Cardiologists advance search for routine vaccine to prevent heart attacks and strokes

July 15, 2003

LOS ANGELES (July 16, 2003) - In their quest for a vaccine that may one day routinely protect against heart attacks and strokes, cardiologists at Cedars-Sinai Medical Center and their colleagues in Sweden have isolated a key step in the mechanism that leads to vascular plaque buildup and blood clot formation.

In mice genetically predisposed to quickly develop atherosclerosis, the researchers were able to trigger a protective immune response, significantly increasing the level of immunoglobulin gamma G (IgG), an antibody known to be important in protection against atherosclerosis. Immunization resulted in reduction of atherosclerosis by about 60 percent, compared with controls.

Heart disease is well established as the nation's leading cause of death, and atherosclerosis is one of the major risk factors. Over the past several years, evidence has mounted that infection and inflammation contribute to this process. Researchers hope, therefore, that by attacking the first link in a complex chain of events, they can shut down a deadly process before it begins.

"Inflammation and infection have been implicated in plaque buildup and blood clot formation, processes that trigger most heart attacks and strokes. It has been observed that influenza may increase the risk of heart attacks and death, especially in the elderly," said Prediman K. Shah, M.D., director of the Division of Cardiology and the Atherosclerosis Research Center at Cedars-Sinai.

Dr. Shah said previous experiments have shown that the influenza virus can accelerate plaque formation and arterial inflammation in mice that are genetically susceptible to high cholesterol and plaque buildup. The virus also may neutralize the protective effects of HDL, the good cholesterol.

"Recent observational studies have provided strong evidence that the flu vaccine can reduce heart attacks, stroke and death by a significant degree, and this is now being evaluated in a randomized trial. Similarly in mice, pneumococcal vaccine has been shown to reduce plaque buildup by a mechanism that does not involve pneumococcal infection," added Dr. Shah, who holds the Shapell and Webb Family Endowed Chair in Cardiology at Cedars-Sinai.

"Our goal is to develop a vaccine that will one day be administered in childhood to interrupt the inflammatory process and save lives from heart attacks and strokes," Dr. Shah said.

A "proof of concept" study, reported in the May issue of the journal Arteriosclerosis, Thrombosis, and Vascular Biology, was conducted by researchers at the Atherosclerosis Research Center at Cedars-Sinai and their colleagues at Malmö University in Sweden. It is one in a series of investigations seeking to discover the processes that contribute to the development of atherosclerosis and to engage the immune system in interrupting them.

The therapy centers on a recently discovered immune response that occurs within oxygen-damaged particles of low-density lipoproteins (LDL), the "bad" cholesterol that is associated with a high risk of developing arterial plaque build-up. Specific protein components of LDL were injected to trigger an immune response. These constituents, called apoB-100 peptide sequences, can be reproduced for the possible development of a vaccine.

Lipoproteins, such as LDL, are substances in the blood consisting of proteins combined with fats. Apoliproteins, such as apolipoprotein B (apoB), are the building blocks of lipoproteins that determine their characteristics, providing structure, receptor sites for interaction with other molecules, and chemicals needed for enzyme production.

When LDL remains in the bloodstream or trapped in arterial structures for an extended length of time, oxidation causes the release of a variety of chemicals. These chemicals damage and inflame the vessel, and as the body tries to repair the injury, plaque builds up on the artery wall.

Mice in the study had a genetic predisposition to quickly develop atherosclerosis. At the age of 10 weeks, a high-fat diet was introduced, leading to extremely high cholesterol levels and even more aggressive atherosclerotic disease. Ten mice were injected at six weeks and again at nine weeks with selected apoB peptides that are known to elicit a potent immune response. Ten other mice did not receive the peptides. At 25 weeks, blood and tissue from the mice were analyzed.

Although the exact mechanisms by which immune responses reduce atherosclerosis are not yet clear, the early results of this therapeutic approach appear promising for the development of a protective vaccine.

In a separate but related article in the same issue of Arteriosclerosis, Thrombosis, and Vascular Biology, the researchers from the centers in Sweden and at Cedars-Sinai reported identifying a large number of "epitopes" within the apoB-100 component of oxidized LDL that provoke an immune response in humans. Epitopes are the specific sites on molecules to which antigens bind. These findings will be instrumental in ongoing studies of the role of immune responses in reducing risk of cardiac problems.
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The studies were supported by grants from the Swedish Medical Research Council, the Swedish Heart-Lung Foundation, the King Gustaf V 8th Birthday Foundation, the Bergqvist Foundation, the Tore Nilsson Foundation, the Crafoord Foundation, the Swedish Society of Medicine, the Royal Physiographic Society, the Malmö University Hospital Foundation, the Lundström Foundation, and a grant from the Eisner Foundation to P.K. Shah, M.D., director of Cardiology at Cedars-Sinai Medical Center.

Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 "Most Wired" hospitals in health care, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.

Citation:
"Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization With ApoB-100 Peptide Sequences" and "Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease." Arteriosclerosis, Thrombosis, and Vascular Biology, May 2003.

Cedars-Sinai Medical Center

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