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

Disclosures

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

Abstract and Introduction

Abstract

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.

Introduction

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).

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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.

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Table 1. Baseline Characteristics of Participants by Baseline PPC Classification, ARIC 1996–1998 (N = 7,514)
	Healthy (n = 1,746)	Periodontal Disease (n = 4,420)	Edentulism (n = 1,348)	P Value
Demographics
Age, y	62 ± 5	63 ± 6	64 ± 6	<0.0001
Male	34	51	43	<0.0001
Race-field center				<0.0001
White-Minneapolis (n = 2,290)	46	28	12
White-Washington (n = 2,236)	15	29	37
White-Forsyth (n = 1,863)	36	20	20
Black-Forsyth (n = 1,75)	1	2	3
Black-Jackson (n = 1,591)	2	21	28
Education^a				<0.0001
Basic	5	16	43
Intermediate	42	44	41
Advanced	53	41	16
Insurance				<0.0001
Other	32	40	54
Medicare/Medicaid	66	54	37
None	2	6	9
Behaviors
Cigarette smoking status				<0.0001
Current	7	14	25
Former	41	45	42
Never	52	41	33
Physical activity^b	2.7 ± 0.8	2.6 ± 0.8	2.4 ± 0.7	<0.0001
Dental
Tooth count	26 ± 3	20 ± 8	0 ± 0	<0.0001
Physiological
Body mass index, kg/m²	27 ± 5	29 ± 5	30 ± 6	<0.0001
Systolic BP, mm Hg	123 ± 17	127 ± 18	130 ± 20	<0.0001
Diastolic BP, mm Hg	70 ± 9	71 ± 10	70 ± 11	<0.0001
Antihypertensive medication	29	38	51	<0.0001
Diabetes mellitus	8	14	25	<0.0001
HDL cholesterol, mg/dL	54 ± 17	49 ± 16	48 ± 15	<0.0001
LDL cholesterol, mg/dL	121 ± 32	123 ± 33	125 ± 34	0.020
Prevalent CHD at visit 4	4	6	10	<0.0001
Prevalent stroke at visit 4	1	2	3	<0.0001
CRP at visit 4	1.6 (0.8–3.5)	1.9 (0.9–4.0)	2.3 (1.1–4.5)	0.0002
CRP at visit 5	1.5 (0.8–2.8)	1.8 (0.9–3.3)	2.2 (1.1–4.1)	<0.0001
NT-proBNP at visit 4, pg/mL	59.9 (31.6–107.3)	51.5 (24.8–99.6)	61.8 (31.5–106.9)	0.002
NT-proBNP at visit 5, pg/mL	127.2 (67.0–241.0)	130.3 (66.0–255.7)	163.0 (86.6–320.5)	<0.0001
Troponin at visit 4, ng/g	1.53 ± 0.52	1.68 ± 0.60	1.77 ± 0.70	<0.0001

Values are mean ± SD, n (%), or median (25th, 75th percentile). P values for difference among categories were obtained from chi-square or analysis of variance tests. ^aEducation variable: Basic = less than a high school degree; intermediate = high school, GED, or vocational school; and advanced = college, graduate, or professional school. ^bPhysical activity data was collected at visit 3.
ARIC = Atherosclerosis Risk In Communities; BP = blood pressure; CHD = coronary heart disease; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PPC = Periodontal Profile Classification.

Table 2. Multivariable Adjusted HRs (95% CIs) for Incident HFrEF or HFpEF From 2005–2018 by Periodontal Category Measured in 1996–1998, ARIC (n = 6,707)
	Healthy (n = 1,646)	Periodontal Disease (n = 3,994)	Edentulism (n = 1,067)	P Value
Incident HFpEF
Events, n	52	204	94
IR (95% CI)^a	2.6 (2.06–3.32)	4.67 (4.14–5.24)	9.31 (7.79–11.05)
Model 1	Ref.	1.66 (1.21–2.28)	2.83 (1.95–4.11)	<0.0001
Model 2	Ref.	1.35 (0.98–1.86)	2.00 (1.37–2.93)	0.001
Model 3	Ref.	1.33 (0.96–1.84)	1.87 (1.27–2.76)	0.004
Model 4	Ref.	1.36 (0.98–1.88)	1.99 (1.36–2.93)	0.001
Model 5	Ref.	1.34 (0.96–185)	2.01 (1.37–2.96)	0.001
Model 6	Ref.	1.39 (0.99–1.95)	2.11 (1.41–3.14)	0.001
Incident HFrEF
Events, n	38	202	79
IR (95% CI)^a	1.92 (1.44–2.52)	4.62 (4.10–5.19)	7.82 (6.43–9.43)
Model 1	Ref.	1.96 (1.37–2.80)	2.97 (1.95–4.53)	<0.0001
Model 2	Ref.	1.69 (1.18–2.43)	2.19 (1.43–3.36)	0.001
Model 3	Ref.	1.74 (1.20–2.54)	2.04 (1.31–3.17)	0.005
Model 4	Ref.	1.82 (1.25–2.65)	2.31 (1.49–3.59)	0.001
Model 5	Ref.	1.82 (1.25–2.65)	2.27 (1.46–3.53)	0.001
Model 6	Ref.	1.74 (1.17–2.59)	2.36 (1.48–3.75)	0.001
Incident HFpEF or HFrEF combined
Events, n	90	406	173
IR (95% CI)^a	4.56 (3.80–5.43)	9.29 (8.54–10.08)	17.13 (15.05–19.43)
Model 1	Ref.	1.79 (1.41–2.27)	2.89 (2.18–3.82)	<0.0001
Model 2	Ref.	1.50 (1.18–1.91)	2.08 (1.57–2.77)	<0.0001
Model 3	Ref.	1.51 (1.18–1.93)	1.93 (1.44–2.59)	<0.0001
Model 4	Ref.	1.55 (1.22–1.98)	2.12 (1.59–2.84)	<0.0001
Model 5	Ref.	1.54 (1.20–1.97)	2.11 (1.58–2.82)	<0.0001
Model 6	Ref.	1.53 (1.19–1.98)	2.19 (1.62–2.97)	<0.0001

^aUnadjusted IR (incidence rate) is per 100,000 person-y. Model 1: Adjusts for baseline age, sex, race/center, education, and insurance. Model 2: Adjusts for model 1 + cigarette status, physical activity, body mass index, LDL, hypertension medication, CHD, diabetes, and systolic BP. Model 3: Adjusts for model 2 + baseline NT-proBNP. Model 4: Adjusts for model 2 + baseline CRP. Model 5: Adjusts for model 2 + baseline troponin. Model 6: Adjusts for model 2 + incident CHD.
HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; other abbreviations as in Table 1.

Table 3. Associations Between Baseline Periodontal Status (1996–1998) and Mean Values of Change in CRP (n = 3,621) or NT-proBNP (n = 3,979) Among Participants in the ARIC Study
	Healthy (n = 1,034)	Periodontal Disease (n = 2,183)	Edentulism (n = 404)	P Value^a
Mean CRP change (visit 5 to visit 4)
Model 1	−0.40 ± 0.08	−0.38 ± 0.05	−0.23 ± 0.12	0.47
Model 2	−0.49 ± 0.08	−0.35 ± 0.05	−0.07 ± 0.11^b	0.02
Model 3	−0.51 ± 0.07	−0.30 ± 0.04^b	−0.03 ± 0.09^b	0.0003
Mean LN NT-proBNP change (visit 5 to visit 4)
Model 1	1.02 ± 0.03	1.06 ± 0.02	1.11 ± 0.04	0.26
Model 2	1.05 ± 0.03	1.06 ± 0.02	1.07 ± 0.04	0.94
Model 3	1.04 ± 0.03	1.06 ± 0.02	1.15 ± 0.04^b	0.06

Results presented as adjusted mean values of change in CRP ± SE mg/L or LN transformed NT-proBNP pg/mL. Inverse probability weights were included for all models. Model 1: Adjusts for baseline age, sex, race/center, education, and insurance. Model 2: Adjusts for model 1 + cigarette status, physical activity, body mass index, LDL, hypertension medication, CHD, diabetes, and systolic BP. Model 3: Adjusts for model 2 + baseline CRP in analyses of CRP change and baseline NT-proBNP in models of NT-proBNP change. ^a P values are 2 df type 3 F-tests. ^b P < 0.05 for comparison with healthy participants.
df = degrees of freedom; LN = natural logarithm; other abbreviations as in Table 1.

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

The ARIC Study

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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Perspectives

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Appendix

Central Illustration.

Central Illustration.

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