Forging the shield

Abstract

Conventional diagnosis and subsequent treatment for atherosclerosis is ultimately based on risk. We focus our efforts primarily on disease-positive patients – be they high or low risk. This approach is arguably somewhat narrow-minded. What are we to make of the low-risk but disease-positive patient, such as a young marathon runner with an inferior infarction? This is the cleanest example of disease susceptibility, but it may well be operative in all patients. Risk and susceptibility are therefore not one and the same, but they must interact to yield the final burden of disease. Indeed, why can two patients who are well balanced with respect to known risk factors have vastly different degrees of coronary artery disease? The converse is important as well, but we turn a blind eye to it. Namely, how do we regard the high-risk but disease-negative patient? At present, such patients are reassured and counselled on risk factor modification. They are frequently referred back to the care of the primary care physician, and further disease-specific assessments and treatments effectively end. However, such patients have valuable lessons to teach. They illustrate the concept of protective factors, or disease resistance. Although the idea seems simple enough, we are only scratching the surface of learning about atherosclerotic resistance factors. The situation is akin to one seen in the realm of HIV infectivity. From the early 1980s, when HIV was first recognized, it was observed that some prostitutes in Kenya and other African countries did not contract HIV, despite being exposed to it on a regular basis. It was not a matter of taking precautions, because such remarkable would-be patients still contracted gonorrhea and other sexually transmitted diseases. Interestingly, it has also been observed that such immunity to HIV wanes as individuals are exposed less frequently. Such observations have spawned major research in HIV resistance. The most well-known finding has been the protective effect of the CCR5-delta 32 mutation. CCR5 chemokine receptor expression on CD4+ lymphocytes is used by HIV-1 to enter and infect the cell; it is the key that the virus uses to gain entry. Reduced CCR5 receptor density has been shown to reduce in vitro infection of CD4+ lymphocytes and has been observed to be associated with a reduced rate of infection in individuals at high risk for HIV (1). Emulating such resistance factors in susceptible individuals will be the next frontier in HIV therapy. Translating disease resistance research to atherosclerosis has proven to be even more difficult. Some progress has been made in determining genetic loci that impart resistance (2–4). However, the most widely recognized resistance factor is high-density lipoprotein cholesterol (HDL-C). To date, the lipid story has centred around low-density lipoprotein cholesterol (LDL-C). If intravascular ultrasound findings are to be used as a surrogate marker for disease, as in the Reversal of Atherosclerosis With Aggressive Lipid Lowering Therapy (REVERSAL) trial, aggressively lowering LDL-C halts progression, but it does not, in fact, promote disease regression (5). A more tantalizing finding has to do with apolipoprotein A1 (apo-A1) Milano – a variant of apo-A1, which is the major constituent of HDL-C. Researchers at the University of Milan in Spain discovered apo-A1 Milano in the 1980s by observing that an Italian family had unusually low levels of HDL-C, but no apparent cardiovascular disease. Infusion of the variant molecule has been shown to reduce the lipid content and inflammation of atherosclerotic lesions in animals. Furthermore, a small, 47-patient study (6) by researchers from The Cleveland Clinic found that the infusion of apo-A1 Milano resulted in a 4% reduction of atherosclerosis after only a few weeks, as measured by intravascular ultrasound. Other strategies to raise HDL-C are undergoing active investigation. These include cholesteryl ester transfer protein inhibitors, peroxisome proliferation-activated receptor agonists and HDL-C mimetics. The benefit and safety of these approaches remains to be established. The spectrum of resistance and susceptibility should be the next major battleground in primary and secondary prevention. From time to time, clinicians are surprised when objective testing yields a result contrary to their clinical predictions. Rather than dismissing such patients as anomalies, we should try to learn from them.