j o u r n a l o f d e n t i s t r y 3 7 ( 2 0 0 9 ) s 5 6 7 – s 5 8 4 S579

immune cells (such as macrophages, Kupffer cells, lympho-

cytes and dendritic cells) live in such close proximity to each

other, both in adipose tissue and liver, when inflammation

takes place, it is more likely to negatively affect immune

function. A recent study comparing diabetics to nondiabetics

illustrated this phenomenon. In diabetic patients, period-

ontitis sites showed a higher frequency of Porphyromonas

gingivalis, Aggregatibacter actinomycetemcomitans, and Campylo-

bacter spp., commonly associated with more aggressive forms

of periodontal disease. In this same study, antibodies to these

periodontopathogens were detected in sera, but the antibody

itself did not seem to be adequately protective to prevent

disease. Defects of neutrophil chemotactic, phagocytic and

microbicidal activities are also seen in diabetes and contribute

to periodontal disease. In a recent study of type 2 diabetic

patients, neutrophil chemotaxis alterations were associated

with greater probing depth measurements.

Finally, hyperglycemia alters collagen synthesis and turn-

over. In animal models of periodontal disease, the presence of

diabetes contributes to an apparent increase in the number of

fibroblasts, accumulation of thick collagen fibers, and distor-

tion of fibers that support the basement membrane. These

changes adversely influence healing in periodontal tissue.

Periodontal disease also negatively affects glucose control

in diabetic patients. Individuals with both diabetes and

periodontal disease have a sixfold higher risk for worsening

glycemic control over time. The presence of periodontal

disease is also associated with a several fold higher risk of

diabetic complications. It is likely that because the period-

ontium is a site of persistent microbial challenge and in

periodontal disease is a constant source of pro-inflammatory

E-mail address: m.j.caulfield@qmul.ac.uk.

activity, insulin resistance is increased in diabetic individuals

with more severe periodontal disease.

Many questions remain with respect to the interaction

between diabetes and periodontal disease. It is unclear whether

periodontal disease leads to early development of diabetes in

those with impaired glucose tolerance. In addition, it is yet to be

determined whether there is a long-term beneficial effect of

surgical periodontal therapy or long-term maintenance on

diabetes control. More research is needed to evaluate the effect

of modulating agents/interventions (e.g., statins and TZDs,

physical activity) on periodontal disease. Finally, questions

remain regarding which mechanisms are most important and

most modifiable in the periodontal disease and diabetes

relationship. Because of the high prevalence of impaired

glucose tolerance and diabetes globally, answering these

questions will have important public health implications for

many individuals throughout the world.

Conflict of interest statement

None declared.

Source of funding

National Institutes of Health-National Institute on Aging

Agency for Healthcare Quality and Research Health Resources

Services Association.

doi:10.1016/j.jdent.2009.05.015

Atheromatous vascular disease and ischaemic stroke inthe UK

Mark Caulfield

John Vane Science Centre, Clinical Pharmacology, The William Harvey Research Institute, Charterhouse Square,

London EC1M 6BQ, United Kingdom

The burgeoning cardiovascular (CV) disease epidemic is now

the leading cause of death worldwide, causing 17.5 million

deaths per annum. The World Health Organisation expects

this will increase to 24.2 million by 2030.1

In the UK CV death disease still accounts for 31% of male

and 23% of female premature deaths.2 These statistics do not

describe the true national burden of disease with more than 2

million people living with angina, 1.2 million having suffered a

heart attack and 0.9 M with heart failure.2 In 2003, CV

treatment cost the nation £26 billion.

It is of note that 30% of all deaths are now directly

attributable to cardiovascular disease. Over 80% of the burden

of this disease is in low and middle income countries. Across

the globe about 20 million people survive a heart attack and

stroke each year. The success of some of our public health

strategies is that these people are burdened with disability

which makes their future care and the care of their family a

major challenge, given lost earnings. In any country, the cost

of cardiovascular disease is not simply the direct treatment

j o u r n a l o f d e n t i s t r y 3 7 ( 2 0 0 9 ) s 5 6 7 – s 5 8 4S580

costs or the cost of prevention. The true financial burden is

largely the social and economic costs of disability at a

premature age, which causes loss of income to the economy

and loss of earnings to families.

It has been estimated that there are presently c. one

billion people with high blood pressure worldwide. Blood

pressure is important in about 69% of stroke and 49% of

ischaemic heart disease cases and leads to about 7.1 million

deaths worldwide each year. This disorder, formerly the

province of Western Societies, in which dietary and lifestyle

measures interacting with genes triggered raised blood

pressure, has now been exported to developing countries.

It is estimated that this will rise to 1.5 billion worldwide by

2016.

Another major risk factor is cholesterol, known to cause 18%

of strokes and to be a dominant risk factor in coronary heart

disease, causing 4.4 million deaths worldwide per annum.

Elevated blood pressure and cholesterol levels, together with

smoking and diabetes contribute to atherosclerosis.

Treatment of myocardial infarction has been revolutionised

over the past 25 years. State-of-the-art heart attack centres are

being established across the UK. They are facilitated by

ambulance-based diagnosis of electrocardiographic (ECG)

changes indicative of a heart attack. The patients are

transferred to heart attack centres, where they are able to

receive primary angioplasty or thrombolytic therapy.

1. Stroke

Data from the Office of National Statistics in 2005 indicate that

the number of deaths from stroke has been progressively

falling, year on year. This parallels very substantial drops in

blood pressure conditions given improvements in screening

and treatment as a result of developments in the General

Practice General Medical Services Contract, which rewards

blood pressure control with points and therefore money. The

UK government has incepted a National Stroke Strategy

whereby all patients should have access to brain attack

centres where a concentration of stroke physicians are

available to interpret early imaging and decide whether

patients could benefit from clot busting drugs, such as those

used in myocardial infarction.

2. Primary prevention of vascular disease

There is good evidence that a combination of simple and cost-

effective measures could result in 50% less vascular disease,

morbidity and mortality. The patient can take action to

reduce blood pressure by reducing salt in the diet, consuming

more fruit and vegetables and increasing exercise, all of

which lower blood pressure. This coupled with control of

weight and alcohol consumption can be very beneficial in

reducing blood pressure and almost as effective in combina-

tion as a dose of blood pressure medication. Indeed, the UK

leads the world in sodium salt reduction from the diet, with a

daily limit of no more than 6 g of consumption of salt. This is

hard to achieve as salt is hidden in many food stuffs, for

example bread.

A second revolution in cardiovascular care has been

the provision on the National Health Service of Smoking

Cessation Patient Support Groups, which provide nicotine

replacement therapy and, if necessary, psychotherapy to

support patients in smoking cessation, notably quitting

cigarettes.

In terms of cholesterol reduction this includes a diet that is

low in diary products and red meat, combined with (if the

cholesterol is above 5 mmol for the total cholesterol and

3 mmol for the low density lipoprotein cholesterol), taking

statins.

The other risk factors that need attention are those that

are increasing dramatically in the population—obesity and

type II diabetes, both of which are linked to a failure of the

body’s cells to respond to pancreatic insulin, and ultimately

failure of the pancreas to supply adequate insulin, leading to

progression to diabetes. The progressive weight gain makes

an individual resistant to therapies and eventually they may

require insulin to which they will respond by putting on more

weight. To combat these measures and to assess a patient

properly, in non-diabetic men and women age-driven risk

scores are used. In the UK individuals who have a 20% 10 year

risk are treated. For hypertension this treatment is char-

acterised by the NICE approved ACD rule, which suggests that

individuals younger than 55 years of age should be started on

so-called A-drugs, either an ACE inhibitor or angiotensin

receptor blocker. Over 55 years of age, patients should start on

a calcium antagonist or diuretic, followed by a series of

steps which results in combination therapy. This is most

commonly seen in the treatment of hypertension, as specified

by the ACD rule.

3. The polypill concept

Wald and Law proposed in a series of papers in the British

Medical Journal in 2003 that a combination of a statin and

half the standard dose of three blood pressure lowering

medicines with aspirin and folic acid could reduce 80% of

cardiovascular disease in those over 55 years of age. This

concept requires further evaluation in long-term outcome

trials, but is a fascinating prospect, given its simplicity for

treating a whole section of the population. This fits with the

fact that most cardiovascular disease deaths are age-driven

and combination tablets would be highly acceptable to many

patients.

4. Conclusion

There are many routes now by which the effects of

cardiovascular risk factors can be attenuated, with multiple

therapeutic strategies for interventions for prevention prior to

an event and to prevent recurrence. These strategies are

widely deployed as public health measures across Western

Societies. The global burden of disease in emerging countries

is a source of worry and the affordability of some of the

therapeutic strategies that are widely used in Western

Societies may limit the access to this type of care in the

growing section of unmet healthcare need.

j o u r n a l o f d e n t i s t r y 3 7 ( 2 0 0 9 ) s 5 6 7 – s 5 8 4 S581

Conflict of interest statement

None declared.

Source of funding

Research has been funded by the Medical Research Council,

the British Heart Foundation and the Wellcome Trust.

E-mail address: pp192@columbia.edu.

r e f e r e n c e s

1. The world health report 2002 - Reducing risks, promotinghealthy life. (World Health Organization, 2002).

2. http://www.heartstats.org/homepage.asp.

doi:10.1016/j.jdent.2009.05.018

Periodontal disease and macrovascular disease:What is the evidence?

Panos N. Papapanou

Periodontics/Oral and Diagnostic Sciences, Columbia University College of Dental Medicine, New York, USA

There are several levels of evidence that need to be fulfilled to

accept that a putative risk factor is causally associated with a

particular disease: These include (i) a biologically plausible

scenario by which the exposure contributes to the outcome;

(ii) supporting data from epidemiologic studies (cross-sec-

tional, case–control and prospective cohort studies); (iii)

evidence from mechanistic, experimental studies; and (iv)

ultimately, evidence from intervention studies, ideally rando-

mized controlled trials.

Periodontal infections clearly fulfill the biological plausi-

bility requirement. The ulcerated epithelium of the period-

ontal pocket has a sizeable surface area and is in constant

contact with a highly organized biofilm that is inhabited by

several bacteria with significant virulence potential. Bacteria

have been shown to enter the circulation after even mild

manipulation of the periodontal tissues, resulting in repeated

transient bacteremias that may facilitate dissemination of oral

microbiota at distant sites. Bacterial products and inflamma-

tory mediators that are produced abundantly, locally within

the diseased periodontal tissues may also enter the circulation

and result in systemic inflammation which may trigger

endothelial activation. Molecular mimicry, i.e. the high degree

of homology between prokaryotic and mammalian proteins,

redirects anti-bacterial antibodies to act also as auto-anti-

bodies, ultimately resulting in activation of, and damage to the

vascular endothelium. The possibility of a certain degree of

confounding due to common risk factors for atherosclerosis

and periodontitis should not, however, be overlooked.

Over the past two decades, cross-sectional and prospec-

tive cohort studies have demonstrated a significant associa-

tion between radiographically and clinically assessed

periodontitis and coronary heart disease (CHD), broadly

defined as myocardial infarction, death due to hospitaliza-

tion due to CHD, or revascularization procedures. Impor-

tantly, these positive associations persist after adjustment

for established risk factors for CHD, including age, gender,

race, poverty, smoking, diabetes, high blood pressure, body

mass index and high serum low density lipoprotein

cholesterol. With few exceptions, the above associations

have been confirmed in several populations with varying

race/ethnicity profiles. Positive associations have also been

reported between periodontitis, defined by clinical mea-

sures or by seropositivity to important periodontal patho-

gens, and non-hemorrhagic stroke. Finally, limited recent

evidence suggests that periodontitis may be associated with

peripheral artery disease after adjustment for concomitant

exposures.

Epidemiologic evidence also exists on the association

between periodontitis and subclinical markers of CVD,

including levels of serum C-reactive protein and seropositivity

for interleukin 6. Heavy colonization by specific periodontal

pathogens was found to be associated with increased intima–

media thickness, while DNA from oral bacteria and, in one

report, viable invasive periodontal pathogens were recovered

from human endarterectomy specimens.

Data from intervention studies suggest that treatment of

periodontitis may result in lower levels of serum inflamma-

tory mediators such as CRP and IL-6, positive alteration of lipid

profiles and improved endothelial function, although the

degree of variability is substantial. A randomized clinical trial

that employed local antibiotics as adjuncts to mechanical

periodontal therapy demonstrated improved endothelial

function 6 months after completion of treatment. Finally, a

pilot, multicenter randomized secondary prevention trial of

18-month duration compared periodontal therapy to com-

munity dental care, but failed to detect any differences in the

incidence of cardiovascular adverse events between the

treatment arms.