Links between Infectious Diseases and Cardiovascular Disease: A
Growing Body of Evidence
Kim Curry; Lauren Lawson
Abstract
It is widely acknowledged that a systemic inflammatory process is involved in
atherogenesis leading to subsequent cardiovascular disease (CVD). Several
types of microbes have been implicated as possible causative agents in
acquired CVD. This article reviews current and emerging links established
between specific microorganisms and cardiac vessel and other vascular
damage. Studies are reviewed that have investigated a possible role for
antibiotics in treatment and prevention; other potential primary and secondary
preventive measures are then explored. Nurse practitioners have an important
role in recognizing and effectively managing the multiple complex processes
involved in the development of CVD.
Introduction
Cardiovascular disease (CVD) is the leading cause of death in industrialized
nations. In the United States and other developed countries, risk factors such as
smoking, high blood pressure, and elevated serum cholesterol levels are widely
known and accepted as having a causative role in arteriosclerosis and the
development of CVD. Much time and effort has been spent by both researchers
and clinicians in investigating and attempting to modify these known risk factors.
However, there is a growing body of evidence that other modifiable risk factors
may also be at work.
It is now widely acknowledged that a systemic inflammatory process is involved
in atherogenesis leading to subsequent cardiac vessel disease and other
vascular damage. Inflammatory markers such as C-reactive protein (CRP),
fibrinogen, tumor necrosis factor alpha (TNF-α), and others can be used to
measure systemic inflammation and risk of CVD. Patients with autoimmune
diseases characterized by chronic systemic inflammation, such as rheumatoid
arthritis (RA) and systemic lupus erythematosis (SLE), demonstrate a
significantly increased risk of CVD.
Several types of microbes are now also being implicated as possible causative
agents in acquired CVD. A few bacterial agents have been the topic of research
for several years. Organisms such as the spirochetes Borrelia burgdorferi
(Lyme disease) and Treponema pallidum (syphilis), and flagellated bacteria
such as the streptococci have well-recognized atherosclerotic potential. Now,
additional studies are beginning to shed light on the possible role played by
other bacterial and viral illnesses and the later development of atherosclerosis
or other cardiovascular damage.
Periodontal Disease
The association between oral health and cardiovascular health has been the
topic of clinical studies for over 20 years. Early studies indicated that patients
with poor dental health were 1.3 to 1.7 times more likely to experience
myocardial infarction than patients with good dental health.[1] Various
mechanisms have been explored in an attempt to explain the relationship
between dental and cardiovascular health.
Periodontal disease involves inflammation and infection of the supportive
structures for the teeth, including soft tissue and bone. Periodontal disease
becomes established when plaque accumulation on the teeth causes an
inflammatory response, resulting in detachment from the gums.[2] The majority
of adults in the United States have a mild form of periodontal disease, but 20%
to 30% of adults have more severe forms.[3]
A number of studies have been conducted to elucidate the relationship between
dental and cardiovascular health. The majority of studies have demonstrated
that periodontal disease is a predictor of subsequent CVD.[4–6] However, not all
studies have concluded that periodontal disease is a significant predictor.
The main mechanism postulated in the subsequent development of CVD is that
the chronic local infection characteristic of periodontitis increases the levels of
systemic inflammatory chemicals. The increased presence of these
inflammatory mediators promotes atherosclerosis.[7] Several periodontal
pathogens have been found in atherosclerotic plaques in carotid arteries. [8]
There are several confounding variables involved in establishing a firm link to
periodontal disease. First, a number of different organisms have been
implicated in periodontitis. These include
Bacteroides forsythus,
Porphyromonas gingivalis, and treponema denticola, among others. Second,
multiple measures and definitions of periodontitis have been employed in the
clinical studies completed to date. Third, there are several common elements
involved in both periodontal disease and atherosclerosis. For example, both are
more likely to occur in the elderly and in those with risk factors such as smoking,
diabetes elevated cholesterol, and hypertension.[9]
In conclusion, periodontal disease may be an independent or contributing risk
factor for CVD. Not all studies have found a causal link, and further studies are
needed to determine the extent of the relationship and whether outcomes are
improved through preventive dental care. In the meantime, this area of health
care is yet another in which inappropriate use of antibiotics is to be avoided.
Patients with oral disease or decay should be referred for definitive dental care,
with systemic medications used in conjunction with corrective treatment.
Chlamydia Pneumoniae
Chlamydia pneumoniae (C. pneumoniae) is a very common bacterial respiratory
pathogen. About 50% of adults in the United States have been infected with C.
pneumoniae by age 20. The germ causes 10% of community-acquired
pneumonia cases in adults. Reinfection is common, as the organism is
ubiquitous.[10] C. pneumoniae belongs to the same genus of organisms as
Chlamydia trachomatas. C. pneumoniae is the most recently identified member
of the genus, having first been cultured in 1965.[11]
A number of studies have been conducted to determine the specific association
between C. pneumoniae and the development of atherosclerotic plaque. This
association was first suggested in 1988, when it was discovered that patients
with CVD or acute myocardial infarction (AMI) were more likely to have
antibodies to C. pneumoniae in their blood.[12] While a causative role has not
been firmly established, C. pneumoniae has been detected in atherosclerotic
plaques.[13]
Arcari et al[14] studied the link between C. pneumoniae seropositivity and AMI in
males aged 30 to 50. The authors found a significantly higher risk of AMI in
patients who had high titers to C. pneumoniae immunoglobulin A (IgA) within
the previous one to 5-year period. This risk persisted after adjusting for other
cardiovascular risk factors.
The complex pathophysiology involved in the development of vascular damage
complicates the ability of researchers to link CVD to any particular cause or
agent. Smoking, an independent CVD risk factor, has also been shown to be an
independent risk factor for C. pneumoniae seropositivity. It has also been
suggested that an exacerbation of C. pneumoniae infection through smoking
cigarettes may increase the potential for a systemic infection and therefore
increase the chance for development of atherogenesis.[15]
Studies are underway to determine whether macrolide antibiotic therapy has a
preventive role in reducing the subsequent development of CVD. However,
controversy still exists concerning the actual cause-effect relationship, as it has
been suggested that CVD may actually increase the susceptibility of the host to
develop a chronic microbial infection, making the presence of C. pneumoniae
an outcome, rather than a source, of CVD.[16]
Helicobacter Pylori
H. pylori is a known causal agent of several gastrointestinal diseases and has
also been implicated in ischemic heart disease (IHD). Several different
mechanisms are proposed for the role of H. pylori in IHD. There is speculation
that H. pylori may act directly on atherosclerotic plaques, because studies have
found its DNA in arterial plaque.[17] Another thought is that H. pylori infection
results in indirect effects related to chronic inflammation, whereby long-term
inflammation raises cytokine levels in the bloodstream.[18] Thus, H. pylori might
serve as a trigger by starting the inflammatory cascade.
Further studies suggest that H. pylori may induce platelet aggregation, and
thereby play a role in the acute phase of IHD.[19] A recent meta-analysis
indicates that infection with certain more virulent strains of H. pylori may
provoke an intense immune response and precipitate coronary events. [20]
Virus-related CVD
Several viruses have been shown to affect the heart. These include the
adenoviruses, Coxsackie viruses, hepatitis A virus, and herpes simplex viruses.
Adenoviruses include multiple serotypes. These viruses are a major cause of
acute respiratory infections, conjunctivitis, and other illnesses. The
adenoviruses can cause myocarditis, but do not appear to have a role in
CVD.[21]
Coxsackie viruses are enteroviruses most commonly associated with hand, foot,
and mouth disease. The Coxsackie B viruses are known to cause myocarditis,
but the relationship to CVD is unconfirmed. A herpes virus known as Marek's
disease virus (MDV) causes a variety of illnesses including lymphoma in its
natural host, the chicken. MDV has been recognized for some time as a causal
agent for atherosclerosis in chickens, much like that seen in humans.[22]
In a study of 391 patients referred for chest pain or other evidence of
myocardial ischemia, Zhu et al[23] found that 52% of the patients had IgG
antibodies for hepatitis A virus (HAV). The actual prevalence of coronary artery
disease was 74% in the patients who were HAV seropositive and 52% in the
patients who were HAV seronegative (P < 0.0001). The association remained
significant after controlling for other cardiovascular risk factors, including other
infectious agents. The authors concluded that HAV might contribute to CAD by
eliciting a chronic inflammatory response. While this study established an
association, it did not establish causality.
Herpes simplex virus 1 (HSV1) and herpes simplex virus 2 (HSV2) have been
found in human atherosclerotic plaque.[24, 25] Cytomegalovirus (CMV), a member
of the herpes virus family, can infect individuals but does not cause signs and
symptoms. Studies have shown both positive[26–28] and negative[29] associations
of CMV with coronary artery disease.
In summary, several organisms have a potential causative role in the
subsequent development of CVD (Table 1). The role of viruses and H. pylori in
CVD is not conclusive. Whether viruses and H. pylori act directly in coronary
vessels or indirectly, with infection stimulating an immune response, is not clear.
Future studies are needed to provide definitive data elucidating the precise role
and mechanisms that viruses and H. pylori play. However, there is a strong
association between C. pneumoniae and CVD.
Table 1. Micro-Organisms With a Potentially Causative Role in the
Development of CVD
Bacteria
Viruses
Chlamydia pneumoniae Cytomegalovirus
Helicobacter pylori
Herpes simplex virus
Borrelia burgdorferi
Hepatitis A virus
Multiple Organisms
Periodontitis
Treponema pallidum
The Role of Antibiotics in Prevention and Treatment
Because substantial data exist associating C. pneumoniae with cardiovascular
disease, studies over the past decade have begun to focus on the possible
benefits of antibiotics in treatment. A number of clinical trials have been done in
an attempt to determine whether antibiotics might play a role in the primary
prevention of cardiac events or in secondary prevention once a cardiac event
has occurred. The presence of C. pneumoniae in atheromatous plaques of
humans and coronary events in patients with elevated titers of antibodies to C.
pneumoniae have prompted researchers to question whether antibiotic therapy
aimed at C. pneumoniae could prevent or attenuate the risk of cardiac events.
Data from studies of the use of antibiotics for atherosclerotic disease in animal
models support this hypothesis.[30, 31] These studies showed that if antibiotic
therapy was given early after inoculation of animals with C. pneumoniae,
atherosclerosis could be prevented or its progression slowed; antibiotics given
later in the process had a little or no effect on progression.
The best treatment for eradicating C. pneumoniae is uncertain at this time.
Studies are needed to determine the level of drug needed to penetrate infected
tissue, because C. pneumoniae can be found inside fatty plaque within the
arteries. C. pneumoniae is sensitive to a number of antibiotics. Macrolides
(azithromycin, clarithromycin), tetracyclines (tetracycline, doxycycline, and
minocycline), fluoroquinolones (ofloxacin, levofloxacin, and gatifloxacin), and
anti-tuberculars (rifapentine and rifampin) are known to be effective against this
bacterium.[32] The antineoplastic antibiotics classified as ansamycins are also
highly effective.[33] The sulfonamides, penicillins, and cephalosporins are not
effective against C. pneumoniae.
The early studies in humans seemed to indicate that prophylactic antibiotics
might lead to reductions in secondary cardiovascular events in patients with
stable coronary heart disease and those with acute coronary syndrome (ACS).
The ROXIS (Roxithromycin in Ischemic Syndromes) trial was the first
randomized pilot study of an antibiotic to be done in patients with acute
coronary syndrome. Gurfinkel et al[34] randomized 202 patients with unstable
angina or non-Q wave MI to placebo or 150 mg oral roxithromycin twice daily for
30 days. They found a statistically significant difference between the placebo
and treatment group after short-term treatment.
Gupta et al[35] studied men post myocardial infarction and stratified them into 3
groups based on level of IgG antibodies to C. pneumoniae. Subjects received
either placebo or azithromycin 500 mg/day for 3 days or 2 courses of
azithromycin 3 months apart. Subjects in the placebo group who had the
highest antibody titers had an approximately 4-fold increased risk of developing
recurrent cardiac ischemia compared to subjects without elevated titers.
Subjects in the highest antibody titer group who were treated with azithromycin
did not have an elevated risk of developing recurrent ischemia. Subjects
receiving 1 and 2 courses of antibiotics had similar results.
Muhlestein et al[36] initiated a secondary prevention trial of azithromycin in
patients with coronary disease and serological evidence of C. pneumoniae. The
ACADEMIC (Azithromycin in Coronary Artery Disease: Elimination of
Myocardial Infection with Chlamydia) trial examined markers of inflammation
and cardiovascular events in 302 patients. Subjects were randomized to either
placebo for 3 months or a 3-month course of azithromycin (500 mg/day for 3
days and then weekly). They found no differences between groups for adverse
ischemic cardiac events, but the group receiving azithromycin had significantly
lower inflammation markers of interleukin-6 and C-reactive protein when
compared to the placebo group.
The findings of these 2 early studies led researchers to think that the newer
macrolides might have an effect on cardiac clinical outcomes or inflammatory
markers or possibly have an effect on both. The question that evolved from
these early studies was whether the drugs were effective because they
eradicated C. pneumoniae or if the beneficial outcomes were due to antiinflammatory properties, because macrolides have anti-inflammatory effects. It
was hypothesized that macrolides might subdue inflammation and stabilize
atheromatous plaque (preventing rupture and vessel occlusion), which could
partially explain some of the benefits in trials involving patients with acute
coronary syndrome.[37]
Noting that the studies focusing on secondary prevention of cardiac events
showed promise, researchers in the late 1990s began to address the question
of whether antibiotics could play a role in primary prevention of CVD. Two major
studies were conducted that involved large retrospective analyses to determine
whether exposure to antibiotics might alter the risk for developing acute MI.
Meier et al[38] examined the medical records of 3315 patients who had an acute
MI (first occurrence and no previously documented risk factors) and compared
them to records of 13,139 controls matched for age, sex, calendar year, and
physician practice group. Records were reviewed for documentation of
prescription of an antibiotic in the 3-year period preceding the acute MI and for
corresponding dates in control subjects. They found a statistically significant
difference in the proportion of controls and MI patients taking tetracyclines and
quinolones in the 3 years preceding their MI. No differences were seen among
groups taking macrolides, sulfonamides, penicillins, or cephalosporins when
compared to controls. Daily users of a regular dose of tetracycline, those taking
higher doses, those taking 1 or 2 prescriptions of a macrolide in the 3 years
prior to MI, and those with 3 or more prescriptions in the 3-year period also had
a lower risk of developing MI.
The second retrospective study examined 1796 cases of patients with MI (who
had previous risk factors for cardiac disease) and compared them with 4882
controls.[39] Researchers documented doxycycline, tetracycline, and
erythromycin prescriptions during the 5-year period pre-MI. Unlike the previous
study, they found no differences between groups in terms of the percentage
experiencing an acute MI. The problem with both the aforementioned studies is
that due to the retrospective designs employed, both the positive and negative
findings may have been the result of other variables or due to chance.
Large randomized clinical trials were needed to determine whether antibiotics
could play a role in secondary prevention of cardiovascular events in patients
with known CVD. The WIZARD (Weekly Intervention with Zithromax for
Atherosclerosis and its Related Disorders) trial enrolled 7724 stable subjects
with previous MI and who were seropositive for C. pneumonia.[40] Subjects were
randomized to placebo or 3 months treatment with azithromycin at 600
mg/week. Primary end points were a composite of death, MI, hospitalization for
unstable angina, or need for repeat revascularization at 3 years. There was only
a 7% nonsignificant reduction in the end point in the group receiving
azithromycin. Further analyses, however, showed a possible benefit during and
shortly after treatment, with a 33% reduction in death or MI at 6 months (P =
0.03). This finding led researchers to question whether a longer period of
antibiotics might prevent future coronary events.
Another trial, called STAMINA (South Thames Trial of Antibiotics in Myocardial
Infarction and Unstable Angina), randomized 325 subjects to a placebo group or
1 of 2 different treatment groups: azithromycin 500 mg/day plus omeprazole 20
mg and metronidazole 400 mg twice daily (for Helicobacter); or amoxicillin 500
mg twice daily plus omeprazole 20 mg and metronidazole 400 mg twice daily. [41]
Subjects were followed for 1 year. There were no significant differences among
groups for major cardiac events. Yet, when the researchers combined the 2
groups receiving antibiotics and compared them to the placebo group, there
were 36% fewer adverse cardiac events at 12 weeks (P = 0.02); the difference
continued at 1 year. Seropositivity to C. pneumoniae or H. pylori had no effect
on outcomes, so the question again arose as to whether the main factors
affecting outcomes were related to the anti-inflammatory properties of the drugs,
rather than their antimicrobial properties.
A large-scale well-designed trial, PROVE-IT (Pravastain or Atorvastatin
Evaluation and Infection Therapy), enrolled 4162 patients hospitalized with
acute coronary syndrome and high cholesterol levels.[42] In a double-blind,
randomized placebo-controlled design, patients received either 400 mg of
gatifloxacin daily for 2 weeks followed by a 10-day course of gatifloxacin every
month, or placebo. The mean duration of follow-up was 2 years. Long-term
treatment with this bactericidal antibiotic had no effect on reducing
cardiovascular events.
In a more recent large-scale trial called the CLARICOR study, patients with
stable coronary disease were randomized to a 2-week course of clarithromycin
500 mg daily or placebo.[43] There were no differences between groups for the
combined end point of cardiac mortality, MI, and unstable angina; however, the
group receiving clarithromycin had a significantly higher cardiovascular mortality
rate, a very unexpected finding.
In view of the conflicting results of antibiotic trials in patients with CVD, several
researchers have conducted meta-analyses in an effort to shed light on the
question of efficacy of antibiotics in preventing cardiac events. A meta-analysis
of studies that used antibiotics effective against C. pneumoniae was conducted
by Wells et al.[44] Only randomized controlled trials were included. Nine studies
with a total of 11,015 participants met the inclusion criteria. Four studies
reported a benefit from antibiotics, while 5 studies found no benefit from
antibiotics in the prevention of cardiovascular events in subjects with known
ischemic heart disease.
The most conclusive results are from a large meta-analysis of studies of
antibiotics in patients with coronary disease.[45] These authors searched
Medline and the Cochrane Central Register of Controlled Trials for studies that
were prospective, randomized, placebo-controlled trials of antibiotic therapy for
C. pneumoniae in patients with coronary artery disease. The 11 studies that met
pre-established criteria and were included in the review enrolled 19,217 patients
and reported all-cause mortality, myocardial infarction, or unstable angina. This
meta-analysis documented that the currently available evidence does not show
an overall benefit of antibiotics in reducing cardiovascular events or mortality.
Despite disappointing results to date, research continues on the topic of
antibiotic therapy for C. pneumoniae. A new class of antibiotics, ansamycins,
show promise for future studies. One of these ansamycins,
benzoxazinorifamycin (marketed as Rifalazil, currently not available in the
United States), is 10 to 1000 times more effective against C. pneumoniae than
azithromycin.[33] There is currently a multicenter, randomized, placebocontrolled study to determine the effects of weekly Rifalazil given over 12 weeks
to patients seropositive for C. pneumoniae.[46] Results are expected later this
year.
At this time, the available evidence does not support the use of antibiotics for
primary or secondary prevention of CVD. Nurse practitioners should continue to
work collaboratively with patients to implement interventions that target known
risks for CVD including controlling hypertension, treating dyslipidemias,
maintaining target blood glucose in diabetics, eliminating smoking, controlling
weight, and increasing physical activity.
Primary and Secondary Prevention
Multiple complex processes are involved in the development of CVD. Currently,
no specific guidelines exist for general preventive measures related to infectious
diseases as a specific causal factor. Indeed, some authors still debate the
sequence of events, and question whether chronic inflammation might
predispose some individuals to infection rather than vice versa. However,
several general mechanisms known to have a role in atherogenesis may
provide clues to the possibility of developing primary or secondary preventive
measures in the future (Table 2).
Table 2. Considerations for Primary and Secondary Prevention
Condition
Patients with chronic
conditions (SLE, RA)
Considerations For Prevention
inflammatory
Close monitoring of other risk factors,
control of inflammation associated with
chronic disease
Existing periodontal disease
Offer definitive dental care
Chlamydia pneumoniae infection
Early treatment with antibiotics
Control of risks associated with
exposure to numerous ubiquitous Support healthy immune system
infectious agents in environment
Patients with existing cardiovascular Patient education
risk factors
lifestyle modification
regarding
risk,
High risk for exposure to infectious
Offer immunization if available
diseases
Other infectious diseases
Early treatment to prevent chronic
colonization
It is known that systemic inflammation is a factor in the development of
atherosclerosis. In addition, patients with significant systemic autoimmune
diseases have a higher risk and prevalence of CVD. Observational research
has linked CVD with autoimmune diseases such as SLE and RA. Both CVD and
autoimmune diseases involve immune system activation and endothelial
dysfunction. HMG-CoA reductase inhibitors, also known as statins, are now
thought to be useful in modulating inflammatory pathways, as well as lowing
cholesterol levels.[47] Thus, statins have potential for use in the reduction of
chronic systemic inflammation.
Multiple oral pathogens are involved in the development of periodontal disease.
These pathogens have been shown in some studies to be linked to subsequent
development of CVD. The prevention of periodontal disease through regular
dental care is an important area for future research. However, many barriers to
the establishment of a dental home exist in the United States, including
statutory restrictions limiting provider availability, lack of a supply of pediatric
dentists to provide early dental care to children, and the unaffordability of dental
care related to the aforementioned statutory restrictions. However, inroads are
being made with such programs as the fluoride varnish program, which provides
reimbursement for ARNPs, PAs, and MDs in some states for performing this
type of primary dental care.
Many of the bacterial and viral microbes implicated in the development of CVD
are ubiquitous. Therefore, general measures to support a healthy immune
system seem prudent, and the ARNP plays a significant role in informing
patients and educating them about methods to prevent long-term sequelae of
basic lifestyle choices such as rest, nutrition, exercise, hygiene, prevention of
exposure to infectious organisms, and avoidance of tobacco use and excessive
alcohol use that may impede normal immune system function. Early treatment
of infectious diseases to avoid chronic colonization and thus inflammation
should also be emphasized.
Conclusions and Implications for Practitioners
While studies have documented a role of various infectious organisms in the
subsequent development of CVD for 2 decades, few steps have been taken to
address the role of prevention from these risk factors. This gap between
research and practice may be causing significant morbidity and mortality in the
United States and other developed countries. Providers should consider several
questions in attempting to bridge this gap.
One obvious question concerns oral health screening. Should we be screening
for periodontitis or other dental diseases in those with other risk factors for
CVD? At least one author, Lowe,[48] has recommended a Dental Health Score
be used. It seems reasonable for ARNPs to conduct a dental screen during
wellness visits and refer clients for decay and other abnormalities. Practitioners
can also advocate for greater availability of community dental services.
Another question concerns the role of antibiotic use. Antibiotic prophylaxis is
indicated for a subset of patients with valvular heart disease, such as those with
artificial heart valves. Should some type of antibiotic prophylaxis be
recommended in high-risk CVD patients, or at a minimum, those with a previous
CVD event? Currently, there is no consistent evidence supporting this, and
clinicians should keep in mind the risks of over-prescribing antibiotics.
A final consideration is the cost of implementing these or other preventive
measures. This cost must be measured against the direct costs of providing
tertiary care as well as pain and suffering for someone with a serious
cardiovascular event. At a minimum, primary care providers can start with
patient education to share these known links and make patients aware that
several self-care steps can be taken with regard to these additional measures to
avoid much more devastating health care problems in the future.
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