Scientific Reports
Coronary atherosclerotic heart disease (CAD) is among the most prevalent chronic diseases globally. Circadian rhythm disruption (CRD) is closely associated with the progression of various diseases. However, the precise role of CRD in the development of CAD remains to be elucidated. The Circadian rhythm disruption score (CRDscore) was employed to quantitatively assess the level of CRD in CAD samples. Our investigation revealed a significant association between high CRDscore and adverse prognosis in CAD patients, along with a substantial correlation with CAD progression. Remarkably distinct CRDscore distributions were also identified among various subtypes. In summary, we have pioneered the revelation of the relationship between CRD and CAD at the single-cell level and established reliable markers for the development, treatment, and prognosis of CAD. A deeper understanding of these mechanisms may offer new possibilities for incorporating "the therapy of coronary heart disease based circadian rhythm" into personalized medical treatment regimens.
Text reproduced verbatim from Version of Record (source); DOI; CC-BY-4.0.
Zhaokai Zhou, Ge Zhang, Zhan Wang, Yudi Xu, Hongzhuo Qin, Haonan Zhang, Pengpeng Zhang, Zhengrui Li, Shuai Xu, Xin Tan, Yiyao Zeng, Fengyi Yu, Shanshan Zhu, Le Chang, Youyang Zheng, Xinwei Han. Molecular subtypes of ischemic heart disease based on circadian rhythm. Scientific Reports. 2024;14(1):14155. https://doi.org/10.1038/s41598-024-65236-5
Molecular subtypes of ischemic heart disease based on circadian rhythm
Transcriptomic CRDscore and coronary-disease subtype analysis, with explicit qualification of repeated samples and reference-dataset identity.
GSE184073 cells are not independent patients. GSE59867 contains repeated follow-up of 111 STEMI patients and 46 stable CAD controls; its 436 expression samples are not 436 independent patients. Follow-up represents post-infarction recovery time points, not 24-hour circadian monitoring of the same individual. External dataset counts are article-reported samples and are not summed into a deduplicated participant total. External validation means retrospective expression-template evaluation, not prospective clinical utility. GSE70049 is a Danio rerio setb morphant expression experiment, not a verified mouse circadian perturbation.
Can circadian-related expression patterns define reproducible molecular subtypes of coronary disease, without treating an expression score as a direct measurement of each patient's physiological circadian rhythm?
This computational study connects single-cell expression structure with bulk transcriptomic subtyping. Its contribution is a research framework for expression-associated heterogeneity, not an established circadian diagnostic test or treatment-selection rule. Repeated sampling and the identity of one cited reference dataset require explicit qualification.
GSE184073 single-cell expression analysis.
| Measure | Value |
|---|---|
| Post-QC cells | 2,237 |
| Analyzed samples | 2 |
| Non-grey modules | 8 |
Source locator: Results: Construction of WGCNA network in scRNA-seq dataset; Fig. 1
Single-cell and bulk expression scoring.
| Measure | Value |
|---|---|
| Formula | CRDscore = Srandom - SCADCRgenes |
| Random features | 1,000 |
| Single-cell cutoff | 75th percentile |
| Bulk cutoff | Median |
Source locator: Methods: Calculation of CRDscore based on circadian-related genes
Identity of a cited reference expression dataset.
| Measure | Value |
|---|---|
| GSE70049 organism | Danio rerio |
| GSE70049 experiment | setb morphant expression experiment |
Source locator: Methods: Data processing; NCBI GEO GSE70049 record
Discovery expression-sample assignment.
| Measure | Value |
|---|---|
| Type1 samples | 124 |
| Type2 samples | 93 |
| Type3 samples | 87 |
| Type4 samples | 132 |
| Total expression samples | 436 |
Source locator: Methods: Construction and validation of the CRD-related subtypes of CAD; Results: subtype identification; Fig. 3A-E
External expression-template evaluation.
Source locator: Methods: Construction and validation of the CRD-related subtypes of CAD; Fig. 4
Subtype-associated expression and computational annotations.
| Measure | Value |
|---|---|
| Contractile markers | Lower expression |
| Immune and collagen pathways | Associated enrichment differences |
Source locator: Results: functional and immune microenvironment analyses; Figs. 5-6
The analysis of GSE184073 constructed a single-cell co-expression foundation related to coronary disease. Post-QC cells: 2,237; Analyzed samples: 2; Non-grey modules: 8. Cells are not independent patients; two analyzed samples do not establish population-level robustness. CRDscore was constructed as a research score from target-gene expression and a random background. Formula: CRDscore = Srandom - SCADCRgenes; Random features: 1,000; Single-cell cutoff: 75th percentile; Bulk cutoff: Median. The score does not directly measure an individual's circadian phase, amplitude or period. The two data-layer cutoffs are not one clinical threshold.
Expression-based subtyping of GSE59867 yielded four groups. Type1 samples: 124; Type2 samples: 93; Type3 samples: 87; Type4 samples: 132; Total expression samples: 436. These are expression-sample groups, not 436 independent patients. The grouping does not resolve independence of repeated follow-up samples or outcome analyses. NTP was used to evaluate subtype assignment in four external expression datasets. Datasets: GSE20680; GSE20681; GSE43292; GSE62646. External expression-template reproducibility is not prospective risk prediction or demonstrated clinical utility.
The article reports external reference-data evaluation, but the use of GSE70049 requires qualification. GSE70049 organism: Danio rerio; GSE70049 experiment: setb morphant expression experiment. The evidence does not establish that all four reference experiments are verified mouse circadian interventions. No intended replacement accession is inferred. Expression-based subtyping of GSE59867 yielded four groups. Type1 samples: 124; Type2 samples: 93; Type3 samples: 87; Type4 samples: 132; Total expression samples: 436. These are expression-sample groups, not 436 independent patients. The grouping does not resolve independence of repeated follow-up samples or outcome analyses.
Type2 showed higher CRDscore and immune-inflammatory expression characteristics. Contractile markers: Lower expression; Immune and collagen pathways: Associated enrichment differences. Computational estimates and expression associations do not establish causal plaque transitions or benefit from immunotherapy or chronotherapy.
Evidence: KF6
| Row ID | Component | Context | Finding | Evidence Level | Scope | Source Locator | Evidence refs |
|---|---|---|---|---|---|---|---|
| evidence-ihd-1 | Single-cell co-expression foundation | GSE184073 single-cell expression analysis. | The analysis of GSE184073 constructed a single-cell co-expression foundation related to coronary disease. Post-QC cells: 2,237; Analyzed samples: 2; Non-grey modules: 8 | Retrospective expression and computational evidence | Cells are not independent patients; two analyzed samples do not establish population-level robustness. | Results: Construction of WGCNA network in scRNA-seq dataset; Fig. 1 | KF1 |
| evidence-ihd-2 | CRDscore construction | Single-cell and bulk expression scoring. | CRDscore was constructed as a research score from target-gene expression and a random background. Formula: CRDscore = Srandom - SCADCRgenes; Random features: 1,000; Single-cell cutoff: 75th percentile; Bulk cutoff: Median | Retrospective expression and computational evidence | The score does not directly measure an individual's circadian phase, amplitude or period. The two data-layer cutoffs are not one clinical threshold. | Methods: Calculation of CRDscore based on circadian-related genes | KF2 |
| evidence-ihd-3 | Reference-dataset qualification | Identity of a cited reference expression dataset. | The article reports external reference-data evaluation, but the use of GSE70049 requires qualification. GSE70049 organism: Danio rerio; GSE70049 experiment: setb morphant expression experiment | Reference-record identity qualification | The evidence does not establish that all four reference experiments are verified mouse circadian interventions. No intended replacement accession is inferred. | Methods: Data processing; NCBI GEO GSE70049 record | KF3 |
| evidence-ihd-4 | Discovery subtyping | Discovery expression-sample assignment. | Expression-based subtyping of GSE59867 yielded four groups. Type1 samples: 124; Type2 samples: 93; Type3 samples: 87; Type4 samples: 132; Total expression samples: 436 | Retrospective expression and computational evidence | These are expression-sample groups, not 436 independent patients. The grouping does not resolve independence of repeated follow-up samples or outcome analyses. | Methods: Construction and validation of the CRD-related subtypes of CAD; Results: subtype identification; Fig. 3A-E | KF4 |
| evidence-ihd-5 | External template assignment | External expression-template evaluation. | NTP was used to evaluate subtype assignment in four external expression datasets. Datasets: GSE20680; GSE20681; GSE43292; GSE62646 | Retrospective expression and computational evidence | External expression-template reproducibility is not prospective risk prediction or demonstrated clinical utility. | Methods: Construction and validation of the CRD-related subtypes of CAD; Fig. 4 | KF5 |
| evidence-ihd-6 | Immune and functional context | Subtype-associated expression and computational annotations. | Type2 showed higher CRDscore and immune-inflammatory expression characteristics. Contractile markers: Lower expression; Immune and collagen pathways: Associated enrichment differences | Retrospective expression and computational evidence | Computational estimates and expression associations do not establish causal plaque transitions or benefit from immunotherapy or chronotherapy. | Results: functional and immune microenvironment analyses; Figs. 5-6 | KF6 |
The analysis of GSE184073 constructed a single-cell co-expression foundation related to coronary disease. Post-QC cells: 2,237; Analyzed samples: 2; Non-grey modules: 8. Cells are not independent patients; two analyzed samples do not establish population-level robustness.
Evidence: KF1
CRDscore was constructed as a research score from target-gene expression and a random background. Formula: CRDscore = Srandom - SCADCRgenes; Random features: 1,000; Single-cell cutoff: 75th percentile; Bulk cutoff: Median. The score does not directly measure an individual's circadian phase, amplitude or period. The two data-layer cutoffs are not one clinical threshold.
Evidence: KF2
The article reports external reference-data evaluation, but the use of GSE70049 requires qualification. GSE70049 organism: Danio rerio; GSE70049 experiment: setb morphant expression experiment. The evidence does not establish that all four reference experiments are verified mouse circadian interventions. No intended replacement accession is inferred.
Evidence: KF3
Expression-based subtyping of GSE59867 yielded four groups. Type1 samples: 124; Type2 samples: 93; Type3 samples: 87; Type4 samples: 132; Total expression samples: 436. These are expression-sample groups, not 436 independent patients. The grouping does not resolve independence of repeated follow-up samples or outcome analyses.
Evidence: KF4
NTP was used to evaluate subtype assignment in four external expression datasets. Datasets: GSE20680; GSE20681; GSE43292; GSE62646. External expression-template reproducibility is not prospective risk prediction or demonstrated clinical utility.
Evidence: KF5
Type2 showed higher CRDscore and immune-inflammatory expression characteristics. Contractile markers: Lower expression; Immune and collagen pathways: Associated enrichment differences. Computational estimates and expression associations do not establish causal plaque transitions or benefit from immunotherapy or chronotherapy.
Evidence: KF6
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