Fibrosis-Related Biomarkers and Incident Cardiovascular Disease in Older Adults

Abstract

Background Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown. Methods and Results We determined the associations of two biomarkers of fibrosis, transforming growth factor- β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction (MI), and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1,371) and PIIINP (n=2,568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β’s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein (CRP) in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per standard deviation [SD]=1.07, 95% confidence interval [CI]: 1.01-1.14) and heart failure (HR per SD=1.08, CI: 1.01-1.16), but not MI or stroke. TGF-β was not associated with any CVD outcomes in the full cohort, but was associated with total CVD (HR per SD=1.16, CI: 1.02-1.31), heart failure (HR per SD=1.16, CI: 1.01-1.34), and stroke (HR per SD=1.20, CI: 1.01-1.42) among individuals with CRP above the median, 2.3 mg/L (P-interaction < 0.05). Conclusions Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

Biomarkers of apoptosis, inflammation, and cardiac extracellular matrix remodelling in the prognosis of heart failure

“…Agarwal et al [50] measured the concentration of TGF-b1 in 1371 older subjects, who were then followed for 14 years. TGF-b1 was not associated with cardiovascular outcomes in the full cohort; however, among individuals with C-reactive protein above the median of the cohort, higher concentrations of TGF-b1 were associated with higher incidences of HF and with total cardiovascular outcomes.…”

Fibrosis markers, hip fracture risk, and bone density in older adults

“…We adjusted for age (continuous), black race, current smoking, alcohol consumption (three categories: 0 is reference, 1-7 drinks/ week, >7 drinks/week), waist circumference, diabetes, kcal expenditure (continuous), falls, thiazide use, estrogen use, glucose (continuous), prevalent CHD, eGFR based on cystatin C levels (continuous), hypertension, log 2 (CRP), and log 2 (albumin/creatinine ratio [ACR]). These results were further stratified by elevated (≥3 mg/L) or non-elevated CRP levels to examine effect modification by inflammation using cut-points we have used previously [5]; we also report p values for interaction using CRP as a continuous variable. In the subcohort with BMD measurements, linear regression analysis was used to estimate the association between TGF-β1 or PIIINP with total hip or total body BMD values.…”

“…PIIINP is a marker of new collagen formation that arises in response to growth factors during growth, fracture healing, use of medications impacting bone turnover, or chronic illnesses. It has been positively associated with a number of outcomes in CHS [5], and we had a large number of incident fractures in the subcohort with measures of PIIINP (n=310). Nonetheless, it appears that markers of ongoing fibrosis when measured late in life are unlikely to be associated with hip fractures in the oldest old.…”

“…Hence, we a priori measured TGF-β1 levels only in samples taken at the two remaining sites. Participant characteristics (including PIIINP measurements) did not differ substantially between sites that were included and excluded [5].…”

“…We also seek to determine whether any adverse effects of TGF-β1 may be amplified in the presence of systemic inflammation (as measured by C-reactive protein [CRP] levels), similar to what we observed previously for total mortality [5]. The cohort for this study is drawn from the Cardiovascular Health Study (CHS), a population-based study of individuals with a mean age of 78 years at the time of biomarker measurement.…”