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ARNI favorably changes biomarkers of ECM homeostasis in HFpEF

onlinejacc.org
Literature - Cunningham JW, Claggett BL, O’Meara E, et al. - J Am Coll Cardiol 2020;76:503–14

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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2. Duprez DA, Gross MD, Kizer JR, Ix JH, Hundley WG, Jacobs DR. Predictive value of collagen biomarkers for heart failure with and without preserved ejection fraction: MESA (Multi- Ethnic Study of Atherosclerosis). J Am Heart Assoc 2018;7:e007885.

3. Zile MR, Jhund PS, Baicu CF, et al., for the PARAMOUNT Investigators. Plasma biomarkers reflecting profibrotic processes in heart failure with a preserved ejection fraction: data from the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved

Ejection Fraction Study. Circ Heart Fail 2016;9:e002551.

4. Zile MR, Desantis SM, Baicu CF, et al. Plasma biomarkers that reflect determinants of matrix

composition identify the presence of left ventricular hypertrophy and diastolic heart failure. Circ Heart Fail 2011;4:246–56.

5. Zannad F, Alla F, Dousset B, Perez A, Pitt B, Rales Investigators. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with

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6. Iraqi W, Rossignol P, Angioi M, et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

(EPHESUS) study. Circulation 2009;119:2471–9.

7. Zile MR, O’Meara E, Claggett B, et al. Effects of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Coll Cardiol 2019;73:795–806.

8. Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial. J Am Coll Cardiol HF 2017;5:471–82.

Find this article online at J Am Coll Cardiol

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