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Be part of the knowledge.™ARNI favorably changes biomarkers of ECM homeostasis in HFpEF
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Introduction and methods
It has been suggested that changes in myocardial extracellular matrix (ECM) homeostasis occur during development of heart failure (HF) in patients with HFrEF and HFpEF. Changes in synthesis, processing, degradation and turnover of proteins such as collagen may result in structural remodeling [1]. These changes can be determined by measuring circulating biomarkers [2-6], including propeptides of collagen (N-terminal propeptide of collagen I [PINP] and N-terminal propeptide of collagen III [PIIINP]), soluble ST2 (sST2) which enhances activation of fibroblasts (collagen-producing myocardial cells), collagen I telopeptides (CITPs) which are released during collagen turnover and degradation, and tissue inhibitor of matrix metalloproteinase (TIMP-1) which inhibits degradation of collagen.
In HFrEF patients, sacubitril/valsartan favorably altered circulating biomarkers [7] and thereby likely inhibits fibrosis. It is unknown whether this is also true for HFpEF patients.
Data from the PARAGON-HF [8] were used to investigate whether 1) circulating biomarkers that reflect determinants of ECM homeostasis are abnormal in HFpEF patients; 2) baseline levels of these biomarkers and changes from baseline predict HF events; and 3) treatment with sacubitril/valsartan compared to valsartan alone favorably changed levels of these biomarkers.
PARAGON-HF was a multicenter, double-blind clinical trial and enrolled patients with chronic HFpEF who were randomized to sacubitril/valsartan or valsartan alone. The primary endpoint, a composite of total (first and recurrent) hospitalizations for HF and CV death, just missed significance in the PARAGON-HF trial .
For this biomarker substudy, data of the five biomarkers sST2, PINP, PIIINP, CITP, TIMP-1 were evaluated. Biomarkers were measured at baseline (n=1135), 16 weeks (n=1113) and 48 weeks (n=1016) after randomization.
Main results
- At 16 weeks, sacubitril/valsartan decreased TIMP-1 by 8% (95% CI: 6% to 10%, P<0.001), sST2 by 4% (95% CI: 1% to 7%, P=0.002), and PIIINP by 3% (95% CI: 0% to 6%; P=0.04) compared with valsartan. CITP was increased by 4% (95% CI: 1% to 8%, P=0.02) with sacubitril/valsartan compared with valsartan. No differences were observed for PINP between treatment groups.
- At 48 weeks, decrease in TIMP-1 and sST2 with sacubitril/valsartan compared with valsartan was maintained.
- Effect of sacubitril/valsartan on biomarkers compared to valsartan was similar in men and women, and those with higher and lower LVEF.
- Higher TIMP-1 levels were independently associated with risk of the primary endpoint in a model including all biomarkers and clinical covariates.
- After adjustment for baseline biomarkers levels and covariates, changes in TIMP-1 (rate ratio [RR]: 1.23 per SD increase; 95% CI: 1.03 to 1.47, P= 0.02), sST2 (RR: 1.15 per SD increase; 95% CI: 1.02 to 1.31, P=0.03), and CITP (RR: 1.26 per SD increase; 95% CI 1.03 to 1.55; P=0.03) were associated with the primary endpoint.
Conclusion
In a subanalysis of the PARAGON-HF trial, higher levels of TIMP-1 were associated with risk of the primary endpoint. Treatment with sacubitril/valsartan resulted in favorable changes in some biomarkers (TIMP-1 and sST2) and changes in TIMP-1 were associated with risk of the primary endpoint. These results suggest that changes in biomarkers reflecting ECM homeostasis may lead to myocardial fibrosis and contribute to HFpEF pathogenesis and prognosis. Sacubitril/valsartan may result in beneficial outcomes by reducing fibrosis in HFpEF patients.
References
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