Sex-specific inflammatory profiles linked to heart disease in Fabry
Separate inflammatory proteins may contribute to problems in men, women
Distinct groups of inflammatory proteins may contribute to the progression of heart problems in men and women with Fabry disease, a study suggests.
While men exhibited a profile associated with a strong pro-inflammatory response, women had a profile that could be linked to accumulating scar tissue. The identified markers may be useful for detecting cardiac problems in Fabry patients early and the findings suggest anti-inflammatory treatments may help slow cardiac progression.
The study, “Sex Differences in Circulating Inflammatory, Immune, and Tissue Growth Markers Associated with Fabry Disease-Related Cardiomyopathy,” was published in Cells.
Fabry disease is caused by mutations in the GLA gene that lead to a lack of functional alpha-galactosidase A (alpha-Gal A) enzyme. Fatty molecules the enzyme would normally be responsible for breaking down accumulate to toxic levels in tissues throughout the body.
Because it’s inherited on the X chromosome, Fabry tends to affect the sexes differently. Generally, men show more severe and earlier-onset symptoms, while the disease course in women is milder and with a later onset, although this can vary significantly.
Heart disease is a common symptom of Fabry. Hypertrophic cardiomyopathy (HCM), where the heart muscle becomes abnormally thick and the heart has a harder time pumping blood, is particularly common. But there are sex differences in Fabry-related heart disease, with data suggesting women are typically affected at a later age than men. Moreover, while men characteristically develop progressive HCM with eventual fibrosis, women sometimes develop early fibrosis before overt HCM develops.
Role of inflammation in Fabry disease
It’s been proposed that inflammation in response to the buildup of fatty molecules may play a key role in Fabry disease progression, including contributing to cardiac damage. This raises the possibility that circulating inflammatory biomarkers could have potential in early screening for cardiac involvement in Fabry patients, said the scientists, who measured blood levels of inflammatory molecules called cytokines in adult Fabry patients and healthy people as part of an observational clinical study (NCT04724083). They also looked at certain growth factors that can drive remodeling of cardiac tissue that contributes to HCM.
The analysis included 45 Fabry patients (21 men, 24 women), of whom 28 had HCM. Twenty healthy people, 10 men and 10 women, served as controls.
While heart disease is generally considered to affect women at a later age, early-onset HCM was not uncommon in the study group. The youngest female with a mild form of HCM was 22 and the youngest male was 21.
“Thus, the early detection of HCM in females with [Fabry disease] is crucial for effective disease management,” the researchers wrote.
Differences in men, women
Biomarker analyses suggested that Fabry patients had differences in inflammatory markers from healthy controls, with distinct profiles in male and female patients. Various biomarkers were also specifically associated with HCM, again with sex-specific differences.
Overall, the biomarker profile in men with HCM suggested activation of the inflammatory NFkB signaling pathway, with markers such as IL-10, IL-2, GM-CSF, and VEGF-A being implicated. This reflects that significant inflammation drives cardiac tissue remodeling that promotes HCM progression in men, said the researchers.
On the other hand, women with HCM showed an inflammatory marker profile consistent with activation of the TNF-alpha, TNFR2, and TGF-beta signaling cluster, which may be related to fibrosis development. This may help explain why women with Fabry often show fibrosis early in the course of cardiac disease.
“The pivotal roles these cytokines and growth factors play may render them valuable as biomarkers for the early detection and clinical staging of HCM,” the researchers wrote. “Such insights are crucial for healthcare providers to develop strategies for the effective management of [Fabry] patients with cardiac manifestations.”
The findings could also inform future treatment strategies, with certain anti-inflammatory treatments having already shown promise for treating cardiovascular disease in the general population.
“These findings support the role of inflammation as a therapeutic target in cardiovascular diseases, including Fabry cardiomyopathy, where adjunctive anti-inflammatory therapies may improve clinical outcomes when combined with disease-specific treatments,” they wrote.
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