Increased Thickness of Heart’s Left Ventricle, Linked to Genetic Disease Severity in Adults with FA

Increased thickness of the lower left chamber of the heart — the left ventricle — is one of the most common structural heart abnormalities found in patients with Friedreich’s ataxia and also correlates with genetic disease severity in adults, a study has found.

The study, “Left ventricular structural and functional changes in Friedreich ataxia – Relationship with body size, sex, age and genetic severity,” was published in the journal Plos One.

Friedreich’s ataxia (FA) is caused by the expansion of a repetition of three nucleotides (the building blocks of DNA) — one guanine (G) and two adenines (A) — in the frataxin (FXN) gene sequence.

Most FA patients (96%) have an excessive number of GAA repeats in both copies (one inherited from each parent) of the FXN gene. However, in the remaining 4% of cases, these repeats are present in only one of the copies and the second copy of the FXN gene contains a different type of mutation — often a deletion or point mutation.

(A deletion is a mutation in which a part of the DNA sequence of a gene is lost, whereas a point mutation is a mutation in which the alteration of a single nucleotide may or may not lead to changes in protein composition.)

Heart disease is frequent among FA patients and is one of the most common causes of death among this population.

The left ventricle — one of two lower chambers of the heart — is responsible for pumping oxygen-rich blood from the heart to the rest of the body. For reasons that are largely unknown, structural changes in the left ventricle have been frequently documented in FA patients.

Some studies proposed that GAA1 — the FXN allele (one of the forms of the gene) with fewer DNA repeats — is associated with structural changes in the heart’s left ventricle. However, this association is not well-established due to conflicting data from different studies.

There also are factors that are independent of the disease and may influence the structure of the heart, including patients’ age, body size, and sex. Therefore, these variables need to be taken into account when investigating structural and functional changes in the hearts of those with FA.

So, a group of researchers in Australia investigated how structural changes in the heart’s left ventricle among those with FA could be influenced by patients’ sex, body size, and age.

They also explored the relationship between left ventricle changes and genetic disease severity, assessed by the length of GAA repeats within GAA1.

To that end, they performed echocardiography — a test that uses sound waves to produce live images of the heart — in 68 children and 148 adults with FA.

This test allowed researchers to measure and calculate several parameters, including the left ventricular end-diastolic internal diameter (LVEDID), septal wall thickness (SWT), left ventricle length (LVEDL), left ventricle volume (LVEDV), relative wall thickness (RWT), left ventricle mass, and left ventricle ejection fraction (LVEF).

LVEDID measures the diameter of the left ventricle after the heart has relaxed and before its next contraction, SWT measures the thickness of the  wall that separates the right and left side of the heart. RWT is a measure of left ventricle hypertrophy (thickening). LVEF measures the amount of blood that leaves the heart each time it contracts.

Findings indicated the most common left ventricle abnormalities found in both adults and children with FA was an increase in RWT and age-normalized RWT.

They also found that in adults with FA who had normal LVEF, all variables related to the left ventricle (except for RWT) were larger in males, regardless of body surface area. Also, all left ventricle variables (except for SWT and RWT) were positively correlated with body surface area.

In children with normal LVEF, SWT, left ventricle mass and length were found to be larger in males after adjusting for body surface area. In combination with sex, body surface area was positively correlated with all left ventricle variables, except for SWT and RWT.

Altogether the findings indicated that “sex and body size are important determinants of most other LV [left ventricle] structural variables in both children and adults,” researchers wrote.

After adjusting for sex and body surface area, GAA1 in adults was found to be positively correlated with SWT and RWT, but not left ventricle mass. In addition, in adults GAA1 inversely correlated with LVEDID, LVEDL, and LVEDV.

However, no correlations between GAA1 and any of the left ventricle variables were found in children with the disease.

Researchers concluded that “increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.”