Heart markers, nerve involvement linked to worse hATTR-CM outcomes
Study: Early diagnosis, disease-specific therapies key to improving prognosis
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Signs of more advanced heart disease and the presence of nerve involvement are associated with a higher risk of worse outcomes, including heart failure, hospitalization due to heart disease, and death, in people with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM).
That’s according to a nationwide study in Spain, which also found that certain disease-causing mutations and disease-specific therapies were associated with longer survival in this patient population.
“This national [patient group] — the largest reported to date — highlights the clinical and genetic [diversity] of [hATTR-CM] in Spain,” researchers wrote. “Early diagnosis and disease-specific therapies are essential to improving prognosis.”
The study, “Predictors of poor prognosis in a large cohort of patients with hereditary cardiac transthyretin amyloidosis,” was published in Revista Española de Cardiología.
Most hATTR patients develop mixed form, with heart, nerve involvement
Hereditary transthyretin amyloidosis (hATTR) comprises a group of conditions caused by mutations in the TTR gene, which result in the production of a faulty form of the transthyretin protein. This abnormal protein forms toxic clumps, called amyloid fibrils, that accumulate in tissues and organs, damaging them.
When these amyloid fibrils build up mainly in the heart, the condition is known as hATTR-CM, or hATTR cardiac amyloidosis. It can lead to symptoms such as irregular heart rhythms, heart failure, and sudden cardiac death, which occurs when the heart suddenly stops beating.
If nerves outside the brain and spinal cord are primarily affected, it is referred to as hATTR with polyneuropathy (hATTR-PN). Most hATTR patients develop a mixed form, with both heart and nerve involvement.
Although disease-modifying therapies can slow hATTR progression, access to treatment varies among countries, and outcomes are generally better when treatment begins early.
“In hATTR, cardiac amyloidosis is one of the main causes of [illness] and mortality,” the researchers wrote. However, “in Spain, data on hATTR with cardiac involvement are scarce.”
Heart disease severity increased during follow-up
To better understand the features of hATTR-CM in the country and identify predictors of poor prognosis in this patient population, a team of researchers in Spain analyzed data from 442 adults diagnosed with hATTR-CM between January 2000 and September 2022 at 39 hospitals nationwide. Patients were followed for a median of 5.6 years from symptom onset and 3.2 years from diagnosis.
Participants had a median age of 65 at diagnosis, and 67.6% were men. The median delay between symptom onset and diagnosis was 18 months, or about 1.5 years. Symptoms outside the heart were the most common initial complaint (34.5%), and nearly two-thirds (64.6%) had nerve involvement.
At the first evaluation, most patients (89.6%) had no or some symptoms of moderate heart disease, such as fatigue, palpitations, or shortness of breath during ordinary activities.
Also, mean blood levels of NT-proBNP, a marker of heart stress, were higher than normal, and mean left ventricular ejection fraction (LVEF) — a measure of how well the heart pumps blood — was 57.2%, indicating generally preserved function.
During follow-up, however, heart disease severity increased. The proportion of patients with advanced heart-related symptoms rose from 8.1% to 17.2%, and those with the most severe symptoms increased from 2.3% to 3.7%. Mean NT-proBNP levels also rose significantly over time, alongside signs of progressive structural heart damage.
Patients who received disease-specific treatment had longer survival
Among the 15 distinct TTR mutations identified in participants, the most common was p.Val30Met (64.9%), which is also the most common hATTR-causing mutation. It was followed by Val122Ile (21.5%) and Glu89Lys (5.2%). People carrying p.Val30Met were significantly more likely to have milder heart disease symptoms and to have neurological involvement.
During follow-up, 36.2% of patients received tafamidis (sold in Europe as Vyndaqel for both hATTR-PN and hATTR-CM, with different dosages for each condition), and 20.8% received patisiran (sold as Onpattro for the treatment of hATTR-PN). Additionally, 18.8% underwent liver transplant — historically a standard treatment for hATTR because transthyretin is mainly produced in the liver — and 5.9% underwent a heart transplant.
Nearly half of participants (48.9%) were hospitalized, most frequently due to a heart-related event (64.8%), and 21.9% died, most often due to heart failure (25.3%) or sudden cardiac death (16.5%).
This retrospective, multicenter study provides real-world evidence in a large Spanish [patient population], reinforcing the importance of early detection, [mutation-specific] management, and disease-specific therapy to improve outcomes.
Most patients (80.2%) were alive five years after symptom onset, and 66.9% were alive five years after diagnosis. Median survival from symptom onset was 19.2 years. Patients carrying the p.Val30Met mutation and those who received disease-specific treatment had significantly longer survival than those carrying Val122Ile or Glu89Lys and untreated patients.
Further statistical analyses showed that severe heart disease symptoms, lower LVEF, higher blood NT-proBNP levels, and the presence of neurological involvement were independent predictors of poor outcomes, including heart failure, heart transplant, hospitalization due to heart disease, and death.
This supports “their clinical utility for risk stratification” in people with hATTR-CM, the researchers wrote.
“This retrospective, multicenter study provides real-world evidence in a large Spanish [patient population], reinforcing the importance of early detection, [mutation-specific] management, and disease-specific therapy to improve outcomes,” the researchers wrote.
