Amyloidosis is a severe, progressive, infiltrative disease developing secondary to the deposition of congophilic fibrils composed of aggregated misfolded proteins [20]. Recent data shows that ATTR accounts for the vast number of CA cases, although there are slight variations in disease presentation and prevalence across different geographical and ethnic populations [6, 21,22,23]. In this study, we identified rare types of ATTR variants. Worldwide, the most frequent variants include Val122Ile, occurring in 3.4% of African Americans [24], while in European countries, in the THAOS registry, Val30Met is the most frequent pathogenic variant, with a high concentration in Portugal; this is followed by Ile68Leu, with the highest number of cases being seen in Italy [25].

Our study employed a non-invasive approach as the primary diagnostic strategy for ATTR. In recent years, imaging techniques have made major advancements and have gained wider clinical acceptance in the diagnosis of CA [5, 26, 27]. Alongside the growing evidence supporting non-invasive diagnostic algorithms for ATTR, novel therapies have emerged, leading to improved survival rates [12,13,14,15,16]. Importantly, recent data has demonstrated that the prevalence of ATTR may be higher in specific patient subgroups, namely HFpEF, elderly patients, and individuals with severe AS [7, 8]. Our findings confirm that ATTR may be underdiagnosed in patients with unexpected increased LV wall thickness, emphasizing the importance of considering ATTR as a potential etiology in these cases.

In a population-based cohort study involving patients with HFpEF, aged 60 years or older, 286 individuals underwent technetium-99 m pyrophosphate ([99mTc]Tc-PYP) cardiac scintigraphy. Among this cohort, 18 patients (6.3%) were diagnosed with ATTR, and the prevalence of ATTR increased to 21% in patients aged 90 years and older (P < 0.001) [28]. Similarly, a prospective study of 120 consecutive HFpEF patients aged 60 years or older with LVH (≥ 12 mm) demonstrated uptake in 16 patients (13.3%) on [99mTc]Tc-DPD scintigraphy. Based on further clinical evaluation, the authors concluded that ATTRwt is an underdiagnosed condition that accounts for a significant number (13%) of HFpEF cases in the elderly population [7]. These findings are consistent with the prevalence of ATTR observed in this study, Moreover, autopsy studies conducted in elderly subjects have revealed the presence of amyloid deposits within the LV in 14–25% of individuals, depending on patient selection and the methodology adopted [29,30,31,32]. Conversely, the prevalence of ATTRwt in individuals aged 75 years or older, with no previous clinical suspicion of amyloidosis, was investigated over a 7-year period [33]. The prevalence of cardiac uptake was 3.88% in males and 0.77% in females, with an age-related increase reaching 13.9% in males aged 85 years or older, and 2.7% in females. In this study, the authors estimated the prevalence for the European standard population aged 75 years or older was 4.15% in males, 1.03% in females, and 2.59% in the general population.

In our study, we emphasize the diagnostic challenges of cardiac amyloidosis, highlighted by a patient case of AL amyloidosis with a positive DPD scan, definitively confirmed through histopathological examination. This case underscores the essential nature of a thorough and multi-disciplinary diagnostic approach in accurately diagnosing and treating this multifaceted condition.

Importantly, ATTR has been reported in patients with AS [8, 11]. A study examining 151 elderly patients with severe symptomatic AS, who underwent transcatheter aortic valve replacement (TAVR), investigated the presence of ATTR using [99mTc]Tc-PYP cardiac scintigraphy. The results revealed that 16% of the patients screened positive for ATTR [8]. Clinically, ATTR was associated with a severe AS phenotype characterized by low-flow, low-gradient with mildly reduced ejection fraction, more pronounced LV thickening, advanced diastolic dysfunction, and more impaired global longitudinal strain (P < 0.05). The average of lateral and septal mitral annular TDI S′ was found to be the best predictor of ATTR. Notably, a TDI S′ value < 6 cm/s conferred 100% sensitivity for predicting a positive [99mTc]Tc-PYP amyloid scan. In our study, patients with ATTR exhibited significantly lower TDI S′ and A′ velocities in both the LV lateral wall and intraventricular septum (p < 0.05). In this study, patients presenting with severe AS were systematically excluded from the analysis to delineate more clearly the phenotypic characteristics and prevalence of ATTR cardiomyopathy within a cohort presenting with unexplained left ventricular hypertrophy. This decision was predicated on the objective to reduce confounding factors attributable to the hemodynamic and structural impacts of AS on the heart, which can mimic or obscure the manifestations of ATTR cardiomyopathy. The exclusion of this subgroup allows for a more precise characterization of ATTR-related cardiac changes, offering clarity in the context of this specific cardiac amyloidosis. However, this methodological choice warrants a discussion regarding its potential impact on the study’s findings and the generalizability of the results. The exclusion of patients with severe AS might lead to an underestimation of the true prevalence of ATTR cardiomyopathy. This is particularly relevant considering that ATTR and AS can coexist, especially in the elderly population, where both conditions are more prevalent. The concurrent presence of AS might not only contribute to the LV hypertrophy observed in ATTR cardiomyopathy but could also serve as a confounding factor leading to underdiagnosis or misdiagnosis of the condition.

Despite the common occurrence of increased LV wall thickness in routine clinical practice, limited data exists regarding the frequency with which ATTR contributes to these lesions. Given the ongoing development of novel therapeutic agents targeting ATTR, it is important to establish a comprehensive understanding of the prevalence of this disease in clinical settings. In a prospective multicenter study, the TTR gene was sequenced in a cohort of patients with LVH, revealing 5% exhibited ATTRm-related CA [9]. Subsequently, an adjusted multivariate model demonstrated that African origin, neuropathy, carpal tunnel syndrome, ECG low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were identified as independent factors associated with ATTRm. Similarly, in our study, neuropathy, carpal tunnel syndrome, and ECG low voltage were also significantly associated with the diagnosis of ATTR. Interestingly, hypertension was found to be present in 50% of the patients, suggesting that the frequency of ATTRm in that particular group could be underestimated in comparison to populations where individuals with any preexisting cause of LV hypertrophy were excluded.

In choosing a left ventricular thickness threshold of 15 mm for inclusion, we aimed to focus on patients potentially exhibiting ATTR cardiomyopathy who present as hypertrophic cardiomyopathy phencopy, distinguishing our cohort from the more general group of patients with ‘any’ hypertrophy (that can be also defined as LV wall thickness > 12 mm). This decision allows for a targeted analysis of ATTR-specific manifestations, acknowledging that a 12 mm threshold often serves as a general red flag for cardiac amyloidosis but may include a wider range of conditions and disease severities.

Our analysis data shows that a significant proportion of patients with unexplained LV thickening are likely affected by cardiac amyloidosis (CA). This finding supports previous reports in the literature suggesting the probable occurrence of this underdiagnosed condition [9]. Considering the critical role of appropriate pharmacological treatment in managing patients with AL and ATTR, it becomes imperative to grasp the implications of CA on the therapeutic pathway. The challenge also lies in accurately interpreting complementary molecular imaging-based diagnostic approaches. Our analysis identifies several factors associated with ATTR, including polyneuropathy, gastropathy, carpal tunnel syndrome, lumbar spine stenosis, low voltage, ventricular arrhythmia, LV maximum wall thickness, LV mass, LV ejection fraction, GLS, E/A, E/E′, RV thickness, right atrium area, RV VTI, TAPSE, apical sparing, ground glass appearance of myocardium, thickening of interatrial septum, thickening of valves, and the “5–5–5” sign. Moreover, ATTR appears particularly likely when increased LV mass coincides with decreased GLS and thickening of RV. Therefore, it follows that patients exhibiting these clinical characteristics should qualify for rigorous medical scrutiny during the interpretation of imaging results.