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New HDL-cholesterol therapy (Published November 10, 2003)

Last week a lot of health media attention was focused on a story of a new approach to reverse atherothrombosis, the process that eventually clogs arteries in the body and is the number one cause of death in the United States. A new agent was infused into a small number of patients with symptoms of inadequate blood flow to the arteries feeding the heart. Using an ultrasound technique to measure the volume of plaque in the walls of the arteries, the investigators found that measurable removal of plaque took place in a matter of weeks. Astounding. But what does this really mean?

The progressive development of atherothrombosis is a complicated process of give and take. The risk factors set the stage. Lifestyles activate the process. All of these are part of the “give”. Modifying lifestyles and taking appropriate medications to reduce the impact of the risk factors slows down and perhaps stabilizes the process.

What this preliminary report suggests is that in the future, there may be ways to expedite the “take”. In other words, actual regression of plaque may be possible.

Much of the development of arterial plaque involves LDL-cholesterol, so called “bad cholesterol”. Statin drugs have been extraordinary in their ability to modulate LDL-cholesterol levels as well as non-blood fat factors that may cause plaques to form and become unstable.

HDL-cholesterol, so called “good cholesterol”, can be thought of as a mediator of “reverse lipid transport”. The more HDL-cholesterol present, the more likely that the modified LDL-cholesterol in plaques can be removed. Conversely, a low level of HDL-C cholesterol is an independent risk factor for the premature development of atherothrombosis. However, it now appears that not just the amount of HDL-cholesterol is important, but the quality of the HDL-cholesterol may be even more important.

In the mid-1970’s, scientists found a population of individuals in a northern Italian village that had extremely low levels (even single digits) of HDL-cholesterol, but who had a history of longevity into their eighties and nineties, mostly dying of non-cardiovascular diseases.

Meticulous epidemiologic and genealogic investigation traced these individuals to a single villager who lived in the late 18th century. This individual apparently had a mutation of a gene that modified a protein that went into the make-up of HDL-cholesterol that affords their HDL-C extraordinary protective characteristics against the ravages of atherothrombosis. The gene has been passed down through many generations, producing a protein identified as ApoA-1 Milano.

It was recombinant ApoA-1 Milano that was infused into these patients weekly for five weeks. The patients that got the real protein were the ones that may have shown regression of their plaques. The patients that got the placebo showed no regression.

The problem with this report is that the conclusions and headlines are extremely premature. This was a small study of only 47 patients, 36 of whom got the real drug. Much larger studies with clinically meaningful endpoints such as reduced rate of heart attacks, strokes and need for angioplasty and stents are going to be required to prove that this agent will be a real addition to our drug armamentarium.

Another critical factor to keep in mind is that this is a horse-has-left-the-barn treatment. You already will have atherothrombotic disease in order to need this treatment. I submit that it will always be better if preventive strategies are employed beforehand to obviate the subsequent need for ApoA-1 Milano treatment.

There are other drugs being developed that actually manipulate the level, and in some cases, the quality, of HDL-cholesterol. These may be useful in patients who have not yet developed plaques in their arteries. The Ventura Heart Institute will likely be involved with these clinical trials once safety and preliminary efficacy issues are sorted out.

Regardless, these are promising times in the fundamental understanding and treatment of the leading cause of death of both men and women in the United States.

Dr. Irving Loh is the medical director of the Ventura Heart Institute in Thousand Oaks, CA. His e-mail address is iklmdvhi@aol.com. The VHI website is www.venturaheart.com

 

 
   
   

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