Heart Imaging Coupled with GAA Repeat Size Can Signal Cardiac Problems Years in Advance, Study Suggests

Catarina Silva, MSc avatar

by Catarina Silva, MSc |

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People with Friedreich’s ataxia should consult their cardiologist on a regular basis, as imaging of the heart considered with disease-related mutation repeats may identify those at high risk of cardiac problems up to five years before symptoms become evident, a study suggests.

The study, “Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study” was published in the American Journal of Cardiovascular Drugs.

Friedreich’s ataxia is a rare and progressive disease that’s caused by the abnormal repetition of three nucleotides — i.e., the building blocks of DNA — one guanine (G) and two adenines (A), in the first intron (part of the gene that does not code for a protein) of the frataxin (FXN) gene. Usually, healthy people have less than 33 GAA repeats, while Friedreich’s ataxia patients can have more than 1,000 GAAs in their FXN gene.

These trinucleotide expansions cause an error that lowers production of the frataxin protein, which protects cells against oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them.

Because of the harmful effects free radicals have on cells, Friedreich’s ataxia patients can have enlarged heart muscle, disturbances in speech and eye movement, and an inability to regulate their blood sugar levels. Every person has two copies of each gene, one inherited from each parent; longer GAA repeats within the shorter copy of the FXN gene are associated with earlier symptom onset, and more severe neurological and cardiac complications.

GAA repeat length is the main prognostic factor in survival, but investigators believe poor left ventricular systolic function may be the most important factor over time. Left ventricular systolic function refers to the ability of the heart’s left side to effectively pump oxygen-rich blood throughout the body.

In the early stages of Friedreich’s ataxia, it’s not easy to pinpoint the moment when cardiac deterioration begins. “Furthermore, wheelchair-bound patients have few symptoms of heart failure, which delays the diagnosis of left ventricular dysfunction and the institution of therapy, contributing to a poor prognosis,” the researchers noted.

A French team set up to identify patients likely to develop worsening left ventricular ejection fraction at an early disease stage. (Ejection fraction is the percentage of blood that leaves the heart each time it contracts.)

A total of 115 patients (52 women and 63 men; mean age of 30) who had at least one cardiac follow-up visit after being included in the study, were clinically followed for 13 years. Their electrocardiograms were retrospectively examined by physicians blinded to the patients’ heart imaging test results.

Genetic testing showed these patients had between 382 and 858 GAAs in the shorter copy of the FXN gene, and a mean disease onset of 15 years. At the study’s beginning, enlargement of the left side of the heart (what scientists call left ventricular hypertrophy) was found in 53% of patients with normal ejection fraction (58-72%).

After a mean follow-up of 13 years, a declining left ventricular ejection fraction (meaning below 50%, considered a sign of heart failure) was observed in 12 patients.

GAA repeat size on the shorter copy of the FXN gene, left ventricle dimension, and septal wall thickness – the wall that separates the heart’s right and left sides – predicted compromised cardiac function in a near future. The left ventricle (one of the four chambers of the heart) was measured after the heart had relaxed and before a next contraction, when the ventricle is the largest; normally, a woman’s left ventricular end-diastolic diameter (LVEDD) varies between 39 and 53 mm, and a man’s ranges from 42 to 59 mm.

Importantly, high-risk patients were identified five years before poorer left ventricular ejection fraction was recorded. People with over 800 GAAs were considered to be at high risk of future cardiac dysfunction; those with 500 to 800 GAAs were at high risk only if they had a left ventricle diameter of 52.6 mm or more, and a septal wall of 13.3 mm or more. Patients with a GAA count of less than 500 were low risk if their left ventricular end-diastolic diameter was below 52.6 mm, and the septal wall was less than 13.3 mm.

“Simple cardiac follow-up by echocardiography taking into account the size of the expanded GAA repeat can identify patients at a higher risk of systolic dysfunction,” the researchers concluded.

“Further studies are mandatory to confirm the validity of the prediction and to investigate whether earlier treatment of heart failure improves outcome in FRDA [Friedreich’s ataxia] patients. These identified high-risk patients could benefit from future therapeutic options,” they added.