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How an ancient mutation may predispose humans to heart disease

Humans are the only mammals to naturally develop atherosclerosis, a narrowing of the arteries that can fuel heart disease. Researchers link this to the loss of a single gene in our ancestors around 2–3 million years ago.
Woman with heart disease
Why do humans develop atherosclerosis?

Heart disease is the leading cause of death worldwide. In the United States, more than 600,000 people die due to the condition each year.

Coronary heart disease is the most common type of heart disease. The underlying cause is atherosclerosis, which is a hardening of the arteries that supply the heart due to a buildup of plaque.

Dr. Ajit Varki, a distinguished professor of medicine and cellular and molecular medicine at the University of California San Diego in La Jolla, has a long standing interest in how atherosclerosis develops in humans.

Several years ago, Dr. Varki and his team noted that while humans are prone to atherosclerosis, other mammals do not develop the condition — unless scientists manipulate their diet or genes in laboratory experiments.

In a new paper, appearing in Proceedings of the National Academy of Sciences of the United States of America, Dr. Varki, along with collaborator Philip Gordts, an assistant professor of medicine, points to a genetic mutation that occurred millions of years ago.

The team describes how this may contribute to our unique predisposition to develop atherosclerosis and, by extension, coronary heart disease.

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Loss of sugar molecule 2–3 million years ago

In a previous paper, Dr. Varki showed that humans — unlike our close relative the chimpanzee — lack a functional version of a gene called CMAH, which stands for cytidine monophosphate (CMP)-N-acetylneuraminic acid (Neu5Ac) hydroxylase.

The protein encoded by the CMAH gene converts a particular molecule called N-acetylneuraminic acid (Neu5Ac) to N-glycolylneuraminic acid (Neu5Gc). Both molecules are sialic acids, a family of sugar molecules which play essential roles in many biological processes.

Dr. Varki's research indicates that human ancestors lost part of their CMAH gene around 2–3 million years ago, leaving modern humans unable to make Neu5Gc. Instead, our cells mostly rely on Neu5Ac as their primary source of sialic acid.

Studying mice that researchers had genetically engineered to lack Cmah, and by extension Neu5Gc, the team saw a 1.9-fold increase in atherosclerosis when they compared them to normal mice.

"The increased risk appears to be driven by multiple factors, including hyperactive white cells and a tendency to diabetes in the human like mice," Dr. Varki comments.

Neu5Gc in red meat and atherosclerosis

In a further set of experiments, Dr. Varki and colleagues tested the effect of a diet high in Neu5Gc on the Cmah deficient mice.

Red meat is a ready source of Neu5Gc, which Dr. Varki's team previously showed causes chronic inflammation in their mouse model.

The researchers saw a 2.44-fold to 3.42-fold increase in atherosclerosis in the Cmah-deficient mice that they fed a diet high in Neu5Gc and fat, in comparison with a diet high in Neu5Ac and fat or a diet high in fat but without sialic acids.

"Human evolutionary loss of CMAH likely contributes to atherosclerosis predisposition via multiple intrinsic and extrinsic [dietary] mechanisms," Dr. Varki comments in the paper.

"Overall, our work may help explain why atherosclerosis and resulting CVD complications are very common in humans, and why these events rarely occur spontaneously in other mammals, in the absence of experimental or dietary manipulation."

Dr. Ajit Varki

Medical News Today asked Dr. Varki how he thought we might reduce our risk of developing atherosclerosis. He suggested that we "realize that, as humans, we are at greatest risk."

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