Periodontal Disease and Atherosclerosis: True, True, Possibly Related, but No Evidence for Treatment to Reduce Cardiovascular Risk
Disclosure: Dr. Newby has no relevant relationships with industry related to the association of periodontal disease with atherosclerotic vascular disease.
Pub Date: Wednesday, April 18, 2012
Author: L. Kristin Newby, MD, MHS
Affiliation: Division of Cardiology, Duke University Medical Center, Durham, N.C.
Citation: Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O, Trevisan M, Levinson ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, Wilson WR, Smith Jr SC, Baddour LM; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, Council on Epidemiology and Prevention, Council on Peripheral Vascular Disease, and Council on Clinical Cardiology. Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association? A Scientific Statement From the American Heart Association. Circulation. 2012: published online before print April 18, 2012.
Atherosclerotic cardiovascular disease remains the leading cause of death and disability in the United States (1), and with continued economic development throughout the world and resultant increasing longevity, the World Health Organization projects that by 2030, although death from all forms of cancer combined will become the leading cause of death worldwide, deaths from ischemic heart disease and stroke will remain the leading single-disease causes of death globally (2). Therefore, the quest to understand the factors related to the development of atherosclerosis and to prevent and treat clinical events (e.g., myocardial infarction, stroke) resulting from atherosclerotic disease is intense. The American Heart Association (AHA) is playing a leading role in the efforts to reduce the development of atherosclerotic vascular disease and prevent associated clinical events. Its bold 2020 impact goal calls for improvement in the cardiovascular health of all Americans by 20% by 2020. A focus on 7 factors for ideal health (smoking, cholesterol, weight, blood pressure, blood glucose control, physical activity and healthy diet) is a cornerstone of this effort (3), providing evidence-based benchmarks for management of known atherosclerotic risk factors through diet and lifestyle interventions and the use of proven therapies. In addition, the AHA is a collaborator in the Department of Health and Human Service’s Million Hearts Initiative, an effort to prevent 1 million cardiovascular events in the US over 5 years (4,5).
In its effort to reduce death and disability from cardiovascular diseases, an important function of the AHA and its volunteer science subcommittees is the critical evaluation of emerging science and evolving healthcare trends that may have implications for cardiovascular health. These writing committees use systematic review of the evidence and development of peer-reviewed scientific publications that inform both physician and lay communities and provide guidance regarding the application of emerging science in clinical practice. Such a paper by Lockhart and colleagues critically examines the relationship between periodontal disease and atherosclerotic vascular disease, an intersection that potentially has implications for treatment of a large segment of the population (6). In doing so, they not only clarify what is known about the clinical and pathophysiological relationships between periodontal disease and atherosclerotic vascular disease, but also carefully highlight the importance of the systematic process of scientific evaluation and development of evidence that is necessary to determine associations and causal links between disease states and to support the introduction of specific treatments into widespread clinical practice.
Importantly, Lockhart and colleagues (6) reinforce that atherosclerotic vascular disease and periodontal disease are both common human afflictions that frequently co-exist in individual patients. They also confirm that these illnesses share many common risk factors (including cigarette smoking, diabetes and obesity) and cause similar, measurable and biologically or mechanistically plausible perturbations in biological pathways believed to be involved in the pathogenesis of atherosclerotic vascular disease, including inflammation and endothelial function. However, they also highlight that co-occurrence of disease states implies neither causality nor independence of the observed relationships. In this case, after careful review of existing published studies, they conclude that periodontal disease is associated with atherosclerotic vascular disease and clinical events and that this association is independent of other shared risk factors like smoking. However, one must always remember that a substantial publication bias may exist, such that studies showing the existence of an association are much more likely to be published than those that find the absence of an association. Further, most of the associations with atherosclerosis or atherosclerotic events were modest (10-50% increase in risk), particularly after adjustment for measured shared risk factors that likely confound the associations. Other factors, including socioeconomic factors, that may confound the relationship between periodontal disease and atherosclerotic vascular disease, were not available. Finally, the associations were identified mostly from weaker study designs (cross sectional and case-control). Therefore, some uncertainty about the existence of independent associations between periodontal disease and atherosclerotic vascular disease remains, and, as pointed out by the authors, none of the studies examined establishes a causal link between these illnesses.
The observed association of periodontal disease with atherosclerotic vascular disease, as well as evidence that periodontal disease is associated with systemic inflammation that is believed to play a role in atherosclerosis and plaque instability (7), has increased interest in using specific periodontal treatments, like mechanical debridement, to reduce the risk of atherosclerotic vascular events. In fact, from their review, Lockhart and colleagues found that these treatments did have favorable effects on endothelial function and inflammatory markers in most cases, but could cause worsening of inflammatory parameters (6).
One needs only to examine the lessons learned from the belief that hormone replacement therapy would prevent cardiovascular disease events in post-menopausal women to understand that associations, biological plausibility and favorable effects on intermediate endpoints are only a small part of the evidence needed to understand the efficacy and safety of a treatment on meaningful clinical endpoints in long term use and follow up. In that example, menopause was independently associated with an increased risk of cardiovascular events in women, and loss of endogenous estrogen at menopause was associated with changes in lipids, inflammatory markers and endothelial function that were mechanistically linked with atherosclerotic vascular disease. In addition, epidemiological studies suggested that women who received hormone replacement therapy had fewer cardiovascular events that those who did not, and randomized trials of hormone replacement therapy using intermediate endpoints, like lipid profiles, inflammatory markers and endothelial function, showed favorable effects of hormone replacement therapy (8,9). However, subsequent trials of hormone replacement therapy, powered for clinical events and with adequate duration of follow up, showed no benefit and potential harm from routine administration of post-menopausal hormones to prevent atherosclerotic vascular events (10-14).
The only randomized clinical trial of periodontal treatment that had clinical event endpoints was neutral, but was challenged by small sample size, treatment crossover and lack of sustainability of improved periodontal status in the intervention group after 6 months (15). It must be remembered that treatment of periodontal disease may have specific benefits for oral health or on endpoints other than atherosclerotic cardiovascular events; thus, may be warranted. However, physicians, researchers, payors and patients must insist on evidence from adequately-powered randomized clinical trials for clinical efficacy and safety before mechanical debridement or other aggressive, costly and potentially detrimental periodontal disease treatments are implemented routinely in clinical practice for the sole purpose of reducing cardiovascular risk.
- Roger VL, Go AS, Lloyd-Jones DM, et al., on behalf of the American Heart Association Heart Disease and Stroke Committee and Stroke Statistics Subcommittee. American Heart Association Heart Disease and Stroke Statistics 2011 Update: A Report from the American Heart Association. Circulation 2011;123:118-e209.
- http://www.who.int/healthinfo/statistics/bodprojectionspaper.pdf, Accessed 04-14-12.
- Lloyd-Jones DM, Hong Y, Labarthe D, et. al. Defining and setting national goals for cardiovascular health promotion and disease reduction: The American Heart Association’s Strategic Impact Goal Through 2020 and Beyond. Circulation 2010;121:586-613.
- Tomaselli GF, Harty MB, Horton K, Schoeberl M. The American Heart Association and the Million Hearts Initiative: a presidential advisory from the American Heart Association. Circulation 2011;124:1795-1799.
- Sacco RL, Frieden TR, Blakeman DE, Jauch EC, Mohl S. What the million hearts initiative means for stroke: a presidential advisory from the American Heart Association/American Stroke Association. Stroke 2012;43:924-928.
- Lockhart PB, Bolger AF, Papapanou PN, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association? A Scientific Statement From the American Heart Association. Circulation 2012; in press.
- Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147-1156.
- The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199-208. Erratum in: JAMA 1995;274:1676.
- Hu P, Greendale GA, Palla SL, Reboussin BA, Herrington DM, Barrett-Connor E, Reuben DB. The effects of hormone therapy on the markers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the postmenopausal estrogen progestin intervention (PEPI) trial. Atherosclerosis 2006;185:347-52.
- Hulley S, Grady D, Bush T, et al., for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613.
- Grady D, Herrington D, Bittner V, et al. for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57. Erratum in: JAMA 2002;288:1064.
- Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
- Magliano DJ, Rogers SL, Abramson MJ, Tonkin AM. Hormone therapy and cardiovascular disease: a systematic review and meta-analysis. BJOG 2006;113:5-14.
- Offenbacher S, Beck JD, Moss K, et al. Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol 2009;80:190-201.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association