Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

The demonstration of increased cardiovascular disease (CVD) from anti
-inflammatory drugs, as reported by Trelle et al,1 is in obvious conflict
with the current hypothesis concerning the origin of CVD, which ascribes
the disease to inflammation induced by oxidized cholesterol. If
inflammation were the cause of CVD, drugs that ameliorate inflammation
should be protective. Since anti-inflammatory drugs actually increase
myocardial infarction, stroke and CVD mortality, decreased inflammation
produced by these drugs must enhance the pathogenic factors causing CVD.

Increasing evidence points to infection by micro-organisms as a key
etiological factor in the pathogenesis of CVD.2 Infectious diseases in
children narrow the coronary arteries and thicken the carotid intima-
media; CVD mortality increases during influenza epidemics; the degree of
atherosclerosis in those who die from an infectious disease is associated
with the length of the preceding infection; and a third of patients with
acute CVD have had an infectious disease immediately before onset.2
Fever, diaphoresis, leukocytosis and elevation of inflammatory markers in
the blood, including CRP, the classical symptoms of an infectious disease,
are common findings in myocardial infarction; and chronic elevation of CRP
in patients with atherosclerosis is also a risk factor for myocardial
infarction. An infectious pathogenesis of CVD also explains the presence
of Chlamydia pneumoniae remnants in the myocardium in acute myocardial
infarction. In addition, remnants of more than 50 different bacterial and
several virus species have been demonstrated within atherosclerotic
plaques, but not a single one in normal arterial tissue.2

How do micro-organisms invade the arterial wall and atherosclerotic
plaques during atherogenesis? A little known but well documented function
of lipoproteins is to bind and inactivate bacteria, viruses, and their
toxic products. Our hypothesis is that aggregates of lipoproteins, micro-
organisms, LDL thiolated by homocysteine, and anti-oxLDL antibodies
obstruct vasa vasorum, causing ischemia, hypoxia, and death of arterial
cells.2 The result is a micro-abscess of arterial wall, the vulnerable
plaque. Extensive pathological evidence supports adventitial vasa vasorum
as the initial site of arterial inflammation in atherogenesis.3,4

1. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B,
Villiger PM, Egger M, J?ni P. Cardiovascular safety of non-steroidal anti-
inflammatory drugs: network meta-analysis. BMJ doi: 10.1136/bmj.c7086.

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. Higuchi ML, Gutierrez PS, Bezerra HG, Palomino SA, Aiello VD,
Silvestre JML, Libby P, Ramires JAF. Comparison between Adventitial and
Intimal Inflammation of Ruptured and Nonruptured Atherosclerotic Plaques
in Human Coronary Arteries. Arq Bras Cardiol 2002;79:20-4.

4. Maiellaro K, Taylor WR. The role of the adventitia in vascular
inflammation. Cardiovasc Res 2007;75:640-8.