Heart rhythm problems common in adults with FAP-causing mutation
Cardiomyopathy less likely for Val30Met carriers; outcomes worse if they have it
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Adults who carry the Val30Met, or V30M, mutation — the most common cause of early-onset hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) — often develop heart rhythm problems early on, a study shows.
Although V30M carriers may be less likely to have cardiomyopathy, or heart muscle disease, those who do experience worse outcomes. V30M is usually linked to hATTR-PN, but some patients show both neurological and cardiac heart symptoms, or even predominantly cardiac symptoms.
“Our findings highlight the need for thorough cardiovascular evaluation in [V30M carriers] due to common [heart rhythm] issues and the significant impact of CM [cardiomyopathy] on outcomes,” the researchers wrote. Their study, “Specificities of Amyloid Cardiomyopathy caused by Transthyretin V30 Mutation,” was published in the Journal of Cardiology and based on data from a national referral center for V30M carriers in Portugal.
Hereditary transthyretin amyloidosis (ATTR) can be hereditary, with mutations in the TTR gene passed down in families, or wild-type, where it develops sporadically with age, usually in older adults. In both forms, the protein transthyretin misfolds and builds up as toxic clumps, known as amyloid fibrils, which damage tissues.
In hATTR-PN, also called familial amyloid polyneuropathy, amyloid fibrils mainly accumulate in the peripheral nerves, those outside the brain and spinal cord, causing neurological symptoms. When the fibrils build up primarily in the heart muscle, they cause ATTR with cardiomyopathy (ATTR-CM), which may or may not be associated with TTR mutations.
More than 120 disease-causing TTR mutations have been identified so far, with varying clinical profiles. A particular early-onset clinical profile, presenting predominantly as hATTR-PN, is highly frequent in Portugal, with V30M as the most common disease-causing mutation.
“Despite this, a mixed or cardiac-dominant V30M FAP, particularly in late-onset cases, is emerging,” the researchers wrote. “Given the limited data on V30M [ATTR-related heart involvement] and its [simultaneous cardiac conditions], deeper research is crucial.”
Outcomes with V30M mutation
A team of researchers in Portugal retrospectively analyzed data from 238 adults (mean age, 54) who carried the V30M mutation, had a cardiology appointment in 2019, and were followed for a median of 57 months, or slightly more than 4.5 years. Most (69.2%) had early-onset symptoms (before age 50), 21.4% had late-onset symptoms, and 9.2% showed no symptoms.
One in every five adults (20%) developed cardiomyopathy and met the criteria for ATTR-CM. Cardiomyopathy was nearly twice as common in the late-onset group as in the early-onset group (30.2% vs. 17%). These patients were significantly older (62.1 vs. 51.9 years) and more likely to be men (77.1% vs. 45.8%) than those who didn’t develop cardiomyopathy. They were also significantly more likely to have orthostatic hypotension, when blood pressure decreases suddenly upon standing (56.3% vs. 28.9%), eye problems (31.8% vs. 15.8%), and to have a liver transplant (50% vs. 27.9%).
The cardiomyopathy group also had significantly higher levels of heart damage markers, were more likely to be hospitalized due to heart failure (12.5% vs. 1.1%), and had lower survival rates.
Further statistical analyses to identify independent predictors of cardiomyopathy showed that being a man was significantly linked to a more than five times higher chance of developing cardiomyopathy relative to being a woman. Also, eye problems were significantly associated with a more than two times higher chance of having cardiomyopathy, and a liver transplant with a more than four times higher chance. With each additional year of age, the odds increased by 8%.
Presence of conduction abnormalities
Significant conduction disease — where the electrical signals that control the heart’s rhythm are disrupted, causing abnormal heartbeats — was present in 31.9% of all V30M carriers, being significantly more common in those with cardiomyopathy (56.3% vs. 25.8%).
The cardiomyopathy group was also significantly more likely to have atrial fibrillation, an irregular and often very rapid heart rhythm (29.2% vs. 5.8%), and to use a pacemaker to normalize the heart’s electrical signals (68.8% vs. 46.8%).
People with significant conduction disease were significantly older, had a longer disease duration, and were more likely to have atrial fibrillation, ATTR-CM, and orthostatic hypotension. “They also had a higher rate of extra-cardiac involvement, with nearly 95 % experiencing neuropathy [nerve damage],” the researchers wrote.
The study also included 44 adults with wild-type ATTR-CM (mean age, 80.7). Most (97.7%) were men and half had conduction disease. Compared with these patients, those with V30M-related ATTR-CM were younger, included fewer men, and were more likely to have conduction problems and orthostatic hypotension.
However, the V30M-related ATTR-CM group was less likely to have atrial fibrillation and reduced heart function, and had lower levels of heart damage biomarkers than the wild-type ATTR-CM group.
Body-wide symptoms — especially neurological, eye, gut, and urinary problems — were more common in V30M carriers, particularly those with early-onset disease. For example, neurological symptoms were observed in all patients with early-onset disease.
“In our sample of patients with … V30M, predominantly with early-onset disease, significant conduction abnormalities were more frequent than overt amyloid cardiomyopathy, occurring in approximately 32 % and 20 %, respectively, with the former being often present without [heart muscle] involvement, particularly in early-onset cases,” the researchers wrote. “Patients with V30M pose different challenges compared to wild-type cases.”
