Early echocardiogram data signal later heart complications in FA

People with Friedreich’s ataxia (FA) develop thickening of the heart muscle wall early on, followed by a gradual decline in pumping function that can take up to three decades to appear, according to a study that examined more than 25 years of echocardiogram records from nearly 600 FA patients.

The study also found that early thickening of the heart walls can help predict later heart complications, including irregular heartbeat, declining heart function, and death.

The study, “Serial assessment of echocardiographic measures in Friedreich ataxia,” was published in American Heart Journal Plus: Cardiology Research and Practice.

FA is caused in nearly all cases by an expanded DNA sequence, called GAA, in both copies of the FXN gene. This reduces the production of frataxin, a protein important for the function of mitochondria, the cell’s energy production centers. Because nerve and muscle cells have high energy demands, they are particularly vulnerable to frataxin loss.

The study also found that patients with longer GAA repeat sections in the FXN gene had notably abnormal echocardiographic findings and a higher likelihood of later complications.

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Sept. 4, 2019 Columns by Matt Lafleur

Checking Up on My Heart’s Health

Heart abnormalities common in FA

Heart abnormalities are common symptoms of FA, affecting about three-quarters of patients. They most commonly occur as hypertrophic cardiomyopathy, a condition in which the muscles lining the heart thicken and enlarge, reducing the heart’s ability to pump blood.

Despite the high prevalence of heart disease in FA, the relationship among the underlying genetics, echocardiogram changes, and long-term outcomes is not clear.

The researchers examined echocardiogram data from 591 FA patients followed at the Children’s Hospital of Philadelphia and other sites, comparing early heart measurements with later outcomes.

Most patients carried repeat GAA expansions, while some (7.6%) had a single-point mutation or deletion (when the alteration affects a single DNA building block) in the FXN gene. The mean age of symptom onset was 10.9, and the mean age at the end of the study was 32.5. Patients were followed for a mean of 11 years.

On average, the hearts of people with FA showed mild to moderate thickening across all visits. Although wall thickness increased with age and duration, it never became severe. Boys and men generally had thicker heart walls across all measurements.

Ejection fraction, the percentage of blood pumped with each beat, and shortening fraction, a related measure of pumping strength, both declined over time.

In a correlation analysis, the thickness of distinct muscular regions within the heart — the septal wall and the posterior wall — was strongly related. This was consistent with concentric hypertrophy, meaning the walls of the heart’s main pumping chamber thicken evenly rather than in a single section.

Although ejection fraction and shortening fraction also correlated, neither was related to heart wall thickness; thus, “correlations of basic measures demonstrate that wall thickness and systolic [heart pumping] function change independently from each other,” the team wrote.

Genetic analysis showed that those with more GAA repeats had changes in certain heart measurements, including a thicker septal wall and a larger diameter of the left ventricle, the heart’s lower chamber.

Longer GAA repeats were also linked to a greater likelihood of later complications. For every additional 100 GAA repeats, the odds of developing an arrhythmia (irregular heartbeat) increased 23%, and the odds of a low ejection fraction (lower than 50%) increased 15%.

By the end of the study, one in 10 patients had died (11.1%) at a mean age of 33. Longer GAA repeat length and younger age of onset were both strongly associated with death, as was an ejection fraction lower than 50% or arrhythmia at any point during follow-up.

Thicker septal and posterior walls at the first visit, as well as greater initial relative wall thickness (wall thickness to chamber size), were each associated with an increased likelihood of death.

Patients who developed an unusually high ejection fraction (higher than 75%) early in the disease course also showed an increased likelihood of earlier death. The team noted that this likely reflects thickened heart muscle in a chamber that has not yet enlarged, rather than unusually strong heart function.

Initial and maximum septal wall thickness, as well as initial posterior wall thickness, also predicted the later development of both low ejection fraction and arrhythmia, “suggesting that early hypertrophy is associated with these later clinical events,” the researchers wrote.

The team said the findings are “consistent with the prevailing … hypothesis that decreased levels of frataxin lead to early hypertrophy, with later cardiac problems manifesting as decreased systolic function, arrhythmias, and death.”