In the last 10 years, cardiac amyloidosis has transitioned from being a rarely diagnosed disease, primarily managed by internal medicine specialists, to a condition included in all diagnostic algorithms for patients with left ventricular hypertrophy and heart failure with preserved ejection fraction. Wild-type cardiac amyloidosis is no longer diagnosed only at advanced ages or with a grim catastrophic prognosis and no treatment options; t is now being identified at ever earlier ages and, crucially, can be treated using various disease-altering approaches.
Similarly, the hereditary form of the disease—transthyretin-mediated amyloidosis (ATTRv)—which was once largely unknown to clinical cardiologists, except in endemic regions, is gaining recognition. The most common form of ATTRv is associated with the p.Val50Met variant. This entity is generally characterized by a mixed phenotype with a greater predominance of polyneuropathy and dysautonomia symptoms. This condition is thus generally followed up by neurology departments.1,2
Other genetic variants besides p.Val50Met were, until recently, rarely seen in Spain and typically identified only in isolated cases. However, in other countries, variants such as p.Val142Ile have been found in 3.5% to 10% of their populations, usually in individuals of African descent.3,4
In an article recently published in Revista Española de Cardiología, Frutos et al.5 present a cohort of patients of European descent with ATTRv due to the p.Val142Ile variant. This is the largest such cohort published to date. The authors analyzed genotype-phenotype correlations in this cohort to determine the frequency of this variant in the Spanish population. As noted by the authors, this retrospective multicenter study has the typical limitations associated with this type of research.
In the study, 16 Spanish centers included both patients diagnosed with ATTRv due to p.Val142Ile and carriers, regardless of phenotype. The authors recorded the participants’ baseline characteristics and any events occurring during follow-up. Population frequency was evaluated using the Spanish National DNA Bank (n=3569) and the Catalan Biobank (n=790).
The cohort comprised 164 individuals: 75 probands (45.7%) and 89 family members (54.3%). Among the probands, the mean age was 73.9 ± 8.5 years and 47 (62.7%) were men. In addition, 67 probands (89.3%) had European ancestry and only 6 participants (8%) were of African descent. Cardiac symptoms were the most common reason for ATTRv diagnosis (n=64; 85.3%). Overall penetrance at 65, 75, and 85 years was 12.8%, 44.3%, and 94.2%, respectively. The estimated population frequency was 0% in the Spanish database and 0.12% in the Catalan database.
The authors concluded that ATTRv caused by p.Val142Ile has a significant prevalence in Spain and is characterized by delayed onset, male predominance, and cardiac injury.
INCREASE IN DIAGNOSES OF TRANSTHYRETIN-MEDIATED AMYLOIDOSISCompared with previous studies, the authors detected a significant increase in ATTRv diagnoses, clearly due to a better understanding of the disease, the availability of a noninvasive diagnostic test, and the widespread access to genetic studies in Spain. We must acknowledge the excellent work of familial heart disease units and specialized cardiomyopathy clinics in Spain. The exemplary teamwork of these centers is evident in their joint publications, such as the present article, in high-impact journals, establishing Spain as a leader in this field. The long-standing incorporation of genetic studies in these clinics has resulted in a surge in ATTRv diagnoses due to the systematic evaluation of patients with hypertrophic cardiomyopathy. Occasionally, patients with ATTRv and cardiac involvement alone can be difficult to distinguish from those with hypertrophic cardiomyopathy caused by sarcomeric gene variants. The inclusion of genes related to genocopies and phenocopies in the massively parallel or next-generation sequencing panels typically used in these studies aids the detection of pathogenic TTR variants. This approach is recommended in the 2023 European Society of Cardiology guidelines, in contrast to recent American guidelines for hypertrophic cardiomyopathy, which advise including these genes only when a phenocopy diagnosis is suspected.2,6 In our opinion, it is incorrect to omit genes related to genocopies/phenocopies (eg, TTR, GLA, and PRKAG2) from the diagnostic panels. This policy could result in delayed diagnoses of diseases with specific treatments that are more effective when initiated earlier.
POPULATION FREQUENCY IN A POPULATION OF EUROPEAN DESCENTThe Spanish population is believed to have one of the most diverse genetic profiles in Europe due to the invasions, migrations, and colonizations of previous centuries. Notably, no cases of ATTRv have been reported in the Cantabrian basin, and most cases have been diagnosed in the Mediterranean region. This difference may be related to the more frequent migration from North Africa in that area. The authors included only 1 homozygous patient in their cohort; this individual had nonconsanguineous parents from different Spanish provinces. In 2019, Marrero Negrín et al.7 (from Las Palmas in Gran Canaria) reported 3 individuals who were homozygous for this variant, all with White consanguineous parents and no African ancestry. These findings support the theory that this variant exists in Spain and has a nonnegligible frequency.
PREDOMINANT CARDIAC INVOLVEMENT AND DELAYED ONSETThe authors did not detect any differences in clinical presentation compared with what has already been reported in the African American population. That is, the patients typically exhibited cardiac involvement with delayed presentation and little neurological involvement. Accordingly, the authors suggest that phenotype development should not be evaluated in carriers until they reach the age of 55 years. Homozygosity was associated with earlier onset, while female sex was related to an older age of onset and a less aggressive disease trajectory.
For the first time, ophthalmologic involvement was reported in 1.8% of the patients. This highlights the importance of evaluating these patients in a coordinated multidisciplinary team, regardless of the causal genetic variant.
It is important to conduct a genetic study of the TTR gene in all patients diagnosed with transthyretin cardiac amyloidosis, irrespective of age, sex, and ethnicity.8 In a previous study performed in Puerta de Hierro Hospital in Madrid of patients diagnosed with transthyretin-mediated amyloidosis and older than 70 years, 5.3% carried a pathogenic variant of the TTR gene.9 Nearly all participants were White (99%). This variant information is vital not only for patients (because the treatment may differ) but particularly for their relatives, because they could be diagnosed at an earlier stage of the disease and benefit more from specific treatments.
In the coming years, we will undoubtedly see an increase in ATTRv diagnoses due to the widespread implementation of genetic testing in our clinics. Thanks to work such as that by Frutos et al.,5 we will better characterize the disease and more frequently initiate early treatment. In the near future, we will determine whether the p.Val142Ile variant is more common in Spain than the p.Val50Met variant. Ultimately, “seek, and you shall find”.
FUNDINGNo funding was received for this editorial.
CONFLICTS OF INTERESTR. Barriales-Villa and J.M. Larrañaga-Moreira have served as consultants for Pfizer and Alnylam and have received support for conference attendance. E. Martín-Álvarez has no conflict of interest.