Background: Cardiac extra-cellular matrix (ECM) fibrosis plays an important role in the pathophysiology of heart failure (HF). It may provide electrical heterogeneity and a substrate for arrhythmogenicity, which may cause sudden cardiac death (SCD). Methods: Twenty-one patients with manifestations of HF and a left ventricular ejection fraction (LVEF) ≤50% were enrolled. The median age was 62 years and median LVEF was 33%. Time- and frequency-domain analysis of heart rate variability (HRV) on 24 h ambulatory electrocardiography recording was assessed. Serum markers of ECM turnover including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. Results: The serum PIIINP concentration was correlated significantly with standard deviation of all normal to normal R-R intervals (SDNN) (r=–0.722, p=<0.001), percentage of adjacent NN interval differences >50 ms (pNN50) (r=–0.528, p=0.014), percentage of adjacent NN interval differences >20 ms (pNN20) (r=–0.545, p=0.002), very low frequency (VLF) (r=–0.490, p=0.024), low frequency (LF) (r=–0.491, p=0.024), and high frequency (HF) (r=–0.513, p=0.018). PINP, MMP-2, -9, TIMP-1 were not correlated with time- and frequency-domain analysis of HRV. Conclusions: PIIINP was significantly correlated with time- and frequency-domain analysis of HRV in HF patients. PIIINP is a potential serological marker to evaluate cardiac autonomic control and risk of SCD in HF patients. Clin Chem Lab Med 2010;48:1821–7.