A General Overview of Transthyretin Cardiac Amyloidosis and Summary of Expert Opinions on Pre-Symptomatic Testing and Management of Asymptomatic Patients with a Focus on Transthyretin V122I

Published: Feb 26, 2025

Abstract

Transthyretin cardiac amyloidosis (TTR-CA) is a pathological condition characterized by the accumulation of misfolded transthyretin (TTR) protein in the heart, leading to restrictive cardiomyopathy. TTR-CA has gained increasing recognition in recent years due to its significant impact on morbidity and mortality. It is typically diagnosed when symptoms of heart failure appear. However, with advancements in non-invasive imaging, early and precise diagnosis of TTR-CA is now possible, enabling clinicians to take advantage of current therapeutic interventions that are more effective when initiated at an earlier stage of the disease. Moreover, genetic testing can now assist clinicians in identifying asymptomatic individuals who are at risk of developing the disease before clinical features manifest. In this review, we provide a general overview of TTR-CA and summarize expert opinions on pre-symptomatic testing and the management of asymptomatic patients, with a particular focus on the V122I mutation. This article aims to provide clinicians with a better understanding of TTR-CA and the current best practices for managing asymptomatic patients with this genetic predisposition.

Keywords:

cardiac amyloidosisexternal link, opens in a new tab; transthyretin V122Iexternal link, opens in a new tab; asymptomatic patientsexternal link, opens in a new tab; ATTRexternal link, opens in a new tab

1. Introduction

Amyloidosis refers to a broad clinical syndrome caused by misfolded precursor proteins that aggregate into amyloid fibrils and deposit throughout tissues and organs, altering their internal architecture and disturbing homeostasis [1]. Amyloidosis is classified according to the organ affected and the precursor protein involved, with the three most common types being monoclonal light chains (AL), transthyretin (TTR), and amyloid A (AA) (Table 1) [1]. Cardiac involvement in transthyretin amyloidosis (ATTR) is referred to as transthyretin cardiac amyloidosis (TTR-CA) and typically presents as heart failure with preserved ejection fraction (HFpEF) [1]. TTR-CA can be acquired through the accumulation and aggregation of wild-type TTR (wtTTR) or through gene mutations via an autosomal dominant hereditary pattern (hTTR) [1].

One of the most common variants worldwide, V122I, affects 3–4% of the African American population and is the most common mutation responsible for hTTR-CA in the United States (U.S.) [2,3,4]. The V122I TTR variant has gained considerable interest in the medical community due to its increasing recognition as a prevalent cause of heart failure and its notable association with mortality, particularly among African American adults above the age of 50 [5,6,7,8,9,10]. The clinical management of TTR-CA has been transformed by the progress in non-invasive diagnostic testing and the development of pharmacological agents that can slow down the amyloidogenic process, emphasizing the importance of early and accurate detection and diagnosis [11]. With the increasing use of genetic screening, many asymptomatic individuals with V122I genes for TTR-CA are encountered. Currently, the data are scarce on how to manage these individuals, including the need and frequency of active surveillance. In this review, we present the current literature on that aspect. Additionally, we provide a general overview of TTR-CA, with an emphasis on the most common genotypes.

2. TTR-Cardiac Amyloidosis

2.1. Pathogenesis

TTR-CA is a progressive infiltrative cardiomyopathy caused by the deposition and accumulation of misfolded TTR proteins in the heart [1]. TTR is a 127-amino acid carrier protein primarily synthesized in the liver, and it can disassemble into amyloid fibrils as a result of the natural aging process (wtTTR) or genetic mutations (hTTR) [1,12]. The precise mechanism underlying the misfolding of TTR proteins in wtTTR remains incompletely understood; however, it is believed that age-related processes likely play a significant role in the destabilization of the protein [12,13].

In contrast, a single-point mutation within the TTR gene is responsible for the misfolding of amyloid fibrils in hTTR. There are over 130 different mutations or variants that have been identified in the literature [14]. These mutations are inherited via an autosomal dominant pattern, with each mutation resulting in a unique phenotype [12]. The most common mutations seen in hTTR-CA are V122I, Val30Met, and T60A [12]. Making up 23% of all ATTR cases, V122I is the most common mutation responsible for hTTR-CA in the U.S. [3]. V122I specifically refers to a point mutation in the TTR gene that results in the substitution of isoleucine for valine at position 122 on the TTR protein. Ultimately, the deposition and accumulation of misfolded TTR proteins in the heart, either by wtTTR or hTTR, can lead to a decline in cardiac compliance. This initially results in diastolic dysfunction and may ultimately progress to a reduction in global systolic function, often complicated by arrhythmias [12,15].

2.2. Clinical Manifestations

In the U.S., TTR-CA classically presents with signs and symptoms of heart failure (HF) in men typically in their fifth or sixth decade of life [16,17]. In general, hTTR-CA has more variability in its clinical trajectory compared to wtTTR-CA. hTTR-CA can present primarily as a cardiomyopathy, peripheral or autonomic neuropathy, or mixed clinical features, depending on the mutation [2,15,18]. Extracardiac manifestations are less common in wtTTR-CA [1]. The extent of cardiovascular involvement is a critical determinant of disease outcomes, with an estimated median survival after diagnosis of 3.6 and 2.5 years for wtTTR-CA and hTTR-CA, respectively [18,19].

TTR-CA has been diagnosed more frequently in men than in women [17,20,21]. Affected females are thought to have less severe symptoms compared to males and a similar mortality rate to non-carriers [8,20,21] However, a recent study showed that significantly more females were being diagnosed with wtTTR-CA after their death, suggesting wtTTR-CA is likely not as uncommon or benign in females as once thought [17]. Following that study, a large nationwide cohort study by Haring et al. examined the relationship between TTR V122I carrier status, cardiovascular disease (CVD), and mortality among African American females [7]. CVD risk included HF, coronary heart disease (CHD), and CVD death events. The study revealed that African American females carrying the V122I genetic variant had a significantly higher risk of CVD and all-cause mortality compared to their non-carrier counterparts [7]. Specifically, female carriers >60 years of age were at a higher risk of CVD, and female carriers ≥65 years of age had a higher risk of all-cause mortality compared to their non-carrier counterparts. Furthermore, the risk increased with age [7].

2.2.1. Wild Type TTR-CA

Wild-type TTR-CA is the most common type of TTR-CA, typically diagnosed in Caucasian males in their 80s; however, symptoms can start in the sixth decade of life [17,18,22]. Although challenging to ascertain accurately due to potential underdiagnoses, the prevalence of wtTTR-CA is estimated to be as high as 25% and 37% in patients above the age of 80 and 95, respectively [18]. Compared to hTTR-CA, wtTTR-CA exhibits less variability in its clinical course, presenting as HFpEF, with peripheral and autonomic neuropathy being less common and less severe when present [18]. The cardiac symptoms most commonly reported at the time of diagnosis include dyspnea reported in 67% of patients, edema in 53%, and atrial fibrillation in 62% [17]. Conduction system abnormalities are more common in wtTTR-CA, with atrial arrhythmias being identified in up to 40–60% of patients at the time of diagnosis and almost all patients experiencing atrial arrhythmias during the natural course of the disease [18]. Ventricular arrhythmias are also common and often require an implantable cardioverter-defibrillator (ICD) [22].

The extracardiac manifestations most commonly reported in wtTTR-CA involve complications of the tenosynovial tissue, most notably carpal tunnel syndrome (CTS), spinal canal stenosis, and brachial biceps tendon rupture [1,19]. Bilateral CTS has been reported in up to 39% of patients at the time of wtTTR-CA diagnosis and can often be the first extracardiac manifestation of TTR-CA, preceding cardiac manifestations by up to 5 to 15 years [17,23,24]. When compared to the general population, the incidence of CTS in TTR-CA patients is significantly higher (20.3% vs. 3.1%) [25]. The standardized incidence rates of CTS were notably higher in males above the age of 80 with TTR-CA, regardless of the form, wild type or hereditary [25]. Furthermore, the same study showed an increased risk of developing TTR-CA over a time span of 5–9 years in patients with CTS [25].

Similar results were found by Fosbøl et al., who reported that in addition to having a higher risk for amyloidosis, patients with CTS also had an increased risk for HF compared to matched control subjects [26]. Additionally, patients with a history of CTS and HF had higher long-term mortality compared to patients without HF [26]. Other studies have also shown a potential link between CTS and future cardiovascular involvement. A study by Sperry et al. showed that approximately 10.2% of men ages ≥50 years and women ≥60 years who underwent CTS surgery had evidence of amyloid in synovial tissue biopsies [27]. Moreover, 20% of these patients were found to have previously undiagnosed cardiac amyloidosis [27].

Another study analyzing patients 5 to 15 years after CTS surgery showed a wtTTR-CA prevalence of approximately 4.8% overall and 8.8% in men [28]. The male prevalence of wtTTR-CA was similar to the prevalence of tenosynovial ATTR deposits in the carpal ligament at the time of CTS surgery (8.8% vs. 9.8%) [28]. As suggested by the authors, the presence of ATTR in the carpal ligament in men at the time of CTS surgery may be a sign of future development of clinically significant wtTTR-CA. However, further studies are needed to confirm this finding [28].

2.2.2. Hereditary TTR-CA

Hereditary TTR-CA has more variability in its phenotypic presentation compared to wtTTR-CA, which can be attributed, at least in part, to the specific genetic mutation involved. Generally, hTTR-CA can manifest as a cardiomyopathy, peripheral or autonomic neuropathy, or a combination of these features [2,15,18]. The distribution of the underlying genetic mutation associated with each hTTR phenotype varies greatly across different geographic locations. Among the mutations observed in hTTR-CA, the most common ones are V122I, Val30Met, and T60A [12].

V122I (Valine to isoleucine at position 122) is the most common mutation responsible for hTTR-CA in the U.S [3]. It is almost exclusively seen in individuals of West African origin and occurs in 3.4–4% of African Americans [3,4]. This may even be underestimated due to healthcare disparities and cardiac amyloidosis underdiagnosis, as these patients are underrepresented in the Southern U.S. despite having larger proportions of self-identified African Americans [29,30].

V122I confers a similar phenotype to that seen with wtTTR-CA, with disease onset typically seen at an earlier age and usually no later than the 7th decade of life [2,5]. Though all V122I carriers over the age of 65 show accumulation of myocardial amyloid to some degree, the severity of accumulation is dependent on unknown factors and varies considerably between individuals. Some experience severe cardiac disease while others’ symptoms are mild or nonexistent [12]. Compared to those with other common mutations, V122I carriers suffer from fewer neurologic complications. In those with neurologic involvement, CTS and spinal stenosis are the most common manifestations [25]. In contrast, compared to patients with wtTTR-CA, V122I hTTR-CA had more neurologic symptoms, which included neuropathic pain and tingling and higher walking disabilities [1,2].

V122I TTR-CA, like other hTTR-CAs, exhibits age-dependent but variable clinical penetrance. In a cross-sectional cohort study carried out by Damrauer et al., 51 out of 116 TTRV122I carriers (44%) had clinical heart failure or cardiac amyloidosis [6]. The prevalence of HF or cardiomyopathy increased to 70% and 100% in patients above the age of 70 and 80 years, respectively. Compared to non-carriers, it was noted that young (<45 years) TTR V122I male carriers had higher rates of left ventricular (LV) hypertrophy and greater interventricular septal wall thickening on transthoracic echocardiography (TTE) prior to overt disease manifestation [6]. In addition to heart failure, mortality has also been reported to be associated with age in V122I carriers. Analysis of the data from the ARIC (Atherosclerosis Risk in Communities) study revealed that TTR V122I carriers with an average age of 50 to 52 were at an increased risk for the development of HF, but no significant difference in mortality was found between carriers and non-carriers [8]. However, when analyzing data from a study population with an average age of 62, the REGARDS (Geographic and Racial Differences in Stroke) study revealed an association between V122I carrier status and increased mortality [9].

Val30Met (Valine to Methionine at position 30) gene mutation is the most common mutation found worldwide [30,31]. This particular gene mutation has been associated with a more rapidly progressive disease [12]. In endemic areas like Portugal, Sweden, and Japan, the age of onset is typically <50 years old and presents with a sensorimotor polyneuropathy with autonomic involvement. If there is cardiac involvement, it will more likely manifest as conduction disturbances. Val30Met has a late-onset variant (>50 years old) in nonendemic areas with a slowly progressive polyneuropathy, more severe motor impairment, and cardiac involvement most commonly manifesting as HfpEF [18,29,32,33,34]. In terms of cardiac manifestations, rhythm abnormalities are more common with late onset compared to early onset, in addition to late onset having significantly more abnormalities on electrocardiogram (ECG) that include pathologic Q waves, increased QRS intervals, and wall thickness [35].

The Thr60Ala (Threonine to Alanine at position 60) hTTR-CA subtype originated in Northern Ireland, where the carrier frequency is about 1%. It is also the most common subtype in the United Kingdom and the second most common type in the U.S., with carriers present in Appalachia, New York, and the Midwest [18,29]. It has a late onset (>60 years old), predominantly affects Caucasians, and has a male predominance, with a phenotypic ratio of 2:1. Cardiomyopathy is the predominant feature of the Thr60Ala subtype, but the conduction system is not commonly affected.¹ However, mixed phenotypes with varying degrees of autonomic and peripheral neuropathy are also common [18,29,33,36].

2.3. Diagnosis

In addition to the above clinical manifestations, the initial laboratory tests might be helpful in providing clues towards cardiac amyloidosis, such as proteinuria, which may or may not be accompanied by elevations of serum BUN, creatinine, and serum bilirubin in patients with kidney disease and congestive hepatopathy. On the other hand, Natriuretic peptides and troponins T and I levels have been commonly reported to be elevated in such patients [37,38].

Other initial laboratory tests include Serum and Urine Protein Electrophoresis (SPEP/UPEP) with Immunofixation, which identifies monoclonal light chains in AL amyloidosis; Serum-Free Light Chain Assay, which detects abnormal free light chain production, which is critical for distinguishing AL amyloidosis from ATTR; and Alkaline Phosphatase, which can be elevated in hepatic involvement, particularly in systemic amyloidosis. These initial laboratory tests, in conjunction with advanced imaging and tissue biopsy, when necessary, play a crucial role in the timely diagnosis of amyloidosis.

An electrocardiogram is another non-invasive, inexpensive, useful test that can provide clues for cardiac amyloidosis, especially in the presence of other clinical manifestations. Atrial fibrillation is a common arrhythmia in patients with cardiac amyloidosis, with about 15 percent prevalence, with the highest prevalence in patients with wtATTR amyloidosis (40%) and lower prevalence with hATTR amyloidosis (11%) and AL amyloidosis (9%) [39]. The hallmark of cardiac amyloidosis is discordance between increased left ventricular wall thickness, usually identified by echocardiography, and QRS voltage, which is often reduced [40]. However, it is important to note that this feature has a low sensitivity, and the prevalence of low voltage varies markedly with etiology, with a higher frequency in patients with AL amyloidosis (60%) than in patients with ATTR amyloidosis (20%) [40]. Thus, the absence of low QRS voltage does not exclude cardiac amyloidosis, particularly in patients with wtATTR amyloidosis [40,41].

Among patients with wtATTR amyloidosis, 30 percent have voltage criteria for LV hypertrophy (LVH) or left bundle branch block, and 70 percent have pseudo-infarction patterns; conduction abnormalities affecting the sinus node and His-Purkinje systems are also common [42]. Thus, the presence of atrioventricular block in an older patient with left ventricular hypertrophy should prompt consideration of cardiac amyloidosis [42].

Speckle-tracking echocardiography (STE) to assess peak global longitudinal strain has emerged as a quantitative technique for accurate assessment of myocardial function using routine two-dimensional echocardiography [43,44]. It provides non-Doppler, angle-independent, and objective quantification of myocardial deformation and left ventricular systolic dynamics. Normal strain values has been reported to be between −18 and −22% [43,44]. The utility of STE emerged after a significant reduction in global longitudinal strain was noted to be one of the earliest markers of cardiac amyloidosis and presents with a characteristic pattern of relative apical sparing of longitudinal strain (Figure 1) [43,44].

Authors

Khalid Sawalha 1,*ORCID andDeya A. Alkhatib 2