Aortic Stenosis (AS) is one of the most common valvular diseases, affecting approximately 5% of adults over 75 years old.^1,2 Cardiac Amyloidosis (CA) is a rare disease primarily affecting the elderly, characterized by the extracellular deposition of insoluble fibrils of low molecular weight proteins.³ Early diagnosis of CA can influence its progression.^4,5

AS and CA are two entities that, despite having distinct etiologies, share pathophysiological similarities, as both can lead to myocardial hypertrophy and comparable hemodynamic repercussions, mainly associated with heart failure (HF).^6-8

The exact prevalence of CA in the general population, as well as in those with AS, is underestimated, as systematic screening is not yet in place.⁶

Recent studies suggest that the coexistence of AS and CA is more common than previously thought, reaching approximately 16%. The potential coexistence of CA and AS may impact the clinical course of elderly patients with these conditions.^6,8,9

This study aimed to estimate the prevalence of CA in elderly patients with moderate to severe AS.

Forty-one elderly patients with moderate or severe AS were evaluated. The mean age of the cases was 79 ± 6 years, 23 (56%) were female, 22 (53%) exhibited some degree of frailty according to the Edmonton Frail Scale, and eight (23%) had cognitive impairment. Thirty-eight (92%) patients had symptomatic AS, with six (15%) patients classified as New York Heart Association (NYHA) functional Class III. Dyspnea was the most commonly reported symptom, with 33 (80%) patients reporting this complaint. (see Table 1).

There was a predominance of patients with classic severe AS pattern with elevated gradient and preserved Ejection Fraction (EF) (56%). Ten patients (24%) had low-flow low-gradient pattern. (see Table 1).

A RAISE score ≥ 2 was found in four patients (9%).

Regarding the assessment of surgical risk scores, 28 (68%) had an STS score of less than four, indicating low surgical risk (see Table 2).

Carpal tunnel syndrome was present in two (4%) patients, and eight (19%) had polyneuropathy.

Table 3 outlines the main electrocardiographic characteristics and cardiac marker levels.

Regarding echocardiographic data, the mean EF was 59.2% ± 15.3%, with 11 (26%) patients having ventricular dysfunction with EF less than 50%. (see Table 4).

The distribution of scintigraphy findings according to Perugini classification was as follows: 8 (19%) patients with no uptake, 24 (58%) with grade 1 uptake, and nine (22%) with grade 2/3 uptake.

Four patients were found to have scintigraphy highly suggestive of ATTR (high uptake in both quantitative and qualitative assessments), with one of them having a genetic mutation of Val122Ile, classified as Variant Transthyretin Amyloidosis (ATTRv). Thus, three patients were classified as Wild-type Amyloidosis (ATTRwt).

A comparison was made between patients with AS diagnosed with CA (scintigraphy with high quantitative and qualitative uptake) and those without CA on scintigraphy. There was no statistically significant difference between the groups for the variables evaluated (see Table 5).

In the group diagnosed with amyloidosis, three (75%) patients were male. NT-proBNP and troponin levels were higher in those with amyloidosis on scintigraphy but with non-significant p-values.

A RAISE score ≥ 2 was found in one patient with amyloidosis and three patients without amyloidosis.

The calcium score was higher in those without CA compared to those with CA, but with non-significant p-values.

AS and CA represent two distinct yet pathophysiologically intertwined conditions, both capable of inducing myocardial hypertrophy and hemodynamic alterations, particularly associated with Heart Failure with Preserved Ejection Fraction (HFpEF).^12,13

This study, conducted at a leading referral center specializing in percutaneous aortic valve implantation, elucidated several noteworthy findings. The majority of patients exhibited classic severe AS, characterized by elevated systolic gradients and preserved EF. Notably, the literature often portrays a different pattern in AS/CA coexistence, frequently presenting as paradoxical low-flow, low-gradient AS with preserved EF.¹⁴

The increased prevalence of low-flow status in CA patients may be attributed to pronounced left ventricular concentric remodeling, worsened ventricular filling, left atrial dysfunction and remodeling, significant longitudinal strain reduction (greater than or equal to −12%), and right ventricular remodeling and dysfunction.^14-16

Remarkably, our study revealed only a small proportion of patients with moderate AS, with one individual demonstrating high tracer uptake on scintigraphy and a diagnosis of wild-type ATTR. This underscores the importance of closely monitoring patients with moderate AS for potential amyloid deposition and its impact on valve disease progression.^11,17,18

In terms of cardiac biomarkers (BNP and troponin), our data indicated persistently elevated levels, indicative of silent myocardial injury despite preserved EF, consistent with the existing literature.¹³

While many studies rely solely on the Perugini score for scintigraphy interpretation, we opted for a comprehensive approach, considering both qualitative and quantitative criteria. This approach allowed us to identify a subset of patients with concomitant AS and CA, shedding light on a potentially underrecognized cohort.^19-21

Although Perugini grade 1 uptake was prevalent among AS patients in our cohort, indicating subclinical amyloid deposition, its clinical significance and progression to CA remain elusive.²² Nonetheless, the existing literature suggests worse outcomes in patients with such findings, emphasizing the need for further investigation.^1,23

Furthermore, our study uncovered a case of hereditary ATTR with the Val122I mutation, a variant commonly associated with cardiomyopathy, particularly among African American populations.²⁴

The concept of occult amyloidosis first emerged in 2016 among patients referred for percutaneous aortic valve implantation, sparking subsequent research endeavors aimed at detecting ATTR. However, the systematic screening of AS patients for amyloidosis using cardiac scintigraphy with bone tracers remains impractical in most cardiology centers.^25,26

The RAISE score offers a valuable tool for integrating various clinical parameters to guide further investigation, such as scintigraphy. While our study did not identify a significant association between the RAISE score and amyloidosis diagnosis, its role in risk stratification warrants further exploration.⁹

Hussain et al. described a sub-cohort of patients with CA who may develop severe AS in the absence of significant calcification (with calcium scores that, according to conventional guidelines, would make the diagnosis of significant AS unlikely). This finding suggests that aortic valve calcium scores may be less applicable in a subset of patients with CA for assessing the severity of AS.²⁷ This study also noted a potential trend of lower calcium scores in patients with high radiotracer uptake on scintigraphy, although the p-value was not significant. This could be attributed to the small sample size, which may increase the risk of overestimating the magnitude of the effects or associations observed.

The primary limitation of this study was the small sample size (41 patients). The sample size estimation was based on a previous study that expected a 16% coexistence rate of AS and CA, estimating a sample size of 52 patients. It is essential to interpret the 10% prevalence found for the coexistence of AS/CA within the context of the study's sample size. In this scenario, a lower statistical power is insufficient to detect a significant difference between the estimated and actual prevalence. A larger sample size would be particularly important for making more meaningful comparisons between patients with positive and negative scintigraphy results in terms of sociodemographic and clinical characteristics. Therefore, we have taken care to report this limitation and acknowledge that these data are preliminary, serving as precursors for future research.

Our study was conducted at a single referral center, limiting the generalizability of our findings. Additionally, the true prevalence of AS/CA coexistence remains uncertain, necessitating further investigation in diverse populations and settings.^26,28

The bone radiotracer used in the scintigraphy for diagnosing TTR amyloidosis was technetium-99m pyrophosphate. At the beginning of the study, there was a period in 2021 when this material was unavailable, which affected the inclusion of a larger number of patients.

Despite the small sample size of this study, a 10% prevalence of AS/CA coexistence was found, a value consistent with that reported in other cohorts.^9,13

This study aimed to evaluate the prevalence of amyloidosis, primarily of the TTR type, in the context of AS. The inclusion criteria focused on patients with high radiotracer uptake on both qualitative and quantitative scintigraphy evaluations, excluding those with grade 1 uptake indicative of subclinical amyloidosis. This approach ensured a more accurate assessment of clinically relevant amyloidosis cases associated with AS.

Despite these limitations, our study provides valuable insights into the prevalence and clinical implications of AS/CA coexistence, laying the groundwork for future research endeavors in this rapidly evolving area of investigation.

The prevalence of CA in patients with moderate to severe calcific AS in our sample was 9%. Due to the low prevalence of the condition, the sample size was insufficient to characterize clinical and echocardiographic differences between patients with or without amyloidosis.

This study was pioneering in attempting to diagnose CA in patients with moderate and severe AS in our population, confirming the coexistence, which may have clinical and prognostic implications.