Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

Q: What are the key findings of this study?

The 30-protein iPACE signature correlated with chronological age and showed higher median residuals in HFpEF patients than controls.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). Intervention: Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) signature and iPACE residual vs. Case-matched controls without HFpEF or Low/Normal iPACE groups. Primary outcome: Median iPACE residual in HFpEF vs. case-matched control group (and correlation with chronological age, ASCVD risk, and mortality) (p=<0.001).

Q: What does this research mean for the field?

A 30-protein serum immuno-proteomic aging signature (iPACE) predicts heart failure with preserved ejection fraction, atherosclerotic cardiovascular disease events, and all-cause mortality in older adults. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To develop a serum immune proteomic signature of biological age and evaluate its ability to predict atherosclerotic cardiovascular disease, heart failure with preserved ejection fraction, and mortality in older adults.

Jordan J. Baechle; Jennifer Arthur; Khiem Nguyen; Fei Wu; Matias Fuentealba; Kirk U. Knowlton; Stacey Knight; Benjamin Davies Horne; Nazish Sayed; Holden Terry Maecker; Daniel A. Winer; Nir Barzilai; Mark Davis; François Haddad; David Furman

doi:10.64898/2026.10.27.762320

November 2, 2026Open Access

Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

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Key result

Proteomic iPACE signature identifies accelerated biological aging in patients with HFpEF.

P<0.001

Why the study?

While age is a primary risk factor for CVD, accumulating evidence suggests the immune system influences the initiation and progression of CVD pathophysiology, particularly in HFpEF and ASCVD, motivating the development of an aging-related serum immune proteomic signature for cardiovascular risk in older adults.

Does a 30-protein serum immunoproteomic aging signature (iPACE) predict HFpEF, atherosclerotic cardiovascular disease risk, and mortality in adults aged 60 years or older?

Key Points

To develop a serum immune proteomic signature of biological age and evaluate its ability to predict atherosclerotic cardiovascular disease, heart failure with preserved ejection fraction, and mortality in older adults.
Calculated sex-adjusted iPACE residuals to classify premature, normal, and delayed aging phenotypes.
Tested the performance and prognostic utility of iPACE in an independent test dataset from the INSPIRE registry comprising individuals aged 60 years or older with HFpEF and case-matched controls.
iPACE correlated with chronological age in the 1KIP training cohort (Pearson R=0.84, p<0.001; MSE range: 4-7 years) and the INSPIRE test cohort (R=0.38, p<0.001; MSE=7.6 years).
Significantly higher iPACE residuals were observed in patients with an ASCVD event during follow-up (n=380, Wilcoxon p<0.001) and in participants with HFpEF compared to case-matched controls (median residual: 1.17 vs. -1.67, one-sided Wilcoxon p<0.001).
Among INSPIRE participants without HFpEF, low iPACE was associated with superior overall and ASCVD-free survival, with Cox proportional hazards regression confirming iPACE as a significant predictor of all-cause and ASCVD-related mortality.

Study Design

Type

Cohort

Multicenter

Yes

Structured PICO

Does a 30-protein serum immunoproteomic aging signature (iPACE) predict HFpEF, atherosclerotic cardiovascular disease risk, and mortality in adults aged 60 years or older?

P

Population

Older adults aged ≥60 years across two independent longitudinal US cohorts (Stanford 1KIP followed over 10 years, including n=380 with ASCVD events, and INSPIRE with HFpEF patients and case-matched controls).

E

Exposure

Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) signature, a 30-protein biological age metric derived from serum immune proteomics using elastic net regression.

C

Comparator

Case-matched controls without HFpEF (in the INSPIRE cohort) and chronological age (cAge); stratification into Low iPACE (iPACE residual <0), Normal iPACE (iPACE residual = 0), and High iPACE (iPACE residual >0) groups.

O

Outcome

Correlation with chronological age, association with HFpEF and atherosclerotic cardiovascular disease (ASCVD) risk, and prediction of all-cause and ASCVD-related mortality.hard clinical

Main Result

Absolute Event Rate: 1.17% vs -1.67%

p-value: p=<0.001

A 30-protein serum immunoproteomic signature of biological aging (iPACE) identifies accelerated aging phenotypes associated with HFpEF prevalence, ASCVD risk, and increased all-cause and cardiovascular mortality in older adults.

Limitations

Retrospective analysis limited in its ability to make causal conclusions
Limited to large healthcare networks in Northern California, Southern Nevada, and Northern Utah, which may not be generalizable to all patient populations
General variability in practice patterns between and within institutions during the study period
Retrospective analysis limited in its ability to establish causality
Geographic restriction to large healthcare networks in Northern California, Southern Nevada, and Northern Utah, which may limit generalizability
General variability in practice patterns between and within institutions during the longitudinal study period
Requires external validation in future clinical and experimental studies to verify prognostic power and pathophysiological roles of individual proteins

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Implication

Supports iPACE for detecting premature aging in HFpEF; leaves open its incremental value for ASCVD risk stratification.

Abstract

Despite advances in clinical care, cardiovascular disease (CVD) remains the leading cause of disability and mortality worldwide. While age alone is a primary risk factor for CVD, accumulating evidence suggests the immune system influences the initiation and progression of CVD pathophysiology, particularly in heart failure with preserved ejection fraction (HFpEF) and atherosclerotic CVD (ASCVD). Here, using two independent cohorts of older adults, we develop a thirty-protein signature of age based on serum immune proteomics, which correlates with HFpEF and ASCVD risk and mortality (Immuno-Proteomic Age of Cardiovascular Etiology, iPACE). We find aging-related circulating immune proteins associated with ASCVD and HFpEF-specific resilience and susceptibility that may be used as potential prognostic, diagnostic, or therapeutic targets.

Discussion

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Cite This Study

Baechle et al. (2026) conducted a cohort in Heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) signature and iPACE residual vs. Case-matched controls without HFpEF or Low/Normal iPACE groups was evaluated on Median iPACE residual in HFpEF vs. case-matched control group (and correlation with chronological age, ASCVD risk, and mortality) (p=<0.001). The 30-protein iPACE signature correlated with chronological age and showed higher median residuals in HFpEF patients than controls.

synapsesocial.com/papers/6aea772189a8acbed9c87aae https://doi.org/10.64898/2026.10.27.762320

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Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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