What does this research mean for the field?

The F2RL1 variant rs1529505 is associated with a 16% increased risk of heart failure-related mortality in a cohort of 20,650 patients. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research explores the influence of protease-activated receptor 2 (PAR2) on heart failure (HF) outcomes and mechanisms of cardiac remodeling.

February 8, 2026

Investigating the role of protease-activated receptor 2 in adverse cardiac remodeling and clinical outcomes in heart failure: insights from translational research

Key Result

The F2RL1 rs1529505 PAR2 variant is linked to 16% higher HF-related mortality and increased adverse cardiac remodeling and inflammation in heart failure patients.

Key Points

This research explores the influence of protease-activated receptor 2 (PAR2) on heart failure (HF) outcomes and mechanisms of cardiac remodeling.
Conducted transvascular right ventricular endomyocardial biopsy in HF patients.
Performed genetic analysis of the HERMES HF cohort to identify F2RL1 variants associated with HF.
Assessed relationship between HF-related mortality and the F2RL1 variant in the UK Biobank cohort.
Utilized ApoE−/− and ApoE−/− PAR2−/− mice on a Western diet for mechanistic studies.
Cardiac PAR2 upregulation is linked to increased complement C3 expression and adverse remodeling on echocardiography.
F2RL1 genetic analysis revealed a strong association with HF, pinpointing rs1529505 as a critical variant.
In the UK Biobank cohort, rs1529505 correlates with a 16% increased risk of HF-related mortality.
PAR2 deficiency in experimental models showed reduced cardiac inflammation and remodeling markers.

Structured PICO

Do genetic variants linked to increased PAR2 expression increase the risk of adverse cardiac remodeling and heart failure-related mortality?

Population

Translational study including heart failure patients undergoing transvascular right ventricular endomyocardial biopsy (n=84), the HERMES HF cohort (n=583,167), the UK Biobank HF cohort (n=20,650), and ApoE-/- mice on a Western diet.

Intervention

F2RL1 (PAR2) genetic variants (specifically rs1529505) and PAR2 deficiency (in experimental mouse models).

Comparator

Non-carriers of the genetic variant; PAR2 wild-type mice.

Outcome

Heart failure-related mortality (in UK Biobank cohort), adverse cardiac remodeling, and cardiac inflammation.hard clinical

Genetic variants linked to increased PAR2 expression are associated with adverse cardiac remodeling, inflammation, and elevated HF-related mortality, highlighting PAR2 as a potential prognostic marker and therapeutic target.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background and Aims Functional inhibition of protease-activated receptor 2 (PAR2) via inhibition of its substrate FXa has been shown to reduce adverse clinical outcomes in various HF subgroups, though the mechanism remains unclear. This study aims to conduct a comprehensive translational investigation of the role of PAR2 in HF. Methods We conducted a biopsy study in HF patients without underlying conditions (n=84) using transvascular right ventricular endomyocardial biopsy (EMB). An exploratory genetic analysis of the HERMES HF cohort (n=583,167) identified F2RL1 (PAR2) variants associated with HF, and the UK Biobank HF cohort (n=18,239) was used to assess the relationship between HF-related mortality and the F2RL1 variant most strongly linked to its expression. Mechanistic studies included ApoE−/− and ApoE−/− PAR2−/− mice on a C57Bl/6 background fed a Western diet (21% fat, 0.15% cholesterol) for four months starting at eight weeks of age. Findings The biopsy study demonstrated that cardiac PAR2 upregulation correlates with increased complement C3 expression, higher NT-proBNP levels, and adverse cardiac remodeling on echocardiography, reinforcing its role in HF progression. Genetic analysis identified a strong association between F2RL1 expression and HF, with rs1529505 emerging as the most robustly linked variant. In the UK Biobank cohort (n = 20,650), rs1529505 was associated with a 16% increased risk of HF-related mortality (OR = 1.16 1.02-1.32, p = 0.025). Experimental models confirmed a protective effect of PAR2 deficiency, leading to reduced cardiac inflammation (reduced IL-6 and C3) and remodeling markers. Interpretation Genetic variants linked to increased PAR2 expression were associated with adverse cardiac remodeling, heightened cardiac inflammation, and elevated HF-related mortality. Notably, the rs1529505 variant emerges as a promising prognostic marker and therapeutic target, potentially paving the way for personalized treatment strategies in HF management.

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