Med Research
Circadian rhythms orchestrate cardiovascular physiology by regulating immune and inflammatory pathways. Disruption of these rhythms profoundly alters vascular homeostasis, thereby promoting the onset and progression of cardiovascular diseases (CVD). Evidence from experimental and clinical studies demonstrates that circadian misalignment aggravates myocardial infarction, stroke, and hypertension by enhancing oxidative stress, dysregulating immune cell function, and activating inflammasomes. At the cellular level, macrophages and neutrophils exhibit rhythmic metabolic and inflammatory activities driven by circadian transcriptional networks such as the CLOCK‐BMAL1 complex, PER/CRY repressors, and secondary loops involving REV‐ERBα and RORγ. Epigenetic regulators including p300, THRAP3, and SRC‐2 further refine this temporal control of vascular inflammation. Disruption of these oscillatory systems increases NADPH oxidase activity, elevates reactive oxygen species (ROS) production, and activates NF‐κB signaling, leading to endothelial dysfunction and vascular injury. Given these temporal dynamics, chronotherapy, defined as the strategic timing of medication administration to synchronize with endogenous biological rhythms, emerges as a crucial determinant for cardiovascular therapeutic efficacy. Chronotherapeutic strategies, including pharmacological targeting of circadian regulators such as REV‐ERBα agonists, hold promise for mitigating vascular inflammation and improving cardiovascular outcomes. This review summarizes current evidence linking circadian rhythm disruption to immunoinflammatory mechanisms in cardiovascular disease and highlights novel avenues for time‐based therapeutic interventions.
Text reproduced verbatim from Version of Record (source); DOI; CC-BY-4.0.
Tian Zhang, Ge Zhang, Tian-Ding Liu, Tianshu Gu, Fengyi Yu, Pengyuan Xu, Wunan Mi, Xuanjiang Zhao, Qian Guo, Honglin Zheng, Taiqi Zhao, Qiang Li, Di Lu, Mingxuan Duan, Chaoyang Yu, Ruhao Wu, Shiqian Zhang, Haonan Zhang, Zeyu Wang, Youyang Zheng, Yan Xiao, Zenglei Zhang, Ge Zhang. Circadian Immunity and Vascular Inflammation in Cardiovascular Disease Chronotherapy Windows: Time for a Re-Assessment. Med Research. 2026;2(2):236–279. https://doi.org/10.1002/mdr2.70052
Circadian Immunity and Vascular Inflammation in Cardiovascular Disease Chronotherapy Windows: Time for a Re-Assessment
Narrative review of circadian immune-vascular mechanisms across cardiovascular disease, distinguishing preclinical chronotherapy rationale from heterogeneous and unresolved clinical timing evidence; no new data were created or analyzed.
This is a narrative review. The 392 bibliography entries include heterogeneous evidence types and are not a systematic count of independent studies, experiments, animals or participants. Study-level denominators must not be summed into a synthetic n. The review reports no newly generated or newly analyzed dataset.
How do circadian clock disruption and time-of-day biology interact with immune-cell trafficking, inflammatory signaling and vascular homeostasis across cardiovascular diseases, and what level of evidence supports translating these rhythms into cardiovascular chronotherapy?
This narrative review synthesizes experimental, mechanistic, epidemiological and clinical literature linking the circadian clock to cardiovascular immune and inflammatory biology. It organizes evidence around the CLOCK-BMAL1 transcriptional network, PER/CRY feedback, REV-ERB/ROR regulation, redox-sensitive signaling, NF-kB and NLRP3 inflammasome activity, cytokine and chemokine rhythms, and time-dependent immune-cell trafficking. These mechanisms are discussed across atherosclerosis, stroke, ischemic heart disease and heart failure. The review further evaluates preclinical chronotherapeutic strategies targeting clock and inflammatory pathways and contrasts them with a more limited and heterogeneous clinical evidence base. It does not report new experimental or clinical data, perform a meta-analysis, establish a universal cardiovascular dosing schedule, or demonstrate clinical efficacy for experimental clock-targeting compounds.
This is a synthesis of prior molecular and experimental literature rather than a new clock experiment.
Source locator: Sections 2.1-2.4; Figures 1-2; Tables 1-2.
These mechanisms derive from heterogeneous experimental systems and should not be represented as one fully demonstrated causal human pathway.
Source locator: Sections 3-4; Figure 3; Table 3.
Timing, phase and mechanisms vary by species, tissue and experimental model.
Source locator: Section 5; Figures 4-5.
Evidence strength and causality differ materially across disease, mechanism and model.
Source locator: Sections 6.1-6.4; Figures 6-8.
This evidence is predominantly preclinical and must not be converted into human treatment-efficacy claims.
Source locator: Section 7.1; Table 4.
Physiological timing effects and mechanistic rationale are not equivalent to proven reductions in clinical outcomes.
| Measure | Value |
|---|---|
| Drug classes and timing | The review discusses aspirin, beta-blockers, melatonin, tPA, SGLT2 inhibitors, colchicine, ACEIs/ARBs, MRAs, ARNI and antihypertensive timing. |
| Conflicting trials | Hygia and related studies reported bedtime-dosing benefits, whereas BedMed did not reproduce a cardiovascular-event benefit. |
Source locator: Section 7.2; Table 5.
These gaps are part of the authors' discussion, not newly experimentally tested findings.
Source locator: Sections 8.1-8.4.
These evidence levels are not interchangeable. Human clinical timing evidence remains incomplete or conflicting for many cardiovascular therapies.
| Measure | Value |
|---|---|
| Human timing evidence | Bedtime aspirin can alter morning platelet reactivity, but cardiovascular event reduction has not been established by a large randomized trial; SGLT2-inhibitor and colchicine timing remain insufficiently tested. |
| Outcome-level uncertainty | Antihypertensive bedtime-dosing studies have reported conflicting cardiovascular outcome results, including the Hygia and BedMed trials. |
Source locator: Section 7.2; Table 5; Sections 8.1-8.4.
| Intervention / drug class | Rhythmic biological rationale | Timing directly tested? | Evidence level | Main endpoint | Hard cardiovascular outcome status | Review locator |
|---|---|---|---|---|---|---|
| REV-ERBα/β agonists — SR9009 / SR9011 | Circadian REV-ERB regulation of inflammatory signaling. | Yes, in selected preclinical models | Preclinical | NLRP3 / inflammatory signaling, MI/R injury, remodeling and cardiac function. | No human cardiovascular outcome validation; mouse ZT06 is not a human dosing recommendation. | Section 7.1.1; Table 4; reference 118. |
| NLRP3 inhibitors — MCC950 and related compounds | Circadian variation in inflammatory and inflammasome signaling. | Limited / largely inferred from rhythmic biology | Preclinical | Inflammation, myocardial injury, atherosclerosis and remodeling in experimental models. | No established human cardiovascular chronotherapy outcome. | Section 7.1.2; Table 4. |
| Aspirin | Circadian variation in morning platelet reactivity. | Yes | Human randomized crossover / physiological evidence | Morning platelet reactivity and related physiological measures. | Overall MI/stroke reduction from bedtime dosing remains unproven. | Section 7.2; Table 5; references 368-370. |
| Beta-blockers | Daily variation in heart rate, blood pressure and autonomic activity. | Limited human evidence | Clinical / pharmacological | Heart rate, blood pressure and autonomic effects. | No universal outcome-based timing recommendation. | Section 7.2; Table 5. |
| SGLT2 inhibitors | Rhythm-integrated dosing remains a proposed rather than validated clinical strategy. | No established rhythm-integrated clinical timing evidence | Clinical efficacy established independent of chronotherapy | Heart-failure and cardiorenal outcomes. | Chronotherapy-specific benefit unknown. | Section 7.2; Table 5. |
| Colchicine | Rhythmic inflammation is a proposed timing rationale. | Not systematically evaluated | Clinical cardiovascular efficacy, but timing evidence lacking | Coronary disease / post-MI inflammatory risk. | Chronotherapy-specific outcome benefit unknown. | Section 7.2; Table 5. |
| RAAS inhibitors / antihypertensive timing | Circadian variation in blood pressure. | Yes | Human randomized clinical evidence | Blood pressure and cardiovascular events. | Conflicting evidence; Hygia reported benefit whereas BedMed did not reproduce a cardiovascular-event benefit. | Section 7.2; Table 5; references 388-392. |
| MRAs / ARNI | A chronotherapy-specific timing rationale remains unvalidated. | Insufficient or absent | Clinical efficacy established for their usual indications; chronotherapy evidence limited | Heart-failure / remodeling outcomes. | No established chronotherapy-specific outcome advantage. | Section 7.2; Table 5. |
These are selected evidence sources used to verify claims on this author-controlled evidence page; they are not the complete reference list of the published review.
Direct preclinical evidence relevant to time-dependent REV-ERB agonist intervention after myocardial ischemia-reperfusion.
Evidence: KF5, KF8
Translational human and experimental evidence linking shift-work-associated circadian disruption with myocardial infarction injury and prognosis.
Evidence: KF4, KF8
Human randomized crossover evidence for aspirin timing effects on physiological and platelet endpoints, not proof of reduced cardiovascular events.
Evidence: KF6, KF8
Human randomized crossover evidence supporting timing-dependent platelet-reactivity effects.
Evidence: KF6, KF8
Trial reporting cardiovascular benefit with bedtime antihypertensive dosing; retain the review's stated concerns regarding generalizability and conflicting subsequent evidence.
Evidence: KF6, KF8
Randomized clinical evidence that did not reproduce the cardiovascular-event benefit reported by Hygia.
Evidence: KF6, KF8
It is a narrative Review Article synthesizing prior evidence. It reports no new experimental or clinical dataset, systematic study-selection workflow or pooled meta-analysis.
Evidence: KF1, KF7
The review centers on CLOCK-BMAL1, PER/CRY and REV-ERB/ROR feedback networks, including redox and epigenetic regulation; these are synthesized from prior work rather than tested as one new experiment.
Evidence: KF1
The review links clock and redox regulation with pattern-recognition receptor, NF-kB and NLRP3 inflammatory signaling, cytokines and chemokines. The underlying models are heterogeneous and do not establish one complete causal pathway in humans.
Evidence: KF1, KF2
Prior evidence discussed for neutrophils, monocytes/macrophages, lymphocytes and dendritic cells indicates rhythmic numbers, trafficking or function, with phase and mechanism varying across species and tissues.
Evidence: KF3
The review discusses atherosclerosis, stroke, ischemic heart disease and myocardial infarction, and heart failure, with hypertension considered in blood-pressure chronotherapy. Evidence strength differs across disease contexts.
Evidence: KF4, KF6
No. REV-ERB agonist chronotherapy is discussed as mechanistic and preclinical rationale, not demonstrated human cardiovascular treatment efficacy.
Evidence: KF5, KF8
No. Clinical evidence conflicts: Hygia and related studies reported bedtime-dosing benefits, while BedMed did not reproduce a cardiovascular-event benefit. The review does not support a universal bedtime recommendation.
Evidence: KF6, KF8
No large randomized trial cited by this review directly establishes reduced overall myocardial infarction or stroke incidence from bedtime aspirin dosing; physiological timing effects do not prove event reduction.
Evidence: KF6, KF8
No. The review discusses these drug classes, but does not establish clinically validated optimal timing or universal cardiovascular outcome benefits for them.
Evidence: KF6, KF8
No. The article reports no explicit systematic-search strategy, PRISMA study-selection workflow or quantitative meta-analysis; its 392 references are bibliography entries, not a systematic count of independent studies.
Evidence: KF7
Constitutive-versus-inducible model differences, immune-subpopulation and spatiotemporal heterogeneity, individualized rhythm variation and high-quality circadian-aware clinical trials remain important gaps.
Evidence: KF7
Study-level author-maintained evidence summary. Not participant-level data and not a ready-to-pool meta-analysis dataset. For formal citation, use the original article DOI.
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