Evaluating natural history and treatment response in cardiac amyloidosis: the evolving role of multimodality imaging.

Introduction

Cardiac amyloidosis, once considered a rare disease, is now recognized as a substantial cause of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). It is caused by the accumulation of misfolded proteins as amyloid fibrils (as well as direct proteotoxicity). The two main forms affecting the heart are immunoglobulin light chain (AL) amyloidosis and transthyretin cardiac amyloidosis (ATTR), the latter being either wild-type (ATTRwt) or variant (ATTRv), which is a familial form due to a transthyretin mutation. Current treatments target amyloid precursor proteins, i.e. amyloidogenic light chains in AL amyloidosis, using plasma cell-directed therapies or TTR proteins using TTR stabilizers or silencers for ATTR. For cardiac ATTRwt, three treatments are presently approved based on their ability to improve survival and reduce heart failure hospitalization compared to placebo: tafamidis and acoramidis (both TTR stabilizers) and vutrisiran (a TTR silencer) ( Table 1 ). Now there is an intense interest in next-generation treatments, including effective precursor protein-directed therapies using gene silencing or CRIPR-cas9 gene editing technology, as well as novel therapies targeting amyloid fibril removal. For AL amyloidosis, the introduction of highly effective cytoreductive treatments aimed at halting amyloid deposition and preserving organ function has significantly transformed treatment strategies since the late 1990s. 1 In 2021, the clinical adoption of monoclonal antibodies, especially daratumumab, has radically altered the disease progression and clinical management ( Table 1 ). 2 More recently, the development of novel therapies, such as investigational antifibrillary antibodies like anti-serum amyloid P component, birtamimab, and anselamimab (also known as CAEL-101), has further accelerated progress in the treatment of AL amyloidosis. 1

Currently approved treatments do not halt disease progression, and ∼ 30–40% of patients continue to experience unfavourable outcomes despite treatment ( Table 1 ). Considering the emergence of new therapeutic options, monitoring disease progression is critical to allow for more personalized and effective treatment strategies. The most commonly used parameters to monitor the disease progression are quality of life, functional capacity, laboratory and echocardiographic markers, but these are influenced by various cardiac and extracardiac confounding factors, and treatment-related changes may take up to 18 months to manifest. 3 Hence, there is an increasing yet unmet need to measure changes over time in treatment. Although numerous studies have reported treatment-related changes in imaging biomarkers, a comprehensive understanding of these changes—particularly across imaging modalities—is still lacking. Comparative data from untreated patients, such as those from the pre-treatment era or placebo-controlled cohorts, are sparsely available, making it difficult to isolate treatment effects from the natural course of the disease. Looking ahead, therapies that actively remove amyloid fibrils—such as monoclonal antibodies—may lead to more pronounced changes in cardiac structure and function.

Imaging, including echocardiography, cardiac magnetic resonance (CMR), and radionuclide imaging, offers a multiparametric approach to stage and monitor cardiac amyloidosis. To serve as a surrogate endpoint for monitoring cardiac amyloidosis, an imaging marker must meet the following criteria: treatment must affect both the true clinical outcome and the surrogate endpoint, the surrogate must be associated with the true outcome, and the treatment’s effect on outcome must be fully mediated by its effect on the surrogate. No imaging biomarker in cardiac amyloidosis has yet fulfilled all these criteria, but future research aims to establish imaging parameters that meet this standard. Echocardiography is widely used to monitor cardiac amyloidosis due to its accessibility, low cost, and safety. 4 However, its utility is limited by high inter- and intrarater variability, lack of specificity for amyloid burden, and delayed response to treatment, making it less effective for early identification of non-responders. 3 Cardiac magnetic resonance provides a detailed structural and functional assessment in cardiac amyloidosis with high reproducibility and less operator dependency than echocardiography, especially in patients with poor acoustic windows. Its unique strength lies in tissue characterization using late gadolinium enhancement (LGE), T1 and T2 mapping. Pre- and post-contrast T1 mapping enables estimation of extracellular volume (ECV), a key marker for staging and tracking disease progression. 5 , 6 In fact, T1 mapping and ECV have demonstrated strong prognostic value and are associated with outcomes, 6 , 7 but they have not yet fulfilled all criteria required for a validated surrogate endpoint. In addition, CMR is time-consuming, costly, and less available outside tertiary centres. 8 Image quality can be hampered by cardiac devices and arrhythmias, and ECV cannot reliably distinguish amyloid from other extracellular components such as fibrosis or oedema. 9 , 10 In addition, quantifying LGE in diffuse disease remains challenging. Radionuclide imaging with planar scintigraphy and SPECT using bone-avid tracers has transformed the diagnosis of ATTR cardiomyopathy (ATTR-CM), offering a non-invasive, widely accessible, and cost-effective alternative to biopsy with high specificity. 11 In the absence of plasma cell dyscrasia, 99m Tc-labelled tracers such as 99mTc -pyrophosphate (PYP), 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), or hydroxymethylene diphosphonate (HMDP) enable specific diagnosis. However, limitations include radiation exposure—especially with serial imaging—and the unclear binding mechanism of these tracers, complicating interpretation of treatment-related changes. 3 Unlike bone-avid SPECT radiotracers, PET radiotracers are specifically designed to bind to amyloid fibrils. 12 Originally developed for Alzheimer’s disease, PET tracers are now increasingly being used for cardiac amyloidosis, although they are not yet approved for this purpose.

This review aims to provide an overview of the main imaging parameters for assessing treatment response in cardiac amyloidosis as well as disease progression in untreated patients, and to list current evidence in echocardiography, CMR and radionuclide imaging metrics.

Echocardiographic monitoring

Cardiac ATTR amyloidosis

Natural history. In untreated cardiac amyloidosis, echocardiographic parameters typically show progressive deterioration over time. 13–15 According to a recent expert consensus statement, left ventricular (LV) wall thickening of ≥ 2 mm, left ventricular ejection fraction (LVEF) drop of ≥ 5%, stroke volume (SV) reduction of ≥ 5 mL, or global longitudinal strain (GLS) increase of ≥ 1% are considered signs of disease progression, while smaller changes may represent measurement errors. 3

Treatment response. A post-hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) investigated the effect of tafamidis on echocardiographic measures that were previously identified as prognostic factors. 4 Over 30 months, patients receiving tafamidis ( n = 176) compared to placebo ( n = 177) showed a less pronounced worsening after 18 months in four echocardiographic measures with least square mean differences of tafamidis vs. placebo of 7 mL for LV SV, −1.0% for LV global longitudinal strain, −3 for septal E/e′, and −2 for lateral E/e′. For LVEF, a similar pattern of reduced decline with tafamidis was observed, but without statistical significance between tafamidis and placebo. No difference was observed for left atrial diameter. Previous studies investigating the use of tafamidis or other stabilizing drugs such as diflunisal reported similar results with stabilization of cardiac function in treated ATTR-CM patients. 13–15

In contrast to tafamidis, patisiran was found to even minimally improve some echocardiographic parameters in ATTRv patients. 16 Least-square mean differences of −1 mm for mean LV wall thickness, + 8 mL for end-diastolic volume, and −1.4% for global longitudinal strain were observed with patisiran compared with placebo. 16 In the HELIOS-B trial, vutrisiran improved diastolic function as early as 12 months and attenuated the decline in LV and right ventricular (RV) systolic function by 18 months. 17 , 18 At 30 months, it attenuated increases in LV wall thickness (least-squares mean difference −0.4 mm and LV mass index (LVMi) −10.6 g/m²), and attenuated declines in LVEF (+2.0%), absolute GLS (+1.2%), and LV SV (+4.1 mL), with reductions in E/e′ (−2.0) and E/A (−0.3) vs. placebo. The preliminary results of echocardiographic data using the antibody NI006 are suggesting improvement as well, but further data is needed. 19

Cardiac AL amyloidosis

In patients with AL amyloidosis, treatment monitoring includes assessment of haematologic response by serological markers and evaluation of changes in organ function. As cardiac involvement is the main determinant of prognosis in this condition, 20 evaluating cardiac response to treatment is particularly important. Early data showed a weak correlation between haematologic response and changes in the E/e’ ratio and LA stiffness, while no significant correlation was found between haematologic response and improvement in GLS ( n = 41). 21 In contrast, in a retrospective analysis ( n = 61), complete responders achieved a significant improvement in longitudinal strain without changes in wall thickness, ejection fraction, or diastolic function. 22 This is supported by a larger study ( n = 915) in which improvement in longitudinal strain was associated with a complete haematological response and improved clinical outcome, supporting the need for deep haematological responses in AL amyloidosis. 23

In summary, currently available studies consistently show stabilization of echocardiographic parameters with tafamidis but no significant improvement. For gene silencers and depleters, such as patisiran, vutrisiran, and the antibody NI006, there is preliminary data that indicates improvement. In AL amyloidosis, a slow improvement in longitudinal strain has been reported repeatedly in patients who achieve a deep haematologic response. In the future, artificial intelligence with its ability to minimize measurement variability 24 could improve the precision of serial echocardiographic evaluations and make echocardiography an even more valuable tool for assessing response to treatment. 24

Disease monitoring by cardiac magnetic resonance

Cardiac ATTR amyloidosis

Natural history. In untreated patients, the natural course of ATTR-CM typically shows a deterioration in cardiac function over time, which is reflected by changes in several key CMR parameters. The natural history of these imaging markers in cardiac ATTR amyloidosis is listed in Table 2 . The absolute changes in Table 2 were presented as weighted averages (and ranges from all studies) from all studies that reported values after 1 year. Of note, all parameters in the table are expressed as relative changes from the baseline values. This approach allows visualization of trajectories independent of absolute baseline values, though it must be noted that the clinical significance of a given percentage change varies between parameters. While ECV increased by +3% (+1% up to +5%), native T1 increased by +15.8 ms (+11.6 ms up to +19 ms) after 1 year. This rise in ECV and T1 in untreated patients correlates with a decline in cardiac function, reflected by decreased biventricular function and GLS. Left ventricular ejection fraction changed by −5.6% (−3.0% up to −7.6%) and right ventricular ejection fraction (RVEF) by −5.9% (−5.4% up to −6.6%) after 1 year. Only Dobner et al. showed an LVEF decrease that was not statistically significant; however, they reported a significant RVEF decline in untreated patients. 27 Finally, the LVMi increased by +4.6 g/m 2 (1 up to 8 g/m 2 ) after 1 year.

Treatment response. In line with the stabilization of echocardiographic biomarkers, most studies report a slowed progression of CMR-derived ECV and native T1 with tafamidis. The response of CMR biomarkers to treatment in cardiac ATTR amyloidosis is listed in Table 3 . Three prospective studies [Rettl et al. ( n = 70), Chamling et al. ( n = 20), Dobner et al. ( n = 27)] showed stable ECV measurements after 12 months. 27–29 One retrospective analysis [Ney et al. ( n = 22)] observed the same preservation at 6 months. 31 Dobner et al. also found a slight but non-significant ECV increase (47.7–51.1, P = 0.145) after 24 months, suggesting that ECV remains largely stable over a longer time with tafamidis therapy 34 ( Graphical Abstract ). Of note, EF and GLS are stable as well in patients with ATTR-CM treated with tafamidis for about 1 year ( Graphical Abstract ). 28 , 29 , 33 , 34

The trend of ECV stabilization was similarly observed with the TTR stabilizer acoramidis. Razvi et al. ( n = 26) found an absolute mean change of +2.0% in ECV after 30 months of acoramidis therapy. 26 Although this mean change was similar to placebo, 13% of acoramidis recipients demonstrated amyloid regression, which was not observed in any of the placebo patients. 26 Similar stabilization was also observed with RNAi therapies. Patisiran and inotersen showed no significant ECV changes after 12 months in patients with ATTRv-CM ( n = 9). 32 Contrary to these findings, Fontana et al. reported a mean decrease of 6% in ECV after 12 months of patisiran compared to an untreated group. 30 In a larger cohort ( n = 65), they found treatment with patisiran led to a reduction in myocardial ECV in 6% of patients, although most patients exhibited disease stability. 25 The only study with ECV reduction following tafamidis treatment included 14 patients with variant A97S ATTR-CM. 33 Over 1 year, ECV decreased from 52% to 49% ( P = 0.041). However, this study focused on patients mostly presenting with NYHA Classes I to II. This could explain the observed ECV reduction, as tafamidis is suggested to be more effective in earlier stages of the disease. The new antibody NI006 showed considerably greater reductions, with an 18% decrease in ECV after 1 year in three patients, suggesting probable amyloid clearance. 19 In addition to ECV, native T1 measurements are particularly useful in cases where contrast use is limited, such as in chronic kidney failure. Across all reported studies, no substantial changes in T1 values were observed following treatment, including the study by Tsai et al. that noted a small reduction in ECV. 33 This discrepancy between ECV and T1 might be explained by the different biological data being measured. While ECV mainly reflects amyloid deposition, native T1 is also strongly influenced by myocardial oedema. 6 , 35 In addition, T1 is sensitive to field strength and acquisition settings, making it scanner-dependent. This is less so for ECV, in part because it is based on a ratio, where scanner-specific components cancel out. Hence, ECV is more reproducible and comparable across scanners, even though there are also minor differences in normal values. The stabilization in ECV and native T1 following treatment with the TTR stabilizing drugs tafamidis and acoramidis was associated with a stabilization of cardiac function, indicated by stabilization of LVEF, RVEF, and GLS on CMR. Tsai et al. , who observed a small decrease in ECV, also found no change in LVEF or strain, suggesting that the stabilization of TTR may not necessarily lead to reverse maladaptive cardiac modelling. Although functional improvements have been observed on echocardiography following patisiran treatment, 16 the described ECV reduction by Fontana et al. following patisiran was not correlated to functional improvements in EF or strain on echocardiography and CMR. As far as LV mass index is concerned, studies have observed no change or a slight decrease in LV mass index after treatment with tafamidis and acoramidis. However, it remains unknown whether the observed reduction in LV mass following therapy is due to reduced amyloid deposition of amyloid fibrils and amyloid clearance or other mechanisms such as myocardial remodelling. 27

Cardiac AL amyloidosis

The response of ECV and T1 values to treatment of AL amyloidosis is listed in Table 4 . In AL amyloidosis, Martinez-Naharro et al. demonstrated for the first time—in a subset of participants but not overall—a reduction in ECV and native T1 following a decrease in free light chains after chemotherapy. 38 As the reduction in ECV and native T1 correlated with regression in other organs by SAP scintigraphy and was associated with a reduction in myocardial oedema, this was considered to be evidence of amyloid regression. There is limited data on the reproducibility of ECV in monitoring cardiac amyloidosis, so the reproducibility examined in this study is of particular importance. Based on their data, an ECV change of ≥ 5% was considered a true change rather than variability. 38 , 39 In a subsequent larger prospective study ( n = 176) followed up at 6, 12, and 24 months, all patients who experienced ECV reduction after chemotherapy had either a complete haematologic response (CR) or a very good partial response. No change in native T1 was observed in regressors, while an increase of 36 ms was observed in progressors at 12 months. Associated functional changes were not seen at 6 months, but at 1 year: the reduction in ECV was associated with improvements in E/E′ and eccentric remodelling, with further improvements at 2 years. In patients with increasing ECV, LVEF was reduced at 1 year, and MAPSE worsened at 2 years. This suggests that ECV changes were detectable as early as 6 months, whereas the detection of other markers indicative of remodelling takes more time. Ioannou et al. ( n = 221) similarly showed that decreases in native T1 at 6–12 months were linked to good haematologic response and improved strain with lower ECV, whereas increases in native T1 were associated with poor response and worsening function. 37 In contrast, in a prospective study of 111 AL amyloidosis patients, only a reduction in RV-ECV was described after 12 months of chemotherapy. 36 Native T1 and LV-ECV did not decrease significantly. This was explained by a more prominent and probably earlier recovery of the right ventricle compared to the left ventricle. A recent prospective study by Clerc et al. , including 60 AL-amyloidosis patients with cardiac involvement (AL-CMP) and 20 without cardiac involvement (AL-non-CMP) showed an increase in ECV at 6 months and a return to baseline at 12 months in AL-CMP. 7 This curved trend was explained by an initially continued amyloid deposition followed by amyloid clearance. Alternatively, some form of remodelling or fibrosis might expand ECV initially. Since no change in T2 mapping was observed, it is more likely that amyloid (or maybe fibrotic remodelling) caused these changes than other factors such as inflammation or oedema. However, considering that ECV also increased at 6 months in AL-non-CMP, interstitial fibrotic remodelling in response to chemotherapy cannot be ruled out. Despite the lack of improvement in ECV, GLS improved at 6 months and improved further at 12 months, consistent with the improvement in GLS observed on echocardiography. 23 This functional improvement (despite the lack of change in ECV at 12 months) could be explained by circulating light chains with direct toxic effects being removed earlier, before cardiac structure is restored. 40 , 41

In summary, CMR-derived ECV measurement is a valuable non-invasive imaging approach to evaluate the efficacy of tafamidis treatment in ATTR and AL-CM. In ATTR-CM, tafamidis appears to maintain ECV levels, whereas ECV significantly rises without treatment. These changes have been linked to stabilization of cardiac function in treated patients and deterioration in untreated patients. Promising results from drugs such as patisiran and antibodies show ECV reduction, indicating amyloid clearance. In AL-CM, ECV changes can be seen as early as 6 months, while changes in cardiac function take longer to appear and might initially be related to clearance of toxic light chains rather than cardiac remodelling.

Disease monitoring by SPECT

Visual, semiquantitative and quantitative assessment

Planar scintigraphy can be interpreted visually using the Perugini score, which compares myocardial to rib uptake. 42 Furthermore, semi-quantitative markers such as the heart-to-contralateral lung (H/CL) or heart-to-whole-body ratio (H/WB) have be used in planar scintigraphy. Quantitative measures in SPECT offer the advantage of objectivity and higher reproducibility, which is particularly important for assessing changes over time. Quantitative measures include the standardized uptake value (SUV), from which mean (SUV mean ), maximal (SUV max ), and peak (SUV peak ) values can be derived. These are radiotracer concentration metrics. Then, there are two total radiotracer activity metrics which are indicative of amyloid burden: cardiac amyloid activity (CAA) and percent injected dose (%ID). They have demonstrated higher diagnostic accuracy and superior prognostic value. 43 , 44 Cardiac amyloid activity is calculated as the product of SUV mean and the VOI volume, while the %ID corresponds to CAA, but without weight correction. 45 The accuracy and clinical value of all these metrics depend on the volume of interest (VOI) definition. The most advanced and robust approach for VOI definition is to select the LV epi- and endocardial contours automatically using thresholding based on blood pool activity measurements. 46 Recently, an automated approach using deep learning-enabled quantification has been proposed and holds great promise to standardize radiotracer quantification. 47

Response to tafamidis

Visual, semiquantitative and quantitative SPECT biomarkers to assess treatment in ATTR amyloidosis have been listed in Table 5 . Many of the currently available studies suggest a decrease in cardiac uptake with tafamidis treatment after 1–3 years. Of note, semiquantitative metrics of tracer uptake (i.e. H/CL ratio, H/WB ratio, and heart-to-thigh ratio) are reduced by an average of −11% in patients with ATTR-CM treated with tafamidis for about 1 year ( Graphical Abstract ). 49 , 51 , 53 , 54 Conversely, tracer uptake remains unchanged in untreated patients. 51 , 54 While many studies describe a reduction in visual scoring and semiquantitative ratios, fewer studies have reported quantitative measures. Vijayakumar et al. observed a significant reduction in SUV max after 2.8 years of tafamidis treatment, with a median decrease in SUV max of −0.75 and a reduction in CAA of −407. 46 However, they did not find significant changes in SUV mean . Rettl et al. observed a reduction of −1.7 g/mL in the retention index and −3.2 g/mL in SUV peak with tafamidis after 9 months. 56 Godoy-Rivas et al. reported relative changes in %ID, supporting these findings. 57

This observed reduction with tafamidis is very surprising as the drug is known to stabilize circulating TTR tetramers but not eliminate aggregated TTR fibrils ( Figure 1 ). Several factors could explain this. First, the mechanisms of uptake for different tracers are not fully understood, so changes in uptake may indicate different phenomena. Tracer uptake may not only indicate a change in amyloid load, but could also reflect variations in the calcium content of amyloid, as the binding of radionuclide-labelled phosphonates to amyloid-containing hearts may depend on the presence of microcalcifications, which do not have a direct association with amyloid fibrils. 55 Moreover, treatment could cause the myocardium to begin healing, leading to changes in the molecular properties of the amyloid fibrils or the surrounding microenvironment, thus reducing tracer affinity. 48 Finally, especially DPD tracer uptake reduction may also reflect redistribution into other compartments, such as soft tissue, muscle, or bone. 58 Independent of the underlying mechanisms, the reduction of myocardial radiotracer activity as a response to disease-modifying treatment reflects longstanding experience in oncology, where—after initiation of chemotherapy— 18 F-FDG uptake in PET/CT is reduced prior to morphological changes. 59 Indeed, patients with a larger reduction of SPECT uptake had more favourable clinical outcomes than those with a smaller reduction, indicating that changes in radiotracer uptake have clinical implications. 50

Despite the majority of studies agreeing on tracer reduction, interpreting these changes in relation to functional markers remains unclear. While most studies did not report significant improvement in functional markers, Rettl et al. observed significant improvements in CMR-derived EF in the cohort with improved SPECT biomarkers. This suggests that changes in SPECT biomarkers may become apparent earlier than functional recovery, similar to what has been observed with ECV.

Response to silencers

For patisiran, Fontana et al. reported a median reduction of 20% in %ID over 1 year that correlated with changes in ECV, although no significant changes in echocardiography were observed. 30 Biomarkers may become apparent earlier than functional recovery, similar to what has been observed with ECV. In contrast, Tingen et al. reported an increase in SPECT tracer uptake with tafamidis. 55 This discrepancy could be explained by the lower dose (20 mg) of tafamidis (for polyneuropathy in ATTRv), as opposed to the 61 or 80 mg used in the other studies. In patients treated with patisiran, Tingen et al. saw a reduction in H/WB ratio, but without associated echocardiographic changes. 55 Similarly, Rettl et al. observed a −1.96 g/mL reduction in retention index in ATTRv patients treated with patisiran and inotersen, but no functional improvements in echocardiography. 32

Regarding vutrisiran, a reduction in normalized total LV uptake of −0.012 and a decrease in the H/CL ratio of −2.8 were reported. 52 The new antibody NI006 also showed a decrease in the H/WB ratio. 19

Response in AL amyloidosis

For AL amyloidosis, there is currently no data using SPECT in monitoring cardiac treatment response. Evidence is limited to extracardiac imaging, where SAP scintigraphy has demonstrated regression of visceral amyloid following chemotherapy. 38

Overall, these studies must be compared with caution since different tracers were used (PYP, DPD, and HMDP) and their exact binding mechanisms are still unknown. In addition to the lack of reproducibility data, this makes interpretation of changes after treatment difficult. Although a reduction in SPECT biomarkers is often observed after tafamidis treatment, these changes mostly do not correlate with functional improvements. Hence, they should not be seen as equivalent to a reduction in amyloid load, and it is unclear whether changes in SPECT uptake can be reliably used as surrogate outcomes in trials. More studies are required to elucidate this relationship, as well as the relationship to parameters from other imaging modalities, such as CMR-derived ECV.

Comparison of imaging techniques and limitations

Echocardiography is a highly accessible and cost-effective tool for assessing structural and functional changes in cardiac amyloidosis. Although useful, it often reveals changes late in the disease course, and measurement variability makes subtle treatment changes difficult to detect. In contrast, CMR and SPECT imaging have demonstrated their value in detecting early changes in interstitial remodelling or molecular disease activity in response to treatment. These modalities provide quantitative markers that can indicate regression or stabilization of amyloid before functional changes become visible. At the current stage, these mechanistic insights are most valuable in disease monitoring by CMR and SPECT imaging. However, these changes on CMR and SPECT should be interpreted cautiously. An important limitation of SPECT studies is that different bone-avid tracers (PYP, DPD, and HMDP) were used in the various studies, and their exact binding mechanisms to amyloid fibrils are not yet fully understood. Although they all enable non-invasive diagnosis of ATTR-CM, differences in their distribution and affinity can influence quantification, especially in serial imaging. For example, a reduction in DPD uptake after tafamidis therapy may be partly due to redistribution to extracardiac compartments such as soft tissue or bone, rather than an actual reduction in myocardial amyloid burden. In contrast, PYP shows no relevant uptake in soft tissue. These differences between the tracers make it difficult to compare serial changes. Furthermore, the reductions in SPECT biomarkers with tafamidis treatment did not reliably correlate with functional improvements so far and should therefore not be taken as proof of amyloid reduction. Further studies are needed to clarify this. Currently, a major limitation for all studies is the lack of reproducibility data, making it difficult to distinguish clinically meaningful changes from measurement variability. As the available studies are mostly small single-centre studies, studies with longer observation periods and larger sample sizes are needed to confirm the current findings, as well as link changes in CMR and SPECT biomarkers with clinical outcomes to establish reliable biomarkers for monitoring treatment response in cardiac amyloidosis.

Amyloid-binding PET tracers

There is currently limited data on the use of PET imaging to assess response to treatment ( Figure 2 ). However, a study investigating treatment response in seven patients with systemic AL amyloidosis who achieved a complete haematological response with chemotherapy showed that PiB-PET can visualize a significant reduction of cardiac AL amyloid deposition after CR. 60 The observed amyloid reduction correlated closely with cardiac biomarkers in serum (i.e. NT-proBNP and troponin T). Two case studies using 124 I-evauzamitide 61 and 11 C-PiB PET/CT 62 further confirmed these findings. In a larger cohort of 58 patients with AL amyloidosis, serial 18F-florbetapir PET/CT demonstrated a significant reduction in myocardial amyloid burden as early as 6 months after initiation of plasma cell therapy. 63 These reductions correlated with changes in NT-proBNP, whereas changes in CMR-derived ECV did not, highlighting the potential of PET to sensitively track treatment response. At least, the data illustrate that molecular amyloid and ECV changes likely reflect different aspects of myocardial remodelling in AL amyloidosis.

Novel tracers and artificial intelligence

At the moment, there are two ongoing Phase III studies on amyloid-binding PET tracers for diagnosing cardiac amyloidosis: One for 18 F-Florbetaben ( NCT05184088 ), which specifically targets AL amyloidosis and another for 124 I-evuzamitide ( NCT06788535 ), a pan-amyloid tracer designed to detect all types of amyloidosis, including ATTR and AL, in various organs. The results of these Phase III studies will lay the foundation for PET tracers to diagnose cardiac amyloidosis. Although the emerging evidence appears promising, larger multicentre studies are needed for PET to assume a more central role in assessing treatment response.

Beyond novel tracers, AI models might gain importance in cardiac amyloidosis. AI models have been applied to multiple imaging techniques used for diagnosing CA, including echocardiography, CMR and scintigraphy. 64 Although there are limitations within these studies, the future holds promise for AI becoming an increasingly integrated component of the diagnostic work-up and monitoring of cardiac amyloidosis. Furthermore, in imaging modalities prone to observer variability, such as echocardiography, and thereby limiting the validity of serial measurements for treatment response, artificial intelligence, with its capacity to minimize measurement variability, 24 presents a unique opportunity to enhance the precision of serial echocardiographic evaluations. By improving reproducibility, AI could enable the detection of more subtle longitudinal changes.

Clinical implications

The goal of imaging is to support clinical decision-making, not just to describe changes. With new treatment options, more and more questions are arising about treatment decisions, making tailored monitoring strategies for the different subtypes of cardiac amyloidosis increasingly important. From a clinical perspective, the following criteria should be met for an imaging marker in order to define subtype-specific monitoring strategies: changes in imaging findings (i.e. ECV or radionuclide uptake) are linked to (i) morphological and functional changes, (ii) to established clinical markers of disease activity (i.e. quality of life, functional capacity, NT-proBNP), and (iii) to outcomes. So far, only ECV has met all of these criteria, although in small sample sizes in a few centres. 25

Still, there are important clinical implications to be drawn from the available evidence about the temporal course of imaging changes in the two main subtypes of cardiac amyloidosis. For ATTR-CM, echocardiography can reveal early diastolic changes as soon as 12 months. 17 Worsening of global longitudinal strain by > 1% and progressive diastolic dysfunction, reflected by increases in E/e′, have been shown to indicate disease progression. 3 While diastolic markers were prognostic and responded to treatment, changes over time were not associated with long-term mortality. 17 Nevertheless, changes in diastolic markers are followed by changes in strain, LVEF, and SV, which typically become apparent at later time points. In cardiac MRI, stabilization of ECV is usually observed by 1 year, whereas structural markers such as wall thickness or LV mass take longer to show changes ( Figure 3 ). Changes in radiotracer uptake occur as early as 9 months after initiation of stabilizer therapy but have not been consistently correlated to changes in structural and functional markers. The lack of understanding of molecular binding limits the application of radionuclide imaging with bone-avid tracers in ATTR-CM. For AL-CM, changes in ECV as well as 18 F-florbetapir PET can appear as early as 6 months, while functional and structural remodelling as well as changes in established clinical markers of disease activity typically lag behind. 7 , 63

Based on current knowledge, a possible actionable finding could be that if a patient with ATTR-CM shows worsening strain of more than 1% after 1 year and this is confirmed by an increase in ECV, a change in treatment strategy should be considered. However, to derive actionable implications from these findings, the effects of discontinuing treatment, changing therapy, and combination therapy need to be elucidated. At present, discontinuing therapy remains a difficult decision (except for apparent scenarios of futility). In addition, there is no clinical trial evidence on switching or the combination of therapies. Therefore, an actionable monitoring approach cannot be defined yet. Nevertheless, the available evidence can inform clinical trial design, where imaging biomarkers are used to guide treatment decisions (e.g. imaging progression triggers switching or combining therapies) ( Figure 4 ).

Conclusion

Monitoring and early detection of disease progression remain major challenges in cardiac amyloidosis. However, there is growing evidence that SPECT and MRI enable sensitive and multiparametric assessment of treatment response. These imaging techniques are particularly promising because they allow detection of early changes in interstitial remodelling or molecular disease activity before functional deterioration becomes apparent. While such imaging markers hold considerable potential as objective surrogates for disease activity and therapeutic response, their clinical value has not been firmly established, as current evidence is limited to small, single-centre studies with heterogeneous methodologies and short follow-up. Looking ahead, larger multicentre investigations with reproducibility testing will be critical to validate these biomarkers and establish their role in guiding routine treatment decisions and enabling more personalized patient care.

Author contributions

Amely Walser (Writing—original draft [lead]), Christoph Gräni (Writing—review & editing [equal]), Simon F. Stämpfli (Writing—review & editing [equal]), Sarah A. M. Cuddy (Writing—review & editing [equal]), Olivier F. Clerc (Writing—review & editing [equal]), Ardel J. Romero Pabón (Writing—review & editing [equal]), Shilpa Vijayakumar (Writing—review & editing [equal]), Osnat Itzhaki Ben Zadok (Writing—review & editing [equal]), Rodney H. Falk (Writing—review & editing [equal]), Sharmila Dorbala (Writing—original draft [supporting]; Writing—review & editing [equal]), and Dominik C. Benz (Writing—original draft [equal]; Writing—review & editing [lead])

Funding

Gräni: Funding from the Swiss National Science Foundation, Innosuisse, CAIM Foundation, GAMBIT Foundation, and Novartis Foundation. Cuddy: Investigator-initiated research funding from Pfizer. Clerc: Research funding from the International Society of Amyloidosis and Pfizer. Romero Pabon: National Institutes of Health (NIH) T32 HL 094301. Vijayakumar: NIH T32 HL 094301; research grant from the Amyloidosis Foundation. Falk: Investigator-initiated research funding from GlaxoSmithKline and Akcea. Dorbala: Investigator-initiated funding from Pfizer, GE Healthcare, Attralus, and Siemens. Benz: Career development grant from the Advanced Clinician Scientist Program, University Medicine Zurich UMZH; research funding from Swiss National Science Foundation, Swiss Heart Foundation, Olga Mayenfisch Foundation, and Immanuel und Ilse Straub Stiftung; investigator-initiated research funding from AstraZeneca and Life Molecular Imaging.

Data availability

No new data were generated or analysed in support of this research.

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