Periodontal Infections and Atherosclerotic Vascular Diseases

Speakers:
Steven Shea, Columbia University College of Physicians and Surgeons
Maurizio Tonetti, European Research Group on Periodontology

Highlights

• The Multi-Ethnic Study of Atherosclerosis revealed that obesity is a major risk for cardiovascular disease and is associated with hypertension, glucose intolerance, greater carotid intimal wall thickness, higher coronary artery calcium scores, and greater left ventricular mass.
• The Hispanic Children's Health Study showed correlations between obesity and insulin resistance and inflammation in two- to three-year-old children living in Manhattan.
• Whether infection/inflammation causes cardiovascular disease is controversial; epidemiological studies suggest yes, but recent intervention trials showed that giving systemic antibiotics did not decrease mortality or cardiovascular events.
• Periodontal disease is an infection; mechanistic studies suggest it could trigger the onset of atherogenesis through its inflammatory components or directly precipitate cardiovascular events.
• Intensive periodontal therapy improves markers of inflammation, but whether or not such treatment influences systemic vascular disease is still an open question.

Heart disease risks

Cardiovascular disease is a leading killer worldwide. And what's particularly worrisome is the fact that today, even very young children are showing risk factors, said Steven Shea of Columbia University College of Physicians. Shea, a principal investigator for the multicenter Multi-Ethnic Study of Atherosclerosis (MESA) and for the Hispanic Children's Health Study in New York City, reviewed data from these observational studies as a means of informing the audience about risk factors for subclinical cardiovascular disease.

Obesity emerged as a major risk in both studies: in MESA, which enrolled adults ages 45–84 with no clinical evidence of heart disease, obesity was associated with hypertension, glucose intolerance, greater carotid intimal wall thickness, higher coronary artery calcium scores, and greater left ventricular mass. In the Hispanic Children's Health Study, which enrolled healthy two- to three-year-olds, obesity was linked to insulin resistance and to increases in markers of inflammation such as c-reactive protein (CRP).

A role for infection?

How do these findings relate to periodontal disease? Maurizio Tonetti of the European Research Group on Periodontology described the efforts of his group and others to draw the connections. He noted that a large portion of the risk factors for atherosclerosis are not known; more than 50% of individuals who have a heart attack or unstable angina do not have "classical" risk factors, such as diabetes, high levels of low-density lipoprotein cholesterol, or hypertension. Epidemiological research as well as mechanistic studies over the past decade suggest that chronic infection increases the risk of cardiovascular disease, and especially early atherogenesis.

Studies have shown an association between periodontitis and increased CRP levels, but this does not prove cause and effect.

However, large intervention trials, such as the Claricor trial, in which people with stable heart disease or angina were given antibiotic therapy or placebo, showed the therapy did not result in a decrease in mortality or cardiovascular events. "So, skepticism [about the link between infection and heart disease] developed, and there's still quite a bit of discussion" about the hypothesis, Tonetti acknowledged. That said, he is among those who are convinced that the connection between infection and heart disease is real. And in this context, periodontitis—which is "just another [form of] chronic infection"—could be an important risk. "When you see a patient with pus oozing out from the gums, tremendous pocketing, and bone loss, no one in the audience would believe that the [rest of the] body isn't sensing what's happening in the mouth," he said.

Two major hypotheses describe plausible mechanisms by which periodontitis might influence cardiovascular health. The inflammatory components of periodontitis might have an impact on the onset of atherogenesis; or periodontitis might, in and of itself, precipitate cardiovascular events. "Both hypotheses are valid and supported by mechanistic studies," Tonetti said. But only intervention trials can provide definitive proof: "If we remove the cause [periodontitis], we should see an attenuation of the effect, and that would prove causality."

Treatment of periodontitis clears up the inflammation.

A number of case-control studies have shown an association between periodontitis and increased CRP levels, but this does not prove a cause-and-effect relationship, Tonetti explained. For example, one study showed that treatment of periodontitis with extraction of hopeless teeth and mechanical removal of plaque, calculus, and the subgingival biofilm that causes periodontal disease cleared up the inflammation. At six months followup, reductions were seen in serum concentrations of interleukin-6, also a marker of inflammation, as well as CRP. Subsequent analyses revealed a dose-dependent effect of periodontal treatment in that people who responded better to the treatment—that is, they had little residual bleeding and few pockets—had a greater reduction in CRP levels.

However, although the number of pockets decreased from 77 to 23 on average after treatment, infection was not eradicated. "This troubled us," Tonetti acknowledged. "We wondered whether standard periodontal treatment is best for a trial. Is standard treatment enough to not only cure the local issue of periodontitis, but to also bring about a systemic effect?"

Exploring interventions

Tonetti and his colleagues explored a number of other treatment approaches, including scaling, root planing (removal of calculus and bacteria by scraping them away from the root surface below the gum line), and oral hygiene instruction and found that the variability in patient response was linked mainly to local disease—pocket depth, location of the pocket, types of pathogens harbored—and not to the systemic state of the patient.

They thought about adding a systemic antibiotic to the treatment plan, since previous studies had shown that antibiotic use improves outcomes significantly in people with severe periodontal disease. But they faced a problem: "We couldn't use systemic antibiotics with scaling and root planing if we wanted to prove causality [between periodontitis and cardiovascular disease]; there would still be a doubt, since we might end up treating an occult chronic infection elsewhere in the body," Tonetti explained.

So the team explored local antibiotic delivery in the periodontal pockets instead. Earlier studies suggested that local drug delivery in combination with scaling and root planing could result in significantly less recolonization of bacteria and consequently better reductions in pockets, gum bleeding, and other manifestations of periodontitis six months after treatment. "Taken together with recent meta-analyses on the effects of local drug delivery at the site of infection, [it seemed that local delivery yielded] the same benefit as did systemic."

With scaling, planing, and local delivery of an antibiotic, "we thought we might finally have a treatment that could show a reduction in systemic infection," Tonetti said. But another problem emerged. Scaling and root planing actually induced a short-term bacteremia, with inflammation, coagulation, and vascular dysfunction. These short-term systemic effects might mitigate the long-term benefit, and so treatment still had to be optimized.

Early indications

Moving ahead, the team conducted two pilot studies in patients with severe periodontitis. The first compared standard periodontal treatment versus intensive treatment—including scaling, planing, subgingival instrumentation, other periodontal measures, plus microspheres of the antibiotic minocycline delivered locally—versus no treatment of periodontitis. Intensive treatment produced better periodontal and systemic outcomes as measured by reductions in CRP, interleukin-6 and other markers of inflammation. Therefore, the study supported the hypothesis that periodontitis is a potential cause of systemic inflammation, Tonetti said.

The second pilot compared intensive versus standard treatment over six months. Here again, intensive treatment gave a greater benefit, earlier than standard treatment, and confirmed that there may be causality between periodontal disease and systemic disease. A recent meta-analysis that examines the effect of periodontal treatment on CRP serum concentrations suggests a significant improvement after intensive periodontal therapy.

The team went on to conduct a primary prevention trial to determine the effect of intensive periodontal treatment on endothelial dysfunction (measured by flow-mediated vasodilatation) compared with standard community-based treatment in adults with severe generalized periodontitis. Intensive treatment was successful in ameliorating periodontitis; at six months, the average number of periodontal lesions went from 82 to 14 in the intensive treatment group, whereas the number of lesions was unchanged in the community treatment group.

Intensive periodontal treatment was associated with improvement in endothelial function at six months, but the studies have limitations.

Intensive treatment also translated into changes in endothelial function in a biphasic manner: one day after treatment, there was a decrease in elasticity of the arteries. But the arteries became more flexible over time so that at six months, intensively treated patients were actually better off than they were at the beginning. There was also an association between flow-mediated dilation and sites with bleeding on probing (a clinical sign of gingival inflammation). "The better the bleeding went, the better the flow-mediated dilation went," Tonetti said. These findings suggest that periodontitis is a possible cause of endothelial dysfunction, and that periodontal treatment might reverse this first step in cardiovascular disease.

But these studies have limitations, in that they are valid only for individuals with very severe periodontitis who are systemically healthy, Tonetti acknowledged. Could periodontal treatment prevent cardiovascular events in a high-risk population? The multi-center Periodontitis and Cardiovascular Events (PAVE) study, a pilot secondary prevention trial, actually asked this question. That study found no statistically significant difference in event-free survival in individuals who underwent intensive periodontal treatment at the study center compared with a community-based control group who received treatment at their own dentist. A definitive study is now needed to answer this question.

Looking ahead

"The results are interesting because they show us the direction we need to go," said Tonetti. "We need to differentiate primary versus secondary prevention, and we need to ask ourselves about the intervention, since it seems that periodontitis may be more difficult to treat than we think. Also, when we look at a population, we need to establish the extent and severity of their periodontitis as well as their systemic status. These issues are likely to be key to the success of future studies."

Policy Implications

Speakers:
Sherry Glied, PhD, Columbia University
Michael Glick, DMD, Arizona School of Dentistry and Oral Health
Richard W. Valachovic, DMD, MPH, American Dental Education Association
David Krol, MD, MPH, FAAP, University of Toledo

Highlights

• Research findings linking oral heatlh and non-oral diseases and conditions have implications for dental and medical education, as well as the financing of dental services.
• Associations between oral health and systemic conditions are exciting, but also wrought with potential biases and misinterpretations.
• Oral health is important for its own sake, not just because of potential connections to systemic health.
• Until recently, there has been no viable effort to integrate the academic and practice components of medicine and dentistry.
• Physicians should be able to provide oral health guidance, and dentists should be involved in screening and referral for relevant systemic conditions.

Separation of mouth and body

In his introduction to this session on the policy implications of the "oral-medical connection," session co-chair Burton L. Edelstein of Columbia University College of Medicine observed that "like mammals and marsupials, medicine and dentistry live side by side but don't mate." He briefly described the origin of the two professions in the United States, which dates back to 1840. At that time, physicians at the University of Baltimore rejected the idea of starting a "department of oral stomatology" for those interested in dentistry. From that point on, medicine and dentistry evolved as separate professions, with separate schools and curricula, licensure, professional groups, care-delivery sites, para-professionals, insurance, and cultures. At the same time, the mouth became "unplugged" from the rest of the body—not included in routine medical care—creating a disconnect that continues today.

Can the mouth now be plugged back into the body? Yes, according to the speakers in this session—but to do so requires "substantive clinical, health systems, and public policy changes," Edelstein acknowledged.

Integrating the systems

One of the consequences of the separation between dental and medical care is that the two are financed differently. And whereas many people have health insurance to cover medical needs, relatively few have dental insurance. As a result, "lots of people are not getting dental care," and the ones who don't tend to be the same lower income individuals who are most at risk for the systemic problems described in the previous sessions, said Sherry Glied of the Mailman School of Public Health. She cited a recent study showing that only about 42% of adults ages 18 to 64 went to the dentist in the previous year—among them, only 38% of pregnant women and 44% of those with heart disease.

In light of the "growing evidence" linking systemic conditions to oral health, "we need a holistic vision of medical care," Glied said. "We need to expand our thinking about what constitutes medicine to include dental health," and to do so will require new models of integration. She suggested following some of the lessons learned over the past 30 years in trying to integrate mental health and medicine.

It would be feasible to embark on a model wherein dental insurance is integrated with medical insurance.

For example, it would be feasible to embark on a model wherein dental insurance is integrated with medical insurance, with insurers playing a key role in making the connection between professions. Rather than doctors and dentists talking to each other about their patients, they would each talk to the insurers about their patients. For this type of model to work, it would have to be "organizationally" based to ensure good communication among all parties, and the medical and dental plans would have to work in concert from a financial perspective—that is, there would have to be "dental carve-outs" embedded in medical health plans. Glied pointed to Aetna as a company that is using this type of model.

But she also warned that "you have to be very careful before you go down this path, based on our experience with mental health. It's dangerous to say that the reason you want to integrate or provide dental insurance is because it's going to save money on medical insurance or do something good on the medical side. Dental care is valuable because oral health is valuable in and of itself. If oral health gives you better treatment for heart disease, that's a bonus. Otherwise, you have to be tremendously convinced by the science that the connection is there, that the intervention [the dentist makes] matters, and also that the intervention saves you money down the line. And that's tremendously difficult to show." The other caveat in going with the insurance-based model is that it misses people who don't have coverage—the population most in need of services, because they're not going to the dentist at all.

Glied suggests using this type of holistic model but at the same time, expanding dental coverage. "The evidence shows that giving people dental insurance really improves oral health, and that expanding dental coverage will not set off an avalanche of use," she concluded.

Professional responsibilities

Once people are going to the dentist, what are the oral health professional's responsibilities in a partnership with other medical and health professionals? Michael Glick of the Arizona School of Dentistry and Oral Health provided a "roadmap" containing five key directives. The first is to "create"—that is, build a knowledge base grounded in education, training, and research. The second is to accurately "interpret" the results of research. He reminded the audience that, for example, the same statistics may sometimes be used to draw opposing conclusions; that epidemiological studies do not show causality; and that odds ratios and relative risks cannot be used to assess an individual patient's risk.

"We need to get it straight because if we come out with different messages all the time, it dilutes the right message. We need to look at data we have, be critical of what we have, and not put in the abstract and conclusion [of a writeup] what we really wish had happened in the study," said Glick, who is editor of the Journal of the American Dental Association. In the context of this event, "getting it straight" means not overinterpreting the current data on the oral-systemic connection. While the associations described earlier and in the literature may be "exciting," they are also "wrought with potential biases and misinterpretations."

The next responsibility, when publishing data, is to "translate" research findings in a forthright way, rather than trying to hedge one's bets by not stating upfront that there are uncertainties.

Dental professionals are also responsible for disseminating accurate information to the public. Glick pointed to an online ad by a law office that stated the following:

If you or someone you know had periodontal disease, diagnosed or undiagnosed, and either ignored or treated unsuccessfully, before or during the same time as any of the mentioned systemic diseases [e.g., diabetes, heart disease, stroke], you may be eligible for damages caused by these systemic diseases.

"Science, not the legal profession, should fuel what we know and what we tell our patients. This [involvement of the legal profession] is what happens because there's a lot of misinformation out there," Glick stressed.

In the future, dentists should also screen for and monitor medical conditions.

Finally, clinicians should be willing to "implement" changes in their practice when data are available. At this point, that means that dentists should provide dental care; recognize changes in the oral cavity; screen for underlying medical conditions; monitor present medical conditions; and intervene to reduce unhealthy behaviors. Carrying out those responsibilities might include doing a blood pressure reading, a chair-side cholesterol test, or glucose screening, he suggested. "There's a lot of spa dentistry out there, and I would love to see medically oriented dental clinics, as well. We would identify individuals at risk for medical conditions and do referrals. Our patients would go to physicians who will make diagnoses and prescribe treatments. And eventually our patients would come back to us, we'd monitor them, and the circle would continue. That's what we need to do, but we're not there yet," he acknowledged. "Fifteen years ago, I would have said I hope every dentist out there does this within the next five years. I'm wiser now, and so I'm saying that if 5% to 10% do something, that will have an impact."

Moving ahead

The session concluded with two speakers who emphasized the need to integrate medicine into the dental curriculum and vice versa in order to "mold" new professionals coming into these fields. Picking up on the theme alluded to by Edelstein, Richard W. Valachovic of the American Dental Education Association described in detail the long-standing separation of medical and dental education in the United States and emphasized that for change to occur, the gap between the two must be bridged. This won't be easy, he affirmed. Most dental schools don't provide a medical knowledge base or have a relationship with a local medical laboratory for routine screening. The curriculum in both dental and medical schools is already "overloaded," he said. "So if we want dentists to recognize systemic problems and refer patients to physicians, and we want physicians to recognize oral health problems and refer patients to dentists, the first thing people in charge of the curricula will say is 'ok, what do we stop teaching [in order to add this new knowledge]?'"

Politically, the time may be ripe to start integrating the two professions.

But somehow, the information has to become part of required learning. Valachovic noted that today, young people have very different expectations from their health professionals than even 10 years ago. So much information is available online, he said, that they'll be wondering, why isn't my dentist asking about systemic issues? Why isn't my doctor looking at oral health?

Politically, the time may be ripe to start integrating the two professions, he continued. Congress is taking an "incredible" interest in dental care—specifically, access to care. New technologies such as salivary diagnostics are overlapping the two professions. "Will routine salivary testing also be part of what we dentists do?" he wondered.

Finally, legal considerations, as depicted by Glick, will continue to have an impact on the direction of such collaborations, Valachovic stressed. The bottom line, he said, is that "we [dentists and physicians] need to learn to collaborate in a more aggressive way, have curricula that reflect that collaboration, and learn to refer to each other as appropriate."

Incorporating oral health into the medical curriculum

In the closing presentation, pediatrician David M. Krol of the University of Toledo College of Medicine addressed the need for more oral health education in medical schools. There's no shortage of places in the curriculum for such information, he noted. At the undergraduate level, oral heath and potential systemic health connections could be taught in anatomy courses, biochemistry, microbiology, pathology, preventive medicine, and in most disciplines—for example, primary care, family medicine, internal medicine, obstetrics/gynecology, pediatrics, emergency medicine, and geriatrics. Those same disciplines could incorporate oral health at the level of graduate medical education. And in fact, the topic could be taught on its own in any continuing medical education program, he added.

Yet studies continue to document the dearth of such education. A recent survey by the American Academy of Pediatrics found that:

• 66% of graduating residents feel pediatricians should conduct oral health assessments;
• 32% received no oral health training during residency;
• 75% had less than three hours of training;
• 14% had clinical observation time with a dentist; and
• The majority of residents want more oral health training.

Similarly, a previous study of continuing medical education among pediatricians found that more than 60% received no instruction in dental health via CME, and among those who did, the mean number of hours of instruction was less than two.

The situation is changing, albeit slowly, Krol said. For example, the current U.S. Medical Licensing Examination specifies disorders of mouth, salivary glands, oropharynx, including dental disorders, under "Nutritional and Digestive Disorders," and lists "teething syndrome, dental caries, stomatitis, disorders of teeth/jaw, and malignant neoplasms of lip, oral cavity, and pharynx" as content areas. Several medical schools are beginning to incorporate dental health into the curriculum, as are some residency programs. Novel continuing medical education programs dealing with oral health are being developed and disseminated.

While these are steps in the right direction, there is still room for improvement, Krol urged. He called for oral health to be included explicitly as part of the required content for primary care graduate medical education, and as content areas covered in board certification examinations in internal medicine and obstetrics/gynecology. Oral health should also be on the radar screen of professional societies and clinicians in practice, he concluded.