Effects of Periodontitis on Heart Rate Variability

Overview

Periodontitis is a chronic inflammatory disease associated with systemic inflammatory burden and possible alterations in autonomic nervous system regulation. Heart rate variability (HRV) has been used as a noninvasive method to assess autonomic modulation and may reflect sympathovagal imbalance associated with inflammatory conditions. This case-control study aims to investigate the association between periodontitis and autonomic modulation assessed by HRV parameters. In addition, the study will evaluate the association between periodontal clinical parameters, HRV indices, and plasma levels of pro- and anti-inflammatory cytokines and biomarkers. Participants with and without periodontitis will undergo periodontal examination, HRV assessment, and blood sample collection for inflammatory marker analyses.

Periodontitis is a chronic multifactorial inflammatory disease associated with dysbiotic dental biofilm and host immune-inflammatory response, leading to progressive destruction of tooth-supporting tissues. In addition to local periodontal inflammation, increasing evidence suggests that periodontitis contributes to systemic inflammatory burden and may be associated with cardiovascular and autonomic dysfunction. The autonomic nervous system plays a central role in cardiovascular regulation and immune-inflammatory modulation. Sympathetic and parasympathetic pathways participate in inflammatory reflex mechanisms capable of modulating cytokine production and systemic inflammatory responses. Alterations in autonomic modulation have been associated with several chronic inflammatory conditions, including rheumatoid arthritis, systemic lupus erythematosus, sepsis, and cardiovascular diseases. Heart rate variability (HRV) is a noninvasive and validated method for evaluating autonomic nervous system modulation and sympathovagal balance. Reduced HRV and increased sympathetic activity have been associated with systemic inflammation, cardiovascular morbidity, and increased mortality risk. However, the relationship between periodontitis and autonomic dysfunction remains incompletely understood, particularly regarding nonlinear HRV dynamics and their association with inflammatory biomarkers. This longitudinal case-control study aims to investigate whether individuals with generalized periodontitis present alterations in autonomic modulation compared with periodontally healthy individuals. The study will evaluate HRV parameters, blood pressure, inflammatory biomarkers, cardiac function, and sympathetic neural activity. In addition, the effects of periodontal treatment on these parameters will be investigated over time. Participants aged between 35 and 50 years will be recruited at the Periodontics Clinic of the School of Dentistry of Ribeirão Preto, University of São Paulo (FORP-USP). Individuals diagnosed with generalized stage III or IV, grade B or C periodontitis according to the 2017 Classification of Periodontal and Peri-Implant Diseases and Conditions will compose the test group. Periodontally healthy individuals or those not meeting periodontitis diagnostic criteria will compose the control group. Groups will be matched according to age and sex. All participants will undergo complete periodontal examination, including probing depth, clinical attachment level, bleeding on probing, plaque index, and tooth loss assessment. Electrocardiographic recordings will be obtained for HRV analysis using time-domain, frequency-domain, symbolic, and nonlinear analyses, including entropy-based methods. Blood pressure measurements and anthropometric evaluations will also be performed. Peripheral blood samples will be collected for analysis of pro-inflammatory cytokines, including IL-1α, IL-1β, TNF-α, IL-6, and IL-17, as well as anti-inflammatory cytokines such as IL-10. C-reactive protein and calcitonin levels will also be evaluated. Gingival crevicular fluid samples will be collected for local inflammatory marker analysis. Supragingival biofilm and fecal samples will be collected for microbiological analysis using 16S rRNA sequencing in order to investigate oral and intestinal microbiome profiles and their association with autonomic and inflammatory parameters. Cardiac structure and function will be evaluated through echocardiography, including conventional and speckle tracking echocardiographic analyses. Sympathetic neural activity will also be assessed by direct muscle sympathetic nerve activity recording through microneurography. Participants diagnosed with periodontitis will receive non-surgical periodontal therapy, including scaling and root planing, oral hygiene instruction, and periodontal maintenance therapy throughout the study. Clinical and laboratory evaluations will be repeated at baseline, 3 months, 6 months, and 12 months after treatment. The primary objective of this study is to determine whether periodontitis is associated with autonomic imbalance characterized by alterations in sympathetic and parasympathetic modulation. Secondary objectives include investigating associations among periodontal parameters, HRV indices, inflammatory biomarkers, blood pressure, cardiac function, and sympathetic activity, as well as evaluating the effects of periodontal treatment on these outcomes. The findings of this study may contribute to a better understanding of the interactions among periodontal inflammation, systemic immune response, autonomic nervous system regulation, and cardiovascular function, potentially supporting new therapeutic and preventive approaches targeting neuroimmune mechanisms associated with chronic inflammatory diseases.