Cardiometabolic health-frailty phenotypes and bidirectional transitions between atrial fibrillation and heart failure: multistate trajectories and proteomic signatures.
- 1Department of Cardiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China.
- 2Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou, 310053, China; School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China; Zhejiang Engineering Research Center for "Preventive Treatment" Smart Health of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Abstract
Objective
To examine whether a joint cardiometabolic health-frailty phenotype is associated with incident atrial fibrillation (AF), incident heart failure (HF) and progression to AF-HF comorbidity, and to identify candidate circulating protein signals related to this phenotype.Methods
Among 319,048 UK Biobank participants without AF or HF, cardiometabolic status (healthy [CMH] or unhealthy [CMU]) and Frailty status (non-frail [NF] or pre-frail/frail [F]) defined four phenotypes. Cox and clock-forward multistate models estimated disease-specific and transition-specific hazards. Proteomic feature selection and exploratory mediation analyses included 28,206 participants with Olink plasma proteomic data.Results
During follow-up, 17,844 participants developed AF, 5,410 developed HF, and 2,403 and 791 progressed from AF and HF, respectively, to comorbidity. Compared with CMH-NF, CMU-F was associated with the greatest risks of incident HF (hazard ratio (HR), 2.76; 95% confidence interval (CI), 2.59-2.95) and AF (HR, 1.49; 95% CI, 1.43-1.55). Corresponding multistate HRs were 2.98 (95% CI, 2.76-3.22) for baseline-to-HF, 1.45 (1.39-1.51) for baseline-to-AF, 1.76 (1.57-1.98) for AF-to-comorbidity, and 1.27 (1.02-1.57) for HF-to-comorbidity. Positive additive interactions indicated excess risk from coexisting cardiometabolic unhealthiness and frailty. Thirteen proteins showed statistical mediation signals for both outcomes; FABP4 yielded the largest positive mediated proportions (AF, 49.8%; HF, 32.9%) and transition-specific signals for baseline-to-AF and AF-to-comorbidity.Conclusions
Coexisting cardiometabolic unhealthiness and frailty identified individuals at greatest risk of AF, HF, and subsequent comorbidity. Exploratory proteomic analyses identified FABP4 as the most consistent preliminary signal, which warrants further validation in independent cohorts.
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BibTeX
@article{cui2026cardiometabolic,
title = {{Cardiometabolic health-frailty phenotypes and bidirectional transitions between atrial fibrillation and heart failure: multistate trajectories and proteomic signatures.}},
author = {Chuanyong Cui and Banghua Liu and Guangji Zhang and Zhongyan Du and Wenke Cheng},
journal = {The journal of nutrition, health \& aging},
year = {2026},
month = oct,
doi = {10.1016/j.jnha.2026.101006},
url = {https://europepmc.org/article/MED/42858504},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cardiometabolic health-frailty phenotypes and bidirectional transitions between atrial fibrillation and heart failure: multistate trajectories and proteomic signatures.
AU - Chuanyong Cui
AU - Banghua Liu
AU - Guangji Zhang
AU - Zhongyan Du
AU - Wenke Cheng
PY - 2026
DA - 2026/10/10
JO - The journal of nutrition, health & aging
DO - 10.1016/j.jnha.2026.101006
UR - https://europepmc.org/article/MED/42858504
AB - Objective To examine whether a joint cardiometabolic health-frailty phenotype is associated with incident atrial fibrillation (AF), incident heart failure (HF) and progression to AF-HF comorbidity, and to identify candidate circulating protein signals related to this phenotype.Methods Among 319,048 UK Biobank participants without AF or HF, cardiometabolic status (healthy [CMH] or unhealthy [CMU]) and Frailty status (non-frail [NF] or pre-frail/frail [F]) defined four phenotypes. Cox and clock-forward multistate models estimated disease-specific and transition-specific hazards. Proteomic feature selection and exploratory mediation analyses included 28,206 participants with Olink plasma proteomic data.Results During follow-up, 17,844 participants developed AF, 5,410 developed HF, and 2,403 and 791 progressed from AF and HF, respectively, to comorbidity. Compared with CMH-NF, CMU-F was associated with the greatest risks of incident HF (hazard ratio (HR), 2.76; 95% confidence interval (CI), 2.59-2.95) and AF (HR, 1.49; 95% CI, 1.43-1.55). Corresponding multistate HRs were 2.98 (95% CI, 2.76-3.22) for baseline-to-HF, 1.45 (1.39-1.51) for baseline-to-AF, 1.76 (1.57-1.98) for AF-to-comorbidity, and 1.27 (1.02-1.57) for HF-to-comorbidity. Positive additive interactions indicated excess risk from coexisting cardiometabolic unhealthiness and frailty. Thirteen proteins showed statistical mediation signals for both outcomes; FABP4 yielded the largest positive mediated proportions (AF, 49.8%; HF, 32.9%) and transition-specific signals for baseline-to-AF and AF-to-comorbidity.Conclusions Coexisting cardiometabolic unhealthiness and frailty identified individuals at greatest risk of AF, HF, and subsequent comorbidity. Exploratory proteomic analyses identified FABP4 as the most consistent preliminary signal, which warrants further validation in independent cohorts.
SN - 1760-4788
ER -