Jonathan W Cunningham1, Brian L Claggett1, Eileen O'Meara2, Margaret F Prescott3, Marc A Pfeffer1, Sanjiv J Shah4, Margaret M Redfield5, Faiez Zannad6, Lu-May Chiang3, Adel R Rizkala3, Victor C Shi3, Martin P Lefkowitz3, Jean Rouleau2, John J V McMurray7, Scott D Solomon8, Michael R Zile9. 1. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 2. Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada. 3. Novartis, East Hanover, New Jersey. 4. Northwestern University Feinberg School of Medicine, Chicago, Illinois. 5. Mayo Clinic, Rochester, Minnesota. 6. Centre d'Investigations Cliniques-Plurithématique 1433, and Institut National de la Santé et de la Recherche Médicale U1116, Centre Hospitalier Regional Universitaire, French Clinical Research Infrastructure Network, Investigation Network Initiative Cardiovascular and Renal Clinical Trialists, Nancy, France. 7. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 8. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: ssolomon@bwh.harvard.edu. 9. Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina; Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina. Electronic address: zilem@musc.edu.
Abstract
BACKGROUND: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone. OBJECTIVES: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death). METHODS: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint. RESULTS: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates. CONCLUSIONS: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
RCT Entities:
BACKGROUND:Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone. OBJECTIVES: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death). METHODS: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint. RESULTS: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates. CONCLUSIONS: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
Authors: Julian C Bachmann; Simon J Baumgart; Anna K Uryga; Markus H Bosteen; Giulia Borghetti; Michael Nyberg; Kate M Herum Journal: Cells Date: 2022-05-17 Impact factor: 7.666
Authors: Yusra Zaidi; Eslie G Aguilar; Miguel Troncoso; Daria V Ilatovskaya; Kristine Y DeLeon-Pennell Journal: Cell Signal Date: 2020-11-15 Impact factor: 4.850