Diastolic Left Ventricular Function in Relation to Urinary and Serum Collagen Biomarkers in a General Population

Abstract

Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e’ decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e’ increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e’ decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p≤0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure.

Conventional and Ambulatory Blood Pressure as Predictors of Diastolic Left Ventricular Function in a Flemish Population

“…Guideline-driven echocardiographic criteria 24,25 to stage patients with advanced diastolic LV dysfunction leave a large proportion of people unclassified in population studies. As we reported previously, 32 the threshold of 7 cm/s for e 0 corresponds with the 10th percentile of the distribution in the current study population and the thresholds 14 for E/e 0 and 34 mL/m 2 for LAVI are equivalent to the 95th percentiles of their distribution. Among 793 Flemish followed up for 5 years, the multivariable-adjusted hazard ratios per 1-SD decrease (P=0.001) in e 0 amounted to 2.50 and 3.66 for cardiovascular and cardiac complications, respectively.…”

Urinary Peptidomic Biomarker for Personalized Prevention and Treatment of Diastolic Left Ventricular Dysfunction

“…The studies summarized below are embedded in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) and Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET) . FLEMENGHO is a family‐based population study, for which recruitment started in 1985.…”

“…This justified the search for novel biomarkers specific for diastolic LV dysfunction at an early stage long before irreversible cardiac damage sets in. The relation of the echocardiographically assessed diastolic LV function (2009 to 2013) with HF1 measured ≈5 years earlier (2005 to 2010) was assessed in 645 FLEMENGHO participants . In multivariable‐adjusted analyses, per 1‐SD increment in HF1, e’ was –0.193 cm s –1 lower (95% CI, –0.352 to –0.033; p = 0.018) and E/e’ 0.174 units higher (95% CI, 0.005 to 0.342; p = 0.043).…”

Predictive Value of Collagen Biomarkers for Heart Failure With and Without Preserved Ejection Fraction: MESA (Multi‐Ethnic Study of Atherosclerosis)

“…No collagen biomarker was associated with hospitalization for HF in participants with HFrEF, and carboxyl‐terminal peptide of procollagen type I was not associated with outcome in the cohort or its subgroups. Zhang et al recruited 782 subjects at random (mean age, 50.5 years) from FLEMENGHO (Flemish Study on Environment, Genes, and Health Outcomes) . They assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus: 182 participants (23.3%) had subclinical diastolic LV dysfunction, on the basis of age‐specific echocardiographic criteria.…”

“…In a smaller subgroup of the CHS (880 participants; mean age, 77 years), serum levels of carboxyl-terminal peptide of procollagen type I, ICTP, and PIIINP were measured in 4 groups: HFrEF (n=146), HFpEF (n=175), controls with CVD risk factors but not HF (n=280), and healthy controls free of CVD (n=279). 17 In healthy controls with CVD risk factors, 25 They assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus: 182 participants (23.3%) had subclinical diastolic LV dysfunction, on the basis of age-specific echocardiographic criteria. They measured serum carboxylterminal peptide of procollagen type I, ICTP, and PIIINP.…”