Periodontal Status, C-reactive Protein, NT-proBNP, and Incident Heart Failure

The ARIC Study

Rebecca L. Molinsky, MPH; Melana Yuzefpolskaya, MD; Faye L. Norby, MPH, PHD; Bing Yu, PHD; Amil M. Shah, MD; James S. Pankow, MPH, PHD; Chiadi E. Ndumele, MD, PHD; Pamela L. Lutsey, MPH, PHD; Panos N. Papapanou, DDS, PHD; James D. Beck, PHD; Paolo C. Colombo, MD; Ryan T. Demmer, MPH, PHD


JACC Heart Fail. 2022;10(10):731-741. 

In This Article

Abstract and Introduction


Background: Periodontal disease (PD), resulting from inflammatory host response to dysbiotic subgingival microbiota, has been linked to cardiovascular disease; however, its relationship to heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) is unexplored.

Objectives: The authors hypothesize that the presence of PD is associated with increased risk of incident HF, HFpEF, and HFrEF.

Methods: A total of 6,707 participants (mean age 63 ± 6 years) of the ARIC (Atherosclerosis Risk In Communities) study with full-mouth periodontal examination at visit 4 (1996–1998) and longitudinal follow-up for any incident HF (visit 4 to 2018), or incident HFpEF and HFrEF (2005–2018) were included. Periodontal status was classified as follows: healthy, PD (as per Periodontal Profile Classification [PPC]), or edentulous. Multivariable-adjusted Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between PPC levels and incident HF, HFpEF, or HFrEF. Additionally, biomarkers of inflammation (C-reactive protein [CRP]) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) were assessed.

Results: In total, 1,178 incident HF cases occurred (350 HFpEF, 319 HFrEF, and 509 HF of unknown type) over a median of 13 years. Of these cases, 59% had PD, whereas 18% were edentulous. PD was associated with an increased risk for HFpEF (HR: 1.35 [95% CI: 0.98–1.86]) and significantly increased risk for HFrEF (HR: 1.69 [95% CI: 1.18–2.43]), as was edentulism: HFpEF (HR: 2.00 [95% CI: 1.37–2.93]), HFrEF (HR: 2.19 [95% CI: 1.43–3.36]). Edentulism was associated with unfavorable change in CRP and NT-proBNP, whereas PD was associated only with CRP.

Conclusions: Periodontal status was associated with incident HF, HFpEF, and HFrEF, as well as unfavorable changes in CRP and NT-proBNP.


Heart failure (HF) is a growing public health burden, affecting >37.7 million people worldwide.[1] In the United States, it is estimated that >8 million people will be living with HF by the year 2030, and projected direct medical costs of HF will be doubling in the next several decades to $53 billion.[1] Despite development of novel therapeutics, the mortality burden of HF remains high: up to one-half of HF patients die within 5 years of initial diagnosis.[2,3]

Among patients with clinical HF syndrome, 2 main phenotypes exist: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The epidemiology of HF has evolved such that overall incidence remains stable, yet the incidence of HFrEF has decreased and that of HFpEF has increased. These trends are largely attributable to the aging population and the rise in risk factors such as diabetes mellitus, obesity, and metabolic syndrome. Although the pharmacological armamentarium to treat HFrEF has expanded, these therapeutics have a neutral effect against HFpEF.

The pathophysiological mechanisms that lead to HF have been the subject of substantial research in the recent years. Chronic elevated levels of systemic inflammation and venous congestion are commonly observed in both HFrEF and HFpEF and are believed to be directly related to disease pathogenesis.[4] Perturbations in the gut microbiota and impairment of gut mucosal barriers, which facilitate entry of endotoxins and gut metabolites into the circulation, have been observed in HFrEF.[5] Such endotoxins and metabolites increase systemic inflammation, potentially contributing to progression of HFrEF. To date, microbiome studies in HF have focused solely on gut microbiota[5] among the HFrEF population, whereas the oral bacterial milieu and HFpEF populations have not been investigated in this context.

Anti-infective periodontal therapy among patients with periodontitis (a condition characterized by destruction of tooth-supporting tissues and subgingival microbial dysbiosis[6]) targeting oral microbial dysbiosis has been shown to reduce systemic inflammation[7] and favorably modulates gene expression in circulating monocytes.[8] Moreover, a previous meta-analysis of 20 randomized controlled trials found reductions in C-reactive protein (CRP) after anti-infective periodontal therapy,[9] a conclusion also supported by an AHA scientific statement.[10] A robust literature exists linking periodontitis to coronary artery disease, ischemic stroke, and adverse cardiovascular outcomes in numerous cohorts, including in the ARIC (Atherosclerosis Risk In Communities) Study.[10–14] However, despite the potential intersection among periodontitis, inflammation, and HF, limited data exists examining the relationship between periodontitis and HF risk in large population-based studies. Additionally, there are no data investigating whether periodontitis is differentially associated with HFrEF vs HFpEF.

Presently, we investigated the relationship between periodontitis and incident HF, including HFrEF and HFpEF. We additionally studied the association between periodontitis and levels of systemic inflammation (CRP) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) in a multicenter, community-based cohort of participants enrolled in the ARIC study (Central Illustration).

Central Illustration.

Periodontal Status and Incident Heart Failure Among Participants With Heart Failure With Preserved and Reduced Ejection Fraction in ARIC
Cox regression of time to first heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) according to periodontal status. Follow-up time began in 2005, when heart failure (HF) adjudication allowed for the distinction between HFpEF and HFrEF. ARIC = Atherosclerosis Risk In Communities; BMI = body mass index; CHD = coronary heart disease; CRP = C-reactive protein; LDL = low-density lipoprotein; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SBP = systolic blood pressure.