SARS-CoV-2 Spike Glycoprotein Persistence, Vascular Endothelial Inflammation, and Atherosclerosis-Mediated Cardiac Pathology Following COVID-19 mRNA-Based Intermediate (Vaccination): A Systematic Review of Mechanistic, Epidemiological, and Autopsy Evidence

Background: COVID-19 mRNA intermediates encode the full-length, proline-stabilised SARS-CoV-2 spike glycoprotein within N1-methylpseudouridine (m1Ψ)-modified mRNA delivered via lipid nanoparticles (LNPs). At the time of emergency authorisation, regulatory submissions indicated that intermediate-derived spike protein would remain localised near the injection site and clear within days to a few weeks. Subsequent independent studies have substantially revised this picture, documenting spike protein or its encoding mRNA in human blood, lymph nodes, cardiac tissue, and exosomes for periods ranging from 28 days to 187 days post-administration. Converging mechanistic, clinical, and epidemiological evidence now indicates that this persistent circulating spike protein exerts pathological effects on vascular endothelium through ACE2 receptor downregulation, NF-κB-driven inflammatory signalling, and disruption of endothelial nitric oxide synthesis — molecular events that collectively constitute the initiating steps of atherosclerotic plaque formation. Objectives: This systematic review synthesises peer-reviewed evidence across four domains: (1) the duration and anatomical distribution of spike protein following mRNA intermediate administration in humans; (2) the molecular mechanisms by which the spike glycoprotein induces vascular endothelial dysfunction and promotes atherogenesis; (3) the spectrum of cardiac pathological outcomes — including myocardial infarction, myocarditis, fatal arrhythmia, and acute coronary syndrome — documented in autopsy series, pharmacovigilance databases, and clinical cohorts; and (4) the existing diagnostic gap in validated biomarker tools for post-administration cardiovascular risk stratification and its potential resolution through a targeted Research Use Only ELISA panel. Methods: PubMed/MEDLINE, EMBASE, Cochrane Library, bioRxiv, medRxiv, and ClinicalTrials.gov were searched from January 2020 to May 2026 without language restriction. Studies were categorised as mechanistic (in vitro/in vivo), clinical/epidemiological, or post-mortem/autopsy. Quality was assessed using the GRADE framework for clinical studies, ToxRTool and ARRIVE 2.0 for mechanistic research, the JBI Critical Appraisal Checklist for case series, and AMSTAR-2 for included systematic reviews. Narrative synthesis was performed, organised by the mechanistic cascade, from spike persistence through endothelial dysfunction, atherogenesis, and myocardial injury. Results: The assembled evidence supports a biologically coherent, multi-step causal pathway from mRNA intermediate-derived spike protein to accelerated atherosclerosis and acute cardiac events. Spike protein has been detected in human plasma by single-molecule array (Simoa) assay and mass spectrometry at up to 187 days post-administration. Germinal centre reservoirs sustain antigen presentation for at least 60 days. Multiple independent research groups have demonstrated that the spike protein alone — in the absence of infectious virus — impairs endothelial function via ACE2 downregulation (Lei et al., Circ Res 2021), activates NF-κB through integrin α5β1 signalling (Robles et al., J Biol Chem 2022), and upregulates VCAM-1, ICAM-1, IL-6, and tissue factor, driving the monocyte recruitment and foam cell cascade characteristic of early atherosclerosis. Population-level pharmacovigilance data from Japan (903 government-compensated deaths), a multinational cohort of 99 million mRNA intermediate recipients (GVDN, Faksova et al., Vaccine 2024), and autopsy-confirmed case series (Hulscher et al., ESC Heart Failure 2024) collectively document excess cardiac mortality and confirmed myocarditis signals temporally associated with mRNA intermediate administration. Conclusions: The convergence of in vitro mechanistic data, human biodistribution studies, clinical biomarker evidence, and autopsy-confirmed fatalities constitutes a plausible and concerning atherogenic pathway mediated by persistent spike protein exposure. A validated Research Use Only biomarker panel — comprising free circulating spike protein, markers of endothelial inflammatory activation, and markers of renin-angiotensin system imbalance — combined with structural vascular imaging represents a critical unmet need for post-administration vascular risk research, pharmacovigilance, and long COVID investigation.