SCAD is a form of infarction that mainly affects women. © Fotalia

Spontaneous coronary artery dissection, more commonly known under the acronym SCAD, is a cause of infarction of which 9 out of 10 of its victims are women in their forties in apparent good health. Still poorly understood, it is often underdiagnosed, which complicates treatment despite the fact that it could represent up to one third of infarction cases in women under 60 years of age. In order to understand its genetic causes and biological mechanisms, a new international study led by Inserm Research Director Nabila Bouatia-Naji at the Paris-Cardiovascular Research Center – PARCC (Inserm/Université Paris Cité) was set up. Its findings show the genetic causes that define the risk of SCAD to be very numerous and distributed across the entire patient genome. The study has identified 16 genomic regions associated with a higher risk of SCAD, paving the way for a better understanding of the biological mechanisms that underlie this disease. The study was published on May 29, 2023 in Nature Genetics.

Unlike the majority of cardiovascular diseases, such as myocardial infarction, which mainly affect older and/or overweight men, spontaneous coronary artery dissection (SCAD) is a form of infarction that affects women in 9 out of 10 cases. Although these women are often in their forties, the disease can occur earlier – in the year after giving birth, or later – during the transition to menopause. Despite being increasingly recognized as a major form of infarction within this population, SCAD remains quite poorly documented due to a lack of data and a lack of knowledge of its specific risk factors – particularly genetic.

Over the past 20 years, considerable progress has been made in detailing the mechanisms of development of coronary diseases such as atherosclerosis and the very rare and syndromic forms of cardiovascular diseases. Such knowledge is essential in order to better understand these diseases and devise improved and personalized strategies for their prevention and treatment.

Nevertheless, research has lagged far behind in the understanding of diseases such as SCAD that affect women at key stages of their lives. It is therefore essential to now focus on this understudied cardiovascular disease and its own specific genetic risk.

The team of Inserm geneticist Nabila Bouatia-Najia conducted a large-scale study on the subject, coordinating a meta-analysis of 8 genome-wide association studies (GWAS)[1].  By comparing the genetic data of over 1900 patients with around 9300 healthy individuals, the scientists identified 16 genomic regions (or loci) of genetic predisposition to SCAD.

Towards a Better Understanding of the Biological Mechanisms

This study began by showing that the genetic variations most commonly found in patients having survived SCAD play a role in the composition of the “cement” that surrounds the coronary artery cells.

However, one of the genes identified is F3 and it encodes the tissue coagulation factor. Normally, the tissue factor initiates coagulation at cell level in order to resorb any hematomas. The results of the study suggest that a lack of F3 expression is often found in patients, constituting a potential cause of poor artery repair, which can lead to tearing. Poor hematoma resorption would therefore be a hitherto unknown genetic cause.

One of the other objectives of this study was to position SCAD in relation to other cardiovascular diseases in order to better understand its epidemiological particularities. Using the data that determine genetic cardiovascular risk factors and clever statistical methods, the scientists revealed a robust link between high blood pressure and risk of SCAD, while confirming that high cholesterol, overweight, and type 2 diabetes had no impact on this risk.

“This finding could therefore be clinically interesting in the longer term, to encourage doctors to closely monitor blood pressure changes in patients at increased genetic risk of SCAD,” explains Bouatia-Naji, Inserm Research Director and last author of the study.

Finally, this study reveals a genetic link between SCAD-related infarction and atherosclerosis-related infarction. Indeed, the researchers have shown that a large number of genomic regions predisposing to SCAD are shared with those of atherosclerosis-related infarction. However, even if these were the same genetic variants, the alleles[2] that are more common in SCAD patients are routinely described as being less common in subjects with atherosclerosis-related infarction.

“This finding is very surprising because they show that, depending on whether you are faced with a young woman with no risk factors, or an older man with risk factors, the genetic causes and biological mechanisms associated with their infarction can be opposed.  Our findings highlight the need to better understand the particularities of cardiovascular diseases in young women in order to improve their follow-up, which is currently identical to that of atherosclerosis-related infarction,” concludes Bouatia-Naji.

Building on these findings, the team is now working to develop new cell and animal models that better account for the genetic factors involved in the disease, particularly in order to better study their impact on the condition of the arteries. Always with a longer-term objective in mind: to shed the spotlight on a cardiovascular disease that is essentially female and all too often neglected, and to improve how it is understood and treated.

[1] Genome-wide association study, widely performed for several years now, which consists of analyzing the entire genome of thousands of healthy and sick individuals in order to identify the genomic regions which contain the genes influencing the vulnerability of people to the condition in question

[2] An allele is a version of a genetic variant resulting from a change in the DNA sequence. Any DNA sequence can have several alleles, which often determine the appearance of different hereditary characteristics.

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