Cardiovascular Disease
Oral Microorganisms and Cardiovascular Disease
Thomas J. Pallasch, DDS, MS, and Jørgen Slots, DDS, PhD
Copyright 2000 Journal of the California Dental Association.
 |
The list of etiological factors for cardiovascular disease is long, complicated, intertwined, and yet to be completed. This paper will evaluate the current evidence for the pathogenic role of certain microorganisms, including those of the oral cavity, in the etiology of cardiovascular disease.
|
The argument has recently been made in various venues that oral microorganisms
may contribute to or even cause cardiovascular disease and low birth weight
infants (preterm birth). Since the claim of a relationship between oral/periodontal
infections and systemic disease can have far-reaching implications in
terms of health care delivery including its medicolegal aspects, it is
appropriate to examine the evidence upon which such proposals are made
and relate it to recent investigations of the possible roles of Chlamydia
pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus
in cardiovascular disease pathogenesis. This comparison may aid in establishing
whether it is reasonable to add oral microorganisms to the documented/potential
list of cardiovascular disease risk factors (Table 1). The role
of periodontal disease in preterm infant births will also be examined
since the concepts are similar.
|
Table 1. |
|
|
Proposed or Potential Markers or Risk Factors (continued) |
|
Age |
VLDL receptor |
|
Sex |
Plasminogen activator inhibiator 1 |
|
Genetics |
Plasmin - alpha 2- antiplasmin complex |
Modifiable Risk Factors |
Vascular/cellular fibrinogen adhesion molecules |
|
Cigarette smoking |
Hyperinsulinemia |
|
Obesity |
Plasminogen |
|
Diabetes mellitus |
TPA |
|
LDL-cholesterol |
Factors V, VII, VIII |
|
Psychosocial factors |
Hepatic lipase |
|
Air pollution |
Clot lysis time |
|
Physical activity |
Serumamyloid A |
|
Hypertension |
Platelet volume |
|
Total cholesterol |
Fibrin degredation products |
|
HDL-cholesterol |
Lipoprotein oxidation |
|
Alcohol intake |
Lecithin-cholesteroal acyl transferase |
|
Diet |
Thrombin-antithrombin III complex |
Proposed or Potential Markers or Risk Factors |
Apolipoprotein E isoforms |
Homocysteinemia |
Lipoprotein (a) |
Fibrinogen |
Thrombin |
PAI-1 |
Von Willebrand antigen |
Cholesterol transfer protein |
LDL receptor |
Apolipoprotein A-1 |
C reative protein |
TPA/PAI-1 complex |
Triglycerides |
Interleukins |
Platelet aggregation |
Platelet size |
Prothombin fragments |
Factors VIIc and VIIa |
Protein C resistance |
The concept that infectious agents might be involved in the etiology of
cardiovascular disease has been espoused since the early 1900s.1,2
The hypothesis gained credence with the demonstration in 1978 that avian
herpesvirus could induce arterial atherosclerotic disease in chickens
resembling that seen in humans.3,4 Possible pathophysiological
mechanisms include either acute precipitation of atherosclerotic plaque
rupture and subsequent thrombosis or the promotion of atherosclerotic
plaque growth via direct endothelial injury, endothelial
dysfunction, smooth muscle proliferation or the production of local inflammation.4
Microorganisms would then initiate or promote ("trigger") the "response
to injury" theory of vascular endothelial dysfunction whereby inflammatory
cells (primarily macrophages) adhere to damaged endothelial walls; become
foam cells; and, along with T lymphocytes and smooth muscle cells, initiate
the "fatty streak" that begins atherosclerotic disease.5 The
resulting inflammatory process gives rise to release of pro-inflammatory
cytokines including tumor necrosis factor-alpha, various interleukins,
and coagulation factors such as macrophage colony stimulating factor and
macrophage chemoattractant protein –1.2 Ongoing inflammation
would then contribute to the formation of complex atheromas and/or destabilization
of the atheroma and subsequent thrombogenesis (ischemia begets ischemia).2
The interest in a microbial causation of cardiovascular disease is fostered
by the realization that many acute coronary events (death, myocardial
infarction) occur in individuals with no apparent cardiovascular risk
factors.6,7 However cardiovascular disease is a classic multifactorial
disease with potentially more than 100 risk factors or markers for the
disease (Table 1).8,9 Nonmodifiable factors include
age, gender, and family (genetic) history.8 Modifiable risk
factors include cigarette smoking, obesity, hypertension, diabetes mellitus,
physical activity, total blood cholesterol, elevated low-density lipid-cholesterol,
low high-density lipid-cholesterol, air pollution, and unaccustomed strenuous
exercise (50 to 100 times greater risk for an acute myocardial infarction).8
Other risk factors include time of day for acute myocardial infarction
(6 a.m. to noon),10 enterovirus infection,11 blood
iron levels,12 thrombomodulin,13 nitric oxide,14
maternal hypercholesterolemia during pregnancy15 and heat shock
proteins.16
Unfortunately, the most significant factor for acute myocardial
infarction or thromboembolic stroke cannot yet be adequately identified:
the "vulnerable" atherosclerotic plaque that, following disruption, may
result in local or systemic thrombogenesis or local blood-flow disurbances.17
Atherosclerosis without thrombogenesis is commonly a benign disease rendered
life-threatening by acute thrombosis resulting in acute myocardial infarction,
unstable angina, or sudden death.17 The reason some atheromas
are thrombosis-resistant while others are vulnerable to disruption, thrombosis
formation, and life-threatening sequellae is a major question yet to be
answered.17
The most dangerous atherosclerotic plaques have a core of soft lipid-rich
atheromatous "gruel" that are unstable and vulnerable to rupture.17
Sclerosed plaques with a thick stable collagen "cap" are unlikely to be
involved in thrombogenesis. Macrophage infiltration at the edge (shoulder)
of the plaque may render it more vulnerable to rupture. Current diagnostic
methods cannot reliably distinguish between plaques that are vulnerable
to disruption and those that are relatively benign.17
The list of etiological factors for cardiovascular disease is long, complicated,
intertwined, and yet to be completed. The ensuing discussion will evaluate
the current evidence for the pathogenic role of certain microorganisms,
including those of the oral cavity, in the etiology of cardiovascular
disease.
Confounding Epidemiological Variables
The following variables may have a profound effect on the course of cardiovascular
disease but are commonly left unaddressed in epidemiological studies on
risk factors. Partly this is due to the difficulty or expense of controlling
for these variables; however, the conclusions of any study must be tempered
with the knowledge that such confounding variables are always present
and may be particularly significant in studies showing relatively low
odds ratios (range 1.5 to 3.0).
Genetics
Coronary artery disease in a population does not segregate as a simple
Mendelian genetic trait attributable to a single gene with large effects
but rather as a large number of genes (possibly up to 50).18
Coronary artery disease is a multifactorial disorder caused by the additive
effect of multiple genes each with a modest effect and confounded by the
gene-environment interaction.19
Ethyl Alcohol
Very few clinical studies -- including those that attempt to relate oral
microorganisms to cardiovascular disease -- address the important variable
of alcohol consumption. The relation between alcohol and total mortality
is depicted as a J shaped curve with the lowest mortality in those who
consume one to two drinks per day and then with increasing mortality with
the greater number of drinks in excess of two per day.20
Heavy alcohol consumption increases the risk for stroke, hypertension,
and cardiac muscle and arterial damage.20 Excess alcohol consumption
is also a suppressant of the immune system,21 particularly
with regard to infectious diseases;22 an independent risk factor
for ischemic cerebral infarction;23 a cause of cardiomegaly,24
cardiac arrhythmias25 and sudden death; and a major factor
in all-cause mortality.26 Inattention to alcohol ingestion
in study subjects could mask both its protective and deleterious effects
on cardiovascular disease.
Homocysteine
The first report that very high blood levels (100 to 450 micromoles/liter)
of homocysteine, a sulfur-containing amino acid, were strongly associated
with atherosclerotic disease appeared in 196927 and has led
to the homocysteine theory of cardiovascular disease: Atherogenesis is
secondary to hyperhomocysteinemia caused by dietary deficiencies in folic
acid and vitamin B6 with cholesterol and low density lipids
(LDL) as carriers of homocysteine to form LDL-HC aggregate precursors
of foam cells in atheroma lesions.28 Homocysteine may damage
vascular endothelial cells by oxidative stress, hydrogen peroxide and
superoxide production and inactivation of nitric oxide leading to endothelial
dysfunction, platelet activation and thrombus formation.28,29
The preponderance of evidence appears to support a role of elevated plasma
levels of homocysteine as a risk factor for atherosclerosis30-40
with a minority view that:
* As more stringent criteria are applied to the clinical studies, the
association weakens;41
* An apparent relationship exists, but no prospective placebo-controlled
interventional studies have been performed;42
* Significant variables in the studies have not been addressed;43
and
* No proven causal effect exists as the association weakens with prospective
studies.44
Studies that support a role of elevated homocysteine in atherosclerotic
disease generally report odds ratios of 1.4 to 3.130,34,37,39,42,43
with some inconsistencies in what precisely constitutes "elevated" homocysteine
blood levels. Five to 15 micromoles/liter in the fasting individual appears
normal, 16 to 30 micromoles is moderate elevation, 31 to 100 is intermediate,
and above 100 micromoles/liter is severe homocysteinemia.38.
The Physicians Health Study indicates that greater than 15.5 micromoles/liter
(the top 20 percent) have a 3.4 odds ratio for cardiovascular disease
as opposed to the bottom 10 percent and that, with each upward 5 micromole/liter
increment, the risk for cardiovascular disease increases 1.6 to 1.8 times.33
The same study indicates that plasma homocysteine levels 12 percent above
the normal upper limit result in a threefold increase in risk for acute
myocardial infaction.37 A meta-analysis of the published literature
prior to 1995 indicates that 10 percent of coronary artery disease may
be attributable to elevated homocysteine levels.45
A healthy diet of fruits and vegetables or a multivitamin containing folic
acid, B6, and B12 38,42 can reduce plasma
homocysteine levels; but the Nutrition Committee of the American Heart
Association has not recommended any general public dietary intervention
to lower blood homocysteine levels.42 No study on the etiology
of microorganisms in cardiovascular disease has included plasma homocysteine
levels as a confounding variable.
Psychosocial Factors
Stress (the reaction of the body to deleterious forces that tend to diminish
normal homeostasis46) can significantly depress the immune
response with resulting decreases in natural killer cell activity, the
proliferative lymphocyte response to mitogens; total CD3+,
CD4+, and CD8+ T lymphocytes; antibody levels; and
enodogenous hormones.47-51 Stress may exacerbate both herpesvirus
infections and periodontal disease.51-53
Psychosocial factors, including low socioeconomic status (with its limited
access to health care), social isolation, mental depression, hostility,
and anger, 54-57 play a significant role in coronary artery
disease. Negative emotional states incur a 2.5 times greater risk for
rehospitalization for cardiac disease symptoms and a five times greater
risk for acute myocardial infarction, death, and out-of-hospital cardiac
arrest.54 The risk rate for cardiac ischemia following negative
emotions rises to 2.6 to 3.0 for tension, sadness, and frustration and
can double the risk of myocardial ischemia some hours later.58
Hostility and anger (not Type A behavior per se) are independent risk
factors for coronary artery disease and acute myocardial infaction,59,60
and their reduction can reduce recurrent myocardial infarction.61
Mental depression and its accompanying stress can result in platelet aggregation
and increased coronary ischemia, acute coronary events, and the risk of
future coronary events.55,56,62-69
In the years from 1900 to 1950, coronary artery disease in the United
States was a disease of affluence possibly because of the greater physical
activity in the lower socioeconomic classes.65 In the mid-1960s,
the burden of cardiovascular disease shifted to the lower socioeconomic
classes with less physical activity.65,66 Cardiovascular disease
rates are inversely proportional to educational level and are lower in
those with greater leisure time activity and health knowledge.67
Social and productive activities (getting out to movies or sporting events,
shopping, gardening, socializing) that do not involve fitness activities
lower all-cause mortality.68 Conversely, employment that is
associated with low personal control, repetitive tasks, less skills and
variety, time pressures, and job insecurity increases the risk for cardiovascular
disease and all-cause mortality.69 These psychosocial factors
(sometimes vaguely addressed as a "socioeconomic status" without further
definition) are often not adequately addressed as confounding variables
in epidemiologic studies. Granted this may be difficult to accomplish,
but without such data caution is warranted in interpreting many cardiovascular
disease studies
Viral and Non-Oral Bacterial Associations With Cardiovascular Disease
Cytomegalovirus
The evidence for an association between cytomegalovirus and cardiovascular
disease is conflicting. Several studies implicate high cytomegalovirus
blood antibody titers with an increased risk for coronary artery restenosis
after cardiac interventional procedures 70-73 or renal artery
stenosis after transplantation.74 However, the majority of
studies do not demonstrate a relation between cytomegalovirus infection
and coronary artery disease or stroke.75-78
The difficulty with cytomegalovirus as with the putative microbial
causes of cardiovascular disease is that the infectious agents can be
ubiquitous: 50 percent of the population is infected with cytomegalovirus
by early adult life and 90 percent older than 60 are infected. It presently
appears that cytomegalovirus may be related to coronary restenosis after
revascularization procedures but has little if any role in the etiology
of cardiovascular disease.
Other Herpesviruses
Herpes simplex virus infections are widespread, and the nucleic acid sequences
of the viruses have been found in atherosclerotic plaque. Herpes simplex
viruses can induce atherosclerosis in animals and cause expression of
growth factors and cytokines by inflamed or infected vascular endothelial
cells.79 However, three clinical studies have not correlated
blood antibody levels against herpes simplex virus with carotid artery
intimal thickening80or increased risk for acute myocardial
infarction or stroke.77,78
Helicobacter Pylori
Most peptic ulcers and probably a significant number of gastric cancers
are related to infection with H. pylori. This organism has been
postulated to be a significant risk factor for cardiovascular disease,81-84
particularly if the strain is of high virulence 81or is found
in patients with large vessel atheromas or diabetes mellitus.82-84
Most evidence, however, does not support the contention that H. pylori
is a risk factor for malignant hypertension,85 intimal thickening
of carotid arteries,86 acute myocardial infarction,84
coagulation defects,87 or total or cardiovascular disease mortality.88,89
A meta-analysis of 18 epidemiological studies (10,000 patients) that measured
serum antibody titers to H. pylori and risk factors for cardiovascular
disease found a low correlation with body mass, blood pressure, HDL-C,
and plasma viscosity, but not for white blood cell count, total cholesterol,
triglycerides, fibrinogen, blood glucose, and C reactive protein.
90 This metanalytic study suggested that claims of an association
between H. pylori and cardiovascular disease were either based
on chance or publication bias (preferential publication of positive studies)
or both.90 Prospective studies have not shown a relationship
between H. pylori blood antibody titers and coronary artery disase.86,91,92
Chlamydia Pneumoniae
The most likely candidate for an infectious etiological agent in cardiovascular
disease is the respiratory pathogen, C. pneumoniae. The organism
(rarely) or its DNA fragments (commonly) have been identified in atherosclerotic
lesions (carotid, coronary, aortic, femoral/popliteal) by polymerase chain
reaction, immunocytochemistry, and electron microscopy.93 The
organism itself has rarely been isolated from atheromas.93
However, in spite of extensive study and some positive correlations with
atherosclerotic disease (odds ratios of generally 1.2 to 2.5), the question
is yet to be answered as to whether C. pneumoniae is a causative
or associative agent of cardiovascular disease or merely an innocent bystander
that finds atheromas a friendly place to survive.4,93-95 Eventually,
data from antibiotic interventional studies may help to clarify the issue
of causation of C. pneumoniae in cardiovascular disease.
C. pneumoniae infections are very common, often repetitive, and
many times subclinical in symptomatology. Alveolar macrophages infected
with Chlamydia pneumoniae may be transported to arteries
where the organism may induce or accelerate the atherosclerotic process.95
Experimental studies indicate that C. pneumoniae may induce atheromas
in rabbits,96-99 thereby establishing biologic plausibility.
Studies have demonstrated associations (odds ratios of 1.2 to 2.5112)
between C. pneumoniae blood antibody titers (seropositivity) and
cardiovascular disease or acute coronary events (acute myocardial infarction,
unstable angina, death).100-111 However, many other clinical
studies do not support a relationship between C. pneumoniae and
acute coronary events or atherosclerosis.2,4,6,7,77,112-124 The
trend of recent prospective studies that employ more stringent epidemiologic
criteria is toward decreasing the significance of C. pneumoniae
in the etiology of cardiovascular disease.
Differences in epidemiological studies on C. pneumoniae can be
due to a number of factors:
* Inattention to confounding variables (alcohol, homocysteine, stress,
socioeconomics);
* Difficulty in readily establishing whether cardiovascular disease due
to C. pneumoniae clearly occurs in populations with a 50 percent
lifetime risk for the disease;
* Inability to identify true incidence/prevalence by the detection methods
used (immunofluorescence tests are particularly subject to interpreter
bias and error);
* No established standards on what blood antibody levels constitute positivity;
* Difficulty in determining when the organism was acquired (past, current
or recurrent);
* Difficulty in isolating C. pneumoniae from atheromas; and
* Generally small sample sizes.
Many studies of antibodies to C. pneumoniae (as well as those with
other proposed viral or microbial etiologies of cardiovascular disease)
commonly take single or only a few blood samples over time, making it
virtually impossible to determine whether the C. pneumoniae
infection is acute, chronic, latent, or a repeat episode. Blood antibody
levels may be short-lived or persist for long periods after exposure to
C. pneumoniae, even though the organism may no longer present
in the host.
The best evidence for possible association or causation between C.
pneumoniae (or other microorganisms) and cardiovascular disease will
come from prospective interventional studies that correlate body levels
of the organism (preventing or eliminating the infection) with the prevention
or change in course of chronic cardiovascular or acute cardiac events.
Two small and underpowered studies125,126 have indicated that
treatment with macrolide antibiotics (azithromycin, roxithromycin) may
be effective in reducing the endpoints of acute myocardial infarction,
unstable angina, or death. Prolonged doxycycline therapy had no effect
on serologic or hemostatic markers for cardiac risk factors in patients
with C. pneumoniae antibodies.127
Preliminary data have been published from two large ongoing prospective
studies utilizing azithromycin with endpoints of reduction of anti-C.
pneumoniae antibody levels128 or acute coronary events.129
A one-month course of azithromycin (total 8 grams) failed to reduce plasma
IgG or IgA antibody titers to C. pneumoniae as determined at six
months.128 A 500 mg dose of azithromycin per day for three
days followed by 500 mg weekly for three months significantly reduced
C reactive protein, IL-6, and IL-1 levels at six months but failed to
reduce anti-C. pneumoniae antibody titers or acute coronary events.129
The conclusion in one of these studies128 was that anti-C.
pneumoniae antibody titers were likely a poor marker for a response
to antibiotic therapy, however other interpretations might also be that
the intervention therapy (antibiotics) does not affect the microorganisms
or that the disease process remains unaffected. This conclusion128
poses another difficulty as many studies on microbial causation
of cardiovascular disease use antibody titers as surrogate markers.
Several additional large ongoing studies (WIZARD, MARBLE, ACES, STAMINA,
CROAATS) may be able to provide more definitive answers to the question
of the relationship between Chlamydia pneumoniae and cardiovascular
disease.130 The WIZARD trial (Weekly Intervention with Zithromax
Against Atherosclerotic-Related Disorders) has enrolled 3,500 subjects
with a history of prior myocardial infarction to receive azithromycin
weekly for 2.5 years. The ongoing ACES trial (Azithromycin Coronary Events
Study) has enrolled 4,000 subjects with coronary artery disease to be
treated for a one year with azithromycin followed by four years of observation.
In the various macrolide intervention studies to date, no dose-response
(effect) relationships have been established for antibiotics employed
in the trials with wide ranges in both the individual doses and length
of therapy (a few days to three months). Also, no information has been
provided to determine if the antibiotic actually reaches the target organism
and, if so, whether it inhibits its replication. C. pneumoniae
can exist in a metabolically active form (reticulate body), outside the
mammalian cell as the elementary body, or in a metabolically inactive
form (persistent body) that is unresponsive to antibiotic therapy.131
If C. pneumoniae is dormant in the atheroma or arterial intima,
then antibiotic therapy will be ineffective.
Oral Microbial Associations with Cardiovascular Disease
Several reviews are available on the putative association of periodontal
microorganisms with cardiovascular disease and other systemic diseases.132-137
The potential role of these microorganisms in the cascade of acute or
chronic inflammatory responses in arteries is similar to that seen with
C. pneumoniae, H. pylori and cytomegalovirus.138,139
The number of clinical studies relating periodontal disease to cardiovascular
disease or acute coronary events are understandably relatively few140-154
in comparison to those investigating C. pneumoniae, H. pylori,
and cytomegalovirus. In general, odds ratios of 1.5 to 3.0 have been described
for an association between periodontal disease and cardiovascular disease.155
These odds ratios are too low to exclude the possibility of significant
bias due to unappreciated confounding variables.155,156 Furthermore,
all published studies to date describe a statistically significant relationship
between periodontal disease and cardiovascular disease. With such a wealth
of confounding variables and the relatively low odds ratios, one might
anticipate future studies that encounter nonsignificant relationships
between periodontal disease and cardiovascular disease.
The clinical studies suffer from several significant difficulties other
than the general problem with confounding variables. No clinical studies
have controlled for the other putative microbial pathogens in cardiovascular
disease (particularly C.a pneumoniae); and the reverse is true
for the studies on C. pneumoniae, H. pylori, and cytomegalovirus.
None have controlled for periodontal disease. Many of the periodontal
studies have been performed in subject populations where cardiovascular
risk factors can be extremely skewed (VA hospitals, homogenous populations
in Finland) and where the influence of heavy alcohol intake may be endemic.
Generally, the studies do not address a central issue: Do people with
significant periodontal disease neglect not only their oral cavity but
also their health in general so that a single element (periodontal disease)
of the general health pattern cannot be readily dissected into a separate
component?
The antibiotics employed in recent interventional studies would also affect
periodontal microbiota. Considering the poor performance of antibiotics
to date, it would appear that more-comprehensive periodontal therapy may
be necessary or that significant caution is indicated about the strength
of the periodontal disease-cardiovascular disease relationship.
The notion of viridans group streptococci, particularly Streptococcus
sanguis, being a causative agent in cardiovascular disease (most
notably in thrombogenesis157-159) suffers from a serious dichotomy.
Viridans streptococci are predominant in the healthy periodontium; and
if they are a significant risk for thrombogenesis and acute coronary events,
then it should follow that periodontally healthy individuals would be
at great risk for acute myocardial infarction, stroke, and unstable angina.
It appears that to induce cardiovascular disease and coagulation disorders
in rabbits with viridans streptococci, doses in the magnitude of 9, 14
and 40 billion colony forming units are required, which then reach concentrations
of 160 million CFU/ml in rabbit blood, which is equivalent to 8 million
CFU/ml in human blood (250 mls in rabbits and 5,000 mls in humans for
total blood volume). In comparison, a dental treatment procedure typically
induces as little as 1-10 CFU/ml in blood, which are usually rapidly cleared,
while a seeding endocarditis-infected cardiac valve produces 10-100 CFU
/ml.160 Also, cardiovascular coagulation disorders are not
specifically caused by viridans group streptococci but can be associated
with gram-positive/gram-negative bacteria and viruses.161
In summary, retrospective and case-control studies have provided data
on the proposed association between periodontal disease and cardiovascular
disease.162 There are only limited prospective data and no
interventional studies to establish possible cause and effect. The present
studies are best described as hypothesis-generating and not hypothesis-proving.163
Possibly the best summation of the evidence to date for an infectious
etiology of cardiovascular disease has been given by Epstein and Zhu163:
"In the end, the hope of achieving definitive conclusions about the intriguing
infection-atherosclerosis hypothesis is probably an elusive goal given
the complexity of the disease, the multitude of pathogens that may contribute
to the disease, and the complexity of host-pathogen interactions. Perhaps
a more realistic goal we might hope to eventually achieve is to agree
simply that there exists a high probability of causality. However, even
this modest conclusion can only be accepted if additional studies on pathogen-induced
disease-related mechanisms, multiple prospective seroepidemiological studies
of different populations, additional investigations using animal models
of disease, and human studies demonstrating that pathogen-targeted therapy
reduces disease incidence or manifestations, convey reasonably consistent
evidence linking infection to atherogenesis."
Periodontal Disease and Preterm Birth
Periodontal disease has also been proposed in the causation of preterm
(low birth weight) infants (born before 37 weeks gestation). The initial
case-control study utilized 124 pregnant or postpartum volunteers who
were examined for periodontal clinical attachment loss by periodontal
residency students.164 The results indicated a very significant
association between preterm birth and clinical attachment loss.
The study did not provide pertinent information about:
* Standardization of probing techniques of the examiners;
* The method of selection of the "volunteers" (potential selection bias);
* The time of clinical attachment loss in relation to the pregnancy (before
or during); and
* The periodontal microbiologic profile of the subjects (no cultures were
taken). The article does not elaborate on the appropriateness of extrapolating
beyond the data that 18.2 percent of the 250,000 low-birth-weight infants
in the United States could now be attributed to periodontal infection
even while the authors were warning that: "The limited scope of this case-control
study does not enable broad generalization regarding the potential health
care impact of these findings" and " caution must be exercised in interpreting
the application of the current data."164
A second case-control study on low-birth-weight infants determined
the presence of four periodontal microbial pathogens, the gingival crevicular
fluid levels of a prostaglandin and an interleukin, clinical attachment
losses, bleeding on probing, and probing depths.165 The results
indicated that periodontal disease activity was slightly worse in women
delivering low-birth-weight infants but did not answer the question of
whether increased periodontal disease was due to lack of personal attention
to oral hygiene or other factors that might influence both low birth weight
and periodontal disease development.
Data suggests that maternal infection (particularly bacterial vaginosis)
accounts for 80 percent of preterm births and is associated with membrane
rupture.166 However, most antibiotic trials do not demonstrate
a protective effect for preterm birth;167 and antibiotics are
not recommended routinely to prolong pregnancy.168 If used,
antibiotics should be directed toward preventing group B streptococcal
sepsis168 with the realization that antibiotic selection of
resistant bacteria may complicate the treatment of neonatal sepsis should
it occur.169
It has been calculated that a definitive study to determine if chronic
maternal periodontal disease is associated with preterm low-birth-weight
infants will require 800 mothers for sufficient power to detect an association
with an odds ratio of 3.0 at 5 percent significance level.170
Until data from such studies become available, any proposed association
between periodontal disease and preterm low birth weight should be viewed
as a hypothesis yet to be tested.
Medicolegal Aspects of Oral Microorganism and Systemic Disease
The resurgence of the focal infection theory of disease has been greeted
with enthusiasm.171,172 The potential link between oral microorganisms
and systemic disease is seductive in its simplicity and possibly far-reaching
in its consequences. Seemingly unappreciated is its potential medicolegal
difficulties for health care providers, i.e., that the systemic disease
could be blamed on dental treatment-induced bacteremias as easily as patient-induced
bacteremias. As discussed in a companion paper173 in this issue,
the focal infection theory of disease is still in the infancy of scientific
testing.
For dental health professionals who would wish to employ the limited database
to imply to patients that causality exits between oral microorganisms
and systemic disease and that expensive dental treatment is in order to
prevent such systemic disease, it should be realized that it is impossible
to determine between the systemic dissemination of oral microorganisms
from normal daily bodily functions and from dental treatment procedures.
Dentistry may then again face from a new direction the dilemma so often
seen in the past with the causation of bacterial endocarditis -- that
any dental procedure done within six to nine months of the systemic infection
may incriminate the dentist. Now that it is firmly established that dental
treatment procedures are a low risk for endocarditis,173 the
notion of focal infection may put dental practitioners at renewed risk
for malpractice litigation.
"Experts" will likely be available to testify that a given dental treatment
or treatment plan was "below the standard of care" and therefore directly
responsible for the deceased patient’s myocardial infarction. Conversely,
if it is ultimately proven that periodontal disease is merely one of many
risk factors for cardiovascular disease, all differing in importance for
each person, then the patient may become indignant that great expense
was incurred for dental treatment that had little effect on his or her
general health.
Conclusions
It is apparent that the relationship between microorganisms and cardiovascular
disease or low-birth-weight premature births remains investigational.
The trend with C. pneumoniae, H. pylori, and cytomegalovirus
appears to be headed toward a weak or no association with somewhat stronger
evidence for C. pneumoniae. Cytomegalovirus may be associated with
coronary artery restenosis. The intervention trials with macrolide antibiotics
against C. pneumoniae have to date been disappointing, and the
final results of several large intervention trials are several years away.
The research on a potential relationship between periodontal disease and
cardiovascular disease or preterm births is in its infancy with many questions
yet unanswered and no interventional trials yet performed. Until adequate
scientific data exist and are verified through independent investigators,
substantial caution should be exercised before assigning or implying causality
between periodontal disease and cardiovascular disease or preterm birth.
The use of the limited evidence garnered to date regarding oral microorganisms
and systemic disease to influence dental patients toward dental treatment
or to criticize another dentist’s efforts is fraught with scientific and
medicolegal difficulties.
Authors
Thomas J. Pallasch, DDS, MS, is a professor of pharmacology and periodontology
at the University of Southern California School of Dentistry.
Jørgen Slots, DDS, PhD, is a professor and chairperson of periodontology
and Associate Dean for Research at USC School of Dentistry.
References
1. Mallory GA, White PO, Salcedo-Salgar J, The spread of healing of myocardial
infarction: A study of the pathologic anatomy in 72 patients. Am Heart
J 18:647-71, 1939.
2. Mehta JL, Saldeen TGP, Rand K, Interactive role of infection, inflammation
and traditional risk factors in atherosclerosis and coronary artery disease.
J Am College Cardiol 31(6):1217-25, 1998.
3. Fabricant CG, Fabricant J, et al, Virus-induced atherosclerosis. J
Exp Med 148(1):335-340, 1978.
4. Danesh J, Collins R, Peto R, Chronic infections and coronary heart
disease: Is there a link? Lancet 350(9075):430-6, 1997.
5. Ross R, The pathogenesis of atherosclerosis: Perspective for the 1990s.
Nature 362(6423):801-9, 1993.
6. Ridker PM, Inflammation, infection and cardiovascular risk: How good
is the clinical evidence? Circulation 97(17):1671-4, 1998.
7. Ridker PM, Are associations between infection and coronary disease
causal or due to confounding? Am J Med 106(3):376-7, 1999.
8. Hoeg JM, Evaluating coronary heart disease risk: Tiles in the mosaic.
J Am Med Assoc 277(17):1387-90, 1997.
9. Ridker PM, Evaluating novel cardiovascular risk factors: Can we better
predict heart attacks? Ann Int Med 130(11):933-7, 1999.
10. Muller JE, Circadian variation and triggering of acute coronary events.
Am Heart J 137(4, Part 2)S:S1-8, 1999.
11. Roivainen M, Alfthan G, et al, Enterovirus infections as a possible
risk factor for myocardial infarction. Circulation 98(23):2534-7,
1998.
12. de Valk B, Marx JJM, Iron, atherosclerosis, and ischemic heart disease.
Arch Int Med 159(14):1542-8, 1999.
13. Salomaa V, Matei C, et al, Soluble thrombomodulin as a predictor of
incident coronary heart disease and symptomless carotid artery atherosclerosis
in the Atherosclerosis Risk in Communities (ARIC) Study: A case-cohort
study. Lancet 353:1729-34, 1999.
14. Kelley RA, Balligand J-L, Smith TW, Nitric oxide and cardiac function.
Circulation Res 79(3):363-80, 1996.
15. Napoli C, Glass CK, et al, Influence of maternal hypercholesterolaemia
during pregnancy on progression of early atherosclerotic lesions in childhood:
Fate of Early Lesions in Children (FELIC) Study. Lancet 354(9186):1234-41,
1999.
16. Wick G, Xu Q, Atherosclerosis -- An autoimmune disease. Exp Gerontol
34(4):559-66, 1999.
17. Dalager-Pedersen S, Pedersen EM, et al, Coronary artery disease: Plaque
vulnerability, disruption, and thrombosis. In Fuster V, ed, The Vulnerable
Atherosclerotic Plaque: Understanding, Identification, and Modification.
Futura Publishing Co, Armonk, NY, 1999.
18. Peyser PA, Genetic epidemiology of coronary artery disease. Epidemiol
Rev 19(1):80-90, 1997.
19. Hamsten A, Molecular genetics as the route to understanding, prevention,
and treatment. Lancet 348(S1):s17-19, 1996.
20. Pearson TA, Alcohol and heart disease. Circulation 94(11):3023-5,
1996.
21. Chiappelli F, Kung M, et al, Alcohol modulation of human normal T-cell
activation, maturation and migration. Alcohol Exp Clin Res 19(3):539-44,
1995.
22. Cook RT, Alcohol abuse, alcoholism, and damage to the immune system
-- A review. Alcohol Clin Exp Res 22(9):1927-42, 1998.
23. Hillbom M, Kaste M, Alcohol abuse and brain infarction. Ann Med
22(5):347-52, 1990.
24. Thomas AP, Rozanski DJ, et al, Effects of ethanol on the contractile
function of the heart: A review. Alcohol Clin Exp Res 18(1):121-31,
1994.
25. Moushmoush B, Abi-Mansour P, Alcohol and the heart: The long-term
effects of alcohol on the cardiovascular system. Arch Int Med 151(1):36-42,
1991.
26. Hart CL, Smith GD, et al, Alcohol consumption and mortality from all
causes, coronary heart disease, and stroke: Results from a prospective
cohort study of Scottish men with 21 years of follow up. Br Med J
318(7200):1725-9, 1999.
27. McCully KS, Vascular pathology of homocysteine: Implications for the
pathogenesis of atherosclerosis.. Amer J Pathol 56(1):111-28, 1969.
28. McCully KS, Homocysteine, folate, vitamin B6, and cardiovascular
disease. J Am Med Assoc 279(5):392-3, 1998.
29. Welch GN, Loscalzo J, Homocysteine and atherothrombosis. New Eng
J Med 338(15):1042-50, 1998.
30. Bostom AG, Selhub J, Homocysteine and arteriosclerosis: Subclinical
and clinical disease associations. Circulation 99(18):2361-3, 1999.
31. Wald NJ, Watt HC, et al, Homocysteine and ischemic heart disease:
Results of a prospective study with implications regarding prevention.
Arch Int Med 158(8):862-7, 1998.
32. Rimm EB, Willett WC, et al, Folate and vitamin B from diet and supplements
in relation to risk of coronary heart disease among women. J Am Med
Assoc 279(5):359-64, 1998.
33. Harjai KJ, Potential new cardiovascular risk factors: Left ventricular
hypertrophy, homocysteine, lipoprotein(a), triglycerides, oxidative stress,
and fibrinogen. Ann Int Med 131(5):376-86, 1999.
34. Graham IM, Daly LE, et al, Plasma homocysteine as a risk factor for
vascular disease: The European Concerted Action Project. J Am Med Assoc
277(22):1775-81, 1997.
35. Nygard O, Nordrehaug JE, et al, Plasma homocysteine levels and mortality
in patients with coronary artery disease. New Eng J Med 337(4):230-6,
1997.
36. Kittner SJ, Giles WH, et al, Homocyst(e)ine and risk of cerebral infarction
in a biracial population: The Stroke Prevention in Young Women Study.
Stroke 30(8):1554-60, 1999.
37. Stampfer MJ, Malinow HR, et al, Prospective study of plasma homocyst(e)ine
and risk of myocardial infarction in US physicians. J Am Med Assoc
268(7):877-81, 1992.
38. Hankey GJ, Eikelboom JW, Homocysteine and vascular disease. Lancet
354(9176):407-13, 1999.
39. Bots ML, Launer LJ, et al, Homocysteine and short-term risk of myocardial
infarction and stroke in the elderly: The Rotterdam Study. Arch Int
Med 159(1):38-43, 1999.
40. Ridker PM, Manson JE, et al, Homocysteine and risk of cardiovascular
disease among postmenopausal women. J Am Med Assoc 281(19):1817-21,
1999.
41. Danesh J, Lexington S, Plasma homocysteine and coronary heart disease:
Systematic review of published epidemiologic studies. J Cardiovasc
Risk 5(4):229-32, 1998.
42. Malinow MR, Bostom AG, Krauss RM, Homocyst(e)ine, diet, and cardiovascular
diseases: A Statement for Healthcare Professionals from the Nutrition
Committee, American Heart Association. Circulation 99(1):178-182,
1999.
43. Eikelboom JW, Lonn E, et al, Homocysteine and cardiovascular disease:
A critical review of the epidemiologic evidence. Ann Int Med 131(5):363-75,
1999.
44. Ray JG, Meta-analysis of hyperhomocysteinemia as a risk factor for
venous thromboembolic disease. Arch Int Med 158(19):2101-6, 1998.
45. Boushy CJ, Beresford SA, et al, A quantitative assessment of plasma
homocysteine as a risk factor for vascular disease: Probable benefits
of increasing folic acid intakes. J Am Med Assoc 274(13):1049-57.
46. Kort WJ, The effect of chronic stress on the immune response. Adv
Neuroimmunol 4(1):1-11, 1994.
47. Herbert TB, Stress and immunity in humans: A meta-analytic review.
Psychosomatic Med 55(4):364-79, 1993.
48. Kusnecov AW, Rabin BS, Stressor-induced alterations of immune function:
Mechanisms and issues. Int Arch Allergy Immunol 105(2):107-21,
1994.
49. Cohen F, Kearney KA, et al, Differential immune system changes with
acute and persistent stress for optimists vs pessimists. Brain Behav
Immunity 13(2):155-74, 1999.
50. De Gucht V, Fischler B, Demanet C, Immune dysfunction associated with
chronic professional stress in nurses. Psychiat Res 85(1):105-11,
1999.
51. Rozlog LA, Kiecolt-Glaser JK, et al, Stress and immunity: Implications
for viral diseases and wound healing. J Periodontol 70(7):786-92,
1999.
52. Logan HL, Lutgendorf S, et al, Immune, stress, and mood markers related
to recurrent oral herpes outbreaks. Oral Surg Oral Med Oral Path
86(1):48-54, 1998.
53. Genco RJ, Ho AW, et al, Relationship of stress, distress, and inadequate
coping behavior to periodontal disease. J Periodontol 70(7):711-23,
1999.
54. Allison TG, Identification and treatment of psychosocial risk factors
for coronary artery disease. Mayo Clin Proc 71(8):817-9, 1996.
55. Rozanski A, Blumenthal JA, Kaplan J, Impact of psychological factors
on the pathogenesis of cardiovascular disease and implications for therapy.
Circulation 99(16):2192-217, 1999.
56. Hemingway H, Marmot M, Psychosocial factors in the aetiology and prognosis
of coronary heart disease: Systematic review of prospective cohort studies.
Br Med J 318(7196):1460-7, 1999.
57. McEwen BS, Protective and damaging effects of stress mediators. New
Eng J Med 338(3):171-9, 1998.
58. Gullette ECD, Blumenthal JA, et al, Effect of mental stress on myocardial
ischemia during daily life. J Am Med Assoc 277(19):1521-6, 1997.
59. Miller TQ, Smith TW, et al, A meta-analytic review of research on
hostility and physical health. Psychol Bull 119(2):322-48, 1996.
60. Dembroski TM, MacDougall JM, et al, Components of type A hostility
and anger in relationship to angiographic findings. Psychosomat Med
47(3):219-33, 1985.
61. Friedman M, Thoreson CE, et al, Alteration of type A behavior and
its effect on cardiac recurrences in post myocardial infarction patients:
Summary results of the Recurrent Coronary Prevention Project. Am Heart
J 112(4):653-65, 1986.
62. Nair GV, Gurbel PA, et al, Depression, coronary events, platelet inhibition,
and serotonin reuptake inhibitors. Amer J Cardiol 84(3):321-3,
1999.
63. Musselman DL, Evans DL, Nemeroff CB, The relationship of depression
to cardiovascular disease: Epidemiology, biology, and treatment. Arch
Gen Psychiat 55(7):580-92, 1998.
64. Barefoot JC, Helms MJ, et al, Depression and long-term mortality risk
in patients with coronary artery disease. Am J Cardiol 78(6):613-17,
1996.
65. Gonzalez MA, Artalejo FR, Calero JDR, Relationship between socioeconomic
status and ischemic heart disease in cohort and case-control studies:1960-1993.
Int J Epidemiol 27(3):350-8, 1998.
66. Kawachi I, Marmot MG, Commentary: What can we learn from studies of
occupational class and cardiovascular disease? Am J Epidemiol 148(2):160-3,
1998.
67. Iribarren C, Luepker RV, et al, Twelve-year trends in cardiovascular
disease risk factors in the Minnesota Heart Survey. Arch Int Med
157(8):873-81, 1997.
68. Glass TA, Mendes de Leon C, et al, Population based study of social
and productive activities as predictors of survival among elderly Americans.
Br Med J 319(7208):478-83, 1999.
69. Marmot MG, Smith GD, et al, Health inequalities among British civil
servants: The Whitehall II Study. Lancet 337(8754):1387-93, 1991.
70. Zhou YF, Leon MB, et al, Association between prior cytomegalovirus
infection and the risk of restenosis after coronary atherectomy. New
Engl J Med 335(9):624-30, 1995.
71. Pandey JP, LeRoy EC, Human cytomegalovirus and the vasculopathies
of autoimmune diseases (especially scleroderma), allograft rejection,
and coronary restenosis. Arth Rheum 41(1):10-15, 1998.
72. Blum A, Giladi M, et al, High anti-cytomegalovirus (CMV) IgG antibody
titer is associated with coronary artery disease and may predict post-coronary
balloon angioplasty restenosis. Am J Cardiol 81(7):866-8, 1998.
73. Bertrand ME, Bauters C, Cytomegalovirus infection and coronary restenosis.
Circulation 99(10):1278-9, 1999.
74. Pouri S, State OI, et al, CMV infection is associated with transplant
renal artery stenosis. Quart J Med 91(3):185-9, 1998.
75. Adler SP, Hur JK, et al, Prior infection with cytomegalovirus is not
a major risk factor for angiographically demonstrated coronary artery
atherosclerosis. J Infect Dis 177(1):209-12, 1998.
76. Matthews-Greer JM, Eggerstedt JM, et al, Investigation of the prevalence
of cardiovascular-associated cytomegalovirus among patients with coronary
artery disease at Louisiana State University Medical Center at Shreveport.
J Infect Dis 178(6):1860-1, 1998.
77. Ridker PM, Hennekens CH, et al, Baseline IgG antibody titers to Chlamydia
pneumoniae, Helicobacter pylori, herpes simplex virus and cytomegalovirus
and the risk for cardiovascular disease in women. Ann Int Med 131(8):573-7,
1999.
78. Ridker PM, Hennekens CH, et al, Prospective study of herpes simplex
virus, cytomegalovirus and the risk of future myocardial infarction and
stroke. Circulation 98:2796-9, 1998.
79. Nicholson AC, Hajjar PP, Herpesviruses in atherosclerosis and thrombosis:
Etiologic agents or ubiquitous bystanders? Arteriosclerosis Thromb
Vasc Biol 18:339-48, 1998.
80. Nieto FJ, Adam E, et al, Coronary heart disease/atherosclerosis/myocardial
infarction: Cohort study of cytomegalovirus infection as a risk factor
for carotid intimal-medial thickening, a measure of subclinical atherosclerosis.
Circulation 94(5):922-7, 1996.
81. Pasceri V, Cammarota G, et al. Association of virulent Helicobacter
pylori strains with ischemic heart disease. Circulation 97:1675-9,
1998.
82. Markus HS, Mendall MA, Helicobacter pylori infection: A risk
factor for ischemic cerebrovascular disease and carotid atheroma. J
Neurol Neurosurg Psychiat 64(1):104-7, 1998.
83. de Luis DA, Lahera M, et al, Association of Helicobacter pylori
infection with cardiovascular and cerebrovascular disease in diabetic
patients. Diabetes Care 21(7):1129-32, 1998.
84. Ossei-Gerning N, Moayyedi P, et al, Helicobacter pylori infection
is related to atheroma in patients undergoing coronary angioplasty. Cardiovasc
Res 35:120-4, 1997.
85. Lip CY, Wise R, Beevers G, Association of Helicobacter pylori
infection with coronary heart disease. Br Med J 312(7025):250-1,
1996.
86. Folsom AR, Nieto FJ, et al, Helicobacter pylori seropositivity
and coronary heart disease incidence. Circulation 98:845-50, 1998.
87. Parent EF, Maconi G, et al, Helicobacter pylori infection and
coagulation in healthy people. Br Med J 314(7090):1318-9, 1997.
88. Strandberg TE, Tilvis RS, et al, Prospective study of Helicobacter
pylori seropositivity and cardiovascular diseases in a general elderly
population. Br Med J 314(7090):1317-8. 1997.
89. Strachan DP, Mendall MA, et al, Relation of Helicobacter pylori
infection to 13-year mortality and incident ischemic heart disease
in the Caerphilly Prospective Heart Disease Study. Circulation
98(13):1286-90, 1998.
90. Danesh J, Peto R, Risk factors for coronary heart disease and infection
with Helicobacter pylori: Meta-analysis of 18 studies. Br Med
J 316(7138):1130-32, 1998.
91. Regnstrom J, Jovinge S, et al, Helicobacter pylori and seropositivity
is not associated with inflammatory parameters, lipid concentrations and
degree of coronary artery disease. J Int Med 243:109-113, 1998.
92. Wald NJ, Law MR, et al, Helicobacter pylori infection and mortality
from ischemic heart disease: Negative result from a large, prospective
study. Br Med J 315(7117):1199-1201, 1997.
93. Grayston JT, Campbell LA, Editorial response: The role of Chlamydia
pneumoniae in atherosclerosis. Clin Infect Dis 28:993-4, 1999.
94. Taylor-Robinson D, Thomas BJ, Chlamydia pneumoniae in arteries:
The facts, their interpretation and future studies. J Clin Pathol
51(11):793-7, 1998.
95. Kuo C-C, Campbell LA, Is infection with Chlamydia pneumoniae
a causative agent in atherosclerosis? Molec Med Today 4(10):426-430,
1998.
96. Fong IW, Chiu B, et al, De novo induction of atherosclerosis by Chlamydia
pneumoniae in a rabbit model. Infect Immun 67(11):6048-55,
1999.
97. Muhlestein JB, Anderson JL, et al, Infection with Chlamydia pneumoniae
accelerates the development of atherosclerosis and treatment with azithromycin
prevents it in a rabbit model. Circulation 97:633-36, 1998.
98. Laitinen K, Laurila A, et al, Chlamydia pneumoniae infection
induces inflammatory changes in the aortas of rabbits. Infect Immun
65(11):4832-5, 1997.
99. Moazed TC, Kuo CC, et al, Experimental rabbit models of Chlamydia
pneumoniae infection. Am J Pathol 148:667-76, 1996.
100. Kontula K, Vuorio A, et al, Association of seropositivity for Chlamydia
pneumoniae and coronary artery disease in hetereozygous familial
hypercholesterolemia. Lancet 354:46-7, 1999.
101. Strachan DP, Carrington D, et al, Relation of Chlamydia pneumoniae
serology to mortality and incidence of ischemic heart disease over 13
years in Caerphilly prospective heart disease study. Br Med J 318(7190):1035-9,
1999.
102. Bartels C, Maass M, et al, Detection of Chlamydia pneumoniae
but not cytomegalovirus in occluded saphenous vein coronary artery bypass
grafts. Circulation 99:879-82, 1999.
103. Thom DH, Grayston JT, et al, Association of prior infection with
Chlamydia pneumoniae and angiographically demonstrated coronary
artery disease. J Am Med Assoc 268(1):68-72, 1992.
104. Saikku P, Leinonen M, et al, Chronic Chlamydia pneumoniae
infection as a risk factor for coronary heart disease in the Helsinki
Heart Study. Ann Int Med 116(4):273-8, 1992.
105. Saikku P, Leinonen M, et al, Serological evidence of an association
of a novel Chlamydia, TWAR, with chronic coronary heart disease
and acute myocardial infarction. Lancet 2:983-5, 1988.
106. Melnick S, Shahar E, et al, Past infection by Chlamydia pneumoniae
strain TWAR and asymptomatic carotid atherosclerosis. Am J Med 95(5):499-504,
1993.
107. Patel P, Mendall MA, et al, Association of Helicobacter pylori
and Chlamydia pneumoniae infections with coronary heart disease
and cardiovascular risk factors. Br Med J 311(7007):711-4, 1995.
108. Wimmer MLJ, Sandman-Strupp R. et al, Association of chlamydial infections
with cerebrovascular disease. Stroke 27:2207-10, 1996.
109. Naidu BR, Ngeow YF, et al, Evidence of Chlamydia pneumoniae
infection obtained by the polymerase chain reaction (PCR) in patients
with acute myocardial infarction and coronary heart disease. J Infect
35:199-203, 1997.
110. Ossewaarde JM, Feskens EMJ, et al, Chlamydia pneumoniae is
a risk factor for coronary artery disease in symptom free elderly men,
but Helicobacter pylori and cytomegalovirus are not. Epidemiol
Infect 1230:93-9, 1998.
111. Mazzoli S, Tofani N, et al, Chlamydia pneumoniae antibody
response in patients with acute myocardial infarction and their follow-up.
Am Heart J 135(1):15-20, 1998.
112. High KP, Atherosclerosis and infection due to Chlamydia pneumoniae
or cytomegalovirus: Weighing the evidence. Clin Infect Dis 28:746-9,
1999.
113. Wong Y-K, Thomas M, et al, The prevalence of Chlamydia pneumoniae
in atherosclerotic and nonatherosclereotic blood vessels of patients attending
for redo and first time coronary artery bypass graft surgery. J Am
Col Cardiol 33(1):152-6, 1999.
114. Nieto FJ, Folsom AR, et al, Chlamydia pneumoniae infection
and incident coronary heart disease. The Atherosclerosis Risk in Communities
Study. Am J Epidemiol 150(2):149-56, 1999.
115. Jantos CA, Nesseler A, et al, Low prevalence of Chlamydia pneumoniae
in atherectomy specimens from patients with coronary artery disease. Clin
Infect Dis 28:988-92, 1999.
116. Ridker PM, Kundsin RB, et al, Prospective study of Chlamydia pneumoniae
IgG seropositivity and risks of future myocardial infarction. Circulation
99:1161-4, 1999.
117. Tiran A, Tio Ra, et al, Coronary angioplasty induces rise in Chlamydia
pneumoniae-specific antibodies. J Clin Microbiol 37(4):1013-7,
1999.
118. Danesh J, Wong Y, et al, Chronic infections with Helicobacter
pylori, Chlamydia pneumoniae, or cytomegalovirus: Population-based
study of coronary heart disease. Heart 81(3):245-7, 1999.
119. Wong Y-K, Gallagher PJ, Ward ME, Chlamydia pneumoniae and
atherosclerosis. Heart 81(3):232-8, 1999.
120. Weiss SM, Roblin PM, et al, Failure to detect Chlamydia pneumoniae
in coronary atheromas of patients undergoing atherectomy. J Infect
Dis 173(4):957-62, 1996.
121. Carlsson J, Miketic S, et al, Previous cytomegalovirus or Chlamydia
pneumoniae infections and risk of restenosis after percutaneous
transluminal coronary angioplasty. Lancet 350(9086):1225, 1997.
122. Paterson DL, Hall J, et al, Failure to detect Chlamydia pneumoniae
in atherosclerotic plaque of Australian patients. Pathol 30:169-72,
1998.
123. Andreasen JJ, Farholt S, Jensen JS, Failure to detect Chlamydia
pneumoniae in calcific and degenerative arteriosclerotic aortic valves
excised during open heart surgery. APMIS 106:717-20, 1998.
124. Fang JC, Kinlay S, et al, Chlamydia pneumoniae infection is
frequent but not associated with coronary atherosclerosis in cardiac transplant
recipients. Am J Cardiol 82:1479-83, 1998.
125. Gurfinkel E, Bozovich G, et al, Randomized trial of roxithromycin
in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet 350(9075):404-7,
1997.
126. Gupta S, Leatham EW, et al, Elevated Chlamydia pneumoniae
antibodies, cardiovascular events, and azithromycin in male survivors
of myocardial infarction. Circulation 96:404-7, 1997.
127. Sinisalo J, Mattila K, et al, The effect of prolonged doxycycline
therapy on Chlamydia pneumoniae serological markers, coronary heart
disease risk factors and forearm local nitric oxide production. J Antimicrob
Chemother 41:85-92, 1998.
128. Jackson LA, Stewart DK, et al, Safety and effect on anti-Chlamydial
pneumoniae antibody titres of a 1 month course of daily azithromycin
in adults with coronary artery disease. J Antimicrob Chemother
44:411-4, 1999.
129. Anderson JL, Muhlestein JB, et al, Randomized secondary prevention
trial of azithromycin in patients with coronary artery disease and serological
evidence for Chlamydia pneumoniae infection: The azithromycin in
coronary artery disease: Elimination of myocardial infarction with Chlamydia
(ACADEMIC) study. Circulation 99(12):1540-7, 1999.
130. Gupta S, Chronic infection in the aetiology of atherosclerosis --
Focus on Chlamydia pneumoniae. Atherosclerosis 143:1-6,
1999.
131. Muhlestein JA, Bacterial infections and atherosclerosis. J Invest
Med 46(8):396-402, 1998.
132. Beck JD, Offenbacher S, Oral health and systemic disease: Periodontitis
and cardiovascular disease. J Dent Ed 62(10):859-70, 1998.
133. Meyer DH, Fives-Taylor PM, Oral pathogens: From dental plaque to
cardiac disease. Curr Opinion Microbiol 1(1):88-95, 1998.
134. Mealey BL, Influence of periodontal infections on systemic health.
Periodontol 2000 21:197-209, 1999.
135. Klokkevold PR, Periodontal medicine: Assessment of risk factors for
disease. J Cal Dent Assoc 27(2):135-142, 1999.
136. Joshipura KJ, Douglas CW, Willett WC, Possible explanations for the
tooth loss and cardiovascular disease relationship. Ann Periodontol
3(1):175-83, 1998.
137. Seymour RA, Steele JG, Is there a link between periodontal disease
and coronary heart disease? Br Med J 184(1):33-8, 1998.
138. Page RC, The pathobiology of periodontal disease may affect systemic
diseases: Inversion of a paradigm. Ann Periodontol 3(1):108-20,
1998.
139. Kinane DF, Periodontal diseases’ contributions to cardiovascular
disease: An overview of potential mechanisms. Ann Periodontol 3(1):142-50,
1998.
140. Mackenzie RS, Millard HD, Interrelated effects of diabetes, arteriosclerosis
and calculus on alveolar bone loss. J Am Dent Assoc 66(2):191-8,
1963.
141. Sryjanen J, Peltola J, et al, Dental infections in association with
cerebral infarction in young and middle-aged men. J Int Med 225:179-84,
1989.
142. Mattila KJ, Nieminen M, et al, Association between dental health
and myocardial infarction. Br Med J 298(6676):779-81, 1989.
143. Paunio K, Impivaara O, Tiekjo J, Missing teeth and ischemic heart
disease in men aged 45-64 years. Europ Heart J 14(SK):54-6, 1993.
144. Kweider M, Lowe GDO, et al, Dental disease, fibrinogen and white
cell count, links with myocardial infarction? Scot Med J 38:73-4,
1993.
145. Mattila K, Valle MS, et al, Dental infections and coronary atherosclerosis.
Atherosclerosis 103:205-11, 1993.
146. De Stefano F, Anda RF, et al, Dental disease and risk of coronary
heart disease and mortality. Br Med J 306(6879):688-91, 1993.
147. Mattila KJ, Valtonen VV, et al, Role of infection as a risk factor
for atherosclerosis, myocardial infarction, and stroke. Clin Infect
Dis 26(3):719-34, 1998.
148. Beck JD, Garcia RG, et al, Periodontal disease and cardiovascular
disease. J Periodontol 67(5):1123-37, 1996.
149. Joshipura KJ, Rimm EB, et al, Poor oral health and coronary heart
disease. J Dent Res 75(9):1631-6, 1996.
150. Mattila KJ, Valtonen VV, et al, Dental infection and the risk of
new coronary events: Prospective study of patients with documented coronary
artery disease. Clin Infect Dis 20:588-92, 1995.
151. Genco R, Chadda S, et al, Periodontal disease is a predictor of cardiovascular
disease in a Native American population. J Dent Res 76(Special
Issue):408, 1997. Abstr # 3158.
152. Garcia RI, Krall EA, Vokonas PS, Periodontal disease and mortality
from all causes in the VA dental longitudinal study. Ann Periodontol
3(1):339-49, 1998.
153. Loesch WJ, Schork A, et al, The relationship between dental disease
and cerebral vascular accident in elderly United States veterans. Ann
Periodontol 3(1):161-74, 1998.
154. Loesche WJ, Schork A, et al, Assessing the relationship between dental
disease and coronary heart disease in elderly U.S. veterans. J Am Dent
Assoc 129(3):301-11, 1998.
155. Beck JD, Offenbacher S, et al, Periodontitis: A risk factor for coronary
heart disease? Ann Periodontol 3(1):127-41, 1998.
156. Friedman GD, Klatsky AL, Is alcohol good for your health? New
Eng J Med 329(25):1882-3, 1993.
157. Herzberg MC, Meyer MW, Effect of oral flora on platelets: Possible
consequences in cardiovascular disease. J Periodontol 67(10) 1138-42,
1996.
158. Meyer MW, Gong K, Herzberg MC, Streptococcus sanguis-induced
platelet clotting in rabbits and hemodynamic and cardiopulmonary consequences.
Infect Immun 66(12):5906-14, 1998.
159. Herzberg MC, Meyer MW, Dental plaque, platelets, and cardiovascular
diseases. Ann Periodontol 3(1):151-60, 1998.
160. Pallasch TJ, Slots J, Antibiotic prophylaxis and the medically compromised
patient. Periodontol 2000 10 :107-38, 1996.
161. Van Gorp ECM, Sukarti C, et al, Review: Infectious diseases and coagulation
disorders. J Infect Dis 180(1):176-86, 1999.
162. Slots J, Casual or causal relationship between periodontal infection
and non-oral disease? J Dent Res 77(10):1764-5, 1998.
163. Epstein SE, Zhu J, Lack of association of infectious agents with
risk of future myocardial infarction and stroke: Definitive evidence disproving
the infection/coronary artery disease hypothesis? Circulation 100:1366-8,
1999.
164. Offenbacher S, Katz V, et al, Periodontal infection as a possible
risk factor for preterm low birth weight. J Periodontol 67(10)S:1103-13,
1996
165. Offenbacher S, Jared HL, et al, Potential pathogenic mechanisms of
periodontitis-associated pregnancy complications. Ann Periodontol 3(1):233-49,
1998.
166. Goldenberg RL, Rouse DJ, Prevention of premature birth. New Eng
J Med 339(5):313-20, 1998.
167. Gibbs RS, Romero R, et al, A review of premature birth and subclinical
infection. Am J Obstet Gynecol 166(5):1515-28, 1992.
168. Gibbs RS, Eschenbach DA, Use of antibiotics to prevent preterm birth.
Am J Obstet Gynecol 177(2):375-80, 1997.
169. Mercer BM, Carr TL, et al, Antibiotic use in pregnancy and drug-resistant
infant sepsis. Am J Obstet Gynecol 181(4):816-21, 1999.
170. Davenport ES, Williams CECS, et al, The East London Study of maternal
chronic periodontal disease and preterm low birth weight infants: Study
design and prevalence data. Ann Periodontol 3(1):213-21, 1998.
171. Position Paper: Periodontal disease as a potential risk factor for
systemic diseases. J Periodontol 69(7):841-50, 1998.
172. Meskin LH, Focal infection: Back with a bang! J Am Dent Assoc
129(1):8, 12-14, 16, 1998.
173. Pallasch TJ, Wahl MJ, The focal infection theory: Appraisal and reappraisal.
J Cal Dent Assoc 28(3):XXXX.
To request a printed copy of this article, please contact/Thomas J. Pallasch,
DDS, MS, USC School of Dentistry, University Park MC-0641, Los Angeles,
CA 90089-0641.
Table 1. Proposed, potential, or documented risk factors or markers for
cardiovascular disease.8,9
Nonmodifiable Risk Factors
Age
Sex
Genetics
Modifiable Risk Factors
Cigarette smoking
Obesity
Diabetes mellitus
LDL-cholesterol
Psychosocial factors
Air pollution
Physical activity
Hypertension
Total cholesterol
HDL-cholesterol
Alcohol intake
Diet
Proposed or Potential Markers or Risk Factors
Homocysteinemia
Fibrinogen
PAI-1
Cholesterol transfer protein
Apolipoprotein A-1
TPA/PAI-1 complex
Interleukins
Platelet size
Factors VIIc and VIIa
VLDL receptor
Plasminogen activator inhibitor 1
Plasmin -- alpha 2-antiplasmin complex
Vascular/cellular fibrinogen adhesion molecules
Hyperinsulinemia
Plasminogen
TPA
Factors V, VII, VIII
Hepatic lipase
Clot lysis time
Serum amyloid A
Platelet volume
Fibrin degredation products
Lipoprotein oxidation
Lecithin-cholesterol acyl transferase
Thrombin-antithrombin III complex
Apolipoprotein E isoforms
Lipoprotein (a)
Thrombin
Von Willebrand antigen
LDL receptor
C reactive protein
Triglycerides
Platelet aggregation
Prothrombin fragments
Protein C resistance
