Atherosclerosis through a new lens

Dr Thomas, what’s the Horus origin story?

Dr. Greg Thomas: It was in 2008, I was in the Royal Mummy room at the Cairo Museum and I saw a name plate for Merenptah: an ancient Pharaoh from 1200 BC. On its plaque it said that he had atherosclerosis, I couldn’t believe it, how would they even know? He had lived 3200 years ago, there were no cigarettes, no trans fats and he would’ve been very active. All the things that we blame heart trouble or atherosclerosis on, were missing. My host, Egyptian cardiologist Adel Allam, and I started thinking how to verify this and came up with calcium scoring, the ability to look at calcium in the arteries. We thought, “Well, calcium’s a hard element, maybe there’s still some in the body. And if we took a CT scan of the mummy, we’d know. I collected a cardiologist team in the States, experts in research and atherosclerosis, and Adel Allam, collected a team of expert Egyptologists there. Then we started scanning. There’s no book on how to scan mummies but on the seventh mummy, we realized that there was a pancake like structure above the spine. And that, it turned out was the aorta - the main blood supply to the body and we saw calcium in it: these mummies did have atherosclerosis!

A HORUS led study generated in close collaboration with Eurac Research scientists was recently published in the European Heart Journal, what does it explain?

GT: Well, we analyzed the CT scans from 237 adult mummies from around the world and found definite or probable atherosclerosis in more than 37% of them. We looked at a total of 7 different ancient cultures going back 5,000 years. All cultures demonstrated atherosclerosis. From Arizona and Utah’s Native Americans to Peruvians who lived almost a stone age life, in stone homes 500 years ago to inhabitants of the Aleutian Islands, each of those cultures, in addition to the Egyptians, had blockages of the arteries. Other cultures too: Italy, different parts of South America and Mongolia. Inuit communities from 500 years ago, who lived in igloos in Greenland had atherosclerosis, even though they were only in their twenties when they died. We’ve found atherosclerosis in all continents except for Antartica and Australia – likely because we’ve only studied one mummy from there. It’s changed how cardiologists around the world think about atherosclerosis – we can't just blame it on lifestyle, there’s a genetic tendency baked into humans.

Ms. Wurst, your latest study deals with the genetic predisposition to atherosclerosis, what exactly did you investigate?

Christina Wurst: We looked specifically for genetic variants in the genetic material of mummies from different eras and cultures, which, thanks to genome-wide association studies, are now known to contribute to an increased risk of atherosclerosis in modern humans. We wanted to see whether our ancestors also carried these risk variants and when – as this helps us to better understand the role of genetics in the development of the disease.

Could you tell us more about your findings?

CW: We examined the DNA of 22 mummified human remains: from Egypt, Peru, Bolivia, Switzerland, Australia and the Alps. We pretty much covered the world at very different time periods. Normally we like to extract old DNA from the petrous bone, a very hard bone in the skull, because this is where the endogenous genetic material is usually best preserved. Teeth are also promising. But with the Egyptian mummies this would not have been possible without unwrapping and further destroying them, so we worked with computer tomography and endoscopy and made do with what we could get from minimally invasive sampling. Since ancient DNA is only present in tiny fragments and mixed with the genetic material of other organisms, we then used a specially developed targeted enrichment approach to fish out the genetic variants we were looking for from the DNA mixture.

GT: Our team also looked at the Tsimane community – a 14,000-person tribe living in the lowlands of the Andes in Bolivia who are hunters and farmers. They don’t have birth control, so the average woman has nine children. And the children run free. They’re living a lifestyle, not too different from the cultures that all of us lived a hundred generations ago. This allows us to go back in time, to look at atherosclerosis in this culture with the amount of activity they do: the equivalent of 17,000 steps a day for the men and women. Their average amount of exercise time is seven hours a day and they too have atherosclerosis, though typically mild. And though atherosclerosis is intrinsic to the genes of humans, Mike Miyamoto of the Horus team coined the term, “One wants to die with atherosclerosis, not because of it.”

Are genetic risk vectors for atherosclerosis present in all the mummies you examined?

CW: Yes, such risk variants were present in mummies from all time periods and regions of origin. But that alone is not very meaningful. Individually, these variations in the genome have varying degrees of impact, but always only minimal: it is their combined effect that is decisive. A so-called weighted polygenic risk score can be used to determine the individual genetic predisposition to developing the disease. We calculated this risk score for all mummies that still contained sufficient endogenous human DNA and then compared the values with those of modern humans. This allowed us to assign the mummies a high, medium or low risk according to today’s definition. Ötzi was one of two mummies with the clearest genetic predisposition to atherosclerosis and he died already 5300 years ago, so we have been carrying this predisposition for at least that long.

GT: We’re born with this tendency, but we don't have to die of it. So, why do we have these genes? Going back to Charles Darwin and colleagues, the most important thing about a species is to perpetuate and have genes that keep the species alive. Now, atherosclerosis doesn't keep us alive, but if it does cause our death or other challenges due to it, it’s typically after we've had children. Some of those genes are a double-edged sword, they’re helpful early and help us fight infections, so we don't die of a childhood disease like diphtheria or tuberculosis or smallpox. In atherosclerosis, when cholesterol gets in the artery walls, it causes inflammation. If we have a strong inflammation response genetically which keeps us alive to the point that we can have children, or until our children can grow up and move on and have their own children, but that causes trouble for us in our fifties or sixties, it may be bad for older people, but it’s good for us as a species. This concept is called antagonistic pleiotropy.

Did the CT results play a role in your study of the ancient DNA?

CW: The results of the computer tomography were an important confirmation of our findings: the mummies with the most pronounced genetic predisposition to atherosclerosis were also those with calcifications in the arteries. This shows that our method is consistent and, in the future, can also be applied to skeletons which are much more frequently available to researchers than mummies. This newly developed approach will therefore contribute to a better understanding of how the interaction between environmental influences and genetics affects the development of atherosclerosis.