Advances in technology and genomics have given rise to many issues, such as the extent to which genetic and lifestyle factors contribute to the individual-level risk for coronary artery disease, and the extent one's genetic risk can be offset by a healthy lifestyle.
Over the years, Valentin Fuster, MD, PhD, director of Mount Sinai Heart and physician-in-chief at The Mount Sinai Hospital in New York City, has focused much of his research on this topic. At the virtual ACC Latin America 2021 conference held last month, the cardiologist spoke about his hypotheses and findings during his opening plenary on imaging genomics, an emerging field that is rapidly identifying genes that influence the brain, cognition, and risk for disease.
Fuster discussed his research (J Am Coll Cardiol. 2021;77:2777-2791, 2020;75:1617-1627, 2019;73:1371-1382, 2017;70:2979-2991, and Circulation. 2015;131:2104-2113) and spoke about his innovative program that looks at cardiovascular health in people from young children to senior citizens. The work has been a process of learning and discovery. "We're beginning to understand how the disease can develop earlier and how we can prevent it from getting worse. There's nothing more beneficial than beginning to see how the disease starts in the arteries — something that we're able to do with imaging technologies that, in the next 2 years, will be available worldwide." And "by using imaging biomarkers in conjunction with genomic biomarkers, we're beginning to get an idea earlier on as to whether the person is at risk."
We need to be talking more about health and healthy arteries and trying to come up with epistemologies that are more modern, Fuster said. "To be able to see who we actually are is fascinating, and all of this is completely new" with imaging genomics.
Developing cardiovascular disease can be identified in people 40 to 60 years of age when seven risk factors — obesity, metabolic syndrome, blood pressure, diabetes, smoking, sedentary lifestyle, and poor nutrition" — are grouped together, he explained. In their 2015 study, Fuster and his colleagues explored, using high-quality 3D ultrasonography, five areas of the body — right and left carotids, aorta, and right and left iliofemorals — in more than 4000 people with no history of cardiovascular disease.
"The first thing I want to point out is that the disease originates in a territory that is not commonly evaluated. And we had no idea. We only learned about this development through imaging tests, assessing plaques. The disease starts in the femoral artery and, in fact, it starts with an inflammatory process — seen at autopsy — that can lead to fibrosis and, in later years, can form lipid-rich vulnerable plaque," he said.
His work has shown an increase in disease progression in groups of people who have been monitored for 20 years. What is most interesting is the way lesions are silent and evolve as the years go by.
"Atherosclerosis appears as a silent phenomenon initially and worsens in the presence of risk factors that trigger its progression," he said.
But can subclinical disease be identified in people who have few or no risk factors? "What we call normal is not, in fact, normal," said Fuster. To not have subclinical disease, LDL-cholesterol needs to be 70 mg/dL and HbA1c needs to be 5% to 6%, according to a 2020 study by Fuster and colleagues.
"The fact that we're seeing people with no apparent risk factors develop atherosclerosis is the reason what we consider normal is not," he said. It is necessary to take into account what happened in the first 40 years of these individuals' lives, he added.
Fuster presented findings on 6000 people 60 to 100 years of age underwent 3D-ultrasonography and were monitored for 12 years. The data have yet to be published, but they indicate that, with this disease, more than just risk factors are at play; atherosclerosis is related to what happens early on in one's life.
In their 2016 study of more than 55,000 participants, Fuster and his team quantified the genetic risk for coronary artery disease with a polygenic risk score derived from an analysis of up to 50 genetic polymorphisms that had been associated with coronary artery disease in previous studies. On the basis of this score, the participants were divided into subgroups by genetic risk: low, intermediate, and high. Genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. For participants at high genetic risk, a favorable lifestyle was associated with a relative risk for coronary artery disease nearly 50% lower than an unfavorable lifestyle.
The risk factors cause the bone marrow to be activated and, when this happens, an inflammatory process occurs in the arteries. This activation is a defense mechanism designed to help monocytes heal the arteries. "When we're dealing with a disease in the arteries, inflammation starts in the bone marrow, where cholesterol is deposited, and there are macrophages that, because there's too much to clean up and they can't keep up, will actually kill themselves. When that happens, they will release substances that will damage the arteries," Fuster reported.
In elderly people, risk factors have an impact not only on the great vessels, they can also lead to cerebral small vessel disease.
"The problem is that, before, we didn't have the technology to make this observation. And this is something critical with respect to late-onset dementia," he said, citing a 2016 study on Alzheimer's disease. Even if risk factors are increasing, the person will not necessarily develop the disease, but there is a greater chance that they will.
Playful activities have a major impact in childhood. With this in mind, Fuster instituted a 6-month, 60-hour educational program for children 3 to 6 years of age. The approach was aimed at teaching children about healthy eating habits and how the human body works. "Children are able to absorb everything we say, but then at age 10, it all goes away," he said. With another intervention that involved the same children, he showed that the benefits were greater than those seen in the first intervention.
"Our hypothesis is that, regardless of age, any program that has to do with prevention needs to be repeated. Repetition will bring more benefits every x years. That's what we're learning."
"We learned that when these children go home, they tell their parents what to do. The program had a greater impact on the children than their parents. So we need to use repetition in prevention efforts directed at young children. And we need to remember that the later we start this kind of work, the less impact it will have. The sooner things start, the greater the benefit and the lower the cost," he concluded.
This article originally appeared in the Portuguese edition of Medscape.
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Cite this: Valentin Fuster: 'Atherosclerosis Starts in the Femoral Artery' - Medscape - Dec 16, 2021.