Scar tissue in the heart linked with genetic disease severity in FA
Fibrotic changes in left ventricle unrelated to other structural changes there
Widespread scar tissue in the lower left chamber of the heart — the left ventricle — correlated with genetic disease severity in people with Friedreich’s ataxia (FA), an imaging study found.
Genetic disease severity refers to the amount of the frataxin protein derived from the least affected of a patient’s two FXN genes, both carrying mutations that are the cause of FA.
The fibrotic changes noted were independent of other disease-related structural changes to the left ventricle, data showed.
The study, “Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement,” was published in the journal PLOS One.
GAA repeats in the FXN gene affect frataxin production and cell energy
The FXN gene provides instructions for frataxin, a protein involved in the functioning of mitochondria, cellular structures responsible for producing the cell’s energy. This gene contains a segment with three DNA building blocks — GAA — that may be repeated more than 1,000 times in people with FA, disrupting the frataxin production and mitochondria. Generally, longer GAA repeats have been linked to greater frataxin deficiencies, resulting in a younger age at disease onset and more severe or rapidly progressing symptoms.
The loss of cellular energy particularly affects nerves and muscles, leading to core FA symptoms such as problems with coordination and balance (ataxia), as well as heart and neurological issues.
Hypertrophic cardiomyopathy is a frequent manifestation of FA-related heart disease, marked by the thickening and enlargement of muscles lining the heart. Scar tissue also can build within the heart muscle, a condition called myocardial fibrosis.
To learn more about how FA affects the heart, a team led by Australian researchers conducted imaging studies focusing on the left ventricle (LV), the side of the heart that pumps oxygenated blood throughout the body. Structural changes in the left ventricle frequently have been noted in FA patients.
Of the study’s 93 patients — 63 adults and 30 children — more than half (53.8%) were male.
Patients’ left ventricle assessed using cardiac imaging, gadolinium enhancement
LV parameters were assessed using cardiac magnetic resonance (CMR), which is similar to an MRI of the heart. Measurements included LV mass (size); LV ejection fraction, the percentage of blood that leaves the left ventricle with each heartbeat; and LV end-diastolic volume, the volume of blood in the ventricle immediately before a heartbeat.
Twenty patients (22%) showed signs of LV hypertrophy, a thickening of the left ventricle muscle wall. A reduced LV end-diastolic volume was found in 36 patients (39%), and nine participants (9.7%) had an LV ejection fraction below the normal range (less than 55%). The ratio of LV mass to end-diastolic volume was elevated in nearly all patients (89%), a sign of structural changes in the ventricle.
Among patients with a normal LV ejection fraction (above 55%), a higher LV end-diastolic volume significantly correlated with a larger body surface area and was higher in males. After adjustment for body surface area and sex, this volume was similar between children and adults. Accordingly, a higher LV mass significantly associated with a larger body surface area and male sex. Older age was an independent predictor of a lower LV mass.
These findings “highlight the importance of taking both body size and sex into account when categorising LV mass,” the team wrote.
Myocardial replacement fibrosis did not associate with GAA1
In adults, a higher LV mass correlated with GAA1, a measure of genetic severity. GAA1 refers to one of the two inherited copies of the FXN gene with fewer GAA repeats, and linked with greater frataxin production.
Two measures of cardiac magnetic resonance, native T1 relaxation time and extracellular volume fraction, were used as markers for LV diffuse myocardial fibrosis, or the presence of scar tissue spread throughout the ventricle’s muscle. Late gadolinium enhancement, which highlighted areas of LV muscle replaced with scar tissue, was also used.
Native T1 time in both adults and children, and extracellular volume fraction in adults, significantly correlated with GAA1, independent of LV mass and end-diastolic volume. This suggested an association between the degree of frataxin deficiency and the amount of LV fibrous tissue, the researchers noted.
Late gadolinium enhancement measures found myocardial replacement fibrosis in 1 in every 5 (21%) patients. Such fibrosis occurred more frequently in patients with reduced LV ejection fraction. Regardless, replacement fibrosis was not linked with GAA1, LV mass, or LV end-diastolic volume.
“The absence of predictors of LGE [late gadolinium enhancement] suggests that there is a different … mechanism underlying the development of replacement fibrosis compared to diffuse fibrosis in the early stages of cardiac disease in [FA],” the researchers wrote.
“An association between diffuse interstitial LV myocardial fibrosis and genetic severity in [FA] was present independently of [disease]-related LV structural changes,” they concluded.
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