Oral health and cardiovascular disease Digital Comprehensive Summaries of Uppsala Dissertations

Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 346
Oral health and cardiovascular
disease
ANDERS HOLMLUND
ACTA
UNIVERSITATIS
UPSALIENSIS
UPPSALA
2008
ISSN 1651-6206
ISBN 978-91-554-7188-0
urn:nbn:se:uu:diva-8708
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PAPERS
I. Holmlund A, Hänström L, Lerner U.H. Bone resorbing activity and
cytokine levels in gingival crevicular fluid before and after treatment. Journal of Clinical Periodontology. 2004; 31:475-482.
II. Holmlund A, Holm G, Lind L. Severity of periodontal disease and
number of remaining teeth are related to the prevalence of myocardial infarction and hypertension in a study based on 4,254 subjects.
Journal of Periodontology 2006; 77: 1173-1178.
III. Holmlund A, Hulte J, Lind L. Tooth loss is related to the presence of
the metabolic syndrome and inflammation in elderly subjects: A prospective study of the vasculature in Uppsala seniors (PIVUS). Oral
Health & Preventive Dentistry 2007; 2: 125-130.
IV. Holmlund A, Holm G, Lind L. Impaired oral health as a predictor
for cardiovascular mortality in a cohort of 7,674 subjects followed
for 12 years. Manuscript
V. Holmlund A, Hedin M, Pussinen P, Lerner UH, Lind L. Porphyromonas gingivalis (Pg) a possible link between impaired oral health
and acute myocardial infarction. Manuscript
Reprints were made with the permission from the publisher.
4
Contents
Abbreviations ................................................................................................7
Introduction...................................................................................................9
Periodontal disease.....................................................................................9
Riskfactors for periodontitis ..................................................................9
Cardiovascular disease .............................................................................10
Risk factors for cardiovascular disease................................................11
Inflammatory response .............................................................................11
In periodontitis.....................................................................................11
Inflammation in the atherosclerotic process (Modified from Ross)48..17
Mutual risk factors for periodontal and cardiovascular disease ...............22
Age.......................................................................................................22
Gender .................................................................................................22
Diabetes ...............................................................................................23
Obesity.................................................................................................23
Race .....................................................................................................24
Smoking...............................................................................................24
Psychological factors ...........................................................................25
Socio-economic factors .......................................................................25
Evidence of association between oral health and cardiovascular disease 25
History .................................................................................................25
Criteria to be fulfilled before oral health can be regarded as a risk factor
for CVD....................................................................................................26
1) Evidence of association between oral health and CVD...................26
2) Strength of association ....................................................................27
3) Risk factor present before debut of the disease ...............................27
4) Specificity of the association...........................................................27
5) Dose-response relationship..............................................................28
6) Biological theories behind association and supporting evidence ....28
7) Support from experimental evidence...............................................28
Studies concerning the relationship between oral health and
cardiovascular disease ..............................................................................30
Table.1 Case-control studies................................................................30
Table 3. Longitudinal studies ..............................................................40
5
Table 4. Relationship of markers of atherosclerosis associated with
human periodontal disease...................................................................47
Aims of the thesis ........................................................................................50
Methods........................................................................................................51
Patient selection........................................................................................51
Investigations ...........................................................................................52
General health......................................................................................52
Oral health ...........................................................................................53
Laboratory analysis ..................................................................................55
Statistical Analysis ...................................................................................55
Results ..........................................................................................................57
Inflammatory response in periodontal disease (Study I) ..........................57
Association between oral health and cardiovascular disease (study II-V) 59
Number of teeth ...................................................................................59
Severity of periodontal disease ............................................................61
Number of periodontal pockets ...........................................................62
Bleeding on probing ............................................................................63
Oral health in relation to systemic markers of inflammation. ..................63
General Discussion......................................................................................65
Inflammatory response in periodontal disease (study I)...........................65
Association between oral health and cardiovascular disease (Study II-V)67
Number of teeth (NT) ..........................................................................67
Severity of periodontal disease (SPD) .................................................67
Number of deepened pockets (NDP) ...................................................68
Bleedings on probing (BOP) ...............................................................69
Oral health in relation to systemic markers of inflammation. ..................69
Limitations ...............................................................................................70
Future perspectives...................................................................................72
Conclusions..................................................................................................73
Acknowledgements .....................................................................................74
References....................................................................................................77
6
Abbreviations
Aa,Aggregatibater
CPI, Community Periodontal Index
actinomycetemcomitan
CPTIN, Caries and Periodontal
ACS, Acute coronary syndrome
AGE, Advanced Glycation End
product
Index Treatment of Needs
CVA, Cerebral Vascular Attack
CVD, Cardiovascular Disease
AL, Attachment Loss
CT, Computer Tomography
AMI, Acute Myocardial Infarction
DM, Diabetes Mellitus
APO-E, Apolipoprotein E
DMF, Decayed, Missing
ARIC, Atherosclerosis Risk
and Filled teeth
in Community
DNA, Deoxyribonucleic acid
B-cells, B-Lymphocytes
ECA, External Carotid Artery
BOP, Bleeding On Probing
ECG, Electrocardiogram
BMI, Body Mass Index
FGF, Fibroblast Growth Factor
BRA, Bone Resorbing Activity
FMLP, N-Formyl-Methionyl-
CAC, Coronary Artery Calcification
Leucyl-Phenylalanine
CAD, Coronary Artery Disease
GCF, Gingival Crevicular Fluid
CAL, Clinical Attachment Loss
G-CSF, Granulocyte Colony-
CCA, Common Carotid Arteries,
Stimulating Factor
CHD, Coronary Heart Disease
GI, Gingivitis Index
CEJ, Cemento-Enamel Junction
HDL, High Density Lipoprotein
CEVD, Cerebrovascular Disease
HT, Hypertension
cIMA, Cross sectional intima
hsCRP, High sensitive
CRP, C - reactive protein
CP, Chronic Periodontitis
C-reactive Protein
ICA, Internal Carotid Artery
7
ICAM, Intercellular Adhesion
RANK, Receptor Activator of
Molecule
ICARAS, Inflammation and Carotid
Nuclear factor B
RANKL, Receptor Activator of
Artery Risk for Atherosclerosis Study
Nuclear factor B ligand
RR, Relative Risk
IgG, Immunoglobulin G
OA, Osteoarthritis
IL-1, Interleukin-1
OR, Odds Ratio
IL-ra, Interleukin Receptor
PAI, Plasminogen Activator Inhibitor
Antagonist
IMT, Cartoid artery IntimaMedia Thickness
INF-, Interferon –
PHS, Periodontal Health Status
PD, Pocket Depth
Pg, Porphyromonas gingivalis
PDGF, Platelet Derived Growth
INVEST, Oral Infections and
Factor
Vascular Disease
PLI, Dental Plaque Index
Epidemiology Study
PMN, Polymorph nuclear leucocytes
LDL, Low Density Lipoprotein
PTI, Panoramic Tomography Index
MBL, Marginal Bone Loss
PVD, Periphery Vascular Disease
MCP, Monocyte Chemotactic Protein SBP, Systolic Blood Pressure
M-CSF, Macrophage ColonyStimulating Factor
MI, Myocardial Infarction
SLI, Silness-Löe index
TGF-, Transforming Growth Factor-
mRNA, Messenger Ribonucleic Acid Th, T-lymphocyte helpercell
NADH, Reduced form of Nicotinamide Adenine Dinucleotid
TIA, Transient Ischemic Attack
TNF, Tumor Necrosis Factor
NCEP/ATPIII, National Cholesterol VCAM, Vascular Cellular Adhesion
and Education Program/ Annual
Treatment Planning III
NHANES, National Health and
Nutrition Examination Survey
RA, Rheumatoid Arthritis
8
Molecule
WBC, White Blood Cell
WHO, World Health Organization
VSMC, Vascular smooth muscle cell
Introduction
“It is what we think we know that prevents us from learning more”.
Albert Einstein
Periodontal disease
Periodontal diseases are very frequent and can affect up to 80% of the
worldwide population. 1 Gingivitis is the mildest form of periodontal disease
and it is caused by a bacterial biofilm that accumulates on the teeth adjacent
to the gingiva if not proper hygiene is performed. If the biofilm is left alone
it will take between 10-20 days to develop gingivitis with clinical symptoms
such as bleeding, swelling and redness of the gingiva. However, this condition is reversible and after removal of the biofilm the gingiva will be normalized in about a week. 2
In 10-15% of the population the gingival inflammation can progress to a
more severe, and nonreversible condition called periodontitis. 3, 4 This is a
chronic inflammatory disease where the inflammation that is triggered by the
bacterial biofilm extends into the deeper parts of the supporting tissues of the
tooth, leading to degradation of connective tissue and alveolar bone. If left
untreated it could finally cause tooth loss. The disease often progresses
without clear symptoms for the diseased person, which makes it difficult for
them to know when to seek help. The classification of periodontal disease
has changed overtime but according to the most recent classification, periodontitis could either be in a localized (i.e affects only a part of the dentition)
or in a more generalized form (i.e affects a major part of the dentition). Both
these forms can appear in an aggressive or a chronic type depending on the
progression rate of the disease. 5 Gingivitis can affect people at all ages.
Periodontitis on the other hand is most common in middle aged and older
people, but it can also appear in young children, although this is unusual.
Riskfactors for periodontitis
Periodontitis has a multifactor etiology where bacteria play an important
role. The bacterial biofilm changes its composition over time from being
colonized mainly by a gram-positive flora in the newly formed biofilm towards a dominant gram-negative anaerobic flora in the older biofilm. Bacte9
ria like Porphyromonas gingivalis (Pg), Tannerella forsythensis (Tf) and
Aggregatibacter actinomycetemcomitans (Aa) (earlier called Actinobacillus actinomycetemcomitans) have been acknowledge as causative factors for
periodontitis. 6 However, there are a number of other micro-organism that
have been associated with periodontitis and most recently were also viruses
suggested as possible etiology factors. 7, 8 As the pocket can harbor around
500 different species 9 and only a fraction of these micro-organisms has been
thoroughly studied, it is still a matter of discussion if above suggested microorganisms are the ones that actually cause the disease or merely are present
because the environment in the diseased pockets favors these microorganisms.
How serum antibody levels against periodontal pathogens relate to disease progression and development still remains unclear, although associations have been reported. 10 Bacteria are essential, but not sufficient to cause
periodontitis. What finally decides if disease develops or not is how the host
response handles the challenge from the micro-organisms in the biofilm. 11, 12
An important factor for the host response is the genetic heritage and it is
estimated that 50% of the individuals with periodontitis have genetic factors
that predisposes for disease development. 13
Behavioral patterns like smoking seriously affect the risk for development
and progression of periodontal disease. 14, 15 Stress has also been suggested
as a risk factor for periodontitis. 16, 17 Systemic diseases can be a predisposing factor for periodontitis and it is well known that diabetes increases the
risk for progression and development of periodontitis, especially if the diabetes in uncontrolled. 18, 19 Rheumatoid arthritis and osteoporosis are other
systemic conditions that recently have been related to periodontal disease. 20,
21
Cardiovascular disease
Cardiovascular disease (CVD), here used as heart and vascular derangements related to atherosclerosis, is responsible for over 50% of the mortality
in the industrialized part of the world. As living standard in the nonindustrialized parts is increasing, CVD will also become a major health
problem in these regions. Although the main symptom related to the heart
disease is angina pectoris, it is the occlusion of arterial vessels leading to
myocardial infarction that are the major cause for mortality in CVD.
CVD develops through changes in the large and medium sized artery
walls by atherosclerosis, which today is considered to be an inflammatory
process starting rather early in life. This leads to plaque formation in the
artery wall and narrowing of the lumen. There has to be a considerable narrowing of the artery lumen before the blood flow is seriously affected and
symptoms occur. In the legs, atherosclerosis with narrowing of the major
10
arteries could lead to a syndrome called Claudicatio intermittens with symptoms such as pain and reduced ability to walk.
Risk factors for cardiovascular disease
CVD has a multifactor etiology where major risk factors are smoking, obesity, diabetes, high blood pressure, high cholesterol levels, lifestyle, heritage
and gender. Heritage and gender are factors we cannot influence, but obesity
and smoking are probably the two most important life style factors with an
extensive impact on the development of CVD that we can do something
about. Obesity is closely link to the development of diabetes type II and to
the metabolic syndrome. 22 The metabolic syndrome (MetS) is a syndrome
that consists of different combinations of cardiovascular risk factors such as
high blood pressure, dyslipidemia, abnormal glucose control, and abdominal
obesity with insulin resistance suggested as a common denominator of the
syndrome. 23-25 The MetS is present if an individual has three of the above
motioned risk factors. In the last decade this syndrome has attracted more
attention as it is closely related to an almost epidemic increase in prevalence
of diabetes type II, which in turn is associated with an elevated risk for cardiovascular disease.
Although there are other definitions for the MetS, the two most commonly used definitions come from the World Health Organization (WHO)
and The National Cholesterol and Education Program/Annual Treatment
Planning III (NCEP/ ATP III). The WHO definition states that the metabolic
syndrome is present if an individual has a fasting blood glucose level >5.6
mmol/l in combination with two of the following conditions, abdominal
obesity, hypertension, dyslipidemia, and micro albuminuria. The NCEP/
ATP III criteria are almost the same except for the micro albuminuria, which
is not included in the NCEP criteria, and that fasting blood glucose level
>5.6 mmol/l is not compulsory for the diagnose.
Despite that these risk factors can explain a major part of the CVD, there
is still a portion of CVD incidence that cannot be explained by above mentioned risk factors. Recently, chronic inflammation has been suggested as a
missing piece in the puzzle. 26
Inflammatory response
In periodontitis
The tooth and its surrounding tissue is the only place in the body where
hard tissue (i.e cementum and enamel) perforate epithelium and communicates with an external environment. A seal is therefore needed and is pro-
11
vided by the junction epithelium, which is the barrier between underlying
connective tissue and the oral cavity. A small fluid transudate will flow from
this seal even in gingival health, minimizing bacterial accumulation mainly
by a mechanical factor. This gingival crevicular fluid (GCF) also contains
leukocytes and macromolecular components derived from serum and underlying connective tissue and this is sufficient to maintain homeostasis in
healthy conditions. However, if the bacterial challenge from the biofilm exceeds a threshold level, the immunological defense will react by initiating a
series of events in the underlying connective tissue, including angiogenesis,
increased vessel wall permeability and accumulation of inflammatory cells,
in attempt to preserve the homeostasis. The release of endotoxin, proteaser
and N-formyl-methioyl-leucyl- phenylalanine (FMLP) from the biofilm will
trigger the defending leucocytes in the area to react with phagocytos and the
production of small very active proteins called cytokines. The amount of
GCF will increase as well as the levels of pro-and anti-inflammatory cytokines such as interlukin-1 (IL-1), tumor necrosis factor-alfa (TNF-) and
interleukin-6 (IL-6). GCF from sites with periodontits contains higher levels
of these and other cytokines than healthy sites. 27, 28 Similarly, these cytokines are also highly expressed in inflamed synovium and synovial fluid
from patients with rheumatoid arthritis. 29, 30
12
Figure 1. Products from the biofilm triggers the recruitment of inflammatory cells
into the connective tissue adjacent to the junction epithelium and stimulate the release of cytokines from stationary cells as well as inflammatory cells. These cytokines stimulate the osteoclastogenesis, bone resorbtion, degradation of the extracellular matrix and decresese bone formation, events leading to loss of tooth supporting
tissues in sites with periodontitis.
When the inflammatory process has started, more leucocytes are recruited
from the blood stream of the adjacent connective tissue due to released cytokines and endotoxin that will enhance the expression of adhesion molecules
such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
molecule-1 (VCAM-1), E-selectin, and P-selectin on the endothelium surface causing more leucocytes to adhere and penetrate the vessel wall. The
recruitment and movement of leucocytes towards the inflamed part of the
tissue is guided by a chemotactic gradient constituted by products from the
innate defense system called “the complement system” and by released
chemokines like interlukin-8 (IL-8). 31, 32 The cell content in the GCF will
mainly be comprised of polymorphonuclear leucocytes (PMN) belonging to
the innate defense. The PMN cells are very important players in the defense
and attack opposing bacteria by phagocytosis and releasing enzymes such as
elastase, lysosyme, lactoferrin and bacterial collagenas. The protective importance of these cells regarding periodontitis can be exemplified by the fact
that individuals that lack PMN-cells (Kostmans syndrome) will develop a
very aggressive form of periodontal disease early in life. Furthermore, individuals suffering from different impairment of PMN-cell function such as
leukocyte adhesion deficiency, Chediak Higashi disease, chronic neutropenia, cyclic neutropenia and Papillon-Lefèvre syndrome are more prone to
develop periodontal disease. 33
Monocytes and lymphocytes are other leukocytes present in the GCF. The
lymphocytes belong to the adaptive immunity and the antibodies present in
the GCF, mainly immunoglobulin G (IgG) are produced by B-lymphocytes
(B-cells). How the different types and levels of antibodies in GCF relate to
disease development and progression of periodontitis is not fully understood
today. 34 In advanced stages of periodontitis, the predominant leukocyte in
the periodontal tissue is the plasma cells (i.e antibody producing B-cells).
The production of antibodies from B-cells is dependent on signals from a Tlymphocyte called T-helpercell (Th). By characterizing the cytokine profile,
three types of Th-cells has been identified. Th1 secrets IL-2, IL-12, Tumor
necrosis factor- (TNF-) and interferon- (INF- ), the Th2 cells mainly
produce IL-4, IL-5, IL-6, IL-10, IL-13; and the Th3 cells secrete transforming growth factor (TGF-). Although, the Th2 subset is more abundant in
periodontitis lesions, the relative importance of the Th1 and Th2 subsets in
periodontal disease is poorly understood. 35
13
Inflammatory bone resorption
Within all sites of the skeleton, bone resorption and bone formation are ongoing processes throughout life in a process called bone remodeling. Normally, these processes are in balance and bone formation equals the bone
resorption. However, processes like inflammation, malignances and hormonal imbalances can alter this balance, causing either of these events to be
more pronounced. If bone formation carried out by cells called osteoblasts
will exceed bone resorption, exerted by activated osteoclasts, the result will
be increased bone mass. On the other hand, when bone resorption is the most
pronounced process the result will be loss of bone mass. A lot of the earlier
mentioned cytokines can influence the balance between bone formation and
resorption. Cytokines such as IL-1, IL-6, IL-11, IL-17, TNF-, leukemia
inhibitory factor (LIF), and oncostatin M (OSM) are all stimulators of bone
resorption. Furthermore, also kinins and thrombin from the kallekrein-kinin
and coagulation cascades can stimulate bone resorption and synergistically
interact with IL-1 and TNF-. On the contrary, cytokines such as IL-4, IL10, IL-12, IL-13, IL-18, INF-E and INF- inhibit osteoclastogenesis and
thereby reduces bone resorption. The amount and combination of these
stimulatory and inhibitory cytokines will determine the extent of bone loss in
the inflammatory process.
The production of estrogen is decreased in women after menopause. As
this hormone suppresses several of the cytokines that stimulate bone resorption, menopause might, apart from increased risk for osteoporosis, also be
associated with an increased risk for marginal periodontits, although final
proof is still lacking.
Generally increased bone resorption is followed by an increased bone
formation. Despite that inflammation induced sclerotic bone formation (increased bone mass as is sometimes the case in the vicinity of other inflammatory conditions), is never seen in radiographs from marginal periodontitis,
increased bone formation can be observed in such sites by using an isotope
that is incorporated during osteoblastic bone formation in combination with
a sensitive bone scan. 36 Similarly, increased bone formation can be seen in
the peri-articular bone at affected joints in patients with rheumatoid arthritis,
osteoarthritis and apical periodontitis. (figure 2)
14
Figure 2. With permission from the designer of the original figure Professor Ulf H
Lerner
Osteoclasts originate from myeloid hematopoetic steam cells. The differentiation of osteoclasts is very closely related to the differentiation of macrophages and the dendritic cells in the immune system. The mononucleated
progenitor cells, differentiating along the osteoclastic lineage finally results
in fusion of the cells into multinucleated osteoclasts at the periosteal and
endosteal surfaces. No osteoclasts can be formed unless osteoclast progenitor cells are activated by the binding of receptor activating of nuclear factor
B (RANK) by RANK-ligand (RANKL), which is expressed by stromal
cells/osteoblast and some other types of cells including T-lymphocytes. This
stimulation can be reduced by osteoprotregerin (OPG), a protein acting as a
decoy receptor for RANKL, thereby preventing RANK on the osteoclasts
progenitor cells to bind to RANKL. (figure 3)
15
Figure 3. With permission from the designer of the original figure Professor Ulf H
Lerner
Increased expression of RANKL has been found in inflamed gingiva from
individuals with periodontal disease, 37 in GCF from patients with periodontitis 38 as well as in synovium from patients with rheumatoid arthritis. 39 Furthermore, in accordance with these observations, expression of OPG was
reported to be reduced in gingiva from patients with peridontitis and the
levels of OPG decreased in GCFs from sites with periodontal disease compared to healthy sites. 37, 38
As earlier mentioned, the inflammatory process in periodontitis has much
in common with what is seen in rheumatoid arthritis, another chronic inflammatory disease. In both diseases, the inflammatory exudates will contain
higher levels of inflammatory mediators such as IL-1, IL-6, and TNF-,
enhancing the number of activated osteoclasts that could degrade the surrounding bone tissue. Furthermore, these cytokines also stimulates cells like
fibroblasts to produce cytokines, prostaglandins and matrix metalloproteinase, resident molecules responsible for the degradation of the extracellular matrix. 27 (For more details regarding inflammatory bone resorption, see
review by Lerner).40
Periodontitis and circulating markers of inflammation
C-reactive protein (CRP) is a pentameric protein synthesized in the liver
mainly as a result from stimulation by IL-6. The main tasks for this protein
are to activate complement and counteract infection. Recent reports have
linked increased levels of high sensitive measurements of CRP (hsCRP) to
both atherosclerotic disease 41, 42 and periodontal disease, indicating that CRP
can be a possible link between the two diseases. 43-45 Other circulating markers of inflammation associated to both atherosclerotic and periodontal disease are increased levels of white blood cell count (WBC) and fibrinogen. 46,
47
These findings indicate that there could be a spill over from the local inflammation in periodontal disease to the systemic circulation.
Inflammation in periodontal disease could be regarded as a double-edged
sword. On one edge, the protective purpose of the local inflammatory action
is to prohibit the bacteria from penetrating into the underlying tissue and
cause serious infection. Once the insult is eliminated, the inflammation resolves. On the other edge, we have the more chronic types of inflammation
as in periodontal disease and rheumatoid arthritis, with persistence of inflammatory mediators that in turn will lead to disturbed tissue remodeling
and in some situations to tissue destruction. Therefore, the main purpose
with all periodontal treatment is to resolve the inflammatory process and
down regulate the host response to the bacterial challenge by trying to remove the bacterial biofilm from the affected teeth.
Hopefully, in a not too distant future we will better understand the complex immune and cytokine regulation of periodontal disease, leading to new
16
options for treatment of the disease and also increased knowledge regarding
the systemic effects generated by the disease.
Inflammation in the atherosclerotic process (Modified from
Ross)48
“We cannot identify unknown aspects of modern life that lead to atherosclerosis until we know the true nature of the characteristic lesion of atherosclerosis”
Earl Bendit
In healthy arteries, there is an intact cell layer closest to the lumen. This
layer is called the endothelium and under healthy conditions it prevents circulating lipoproteins from penetrating into the wall. The intima is the next
section of the artery wall and consists of mainly connective tissue. Underlying the intima is the media which is made up of smooth muscle cells. Outside the media is the adventitia that separates the artery wall from surrounding tissues (figure 4)
Atherosclerosis is the cause for CVD. It starts rather early in life and progresses slowly, usually without symptoms until middle age. The atherosclerotic lesions occur in large and medium sized arteries, most frequently at
sites where there is a change in the blood flow, with decreased shear stress
and increased turbulence such as in areas with bifurcations, branches and
curvatures.
The response-to-injury hypothesis is a pathophysiologic theory of the
mechanisms behind atherosclerosis. Endothelial denudation was earlier suggested to be the first step of the process, but more recently has endothelial
dysfunction, rather than denudation been suggested to be the initiating process. Whatever process that is ongoing in the development of atherosclerosis,
different lesions represent different stages of chronic inflammation in the
arteries. (figure 4)
17
Figure 4. Endothelial dysfunction in atherosclerosis (used with permission from
New England journal of medicine). The earliest changes that precede the formation
of lesions of atherosclerosis take place in the endothelium. These changes include
increased endothelial permeability to lipoproteins and other plasma constituents and
migration of leukocytes into the artery wall, which is mediated by oxidized lowdensity lipoprotein, monocyte chemotactic protein 1, interleukin-8, platelet-derived
growth factor, macrophage colony stimulating factor, and osteopontin.
The earliest type of lesion is the fatty streak that can be seen in infants
and young children. This is a pure inflammatory lesion consisting of macrophages and T-lymphocytes and is reversible. The endothelial dysfunction
leads to compensatory response altering the normal homeostasis of the endothelium. Endothelial permeability, together with the adherence of leukocytes,
is one of the earliest changes. Leukocytes adhere to and migrate across the
endothelium to the intima layer under the influence of adhesion molecules
like ICAM-1 and VCAM-1 expressed on the endothelial surface and
chemokines. Accumulation of low density cholesterol (LDL) in the intima
has an important role in the development of atherosclerosis.
The three most important cells in the vessel wall, endothelial cells, vascular smooth muscle cells (VSMC) and macrophages, produce waste products
with free radical activity, e.g superoxide anions, into the extracellular matrix,
creating a pro-oxidative environment in the intima. 49 LDL trapped in the
artery wall can be oxidized and internalized (i.e ingested) by macrophages
through binding to scavenger receptors expressed on the surface of these
cells. Furthermore, products from the oxidation of LDL increase the expression of adhesion molecules on the endothelial surface enhancing the recruitment of new leukocytes into the lesion. Well inside the macrophage, the
LDL leads to formation of lipid peroxides and facilitates the accumulation of
18
cholesterol esters finally resulting in formation of foam cells when the cell
cannot handle any more cholesterol.
The degree to which LDL is modified can vary greatly but once taken up
by the macrophage, LDL will cause an activation of the macrophage. Modified LDL upregulates the gene expression for macrophage colonystimulating factor (M-CSF) and monocyte chemotactic protein (MCP) in the
endothelium, leading to increased inflammatory response by recruiting more
monocytes into the lesion and increase the replication of macrophages. The
macrophage can also present parts of the oxidized LDL to T-lymphocytes,
causing them to produce cytokines and growth factors such as IL-2, granulocyte colony stimulating factor (G-CSF), platelet derived growth factor
(PDGF), tumor necrosis factor- (TNF-), transforming growth factor-
(TGF-) and fibroblast growth factor-2 (FGF-2) further amplifying the inflammatory response, leading to an asymmetrical intimal thickening by migration of smooth muscle cells from the underlying media and production of
extracellular matrix. These are all steps in the first stage of atherosclerosis
with fatty streak formation (figure 5).
Figure 5. Fatty streak formation. (used with permission from New England journal of medicine). Fatty streak initially consist of lipid-laden monocytes and macrophages (foam cells) together with T-lymphocytes. Later they are joined by various
numbers of smooth-muscle cells. The steps involved in this process include smooth
muscle migration, which is stimulated by platelet-derived growth factor, fibroblast
growth factor 2, and transforming growth factor E; T-cell activation, which is mediated by tumor necrosis factor D (TNF-D), interleukin-2, and granulocytemacrophage colony-stimulating factor; foam cell formation, which is mediated by
oxidized low-density lipoprotein, macrophage colony-stimulating factor, TNF-D,
interleukin-1; and platelet adherence and aggregation which are stimulated by in-
19
tegrins, P-selectin, fibrin, thromboxane A2, tissue factor, and factors responsible for
adherence and migration of leucocytes.
The inflammatory response itself will enhance the inflammation in the lesion by increasing the production of inflammatory mediators such as IL-1,
TNF- and G-CSF, resulting in elevation of the number of adhesion molecules on the endothelial surface, recruitment of monocytes, T-lymphocytes
and increase levels of LDL. It is therefore not surprising that one of the most
important protective roles of the macrophage concerning the artery wall is to
remove modified LDL, thereby minimizing the effects of oxidized LDL on
the endothelium and smooth-muscle cells.
When the fatty streaks progress to more advanced lesion, a fibrous cap is
developed in order to wall off the lesion which could be regarded as a healing response to the injury. This fibrous cap will encapsulate a mixture of
leukocytes, lipid and degradation products which makes up a core. The development of the fibrous cap is to a large extent stimulated by cytokines like
PDGF, TGF-, IL-1, TNF- and osteopontin (figure 6)
Figure 6. Formation of an advanced, complicated lesion of atherosclerosis (used
with permission from New England journal of medicine). As fatty streak progress to
intermediate and advanced lesions, they tend to form a fibrous cap that walls off the
lesion from the lumen. This represents a type of healing or fibrous response to injury. The fibrous cap covers a mixture of leukocytes, lipid, and debris, which may
form a necrotic core. These lesions expand at their shoulders by means of continued
leukocyte adhesion and entry caused by the same factors listed in figure 4 and 5. The
principal factors associated with macrophage accumulation include macrophage
colony-stimulating factor, monocyte chemotactic protein 1, and oxidized lowdensity lipoprotein. The necrotic core represents the result of apoptosis and necrosis,
increased proteolytic activity and lipid accumulation. The fibrous cap forms as a
20
result of increased activity of platelet-derived growth factor, transforming growth
factor E, interleukin-1, tumor necrosis factor D, and osteopontin and of decreased
connective tissue degradation.
In the final step, the inflamed lesion becomes an unstable fibrous plaque.
Rupture of the plaque usually occurs at the shoulders of the lesion as a result
of thinning and erosion of the fibrous cap. Activated T-cells produce cytokines that can stimulate macrophages in the lesion to produce matrix metalloproteinase that will degrade the extracellular matrix, promoting the thinning and rupture of the fibrous cap. The lipid containing mass of the core
will then come out into the lumen of the artery and initiate the coagulation
process by activating platelets and the coagulation cascade, which in the
worst case leads to occlusion of the artery (figure 7)
Figure 7. Unstable fibrous plaque in atherosclerosis (used with permission from
New England journal of medicine). Rupture of the fibrous cap or ulceration of the
fibrous plaque can rapidly lead to thrombosis and usually occurs at sites of thinning
of the fibrous cap that covers the advanced lesion. Thinning of the fibrous cap is
apparently due to the continuing influx and activation of macrophages, which release metalloproteinases and other proteolytic enzymes at these sites. These enzyme
cause degradation of the matrix, which can lead to hemorrhage from the vasa
vasorum or from the lumen of the artery and can result in thrombus formation and
occlusion of the artery.
Although, most individuals will to some extent be exposed to plaque formation in the arteries, not everyone develops CVD. The main issue is not if
we have plaque or not in our vessels, but how it is composed. A calcified
plaque might considerably reduced the lumen of the vessel, but if it has a
low content of cholesterol and a low degree of inflammation, the plaque will
21
be stable with little risk for rupture. On the other hand, the unstable plaque
with high risk for rupture does not necessarily cause reduction of artery lumen, but it has a high content of cholesterol with an ongoing inflammatory
process which makes the plaque vulnerable.
Mutual risk factors for periodontal and cardiovascular
disease
Age
Physiological changes such as decreased turnover for cells and reduced
healing capacity occur with increasing age. The most important reason for
age as a risk factor for periodontitis is not the ageing process itself, but the
fact that the longer we live, the longer is the possible exposure time from
micro-organisms. 50-52
Age is also a dominant risk factor for cardiovascular disease and ageing is
associated with a number of alterations regarding structural and functional
properties of the large arteries, including diameter, wall thickness, wall stiffness and endothelial function as recently reviewed by Najjar et al. 53 Although there is mounting evidence that these age-related changes can be
accelerated by cardiovascular diseases, new insights of the mechanisms involved will hopefully provide new methods to retard the arterial ageing.
Gender
There are reports concerning periodontitis indicating that men experience
more clinical attachment loss than women. 54 The fact that men tend to seek
help to a lesser extent can be one explanation for this difference. However,
the importance of menopause concerning bone loss in women is still unclear,
but there are data indicating that the estrogen reductions after menopause
could increase the risk for bone loss around the teeth. 55 If that is the case,
attachment loss as well as the atherosclerotic process may be increased in
women after menopause and in the end become equal to that of men.
There is a significantly lower age-specific risk for women to die from
CVD compared to men. Men that die of CVD are roughly 10 years younger
than women. Estrogen is considered to have a major impact on this difference and intake of postmenopausal estrogen is associated with a reduced risk
for CVD. 56, 57 As reviewed elsewhere, 58 there are multiple mechanisms
whereby estrogen might protect against CVD, including favorable changes
in lipids, lipoproteins, fibrinogen, plasminogen activator inhibitor (PAI-1)
and antioxidants. There are also other gender differences that may influence
the development of CVD. For instance, the distribution of fat is different in
22
women and men and before menopause are the levels of LDL cholesterol
lower in women. Furthermore, will gender differences in how the arterial
tree ages influence hemodynamic settings, control of heart rate and pulse
pressure. 59
Diabetes
Individuals with diabetes mellitus (DM) have about two times higher risk
for progression and development of periodontal disease and the risk is more
pronounced if the blood glucose level is poorly controlled. 60, 61 Individuals
with periodontitis seem to be more prone to develop complications such as
retinopathy, nephropathy and CVD. 19 The biologic mechanisms underlying
the increased risk for periodontitis in diabetic patients, is not fully understood, but we know that the immune system and inflammation are involved
in the pathogenesis of both diabetes and periodontitis. 11, 62-64
As there are studies indicating that treatment of periodontal disease both
can and cannot influence the level of glycosylated hemoglobin, we still lack
convincing evidence that periodontitis directly can affect diabetes. 65, 66
Diabetes is a well known risk factor for CVD. A recent study reported an
increased risk for CVD with a hazard ratio 2.5-3.0 in patients with DM. 67
There are several pathophysiologic mechanisms by which diabetes can affect
the risk for CVD. For instance, increased levels of advanced glycation end
products (AGEs) that bind to AGE receptors will promote atherosclerosis by
increasing inflammatory reaction in the vessel. Dyslipidemia and endothelial
dysfunction associated with diabetes are other important factors for the elevated risk for CVD in diabetic patients. 68, 69
Obesity
Periodontal disease has also been related to obesity in a number of studies, 70, 71 but more studies are needed to confirm this association. The mechanisms behind this association remain unclear, but it is possible that endotoxins from the biofilm and cytokines from the local inflammatory response
process might enter the circulation and influence the lipid metabolism. However, there is a possibility that social-economic factors constitute the link
between above mentioned association as obesity is more prevalent in lower
socio-economic classes.
Obesity and especially abdominal obesity increases the risk for CVD.
There can be many factors behind the higher risk for CVD in obese individuals, but the increased risk for development of insulin resistance and the
low-grade inflammation that obesity leads to may be two of the most important factors as reviewed elsewhere by Luc. 72
23
Race
African ethnicity seems to have the highest prevalence of periodontal disease followed by Hispanics and Asians. 73 One important factor for these
differences can be related to socio-economic factors as there are disparities
in periodontal health between poor and rich people. However, Borell et al.
reported that high-income blacks exhibit a higher prevalence for periodontits
than low-income blacks and high-income whites. 74 There can also be a genetic difference between races as described by Armitage et al. concerning
the prevalence of polymorphism of interleukin 1/ genotype in Chines and
European populations. 75
As for periodontitis, there are racial differences in prevalence of CVD.
Socio-economic status has also here been suggested as a key factor. 76 However, a recent report found ethnic differences in the association between
polymorphisms in the CRP gene and CVD, indicating that there might be a
genetic explanation for the differences in prevalence of CVD seen between
races. 77 More research, however, is needed to elucidate the true cause for the
ethnical differences.
Smoking
This is probably one of the strongest risk factors for both periodontal and
cardiovascular disease. The literature pointing to smoking as a risk factor for
both diseases is substantial.
A lot of biologic events are affected by smoking such as impaired phagocytosis and chemotaxis of neutrophil leukocytes, increased release of superoxide, hydrogen peroxide, proteolytic enzymes, and cytokines, all of which
could contribute to the more pronounced tissue destruction seen in smokers.
78
Although smoking has a variety of effects on the tissues, we still lack detailed knowledge about which biological effects of smoking that increases
prevalence of the diseases.
In a meta-analysis, smoking increased the risk ratio for severe periodontal
disease with 2.8. 79 A 10-year prospective study revealed that periodontal
health in smokers is compromised, presenting more diseased sites, and more
extensive bone loss, than in non-smokers. 80 The relative risk for tooth loss is
also increased in smokers. 81
Smoking is also a major risk factor for CVD and in a large study including
27,089 participants from 52 countries, an increased risk for non-fatal acute
myocardial infarction was reported in current smokers with an odd-ratio of
2.95. 82 Smoking can cause impaired endothelium function, increased levels
of WBC, CRP, fibrinogen, and plasma viscosity, indicating that inflammation might be an important way by which smoking could influence the development of CVD. 83, 84
24
Psychological factors
In the last two decades, psychological factors have attracted more attention as a potential risk factor for periodontal disease and studies have reported a relationship between these factors and periodontitis. 85, 86 However,
lack of relationship has also been reported and the pathophysiology underlying the relationship is still unclear. 87
Psychological stress can have many faces and has for a long time been
suggested in the pathogenesis of CVD and with development of new technologies, knowledge about the biological mechanisms by which stress exerts
its negative effect on vasculature is rapidly growing, as reviewed elsewhere
by Rozanski. 88
Socio-economic factors
Socio-economic factors influence the risk for both periodontal disease and
CVD. 89-91 A possible common denominator for the influence of socioeconomic factors on development of both diseases could be that low socioeconomic status is associated with increased levels of high-risk behavior,
including lack of physical activity, smoking, poor diet, obesity and alcohol
consumption. 92, 93
Evidence of association between oral health and
cardiovascular disease
History
In the beginning of the 20th century, Miller and Hunter suggested that oral
infections could cause a variety of diseases such as RA, anemia, chronic
kidney diseases, fever conditions etc. This started ”the focal infection theory” which was widespread during 1910-1930 and millions of teeth were
extracted because of this theory. However, in 1938, R Cecil, a former supporter of the focal infection theory, published a systematic review on 200
patients suffering from RA and concluded that their condition was not improved by the extractions and tonsillectomy performed. This was the beginning of the end for the focal infection theory and in the fifties it disappeared.
As early as 1823, Rayer suggested that morbid ossification of the arteries
is the result of inflammation of the fibrous layer and in 1889 Gilbert and
Lion, published experimental research on infection and atherosclerosis.
Osler in his Modern Medicine from 1908, pointed out four great factors in
the causation of arteriosclerosis: normal wear and tear of life; acute infections; intoxication (including smoking, diabetes and obesity) and combina25
tions which kept the blood tension high, as reviewed by Nieto 94. However, it
was not until the end of 1980 that infection as a possible etiologic factor for
development of CVD appeared again, this time in an article by Saiku et al in
the Lancet, about the association between antibody titers against Chlamydia
pneumonia and CHD and MI 95. One year later, Mattila et al. published a
case-control study where bad oral health increased the risk for myocardial
infarction (MI) 96. Since then there has been a lot of research done about this
association, but a lot of questions still remain unanswered regarding the relationship between oral health and cardiovascular disease.
Criteria to be fulfilled before oral health can be regarded
as a risk factor for CVD
At the consensus conference held in Chapell Hill 1997, it was concluded
that if a suspected risk factor such as peridontitis was to be regarded as a true
risk factor for CVD the following criteria should be fulfilled:
1) There should be a continuous association between the suspected risk
factor and the disease.
2) The association should be strong.
3) The risk factor should be present before the debut of the disease.
4) Specificity of association.
5) Presence of a dose-response relationship between the factor and the
disease.
6) A plausible biological explanation for the association.
7) Support from experimental evidence, with the strongest evidence being randomized controlled intervention studies, disclosing that removal of the potential risk factor leads to a reduced incidence of the
disease.
Today, we are still far from fulfilling these criteria, but during the years as
more research in this field has been concluded, more of these criteria have
been achieved.
1) Evidence of association between oral health and CVD
Since 1989, at least 10 additional case-control studies have found an association between different measures of oral health and CVD and in two
studies no relationship was reported (for details see table1). Furthermore, of
20 cross-sectional studies, 18 presented an association between the diseases
(table 2). Of the longitudinal studies a relationship between oral health and
CVD was present in 17 studies, while in 5 studies no relationship was found
(table 3).
Although, no relationship was observed in some of the studies, the major
portion of them did find an association. The variation of the oral health pa26
rameter used in different studies makes it very difficult and sometimes impossible to compare the results from different studies. For instance, in some
studies have an old index been used such as the Russel periodontal index
which was abandon about 15 years ago. Then in other studies have the oral
health parameters been either gingivitis, deepened pockets (PD), bone loss,
tooth loss or combinations between bone loss, PD, bleeding on probing
(BOP), plaque index (PLI), apical lesions and caries (table1-3). Furthermore,
in a number of studies have questionnaires with self-reported periodontal
health been used, and there is a substantial risk for misclassification as
periodontal disease can exist without any for the individual evident symptoms.
2) Strength of association
Case-control and cross-sectional studies reporting an association between
oral health and CVD presented odd-ratios which for the major part of the
studies could be regarded as weak to moderate in strength. Also for the longitudinal studies where an association between the diseases was evident, the
strength of association was mainly weak to moderate (for detail see table 13).
As earlier mentioned it is difficult to compare studies as different methods
have been used to classify periodontal disease and oral health. However, two
recent meta-analyses have presented data regarding the relationship between
periodontal disease and CVD. In one of these two studies, subjects with
periodontal disease had an overall adjusted risk for CVD of 1.19 and if only
subjects 65 years was included, the relative risk increased to 1.44. 97 In the
other study the risk for CHD was 1.15 and for cerebrovascular disease it was
1.13. 98 Although an increased risk for CVD with only around 20% for subjects with periodontal disease seems low, it can still have a profound impact
on public health as periodontitis is a rather widespread disease.
3) Risk factor present before debut of the disease
To evaluate this issue, we have to look at the longitudinal studies where
periodontitis was present before any CVD was diagnosed. For most of these
studies, a relationship was found between oral health and different manifestations of the CVD. However, in 5 studies no relationship was seen (See
table 3).
4) Specificity of the association
Optimal for proving causality in a relationship is that the suspected risk
factor only associates with the investigated disease, which in this case is
CVD. However, this does not apply for periodontitis as it also has been suggested to be a risk factor for diabetes, preterm birth, respiratory diseases and
27
osteoporosis. 21, 99-101 While a specific association may more likely be causal,
we cannot justify the rejection of a possible risk factor because it is related to
other diseases. Many diseases have a multifactor etiology and a single factor
may be involved in many diseases.
5) Dose-response relationship
In three studies, where periodontal disease was divided into four categories depending upon the amount of bone loss measured on radiographs, was
a dose-dependent relationship to CHD present. 102-104A dose-dependent association between attachment loss and CHD was also reported by Arbes et al
when 3mm attachment loss around 0%, 1-33%, 34-67% and >67% of sites
was used to categorize the degree of periodontal disease. However, after
adjustment for relevant confounders, a significant correlation remained only
for the two most severe groups of attachment loss. 105
6) Biological theories behind association and supporting
evidence
It is well known that inflammation markers such as CRP, WBC, IL-6 and
fibrinogen are associated with higher risk for CVD. 42, 106, 107 The biological
mechanisms by which periodontal disease could influence cardiovascular
disease still remain unknown. We know that the bacterial biofilm in periodontitis causes a local inflammation that leads to degradation of the tooth
supporting tissues. To what extent this local inflammation could induce a
systemic inflammatory reaction is unclear. However, individuals suffering
from periodontitis have been shown to have increased levels of systemic
inflammatory biomarkers compared to periodontal healthy subjects, which
indirectly indicates that a low-grade systemic inflammation could be caused
by periodontal disease (see table 4). Another indirect evidence, indicating
that periodontitis might be involved in the development of atherosclerosis is
that subjects with periodontitis seem to have a more atherogenic lipid profile
than subjects without the disease. 108
7) Support from experimental evidence
Bacteria strongly associated with periodontal disease have been found in
atherosclerotic plaque, and recently, also viable bacteria have been extracted
from atherosclerotic plaque. 109 There are some interesting biological properties regarding the periodontal pathogens detected in atheromas which could
implicate them in the development of atherosclerosis. For instance, Pg has in
apolipoprotein E (APO-E) deficient mice been attributed to increased size of
atherosclerotic lesions, and in vitro been able to aggregate platelets, which is
a crucial part in the thrombus formation. 110-112 Pg could also in vitro induce
28
NADH oxidase in the endothelial cells which might increase the conversion
of LDL to oxidized LDL, further implicating that this bacteria might influence the atherosclerotic process. 113
In patients with periodontitis, it is very likely that bacteria from the periodontal pockets with abilities to influence the development of atherosclerosis,
such as Pg could enter the circulation and affect the progression of cardiovascular disease.
How serum antibody levels against periodontal pathogens relates to cardiovascular disease is to a large extent unknown, but serum antibody levels
against Pg and A.a has been associated with both coronary heart disease and
stroke, indicating a possible role for periodontal pathogens in the development of CVD. 115-118
Recent treatment studies have reported that successful periodontal treatment could significantly reduce the levels of circulating CRP and improve
endothelial function, further implicating that oral health could exert an effect
on the vasculature. 43, 119 (For more details regarding associations between
oral health and CVD see review by Meurman et al.) 114
However, we still lack the strongest evidence for a causal relationship,
i.e. proof that periodontal therapy lowers the risk for CVD.
29
Indices based on sum scores from
periodontal probing, furcation
lesion, radiographic examination,
enumerating number of caries
teeth, impact teeth, periapical
lesions and vertical bone loss
Cases: 85 male and
female with proven
CVD
Controls: 53 age and
gender matched
Mattila, Asikainen et al
2000 122
30
Subjects with diagnosed clinically or
angiographic proven
MI
Age, gender, smoking,
lipid levels, HT and
social-economic status
No significant correlation
between MI and oral health
Significantly worse dental
health in patients with MI.
Modified total dental index, range Diagnosed incidence of Age, smoking, diabeAssociation between poor oral
from 0-14 (sum of scores for
ischemic stroke or TIA tes, pre-existing
health and CEVD. OR=2.6
caries, periodontal disease, periwith established criteria CEVD, low social class
apical infection and pericoronitis
built on clinical and radiological
examination).
Age, smoking, diabetes, serum lipid concentration and social
class
Cases: 69 with cerebral
ischemia
Controls: 60 hospitalized patients with no
cerebrovascular or
inflammatory disease.
No alcohol derived or
paraneoplastic neurological disorders.
Evidence of MI from
ECG and elevated
enzyme levels
Grau, Buggle
et al. 1997 121
120
Total dental index 0-10 (sum of
scores for caries, periodontal
disease, periapical infection and
pericoronitis.
Panoramic tomografi index (sum
of number of residual roots, vertical bone pockets, perapical infections, furcation, caries and pericoronitis lesions seen on radiographic pictures).
Conclusion
Cases 40 males 50
years old and 60 men
and women <65
Controls: 102 age and
gender matched
Adjusted for
Mattila 1989
Cardiovascular
assessment
Oral assessment
Study population
Author and
year
Table.1 Case-control studies
modified after Scannapieco et al 2003. Only studies with adjustments for confounders and with at least 50 subjects
in the case group were included
Studies concerning the relationship between oral health and cardiovascular disease
Cases: 108 men and
women with CAD,
mean age 59.2y
Controls: 62 men and
women randomly selected and presumably
healthy, with mean age
57.7y
MI less than 6 month
prior to the study
Patients suffering from
clinical verified AMI
Diagnosed MI or Angiographic evidence of
coronary disease
Cardiovascular
assessment
Periodontitis= (1 pocket with PD Patients suffering from
5mm), other clinical data colangina pectoris or MI
lected was BOP, PLI, furcation
involvements and tooth mobility
Four different indices based on
the number of vertical bones defects, periapical lesions, caries,
pericoronitis, furcation lesions,
pocket depth, BOP and pus measured clinical and on x-ray.
Montebugnoli, Cases: 63 males mean
Servidio et al. age 52.3y with CHD.
2004 125
Controls: 50 matched
for age, residence and
socio-economic factors
Geerts, Legrand et al.
2004 126
Severity of periodontitis was
categorised as 10 %, 20 %, 30 %,
40 %, 50 % and 60 % of teeth
with a bone loss that exceeded
4mm measured from CEJ to the
alveolar bone.
Persson, Ohls- Cases: 80 men and
son et al. 2003 women with AMI,
124
mean age 63.4y
Controls: 80 men and
women, presumably
healthy, mean age 61.9
years
Oral assessment
CPITN
Study population
Katz, Chaushu 1,094 Israeli army seret al. 2001 123 vicemen aged 25-53
years
Case group 151 with
CHD
Control group 943
healthy subjects
Author and
year
Table.1 (continued)
Age, sex, smoking,
alcohol consumption,
diet, physical activity,
HT, diabetes and lipids
Age, smoking, HT,
diabetes, education,
Social class, BMI,
Lipids and glucose
Age, sex, smoking,
ethnicity, cholesterol,
triglyceride, and diabetes
Age, diabetes, lipids
and HT
Adjusted for
Periodontitis associated significantly with CAD, OR=6.5.
The other clinical parameters
were increased in CAD, and
they had less remaining teeth.
All indices showed significant
correlation to CHD
Periodontitis was significantly
associated to AMI with an OR
varying between 9.1-14.1,
expressing the highest OR
when bone loss exceeding
4mm was present in 50 %
of the sites
No association to CHD.
Conclusion
31
Cases: 143 women with
diagnosed CHD. Mean
age 65.9 years
Controls: 50 women
with no CHD, mean age
64.5 years
Buhlin,
Gustafsson et
al. 2005 129
32
Number of PD >4mm, number of
teeth, radiographic bone loss,
assessment of oral hygiene and
BOP.
GI, PLI, decayed surfaces, bone
loss as percentage of root length
(in a major part of the cases and
controls), and number of teeth.
Severity of periodontitis was
graded according to AL and analysed as a continuous variable
stratified into 1) no or mild periodontitis, defined as mean CAL
3mm and with steps of 1.5mm, 2
)mean CAL >3 to 4.5, 3) mean
CAL >4.5 to 6mm and 4) mean
CAL >6mm was defined as severe
periodontitis
Cases: 82 randomly
periodontal disease was defined as
selected from 286 indi- presence of at least one site with a
viduals with periodonti- pocket depth of 5mm.
tis at the basic examination 1985
Controls: 31 randomly
selected from 1390
without periodontitis in
1985
Söder, Söder
et al 2005 128
Cases: 303 subjects
with ischemic stroke or
TIA.
Controls: 468 subjects
of whom 300 were
randomly selected from
the population aged
between 18-74y, and
168 were patients in the
hospital with no vascular or inflammatory
diseases.
Grau, Becher
et al 2004 127
Oral assessment
Study population
Author and
year
Table.1 (continued)
Adjusted for
Diagnosed CAD
IMT and cIMA was
assessed by carotid
ultrasonography at the
time of re-examination
2001-2003.
Age, diabetes, BMI,
Smoking, education
and place of birth
Age ,gender, diabetes,
smoking, education,
cholesterol and BMI
Diagnosed incidence of hypertension, diabetes,
ischemic stroke or TIA smoking, previous
with established criteria stroke, fathers profession, and stratified by
age and sex
Cardiovascular
assessment
Periodontitis ( 10 diseased
pockets) significantly correlated with CAD with an
OR=3.8
periodontal disease was an
independent predictor for
increased cIMA OR=5.2, and
for increased IMT OR=4.64...
Periodontitis was a risk factor
for first ever stroke or TIA
incidence in men and younger
subjects, but not in women
and older subjects (>60
years). In a multivariate
analyses severe bone loss and
severe gingivitis (when GI
>1.2) was associated to cerebral ischemic OR 2.76 and
9.01, respectively.
Conclusion
Number of teeth and PTI (sum of
number of residual roots, vertical
bone pockets, periapical infections, furcation, caries and pericoronitis lesions seen on radiographic pictures).
Oral bacterial load
Cases: 117 males aged 3369 years that died in sudden cardiac death.
Controls: Of these 183
subjects did 120 die of
unnatural causes and 63
died of non–cardiac disease
Cases: 161 consecutive
subjects with ACS.
Controls: 161 subjects
matched for age, gender,
socioeconomic level and
smoking.
Oral assessment
Study population
Clinical verified
diagnose of ACS
with ECG and enzyme levels
Cardiovascular
assessment
Sudden cardiac
death
Age, gender, smoking
and socioeconomic
level
Age, BMI, smoking,
diabetes, HT, educational level
Adjusted for
Patients with ACS had higher
bacterial load compared to
controls, significant for 26 of
40 species.
Number of teeth was significantly associated to sudden
cardiac death for subjects <50
years of age (P=0.009) and
almost significantly related
for all subjects (P=0.053).
Conclusion
AMI= Acute myocardial infarction, ACS= Acute coronary syndrome, BMI= Body mass index, BOP= Bleeding on probing, CAD= Coronary artery disease,
CAL= Clinical attachment loss, CEJ= Cemento-enamel junction, CEVD= Cerebrovascular disease, CHD= Coronary heart disease,
cIMA= Cross sectional intima, ECG= Electrocardiogram GI= Gingivitis index, HT= Hypertension, MI= Myocardial infarction, OR= Odds ratio,
PD= Pocket depth, PLI= Dental plaque index, PTI= Panoramic tomography index, TIA= Transient ischemic attach.
Renvert, Pettersson et al
2006 131
Author and
year
Karhunen,
Forss et al
2006 130
Table.1 (continued)
33
Dental severity index (sum of
scores for caries, periodontal
disease, periapical infection
and pericoronitis
100 subject (88 men and
12 women ) aged 28-68
years
320 veterans >60 years old Number of teeth (0, 1-14 or
15-28), PD, attachment level,
PLI and gingival bleeding and
xerostomia
5,564 subjects 40 years
old
Mattila, Valle
et al. 1993 133
Loesche,
Schork et al
1998 134
Arbes et al
1999 105
34
Missing teeth
1,384 Finnish males aged
45-64 years
Paunio, Impivaara et al
1993 132
Diagnosed MI, Bypass
surgery, ECG, Enzyme
levels, angiography,
response to heart
treatment
Extent of coronary
artery occlusion by
angiography
Screening examination
and interviews about
previous disease, Xray, ECG, Blood pressure. CHD defined as
angina pectoris or previous MI
Cardiovascular
assessment
Percentage of sites with atSelf-reported MI
tachment loss 3mm categorized in 4 levels: 0 %; >0-33
%; >33-67 %; and >67 %
based on measurements from
one randomised upper and one
lower quadrant in each subject.
Oral assessment
Study population
Author and
year
Table 2. Cross-sectional population studies
Age, race, gender,
smoking, HT, serum
total cholesterol
levels, BMI, poverty
and diabetes
Age, smoking, serum cholesterol
levels, BMI and
diabetes
Age, lipids, BMI,
HT, smoking and
social class
Age, HT, smoking,
education and residence
Adjusted for
Unadjusted, there was a dosedependent association between
attachment loss and coronary
heart disease but after adjustment, only evident for the two
most severe categories with OR
of 2.3 and 3.8, respectively
Several oral health variables
were risk indicators for CHD,
and subjects with CHD were
2.64 times more likely found in
subjects with 1-14 teeth compared to those with 0 or 15-28
teeth.
Dental infection significantly
associated to severe coronary
atheromatosis in men, but not in
women.
Week, but significant association between missing teeth and
ischemic heart disease.
Conclusion
Periodontitis was defined by exCarotid artery intimatent of attachment loss 3mm:
media thickness
None/mild <10 % , moderate 10 to (IMT) 1mm
< 30 %, and sever 30 % of the
sites
Self reported oral health and dentures
Self reported. If they
had any type of CVD
in the last 9 years, and
if yes, specified on
type (MI, stroke, angina pectoris, atherosclerosis and HT)
Self reported oral health and num- Self reported. If they
ber of teeth
had any type of CVD
in the last 9 years and
if yes specified on
type (MI, stroke, angina pectoris, atherosclerosis and HT
Percentage of sites with AL >3mm Ischemic stroke and
categorised into quartiles: 0 to
TIA
<6.5 %, 6.5 to <15.4 %, 15.4 to
<31.4 %, and 31.4 %. Number of
teeth was also registered
6,017 subjects form the
ARIC study 1996
4,811 individuals received
a questionnaire. 2839 answered (59 % ), and of
them were 1,577 >40 years
of age
723 men and women aged
20-84 years.
9,415 dentate and 1,491
edentulous subjects aged
52-75 years from the ARIC
study were investigated for
stroke and TIA. Periodontal
examination was performed
in a subset consisting of
6,436 individuals.
Beck, Elter et
al. 2001 135
Buhlin,
Gustafsson et
al. 2002 136
Buhlin,
Gustafsson et
al. 2003 137
Elter, Offenbacher et al.
2003 138
Cardiovascular
assessment
Oral assessment
Study population
Author and
year
Table.2 (continued)
Periodontitis may influence
atheroma formation. There
was an OR=1.31 for IMT
1mm in subjects with severe
periodontitis.
Conclusion
All kinds of CVD
risk factors
Week association between
stroke/TIA and edentulism or
attachment loss in the highest
quartile of.
Age, gender diabetes, Bleeding gums was related to
smoking, education
CVD with an OR 1.7 for the
and civil status
hole sample and 2.69 for the
oldest group alone (75-84y)
Age, gender diabetes, In subjects >40 years of age
smoking, education
was bleeding gums and wearand civil status
ing of dentures related to
CVD with an OR= 1.6 and
1.57, respectively.
All kinds of CVD
risk factors
Adjusted for
35
Oral assessment
36
All kinds of No significant association.
CAC was estimated
using CT and Agastone risk factors
for CVD
score calculated. Cut
off levels for the score
was <100 and 100
used.
Based on AL was periodontitis
stratified with into 2 groups:
no/mild <10 % of the sites with
AL 3mm, moderate/severe
>10 % of the sites with AL
3mm.
Long-term exposure to periodontitis and tooth loss was significantly
related to subclinical atherosclerosis in men, but not in women
46 % of subjects with 0-9 missing
teeth had plaque somewhere in the
carotid artery in contrast to 60 %
of those with 10 missing teeth.
Tooth loss as a marker for past
periodontal disease was related to
subclinical atherosclerosis.
Cohort of 269 from the
Nakib,
Pankow et al. ARIC study
2004 141
All kinds of
risk factors
for CVD
All kinds of
CVD risk
factors
Adjusted for Conclusion
Ultra sound was used to
access if any plaque was
present in the CCA, ICA
and ECA further more to
measure the IMT of the
fare wall in of the CCA.
Cardiovascular
assessment
711 subjects aged 55
Severity of periodontal disease
High resolution
years ( Mean age 66 y) with defined as percentage of sites with ultra sound was used to
no baseline history of
PD 5mm and AL 4mm.
access if any plaque,
stroke or MI enrolled in
Tooth loss was divided into 4
defined as an area with
INVEST study
categories: 0-9, 10-19, 20-31 and focal wall thickening was
edentulous
present in the common
carotid arteries, internal
and external carotid arteries
Study population
1,710 randomly enrolled
Desvarieux,
Ongoing periodontitis measured as
Schwahn et al. males and females aged 45- 10 % of sites with PD 5mm.
75 years
2004 140
Long time exposure of periodontitis measured as % of sites with AL
4mm.
Number of teeth was categorised
into 0 to 8, 9 to 15 and 16 to 31
teeth
Author and
year
Desvarieux,
Demmer et al.
2003 139
Table.2 (continued)
8,363 subjects
aged 52-75 years
from the ARIC
study
Study population
Number of teeth.
Extent of AL measured as % of sites
with AL 4mm ( this was done on a
subset of 1,690 individuals)
In total 4,561 subgingival microbiologic samples were taken on average
from 7sites/subject. These were analysed for the presence or absence of 11
known periodontal pathogens by DNADNA checkerboard hybridization
2,341 subjects
aged 45 years
1,056 individuals
with no history of
stroke or MI was
enrolled in (INVEST) and microbiologic samples
were collected
form 657 dentate
subjects.
Desvarieux,
Dremmer et
al. 2005 145
Chronic periodontitis (CP) exposure
was categorised depending on the
amount of bone loss into no/mild/moderate periodontitis if the bone loss was
<50 % and severe periodontitis if it was
>50 %
Ultra sound was used to
investigate the Intima-media
thickness (IMT) of carotid
artery. Furthermore were
values of CRP levels and
white blood cell count obtained.
Two dimensional M-mode
and Doppler echocardiography was used to evaluate
aortic valve sclerosis.
High resolution ultrasound
was used to identify presence
or absence of plaque in the
internal, common carotid
artery and bifurcations.
Cardiovascular
assessment
Four categories were formed using % of CHD defined and diagnosed
sites with attachment loss 3mm toas MI or revascularisation
gether with number of teeth: low atprocedures.
tachment and low tooth loss (<10% AL
and 17 teeth left), low AL and high
tooth loss (<10 % AL and <17 teeth
left), high AL and low tooth loss, (10
% AL and 17 teeth left), and high AL
and high tooth loss (10 % AL and <17
teeth left).
Oral assessment
Volzke,
Schwahn et al
2005 144
Engebretson et 203 stroke free
al 2005 143
subjects aged 5494 years from the
INVEST
Author and
year
Elter, Champagne et al.
2004 142
Table.2 (continued)
Conclusion
Severe periodontitis was associated with an increased risk
for presence of plaque in the
carotid artery. OR=3.64
All kinds of risk
factors for CVD
Overall bacterial burden was
related to carotid IMT, but
CRP levels were unrelated to
periodontal microbial status.
These data indicates a relationship between periodontal
microbiology and subclinical
atherosclerosis independent of
CRP.
All kinds of CVD Number of teeth was inderisk factors
pendently associated to Aortic
valve sclerosis. OR=0.98
Age, smoking,
gender, diabetes,
HT and serum
Cholesterol.
All kinds of CVD Edentulous subjects and those
risk factors
with high AL and high tooth
loss had significantly more
CHD compared to those with
low AL and low tooth loss OR
1.5 and 1.8, respectively.
Adjusted for
37
Age, gender,
smoking, BMI,
education, diabetes, dietary pattern
and antihypertensive medication
Adjusted for
38
5,123 subjects
from the
NHANES III
study 60 years
of age
Questionnaire if a doctor
All kinds of CVD
ever told them that they had risk factors.
a stroke
PHS I
1) <45% of the sites with CAL 2mm; 2)
>45% of the sites with 2mm CAL.
PHS II
1) <45% of the sites with CAL 3mm; 2)
>45% of the sites with 3mm CAL.
PHS I and PHS II were also combined with
tooth loss.
Cardiovascular
assessment
HT was defined as a systolic blood pressure >140
mmhg or a diastolic blood
pressure >90mmhg or antihypertensive medication
Lee et al
2006 147
Number of teeth
Oral assessment
PD, BOP, PLI and number of teeth was reg- Self reported MI and medi- Age, gender and
istered. Bone loss for each subject was meas- cation for HT
smoking
ured on radiographs and depending mainly
on the amount of bone loss the severity of
periodontitis was stratified into: no, mild,
moderate or severe periodontitis.
Study population
4,185 subjects
from a population based study
of health of
which 2,150
were women.
Holmlund et al 4,254 subject,
2006 104
3,889 referred
for periodontal
treatment and
907 randomly
selected from
same population.
Mean age 53
years
Author and
year
Volzke,
Schwahn et al
2006 146
Table.2 (continued)
There was a significant
dose-response association
between number of teeth
(hole sample), periodontitis
(in subjects aged 40-59
years) and MI. with OR
1.3-1.5. HT was associated
to periodontitis and number
of periodontal pockets, but
not to number of teeth.
No association between
stroke and PHS
Men with 0-6 teeth had
significantly higher systolic
blood pressure compared to
those with 27-28 teeth. OR
1.91. No relationship was
evident for women
Conclusion
PLI, BOP, CAL 5mm, bacterial count
201 patients
referred for
coronary angiography
Cohort study of
1,016 subjects
aged 70 year
Gotsman,
Lotan et al
2007 148
Holmlund et
al 2007 149
The metabolic syndrome
classified by NCEP/ATP III
Severity of coronary disease
was graded depending on
number of obstructed coronary arteries and the degree
of narrowing based on highquality film angiograms
Cardiovascular
assessment
Age, gender,
smoking,
WBC, HT,
and education
level
Age, smoking,
diabetes, and
family history
of CAD.
Adjusted for
Number of teeth was significantly associated to the
metabolic syndrome
CAL 5mm was significantly related to CAD and
percentage of Porphyromonas gingivalis was
related to ACS.
Conclusion
39
ACS= Acute coronary syndrome, AL= Attachment loss, ARIC= Atherosclerosis Risk in Community, BMI= Body mass index, BOP= Bleeding on probing,
CAC= Coronary artery calcification, CAD= Coronary artery disease, CAL= Clinical attachment loss, CCA = Common carotid arteries, CHD= Coronary heart
disease, CRP= C-reactive protein, CP= Chronic periodontitis, CT= Computer tomography, CVA= Cerebral vascular attach, CVD= cardiovascular disease,
DNA= Deoxyribonucleic acid, ECA= External carotid artery, ECG= Electrocardiogram, GI= Gingivitis index, HT= Hypertension, ICA= internal carotid artery, IMT= Cartoid artery intima-media thikness, INVEST= Oral Infections and Vascular Disease Epidemiology study, MI= Myocardial infarction,
NCEP/ATPIII = National Cholesterol and Education Program/ Annual Treatment Planning III, OR= Odds ratio, PHS= Periodontal health status, PD= pocket
depth, PLI= Dental plaque index, TIA= Transient ischemic attach, WBC= White blood cell count.
Self-reported number of teeth
Oral assessment
Study population
Author and
year
Table.2 (continued)
40
Joshipura,
Rimm et al
1996 152
Mattila, Valtonen et al
1995 151
9,760 subjects enrolled in
Number of decayed teeth; Perithe NHANES I from 1971 to dontal classification: (no disease,
1974. Follow up until 1982. gingivitis, periodontitis with
>4mm pockets, and no teeth);
Periodontal index: eache tooth
were given a score 0-8 depending on degree of periodontitis
and the index was an average of
all scored teeth. Also a oral
hygiene index was registered.
In all 214 subjects, median
Total dental index 0-10 (sum of
follow-up time of 2.2 years. scores for caries, periodontal
70 males aged 50 years
disease, periapical infection and
with MI or admitted for
pericoronitis.)
angiographic examination
Panoramic tomografi index (sum
1983-85.
of number of residual roots,
60 subjects, males 60 years vertical bone pockets, perapical
and women 65 years eninfections, furcation, caries and
rolled 1985-86 with diagpericoronitis lesions seen on
nosed MI.
radiographic pictures).
100 enrolled for diagnostic
coronary angiography and
some of these already belonged to previous groups.
44,119 men. (58% were
Self reported number of teeth
dentists), 40-75 years of age. and history of periodontal disFollow up after six years.
ease
DeStefano,
Anda et al.
1993 150
Oral assessment
Study population
Author and
year
Table 3. Longitudinal studies
No association between
periodontal disease and
CHD, but a small significant relationship between
tooth loss and CHD.
RR=1.67 for those with 110 teeth.
Fatal/ non-fatal MI, sudden Age, CHD risk
death. Re-vascularisation
factors and smokprocedures were excluded ing
as endpoint
Periodontal disease is associated with a small increased risk for CHD
RR= 1.25 for all and 1.72
for men 25-42 years
Conclusion
Poor oral health is associated with new fatal and
non-fatal cardiac events.
Age, smoking
(partly), alcohol,
race, SBP, education, BMI, exercise, and poverty
Adjusted for
Age, gender, previous MI, diabetes, BMI, smoking, HT, serum
lipids, and socioeconomics
Endpoints fatal and nonfatal MI and all cause morality.
Admission to hospital for
CHD treatment. Mortality
due to CHD.
Cardiovascular
assessment
Morrison,
Ellison et al
1999 154
10,368 subjects from Nutrition Canada Survey. 35-84
years old.
Age, total cholesterol, Systolic
blood pressure,
BMI, and partly
for smoking
Adjusted for
Age, gender,
smoking, HT,
serum total cholesterol and diabetes
PVD was defined accord- All kinds of risk
ing to following criteria: 1) factors for CVD
Intermittent claudicato 2)
extra cranial cerebrovascular disease. 3) atherosclerosis (including aortic, renal
and mesenteric disease)
4) arterial embolism and
thrombosis
Total CHD determined as
cases of non-fatal MI,
angina and CHD death.
Stroke diagnosed with
means of history and
physical examination
Cardiovascular
assessment
Periodontitis classified as no
Death from coronary heart
disease, mild and severe gingivi- and cerebrovascular distis, obvious pockets, loose teeth, ease
and edentulous.
Alveolar bone loss estimate on
radiographic films using a Schei
ruler. A mean whole mouth
alveolar bone loss of >20% was
regarded as significant periodontal disease.
Alveolar bone loss measured
using a Schei ruler, (0 to 20 %,
>20 to 40 %, >40 to 60 % and
>60 %). Worst PD per tooth
1,147 subjects from Veteran
dental longitudinal study a
component of the Normative
aging study
Beck, Garcia
et al 1996 102
Mendez, Scott Cases 80 subjects with PVD
et al 1998 153 and 1,030 controls were
enrolled from 1,231 subjects
belonging to the Dental longitudinal study of the US
department of veteran affairs
which is a subgroup to the
Normative aging study.
Follow up time was 25-30
years
Oral assessment
Study population
Author and
year
Table.3 (continued)
Severe gingivitis and being
edentulous was associated
to increased risk for fatal
CHD with RR =2.15 and
1.9, respectively
Periodontal disease was an
independent risk indicator
for PVD in a multivariate
analysis.
Subjects with clinical significant periodontal disease
at baseline had a 2.27 increased risk of developing
PVD after the exclusion of
other vascular conditions
from the control group and
stroke from the case group.
OR=1.5 for bone loss and
total CHD (this was not
adjusted for smoking), OR=
1.9 for fatal CHD and OR
=2.8 for bone loss and
stoke (both adjusted for
smoking). Dose-response
relationships were seen
between severity of bone
loss and cumulative incidence of CHD and fatal
stroke.
Conclusion
41
42
Number of missing teeth, apical
Death due to CVD
lesions, carious and marginal bone
loss (MBL) expressed as % of the
distance between apex to CEJ. Oral
health score, a combination of missing teeth, MBL, number of teeth
with carious and apical lesions.
1,393 subjects aged 18Jansson,
Lavstedt et 66 years from the
al. 2001 157 County of Stockholm
admitted to the study
1979. Follow up in
1997
Death from CHD, hospitalization
due to CHD or revascularisation
procedures obtained from death
certificates and medical records.
Periodontitis defined as 1 periodontal pocket with attachment loss,
Gingivitis= inflammation with no
attachment loss.
Periodontal health= no inflammation or attachment loss
Incident cases of CVA meeting at
least one of the following criteria:
death cause CVA or one or more
Hospital/nursing home stay during
follow-up period with discharge
diagnose CVA.
Cardiovascular
assessment
Hujoel,
8,032 dentate adults
Drangsholt aged 25-74 years from
et al 2000 NHANES I epidemi156
ologic follow up study.
Based on questionnaire
Oral assessment
1) No periodontal disease if 1
tooth had mild gingivitis and 20
teeth were present, 2) Gingivitis 1
tooth with mild gingivitis or worse
condition that did not fit 1 or 3, 3)
Periodontitis 4 teeth with overt
pockets or worse, 4) Edentulousness
Study population
Wu, Trevi- 9,962 subjects aged 2574 years from
san et al.
NHANES-1, 1971-74
2000 155
and the follow-up study
1992.
Author
and year
Table.3 (continued)
Age, gender
and smoking
All kinds of
CVD risk factors including
Age and smoking,
All kinds of
CVD risk factors including
Age and smoking
Adjusted for
Oral health was significantly
related to fatal CHD in subjects <45 years old with OR
2.7
Poor oral health in combination with smoking is a risk
indicator for CVD.
Compared with no periodontal disease the RR for nonhemorrhagic stroke in subjects with periodontitis was
2.11, and 1.66 for total CVA.
There was no significant
correlation to gingivitis or
edentulousness.
No association
Conclusion
Jansson, Lavstedt et al.
2002 161
697 octogenarians in
Fukoaka. Prefecture.
277male and 420
female aged 80
years.
1,393 subjects aged
18-66 years from the
County of Stockholm admitted to the
study 1979. Follow
up in 1997
Abnormal ECG findings
CPI 0-4. 0=health, 1= gingival
bleeding, 2=presence of calculus, 3=
presence of PD 4-5mm, 4= presence
of PD 6mm.
Tooth loss
Oral health score a combination of
Death due to CVD
missing teeth, MBL number of teeth
with carious and apical lesions.
Marginal bone loss (MBL) expressed as % of the distance between
apices to CEJ.
A CVD event was confirmed
by an end point committee
after examination of all information blinded to the participant’s periodontal status.
Death due to CVD was confirmed by reviewing death
certificates
Howell, Rid- 22,037 male subjects Self reported presence or absence of
ker et al. 2001 aged 40-84 years
periodontal disease at study entry
159
from the Physician
Health Study I.
Based on questionnaire. Average follow-up of 12.3 years
Takata, Ansi
et al. 2001 160
Death from CHD, hospitalization due to CHD or revascularisation procedures obtained
from death certificates and
medical records.
4,027 subjects from Comparison of subjects with perioNHANES-I based on dontitis= (PD 4mm on any teeth)
questionnaire
and subjects with edentulism.
Cardiovascular
assessment
Hujoel,
Drangsholt et
al 2001 158
Oral assessment
Study population
Author and
year
Table.3 (continued)
Edentulouse individuals did
not have lower risk for
CHD compared to subjects
with periodontal disease.
Conclusion
Age, gender and
smoking
Poor oral health is a risk
indicator for all-cause mortality
All kinds of CVD Tooth loss may be a predicrisk factors includ- tor for abnormal ECG finding Age and smok- ings in the very elderly.
ing
All kinds of CVD No association
risk factors including Age and smoking
All kinds of CVD
risk factors including Age and smoking
Adjusted for
43
44
Hung, Willett
et al. 2003 164
Eligible was 45,136
men, aged 4075years that were
professional health
workers. Follow up
time 12 years
Inclusion: History of CVD
based on yes on 4 questions, has a doctor ever told
you that you had a heart
attack, heart failure or a
stroke in past 6 months or
do you take any drugs for a
weak heart
Cardiovascular
assessment
Questionnaire about their oral health
including: number of teeth lost and
periodontal disease
Diagnostic and selfreported PAD
Periodontal disease classified as 1) no
Death in CHD
disease, 2) gingival inflammation, 3) PD
4-6mm, 4) PD >6mm. Patients were
categorized according to the worst quadrant.
Number of teeth and PLI was also registered
Periodontitis = increased PD of 4 teeth
with attachment loss
Gingivitis= inflammation with no attachment loss.
Periodontal health= no inflammation or
attachment loss
636 dentate individuals initially
enrolled in
NHANES-I who had
both medical and
dental examinations
and a prior history of
CVD. Based on
questionnaire
Hujoel,
Drangsholt et
al 2002 162
6,527 men and
Tuominen,
Reunanen et al women aged 30-69
years from the Mini2003 163
Finland Health survey. Mean follow up
time 12 years
Oral assessment
Study population
Author and
year
Table.3 (continued)
All kinds of CVD
risk factors
Age, gender, diabetes, smoking,
HT, lipids and
education
All kinds of CVD
risk factors including Age and smoking
Adjusted for
Baseline number of teeth
was not related to PAD.
However, tooth loss during
follow up time and periodontal disease was associated to PAD, RR 1.39 and
1.41, respectively. Tooth
loss in men without periodontal disease was not
related to PAD
No association
No association.
Periodontitis does not increase risk for CHD in
subjects with prior heart
attack or self reported
CVD.
Conclusion
Schillinger,
Kluger et
al.2006 167
411 randomly selected
subjects from 1,268 participants in the Inflammation and Carotid Artery
Risk for Atherosclerosis
study (ICARAS).
Abnet, Qiao et 29,584 healthy subject
aged 44-69 years at baseal. 2005 166
line was followed for 15
years
DMFT, SLI; CPITN and edentulousness was calculated for each
individual and compared to atherosclerosis of the carotid artery.
Tooth loss
Eligible was 41,380 men, Questionnaire about their oral health
aged 40-75 years that were including: number of teeth lost and
professional health work- periodontal disease
ers. Follow up time 12
years
Joshipura,
Hung et al.
2003 165
Oral assessment
Study population
Author and
year
Table.3 (continued)
Conclusion
Age, sex, smoking ,weight,
height, and SBP
DMFT, SLI and CPITN was
significantly related to baseline degree of carotid stenosis, but only DMFT and SLI
were significant predictors
for progression of the atherosclerosis in the carotid artery
with OR 1.11 and
1.77,.respectively
Tooth loss was related to
death in heart disease with a
RR of 1.28 and to stroke with
a RR of 1.11
All kinds of
Men with <25 teeth at baseCVD risk factors line were at higher risk for
stroke, HR 1.57. Periodontal
disease at baseline was moderately related to ischemic
stroke, HR 1.33
Adjusted for
Uni or bilateral proAll kinds of
gression of carotid
CVD risk factors.
atherosclerosis in the
extra-cranial internal
carotid from baseline
to follow up after 6 to 9
months
Death in heart disease
Fatal and non-fatal
stroke confirmed by
medical records and
sub classified into:
ischemic stroke; hemorrhagic stroke; and
unknown type
Cardiovascular
assessment
45
3,273 randomly
selected subjects
aged 30-40 years.
1,676 of these were
clinically examined
and followed for 16
years
1,203 men in the
VA Normative Aging and Dental
Longitudinal Studies
followed up with
triennial comprehensive medical and
dental examinations
up to 35 years (median 24 years)
Baseline tooth loss as continuous variable was not
related to mortality. However, when tooth loss was
treated as categorical variable, a HR 1.35 for mortality in CVD was seen for
subjects with >8 missing
compared to those with <5
missing teeth.
Age, gender, BMI.,
education, systolic
blood pressure and
socio-economic
factors
Bone loss was assessed on x-ray for eache CHD fatal or non-fatal
tooth and the amount of bone loss was
divided with 20 % increments ( 0 = no
bone loss; 1=bone loss 20%; 2= bone
loss >20% 40%; 3= bone loss > 40%
60%; 4= bone loss >60% 80%; and 5=
>80%).
Number of pockets were categorised into:
0-3mm; >3mm to 5mm and >5mm.
Number of teeth were also assessed
All kinds of CVD
risk factors
Dose dependent association
between periodontitis and
CHD among men <60 years
old, HR 2.12 comparing
highest versus lowest group
of bone loss. Edentulous
men 60 years tended to
have a higher risk for CHD
than dentate men with the
lowest bone loss, HR 1.61
and lowest pocket depth,
HR 1.72.
Missing molar teeth in subjects with periodontitis was
associated to all cause of
mortality with. OR 3.62
Conclusion
Adjusted for
Missing teeth, PLI, GI, PD, and Calculus. Cause of death according to Age, gender,
Periodontitis was defined as one tooth
ICD classification
smoking, sociowith PD 5mm
economic status,
and education
Cardiovascular
assessment
Mortality in CVD, other
external causes and lung
cancer.
46
BMI= Body mass index, CEJ = Cemento-enamel junction, CHD= Coronary heart disease, CPI= Community periodontal index, CPTIN = Caries and periodontal index treatment of needs, CHD= Coronary heart disease, CVA= Cerebral vascular attach, CVD= Cardiovascular disease, DMFT= Decayed, missing and
filled teeth, ECG= Electrocardiogram, HT= Hypertension, ICARAS= Inflammation and Carotid Artery Risk for Atherosclerosis study, MBL= Marginal bone
loss, MI= Myocardial infarction, NHANES = National Health and Nutritional Survey, OR= Odds ratio, PAD= peripheral artery disease, PD= Pocket depth,
PLI= Dental plaque index, PVD= Peripheral vascular disease, RR= Relative risk, SBP= Systolic blood pressure, SLI= Silness-Löe index
Dietrich et al.
2008 103
Söder, Jin et
al. 2007 169
Author and
Study population
Oral assessment
year
12,631 out of 15,322 Number of missing teeth, number of filled
Tu, Galobardes et al. 2007 eligible students
and decayed teeth.
168
from the University
in Glasgow were
included. 9,569 men
and 2,654 women
aged 30 years or
younger at baseline.
Follow-up period of
57 years.
Table.3 (continued)
Loos, Craandijk Case-control study
et al. 2000 44
107 consecutive periodontal patients
and 43 periodontal healthy controls
Subjects with periodontitis had higher median
CRP and plasma IL-6 levels than healthy controls.
Periodotitis is associated with higher levels of
systemic inflammation markers such as Il-6 and
CRP that also have been associated with increased risk for CVD.
Periodontal status may influence systemic markers of inflammation
Poor Periodontal health measured as CPITN
strongly associated with High WBC count. Total
cholesterol and triglyceride were not associated
with periodontal status
A cross-sectional study with 517
males and 113 females 23-83 years
old
Wakai, Kawamura et al 1999
170
Dental index (PLI, GI, CPITN) correlated signifi- Oral health may influence fibrinogen and WBC
cantly with fibrinogen and WBC count
count
Case-control study
50 consecutive patients from dental
hospital.
50 periodontal healthy from the hospital staff
Conclusion
Kweider, Lowe
et al. 1993 46
Outcome
Study population
Reference
Table 4. Relationship of markers of atherosclerosis associated with human periodontal disease
47
Correlation between CRP and periodontal disease may be a pathway in the association between periodontitis and CVD.
48
Increased CRP levels in subjects with periodontitis
compared to periodontally healthy subjects. Presence of periodontal pathogens Porphyromonas
Gingivalis (Pg.), Prevotella Intermedia (Pi), Camphylobacter recta (Cr) and Tanderella forsythus
(Tf) were positively associated to CRP levels.
Noack, Genco
et al. 2001 45
Cross-sectional study
174 subjects randomly selected from
a cohort of 1.250 subjects. 50 with
moderate periodontal attachment loss,
50 with severe attachment loss, and
65 periodontally healthy subjects
served as controls
CRP and fibrinogen levels can be a possible link
for periodontal disease to increased risk for
CVD
Wu, Trevisan et 10.146 subjects from Third NHANES Significant association between indicators of poor
study and its follow-up
oral health (Gingival bleeding index, calculus inal. 2000 172
dex, PD, and attachment loss) and increased levels
of CRP and fibrinogen
171
Periodontal disease and edentulism were associated with higher levels of CRP most pronounced
in individuals with no established risk factors
for elevated CRP.
12.949 dentate subjects >18 years old Periodontal health measured as percentage
and 1.817 edentulous subjects >18
PD>4mm categorised into: 0%, 0-10%, and > 10%.
years old from the Third NHANES
CRP was dichotomised in <10mg/l or 10mg/l.
In a multivariate analysis including diabetes, arthritis, emphysema, smoking, socio-demographic factors and anti-inflammatory medication, the CRP
levels were higher in subjects with extensive periodontits.
Conclusion
Slade, Offenbacher et al. 2000
Outcome
Study population
Reference
Table 4 (continued)
CRP levels were significantly reduced after
extraction. Furthermore, the extraction therapy
significantly reduced the total white blood cell
count and number of platelets.
Taylor et al
2006 173
49
BOP= Bleeding on probing, CHD= Coronary heart disease, CPTIN = Caries and periodontal index treatment of needs, CRP= C-reactive protein,
CVD= Cardiovascular disease, DMFT= Decayed, missing and filled teeth, GI= Gingival index, HT= Hypertension, ICARAS= Inflammation and Carotid Artery Risk for Atherosclerosis study, IL-6= Interleukin-6, NHANES = National Health and Nutritional Survey, PD= Pocket depth, PLI= Dental plaque index,
index, SLI= Silness-Löe index, WBC= White blood cell count.
Treatment of periodontal disease may lower
cardiovascular risk
Periodontitis may add to the inflammatory burden of the individual that may result in increased levels of CRP and thereby higher risk
for CVD
Levels of CRP were divided into 3 groups: low=
CRP <1mg/l, medium CRP=1-3mg/l, and
high=>3mg/l.
Treatment reduced the number of individuals
with CRP levels belonging to the medium and
high groups.
D’Aiuto, Ready 94 Systemically healthy subjects with
severe periodontal disease received
et al. 2004 43
periodontal treatment
67 adults with advanced periodontitis in
need full-mouth extraction. Blood samples were taken 1) at initial presentation.
2) 2-3 weeks later before all teeth were
removed. 3) 12 weeks after full- mouth
extraction.
Conclusion
Study population
Outcome
Reference
Table.4 (continued)
Aims of the thesis
Paper I.
Study local inflammatory response in periodontal disease by
x Intra-individually investigate the levels of IL-1D, IL-1E, IL-1ra
and bone resorption activity in gingival crevicular fluid from
healthy and diseased sites before and after treatment. Furthermore, study if changes in BRA activity and levels of IL-1 were
correlated and if they could be related to probing pocket depth
Paper II.
In a cross-sectional study based on 4,254 subjects investigate
x If oral health is related to the prevalence of myocardial infarction and hypertension in a dose-dependent manner.
Paper III.
In a cohort study investigate
x If self-reported tooth loss in 1,016 elderly subjects is related
to the presence of the metabolic syndrome and to general
markers of inflammation.
Paper IV.
With a prospective study based on a cohort of 7,674 subjects investigate
x If oral health in dose-dependent manner is associated to allcause mortality, mortality in cardiovascular disease, in coronary
heart disease, and in stroke.
Paper V.
In a case-control study including 100 cases and 100 age-and gender
matched controls investigate
x If oral health is impaired in patients with acute myocardial
infarction (MI), and if antibody levels against the periodontal
pathogens Porphyromonas gingivalis and Aggregatibacter
actinomycetemcomitans could be a link between oral health
and MI.
50
Methods
Patient selection
Study I
Included were ten consecutive patients with moderate to advanced periodontitis referred to the Department of Periodontology, at the Gävle County
Hospital in Sweden, for periodontal treatment. The mean age was 51 years
(46-66 years). Six of the patients were smokers. To be included, each patient
should have 2 healthy sites and at least 4 diseased sites (i.e pockets >4 mm
deep showing ongoing inflammation such as bleeding on probing or pus and
manifestation of bone loss on X-ray). Neither did any of the patients suffer
from systemic illness nor had they taken any antibiotic medication 6 months
or anti-inflammatory drug 3 months, prior to the investigation. At the followup examination 12 month after treatment, one patient was lost because he
moved to Africa and in one patient a tooth with angular bone loss was lost
due to extraction.
Study II
The study included 4,254 subjects aged between 20-89 years of which
3,352 were referred to the Department of Periodontology, at Gävle County
Hospital Sweden, for periodontal treatment between the years 1976-2000,
and 902 individuals participated in dental health surveys (218 subjects in
1979; 376 subjects in 1989; and 308 subjects in 1999 and not 392 in 1989 or
311 in 1999 as it says in the article) from five different parts of the same
geographic area.
Study III
2,025 subjects aged 70 years were invited to participate in the Prospective
Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. 1,016 of
the invited subjects were willing to participate, giving a participation rate of
50.1%.
Study IV
The study population consisted of 7,674 individuals, mean age 51.7 r13,8
years of whom 6,788 were patients referred to the Department of Periodontology, at Gävle County Hospital Sweden, for periodontal treatment between
the years 1976 and 2002. An additional 886 randomly selected individuals
from the same geographic area that participated in dental health surveys (217
51
subjects in 1979; 359 subjects in 1989; and 310 subjects in 1999) were included in the sample to assure a certain number of orally healthy individuals.
Censor data for follow-up was June 30th 2004.
Study V
100 patients admitted at Gävle County Hospital, Sweden, because of
acute myocardial infarction (MI) and 100 apparently healthy, age-and sex
matched controls randomly chosen from the general population of the same
geographic area.
Investigations
General health
In study I, all participants were asked if they suffered from any systemic
illness, if they had received periodontal treatment or antibiotics within the
preceding 6-months or any anti-inflammatory drugs 3 weeks prior to the
study. Smoking habits were registered as a dichotomised variable smokers (1) or non-smokers (0).
In study II, during the appointment for the clinical oral investigation the
patients were interviewed about their general health. This study is based on
self-reported incidence of myocardial infarction and antihypertensive medication. Smoking habits were registered in the same manner as in study I.
In study III, the participants were all asked to answer a questionnaire
about their medical history, smoking habits, regular medication, and education level. Smoking was dichotomised in the same way as in study I. The
educational level was divided into three different categories: six years in
school or less; 7-12 years in school; and/or university studies. The medical
examinations were performed in the morning after an over-night fast. No
medication or smoking was allowed after midnight. After recordings of
height, weight, abdominal and hip circumference, an arterial cannula was
inserted in the brachial artery for blood sampling. Blood pressure was measured by a calibrated mercury sphygmomanometer in the non-cannulated arm
to nearest mmHg after at least 30 minutes of rest and the average of three
recordings was used.
The metabolic syndrome was defined according to the NECP/ATP III criteria 174 and three of the following five criteria should be fulfilled: Blood
pressure >130/85 mmHg or antihypertensive treatment; fasting blood glucose >5.6 mmol/l; serum triglycerides >1.7 mmol/l; waist circumference >
102 cm in men and >88 cm in women; and HDL-cholesterol <1.0 mmol/l in
men and <1.3 in women.
In study IV, data concerning general health were not available for all subjects. However, the year and month when the oral investigation was per-
52
formed as well as data regarding smoking habits were accessible for all participants. Smoking habits wa registered as in study I.
In study V, myocardial infarction (MI) was verified by typical changes in
the electrocardiogram (ECG) readings in combination with elevation of biochemical markers in serum such as creatinine kinase isoenzyme and troponin
T. All subjects answered a questionnaire about there smoking habits, education level and there medical condition prior to the infarction. The educational
level was divided into the same categories as used in study III. Smoking was
defined as in study I. Subjects who quit smoking in connection to the infarction were registered as current smokers. Information concerning height,
weight and medication were in the MI group collected from the medical
records, but in the control group by interview. Hypertension was defined by
antihypertensive medication prior to infarction in the MI group, and as a
systolic blood pressure >139 mmHg, and/or diastolic blood pressure >89
mmHg measured after 15 minutes rest in the control group. Diabetes was
defined as fasting plasma glucose >6.9 mmol/l or if subjects were taken antidiabetic medication.
Oral health
Participants in study I, II, IV and V received a full mouth examination
conducted by a specialists in periodontology, including registration of
number of teeth, number of sites with visible plaque, bleeding on probing, tooth mobility, furcation involvement and probing pocket depth >4
mm. Also a full mouth set of radiographs were taken. The plaque was
made visible by gently scraping with a probe along the gingival margin
and surfaces with bleeding on probing (BOP) were registered after gently
probing the pocket depth.
Severity of periodontal disease/ periodontal bone loss.
In study I, each participant should have two healthy sites and four disease
sites, of which two should present angular bone loss, and two sites horizontal bone loss. A site was regarded to have bone loss if >2 mm bone
loss was observed on radiographs measured from cemento-enamel junction to the alveolar crest.175 Sites where the bone loss presented an intraosseous defect t3 mm were regarded as being of an angular type. Bone
loss of a horizontal or angular type in combination with pocket depth >4
mm, bleeding on probing or pus was regarded as a site with ongoing disease. A healthy site was defined as a site with bone loss not exceeding 2
mm, and pocket depth 3 mm with no bleeding on probing or pus. GCF
was collected from 6 sites in eache individual using a filter paper technique. All subjects received periodontal treatment in terms of open flap
surgery performed by the same surgeon in combination with systemic
antibiotics, Doxycykline“ 100 mg/day administered for 15 days.
53
To asses bone loss in study II, IV and V, a ruler with a graded scale on a
transparent sheet was applied over the root on the apical x-ray, dividing the
root into three parts from the enamel-cemental junction (ECJ) to the apices.
Bone loss 2 mm was regarded as no loss. The site with the largest amount
of bone loss was chosen to represent the bone loss of that particular tooth. In
study II and IV, depending on the degree of bone loss (BL), presence or absence of bleeding on probing (BOP) and furcation involvement, a value from
0 to 4 was given to each tooth: (0) = no BOP or BL; (1) =BOP, but no BL;
(2) =BL >2mm 1/3 of the root length; (3) =BL >1/3 and 2/3 of the root
length; and (4) = if the loss were > 2/3 of the root length or if it was of an
angular type or if furcation involvement degree 2 and 3 was present. No
pockets exceeding 4 mm were allowed for the values (0) and (1). The values
for all teeth were summarised and the total sum was divided by the number
of teeth giving a periodontal severity index (PDSI) for each individual.
Based on the PDSI the subjects were stratified into 4 categories; no; minor;
moderate; and severe periodontal disease.
In study V, severity of periodontal disease was calculated in almost the
same way as in paper II and IV, with the exception that BOP and furcation
involvement were not included at all. A possible value for bone loss (BL)
from 0 to 3 was registered for each tooth: (0) = no BL; (1) = BL >2mm 1/3
of the root length; (2) = BL >1/3 and 2/3 of the root length; and (3) = if the
loss were >2/3 of the root length or if it was of an angular type. The value
for each tooth was summarised and divided by number of teeth giving a
periodontal bone loss (PBL) score. Depending on the PBL the subjects were
divided into 3 categories; no/minor; moderate; and severe bone loss.
Number of diseased pockets
In study II, IV and V, a periodontal pocket was regarded as being deepened
or diseased if probing pocket depth exceeded 4 mm. The number of diseased
pockets (NDP) was in study II used as continues variable, but in study IV it
was stratified into four groups: 0, 1-15, 16-30, and >30 deepened pockets,
and in study V into two groups; 0-4 pockets or >4 deepened pockets.
Bleeding on probing
Percentage of surfaces with BOP was in study IV, V as well as in the reanalysis of study II used as categorised variables. BOP was stratified into
following groups in study IV: 0-19 %, 20-39 %, 40-60 %, and >60 %, and
into the groups: 0-20 % and >20 % of the surfaces with bleeding on probing
in study II and V.
Number of teeth
Number of teeth (NT) was also used as a categorised variable in study II, IV
and V, but as a continuous variable in study III. In study II and IV, NT was
54
stratified into five groups: 0-9, 10-14, 15-19, 20-25, and >25 teeth, and in
study V, into two groups: <21 and >20 teeth. NT was self-reported in study
III, and 947 of the 1,016 answered the question about number of teeth.
Laboratory analysis
Laboratory analyses were used in study I, III and V. The GCFs fluids in
study I were absorbed with the paper strips and eluated with 200 Pl of sterile
sodium chloride (NaCl) in combination with centrifugation and frozen at 70° C until45analysed. Bone resorption was quantified by analyzing the percentage of Ca release from prelabelled bones
dissected from mice that were
45
injected at an age of 1-2 days with 1.5 PCi Ca. The IL-1D, IL-1E and IL1ra concentrations in GCF eluates were assessed by using commercially
available ELISA kits.
Lipid variables, leukocyte count, and fasting blood glucose were in study
III measured by standard laboratory techniques and high sensitive CRP
(HsCRP) was measured in human serum by an ultra sensitive particle enhanced immunoturbidimetric assay.
In study V, the plasma glucose level, fasting triglyceride levels, total cholesterol, high density lipoprotein (HDL), and HsCRP were analysed at the
accredited laboratory for chemical analyses, Gävle County hospital. The
levels of IL-6 and antibody titres against Porphyromonas gingivalis and
Aggregatibacter actinomycetemcomitans were analysed using Enzymelinked immunosorbent assay (ELISA).
Statistical Analysis
StatView 5.0 for windows was used in all studies for analysing data. In study
I, Wilcoxon signed rank test was used to investigate differences of IL-1 levels and BRA in GCFs from diseased and healthy sites before and after treatment, with Bonferroni correction for multiple testing taken into account
where appropriate. To analyse possible correlations, the nonparametric
Spearman coefficient for ranked data was used.
A logistic regression analysis was used in study II to analyse if severity of
periodontitis or number of remaining teeth were related to the prevalence of
myocardial infarction and hypertension. Mann-Whitney test was applied to
analyse how the number of diseased pockets related to the prevalence of
myocardial infarction and hypertension. A multiple logistic regression analysis was then used to investigate the interaction of possible confounding variables such as age, gender and smoking.
Differences between groups in study III were evaluated with ANOVA and
relationships between pairs of variables were evaluated by Pearson´s correla55
tion coefficient. A multiple regression analysis was applied to relate several
independent variables to a dependent variable.
In study IV, a Cox proportional hazard analyses was performed to investigate any dose-dependent relationship between four oral health parameters
and all-cause mortality, mortality in cardiovascular disease (CVD), in coronary heart disease (CHD) and in stroke. Adjustment was made for the confounders age, gender and smoking. Kaplan-Meier curves were used to visualise how the number of teeth was related to all-cause mortality and mortality in CVD.
Contingency tables and chi-square analysis were in study V used to compare proportions between nominal variables. Differences between normally
distributed groups were evaluated with ANOVA and ANCOVA. A logistic
regression analysis was applied to analyse associations between acute myocardial infarction and the oral health parameters with adjustment for major
confounders. Finally, a logistic regression model was used to analyse if MI
as dependent variable was related to the oral health parameters, and antibody
levels
against
Porphyromonas
gingivalis
and
Aggregatibacter actinomycetemcomitans, after age, gender and smoking were adjusted
for. In all papers a two-tailed probability (P) 0.05 was regarded as statistically significant.
56
Results
Inflammatory response in periodontal disease (Study I)
GCF eluates harvested before treatment from sites with horizontal and vertical bone loss caused 1.81- and 1.96-fold stimulation, respectively, of 45Ca
release. The stimulatory effect of eluates from the two diseased groups of
pockets was significantly higher than eluates from healthy sites (P<0.001)
but no difference was seen between the two diseased groups of sites. Although a majority of diseased sites showed a decrease in BRA activity after
treatment (15 of 18 sites with horizontal bone loss and 13 of 17 sites with
vertical bone loss), significant difference between pre- and post treatment
values was only observed in sites with horizontal bone loss (p<0.01).
The levels of IL-1D, IL-E and IL-1 receptor antagonist (IL-1ra) in GCFs
were significantly higher from diseased sites before treatment compared to
healthy ones (p<0.001 for all variables). Treatment decreased levels of IL-1D
in GCF in all diseased sites (p<0.001) (figure 8). Also levels of IL-1E in
GCFs were significantly reduced (p<0.001 for sites with horizontal bone loss
and p<0.01 for sites with vertical bone loss). Although the levels of IL-1ra in
GCF were decreased in most diseased sites, significant reduction was only
seen in those with horizontal bone loss (p<0.01). No difference in BRA and
IL-1 levels before and after treatment was observed in GCFs from healthy
sites.
With the aim to elucidate if BRA found in the GCFs due to the presence
of molecules already known to stimulate osteoclastogenesis and bone resorption we analysed if there was any correlation between the amounts of IL-1D,
IL-E and IL-1ra and the degree of 45 Ca release. In diseased sites with angular bone loss, BRA was correlated to IL-1D and IL-1E before (p< 0.014, rs =
0.58 and p<0.0013; rs=0.76 respectively), and after treatment (p<0.016;
rs=0.6 and p< 0.008; rs =0.66 respectively). However, there were no significant correlations between the individual changes in each site of BRA and the
corresponding changes of IL-1D, IL-1E, and IL-1ra.
57
Figure 8. The concentration of interleukin-1D (IL-1D) in gingival crevicular fluids
from sites with healthy gingiva and from sites with horizontal or vertical bone loss
before treatment (a). Values represent means±SEM. The IL-1D concentrations in the
sites from the two diseased groups were significantly different from healthy sites
(P<0.001). In (b) – (d) are shown the concentrations of IL-1D in gingival crevicular
fluids before and 12 months after treatment. The decrease after treatment was statistically signficant for both diseased sites (P<0.001).
Initially, mean probing pockets depth was deeper in pockets presenting
angular bone loss compared to sites with horizontal loss; 8.1 r 0.6 and 6.7 r
0.3 mm, respectively. Treatment resulted in a significant decrease of 3.5 r
0.5 mm (p<0.001) in sites with angular bone loss and 2.8 r 0.3 mm
(p<0.001) in sites with horizontal bone loss. There was a significant correlation between BRA and probing pocket depth (p<0.01, rs=0.52) only in pretreatment GCFs from sites with angular breakdown.
58
Association between oral health and cardiovascular
disease (study II-V)
Number of teeth
Number of teeth (NT) was the only oral health parameter consistently related to CVD in this thesis. NT related to MI in a dose-dependent manner
with an OR of 0.8 (p<0.03) after adjustment for age, gender and smoking
(figure 9). NT was also related to HT in an unadjusted analysis, but this relationship did not remain significant after correction for confounders (study
II).
Figure 9. Prevalence of myocardial infarction (MI) in relation to remaining teeth
(p<0.0001 for trend).
The metabolic syndrome (MetS) was present in 23% of the subjects and
they had significantly lower number of teeth compared to those without the
syndrome after controlling for confounders (figure 10). Furthermore, NT
was also related to the number of criteria included in the definition of MetS
(study III).
59
Figure 10. Number of teeth in subjects with the metabolic syndrome (MetS, n=219)
and in those without (n=728). Means and SEM are given.
NT was significantly associated also to all-cause mortality, mortality in
CVD, and in CHD in a fairly dose-dependent manner after the adjustment
for age, gender and smoking (figure.11) (for the group with 20-25 teeth
p=0.031, p= 0.0015 and P=0.0099, respectively, and for all the other strata of
teeth with p<0.0001). The hazard ratio (HR) for mortality in coronary heart
disease was 7 times higher for individuals with <10 teeth compared to those
with >25 teeth (study IV).
60
Figure 11. Cumulative survival plot with the number of teeth as grouping variable,
mortality in cardiovascular disease (CVD) as censor variable, and follow-up time
given in years, (log-rank p-value <0.0001 for the difference between groups).
Furthermore, in study V, we found that NT was independently related to
MI (p=0.007) even after controlling for major confounders.
Severity of periodontal disease
Severity periodontal disease (SPD) was in study II found to be significantly related to myocardial infarction (MI) (figure 12) and to hypertension
(HT) (figure 13) in a dose-dependent manner after adjustment for age, gender and smoking. However, the relationship to MI was significant only in the
middle-age group (40-60 years), with an odds ratio (OR) of 2.7 (p<0.03)
after the subjects were stratified into the age categories (<40, 40-60 and >60
years). Also in study V, using an unadjusted analysis of proportion, SPD was
found to be related to MI in a dose-dependent manner, but the correlation
disappeared after correction for confounders. SPD was associated to hypertension in the total sample with an OR 1.32 (p<0.005), but only in elderly
subjects >60 years (p=0.0029) after stratification into above mentioned age
groups (study II).
SPD related neither to all-cause mortality nor to mortality in any kind of
cardiovascular disease (CVD) analysed in the study IV.
61
Figure 12. Prevalence of myocardial infarction (MI) in relation to periodontal disease (p<0.004 for trend)
Figure 13. Prevalence of hypertension (HT) in relation to periodontal disease
(p<0.0001 for trend)
Number of periodontal pockets
Number of diseased pockets (NDP) was not related to MI in study II.
However, in study V a relationship to MI was seen in subjects with >4 deepened pockets, even after adjustment for major confounders (p=0.0029).
62
In study II, subjects with HT had significantly more NDP than those without HT (in those with HT: median 15; range 0-89; in those without HT: median 11; range 0-89, p< 0.0001). Unfortunately, in the published article the
opposite was stated (in those with HT: median 11; range 0-89; in those without HT: median 15; range 0-89). Another fault in the published abstract of
study II is the statement that we have adjusted for the number of teeth, which
was true only for the analyses of NDP in relation to MI and HT.
After stratification into the three age groups along with correction for age,
gender, smoking and NT, a relationship was still present between NDP and
HT in the two oldest age groups 40-60, and >60 years, (p<0.001 and p<
0.01, respectively).
Finally, no dose-dependent association between NDP and mortality in
CVD was seen in study IV.
Bleeding on probing
Bleeding on probing (BOP) >20 % of the surfaces was found to be related
to MI in study IV, even after major confounders were adjusted for (P=0.035).
In study II, BOP in relation to MI and HT was not analysed before the article
was published. After going back to the data sheet using the same logistic
regression analysis, the same stratifications as in study V, with adjustment
for age, gender and smoking, no association between BOP and MI was observed. However, when BOP was analysed against HT, BOP>20 % of the
surfaces was associated to HT in the total sample, OR 1.6 (p=0.0001) and
after age stratification, in subjects 40-60 years, OR 1.61 (p=0.0007), and >60
years, OR 1.54 (p=0.0017). As for NDP, no dose-dependent association between BOP and mortality was seen in study IV
Oral health in relation to systemic markers of
inflammation.
Systemic markers of inflammation such as CRP, and ICAM-1, were in an
unadjusted analysis significantly related to NT (p=0.0023 and p=0.0001,
respectively). However, after including all parameters that were significantly
related to NT, using a backward stepwise multiple regression analysis, only
the leukocyte levels remained significantly related to NT (p=0.043) (Study
III).
IgG antibody levels against Porphyromonas gingivalis (Pg IgG) was associated to MI (p=0.036) and to the oral health parameters, >4 deepened
pockets (p=0.042), BOP >20% (P=0.001), and periodontal bone loss
(P=0.0005), but not to NT after adjustment for age, gender and smoking.
63
However, when the oral parameters together with Pg IgG as covariates were
included in a logistic analysis with MI as dependent variable, the relation
between Pg IgG and MI disappeared (p=0.55) (table 1). (study V)
Table 1. Logistic regression model with myocardial infarction as dependent variable
versus antibody level against porphyromonas gingivalis (Pg.IgG) adjusted for age,
gender smoking and oral parameters (in the second model only). OR= Odds ratio,
BOP= Bleeding on probing.
Independent
variables
Pg IgG
Age
Gender
Smoking
Number of teeth
<21
Moderate periodontal bone loss
Severe periodontal bone loss
>4 pockets
>4mm deep
BOP on >20%
of the surfaces
64
Adjusted for age,
gender and smoking
Adjusted for age, gender,
smoking and oral parameters
OR
P-value
1.16
0.55
0.93
0.048
1.55
0.32
2.31
0.02
6.99
0.0016
OR
1.57
0.97
1.24
4.12
-
p-value
0.033
0.30
0.58
<0.0001
-
-
-
0.83
0.66
-
-
1.87
0.48
-
-
3.22
0.008
-
-
3.19
0.0089
General Discussion
Over a long period of time the oral cavity has been treated as a separate entity with no, or only marginal, influence on other tissues and organs in the
body. During the two last decades however, there has been a mounting interest for oral health as a possible etiological factor for systemic conditions
such as cardiovascular disease, diabetes, rheumatoid arthritis, preterm birth
weight and respiratory diseases. Although reports have shown an association
between oral health and CVD, the biological mechanisms responsible for the
relationship remain unravelled. The aims of this thesis were to study oral
inflammation and the relationship between oral health parameters and cardiovascular diseases.
Inflammatory response in periodontal disease (study I)
That BRA as well as IL-1 were enhanced in GCF from sites with periodontal
disease, compared to healthy ones, is in agreement with earlier findings from
our group. 176 In the present study we investigated how periodontal treatment
affects BRA and the levels of IL-1 and IL-ra. We could show that both BRA
and levels of IL-1 was reduced 12 months after treatment, but that the reduction of BRA was significant only in sites with horizontal bone loss. Why
BRA was not significantly reduced in sites with angular bone loss could be
due to large standard deviations in combination with a too small sample size
or, alternatively due to regression of the disease process.
The opinion that the periodontitis is more aggressive in sites displaying
angular bone loss compared to those with horizontal loss is not supported by
our findings. There was no difference in BRA or in cytokine levels when
GCFs from sites with both types of bone loss were compared. Maybe the
type of bone loss is more a consequence of the bone anatomy in the area than
the degree of inflammation and bone loss in areas where the tooth is surrounded by thick bone will therefore be of an angular type while bone loss in
diseased sites surrounded with thin bone are more likely to be horizontal.
It has previously been demonstrated that molecules causing the BRA in
GCFs from patients with periodontitis has a molecular weight of 3-30 kDa,
is temperature sensitive, is not due to LPS contamination and is not caused
by prostaglandin E2. These observations support the view that the BRA is
caused by an osteotropic cytokine. Using GCFs pooled from several patients,
65
antiserum specifically neutralizing IL-1E had no or only marginal effect on
BRA whereas anti-IL-1D had a more profound, but still in some cases only a
partial inhibitory effect. 176 These data indicate that IL-1D, but not IL-1E,
contribute to but is not fully responsible for the BRA in GCFs from parodontitis patients. In the present study, we evaluated the importance of IL-1D, IL1E and IL-1ra by investigating, if any correlation could be found between
cytokine levels and degree of BRA in GCFs from individual sites. Although
BRA was correlated to IL-1D and IL-1E before as well as after treatment,
there were no significant correlations between the individual changes of
BRA and corresponding changes of IL-1D, IL-1E and IL-ra. These data also
argue for the view that IL-1 is important but not the sole stimulant of bone
resorbtion in patients with periodontal disease.
Although probing pocket depth was significantly reduced after treatment,
the reduction was not correlated to the BRA or to IL-1 levels. An explanation could be that the BRA and IL-1 levels in GCF only reflect the degree of
the inflammation at the moment when the GCF was harvested. These levels
could rapidly change depending on the degree of inflammation in the surrounding tissues. Pocket depth, on the other hand, needs a longer period of
time to be altered as it involves either degradation or regeneration of tooth
supporting tissues. As periodontal disease does not progress continuously,
but in periods with burst of activity, it is likely that levels of BRA stimulating cytokines such as IL-1 could be substantially altered without any noticeable change in pocket depth. Another explanation for the discrepancy which
is supported by the findings in paper I, is that other molecules besides IL-1
are involved in the inflammatory process as no correlations were seen between the individual changes in each site of BRA and the corresponding
changes of IL-1D, IL-1E, and IL-1ra.
Bone resorption is not only associated with the inflammatory process in
periodontal disease but is also associated with inflammatory process in joint
synovial tissues in patients with RA, osteoarthritis (OA) or loosening joint
prosthesis. Enhanced levels of osteotropic cytokines have similar to GCFs,
been found in synovial fluid from these patient groups. 27, 29 Attempts have
been made to block BRA in synovial fluids from OA patients and from patients with loosened joint prosthesis by using antisera neutralizing IL-1D, IL1E, TNF-D, IL-6 or IL-17 but such antisera have only occasionally displayed
an inhibitory effect. 177 These data show that neither in synovial fluid is IL1 the sole stimulator of bone resorption. Ongoing studies will reveal if BRA
in these two inflammatory exudates is due to the presence of known cytokines affecting osteoclast formation, or if this activity is also due to previously unknown osteotropic cytokines.
Bone resorption in mouse calvariae, induced by synovial fluids from patients with OA or loosened joint prosthesis, is associated with enhanced
RANKL expression. 177 In preliminary studies, we have observed that bone
66
resorption induced by GCF is also associated with a substantially increased
mRNA expression of RANKL (Holmlund & Lerner, ongoing studies).
Association between oral health and cardiovascular
disease (Study II-V)
Number of teeth (NT)
In paper II, NT related to MI in a dose-dependent manner, but not to HT.
In addition, in paper V the group with NT <21 was associated to MI, even
after adjustment for major confounders. These findings are in accordance
with earlier reports. 134, 139, 142, 144, 146, 160, 166
The metabolic syndrome (MetS), a syndrome constituted of a number of
cardiovascular risk factors, was an independent predictor for NT (paper III).
To our knowledge this is the first study to report a significant relationship
between the MetS and NT. Subjects with the MetS had an average of three
teeth less than those without the syndrome, indicating that oral health also
relates to a combination of cardiovascular risk factors, which is in line with
the findings from another recent study. 178
NT was also related to all-cause mortality, mortality in CVD, and mortality in coronary heart disease (CHD) in a dose dependent manner, but not to
mortality due to stroke. A subject with <10 teeth had 7-times higher risk to
for mortality in CHD than a subject with >25 teeth (paper IV). NT has previously been associated with mortality in CVD 166, 168, 169 but a dose dependent
relationship has never been reported before. As the majority of teeth are
removed due to some kind of oral infection, NT could be regarded as a reflection for the cumulated amount of oral inflammation which could have
influenced the progression of atherosclerosis over time. 139 This might be an
explanation as to why NT predicts mortality in CVD.
Although Joshipura has reported a relationship between NT and stroke,
no such relationship was observed in paper IV. 165 The relatively few subjects that died due to stroke could be an explanation why no association to
mortality in stroke was observed in this paper.
In this thesis, NT was the only oral health parameter that consistently associated to CVD, suggestig that NT, at least for the time being, might be the
best oral health parameter to use when associations between oral health and
CVD are investigated.
Severity of periodontal disease (SPD)
In papers II, IV and V we investigated if there was a dos-dependent relationship between SPD and cardiovascular disease (CVD). SPD was dose67
dependently related to both the prevalence of self-reported myocardial infarction (MI) in the middle-aged group (40-59) and to hypertension (HT) in
the total sample after adjustment for age, gender and smoking (paper II).
This is in agreement with other studies, 102, 105, 133, 135, 138, 165, 166 however, only
a few of them have presented a dose-dependent relationship. 102, 103 Furthermore, the association between oral health and HT apart from paper II,
has only sparsely been investigated. 144, 179
In contrast to the findings in paper II, no relationship between SPD and
MI was observed in paper V after the correction for confounders. An explanation for this could be that the sample size in study V was too small to disclose any dose-dependent relationship. Neither could any relationship between SPD and mortality in CVD be observed in study IV. However, other
studies have also failed to find any association between periodontal disease
and CVD. 123, 156, 158, 159, 162, 163 The inconsistency of the association indicates
that there are other factors influencing the relationship. For instance, the use
in different studies of different confounders such as age, gender, smoking,
cholesterol, diabetes, obesity, hypertension and socio-economic factors
probably contributes to this inconsistency. Other factors that also might influence the variation of the relationship between periodontal disease and
CVD are the use of different oral parameters and different threshold values
to define the presence of periodontal disease. Usually, we have no knowledge about the periodontal conditions around teeth that already have been
removed, but we can assume that a major part of them had worse periodontal
conditions than the remaining teeth. Obviously, there is a substantial risk that
severity of periodontal disease could be underestimated in subjects where
teeth have been removed prior to their oral examination in the studies, which
also might affect the above mentioned relationship. It would therefore be
desirable if future investigations concerning the relationship between periodontal disease and CVD had a more consistent way of defining the presence
of periodontal disease and in some way also included the number of missing
teeth into the estimation of the severity of the disease.
Number of deepened pockets (NDP)
In paper II, NDP was associated to hypertension, but not to the prevalence of MI. However, in paper V there was an association between NDP
and MI in subjects with >4 deepened pockets. The discrepancy in the relationship between NDP and MI in paper II and V could to some extent be due
to an underestimation of the prevalence of MI in paper II as it was selfreported. A difference concerning the time sequence between the incidence
of MI and the oral investigation in the above mentioned studies might also
have influenced the relationship. Although other studies have shown that
NDP is related to CVD, 126, 128, 129 so far no study has reported an association
between NDP and mortality in CVD. This is in agreement with the result in
68
paper IV, where no dose-dependent association was seen between NDP and
mortality in CVD.
It seems that NDP, being an indicator of ongoing periodontal disease is
more related to different expressions of atherosclerosis such as MI and HT
than to the accumulated result of the process, here represented by mortality
in CVD.
Bleedings on probing (BOP)
BOP could also be regarded as an indicator of ongoing periodontal inflammation and, as was observed for NDP, a significant relationship between BOP and MI was seen in subjects with BOP >20% of the surfaces,
even after the correction for major confounders (paper V).
Paper II, did not include an analysis of a possible association between
BOP and MI or HT. After reanalysing the data in paper II, the same pattern
that was seen for NDP regarding the relationship to CVD appeared, namely
that BOP related to HT, but not to MI. The same reasons that were given for
the diversity regarding the relationship between NDP and MI in paper II and
V could also provide an explanation as to why BOP related differently to MI
in these studies.
Similar to NDP has BOP previously been related to CVD 127, 137, 180 and in
accordance with what was seen for NDP, no dose-dependent relationship
between BOP and mortality in CVD could be observed in paper IV. So far
there is no report in the literature of a dose-dependent relationship between
BOP and mortality in CVD.
NDP and BOP are indicators of ongoing oral inflammation which might
influence the degree of inflammation in the atherosclerotic plaque, promoting fibrous cap rupture and the acute infarction, explaining why NDP and
BOP were associated to MI. However, in contrast to NT, both NDP and BOP
are easily affected by periodontal treatment and therefore do not reflect the
past exposure of oral inflammation. This might explain why NDP and BOP
were not related to mortality in CVD.
Oral health in relation to systemic markers of
inflammation.
The use of clinical parameters to investigate possible associations between
oral health and CVD has been criticised because it does not include any systemic effect evoked by impaired oral health. It was only in paper III and V
that we had the opportunity to study systemic effects related to impaired oral
health.
69
Higher levels of leukocytes in subjects with peridontitis compared to
healthy subjects have earlier been reported. 44 In line with these results the
levels of leukocytes in paper III, was an independent predictor for number of
teeth, further emphasizing that oral health might induce a systemic lowgrade inflammation.
In agreement with earlier studies, 115, 117 the IgG antibody levels against
Porphyromonas gingivalis (Pg IgG), a bacteria considered to be a risk factor
for periodontal disease, were related to MI (paperV). Also in line with other
reports, the Pg IgG levels in paper V were associated to the oral health parameters. 10, 181 However, when MI as a dependent variable together with the
oral health parameters and Pg IgG as covariates were included in a logistic
regression analyses, the association disappeared between Pg IgG and MI,
indicating that Pg could be a link between oral health and CVD. This is to
our knowledge the first case-control study that explores how Pg relates to
oral health parameters as well as to MI.
P. gingivalis have a number of qualities that could influence the atherosclerotic process such as the ability to induce the coagulation cascade, 111, 112,
182
to convert Big-endothelin to endothelin, 183 to induce cross-reactivity to
human heat shock protein 60 184 and to invade endothelial and epithelial
cells. 185 56 Viable Pg have also been harvested from atherosclerotic plaque
109
and the progression of atherosclerosis was accelerated when APO-E deficient mice were infected with Pg, further indicating that Pg could influence
the atherosclerotic process. 110
P gingivalis, being a risk factor for periodontal disease along with its ability to influence the atherosclerotic process, could be a possible biological
link between oral health and CVD.
Limitations
The sample size in pape I might have been too small to disclose significant
correlations as the standard deviations were rather large.
In paper II, a cross-sectional study was performed in a retrospective manner and suffers therefore from inherent limitations. No causality in the relationships can be concluded from this type of study. Furthermore, the prevalence for MI and hypertension was probably underestimated as it was selfreported. Adjustments for possible confounders in this study were limited to
age, gender and smoking and because smoking habits were only registered
as current or non-smokers, adjustment for all of the possible effects of smoking could not done.
In paper IV, the time period for inclusion of subjects was very long, with
only one follow-up examination and the adjustment for smoking habits and
confounders suffered from the same limitations as in study II.
70
Paper III, a cross-sectional study where the number of teeth was selfreported. Although there might be a lack of confidence in self-reported number of teeth, studies have shown that the self-estimation of this oral parameter is rather good.180 Other limitations in this study were the rather low participant rate (50.1%) and that data regarding number of teeth in nonparticipants was not available. However, this would probably only cause an
underestimation of any potential relationship investigated in this study. As
the study cohort consisted only of elderly subjects, the results might not be
valid for other age groups.
Paper V, with a case-control design, is only hypothesis generating. A
limitation concerning this study is that the prevalence of hypertension in the
MI group may have been somewhat underestimated as only hypertensive
medication prior to the infarction was used as a definition for hypertension.
However, hypertension showed an odd-ratio for MI in this paper, which is
similar to what is generally seen in other studies. Another limitation in this
study is the sample size, which could have been too small to disclose significant relationships. Furthermore, as we lacked data on number of years the
subjects had been smoking, correction for pack years could not be performed.
Finally, as the population samples in paper I-V mainly consist of subjects
with Caucasian heritage, cautions should be taken when drawing conclusions
for other ethnic groups.
71
Future perspectives
Although this thesis using different study designs, presents a consistent relationship between oral health and cardiovascular disease, no conclusions regarding the causality of the relationship can be drawn. More studies are
needed to clarify the inflammatory response in periodontal disease and by
which biological mechanisms oral health could influence the atherosclerotic
process and other systemic conditions.
It seems from the results of our studies that different oral health parameters such as severity of periodontitis, number of teeth, number of deepened
pockets and bleeding on probing could be related to different stages of the
atherosclerotic process, however, this needs further investigation.
The use of different oral health parameters and threshold levels to define
when periodontal disease is present as well as grading of the severity of periodontitis are other matters that need more attension. In order to avoid underestimation, we need to somehow involve the missing teeth in the estimate
of disease severity.
To finally prove the causality of the relationship, prospective treatment
studies with a randomised controlled design must show that treatment of
periodontal disease could lower the prevalence of cardiovascular disease.
Since these studies are time-consuming and expensive to perform, it is not
likely that we will see, at least in the near future, any final evidence of the
causality in the relationship.
What we can state today with rather convincing scientific evidence is that
there exits an association between oral health and cardiovascular disease. As
there are a number of mutual risk factors influencing both oral health and
cardiovascular disease, there is a possibility that the relationship only exits
because individuals prone to develop periodontal disease also are more disposed for CVD. Even though oral health might not be a risk factor, it could
still be an easily obtained risk indicator for CVD and as such oral health can
be an important tool in the prevention of cardiovascular disease.
In Sweden at least most people go for a dental examination on a rather
regular basis. In contrast to the dental visits, most of the individuals contacts
with regular health service are limited to the times when they need treatment
for a serious illness.
Regardless of the reasons for the relationship between oral health and
CVD or if causality does or does not exist, the results from this thesis and
from other studies indicate that oral health is a risk indicator for CVD.
Maybe, in a not to a distant future, individuals with severely impaired oral
health will be considered for a general health examination.
72
Conclusions
x
Diseased periodontal pockets exhibit more bone resorption activity (BRA) and higher levels of interleukin-1 (IL-1) than
healthy ones. Treatment significantly reduced levels of IL-1 in
diseased sites and BRA in sites with horizontal bone loss. However, the individual changes of BRA and IL-1 before and after
treatment in each site were not correlated, indicating that other
molecules besides IL-1 are involved in the stimulation of BRA.
x
Oral health was related to myocardial infarction, hypertension, the metabolic syndrome, all-cause mortality, and to
mortality in cardiovascular disease and in coronary heart disease, but not to death caused by stroke.
x
The number of teeth was the only oral health parameter that
consistently correlated to cardiovascular disease.
x
Antibody levels against the periodontal pathogen Porphyromonas gingivalis, as an indication of a systemic response due
to periodontal disease, was associated both to acute myocardial infarction and to the oral health parameters, suggesting
the possibility that this bacteria might be a link between oral
health and cardiovascular disease.
73
Acknowledgements
I wish to express my deepest gratitude to everyone who has contributed to
thesis in different ways.
My special thanks go to
Professor Lars Lind, my principal supervisor, co-author, dear friend and
tennis opponent, for guiding me into the scientific world with never lasting
patience. Thanks for your inspiring enthusiasm for science, your support and
for always finding time for discussions and help. Without your scientific
mind, your vast knowledge of cardiovascular research together with your
pedagogical skills this thesis would not have been possible. For the future, I
sincerely hope, we will continue our scientific collaboration and also the
meetings at our summer houses with interesting discussions, good food and
good wine.
Professor Ulf. H Lerner, my co-supervisor and co-author, for helping me
with the analyses of bone resorbing activity and cytokines, for all rewarding
discussions regarding my scientific work and for sharing your extensive
knowledge and true passion for science and inflammation. You can really
make bone a living and fascinating tissue. I have enjoyed our sessions at the
University of Umeå and hope that our collaboration can continue in the future.
Gunnar Holm, my co-author and former colleague, for inspiring me to become a specialist in periodontology, for all stimulating discussions and for
being so far-sighted in the importance of registering data regarding oral and
general health into a database. Two of the articles is thesis had not been possible without your excellent work.
Professor Lennart Hänström, co-author and former colleague, for all inspiring discussion and lectures in the field of periodontology.
Associated professor Johannes Hulte, co-author and for analysing HsCRP
Professor Pirkko Pussinen, co-author and for analysing antibodies against P
gingivalis and A acinomycetemcomitans.
74
Associated Professor Måns Hedin, co-author and for measuring periodontal
bone loss on radiographs.
Professor Marianne Högmann and her eminent staff at FoU-forum County
Council of Gävleborg, for all encouragement during the ups and downs of
my scientific work and for financial support. Inga-Lill Stenlund for always
being service-minded and helpful, Lawrence Teeland for all valuable comments regarding the English language and finally, Hans Högberg for taking
time to discuss and shear your great knowledge in statistics. You have all
meant a lot to my
The department of cardiology, Gävle County Hospital, for helping me to
recruit patients to the case control study.
Dental nurses Kerstin Larsson and Christina Nilsson at the department for
specialist dentistry at Gävle County Hospital, for your engagement in my
research work, for helping me out with the clinical investigations and for
straighten out all problems that I have created by rescheduling appointments.
Laboratory assistant Kerstin Marttala at Uppsala University and Karin
Hagman at Gävle County Hospital, for handling blood samples, samples
with gingival crevicular fluid, sorting and arranging transportations of the
samples.
Hartmut Feldmann, head of the department for specialist dentistry at Gävle
County hospital and Folktandvården AB Gävleborg for helping with support
and founding of this thesis.
My colleagues and friends at the clinic for specialist dentistry at Gävle
County Hospital, for all support and encouragement and a special thanks to
my dear colleague Catrine Isehed for taking an extended work load during
my absence.
To all my friends and relatives for being there for me, you are all important
in my life.
Finally, to the most precious persons in my life.
My beloved wife Annika for your endless love and support. Thank you for
your patience and for shearing lives ups and downs with me. You have also
given me the two most precious things in my life, my daughters Johanna
and Maria. Despite my shortcomings as a father, you are always there for
me with your love and support. My son in-law Johan for being like a son to
me, for making the cover and some figures of this theses and for being partly
75
responsible for a new fantastic experience in my life, to become grandfather
to Ellen.
76
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from the Faculty of Medicine 346
Editor: The Dean of the Faculty of Medicine
A doctoral dissertation from the Faculty of Medicine, Uppsala
University, is usually a summary of a number of papers. A few
copies of the complete dissertation are kept at major Swedish
research libraries, while the summary alone is distributed
internationally through the series Digital Comprehensive
Summaries of Uppsala Dissertations from the Faculty of
Medicine. (Prior to January, 2005, the series was published
under the title “Comprehensive Summaries of Uppsala
Dissertations from the Faculty of Medicine”.)
Distribution: publications.uu.se
urn:nbn:se:uu:diva-8708
ACTA
UNIVERSITATIS
UPSALIENSIS
UPPSALA
2008
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