References

Introduction:

Cardiovascular disease (CVD) is the leading cause of death in developed countries.  The established risk factors associated with the disease are:

1) Lifestyle: smoking, diet, excessive alcohol consumption and physical inactivity.

2) Biochemical and physiological: elevated blood pressure and LDL cholesterol, hyperglycemia and diabetes, obesity

3) Personal: age, sex, family and personal history  (1). 

It has been noted, however that a fair proportion of people with CVD do not have the traditional risk factors. The search is on to find another factor (or factors) that would complete the etiological picture of cardiovascular disease.

One possibility currently being investigated is the association of infectious disease with CVD;  either as a risk factor itself or an intensifier of other risk factors  (2).  This is not a new idea.  Sir William Osler first proposed a causative role for infection in heart disease in 1908 (3).

Biochemical Basis:

The main pathological process underlying both cardiovascular and cerebrovascular diseases is atherosclerosis, or the accumulation of lipid-containing material within the blood vessels, causing arterial occlusion (2)
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Various mechanisms have been offered to support the idea that infection and the inflammatory process affects the arteries and leads to disease onset.  One scenario suggests that when bacteria attack the vessel wall the inflammatory response leads to an increase in lymphocytes and macrophages and in the production of cytokines and tissue growth factors. Tissue growth factors are within the clotting cascade.  Lipid metabolism is also regulated during this response; lipoproteins are scavengers of foreign materials such as bacterial endotoxins. Cytokines are a mediator in this response and they also can increase very low-density lipoprotein levels, another risk factor for CVD (4)

Pesonen et al. (5) found an association between thickening of the inner coat of blood vessels and infectious disease based on autopsied children. They concluded that infections in general were associated with this thickening and suggested this association may predispose coronary arteries to atherosclerosis.

Repeated fibroproliferative events lead to atherosclerosis (6) Response-to-injury theory states that various factors, such as infection, can cause these events and damage endothelial cells. 

Evidence:

The conditions or infectious agents most frequently studied include the Chamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus and periodontitis.   The focus of current research is on the association of C. pneumoniae and atherosclerosis. Evidence for a possible association comes from two types of studies: seroepidemiology and the demonstration of the organism within atherosclerotic tissue.

Saikku et al. (7) found that chronic Chlamydia infection was higher in patients with acute myocardial infarction and chronic coronary heart disease than in controls.  They concluded that chronic infections could be a factor in the pathogenicity of CVD.  Further work by these investigators (8)showed elevated titers against C. pneumoniae were associated with an increased risk of developing a cardiac event six months later, again suggesting a risk role for Chlamydia in the development of CVD. 

Grayston (9) reported 38 studies in seroepidemiology confirming the association between C. pneumoniae and atherosclerosis.  Several others did not.  Danesh (10) from his meta-analysis of prospective studies concluded no strong evidence to support an association between CHD and C. pneumoniae or any of the other infectious diseases investigated. (Combined RR of 1.22; 95% C.I. 0.96 – 1.54.)

Other evidence for an association comes from the finding of the organism in the cells of atherosclerotic lesions (11).  And in animal studies atherosclerotic-lesions have been found in the aorta of rabbits introduction of C. pneumoniae (12).  Grayston (9) reported 44 studies finding the presence of this organism, 3 did not.

The evidence for an association between CVD and C. pneumoniae is based primarily on studies of antibodies to  these organisms present in clinical manifestations of the disease.  Clinical and epidemiological studies, however, are ‘conflicting and difficult to interpret’ (1). 

Some problems noted by Grayston (9):  a high percentage of older adults with the antibodies and the sensitivity of microimmunofluorescence (MIF) as a serological test. He commented that although MIF  it is well-established as the most sensitive method to detect acute infection, there is little evidence that it can separate subjects with prior infection from those with chronic infection. 

Danesh (10) had this to say..  None of the available studies corrected for fluctuations in serum antibody levels over time. Reinfection with C. pneumoniae is common and he cautioned that random measurements errors can be substantial. He recommended serial measurements to correct for what he called  “regression dilution.” 

Leinonenn  and Saikku (13)  suggest that C. pneumoniae interacts with other risk factors of atherosclerosis.  They found that the risk of a cardiac event was increased 4.6-fold when markers for atherosclerosis (obesity, elevated systolic blood pressure and blood glucose and lowered HDL cholesterol) were combined with markers of chronic C. pneumoniae infection. 

So the picture is not complete.  The association between cardiovascular disease and infection is biologically plausible, there is some evidence to support an association, but it is inconclusive. 

There are two other possible pieces to the picture:  the so-called iron hypothesis and sex-specificity of infection and CVD.

Iron hypothesis:

The proposal  is that iron depletion protects against ischemic heart disease Experimental evidence  was cited (14, 15)  that iron overload enhances and iron depletion decreases formation of atherosclerotic plaque. 

 Various facts support this hypothesis.  It helps to explain the striking sex difference in heart disease. In premenopausal women, incidence of atherosclerosis and CVD is less than half that of age-matched men. 

Depletion of iron stores by regular menstrual blood loss may be a source of protection in premenopausal patients (16) Menstruating women maintain the negligible levels of stored iron found in both men and women prior to age 20.Men lacking the menstrual iron ‘leak’ undergo progressive accumulation of iron rising rapidly with age. At age 45 men have roughly 4 times more iron in storage than women.

One study  looked at the association between serum ferritin concentrations and the 5-year progress of carotid atherosclerosis.  The researchers claim their  present  ‘strong’ epidemiological evidence for a role of iron stores in early atherogenesis. They  further suggest that the promotion of lipid peroxidation is the underlying pathomechanism. Volunteer blood donation has also been to be associated with a significant decrease in atherosclerosis and vascular events (16).

The iron hypothesis may help explain the low heart disease rates in third world countries where  diets are high in fiber that retards iron absorption.  Parasites also cause blood loss from the gut and the bladder.  The  effect of aspirin on reducing disease rates may be due to  the gastrointestinal microbleeding caused by its daily use (15)

And iron is essential for the development of some microbiotic infections (17).  No information was found on whether or not C. pneumoniae is an iron-lover.

Gender specificity.

One curious anomaly persists.  Men are more prone to heart disease in early life than women.  Are men also more prone to infectious diseases than women?

O’Neill (18)  found more males seropositive (for C. pneumoniae)  than females  (72.9 vs. 67.0).  The  difference was not found to be statistically significant (chi 2 = 1.6, p. = 0.21). These authors commented that it is ‘intriguing to speculate’ that a gender difference in infection with  C. pneumoniae might contribute to the sex-specific difference in incidence of cardiovascular disease.  They concluded, however that further investigations are need to establish a higher prevalence of infection in males.

Almiral (19)  looked at the epidemiology of a community-acquired pneumonia.  The two most common pathogens are Streptococcus pneumoniae and Chlamydia pneumoniae. Their data show an increase in incidence rate with age and a higher incidence rate in males than females. (A graph was shown, but no data.)

In the original study which isolated C. pneumoniae in acute respiratory tract infections, Grayston et al.  (20)  found a higher frequency of antibody to the strain in males than females (42% vs. 35%).

The S.C. Budget and Control Board’s Office of Research Statistics (www.ors.state.sc.us) provided data on rates of patients discharged from short-term general hospitals by primary diagnosis category, age, rage and sex.  The pertinent diagnosis used was Infective and Parasitic Diseases.  The 1999 data for the State and Charleston County are seen in Figures 1-4.  Looking at the total males vs. total females the rates of infection are similar for both genders.  Rates for both increase remarkably with age.  However when viewed with race as a category, black males can be seen to have a considerably higher rate than the other three gender/race groups. (This last is part of another, but connected, question regarding cardiovascular disease, i.e., racial disparity.)

Future Research

As one researcher commented  there is  ‘accumulating’ evidence to suggest a causal relation between C. pneumoniae infection and atherosclerosis, but that it is not well established “ (2) Larger clinical trials and further animal models are needed to provide evidence for causality.

Danesh (10) called for investigations with larger samples sizes, and from socially homogenous populations. He also recommended serial measures to reduce random variation in measures.  Since any real association between infection and CHD are generally stronger with early-onset cases than at older ages, he recommended studying those cases.

Prospective studies are more reliable in this instance than retrospective due to:

1) CHD events recorded after baseline blood collection are less prone to selection biases since cases are compared with ‘internal controls’ with in the same contemporaneous cohort.

2) They limit influence of disease on the factors being investigated, especially important when studies diseases prone to reinfection or reaction as are C. pneumoniae. (10).

The larger prospective studies would be less prone to preferential reporting of more extreme associations thus avoiding pubication bias.

With regard to the iron hypothesis   proponent Sullivan (15) commentedthat after more than a decade of investigation and adversarial discussion,the hypothesis has not been invalidated .  Information from clinical trials are needed before recommendations can be made regarding lowering iron stores to decrease the risk of CVD and  which groups should be targeted for such therapy (16). 

And there still remains the question:  Is there a gender-specificity for some diseases?

Stay Tuned!

Figures 1 and 2: State of South Carolina 1999; Figures 3 and 4 Charleston County 1999 
 
 
 

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References:

1. Wood D. on behalf of the Joint European Societies Task Force,London, U.K. Established and emerging cardiovascular risk factors. Amer. Heart J. 2001;141(2): S49-S57.

2. Fong I. Emerging relations between infectious diseases and coronary artery disease and atherosclerosis. Can. Med. Assn. J. 2000; 163(1):49-56.

3. Osler, W. Diseases of the arteries. In: Osler W. ed. Modern medicine: its practice and theory. Philadelphia: and Febiger, 108; 429-47.  Cited in  Gupta S , Leatham EW. The relation between Chlamydia  pneumoniae and atherosclerosis (Editoria) Heart 1997: 23-24.

4. Grunfeld C, Fiegold KR. Regulation of lipid metabolism by cytokines during host defense. Nutrition 1996; 12(Suppl):S24-6.

5. Pesonen E, Paakkari H, Rapola J. Infection-associated intimal thickening in the coronary arteries of Children. Atherosclerosis 1999; 142(2):425-429.

6. Ross R and Glomset J. The pathogenesis of atherosclerosis. NEJM 1976; 295(7):369-377.

7. Saikku P, Leinonen M, Mattila K, Ekman, M-R, , et al. Serolgical evidence of an association of a novel Chlamydia TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet  1988, 983-985.

8. Saikku P, Leinonen M, Tenkanen L. et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart study.  Ann.Int. Med. 1992;116:273-278.

9. Grayston JT, Background and current knowledge of Chlamydia pneumoniae and atherosclerosis. J. Infect. Dis. 2000;181:S402-S-410.

10. Danesh J. Coronary heart disease, Helicobacter pylori, dental disease, Chlamydia pneumoniae and cytomegalovirus: Meta-analysis of prospective studies. AHL 1999; 138(5): S434-S437.

11. Grayston JT, Kuo CC, Couson AS, et al. Chlamydia pneumoniae in atherosclerosis of the carotid artery. Circulation 1995;92:3397-400.

12. Laitinen K, Laurila A, Pyhala L, et al.Chlamydia pneumoniae infection induces inflammatory changes in the aorta of rabbits. Infect. Immun. 1997;65:4832-5.

13. Leinonen M and Saikku P. Interaction of Chlamydia pneumoniae infection with other risk factors of atherosclerosis.  Am. Heart J. 1999; 138:S504-S506.

14. Sullivan JL. Iron and the sex difference in heart disease risk. The Lancet, June 13, 1981, 1293-94.

15. Sullivan JL,Iron therapy and cardiovascular disease. Kidney Int. 1999; 55: suppl. 69:S-135-S137.

16. Kiechl S, Willeit J, Eggner G,  et al. Body Iron Stores and the Risk of Carotid Atherosclerosis.  Circulation 1997; 96(10):3300-3307.

17. Mietzner TA, Morse SA. The role of iron-binding proteins in the survival of pathogenic bacteria. Ann. Rev. Nutr. 1994;14:471-93.

18. O’Neill C, Murray LJ, Ong  GML, et al. Epidemiology of Chlamydia pneumoniae infection in a randomly selected population in a developed country. Epidemio. Infect. 1999; 122:111-116.

19. Almirall J, Bolibar I, Vidal J et al. Epidemiology of community-acquired pneumoniae in adults: a population-based study. Eur. Respir. J. 2000; 15:757-763.

20. Grayston JT, Kuo C-C, Wang S-P et al.A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N. Eng. J. Med. 1986;315(3):161-168.