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Two studies offer clues to better treatment of cardiovascular ills

Physicians can prescribe a number of effective measures for warding off cardiovascular disease, among them a healthy diet, exercise, and the popular drugs called statins.

Physicians can prescribe a number of effective measures for warding off cardiovascular disease, among them a healthy diet, exercise, and the popular drugs called statins.

Yet this family of disease remains the number-one killer in the United States, worse than all cancers combined. Now, two new studies by Philadelphia researchers have yielded intriguing clues toward possible better treatments.

Separately, a new class of drugs already in clinical trials appears to rival statins in improving cholesterol levels, though the new drugs have not yet been shown to reduce heart disease.

One of the new studies, led by researchers at Children's Hospital of Philadelphia, identified 21 new genetic variants that are connected to levels of cholesterol in the blood, using a small chip that scanned the genomes of thousands of patients. The hope is that one of these genes could be the target for new drugs.

The other study, led by scientists at the University of Pennsylvania's Perelman School of Medicine, provided a partial explanation for a nagging mystery about HDL cholesterol - the so-called "good" cholesterol.

Current evidence suggests that having a higher level of HDL particles in the blood does not have much effect, if any, on disease - even though the particles play a key role in removing cholesterol from cells. But the new study found that at least one subtype of HDL does seem to lower risk of disease: the kind that contains a protein called apoE.

The authors of the study, published this month in the journal Cell Reports, reported that apoE seems to play a role in keeping arteries soft and flexible. They analyzed mice that were genetically altered so they could not make apoE, and found that these animals had stiffer arteries, said senior author Richard K. Assoian, a professor of pharmacology at Penn.

Stiffness of the arteries is different from what is popularly called hardening of the arteries, though the former can lead to the latter.

Stiffness is caused by a matrix of collagen and other molecules outside the cells of the arterial wall, and it appears to make arteries more prone to hardening - the development of harmful fatty plaques, more properly called atherosclerosis.

The scientists were able to soften the stiff arteries in the genetically altered mice by administering a drug, though it was not one that would be used on humans because it interferes with multiple biochemical pathways. Still, the effect was dramatic: these treated mice had healthier arteries even though their total cholesterol remained high.

Assoian and his Penn colleages were joined by collaborators from Children's and from the Wistar Institute.

"The current thinking is that HDL quality rather than quantity is important," said Michael C. Phillips, one of the coauthors from Children's.

The study that identified the 21 gene variants, meanwhile, relied on a genome-scanning device called the Cardiochip, which was invented by Brendan J. Keating, also of Children's.

Each chip, measuring about half the size of a credit card, contains millions of beads that are tailored to "read" specific genetic variations.

Individually, the genetic variants identified by Keating and his coauthors do not appear to contribute much to a person's cholesterol levels, but they will help guide researchers in the search for new drug targets. Collectively, the genes identified in the study were linked to about 10 percent of the variation in both good and bad cholesterol.

"It doesn't necessarily sound like a lot, but when it's added to everything that's known, we are starting to be able to assign someone a genetic risk," Keating said.

The new class of drugs is called PCSK9 inhibitors. One drug in the family, the result of a collaboration between Sanofi and Regeneron Pharmaceuticals Inc., reduced LDL cholesterol by an average of 73 percent, in combination with a statin drug. Patients who got a statin alone saw their LDL cholesterol drop by 17 percent.

The results were published online last month in the New England Journal of Medicine. One drawback: The drug must be injected, rather than swallowed. A few patients also reported headaches and diarrhea. The companies are in the process of recruiting patients for a phase 3 trial, a requirement for approval, so it would be several years before it came to market.

Statins, which do not work for everyone, block cholesterol production in the liver. The new drugs work by inhibiting an enzyme that interferes with clearing LDL cholesterol from the blood.