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PD is linked to systemic inflammation and endothelial dysfunction, which associate it with cardiovascular disease (CVD). This systematic review explores the molecular and microbial mechanisms through which periodontal pathogens, including \u201cRed Complex\u201d bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) and Fusobacterium nucleatum, influence cardiovascular health via inflammatory pathways, immune modulation, and microbial dissemination. Methods: A systematic review was conducted following PRISMA guidelines. A literature search was conducted in the PubMed and ScienceDirect databases using relevant keywords, with strict inclusion and exclusion criteria, from the first week of September 2024 to the first week of October 2024. Studies addressing the relationship between PD and CVD were assessed for methodological rigor, relevance, and data availability. The outcomes were synthesized using a descriptive narrative approach. Out of 591 records screened, 421 full-text articles were sought for retrieval. The final review included 58 articles providing supplementary aggregated data after eligibility assessment. Results: The pathogenesis of PD involves the activation of immune cells and the release of pro-inflammatory cytokines (such as IL-1, IL-6, TNF-\u03b1, and PGE2) and chemokines (including IL-8 and MCP-1) along with oxidative stress driven by reactive oxygen species (ROS). Periodontal pathogens trigger endothelial oxidative stress and systemic inflammation via Toll-like receptors (TLRs), NF-\u03baB signaling, and nitric oxide (NO) dysregulation, contributing to endothelial dysfunction and atherogenesis. Biomarkers, such as C-reactive protein, interleukins, and matrix metalloproteinases (MMPs), further highlight the systemic inflammatory response. Conclusions: This review underscores the significant role of periodontal pathogens and inflammatory mediators in systemic health, particularly in the progression of CVD. Although existing evidence illustrates these associations, the underlying molecular mechanisms remain inadequately understood, indicating a need for further research to advance precision medicine and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/dj13030098","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T12:01:17Z","timestamp":1740484877000},"page":"98","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Unveiling the Molecular Crosstalk Between Periodontal and Cardiovascular Diseases: A Systematic Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-6020","authenticated-orcid":false,"given":"Gunaraj","family":"Dhungana","sequence":"first","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dollada","family":"Srisai","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-227X","authenticated-orcid":false,"given":"Chethan","family":"Sampath","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regan M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honar Y.","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrahman","family":"Sedik","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3163-8398","authenticated-orcid":false,"given":"Edilberto","family":"Raynes","sequence":"additional","affiliation":[{"name":"Department of Professional and Medical Education, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9567-6143","authenticated-orcid":false,"given":"Alexys","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-4367","authenticated-orcid":false,"given":"Leela Subhashini Choudary","family":"Alluri","sequence":"additional","affiliation":[{"name":"Department of Periodontology, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7259-570X","authenticated-orcid":false,"given":"Pandu R.","family":"Gangula","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Perera, M., Al-Hebshi, N.N., Speicher, D.J., Perera, I., and Johnson, N.W. 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