Transtyretin Cardiac Amyloidosis in Elderly Patients: Always a Wild Type?

Abstract Background Transthyretin amyloidosis (ATTR) exists in two forms: a genetic form transmitted by autosomal dominant inheritance (ATTRv) and a wild type form (ATTRwt). Clinically, the hereditary form tends to have an early onset in adulthood and it is characterized by a particular tropism for nervous as well as cardiac tissue. In contrast, the "wild type" form has a later onset with major cardiac involvement and neurological manifestations usually limited to carpal tunnel syndrome. Methods and Results In our centre, from September 2021 to June 2023, 52 patients older than 70 years received a diagnosis of cardiac ATTR (87% male, 13% female, mean age 81±5y). In all patients, blood tests showed a significant and stable increase in the values of troponin Ths (0.079 microg/L±0.074) and NT–proBNP (2000±1800 pg/ml), with the absence of a monoclonal component in the blood and urine, and miocardial bisphosphonate scintigraphy positive grade 2/3. All patients underwent genetic testing by amplification of exons 2,3 and 4 of the TTR gene with subsequent sequencing. Unexpectedly, in 10 elderly (70%male, 30% female, mean age 77±4 y) patients (19%) the genetic test resulted positive with 4 different mutations of pathogenetic significance (Val30Met; Ile68Leu; Val142Ile;, Phe84Leu). Three patients showed peripheral neuropathy with the presence of carpal tunnel syndrome, while isolated carpal tunnel syndrome was present in the remaining 7 cases. The three patients with neurologic involvement started Patisiran therapy, and 7 patients were treated with Tafamidis. First–degree relatives (16 consanguineous, average age 49±12 years) agreed to be subjected to genetic screening; of these 9 (3 male and 6 females, age 47±8 years) were positive for the corresponding mutation and underwent echocardiogram, MRI and myocardial scintigraphy. These tests were normal in 8 probands, included in an annual follow–up protocol to identify an early manifestation of the disease, and was diagnostic for amyloidosis in 1 patient who started specific therapy. Conclusions Our experience shows that 19% of patients older than 70 years with a diagnosis of cardiac ATTR may be affected by a genetic form. Making genetic diagnosis in this context is particularly important for screening family members: current therapies are in fact much more effective if started early before organ damage occurs.