Effects of beta-blocker treatment on circulating biomarkers of fibrosis in patients with myocardial infarction without heart failure: A substudy of the BETAMI-DANBLOCK trial
I Lunde, L Dahle, A N Chuhan, V Bratseth, S Palmero, A Bakken, K Vikenes, P S Deeg, S Halvorsen, J Munkhaugen, D Atar, T OmlandAbstract
Background
Myocardial infarction (MI) is caused by ischemia, leading to irreversible myocardial injury, chronic inflammation and collagenous scarring, i.e., fibrosis. Beta-blockers (BB) reduce the risk of heart failure progression in MI patients with reduced ejection fraction (EF), however their use and effects in patients with preserved (pEF) or mildly reduced (mrEF) EF is debated.
Purpose
To evaluate circulating levels of fibrillar collagen peptides in MI patients without heart failure, randomized to prolonged use of BB or not.
Methods
The BETAMI-DANBLOCK trial (beta blockers after myocardial infarction in patients without heart failure) randomized patients with MI and EF≥ 40% to BBs or not. Patients (n= 5574) were followed for 3.5 years for clinical endpoints. The biobank consisted of n=490 participants (median age 61, 19% women) recruited at four sites in Norway within 7 days of the index event, where n=65 had a primary endpoint. Procollagen has peptides at amino and carboxy termini that are cleaved off by proteases prior to fibril incorporation. They can reach the circulation, e.g. type I collagen C-terminal propeptide (PICP), which provides a stoichiometric representation of collagen type I synthesis. PICP was measured by ELISA (Microvue) in serum at baseline (n=436) and after six months (n=343). Cox proportional hazards regression was used to analyze time to primary composite endpoint, i.e., all-cause death and recurrent cardiovascular event.
Results
Median (IQR) of PICP was 76 (62, 100) ng/mL at baseline and increased to 97 (77, 126) ng/mL after six months (p<0.001). Baseline PICP was higher in those with age>median vs. those <median (80 vs. 73 ng/ml, p=0.03), but not different in those with pEF (n=393; 76 (62, 99) ng/ml) vs. mrEF (n=44; 80 (61, 107) ng/ml), p=0.533. Baseline PICP was lower in those experiencing a primary endpoint vs. those without (median 70 vs. 77 ng/mL, p=0.043). ΔPICP was increased in both groups; BB users: n=116 up/30 down, and no users: n=122 up/28 down (both p<0.001), with no difference in ΔPICP between BB users (+20 (+2, +41) ng/mL) vs. no users (+24 (+5, +40) ng/mL), p=0.371 (Table). In multivariable analysis, PICP was not associated with the primary composite endpoint (hazard ratio 0.842=[95% confidence interval, 0.074, 9.530]), p=0.889. The treatment effect of BB on clinical endpoints was not modified by baseline PICP concentrations (p-for-interaction=0.404).
Conclusion
Circulating levels of PICP were lower 7 days and 6 months post-MI, in EF≥ 40% patients with a primary endpoint, suggestive of an impaired fibrotic response. PICP levels were unaffected by 6 months of BB treatment. A recent meta-analysis incorporating BETAMI-DANBLOCK reported neutral effects of prolonged BB therapy in MI patients with preserved EF, and our data provide a mechanistic correlate to this conclusion.Table