Clinical & Experimental Cardiology
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Transthyretin and Apolipoprotein AI-Type Amyloid Deposition in Aortic Valves of Patients with Aortic Stenosis: A Contemporary Review

Kohei Honda and Aya Miyagawa-Hayashino^{* *}Correspondence: Aya Miyagawa-Hayashino, Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan, Email:

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Description

Transthyretin Amyloidosis (ATTR) with Cardiomyopathy (ATTR-CM) is a frequent complication in patients with Aortic Stenosis (AS). Recent therapeutic advances for treating ATTRCM, including the introduction of tafamidis, which suppresses amyloid formation by stabilizing the tetrameric structure of transthyretin, have increased research interest in amyloid precursor proteins in AS-affected aortic valves [1-5]. Here, we summarize previous studies on the detection and effects of amyloid deposition on aortic valves as well as its relationship with cardiac function, focusing particularly on ATTR amyloid deposition on aortic valves.

Prevalence of aortic valve amyloid deposition associated with AS

Amyloid deposition in aortic valves was first described in the 1980s. In several studies examining aortic valves resected for treatment of diseases such as AS, Goffin et al., reported amyloid deposition in 18 of 106 (17%) valves, whereas Iwata et al., reported amyloid deposition in 29 of 59 (44%) valves using Congo-Red (CR) staining in addition to electron microscopy [6,7]. Cooper et al., and Ladefoged et al., reported amyloid deposition in 59 of 90 (66%) and 45 of 51 (88%) aortic valves, respectively [8,9]. Later studies revealed that the prevalence of amyloid deposition in aortic valves is high in AS patients undergoing Aortic Valve Replacement (AVR) [10-14]. Amyloid detection rates ranging from 45% to 74% have been reported in aortic valves with severe AS [10-14]. These amyloid deposits are found in fibrotic tissue in the vicinity of calcified foci and have been implicated in high hemodynamic stress, inflammation, oxidation and extracellular matrix remodeling [11,15]. Subsequent studies have attempted to identify the precursor proteins in aortic valves affected by AS. Immunohistochemistry (IHC) is commonly used to identify the type of amyloid present. Kristen et al., identified AApoAI as the amyloid deposited on aortic valves in 4 of 6 cases they examined, but Audet et al., did not report the detection rate of AApoAI [11,12]. ApoAI is a type of apolipoprotein that binds to lipids in the blood to form highdensity lipoproteins [11,12]. Thus, amyloid deposits in aortic valves are generally assumed to be AApoAI and considered to represent a localized form of amyloidosis affecting the valves.

Transthyretin as an amyloid precursor protein deposited on aortic valves and methods for its detection

Although amyloid precursor proteins in aortic valves of patients with AS are attracting clinical attention, no studies have determined whether transthyretin is deposited as amyloid on aortic valves of patients with AS [10-12]. We previously demonstrated ATTR deposition on aortic valves of patients with wild-type ATTR-CM with severe AS using IHC and Laser Microdissection (LMD)-Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) [16]. Using IHC alone, Singal et al., reported deposition of ATTR on the aortic valves of 46 patients with severe AS [13]. However, the background nonspecific staining was high and the CR-positive and ATTR-positive areas did not match well morphologically, making it difficult to determine whether the ATTR-positive area was a true amyloid deposition site [13]. When examining reports from the 1990s, the results of IHC analyses of aortic valve tissues must be interpreted carefully. Areas of non-specific staining that do not match the morphology of CR-positive regions are often seen, particularly in calcified foci. Amyloid cannot be detected in these areas using LMD–LC-MS/MS. Therefore, such staining should be considered a false-positive result [14]. Accurate amyloid typing using IHC requires contrast with the morphology of CR-positive regions, which can be combined with LMD–LCMS/ MS for more reliable typing. By adopting these techniques, our recent study demonstrated ATTR in 30 (68%) and AApoAI in 33 (75%) of 44 amyloid-positive, surgically removed aortic valves of 97 patients with AS [14]. In addition to AApoAI, which is well known, ATTR was detected at a high frequency in ASaffected aortic valves [14].

Association between ATTR-CM and valvular ATTR deposition in AS

Due to the emergence of bone scintigraphy (99mTc-DPD, 99mTc-HMDP, 99mTc-PYP) as an excellent technique for detecting ATTR-CM, it is now known that ATTR-CM is not a rare concomitant disease with AS but instead affects 4% to 16% of patients with severe AS. Not surprisingly, ATTR-CM is more common in patients who have undergone transcatheter-based AVR for severe AS than in those who have undergone surgical AVR. Treibel et al., demonstrated occult wild-type ATTR in myocardial tissue in 6 of 146 (4.1%) patients undergoing surgical AVR for severe AS [2]. Other studies detected ATTR-CM in 12% to 16% of AS patients who underwent transcatheter-based AVR. Among patients with AS who underwent transcatheterbased AVR, Castaño et al., found concomitant ATTR-CM proven using bone scintigraphy in 24 of 151 (16%) patients, whereas Scully et al., identified it in 26 of 200 (13%) patients and Nitsche et al., in 47 of 407 (12%) patients [3-5]. According to these previous reports, AS with ATTR-CM tends to occur at older age and is characterized by lower peak velocity and mean pressure gradients and worse cardiac remodeling and diastolic dysfunction than AS alone [2-5].

The relationship between AS and ATTR-CM has been frequently discussed, and an important question is whether AS appears as a type of amyloid deposit-related organ damage associated with systemic ATTR. None of the abovementioned previous studies assessed amyloid deposition in the aortic valve. In the study by Singal et al., both myocardial tissues and excised native aortic valves were examined in patients with severe AS in the Indian population [13]. None of the interventricular septum biopsy specimens showed amyloid deposits, whereas 33 of 46 (72%) native aortic valves showed amyloid deposits, of which 19 (58%) exhibited ATTR deposition [13]. In our recent study, of 7 patients who underwent bone scintigraphy after the detection of ATTR deposition in aortic valves, ATTR-CM was confirmed in 1 patient, although only a limited number of recent cases were examined using bone scintigraphy [14]. Thus, whether ATTR deposition in aortic valves can manifest as early lesions of systemic ATTR amyloidosis including the myocardium or a localized form of amyloidosis affecting the valves remains unclear.

Clinical correlation with amyloid deposition on aortic valves

Do these amyloid deposits in the aortic valve affect AS? Although Kristen et al., reported no significant association between amyloid deposition and hemodynamic measurements, in our recent study, patient age and the ratio of transmitral early filling velocity to mitral annular early diastolic velocity (E/e’) were significantly lower in amyloid-positive cases compared with amyloid-negative cases [11]. In addition, among amyloid-positive cases, serum brain natriuretic peptide levels were significantly lower in ATTR-positive cases, and fractional shortening and left ventricular ejection fraction were significantly higher in ATTRpositive cases than in ATTR-negative cases, but there were no significant differences between the two groups in effective orifice area or peak velocity [14]. These results indicate that AS with ATTR deposition in the aortic valve tends to exhibit betterpreserved cardiac function than AS without ATTR deposition, suggesting that ATTR may accelerate the progression of AS. Whether pressure overload due to severe AS induces occult ATTR deposition in aortic valves or ATTR deposition in aortic valves contributes to the progression of AS, or whether cardiac overload associated with AS induces left ventricular remodeling and promotes ATTR deposition in the left ventricle, remains to be determined. Follow-up using bone scintigraphy in patients with AS may thus be desirable.

Details regarding amyloid deposition on the aortic valve in AS patients are gradually emerging in terms of the deposition mechanisms and amyloid types. Due to progress in the treatment of ATTR amyloidosis using agents such as tafamidis, ATTR in particular has received increased attention, and investigations into the association with AS and amyloid cardiomyopathy are continuing [1]. A particularly important issue for consideration is the association between amyloid deposition in the aortic valve and AS, as research in this area could lead to the development of new treatments for AS.

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