Almost desperate responses among periodontal pundits and likewise clinicians in the U.S. and Europe after the publication of a very thorough review of the available literature about the association between periodontitis and atherosclerotic vascular disease by Lockhart et al.  had always reminded me of the 2007 National Intelligence Estimate on Iran’s military nuclear program which might actually have prevented George W. Bush and Dick Cheney from unleashing another war in the Middle East. The 16 intelligence agencies in the U.S. had then concluded (with confidence) that Iran had in fact such a program but abandoned it in 2003 and had not made a decision to resume it (in 2007) .
While dental infection focal theory has been around since W.D. Miller working in Robert Koch’s laboratory in Berlin in the 1890s, the possible link between periodontitis (and other dental infections) and atherosclerotic vascular disease had been revived almost 25 years ago by Finnish research group around Kimmo Mattila [pdf]. What followed culminated in dental profession recommendation Floss or Die! and skepticism on the other hand.
Now, systematic reviews are primarily meant either to bring an end to open issues or at least identify unresolved questions to be addressed in future studies. Since many dental professionals have continued over the years to disconcert the public with sometimes unwarranted claims about a causal relationship between periodontitis and cardiovascular disease and in particular myocardial infarction, the American Heart Association’s Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease had convened a review group including representatives from Dentistry to assess what we know about the association between the two disorders.
The review is extraordinarily thorough. Results from studies at numerous evidence levels had been assessed, for instance cross-sectional and prospective epidemiological studies, including those where surrogate and subclinical markers of artherosclerotic vascular disease were assessed, detection of DNA of periodontal and other pathogens in atheromas, as well as recent intervention studies involving periodontal treatment. Insofar Bradford Hill’s criteria [pdf] (or recent attempts [pdf] of organizing them or most of them into direct evidence such as intervention studies, mechanistic evidence such as biological action; and parallel evidence indicating coherence, replicability and similarity of study results) were vigorously tested (or applied). The main conclusions by Lockhart et al. (2012) regarding the association between periodontal (PD) and artherosclerotic vascular disease (ASVD) were summarized as,
“Extensive review of the literature indicates that PD is associated with ASVD independent of known confounders. This information comes mostly from observational studies, however, and therefore does not demonstrate that PD is a cause of ASVD, nor does it confirm the contention that therapeutic periodontal interventions prevent heart disease or stroke or modify the clinical course of ASVD. Although a contribution of PD to ASVD is biologically plausible, periodontal and cardiovascular diseases share multiple risk factors that are prevalent and powerful promoters of disease, including tobacco use, diabetes mellitus, and age.
The role of tobacco use in the observed association between PD and ASVD outcomes is a critical one, because smoking is a major risk factor for both conditions, and smoking cessation is a critical component of health maintenance and prevention of many diseases, including both PD and ASVD. Recent evidence indicates that the observed association between PD and ASVD is independent of smoking, because it has been shown retrospectively and longitudinally that PD and ASVD are associated both in smokers and in never-smokers.
Available data indicate a general trend toward a periodontal treatment-induced suppression of systemic inflammation and improvement of noninvasive markers of ASVD and endothelial function. The effects of PD therapy on specific inflammatory markers are not consistent across studies, and their sustainability over time has not been established convincingly, however, and determinants of variability in these responses remain poorly understood. In addition, transient proinflammation and damaged endothelial functions are observed after intensive therapy for PD.” (Emphasis added.)
Plausibility of the observed association is discussed at length as well. Meta-analyses of, for instance, prospective cohort studies were generally abandoned in favor of rather reporting whether associations were significant or not, most probably due to observed heterogeneity of older studies with poor or questionable designs. This might in fact be somewhat misleading since the strength of “significant” associations may be easily missed .
Lockhart et al. address the issue that we do not have sufficient data yet but sound also an explicit warning,
“This review highlights significant gaps in our scientific understanding of the interaction of oral health and ASVD Identification of clinically relevant aspects of their association or therapeutic strategies that might improve the recognition or therapy of ASVD in patients with PD would require further study in well-designed controlled interventional studies. Such investigations should reflect the longitudinal effectiveness of different approaches to managing periodontal health, given the possibility of PD recurrence after therapy and the extended time course of evolution of ASVD and its manifestations. Uniform criteria for PD case definitions, extent, and severity; standardized treatment protocols; and consideration of time course, important confounders, and effect modifiers on the association of PD and ASVD would also improve future studies. Finally, the implication of the observed transient detrimental effects of PD therapy on markers of inflammation and endothelial function should be clarified. In the meantime, statements that imply a causative association between PD and specific ASVD events or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted.”
In a press release, which unfortunately cannot be found on the net anymore, the review’s conclusions had been further downplayed by the first author in a rather sober way, not really encouraging further research into the topic. I remember that Peter Lockhart uttered that if there was a causal relationship between the two conditions, it would have been discovered after almost 25 years. And, new oberservational studies possibly confirming the independent association of which we know right now are not warranted either. On April 18, the day when the systematic review went online, HealthDay reported on it quoting Peter Lockhart. “So far, there is no conclusive evidence [of a cause-effect relationship].” “If cause and effect is someday proven, it will probably be fairly minor.” Then president of the American Academy of Periodontology, Pamela McClain, who is no academic but just a periodontist in Aurora, Colorado,
had to disagree disagreed in part with this assessment. “The academy agrees that science doesn’t support a causal relationship between periodontal disease as a direct cause of cardiovascular disease.” But “[i]t’s hard to predict [that if a cause-effect relationship is found, it will be minor]. We may find a stronger link.”
The following outcry was predictable. What is amazing is that a dental journal, JADA, asked co-authors of the paper by Lockhart et al. to write a commentary (even a guest editorial)  to, well, in a way correct the conclusions of the systematic review. In particular the above final warning is apparently being downplayed when Papapanou and Trevisan write,
“Periodontal therapy results in improved endothelial function and reduced systemic inflammation, both important markers of cardiovascular health. No studies have been conducted yet to test the effect of periodontal therapy on future AVD [atherosclerotic vascular disease]-related clinical events.”
While the systematic review by Lockhart et al. (2012) had pointed to the latter it had identified an area of unresolved problems regarding the former. As fact of the matter, studies have indeed shown that both endothelial function and systemic inflammation are improved after most therapeutic interventions or following smoking cessation but not, at least immediately, after periodontal therapy.
In the absence of any further large well-controlled interventional study reflecting “the longitudinal effectiveness of different approaches to managing periodontal health, given the possibility of PD recurrence after therapy and the extended time course of evolution of ASVD and its manifestations,” I was rather confident that there is currently no need for another systematic review of the issue. As to my surprise, a colleague from Idaho informed me recently about a joined workshop which had been organized by the European Federation of Periodontology and the American Academy of Periodontology and held in Segovia, Spain, on November 11-14. Three groups tackled once more periodontal disease and diabetes mellitus, adverse pregnancy outcomes and cardiovascular disease. Proceedings are to be published soon in EFP’s Journal of Clinical Periodontology and AAP’s Journal of Periodontology. Participants were carefully picked as usual (they seem to be pleased to be called “thought leaders” now, a new concept as “opinion leaders” are obsolete in times of evidence-based medicine) and I got the impression that there is hardly anybody who would be critical to claims despite lack of evidence, in particular in case of artherosclerotic vascular disease related to periodontitis.
One gets a bit the impression the motto for this workshop was Just ignore! what the American Heart Association had to say about this in April this year. This topic won’t be buried easily. Let’s see if and how conclusions will differ when the Perio pundits have their say.
It won’t help. I assume that cardiologists will now finally lose any interest in periodontal disease. It had been dampened already in 2009 when the US Preventive Services Task Force had recommended not to screen asymptomatic subjects with no history of coronary heart disease for non-traditional risk factors such as periodontitis to prevent respective events.
 Lockhart PB, Bolger AF, Papapanou PN Osinbowale O, Trevisan M, Levison ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr, Baddour LM. Periodontal disease and atherosclerotic vascular disease: Does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation 2012;125:2520-2544. [pdf]
 The 2007 National Intelligence Estimate actually prevented an attack on Iran. All 16 intelligence agencies in the U.S. had made clear, with confidence, that Iran had abandoned its military nuclear program already in 2003. In order to win the public for another adventure (after the illegal attack on Iran in 2003) the truth has to be concealed, not revealed. For George W. Bush this NIE was a disaster as one can read, if interested in such things, in his book Decision Points of 2011.
 More than a decade ago I had conducted and published meta-analyses regarding prospective cohort studies in which periodontal disease could be assessed as a risk factor for the development of coronary heart and cerebrovascular diseases where I wrote (translated from German) even then,
“The role of chronic infections in the initiation of atherosclerotic lesions has been vividly discussed in recent years. A possible causal relationship between cardiovascular diseases and infections with, e. g., Chlamydia pneumoniae, Helicobacter pylori, or herpes viruses had also been established for chronic periodontitis, in particular after discovery of DNA of typical periodontal pathogens in atheromatous plaques. Especially in longitudinal epidemiologic studies, a low or moderate association between existing periodontitis and the development of, e. g., coronary heart disease or non-haemorrhagic stroke had been observed. In this article the respective literature is critically reviewed. In particular, the influence of incomplete or inappropriate adjustment for common risk factors for both diseases, i. e., cardiovascular disease and periodontitis should be analysed. In metaanalyses of prospective studies, in which the respective endpoint occurred after the investigation had commenced, relative risks of periodontitis of 1.12 (95 % confidence interval 0.95-1.33) for coronary heart disease and 1.73 (0.89-3.34) for ischaemic stroke were calculated. Whether chronic periodontitis actually represents an important risk for the development of cardiovascular diseases remains questionable. Already planned intervention studies appear to be premature and ethically highly problematic.” (Müller HP. Does chronic periodontitis play a role in the pathogenesis of cardiovascular and cerebrovascular diseases? [in German] Gesundheitswesen 2002; 64: 89-98).
So, at that time associations found in longitudinal cohort studies with questionable or poor designs were weak if even existing. Subsequent meta-analyses by Khader et al. (J Periodontol 2004;75:1046-1053), Bahekar et al. (Am Heart J 2007;154: 830-837) and, most recently, Humphrey et al. (J Gen Intern Med 2008;23:2079-2086) similarly reported on low relative risks of 1.24-1.35 for coronary heart disease and stroke, respectively. And, after ten years of, well, feverish research, new emerging evidence still does not convince the skeptical reader.
13 December 2012 @ 2:23 pm
Last modified December 13, 2012.