Introduction

Cardiac amyloidosis is a progressive and often fatal condition characterized by the extracellular deposition of insoluble amyloid fibrils within the myocardium. These deposits disrupt the normal architecture and function of the heart, leading to restrictive cardiomyopathy, heart failure, and significant morbidity and mortality. The two main types of cardiac amyloidosis, transthyretin (TTR) amyloidosis and light chain (AL) amyloidosis, present substantial diagnostic challenges due to their overlapping clinical presentations and the diverse nature of amyloid fibrils.

TTR amyloidosis can be further classified into hereditary and wild-type forms. The hereditary form results from mutations in the transthyretin gene, whereas the wild-type form is associated with age-related amyloid deposition. AL amyloidosis, on the other hand, is caused by the misfolding of immunoglobulin light chains produced by clonal plasma cells. Both types lead to similar cardiac manifestations, including increased ventricular wall thickness, diastolic dysfunction, and eventually, heart failure. The clinical presentation often includes symptoms such as fatigue, dyspnea, edema, and in advanced stages, syncope and arrhythmias.

Early diagnosis of cardiac amyloidosis is critical for improving patient outcomes and guiding appropriate therapeutic interventions. However, the overlapping clinical features with other forms of cardiomyopathy, such as hypertrophic cardiomyopathy, often lead to misdiagnosis or delayed diagnosis. Conventional diagnostic methods, including echocardiography and cardiac MRI, provide valuable insights into the structural and functional changes associated with amyloid deposition. However, these imaging modalities have limitations in specificity and sensitivity, particularly in the early stages of the disease.

Biomarkers have emerged as powerful tools for the early detection, monitoring, and prognostication of cardiac amyloidosis. They offer a non-invasive means to assess the biochemical and molecular changes associated with amyloid deposition in the heart. Established biomarkers like N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponins are widely used in clinical practice to evaluate cardiac function and injury. Elevated levels of NT-proBNP are indicative of increased cardiac wall stress and heart failure, while troponins reflect myocardial injury.

In addition to NT-proBNP and troponins, novel biomarkers are being investigated for their potential to improve the diagnostic accuracy and prognostic assessment of cardiac amyloidosis. These include serum amyloid P component, which binds specifically to amyloid fibrils, and light-chain assays, which are particularly useful in AL amyloidosis. ^, The development of these biomarkers aims to enhance the early detection of amyloid deposits, differentiate between amyloidosis subtypes, and provide insights into disease progression. As depicted in the Central Illustration, these biomarkers are central to guiding the clinical management of cardiac amyloidosis by improving diagnostic precision and prognostic evaluations.

Despite the advances in biomarker research, there remains a limited understanding of the correlation between biomarker levels and imaging findings. This gap hinders the ability to fully leverage biomarkers for comprehensive diagnostic and prognostic evaluation. Additionally, there is a need for biomarkers that are specific to the different subtypes of amyloidosis, as current markers may not distinguish adequately between TTR and AL amyloidosis.

This systematic review and meta-analysis aims to evaluate the latest biomarkers for early detection, disease progression, and prognosis in cardiac amyloidosis. By synthesizing the available evidence, we seek to identify the strengths and limitations of each biomarker, assess their correlation with imaging findings, and highlight areas for future research. Our goal is to provide a comprehensive overview that can guide clinical practice and improve patient outcomes in cardiac amyloidosis.

Methods

Search Strategy: We conducted a comprehensive and systematic search of multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published from January 2000 to June 2024. The search strategy was designed to capture a broad range of literature on biomarkers in cardiac amyloidosis. Keywords and Medical Subject Headings (MeSH) terms included “cardiac amyloidosis,” “biomarkers,” “NT-proBNP,” “troponins,” “serum amyloid P component,” and “light-chain assays.” Boolean operators (AND, OR) were used to combine search terms effectively. Additionally, we manually searched the reference lists of relevant articles and reviews to identify any studies that might have been missed in the database search.

Inclusion Criteria: Studies were included if they met the following criteria:

• 1.
  

  Study Focus : Evaluated the diagnostic and prognostic value of biomarkers in cardiac amyloidosis.

  
  
• 2.
  

  Outcome Measures : Provided data on sensitivity, specificity, and prognostic significance of biomarkers.

  
  
• 3.
  

  Language : Published in English.

  
  
• 4.
  

  Study Design : Included observational studies, cohort studies, case-control studies, and randomized controlled trials (RCTs).

Exclusion Criteria: Studies were excluded based on the following criteria:

• 1.
  

  Study Type : Case reports, review articles, editorials, and opinion pieces.

  
  
• 2.
  

  Data Insufficiency : Studies with insufficient data on biomarkers or outcomes.

  
  
• 3.
  

  Duplicate Publications : Duplicate studies or those with overlapping populations were excluded, with preference given to the most comprehensive and recent publication.

Data Extraction: Two independent reviewers conducted the data extraction using a pre-defined data extraction form. Discrepancies were resolved through discussion or consultation with a third reviewer. Extracted data included:

• •
  

  Study Characteristics : Author(s), year of publication, study design, and sample size.

  
  
• •
  

  Population Demographics : Age, gender, type of cardiac amyloidosis (TTR or AL).

  
  
• •
  

  Biomarker Details : Type of biomarker (e.g., NT-proBNP, troponins, serum amyloid P component, light-chain assays), assay methods, and cutoff values.

  
  
• •
  

  Diagnostic Accuracy : Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

  
  
• •
  

  Prognostic Outcomes : Mortality, heart failure progression, and other relevant clinical outcomes.

  
  
• •
  

  Correlation with Imaging : Data on the correlation between biomarker levels and imaging findings (e.g., echocardiography, cardiac MRI).

Quality Assessment: The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. This tool evaluates the risk of bias and applicability across four domains: patient selection, index test, reference standard, and flow and timing. Each study was independently assessed by two reviewers, and any disagreements were resolved through consensus or consultation with a third reviewer.

Statistical Analysis: Sensitivity, specificity, and diagnostic odds ratios (DORs) for each biomarker were calculated using a random-effects model to account for study heterogeneity. The I² statistic assessed heterogeneity, with values of 25 %, 50 %, and 75 % indicating low, moderate, and high heterogeneity, respectively. Subgroup analyses and meta-regression explored heterogeneity sources. Publication bias was evaluated using funnel plots and Egger’s test. Pearson’s correlation coefficient assessed the relationship between biomarker levels and imaging findings. Sensitivity analyses confirmed the robustness of results by excluding high-risk bias and outlier studies.

Data Synthesis and Reporting: The results of the meta-analysis were synthesized and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Forest plots were generated to visually display the diagnostic accuracy and prognostic value of biomarkers, and summary tables provided detailed information on study characteristics, biomarker performance, and correlation with imaging findings.

Results

Study selection

A comprehensive search yielded 1,234 articles, from which 45 studies were included in the meta-analysis after applying relevance and inclusion criteria. These comprised observational studies, cohort studies, case-control studies, and randomized controlled trials ( Fig. 1 ).

PRISMA flow diagram.

Diagnostic value of biomarkers

NT-proBNP : NT-proBNP demonstrated high diagnostic accuracy for early cardiac amyloidosis, with a sensitivity of 87 % (95 % CI: 83-91, p < 0.001) and specificity of 83 % (95 % CI: 78-88, p < 0.001). Elevated levels were closely associated with amyloid burden and cardiac dysfunction ( Table 1 , Fig. 2 ).

Table 1

Summary of diagnostic and prognostic values of biomarkers.

Biomarker	Sensitivity (%)	Specificity (%)	Diagnostic odds ratio (DOR)	p-value
NT-proBNP	87	83	30.4	< 0.001
Troponins	70	85	20.5	< 0.001
Serum Amyloid P Component	75	80	18.9	< 0.01
Light-Chain Assays	80	87	27.8	< 0.001

 

Sensitivity and specificity of cardiac biomarkers.

Troponins : Troponins showed moderate sensitivity (70 %, 95 % CI: 65-75, p < 0.001) and high specificity (85 %, 95 % CI: 80-89, p < 0.001) in detecting cardiac amyloidosis. Elevated troponin levels were indicative of myocardial injury and correlated with worse cardiac outcomes ( Table 1 , Fig. 2 ).

Serum Amyloid P Component : This emerging biomarker showed a sensitivity of 75 % (95 % CI: 69-81, p < 0.01) and specificity of 80 % (95 % CI: 74-85, p < 0.01). While data were limited, initial results are promising for subtype differentiation and early detection ( Table 1 , Fig. 2 ).

Light-Chain Assays : Light-chain assays exhibited high diagnostic accuracy, with a sensitivity of 80 % (95 % CI: 75-85, p < 0.001) and specificity of 87 % (95 % CI: 82-91, p < 0.001). These assays were particularly effective in distinguishing AL amyloidosis and correlated with disease progression ( Table 1 , Fig. 2 ).

Prognostic Value of Biomarkers : Elevated levels of NT-proBNP and troponins were strong predictors of mortality and adverse cardiac events, underscoring their prognostic value. Novel biomarkers like serum amyloid P component and light-chain assays provided additional insights, particularly in differentiating amyloidosis subtypes and predicting disease progression.

Correlation with Imaging Findings : NT-proBNP and troponins moderately correlated with echocardiographic and cardiac MRI findings. Elevated levels were associated with increased left ventricular wall thickness, reduced ejection fraction, and myocardial fibrosis (Pearson’s correlation coefficient: 0.47, p < 0.001), supporting their combined use with imaging for comprehensive disease assessment ( Table 2 ).

Table 2

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Associations between central and brachial blood pressure in patients with hypertension and aortovascular disease: Implications for clinical practice
2. Left atrial appendage occlusion devices vs direct oral anticoagulants for atrial fibrillation: An updated systematic review and meta-analysis
3. Determinants of cardiovascular health indices among physicians in a tertiary centre
4. Response to “Five-year risk of all-cause death and cardiovascular events in women with gestational diabetes and hypertensive disorders of pregnancy”

Stay updated, free articles. Join our Telegram channel

Join