Cardiac Amyloidosis: A Comprehensive Review of Pathophysiology, Diagnostic Approach, Applications of Artificial Intelligence, and Management Strategies

Published: Jul 02, 2024
Category
Patient Education
Key Information
Source
National Library of Medicine
Year
2024
summary/abstract

Cardiac amyloidosis (CA) is a serious and often fatal condition caused by the accumulation of amyloid fibrils in the heart, leading to progressive heart failure. It involves the misfolding of normally soluble proteins into insoluble amyloid fibrils, with transthyretin and light-chain amyloidosis being the most common forms affecting the heart. Advances in diagnostics, especially cardiac magnetic resonance imaging and non-invasive techniques, have improved early detection and disease management. Artificial intelligence has emerged as a diagnostic tool for cardiac amyloidosis, improving accuracy and enabling earlier intervention through advanced imaging analysis and pattern recognition. Management strategies include volume control, specific pharmacotherapies like tafamidis, and addressing arrhythmias and advanced heart failure. However, further research is needed for novel therapeutic approaches, the long-term effectiveness of emerging treatments, and the optimization of artificial intelligence applications in clinical practice for better patient outcomes. The article aims to provide an overview of CA, outlining its pathophysiology, diagnostic advancements, the role of artificial intelligence, management strategies, and the need for further research.

Keywords: artifical intelligence, al cardiac amyloidosis, transthyretin amyloid cardiomyopathy, ttr cardiac amyloidosis, cardiac amylodosis

Introduction and background

Amyloidosis is a disease of multisystems in which extracellular accumulation of amyloid (a material detected on Congo red staining followed by apple-green birefringence under polarized light) damages multiple organs. It is caused by normal soluble proteins becoming insoluble amyloid fibrils by conformational change []. Nine of the approximately thirty amyloid precursor proteins significantly impact the heart. These include transthyretin (TTR), which causes transthyretin amyloidosis (ATTR) in both familial/hereditary ATTR (variant ATTR [ATTRv]) and wild-type/non-hereditary (ATTRwt) forms, and light chains, which causes AL amyloidosis. Other less common forms include fibrinogen A-α, gelsolin, β2-microglobulin, apolipoproteins, and serum component A. The two leading causes of amyloid cardiomyopathy (CM) are AL-CM and ATTR-CM, with ATTR-CM recently becoming more common in developed nations []. ATTRv amyloidosis is caused by destabilizing mutations in the TTR gene, which can arise in younger adults, whereas the more common ATTRwt amyloidosis is linked to aging []. By February 2023, the Cardiac Amyloidosis Registry Study (CARS) had enrolled 1415 patients from 20 US centers. 82% of the patients had ATTR cardiac amyloidosis, with 71% of them having the wild-type and 68% with the p.V142I mutation. In addition, females were more prevalent in the AL group (39%) than in the ATTR group (13%) []. Two prospective studies identified 13% and 18% prevalence for ATTRwt among individuals over 60 with heart failure with preserved ejection fraction (HFpEF) and wall thickness greater than 12 mm. Furthermore, ATTR-CM prevalence was noted at 9% in patients having heart failure with reduced ejection fraction (HFrEF) of unknown etiology. The studies excluded participants with other potential heart failure origins, like significant valvulopathies or previous coronary diseases, suggesting a possible underrepresentation of ATTR-CM prevalence [-]. Cardiac magnetic resonance (CMR) imaging and an image-based methodology that permits diagnosis without tissue biopsy in roughly 70% of cases have led to a notable increase in ATTR-CM diagnosis. As a result, more patients are recognized earlier in the disease, which is associated with improved heart structure and preservation of function []. A 20-year UK study found that diagnoses of ATTR-CM, especially wild-type, were much higher, with almost 60% of recent diagnoses (2017-2021) being at an early stage []. This pattern has improved our knowledge of how diseases progress and the variables affecting their clinical variability. This review aims to discuss the pathophysiology of CA, management strategies, and diagnostic approaches, including the current advancement of artificial intelligence in the field.

Review

Pathophysiology

TTR, a plasma protein primarily generated in the liver, choroid plexuses, and retina, is deposited to cause ATTR. TTR is responsible for transporting retinol-bound protein and thyroxine. Age-related factors in ATTRwt or genetic mutations in ATTRv cause TTR to split into dimers and monomers. For still unclear reasons, these monomers combine to create fibrils and deposit primarily in the heart and nervous tissue []. In vitro, when the tetrameric structure of TTR becomes unstable, the protein breaks down into monomers and dimers, resulting in misfolding into an inactive conformation. This process is crucial for the formation of amyloid fibrils. Simulations of molecular dynamics show that dissociation of the tetramer is a multi-step process, with the most notable energy barrier occurring during the transition. Improper posttranslational modifications, altered proteostasis, and metal cations play a role in the instability of the TTRwt structure. TTR monomers may misfold, forming a stable "misfolded state" prone to aggregation. Misfolded TTR monomers interact to form dimers, which then combine to create spherical hexamers, serving as building blocks for cytotoxic oligomers. The amyloid formation kinetics consist of three phases: nucleation, growth, and saturation []. Prior research on ATTRwt has focused chiefly on its effects on cardiac tissue. Research on cardiac fibroblasts has shown that the presence of TTR in the extracellular matrix of the tissue may impact the genetic composition, capabilities, and expression of these cells. Transcriptional sequencing and cytokine proteomic analysis revealed increased inflammatory genes that may exacerbate cardiac inflammation and fibrosis. Additionally, TTRwt amyloid toxicity causes mitochondrial dysfunction, oxidative stress in cardiomyocytes, and disruptions in calcium levels and cycling, which may result in cardiac dysfunction [].

Over 150 mutations have been found, most linked to ATTRv. The Val122Ile is the most prevalent form in the USA, affecting African and Caribbean descent. The disease onset is late, usually after 60, and patients accumulate myocardial amyloid. Men are more likely to be affected than women. The second most common type of ATTRv genotype is Thr60Ala amyloidosis, predominantly affecting Caucasians. Epigenetics may determine which carriers will develop ATTRv disease. Genetic counseling should accompany ATTRv testing decisions. To determine the effectiveness and financial feasibility of genetic testing, early intervention, and surveillance, further research is necessary []. A study in Bologna, Italy, analyzed 325 patients with ATTRv mutations between 1984 and 2022. TTR gene variants were identified in the study, with the most prevalent ones being Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%). After 51 months, 38.3% of patients died, and 11.5% developed ATTRv. Key factors influencing survival included age at diagnosis, NYHA class III, left ventricular ejection fraction (LVEF), and disease-modifying therapy. Family screening programs are essential for early detection and managing ATTRv to reduce mortality []. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry, initiated in 2007, is the largest and oldest global study on ATTR amyloidosis. The most recent update includes 3,779 symptomatic patients and 1,830 asymptomatic TTR mutation carriers from 23 different countries. Among the symptomatic individuals, 16.6% had a mixed phenotype, 40.7% had a cardiac phenotype, and 40.1% had a neurologic phenotype [].

Clinical manifestation and diagnosis

A majority of patients initially present with nonspecific symptoms such as fatigue, weight loss, and edema, followed by the development of more focused symptoms []. The delayed diagnosis of cardiac amyloidosis is often caused by its numerous nonspecific symptoms []. For instance, upon diagnosis of AL amyloidosis, around 67% of patients have kidney involvement, and 50% have heart involvement, with up to 90% of patients experiencing heart involvement as the disease progresses [,]. Arrhythmia and heart failure account for about 75% of deaths from AL amyloidosis [].

Red flags and clinical clues associated with cardiac amyloidosis can be broadly classified into two categories: extracardiac manifestations (such as history of proteinuria, autonomic/peripheral neuropathy, spinal stenosis, carpal tunnel syndrome, knee or hip replacement, or previous shoulder surgery) and cardiac features (such as left ventricular hypertrophy without the presence of cardiac valvular disease or hypertension, diastolic abnormality, symptoms of heart failure (HF), atrial fibrillation [AF], conduction defect, raised cardiac biomarkers) []. Significant overlap exists in the clinical, radiological, and electrocardiographic characteristics of AL and ATTR amyloidosis, making cardiac symptoms insufficient to differentiate the two conditions. Pathognomonic extracardiac signs of AL amyloidosis include periorbital purpura secondary to increased fragility of capillary, acquired Factor X insufficiency, and enlarged tongue/submandibular gland due to involvement of soft tissue. Conversely, ATTR amyloidosis is exclusive to musculoskeletal symptoms such as spontaneous rupture of the biceps tendon and spinal stenosis. Peripheral neuropathy, orthostatic hypotension, GI involvement, and CM are frequent organ systems impacted by both ATTR and AL amyloidosis [,]. 

ATTR cardiac amyloidosis (CA) follows a more gradual and slow-developing course compared to AL-CA. Patients with cardiac involvement in ATTR have a considerably better prognosis, with an average of five more years of survival compared to those with cardiac involvement in AL amyloidosis. However, the initial slow progression of ATTR-CA often leads to under-recognition. []. When diagnosing cardiac amyloidosis (CA), the following criteria are considered: unexplained left ventricular (LV) thickness (≥12 mm), specific echocardiography findings, and a multiparametric echocardiographic score. To confirm CA using echocardiography, at least two of the following must be present: diastolic dysfunction grade 2 or more, decreased tissue Doppler s', e', and a' wave velocities (<5 cm/s), and reduction in LV global longitudinal strain (LGLS) less than < −15%. Additionally, a multiparametric echocardiographic score of ≥8 is used, which includes criteria such as relative LV wall thickness >0.6 (3 points), LGLS absolute value of ≤ −13% (1 point), Doppler E/e' wave velocities >11 (1 point), TAPSE (tricuspid annular plane systolic excursion) of ≤19 mm (2 points), and systolic longitudinal strain apex to base ratio >2.9 (3 points). For cardiac magnetic resonance (CMR), both diffuse transmural or subendocardial late gadolinium enhancement (LGE) and abnormal gadolinium kinetics must be present. An extracellular volume (ECV) ≥0.40% is strongly indicative but unessential for diagnosis [].

Bone scintigraphy, using 99mTechnetium (Tc) labeled tracers such as 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), hydroxymethylene diphosphonate (HMDP), and pyrophosphate (PYP), is an important non-invasive method for diagnosing CA. It can detect intense cardiac uptake, indicating the presence of the disease. This method has high sensitivity and specificity, particularly for ATTR CA, with clinical studies showing sensitivity and specificity of over 90%. This reduces the need for invasive biopsies and allows for early and accurate treatment interventions. Additionally, AI systems further enhance diagnostic accuracy []. Bone scintigraphy with technetium 99 m should be performed on patients with suspected CA, either concomitantly with monoclonal protein evaluation or after a negative protein assessment. The results are interpreted in a semi-quantitative way, with Grade 0 showing no tracer myocardial uptake and normal bone uptake, Grade 1 showing lower myocardial uptake compared to bone level, Grade 2 showing equal myocardial and bone uptake, and Grade 3 showing greater myocardial uptake compared to bone. A quantitative analysis of scintigraphy results determining the ratio of tracer uptake between the heart (H) and the contralateral half of the lung (CL) can be applied, with values > 1.5 considered positive. Bone scintigraphy should always be combined with single-photon emission computed tomography (SPECT) imaging to avoid false positive results due to blood pooling in the heart [].

Authors
Alexander Muacevic and John R Adler