Unraveling the choline pathway in heart failure risk and outcomes: a systematic review and meta-analysis
Bibliographic record
Abstract
Abstract Background Metabolomics has emerged as a powerful tool to elucidate novel biomarkers and mechanisms in heart failure (HF) pathophysiology. Choline and its metabolites—phosphatidylcholine (PC), trimethylamine N-oxide (TMAO), betaine, and dimethylglycine (DMG)—play crucial roles in metabolism, inflammation, and cardiovascular function, yet their associations with HF risk and progression remain incompletely understood. Purpose This systematic review and meta-analysis aimed to evaluate the relationship between circulating levels of choline, PC, TMAO, betaine, and DMG with the development of new-onset HF and adverse clinical outcomes in patients with established HF. Methods A comprehensive search of MEDLINE, EMBASE, and PubMed was conducted from inception to February 2025. Prospective cohort studies examining plasma choline, PC, TMAO, betaine, and DMG in relation to HF incidence or adverse clinical outcomes were included. Pooled hazard ratios (HR) with 95% confidence intervals (CI) were calculated using random-effects meta-analyses. Results Nine prospective cohort studies comprising ten populations (n=267,569) were analysed. Elevated choline levels were significantly associated with increased HF incidence (HR 1.33, 95% CI 1.07–1.66, p=0.0107). In patients with HF, choline showed a positive but non-significant association with a composite of adverse HF outcomes (HR 1.13, 95% CI 0.91–1.40, p=0.2737). Higher PC levels were significantly associated with an increased HF incidence (HR 1.25, 95% CI 1.16–1.34, p<0.0001). Among patients with established HF, elevated betaine levels were significantly associated with a composite of adverse clinical outcomes, including cardiovascular death, all-cause mortality, and HF hospitalisation (HR 1.15, 95% CI 1.02–1.30, p=0.0206). TMAO, DMG, and betaine showed a trend towards increased HF incidence. Conclusions This meta-analysis provides evidence that metabolites in the choline pathway predict the development of HF. These findings highlight the potential of choline-related metabolites as biomarkers for HF risk stratification and prognosis. Understanding the mechanism whereby the choline pathway leads to HF and its adverse outcomes may lead to novel therapeutic targets for HF prevention and management.Choline Metabolism Pathway
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.013 | 0.024 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.021 | 0.036 |
| Bibliometrics | 0.008 | 0.009 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".