Why do some people survive long periods with their coronary arteries almost blocked while others succumb to infarction with a barely visible stenosis? Inflammatory changes around a dysfunctional endothelium are providing an increasingly convincing answer, raising the possibility that cardiovascular disease could soon be classed alongside asthma and arthritis as an inflammatory disorder. This, in turn, has led to intense research into possible non-lipid effects of the statin drugs. Jenny Bryan reports
Although it was Howard Florey of penicillin fame who, in the 1950s, first drew attention to the early appearance of monocytes in atheromatous lesions, it is the more recent arrival of the statins which has helped to focus attention on inflammatory changes in arterial walls.
When the results of the West of Scotland Coronary Prevention Study (WOSCOPS) were published, lipidologists questioned whether the 26 per cent fall in LDL-cholesterol could entirely account for the 31 per cent reduction in non-fatal infarction or death seen in the trial. And subsequent analysis did indeed show that, for the same reduction in LDL-cholesterol, pravastatin-treated patients were less likely to have a coronary event than those who achieved their cholesterol reduction by changing their diet. There seemed to be something special about using a statin.1
In investigating the "add-on" effects of statins, researchers have begun to expand on Florey's original observations and, at each international cardiology meeting, the picture becomes more complex.
At the European Atherosclerosis Society (EAS) meeting in Athens last year, Professor Peter Weissberg (British Heart Foundation professor of cardiovascular medicine, Addenbrooke's hospital, Cambridge) described the sequence of events which transforms a sick piece of endothelium into a heart attack waiting to happen.
First, oxidised lipids begin to accumulate in the arterial wall, just beneath the endothelium - the single layer of cells which lines the vessel and separates blood from tissues. No-one is quite sure whether the lipids trigger changes in the endothelium so they can get through the barrier or take advantage of sections that are already damaged.
Nor are lipids the only things that can trigger an inflammatory response. Chlamydia pneumoniae is the micro-organism most closely linked to arterial disease, though persistent infection with other bacteria and viruses has also been proposed as a significant cause of arterial inflammation.
Whatever the stimulus, endothelial cells respond by expressing adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which attract monocytes to the area. When lipids are the trigger for the inflammatory response, these monocytes migrate into the vessel wall and gradually develop into macrophages which ingest the oxidised lipids to form foam cells. These activated inflammatory cells produce chemokines and cytokines which attract more cells to the area, notably smooth muscle cells (SMCs).
Faced with a growing army of cells bulging with lipids, SMCs have developed a remarkable ability to change their appearance and function. They lose their contractile properties and instead take on a repair and remodelling role, producing a thick fibrous cap around the lipid core lying beneath the endothelium.
As long as this cap is fixed firmly in place, the lesion (plaque) remains stable and thrombosis is unlikely, even if there is significant narrowing of the blood vessel. But, as Professor Weissberg explained, the SMCs in the cap can become sickly, age prematurely and die, leaving the cap thin and vulnerable.
"When plaques rupture, there are very few smooth muscle cells in the lesion and a lot of inflammatory cells - something which makes the plaque unstable," he pointed out. What was needed, he said, was for the atherosclerotic balance to tip away from inflammatory activity and plaque instability and towards the repair and renewal mechanisms co-ordinated by SMCs.
Laboratory experiments have demonstrated that at least two statins, pravastatin and cerivastatin, reduce the proliferation of inflammatory cells, such as macrophages.2,3 But further research is needed to demonstrate the same anti-inflammatory activity in human blood vessels.
Plasma level of C-reactive protein (CRP) is proving a useful marker of inflammatory activity and a predictor of coronary events. Aspirin - the most famous anti-inflammatoryflammatory agent of them all - has been associated with significant reductions in infarction rate when administered to patients with the highest CRP levels, but these effects are hard to separate from the other vascular effects of the drug.4
Analysis of data from the Cholesterol and Recurrent Events (CARE) trial showed that subjects with the highest CRP levels were most likely to have recurrent coronary events —something which was attenuated with pravastatin but not with a placebo.5
In at least two trials, antibiotic treatment of arterial inflammation linked to C pneumoniae infection has been associated with reduced coronary events,6,7 and further studies are under way.
An anti-inflammatory approach to heart disease prevention is clearly promising. But what of the pathological processes going on above the endothelium? Would plaque rupture really matter without thrombus formation on the exposed lipid core?
The endothelium is a great deal more than a simple physical barrier. At the International Congress on Cardiovascular Pharmacotherapy, in Amsterdam last year, Professor Ton Rabelink (University hospital, Utrecht) described a wide range of substances released from the endothelium which dilate or constrict blood vessels, promote or inhibit growth and inflammation, and exert pro- or anti-thrombotic effects. Just as an imbalance between the inflammation and repair mechanisms beneath the endothelium can have far reaching consequences for atherosclerosis development, so can imbalances between substances released from the surface.
"Endothelial dysfunction may be one of the earliest manifestations of cardiovascular disease," he said.
Professor Rabelink described a series of studies with novel endothelin receptor (ET) antagonists which reduce the activity of endothelin, a peptide released from the endothelium in response to thrombin and other substances.
Most endothelin is secreted towards the subendothelial space where it acts on SMCs through type A (ETA) receptors to cause vasoconstriction. But some is released towards the lumen where it activates type B (ETB) receptors to stimulate nitric oxide (NO) in a feedback mechanism which leads to vasodilatation.
Thus, when the endothelium is healthy, a balance is maintained between relaxation and constriction of an artery. But, when it is damaged or diseased, there is a shift towards vasoconstriction as more endothelin and other mediators are released into the subendothelial space and make the smooth muscle contract.
Professor Rabelink described a series of new ET antagonists which are being developed for cardiovascular disease. Most work only at the ETA receptor, thus leaving the NO stimulatory mechanism intact. But studies with a mixed ETA/B receptor antagonist, bosentan, have produced reductions in blood pressure in hypertensive patients comparable to those achieved with enalapril. So NO-mediated vasodilatation may not play a very significant role in keeping blood pressure down.
Another balance which is disturbed when the endothelium is sick is that between thrombosis and fibrinolysis. If the endothelium is damaged or diseased, levels of thrombogenic factors such as plasminogen activator inhibitor-1 (PAI-1) are increased. PAI-1 is the main inhibitor of fibrinolysis and raised levels of the substance are predictive of ischaemic heart disease.
Variable effects on thrombotic factors have been seen with different statins, with pravastatin apparently having consistently beneficial effects against most mechanisms.8
It comes as no surprise that statin manufacturers are supporting a number of studies examining the effects of their drugs on stroke - a condition not usually linked strongly with cholesterol levels but which has been shown to respond to lipid lowering drugs. Cerivastatin, fluvastatin, atorvastatin and pravastatin are all on trial, with results expected over the next five years.
Beneficial effects would again support the concept of non-lipid effects of statins - anti-inflammatory and/or antithrombotic. But only a combination of laboratory and clinical studies will ultimately show how important endothelial damage is to arterial disease, and which drugs prevent it most successfully. In the meantime, the debate should enliven cardiology conferences in 2000 just as it did around the world in the last millennium.
References1. WOSCOPS Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440-5. 2. Shiomi M, Ito T, Tsukada T, Yata T, Watanabe Y, Tsujita Y et al. Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques: effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits. Arterioscl Thromb Vasc Biol 1995;15:1938-44. 3. Shiomi M, Ito T. Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol 1999;126:961-8. 4. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New Engl J Med 1997;336:973-9. 5. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98:839-44. 6. Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-7. 7. Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes. The final report of the ROXIS Study. Eur Heart J 1999;20:121-7. 8. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. JAMA 1998;279:1643-50. |