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Letter to Journal of the American College of Cardiology; sent on December 21, 2009

Inflammation in atherosclerosis. Roles of microbes and the lipoprotein immune system  

Ravnskov U, McCully Kilmer S.

In their review concerning the role of inflammation in atherosclerosis¹  Libby et al did not discuss the anti-infectious role of lipoproteins.  Although extensively documented for many years, the function of the lipoproteins in binding and inactivating bacteria, viruses, protozoans and their toxins and participating in innate immunity is not widely appreciated.² 

The involvement of micro-organisms in some way in creation of atherosclerotic inflammation seems obvious.  For instance, remnants of more than 50 different bacteria and viruses have been identified in atherosclerotic plaques, but not a single one in healthy arteries.^3,4   This role of microorganisms has been discussed in more than a hundred reviews, but most authors regard their presence as a secondary phenomenon. Obviously they have been unaware of the anti-infectious role of the lipoproteins. A number of observations indicate that micro-organisms may have a more central role in atherogenesis and that lipoproteins may be protective.  For instance, low total- and LDL-cholesterol are associated with increased morbidity and mortality from infectious diseases.⁵   Cardiovascular mortality increases during influenza epidemics.⁶   The coronary arteries in children who have died from an infectious disease are narrowed,⁷ and the intimal-media thckness is thickened in children who survive,⁸ and eradication of periodontal infections improved angiographic changes more than ever obtained in a cholesterol lowering trial.⁹   Unique lipids from a common periodontal infection have been found to enhance autoimmunity through interaction with the toll-like receptor,¹⁰   and autoimmunity is  a prominent feature of the atherosclerotic process.

If inflammation itself is the cause of atherosclerosis, treatment with anti-inflammatory drugs should be beneficial, but, as the authors mention, this has not been the case.  On the contrary, such treatment increases cardiovascular mortality.¹¹   

Altogether these observations and experiments suggest that microbes participate in the primary process of atherogenesis.  We have recently presented a hypothesis ²  explaining many observations that are difficult to explain by the current view.  In summary, we propose that aggregates, formed by complexes of lipoproteins, micro-organisms, anti-oxLDL antibodies and homocysteinylated LDL, obstruct arterial vasa vasorum  because of the high extracapillary pressure and because of endothelial dysfunction within these vessels.¹²  This obstruction may cause local ischemia, hypoxia and infection of the arterial wall, resulting in the formation of a microabscess, the vulnerable plaque.  This hypothesis explains why the temperature of the vulnerable plaque is higher than surrounding arterial wall,¹³  why bacteriemia may be present in cardiogenic shock,¹⁴  and why the symptoms and laboratory findings in acute myocardial infarction are similar to those seen in most infectious diseases. 

References

1.   Libby P, Ridker PM, Hansson GK.  Inflammation in atherosclerosis.  From pathophysiology to practice.  J Am Coll Cardiol 2009;54:2129-2138.

2.   Ravnskov U, McCully KS.  Review and hypothesis:  Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies.  Ann Clin Lab Sci 2009;39:3-16.

3.   Ott SJ, El Mokhtari NE, Musfeldt M et al.  Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.  Circulation 2006;113:292-937.

4.   Shi Y, Tokunaga O.  Chlamydia pneumoniae  and multiple infections in the aorta contribute to atherosclerosis.  Pathol Int 2002;52:755-763.

5.   Ravnskov U.  High cholesterol may protect against infections and atherosclerosis.  Q J Med 2003;96:927-934.

6.   Smeeth L, Thomas SL, Hall AJ et al.  Risk of myocardial infarction and stroke after acute infection or vaccination.  N Engl J Med 2004;351:2611-2618.

7.   Pesonen E. Infection and intimal thickening: evidence from coronary arteries in children. Eur Heart J 1994;15 Suppl C:57-61.

8.   Liuba P, Persson J, Luoma J, Yla-Herttuala S, Pesonen E. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media. Eur Heart J 2003;24:515-21.

9.   Nichols FC, Housley WJ, O’Conor CA et al.  Unique lipids from a common human bacterium represent a new class of toll-like receptor 2 ligands capable of enhancing autoimmunity.  Am J Pathol 2009;175:2430-2438.

10.  Piconi S, Trabattoni D, Luragli C et al.  Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness.  FASEB J 2009;23:1196-1204.

11.  Johnsen SP, Larsson H, Tarone RE et al.  Risk of myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDS:  a population-based case-control study.  Arch Intern Med 2005;165:978-984.

12.  McCully KS.  Chemical Pathology of Homocysteine IV.  Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation.  Ann Clin Lab Sci 2009;39:219-232.

13.  Madjid M, Naghavi M, Malik BA et al.  Thermal detection of vulnerable plaque.  Am J Cardiol 2002;90:36L-39L.

14.  Kohsaka S, Menon V, Lowe AM et al.  Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock.  Arch Intern Med 2005;165:1643-1650.

The above letter was rejected. Here is the answer from the editor:

5 January 20101

Dear Dr. Ravnskov:

The editors have discussed your Letter to the Editor at their weekly meeting. Regrettably, the consensus is that it does not achieve a priority high enough to warrant publication. Because of space limitations, we are able to publish only a few letters addressing controversial topics.

Thank you for your interest in the journal.

Sincerely,

Anthony N. DeMaria, M.D.
Editor-in-Chief
Journal of the American College of Cardiology

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