The complexity of the inflammatory response continues to puzzle the medical world. Arterial plaque in the coronary vessels predisposes to heart disease, but why does it develop? Is it due to high cholesterol levels (seeing as cholesterol is present in them) or primarily due to intimal inflammation? Non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation but increase cardiac risk. Treating an “inflammatory” disease such as rheumatoid arthritis (RA) with a disease-modifying drug – and RA has a high cardiac risk – appears to diminish that risk, but using an NSAID increases it. If inflammation is a single entity these facts conflict.
The answer to what causes the increased cardiovascular (CV) risk from NSAIDs appears to lie in the cyclooxygenase pathway and I am grateful to Fred Kummerow of THINCS for my Damascene moment. The enzymes COX-1 and COX-2 (primarily COX-2) are principal agents in the genesis of prostacyclin, which is a vasodilator, and of platelet aggregation inhibition. Thus suppressing them leads to a reduction of prostacyclin and an increase in platelet aggregation, and suppression of COX-2 will produce a greater effect than suppression of COX-1. Arterial plaque is irregular and platelets will stick to it – which will trigger aggregation. So although the COX enzyme by-products are inflammatory, inhibiting them will increase the risk of platelets sticking to plaque, and the reduction of prostacyclin will mean the vessels, plaque or no, will be narrower than they would otherwise.
That explains not only the increased risk, but also the reason why COX-2 inhibitors have a worse effect on cardiovascular disease than COX-1 inhibitors. Of course, research into RA has shown that the inflammatory cascade is unbelievably complex, with the interaction of T- and B-lymphocytes, tumour necrosis factor, interleukins (and we number them in dozens), complement, autoantibodies, immunoglobulins and other immune mediators. Of interest is that nitric oxide, which plays a part in vascular integrity, may also be important in RA.
There does not appear to be any evidence supporting a hypothesis that cholesterol plays any part in altering COX enzyme levels. There is, however, evidence that exposure to trans fats does. These are found in partially hydrogenated oils, and ingestion of these produces substantial reductions in prostacyclin release. The belief that trans fats were no different from other fats has been upset both by this finding and by the chemical analysis of them showing that there are subtle differences in molecular structure with the production of isomers that do not occur in nature. These are recognised as foreign by the body and provoke an inflammatory reaction. There is also good evidence to show that the increase in CV mortality during the last years of the 20th century has a direct relationship with trans fat intake, and likewise the removal of trans fat from consumables has been mirrored by a reduction in mortality.
Plaque generation per se is not related to lipid levels either. The fact that cholesterol is found in plaques is simply an expression of what happens when intimal damage is followed by an attempted repair process. Reducing cholesterol will not reduce the risk of plaque formation, as it is not the cause of the initial intimal damage. Neither will reduction alter vascular calibre or interfere with surface platelet aggregation on an arterial plaque. There is now too much evidence and too many “Black Swans” that contradict a direct link between cholesterol and vascular disease for this link to be acceptable. There is plenty of evidence to explain both the causes and mechanisms of vascular disease, but I hope to see an understanding that statins are, population-wise, a costly mistake. There is good reason to suppose that aspirin, which is a potent inhibitor of platelet aggregation, is of more use in CV protection that cholesterol-lowering drugs. I have a personal reason to suppose this is true. I have suffered from migraine from the age of 12 (when it might reasonably be supposed that my blood vessels were clear of cholesterol-laden plaque despite my high blood levels). Migraine is a condition in which an aura, is followed by a typical headache. It was hypothesised many years ago in an article in “The Lancet” that the cause of the aura was ischaemia as a result of localised platelet aggregation, which with the subsequent release of prostacyclin as a response resulted in vasodilatation which caused the headache. I began taking aspirin and my attacks, which were severe and occurring monthly or more often, stopped completely. After five or six years of symptom-free life I stopped the aspirin without ill effect, but after a decade the attacks re-started, interestingly with the same intensity of aura but a much reduced subsequent headache. I began taking aspirin once more and my auras vanished again. While I accept that I am treating a condition on the basis of a hypothesis I have been unable to find another sensible explanation of the aspirin effect.
 Kummerow FA. In Fat and Cholesterol Don’t Cause Heart Attacks and Statins are Not the Solution (Ed Paul J Rosch) 2016: Chapter 4, pp65-71.