- Email: [email protected]
Atheromatous vascular disease and ischaemic stroke in the UK
journal of dentistry 37 (2009) s567–s584
immune cells (such as macrophages, Kupffer cells, lymphocytes 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, periodontitis sites showed a higher frequency of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Campylobacter 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 turnover. 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 distortion 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 periodontium is a site of persistent microbial challenge and in periodontal disease is a constant source of pro-inflammatory
S579
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 in the 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
E-mail address: [email protected].
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
S580
journal of dentistry 37 (2009) s567–s584
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 costeffective 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 combination 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 characterised 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.
journal of dentistry 37 (2009) s567–s584
Conflict of interest statement
S581
references
None declared.
Source of funding
1. The world health report 2002 - Reducing risks, promoting healthy life. (World Health Organization, 2002). 2. http://www.heartstats.org/homepage.asp.
Research has been funded by the Medical Research Council, the British Heart Foundation and the Wellcome Trust.
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-sectional, case–control and prospective cohort studies); (iii) evidence from mechanistic, experimental studies; and (iv) ultimately, evidence from intervention studies, ideally randomized controlled trials. Periodontal infections clearly fulfill the biological plausibility requirement. The ulcerated epithelium of the periodontal 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 inflammatory 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-antibodies, 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 prospective cohort studies have demonstrated a significant association between radiographically and clinically assessed periodontitis and coronary heart disease (CHD), broadly defined as myocardial infarction, death due to hospitalizaE-mail address: [email protected].
tion due to CHD, or revascularization procedures. Importantly, 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 measures or by seropositivity to important periodontal pathogens, 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 inflammatory 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 community dental care, but failed to detect any differences in the incidence of cardiovascular adverse events between the treatment arms.
immune cells (such as macrophages, Kupffer cells, lymphocytes 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, periodontitis sites showed a higher frequency of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Campylobacter 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 turnover. 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 distortion 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 periodontium is a site of persistent microbial challenge and in periodontal disease is a constant source of pro-inflammatory
S579
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 in the 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
E-mail address: [email protected].
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
S580
journal of dentistry 37 (2009) s567–s584
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 costeffective 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 combination 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 characterised 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.
journal of dentistry 37 (2009) s567–s584
Conflict of interest statement
S581
references
None declared.
Source of funding
1. The world health report 2002 - Reducing risks, promoting healthy life. (World Health Organization, 2002). 2. http://www.heartstats.org/homepage.asp.
Research has been funded by the Medical Research Council, the British Heart Foundation and the Wellcome Trust.
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-sectional, case–control and prospective cohort studies); (iii) evidence from mechanistic, experimental studies; and (iv) ultimately, evidence from intervention studies, ideally randomized controlled trials. Periodontal infections clearly fulfill the biological plausibility requirement. The ulcerated epithelium of the periodontal 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 inflammatory 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-antibodies, 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 prospective cohort studies have demonstrated a significant association between radiographically and clinically assessed periodontitis and coronary heart disease (CHD), broadly defined as myocardial infarction, death due to hospitalizaE-mail address: [email protected].
tion due to CHD, or revascularization procedures. Importantly, 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 measures or by seropositivity to important periodontal pathogens, 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 inflammatory 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 community dental care, but failed to detect any differences in the incidence of cardiovascular adverse events between the treatment arms.