Salivary Lysozymes, Anti-inflammatory Cardiac Medications, and Cardiovascular Mortality

INTRODUCTION: Infections and subsequent innate immune activation may contribute to atherogenesis. Salivary lysozyme (SLZ) is a bactericidal enzyme expressed by neutrophils and macrophages in the innate immune system. SLZ hydrolyzes peptidoglycan (PGN) in the bacterial cell wall and generates muramyl dipeptide (MDP), a ligand for nucleotide-binding oligomerization domain-containing receptors that can trigger innate immune activation, which is an established pathway to atherogenesis. OBJECTIVES: We examined the association between baseline SLZ levels and cardiovascular disease (CVD) mortality in a prospective follow-up study with a median follow-up of 18.8 y. METHODS: Using Cox regression analyses among 471 subjects, we evaluated the association between CVD mortality and SLZ using restricted cubic spline analyses. We compared CVD mortality in group Q1 (SLZ between 25%ile and 75%ile) and Q2 (SLZ ≥ 75%ile) to the reference group Q0 (25%ile) adjusting for age, sex, smoking status, hypertension, diabetes, dyslipidemia, and education. Next, we tested if innate immunity assessed by SLZ is independent of metabolic inflammation measured by the median C-reactive protein level (CRP). Lastly, we assessed whether anti-inflammatory cardiac medications alter the association between SLZ and CVD mortality, given that angiotensin-converting enzyme inhibitors (ACE-i) and statins are known to decrease systemic inflammation. RESULTS: The multivariable-adjusted hazard ratio for CVD mortality for Q1 was 2.53 (95% confidence limit [CL]: 1.38 to 4.64) and for Q2 was 2.86 (CL: 1.45 to 5.66). The association between SLZ and CVD mortality was independent of CRP level or cardiac anti-inflammatory medications. However, adjusting for some cardiac medications such as ACE-i or statins slightly increased the association between SLZ and CVD mortality. CONCLUSIONS: Oral innate immune activation assessed by SLZ was associated with an increased risk of CVD mortality. This association was independent of metabolic inflammation or anti-inflammatory actions of cardiac medications.Knowledge Transfer Statement:The current article reports that salivary lysozymes are markers for oral innate immune activation, which is triggered by many oral infections such as aphthous ulcers, dental caries, gingivitis, and other soft-tissue infections. Our results can be used by clinicians, researchers, and policymakers. Future randomized trials are warranted to corroborate or refute the results presented in this article.