleagues aimed to determine if NT-proBNP levels predict AF in an ethnically diverse cohort from the Multi-Ethnic Study of Atherosclerosis (MESA) of over 6800 participants between the age of 45 and 84 years, comprised of approximately 38% white, 28% Black, 22% Hispanic and 12% Asians.^5,6 A final total of 5518 participants free from existing AF were included in the analyses. NT-proBNP levels were measured from frozen samples that had been obtained at the index visit and were analyzed using standard immunoassay (Roche Diagnostics, Indianapolis, IN). Participants were followed for 7.6 years for evaluation of the primary endpoint of incident AF or atrial flutter diagnosed by MESA event detection protocol or CMS reporting.

Of the 5518 participants, 267 (4.8%) developed AF. The factors associated with incident AF were advanced age, male sex, white race, higher systolic blood pressure, and increased LV mass and low LV ejection fraction on MRI. Body mass index (BMI) and diabetes were not associated with incident AF. When analyzed continuously, NT-proBNP levels were very strongly associated with incident AF, with unadjusted hazard ratios (HR) of 2.6 (95% CI 2.4 to 3.0) per SD and adjusted HR of 2.2 (95% CI 1.9-2.5) [adjusted for age, sex, race, BMI, height, smoking, hypertension and diabetes]. When categorized into quintiles, the highest quintile of NT-proBNP had an 11-fold increased risk of incident AF compared to the lowest quintile (adjusted HR 11.4 [95% CI 5.1 to 25.3]). In addition, NT-proBNP was a stronger predictor of AF in women (HR 3.5 vs. 2.5, respectively; p value for interaction of <0.01) and in younger subjects (HR 3.0 vs. 2.0, respectively; p value for interaction of <0.05). There were no statistical interactions by ethnicity in the association of NT-proBNP and incident AF.

The authors concluded that a single baseline level of NT-proBNP was a strong predictor of incident AF in a large heterogeneous population from the MESA study. The association was found to be stronger in women and in younger participants. There were racial differences in the incidence of AF; however there was no statistically significant difference noted in the association of NT-proBNP with AF between various ethnic groups.

Commentary

This is an interesting study by Patton and colleagues investigating the association of NT-proBNP with incident AF in a large heterogeneous population from the MESA study. Consistent with existing literature,^7,8 the study showed that older age, male sex, white race, and hypertension were significantly associated with incident AF. However, contrary to previous studies, diabetes and body mass index were not associated with AF.^9,10

One likely explanation for this association is the chronically elevated cardiac filling pressures in these subjects, leading to atrial stretch and associated changes, leading to atrial remodeling and fibrosis. These changes predispose to AF and are also known to elevate levels of NT- proBNP.^11,12 Conditions such as left ventricular hypertrophy and subsequent diastolic dysfunction increase the risk of AF ¹⁰ and are associated with increased levels of NT-proBNP. ¹³ However, in the study, association of NT-proBNP with AF remained significant even after adjustment for LV mass as measured on MRI, suggesting other factors likely also play a role in incident AF.

There are several strengths of the study. The study describes the risk factors of AF in a large, ethnically diverse population. So far studies previous studies have only looked at relatively homogeneous populations.^4,5 It confirms that baseline NT-proBNP performs equally well in predicting incident AF across various ethnicities but also suggests improved performance among women and younger individuals, suggesting a possible target population for clinical application.

The main limitation of this study is that incident AF may have been underestimated due to missed cases of paroxysmal and asymptomatic AF. That said, the association between baseline NT-proBNP and clinically relevant AF was significant even when adjusted for risk factors. NT-proBNP is known to be stable in frozen state for several months; however, stability for over 7 years is unknown.¹⁹ Lastly, there were no direct comparisons with other markers of structural disease such as troponins.

In conclusion, this study shows baseline NT-proBNP levels to be a strong independent predictor of incident AF in a large, heterogeneous population and lends support to the concept that pressure and volume overload leading to ventricular stretch (elevated NT-proBNP) likely increases the load on the atria and subsequent risk for atrial arrhythmias. The incorporation of routine measurement of NT-proBNP levels to predict new onset AF in healthy population will require demonstration of improved performance of risk prediction models, and the clinical utility of NT-proBNP measurement for assessing AF risk will require therapies that lower NT-proBNP levels and reduce risk of AF.

References

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3. Patton KK, Ellinor PT, Heckbert SR, Christenson RH, DeFilippi C, Gottdiener JS, Kronmal RA., et al. N-terminal pro-b-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the cardiovascular health study. Circulation 2009; 120:1768–74.
4. Rienstra M, Van Gelder IC, van den Berg MP, Boomsma F, van Veldhuisen DJ. Natriuretic peptides in patients with atrial fibrillation and advanced chronic heart failure: determinants and prognostic value of (NT-) ANP and (NT-pro) BNP. Europace 2006; 8:482-7.
5. Patton KK, Heckbert SR, Alonso A, Bahrami H, Lima JA, Burke G, Kronmal RA. N-terminal pro-B-type natriuretic peptide as a predictor of incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis: the effects of age, sex and ethnicity. Heart 2013; 99:1832-6.
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10. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998; 82(8A):2N-9N.
11. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96:1180-4.
12. Grewal J, McKelvie R, Lonn E, Tait P, Carlsson J, Gianni M, Jarnert C, Persson H. BNP and NT-proBNP predict echocardiographic severity of diastolic dysfunction. Eur J Heart Fail 2008; 10: 252-9.
13. Costello-Boerrigter LC, Boerrigter G, Redfield MM, Rodeheffer RJ, Urban LH, Mahoney DW. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006; 47:345-53.
14. Yeo KT, Wu AH, Apple FS, Kroll MH, Christenson RH, Lewandrowski KB, Sedor FA, Butch AW. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta 2003; 338: 107-15.

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Biomarkers, Myocytes, Cardiac, Natriuretic Peptide, Brain, Neurotransmitter Agents, Peptides, Risk Factors, Ventricular Dysfunction

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