is a contribution from members of THINCS,
The International Network of Cholesterol Skeptics
to Journal of the American College of Cardiology; sent on December 21, 2009
in atherosclerosis. Roles of microbes and the lipoprotein immune system
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
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
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.
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
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
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.
Libby P, Ridker PM, Hansson GK.
Inflammation in atherosclerosis.
From pathophysiology to practice.
J Am Coll Cardiol 2009;54:2129-2138.
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.
SJ, El Mokhtari NE, Musfeldt M et al. Detection
of diverse bacterial signatures in atherosclerotic lesions of patients with
coronary heart disease. Circulation
Shi Y, Tokunaga O. Chlamydia pneumoniae and
multiple infections in the aorta contribute to atherosclerosis.
Pathol Int 2002;52:755-763.
U. High cholesterol may protect
against infections and atherosclerosis.
J Med 2003;96:927-934.
L, Thomas SL, Hall AJ et al. Risk
of myocardial infarction and stroke after acute infection or vaccination.
Engl J Med 2004;351:2611-2618.
Pesonen E. Infection and intimal thickening: evidence from coronary
arteries in children. Eur Heart J 1994;15 Suppl C:57-61.
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.
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.
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.
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.
McCully KS. Chemical
Pathology of Homocysteine IV. Excitotoxicity,
oxidative stress, endothelial dysfunction, and inflammation.
Ann Clin Lab Sci 2009;39:219-232.
Madjid M, Naghavi M, Malik BA et al.
Thermal detection of vulnerable plaque.
Am J Cardiol 2002;90:36L-39L.
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.
above letter was rejected. Here is the answer from the editor:
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.
Anthony N. DeMaria, M.D.
Journal of the American College of Cardiology
Other unpublished contributions