Collagen Biomarkers and Incidence of New Onset of Atrial Fibrillation in Subjects With No Overt Cardiovascular Disease at Baseline

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Investigation of atrial fibrosis in the pathogenesis of atrial fibrillation (AF)

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Atrial fibrillation (AF) is an irregular and often rapid heart rate that can increase the risk of stroke, heart failure, and other heart-related issues. It may lead to severe complications with significant rates of morbidity and mortality. Atrial fibrillation can lead to blood clots forming in the heart that may circulate to other organs and block blood flow. Treatments for AF include medications and other interventions seeking to alter the heart’s electrical system. With changes in their heart rate, patients suffering from AF for extended periods of time also experience profound modification in heart structure.
Atrial fibrosis has emerged as an important pathophysiological contributor and has been linked to AF recurrence, resistance to therapies, and severe complications. Cardiac fibroblasts are essential cell types in the heart, responsible for homeostasis of the extracellular matrix. However, upon injury, these cells transform into myofibroblast phenotypes and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy, and apoptosis, and ultimately leads to the progression of heart failure.
What if clinicians could find a way to track, over time, the genesis of cardiac fibrosis that could lead to atrial fibrillation?
That is exactly what Daniel A. Duprez discloses in this article. He conducted a clinical study over 10 years on a multi-ethnic population of more than 3,000 patients. With none of the patients having overt cardiovascular disease at the beginning of the study, he followed-up on the appearance of atrial fibrillation among them over time.
He paid particular attention to monitoring the procollagen type III N-terminal propeptide (PIIINP), which reflects collagen synthesis and degradation during fibrosis. He showed that elevated levels of plasma PIIINP could be correlated with an increased risk of contracting atrial fibrillation.
The predictive value of this collagen biomarker for AF offers new perspectives in the early detection of patients and will prevent more severe cardiovascular diseases and complications.
Improved understanding of the mechanisms controlling atrial fibrosis, including monitoring PIIINP, will open new opportunities for AF prevention and management


Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). Plasma procollagen type III N-terminal propeptide (PIIINP) reflects collagen synthesis and degradation while collagen type I carboxy-terminal telopeptide (ICTP) reflects collagen degradation. We aimed to study baseline plasma PIIINP and ICTP and their associations with incident AF in participants initially free of overt cardiovascular disease.
In a stratified sample of the Multi-Ethnic Study of Atherosclerosis, initially aged 45-84 years, 3071 participants had both PIIINP and ICTP measured at baseline. Incident AF in 10-year follow-up was based on a hospital International Classification of Diseases code for AF or atrial flutter, in- or outpatient Medicare claims through 2011 (primarily in those aged 65-84 years), or ECG 10 years after baseline (n=357). The associations of PIIINP and ICTP with incident AF were estimated using Poisson regression with follow-up time offset.
Baseline PIIINP (5.50±1.55 µg/L) and ICTP (mean±SD, 3.41±1.37 µg/L) were positively related (both P<0.0001) to incident AF in a model adjusting for age, race/ethnicity, and sex, with an apparent threshold (relative incidence density 2.81 [1.94-4.08] for PIIINP ≥8.5 µg/L [3.5% of the sample] and 3.46 [2.36-5.07] for ICTP ≥7 µg/L [1.7% of the sample]). Findings were attenuated but remained statistically significant after further adjustment for systolic blood pressure, height, body mass index, smoking, and renal function. Additional adjustment for other risk factors and biomarkers of inflammation did not alter conclusions. Plasma collagen biomarkers, particularly at elevated levels, were associated with excess risk for AF.


Circulation: Arrhythmia and Electrophysiology. 2018 Oct;11(10).

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