Atherosclerosis — the clogging of arteries with fatty deposits — is the cause of one-third of deaths worldwide due to cardiovascular disease. There are many known risk factors, including blood cholesterol, physical inactivity, age, hypertension, obesity and smoking, but in roughly 15 percent of first-time cardiovascular disease events (CVD) due to atherosclerosis, none of these factors apply.

A decade ago, Nissi Varki, MD, professor of pathology at UC San Diego School of Medicine, with co-author Ajit Varki, MD, Distinguished Professor Of Medicine and Cellular And Molecular Medicine, and colleagues noted that naturally occurring coronary heart attacks due to atherosclerosis are virtually non-existent in other mammals, including closely related chimpanzees in captivity which share human-like risk factors, such as high blood lipids, hypertension and physical inactivity. Instead, chimp “heart attacks” were due to an as-yet unexplained scarring of the heart muscle.

In the new study, the Varkis, and Philip Gordts, PhD, assistant professor of medicine, and others report that mice modified to be deficient (like humans) in a sialic acid sugar molecule called Neu5Gc showed a significant increase in atherogenesis compared to control mice, who retain the CMAH gene that produces Neu5Gc.

The researchers — members of the Glycobiology Research and Training Center and/or the Center for Academic Research and Training in Anthropogeny at UC San Diego — believe a mutation that inactivated the CMAH gene occurred a few million years ago in hominin ancestors, an event possibly linked to a malarial parasite that recognized Neu5Gc.

In their findings, the research team said human-like elimination of CMAH and Neu5Gc in mice caused an almost 2-fold increase in severity of atherosclerosis compared to unmodified 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,” said Ajit Varki. “This may help explain why even vegetarian humans without any other obvious cardiovascular risk factors are still very prone to heart attacks and strokes, while other evolutionary relatives are not.”

But in consuming red meat, humans are also repeatedly exposed to Neu5Gc, which researchers said prompts an immune response and chronic inflammation they call “xenosialitis.” In their tests, human-like mice modified to lack the CMAH gene were fed a Neu5Gc-rich, high-fat diet and subsequently suffered a further 2.4-fold increase in atherosclerosis, which could not be explained by changes in blood fats or sugars.

“The human evolutionary loss of CMAH likely contributes to a predisposition to atherosclerosis by both intrinsic and extrinsic (dietary) factors,” wrote the authors, “and future studies could consider using this more human-like model.”

In previous work, the Varkis and colleagues have shown that dietary Neu5Gc also promotes inflammation and cancer progression in Neu5Gc-deficient mice, suggesting that the non-human sugar molecule, which is abundant in red meat, may at least partially explain the link between high consumption of red meat and certain cancers.

Interestingly, the evolutionary loss of the CMAH gene appears to have produced other significant changes in human physiology, including reduced human fertility and enhanced ability to run long distances.

Co-authors include: Chirag Dhar and Raymond Do, UC San Diego and first author Kunio Kawanishi, UC San Diego, now at University of Tsukuba, Japan.

Falling off a bike with a helmet on, having a fender-bender in one’s car, taking a tumble on the ski slopes, slipping on ice and hitting one’s head — these kinds of minor accidents can provoke the same kinds of olfactory and anxiety problems, the researchers found.

In a study published in Brain Injury, an international team led by Université de Montréal neuropsychologists compared 20 hospital patients who had mild concussions to 22 who’d broken limbs but had no concussion. Within 24 hours of their accident, just over half of those with mild concussions had a reduced sense of smell, versus only 5 per of the patients with broken bones. A year later, although their sense of smell was back to normal, the first group of patients had significantly more anxiety than the control group.

“A lot of people will suffer a mild concussion at some point in their life, so realizing they have trouble smelling is the first step to telling their doctor about it,” said lead author Fanny Lecuyer Giguère, who did the research as part of her doctoral thesis in neuropsychology supervised by UdeM associate professor of psychology Johannes Frasnelli. “It’s important that patients report any loss of smell, because it’s not something their general practitioner or emergency-room physician normally asks about.”

Identifying the problem is a short step to getting personalized treatment, she added, with closer follow-up to see if the loss of smell and anxiety persist, indicating the severity of the injury. Physicians should also educate their patients so that they check whether symptoms crop up in the weeks following their accident, she said. “It’s a question of raising awareness: the more people are told to watch for signs of olfactory loss and anxiety, the easier it will be for doctors to respond.”

To test their capacity to identify smells, Lecuyer Giguère visited hospital patients in the alpine ski resort of Visp, Switzerland between December 2016 and February 2017. Almost all those with mild concussions had had a skiing accident. They were all seen within the first 24 hours following their accident, as were those with fractures but no concussion. With scented “Sniffin’ Sticks’ (felt-tip pens) to smell, they were asked to identify synthetic odours of roses, garlic, cloves and solvent, and more.

A year later, the patients were sent a follow-up questionnaire and a set of scratch-and-sniff booklets. By comparing the two groups of patients’ results in the day following their injury and 12 months later, the researchers were able to determine that most who’d lost their sense of smell gained it back within six months of their accident.

What did not significantly diminish, however, were their symptoms of anxiety: thoughts that made them worry, difficulties to relax, and sudden feelings of panic. About 65 per cent of the concussed patients reported such symptoms.

Future studies should look at a larger sample of patients to better examine the association between anxiety and olfaction, the authors concluded.

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Materials provided by University of Montreal. Note: Content may be edited for style and length.