Introduction

Amyloidosis is a rare systemic disorder, either inherited or acquired, characterized by the extracellular deposition of misfolded proteins.1 More than 30 proteins with amyloidogenic potential have been identified, each capable of adopting abnormal conformations that predispose to aggregation.2 Protein misfolding may occur through various mechanisms, such as intrinsic age-related destabilization, elevated circulating precursor concentrations, or single amino acid substitutions in hereditary cases.1 These structural instabilities can be further exacerbated by environmental factors, such as temperature fluctuations, enzymatic proteolytic activity, or metal ion interactions. The amyloid fibrils accumulate within tissues, where they disrupt tissue architecture, interact with cell surface receptors, and trigger inflammatory, oxidative, and apoptotic pathways, ultimately contributing to organ dysfunction.1 While amyloid can accumulate in many parts of the body, including the spleen, liver, nervous system, kidneys, and blood vessels, this article focused on its effects on the heart.1

In cardiac amyloidosis (CA), amyloid fibrils deposit in the interstitial spaces of the myocardium, impairing cellular function and contributing to increased rigidity, which in turn limits cardiac compliance.3 This process can result in a range of cardiac manifestations, including heart failure with preserved ejection fraction (HFpEF), hypertrophic cardiomyopathy (HCM) phenotype, and restrictive cardiomyopathy pathophysiology.4 Patients with CA may also present with HF with mildly reduced or reduced EF (HFmrEF or HFrEF), particularly in the presence of advanced disease or coexisting cardiovascular conditions. Although CA is relatively rare, its diagnosis has become more frequent in recent years due to population aging and advances in diagnostic methods.3,4 Despite these improvements, the disease remains frequently overlooked, as it often imitates more common cardiac disorders, and its early signs and symptoms are typically nonspecific.2 Molecular imaging, particularly whole-body planar scintigraphy, has significantly improved early detection.5 Incorporating these techniques into clinical guidelines facilitates earlier recognition, potentially before irreversible cardiac damage occurs, and improves patient outcomes.2 The potential of nuclear imaging in CA lies not only in detecting the disease earlier but also in accurately distinguishing between its major subtypes: transthyretin (ATTR) amyloidosis and light-chain (AL) amyloidosis. A clear understanding of their pathophysiology, systemic manifestations, and prognostic differences is essential for guiding both imaging interpretation and treatment strategies.

Transthyretin and light-chain cardiac amyloidosis: an overview

CA most commonly arises from either ATTR or AL subtypes, together accounting for more than 90% of all cases.2 Furthermore, ATTR amyloidosis occurs in 2 forms: a hereditary variant caused by transthyretin gene variants and a wild-type form, which is associated with aging.3 By contrast, AL amyloidosis results from misfolded immunoglobulin light chains produced by clonal plasma cells.4 Although both subtypes share the same basic mechanism of amyloid fibril deposition in the myocardium, they differ in their underlying cause, systemic involvement, and prognosis, making accurate diagnosis critical for targeted therapy.

Systemic disease manifestations relevant to imaging

Beyond the heart, amyloidosis often presents with a wide range of extracardiac manifestations. These features may appear earlier than clinically evident cardiac disease, which can be particularly valuable in raising diagnostic awareness.2 As summarized in Table 1, the broad range of cardiac and extracardiac manifestations underlines the diagnostic complexity of amyloidosis. Recognizing this variability may aid in understanding why distinguishing its 2 subtypes is not only diagnostically important but also clinically consequential.

Table 1. Clinical “red flags” suggestive of cardiac amyloidosis

Type

Red flags

Cardiac

  • Unexplained LV hypertrophy;
  • HFpEF disproportionate to comorbidities;
  • Low QRS voltage despite LV hypertrophy;
  • Pseudo-infarct ECG pattern;
  • Intolerance to β-blockers/ACE inhibitors;
  • Arrhythmias (AF, conduction disease);
  • “Apical sparing” pattern in GLS assessment

Extracardiac

  • Bilateral carpal tunnel syndrome;
  • Lumbar spinal stenosis;
  • Biceps tendon rupture;
  • Neuropathy (sensory, autonomic);
  • Renal impairment;
  • Hepatomegaly

General

  • Fatigue;
  • Weight loss;
  • Orthostatic hypotension;
  • Intolerance to standard heart failure therapy

Demographic

  • Age >65 years (especially men);
  • Family history of amyloidosis or polyneuropathy

Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ECG, electrocardiography; GLS, global longitudinal strain; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular

Prognostic implications of accurate subtyping

The prognosis of CA is strongly influenced by its underlying subtype. Patients with AL amyloidosis typically experience a more aggressive disease course due to rapid fibril deposition and direct cardiotoxicity of circulating light chains, leading to a median survival rate measured in months without treatment.1 By contrast, ATTR amyloidosis, particularly its wild-type form, often progresses more slowly, with survival extending over several years with treatment. Therefore, accurate diagnosis provides essential prognostic information, guiding both therapeutic strategies and patient counseling.3

Bone-avid radiotracers in cardiac amyloidosis

Historical context and current role

For decades, the diagnosis of CA relied primarily on invasive endomyocardial biopsy, which was traditionally considered the gold standard for confirming the presence and subtype of the disease. However, as with most invasive procedures, biopsy carries inherent risks and limitations.6 A pivotal multicenter study demonstrated that the use of cardiac scintigraphy with technetium-99m (99mTc) and bone-avid radiotracers, such as pyrophosphate (PYP), 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), and hydroxymethylene diphosphonate (HMDP), could serve as a reliable and noninvasive diagnostic tool replacing biopsy.7 Among individuals with histologically confirmed amyloid deposition, myocardial radiotracer uptake on bone scintigraphy demonstrated sensitivity exceeding 99% and specificity of 86% for the identification of cardiac ATTR amyloidosis, with false-positive findings occurring almost exclusively in patients with AL-CA.7 Importantly, the combination of grade 2 or 3 myocardial tracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine yielded 100% specificity and positive predictive value for ATTR amyloidosis (positive predictive value CI, 98–100).7 Not only do these tracers facilitate differentiation between ATTR and other forms of CA, but they also play a vital role in the early detection of the disease. This led to including their use in international guidelines.6 Initially, the imaging was carried out using planar scintigraphy with visual grading and heart-to-contralateral-lung (H/CL) ratio (Table 2). Later, the method was refined for using single-photon emission computed tomography with computed tomography (SPECT/CT), allowing for a more accurate assessment of myocardial uptake vs blood pool activity.8 Patients presenting with either clinical features or cardiac magnetic resonance imaging (cMRI) / echocardiography results that suggest CA should be referred for scintigraphy with bone-avid radiotracers. Scintigraphy with [99mTc]Tc-PYP/DPD/HMDP should be considered in all patients with unexplained left ventricular (LV) hypertrophy, HFpEF, familial amyloid polyneuropathy, family history of amyloidosis, or if an elderly patient’s history is suggestive of low-grade aortic stenosis.4 Since the uptake of radiotracers is different in normal myocardium than in a myocardium affected by amyloid, these techniques provide highly sensitive and specific diagnostic information for detecting ATTR cardiac involvement and identifying disease at an early stage.4

Table 2. Interpretation criteria of scintigraphy in suspected cardiac amyloidosis

Variable

Grade

Description

[99mTc]Tc-PYP/DPD/HMDP uptake grading in planar imaging

Grade 0

No myocardial uptake and normal rib uptake

Grade 1

Myocardial uptake less than rib uptake

Grade 2

Myocardial uptake equal to rib uptake

Grade 3

Myocardial uptake greater than rib uptake with mild / absent rib uptake

H/CL uptake ratioa

H/CL ≥1.5

Positive (required SPECT acquisition for confirmation)

H/CL 1–1.5

Neutral

H/CL <⁠1

Negative

a The fraction of heart ROI mean counts to contralateral lung ROI mean counts value (criteria developed for [99mTc]Tc-PYP)

Abbreviations: DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; H/CL, heart / contralateral lung; HMDP, hydroxymethylene diphosphonate; PYP, pyrophosphate; ROI, region of interest; SPECT, single-photon emission computed tomography; 99mTc, technetium-99m

Visual scoring and interpretation

Planar scintigraphy images are assessed by qualitative and semiquantitative analysis performed 2–3 hours after radiotracer injection, based on the degree of radiotracer uptake in the cardiac region. Currently the Perugini scale2 is recommended, and patients are graded on a scale from 0–3, where 0 indicates no cardiac uptake and normal bone uptake, 1 means mild cardiac uptake and inferior bone uptake, a score of 2 shows moderate cardiac uptake and attenuated bone uptake, and 3 points to strong cardiac uptake and mild or no bone uptake. A score of 2–3 is highly sensitive and specific for diagnosing ATTR-CA.2 Moreover, myocardial uptake correlates with LV wall thickness and cardiac biomarkers.2,4,5

Although the results are promising, it is important to note certain limitations in interpretation. PYP has been found to have a high affinity for calcium in necrotic tissue, which can lead to increased myocardial uptake in certain settings, such as recent infarction or pericarditis.4 It is also possible to spot a regional radiopharmaceutical uptake in the case of muscle damage caused by chemotherapy agents and general drug toxicity, which can potentially skew results.4 In addition, the mechanism responsible for tracer binding has not been fully clarified. The current hypothesis is that radiopharmaceuticals bind to microcalcifications, and subsequently, those areas of microcalcifications are larger in ATTR than in AL amyloidosis. However, certain cases of confirmed ATTR amyloidosis show no signs of uptake in the heart, suggesting that other mechanisms are at play.2

Integration with clinical and laboratory data

Scintigraphy with bone-targeting radiotracers provides an excellent noninvasive approach to detect CA and extracardiac amyloid deposits (Figure 1). Despite being called a rare disease, ATTR amyloidosis may be underrecognized, particularly in older adults. The condition can mimic HCM and present features, such as increased myocardial wall thickness, greater cardiac mass, or altered structure of valves.9 In a prospective multicenter study of 298 patients with increased LV wall thickness evaluated in primary cardiology clinics, sequencing of the transthyretin gene identified pathogenic variants in 5.7% of the cases, with 5% fulfilling diagnostic criteria for hereditary ATTR amyloidosis.9 The most prevalent mutations were V142I, V50M, and I127V, and the affected patients more frequently exhibited neuropathy, carpal tunnel syndrome, electrocardiographic low voltage, and late gadolinium enhancement (LGE) on cMRI.9 In a multivariable analysis, African origin and these clinical and imaging features were independently associated with ATTR amyloidosis, supporting the role of targeted genetic screening in elderly patients with unexplained LV hypertrophy.9 Given that the degree of cardiac involvement determines the prognosis, timely recognition and diagnosis remains crucial.9

Figure 1. Diagnostic criteria of cardiac amyloidosis based on the definition proposed by Garcia‐Pavia et al32

Abbreviations: ATTR, transthyretin amyloidosis

Single-photon emission computed tomography and single-photon emission computed tomography with computed tomography: added value

Role of hybrid imaging

The combined use of SPECT/CT allows for precise quantification of radiotracer uptake, providing deeper insight into both the extent and distribution of cardiac amyloid deposition.6 Among the quantitative measures involved in the evaluation of ATTR are the maximum standardized uptake value (SUVmax) and various volume-of-interest-delivered analyses. SUVmax denotes the highest voxel value of radiotracer uptake within a region of interest on positron emission tomography (PET) imaging, normalized to the injected dose and body weight, and serves as a widely used semiquantitative measure of tracer accumulation. In addition, recent studies are investigating the utility of SPECT/CT in characterizing right ventricular (RV) and LV involvement, which has a significant prognostic value (Figure 2).10 As myocardial amyloid infiltration becomes more severe, the extent and intensity of radiotracer uptake increase correspondingly in both ventricles.10

Figure 2. Imaging results consistent with advanced biventricular cardiac involvement in the course of transthyretin amyloidosis; A – whole-body scintigraphy using [99mTc]Tc-DPD radiotracer with grade 3 uptake; B – hybrid single-photon emission computed tomography with computed tomography showing biventricular cardiac involvement in the course of transthyretin amyloidosis

Abbreviations: see Table 2

Diagnostic performance and prognostic insights

Planar imaging and SPECT/CT allow for superior spatial resolution, as well as improved diagnostic accuracy, prognostic value, and the ability to monitor the treatment response in patients with ATTR amyloidosis.10 Both the Perugini visual scale and semiquantitative methods applied to SPECT/CT imaging show strong correlations with histological amyloid load.10 Moreover, greater RV amyloid burden has been linked to more advanced stages of disease, and serves as an important indicator for both outcome and treatment monitoring in patients with ATTR amyloidosis.11 Patients showing higher LV and RV Tc-DPD uptake measured using SPECT/CT showed a decrease in 5-year survival rates, as compared with those with lower uptake (P <⁠0.01).10 Apical sparing patterns of radiotracer uptake are also associated with worse 5-year survival, underlining the significance of regional uptake distribution.10 Even beyond diagnostic value, all quantitative methods were found to show an increased risk of HF or cardiovascular death.10

Positron emission tomography imaging: a new frontier

In recent years, PET has emerged as a potential tool in the evaluation of CA, largely inspired by its success in detecting β-amyloid deposition in Alzheimer disease.12,13 Early work demonstrated that tracers, such as carbon-11–labeled Pittsburgh compound B (11C-PiB) could identify myocardial amyloid, extending the application of neuroimaging tracers into cardiology.14,15 Despite its ability to provide molecular level specificity, higher spatial resolution, and quantitative measures of amyloid burden, PET currently remains an exploratory modality in CA. This contrasts with scintigraphy, which is an established first-line imaging approach in ATTR amyloidosis.16 PET, therefore, occupies a complementary but less impactful role, offering unique insights into research and selected diagnostic dilemmas rather than routine practice.

Amyloid-specific tracers: carbon-11–labeled Pittsburgh compound B, ¹8F-florbetapir, and ¹8F-flutemetamol

The first amyloid PET tracer developed, ¹¹C-PiB, binds fibrillar amyloid deposits.15,17 Early pilot studies demonstrated myocardial uptake in both AL and ATTR subtypes, with uptake correlating with histological amyloid burden.18 Its limitations include short half-life of carbon-11 (20 min), restricting its use to centers with an on-site cyclotron.18 On the other hand, ¹⁸F-florbetapir, approved for β-amyloid imaging in the brain, benefits from a longer half-life (110 min). Pilot studies in CA have demonstrated significant myocardial uptake, with higher retention indices in AL than ATTR amyloidosis, and the ability to detect RV involvement even before structural changes became evident.18 Structurally related to PiB, ¹⁸F-flutemetamol has also shown promise, with a longer half-life of 110 minutes.19 Small studies have reported significant uptake in CA patients, as compared with controls, though results vary depending on acquisition timing and patient subtype.20 Other tracers include ¹⁸F-florbetaben, which has shown diagnostic potential and may help differentiate AL from ATTR amyloidosis due to higher affinity for AL deposits. Novel agents, such as iodine-124–labeled pan-amyloid tracers (eg, ¹²⁴I-evuzamitide) are under investigation.18

Evidence for positron emission tomography use in transthyretin and light-chain amyloidosis

Evidence suggests important differences in tracer performance across amyloid subtypes. In ATTR amyloidosis, PET tracers demonstrate myocardial uptake, but the degree of retention is generally lower than with bone-avid tracers, limiting diagnostic advantage.16 In AL amyloidosis, however, several studies report stronger PET signal intensity, as compared with ATTR amyloidosis, suggesting higher tracer affinity for light-chain fibrils. This differential binding raises the possibility of using PET not only for detection but also for subtype discrimination. For instance, 11C-PiB uptake is typically higher in AL than ATTR amyloidosis, while ¹⁸F-sodium fluoride (¹⁸F-NaF) tends to favor ATTR deposits. Small patient cohorts and proof-of-concept studies form the bulk of the current evidence underscore PET’s role as a complementary technique alongside biopsy, cMRI, and bone scintigraphy.21

Comparative sensitivity, specificity, and potential in early disease

Meta-analyses indicate that amyloid PET has excellent pooled sensitivity (97%) and specificity (98%) for detecting CA.22 By contrast, ¹⁸F-NaF PET shows lower sensitivity (63%) but maintains high specificity (100%).22 Importantly, PET tracers appear capable of detecting early myocardial amyloid infiltration, even prior to overt hypertrophy or biomarker elevation. Specificity-related challenges remain, particularly in distinguishing ATTR from AL amyloidosis, as uptake patterns overlap. Correlative use of biomarkers (eg, serum light chains, TTR genotyping) remains essential. As compared with bone scintigraphy, PET offers little incremental value in ATTR amyloidosis detection but may hold advantages in AL amyloidosis, where bone tracers are less reliable. The quantitative nature of PET supports potential application in monitoring disease progression and therapeutic response.22

Challenges in availability, standardization, and interpretation

Despite its promise, several barriers limit clinical adoption of PET for CA.21 Tracer availability is restricted, particularly for 11C-PiB, which requires a cyclotron, and for ¹⁸F compounds, which are not yet approved for cardiac use.21 Standardization remains a challenge: acquisition protocols, quantitative thresholds, and optimal imaging windows vary across studies. Interpretation difficulties include physiological myocardial uptake, background blood pool activity, and intertracer variability in binding affinity. Finally, the question of clinical utility vs practicality persists. Bone scintigraphy is simpler, cheaper, and widely validated, whereas PET is best suited for research, ambiguous cases, or prognostic evaluation.16 Future directions include multicenter studies, harmonization of imaging criteria, and development of novel fibril-specific tracers that may broaden the role of PET role in routine clinical practice.

Nuclear imaging in the diagnostic algorithm

Diagnostic pathways

Diagnostic pathways for CA have evolved due to the advances in multimodality imaging. The approach has shifted from a biopsy-centric to a mainly noninvasive and imaging-led process. According to the 2023 American College of Cardiology (ACC) expert consensus pathway, CA is usually recognized through cardiac red flags, such as LV hypertrophy (>12 mm) on echocardiography, HFpEF, and low electrocardiography (ECG) voltage, despite the LV hypertrophy or impaired diastolic function.23 The pathognomonic sign of ATTR amyloidosis in echocardiography is the presence of an “apical sparing” pattern delivered from global longitudinal strain (GLS).24 This sign was confirmed in large cohorts of patients, and is considered highly specific for CA.25,26 If echocardiography is indeterminate, cMRI with LGE, native T1-mapping, and extracellular volume (ECV) quantification, may provide further information on tissue characteristics.27

Current international guidelines and Polish Cardiac Society statements provide noninvasive and invasive criteria while encouraging the use of noninvasive diagnostic pathway based on scintigraphy.2,4 While invasive diagnostic criteria apply to all types of CA, noninvasive criteria should be utilized only for the diagnosis of ATTR and AL amyloidosis. The diagnostic algorithm generally includes scintigraphy with SPECT and hematologic tests, which may be accompanied by cMRI. In addition to these initial tests, cardiac biopsy might be required in some types of CA, where AL amyloidosis cannot be excluded. However, it is used rarely due to procedural risks, such as sampling errors and limited availability in some medical centers.

Noninvasive differentiating transthyretin amyloidosis from light-chain amyloidosis

Noninvasive diagnosis of ATTR-CA and AL-CA is primary based on bone scintigraphy and laboratory tests.28 Initially, AL amyloidosis is excluded in all cases through laboratory tests. The ACC and joint American Society of Nuclear Cardiology / Society Expert Consensus states that a negative free light chain (FLC) test, serum, and urine protein electrophoresis (SPIE, UPIE) have 99% sensitivity to rule out AL.2,23 Importantly, utilizing noninvasive diagnostic algorithm for ATTR amyloidosis without performing organ biopsy is only possible if the appropriate laboratory tests (FLC, SPIE, and UPIE) yield negative results. This laboratory screening should be performed in all patients with suspected CA before interpreting bone scintigraphy findings (Table 3). The definite diagnosis of ATTR amyloidosis can be established with grade 2 or 3 myocardial uptake on scintigraphy, in addition to negative FLC, SPIE, and UPIE results.7 Conversely, if AL amyloidosis cannot be excluded, biopsy is still required to confirm the disease. This framework of minimally-invasive diagnostic pathways is especially advantageous in elderly populations where ATTR amyloidosis is common, and biopsy carries higher procedural risks.

Table 3. Comparison of transthyretin and amyloid light-chain cardiac amyloidosis

Parameter

ATTR amyloidosis

AL amyloidosis

Etiology

Misfolded transthyretin (wild-type or mutated)

Misfolded immunoglobulin light chains from plasma cells

Demographics

  • ATTRwt: older men;
  • ATTRv: family history, variable age
  • Any age;
  • Often with plasma cell dyscrasia

Clinical course

  • Progressive;
  • If treated, survival often in years
  • Aggressive;
  • If untreated, survival often in months

Cardiac involvement

  • LV hypertrophy;
  • Restrictive physiology;
  • Arrhythmias
  • Rapid infiltration;
  • Severe diastolic dysfunction;
  • Direct light chain cardiotoxicity

Extracardiac features

  • Carpal tunnel syndrome;
  • Spinal stenosis;
  • Neuropathy
  • Nephropathy;
  • Hepatomegaly;
  • Macroglossia;
  • Purpura

Imaging findings

  • Strong uptake on bone scintigraphy
  • Typically, absent uptake (possible false negatives and positives)

Treatment

  • Tafamidis;
  • Acoramidis;
  • Patisiran;
  • Inotersen;
  • Vutrisiran;
  • Eplontersen
  • Chemotherapy;
  • Stem-cell transplant

Abbreviations: AL, amyloid light chain; ATTRv, hereditary transthyretin; ATTRwt, wild-type transthyretin; others, see Table 1 and Figure 1

Role of imaging in monitoring and follow-up

Following diagnosis, nuclear imagining may play a vital role in monitoring disease progression and assessing treatment response in CA. For initial diagnosis of the disease, patients who present with red flags and abnormal echocardiography/cMRI findings should be referred for scintigraphy. For those with established ATTR-CA diagnosis, surveillance with GLS is optimal to monitor progression over time.29 In the recent retrospective ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) project, lesions identified on echocardiography were used to measure the efficacy of tafamidis.30 Furthermore, myocardial work index may be a robust imaging marker.31 Echocardiography is recommended as a surveillance modality to be used for ATTR-CA every 6–12 months.32 While cMRI has also been proved to be an effective monitoring modality, cost and resource issues limit its application.33 This technique is also recommended in other clinical trials that encourage the use of cMRI as a monitoring tool in the future (Table 4).29,34

Table 4. Diagnostic accuracy of imaging modalities in cardiac amyloidosis

Diagnostic tool

Key findings

Strengths

Limitations

Echocardiography

  • LV thickening;
  • Restrictive filling;
  • “Apical sparing” on GLS
  • Widely available;
  • First-line tool;
  • Prognostic value
  • Nonspecific;
  • Operator-dependent

cMRI

  • LGE;
  • T1 mapping;
  • ECV quantification
  • Excellent tissue characterization;
  • Prognostic value
  • Limited in renal dysfunction;
  • Cost

Scintigraphy

  • Perugini grading;
  • H/CL ratios
  • High sensitivity / specificity for ATTR;
  • Noninvasive
  • Cannot exclude AL;
  • Artifacts possible

SPECT/CT

  • Uptake quantification;
  • LV/RV involvement
  • Improves accuracy;
  • Provides prognostic data
  • Lesser availability;
  • Standardization needed

PET

  • Amyloid-specific tracers (11C-PiB, ¹8F compounds)
  • Quantitative, molecular specificity;
  • Potential in AL
  • Investigational, limited tracer access;
  • Cost

Abbreviations: 11C-PiB, carbon-11–labeled Pittsburgh Compound B; cMRI, cardiac magnetic resonance imaging; ECV, extracellular volume; ¹8F, fluorine-18; LGE, late gadolinium enhancement; PET, positron emission tomography; RV, right ventricular; others, see Tables 1 and 2 and Figure 1

Cardiac biomarkers are also essential in monitoring disease course and treatment response in CA. Namely, current guidelines defining cardiac response in AL-CA are primarily based on N-terminal pro–B-type natriuretic peptide (NT-proBNP) reduction, where a decrease of over 30% and over 300 ng/l from baseline is considered clinically significant.35 Conversely, a notable limitation of NT-proBNP is its low specificity, as elevations may be present in response to any physical myocardial damage, not exclusively amyloid burden. On the other hand, echocardiographic strain imaging provides prognostic value, although meaningful recovery generally requires nearly 12 months, whereas disease progression can manifest as early as in 6 months due to the inherent resistance of amyloid fibrils to degradation.36 Importantly, patients who demonstrate an improvement in GLS and achieve hematological complete response (CR) at 12 months have significantly better survival rates, as comapred with those achieving hematological CR alone, which makes it an additive prognostic impact of multimodal monitoring. The role of cMRI in AL amyloidosis is rapidly developing, especially with the use of ECV quantification and T1 mapping emerging as powerful tools for monitoring treatment response. A recent prospective study demonstrated that regular assessment during chemotherapy not only detects cardiac regression but also provides independent prognostic value for survival.37 These findings suggest that cMRI has a highly important role in long-term monitoring and prognostication in AL-CA.

Red flags and multimodal integration

The diagnosis of CA requires a multimodal strategy, as no single diagnostic test is sufficient to establish or exclude the disease unequivocally. Nuclear imaging, particularly scintigraphy, provides high specificity for ATTR amyloidosis, while cMRI yields detailed tissue-level characterization LGE, T1 mapping, and ECV quantification. Emerging guidelines emphasize a stepwise diagnostic framework, beginning with the recognition of clinical and imagining “red flags,” followed by laboratory exclusion of AL amyloidosis and radionuclide scintigraphy for ATTR amyloidosis diagnosis. Biopsy is now reserved only for ambiguous cases, thereby expediting diagnosis and sparing many patients from unnecessary invasive procedures.23

The importance of clinical “red flags” in guiding diagnosis has been discussed in the literature. In a prospective study evaluating patients with HFpEF for potential amyloid infiltration, ATTR-CA was diagnosed in 11.3% of the patients.38 In the multivariate analysis, advanced age (odds ratio [OR], 7.8), pseudoinfarct ECG pattern (OR, 6.8), low QRS voltage disproportionate to LV wall thickness (OR, 16.9), and GLS (OR, 1.2) were associated with ATTR amyloidosis.38 Further cardiac “red flags” may include HF symptoms, especially due to right-sided involvement, fatigue, and intolerance to β-blockers or angiotensin-converting enzyme I.39 Extracardiac symptoms may involve hand nails abnormality, digestive dysautonomia, vascular dysautonomia, or renal failure.40

Impact on clinical decision-making and therapy

Disease staging and prognostic implications

Biomarkers contribute to early suspicion and diagnosis of CA, as their role is usually to aid with risk stratification and monitoring therapeutic efficacy. In AL amyloidosis, the Mayo Clinic staging system integrates FLC, NT-proBNP, and cardiac troponins T.41 This system predicts median overall survival by assigning 94, 40, 14, and 6 months to each stage from I to IV, respectively.41 For example, in advanced stage III AL amyloidosis, additional parameters, including NT-proBNP above 8500 ng/l and systolic blood pressure below 100 mm Hg, indicate an ultra-high-risk subset (3b according to the Mayo Clinic system) with significantly worse prognosis.42 By combining these biomarker-based staging with more information obtained from nuclear imaging, we can identify patients who may benefit from intensive therapies and monitoring treatment response.

In terms of imaging predictors, a recent study demonstrated the utility of quantitative SPECT/CT in diagnosing CA.43 It was concluded that presenting the radiotracer uptake by using SUV and a composite SUV retention index significantly improved diagnostic accuracy, as compared with conventional planar imaging methods.43 This highlights that visual grading is simple and reproducible, but SPECT/CT provides a more objective measure of the amyloid burden, which is essential for accurate diagnosis and further follow-up of CA patients.

Guiding disease-modifying therapies

Therapeutic options for ATTR-CA are currently guided initially by scintigraphic-based diagnosis, but echocardiography, cMRI, and SPECT/CT may have a role in monitoring response to therapy.44 Stabilization of transthyretin tetramers with tafamidis and acoramidis are prioritized in patients that demonstrate early or moderate amyloid deposits, while higher cMRI-derived ECV or persistent uptake of tracers may suggest the necessity of RNA-targeted therapies, including patisiran, vutrisiran inotersen, eplenotersen, or novel anti-amyloid strategies, such as clustered regularly interspaced short palindromic repeats–associated protein 9 editing or depletors.44

The 2023 American College of Cardiology Expert Consensus Decision Pathway has established a framework integrating multimodal imaging, biomarkers, and clinical parameters to enhance risk stratification and guide prognostic assessment in CA.23 Moreover, elevated native T1 values and increased ECV correlate strongly with adverse outcomes, including HF progression and mortality.45 Similarly, nuclear imaging not only confirms ATTR amyloidosis diagnosis but can also stratify disease severity by quantifying myocardial uptake; higher Perugini grades or H/CL ratios have been associated with worse prognosis (Table 5).46 Notably, the pathway encourages the integration of imaging biomarkers with established AL-CA staging pathways (eg, the Mayo Clinic system) and functional biomarkers (eg, NT-proBNP, troponin T), enhancing individualized risk prediction and treatment.

Table 5. Nuclear imaging and prognostic implications

Imaging technique

Method

Prognostic association

Perugini grade 2–3

Planar scintigraphy

  • Diagnostic for ATTR if AL excluded;
  • Correlates with survival

H/CL ratio ≥1.5

99mTc-PYP scintigraphy

  • Higher ratio associated with worse prognosis

Quantitative SUV (SPECT/CT)

Tc-DPD uptake (SUVmax, retention index)

  • Strong correlation with amyloid burden;
  • Predicts mortality

RV uptake on SPECT/CT

DPD scintigraphy

  • Associated with advanced disease; Poorer survival

PET retention indices

11C-PiB and ¹8F tracers

  • Higher uptake in AL;
  • Potential for subtype differentiation and treatment monitoring

Abbreviations: CT, computed tomography; SUV, standardized uptake value; others, see Tables 1, 2, and 3 and Figure 1

Future directions

Role of quantitative positron emission tomography in disease monitoring

Quantitative PET imaging is utilized due to its ability to offer noninvasive, precise measurements of amyloid burden in CA. This technology can provide accurate staging of the disease, monitor response to treatment, and assess the prognosis. Quantifying amyloid deposits helps guide therapeutic decisions and allows for earlier detection of changes in disease status, as compared with more traditional imaging techniques.

Combined assessment of myocardial amyloid and inflammation

Emerging imaging approaches aim to simultaneously evaluate amyloid deposition and myocardial inflammation. It has been reported that in patients with AL amyloidosis, intramyocardial inflammation correlates significantly with increased mortality.47 Another recent study reported that diffuse myocardial ¹⁸F-fluorodeoxyglucose PET uptake may represent inflammation in CA, and compared it to cMRI features in CA. It displayed a benefit of interpreting PET alongside cMRI for a more accurate disease assessment.48 The strategy of combined assessment of myocardial amyloid and inflammation allows for a better understanding of disease activity, and may potentially predict which patients will respond to specific therapies.

Molecular imaging of other systemic organs

Since amyloidosis often affects multiple organs, PET/CT is being increasingly used to evaluate the deposition in other organs, such as the kidneys, spleen, and liver. Namely, PET/CT imaging with 124I-p5+14 radiotracer allows for detection of clinically undetected AL amyloid deposits in multiple organs. Using this type of imaging can contribute to a more comprehensive view of systemic disease staging in CA, and may be a useful method for monitoring changes in disease progression.49

Emerging tracers and theranostic applications

The development of new PET tracers has improved the sensitivity and specificity of amyloid imaging. A recent study demonstrated that radiotracers, such as 11C-PiB, 18F-flutemetamol, 18F-florbetapir, and 18F-florbetaben have a potential to aid in determining prognoses, differentiate amyloidosis subtypes, and monitor responses to treatment.50 Theranostics refers to drugs or methods that are used simultaneously for diagnosis and treatment. It provides patients with a personalized, image-guided treatment strategy. Theranostic applications are typically used in the setting of cancer and immunotherapies. It enables both imaging and targeted amyloid clearance, representing a promising combination of diagnostics and treatment; however, its role remains to be validated in CA.51,52

Imaging in preclinical stages

Bone scintigraphy plays an important role in the screening of high-risk populations for ATTR, particularly among patients with conditions, such as HFpEF and HCM, where the disease may be underrecognized.53,54 Importantly, it may also facilitate early detection in individuals at an increased genetic risk, including asymptomatic carriers of pathogenic TTR variants in the preclinical stage of the disease55. However, clinicians should be aware that bone scintigraphy may yield false-negative results in certain cases, particularly in early disease stages or specific genetic variants56. Consequently, the development of novel SPECT tracers with improved sensitivity may further enhance the diagnostic performance of nuclear imaging in this setting.

Conclusions

In recent years, CA has transitioned from a historically underdiagnosed condition to a disease increasingly recognized in routine clinical practice, largely owing to advances in nuclear cardiology. Scintigraphy with technetium-labeled bone-avid tracers provides a reliable, widely validated, and noninvasive means of diagnosing ATTR amyloidosis, while SPECT/CT offers additional value through improved anatomical localization and quantification of amyloid burden. Although PET remains investigational, it offers molecular specificity, and may become particularly relevant in AL amyloidosis and for monitoring therapeutic response. The integration of nuclear imaging has redefined diagnostic algorithms, facilitating earlier and more accurate diagnosis, enabling subtype differentiation, and informing prognostication. These developments support more effective therapy stratification, align with the growing landscape of disease-modifying treatments, and highlight the central role of imaging in delivering personalized care. Future progress will depend on the refinement of quantitative techniques, standardization of acquisition and interpretation protocols, and the development of novel tracers with theranostic potential.