Cardiac amyloidosis shares several common features with AS, including concentric LVH, LV diastolic dysfunction, abnormal LV longitudinal strain (LS) (sometimes with apical sparing), and ultimately HF.8,85 Thus, distinguishing between isolated severe AS and severe AS with coexisting CA is challenging. Additionally, as the prevalence of both conditions increases with age,78,86 their coexistence is not uncommon in the elderly.

Recent studies have prospectively investigated the prevalence of CA in patients with AS42–46,87–95 (Table 6).

The prevalence of CA ranged between 4.0% and 16.0% in patients with severe AS referred for transcatheter (TAVR) or surgical (SAVR) aortic valve replacement, reflecting different study populations and diagnostic methods.42–46,87–94 In patients with moderate or severe AS referred for cardiac magnetic resonance (CMR), the prevalence of CA was 8%.95 ATTRwt-CM accounted for the majority of cases, but in three studies AL-CA represented 5–6% of CA associated with AS, which underlines the importance of searching for a monoclonal protein to avoid missing patients with AL-CA.87,89

CA is thus relatively common in patients with severe AS. The unanswered question is which patients have increased risk and warrant CA screening. Interestingly, the prevalence of CA did not increase significantly (7–11.6%) in two studies that only included patients with one or more red flags for CA.89,93

Patients with severe AS superimposed on CA tend to be older and have a higher prevalence of carpal tunnel syndrome, higher troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, higher LV mass index, lower stroke volume index and greater diastolic dysfunction on echocardiography and lower Sokolow criteria on electrocardiography.42–46,87–95 Even so, none of these parameters had sufficient discriminatory ability or an optimal cutoff to guide CA screening in patients with AS in previous studies.44,87,89–92,94,96 Studies also report that patients with AS and concomitant CA have a higher prevalence of low-flow low-gradient AS (LFLG-AS). Nevertheless, 14–69% of patients with AS and CA present high-gradient severe AS, so restricting CA screening to patients with LFLG-AS does not seem appropriate.42,44,87,88,90–94 Similarly, a multicenter study developed a clinical score (the Remodeling, Age, Injury, System, and Electrical [RAISE] score) to predict CA,45 but the generalized and systematic implementation of scores in daily clinical practice may not be easy.

Furthermore, identification of CA in patients with severe AS is also important to guide the therapeutic choice for AS, since previous studies report worse outcomes after SAVR than after TAVR and worse prognosis for patients with severe AS and concomitant CA, if left untreated.43,44,88,89,94,95,97 In addition, identification of CA in this subset of patients enables the early detection of patients who may benefit from disease-modifying therapy after AS treatment. Finally, the prognostic benefit from novel ATTR-CM therapies was shown to be greater when the treatment was started earlier.98

Based on these arguments, this Task Force recommends the systematic screening of CA in patients diagnosed with severe AS at ≥65 years of age.

The age cutoff of 65 years, although arbitrary, reflects the increased prevalence of CA, in particular ATTRwt-CM, in the elderly, and follows the ESC recommendations.8,80 Furthermore, to the best of our knowledge, the mean age of CA patients in the studies that explored CA prevalence in severe AS patients was 70 years or older.42–46,87–95 Thus, screening all patients diagnosed with severe AS at ≥65 years of age would enable detection of the vast majority of patients with both conditions. Recently, myocardial ECV quantification by computed tomography (CT) imaging has been proposed as a CA screening tool in patients undergoing routine CT evaluation for TAVR.99–101 Amyloid fibril deposition causes interstitial expansion and a massive increase in ECV, which can be detected with high diagnostic accuracy by CT or CMR imaging.102,103 ECV-CT avoids some limitations associated with CMR imaging and could be analyzed in patients already undergoing routine CT assessment for TAVR. Two studies have proposed an ECV-CT cutoff of 31.4% and 33.7% in patients with severe AS.99,100 However, ECV measurements may also be affected by the presence of comorbidities, the type of CT scanner, contrast dose and timing of imaging, and the proposed ECV thresholds need further validation.101 Likewise, CT-derived four-dimensional cardiac parameters such as LV mass index, LV and left atrial GLS and relative apical LS may help identify CA.104

In summary, this Task Force recommends systematic screening for CA in all patients diagnosed with severe AS at ≥65 years of age with the non-invasive diagnostic algorithm for CA, which includes 99mTc-DPD/hydroxymethylene diphosphonate (HMDP)/pyrophosphate (PYP) scintigraphy and monoclonal protein testing and, if necessary, extracardiac and/or endomyocardial biopsy (Figure 3). The incorporation of ECV-CT measurement in patients undergoing routine CT evaluation for TAVR may assist CA screening as a gatekeeper to the proposed non-invasive diagnostic algorithm.

Figure 3.

Recommendations for the screening of cardiac amyloidosis in four clinical settings with a strong epidemiological association with the disease. ATTRv: hereditary transthyretin amyloidosis; CA: cardiac amyloidosis; HCM: hypertrophic cardiomyopathy; HFpEF: heart failure with preserved ejection fraction; LVH: left ventricular hypertrophy; LVWT: left ventricular wall thickness; TTR: transthyretin.

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CA leads to LVH that may appear morphologically like HCM. Distinguishing between these two entities is critical due to differences in symptom management, sudden cardiac death risk stratification and prevention, and specific treatment, which has recently emerged for both entities.80

The prevalence of CA in patients with unexplained LVH has been assessed in six prospective studies105–110 (Table 7).

Two prospective studies determined the exclusive prevalence of ATTRv-CM and demonstrated prevalences of 0.5% and 5%, with the difference likely being related to differences in ethnic composition, older age of the cohort with the higher prevalence, and prior exclusion of clinically suspected or confirmed HCM phenocopies including CA in the cohort with lower prevalence.105,106

A single-center study and a large multicenter multinational study investigated the prevalence of ATTRv-CM and ATTRwt-CM in patients with presumed HCM.47,107 The single-center study found no cases of ATTRv-CM, but revealed an ATTRwt-CM prevalence of 3% in patients with HCM aged 60 years or older, corresponding to 8% of patients with nonobstructive HCM and none with obstructive HCM.107 The multicenter study demonstrated a prevalence of 18.8% of ATTR-CM (16.1% ATTRwt-CM, 1.4% ATTRv-CM, 1.3% unavailable results) in patients aged 50 years or older with HCM with no previously identified etiology based on clinical history and prior testing.47 The prevalence of ATTR-CM rose with increasing age, ranging from 5.2% in patients aged 50–60 years to 33.5% in those aged >80 years.47 Notably, classic echocardiographic signs described in HCM, such as asymmetrical hypertrophy and LV outflow tract obstruction, were observed in 20% and 13% of ATTR-CM patients, respectively.47

Furthermore, the prevalence of ATTRv-CM, ATTRwt-CM and AL-CA was explored in two studies in patients with an initial diagnosis of HCM.108,109 A study that applied the stepwise diagnostic algorithm recommended in the consensus documents revealed a prevalence of CA of 18% (8% ATTRwt-CM, 4% ATTRv-CM, 5% AL-CA, and 1% AA amyloidosis) in adult patients with unexplained LV wall thickness (LVWT) >15 mm.108

In a study that included 343 patients aged 40 years or older with an initial diagnosis of HCM, all patients underwent clinical evaluation and genetic testing with an HCM panel that included the TTR gene.109 HCM gene panel testing revealed that 3% had pathogenic/likely pathogenic variants in the TTR gene.109 Mutation-negative patients were then referred for further workup and those with at least one red flag for CA underwent bone scintigraphy, monoclonal protein testing and extracardiac biopsy if a monoclonal protein was detected. The prevalence of CA in the cohort was 9% (3% ATTRv-CM, 5% ATTRwt-CM and 1% AL-CA).109 CA prevalence increased with age, from 2% in patients aged <60 years to 26% at age ≥80. Interestingly, before 60 years of age, CA diagnosis was confined to AL-CA and to largely asymptomatic ATTRv-CM identified by genetic testing.109 After the age of 70 years, most CA diagnoses were predominantly in symptomatic patients with ATTRwt-CM and ATTRv-CM, with a clear higher prevalence of the former.109

An age-related screening strategy in patients diagnosed with HCM may therefore improve the yield of screening for CA. Based on these findings, in patients diagnosed with HCM under 65 years of age and with no red flags for CA, CA screening is recommended to be performed by HCM genetic testing with a panel that includes the TTR gene to detect ATTRv-CM (Figure 3). In patients diagnosed with HCM at ≥65 years of age, we recommend application of the non-invasive diagnostic algorithm for CA screening, which includes 99mTc-DPD/HMDP/PYP scintigraphy and monoclonal protein testing, and, if necessary, extracardiac and/or endomyocardial biopsy (Figure 3). The recommendation to perform systematic non-invasive screening in all patients diagnosed with HCM at ≥65 years of age is justified by the significant prevalence of CA in the elderly, the feasibility of the non-invasive stepwise diagnostic algorithm, and the availability of disease-modifying therapies. This is valid for both obstructive and non-obstructive HCM, as LV outflow tract obstruction may occur in CA.47

We also believe that these recommendations should apply to patients with and without arterial hypertension and with or without HF. Hypertension is a common comorbidity in patients with CA105 and excluding hypertensive patients from screening could potentially delay or prevent CA diagnosis and treatment. Likewise, as earlier treatment seems to provide prognostic benefit,98 CA screening of patients with LVH but without HF symptoms is appropriate, as it allows earlier diagnosis and may enable earlier initiation of disease-modifying therapy.

Finally, according to the ESC consensus document, the recommended LVH cutoff is an LVWT of 12 mm or more, which, if combined with one or more red flags, should prompt CA screening.8,80 A prospective study assessed the prevalence of CA among patients aged 55 years or older and a ‘CA compatible’ echocardiogram, defined as a non-dilated hypertrophic left ventricle (LV ejection fraction [LVEF] ≥50%, interventricular septum ≥13 mm in men and ≥12 mm in women, and LV end-diastolic volume index ≤85 ml/m2).110 CA compatible echocardiograms with one or more red flags (restrictive filling pattern, myocardial granular sparkling, apical sparing, interatrial septal thickness >5 mm, atrioventricular valve thickness >5 mm, or pericardial effusion) were defined as ‘CA suggestive’. The estimated prevalence of CA in patients with a ‘CA suggestive’ echocardiogram was 28.6% (23.5% ATTR-CM, 5.1% AL-CA). Notably, the prevalence of CA in patients with a ‘CA compatible’ echocardiogram was 4.4%, highlighting the value of widening CA systematic screening to patients with LVH with IVS thickness ≥13 mm in men and ≥12 mm in women.110 Another study showed a prevalence of ATTR-CM of 19% in patients older than 65 years with interventricular septum ≥12 mm and permanent pacemaker.111 Thus, we also recommend performing systematic non-invasive screening in patients diagnosed at ≥65 years of age with unexplained LVH with LVWT of 12–14 mm (Figure 3).

HFpEF is a heterogeneous syndrome with various underlying etiologies, including CA.112 However, CA is often under-recognized and underdiagnosed as a cause of HFpEF.112

Studies assessing the prevalence of CA in HFpEF had heterogeneous inclusion criteria, enrolling patients with and without LVH and with LVEF of 40%, 45%, 50% or higher38–40,113–118 (Table 8).

Six studies performed systematic screening in HFpEF patients using the recommended non-invasive diagnostic algorithm. The prevalence of CA ranged from 4.8% to 31%, reflecting the different study populations.39,40,113–116 ATTRwt-CM accounted for the vast majority of cases.39,40,113–116 A study that only employed 99mTc-DPD for systematic screening in HFpEF patients with LVH aged 60 years or older revealed an ATTRwt-CM prevalence of 13.3%.117 Another study that used myocardial biopsy as the single diagnostic modality also revealed a CA prevalence of 14% (6.5% ATTRwt-CM; 3.7% ATTRv-CM; 2.8% AL-CA; 0.9% AACA) in patients with HFpEF referred for endomyocardial biopsy for etiological assessment.118

As expected, patients with HFpEF due to CA were older and had a higher prevalence of cardiac and extracardiac red flags, including LVH, pericardial effusion, higher troponin and NT-proBNP levels, carpal tunnel syndrome and lumbar spinal stenosis.39,40,114–118

Notably, one study investigated the prevalence of CA in HFpEF patients without LVH using the recommended non-invasive diagnostic algorithm and reported a non-negligible ATTRwt-CM prevalence of 5.6%.38 This suggests that CA screening can be performed in specific clinical scenarios to detect CA in very early stages, before the development of LVH.

Thus, the prevalence of CA, especially ATTRwt-CM, is significant in HFpEF and its diagnosis may have therapeutic implications in the choice of the most suitable HF medications and in the initiation of CA-specific therapy.119 The high prevalence of CA was seen in systematic screening of all consecutive patients with HFpEF, regardless of the presence of red flags that suggested CA.

Based on these findings, CA screening is recommended in patients diagnosed with HFpEF at ≥65 years of age. As the mean age of HFpEF patients with CA was over 70 years in the studies that investigated its prevalence, the age cutoff of 65 years was considered appropriate for CA screening and follows the ESC recommendations.8

Table 9 summarizes our recommendations for CA screening. We recommend systematic screening with the noninvasive diagnostic algorithm for CA in patients with severe AS or unexplained LVH or HFpEF diagnosed at ≥65 years of age. In patients with HCM diagnosed under 65 years of age, and with no red flags for CA, CA screening is recommended to be performed with HCM genetic testing using a panel that includes the TTR gene to detect ATTRv-CM.

Identification of one or more red flags for CA in patients with unexplained LVH or HFpEF, with no other identified alternative diagnosis, should also prompt use of a non-invasive diagnostic algorithm for CA screening.

These recommendations widen systematic screening for CA in clinical conditions with a strong epidemiological link to CA and aim to simplify red flags to enable early diagnosis and initiation of disease-modifying therapy.

In the past, ATTR-CM was classically diagnosed through the detection of TTR amyloid fibrils in cardiac tissue. More recently, a non-invasive strategy for the diagnosis of ATTR-CM was defined by consensus, given the high diagnostic accuracy of the combined use of 99mTc-DPD/HMDP/PYP scintigraphy, cardiac imaging and hematological tests8,14,80,120 (Figure 4).

Figure 4.

Diagnosis of transthyretin amyloid cardiomyopathy. 99mTc: 99mTechnetium; ATTR-CM: transthyretin amyloid cardiomyopathy; DPD: 3,3-diphosphono-1,2-propanodicarboxylic acid; HMDP: hydroxymethylene diphosphonate; PYP: pyrophosphate.

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Nevertheless, in cases in which a non-invasive diagnostic strategy is unavailable or inconclusive and the clinical suspicion of CA remains high, a biopsy is recommended8,120 (Table 10).

The gold standard for diagnosing ATTR-CM is the detection of TTR amyloid fibrils in cardiac tissue, obtained through an endomyocardial biopsy8,14,80,121 (Figure 5 and Table 10).

Figure 5.

Endomyocardial biopsy in a patient with transthyretin amyloid cardiomyopathy (ATTR-CM). Immunoperoxidase technique was used on paraffin sections. Transthyretin deposition was detected in the myocardium (A), while screening for lambda light chains (B), kappa light chains (C) and serum amyloid A (D) proved to be negative, thus confirming the diagnosis of ATTR-CM. Image courtesy of Helena Sousa, MD, Nephrology Department, Unidade Local de Saúde de S. José, Lisboa, Portugal.

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Endomyocardial biopsy is, however, an invasive test that carries risks of severe complications, such as ventricular perforation with cardiac tamponade, ventricular dysrhythmias and complete atrioventricular block.122 In a study assessing the safety of endomyocardial biopsy in CA, four complications occurred after 73 procedures, resulting in a complication rate of approximately 5.5%.123 Therefore, the use of less invasive methods for the diagnosis of ATTR-CM is generally accepted by consensus.8,14,80

Extracardiac biopsy may be performed in a clinically affected organ or at a surrogate site, and is useful for the diagnosis of systemic amyloidosis. However, a histological diagnosis of localized CA can only be made by endomyocardial biopsy.124

Abdominal fat biopsy is a suitable surrogate biopsy site, as it is less invasive and has fewer risks than biopsy of other organs. However, abdominal fat biopsy has variable sensitivity depending on the type of amyloid deposits: 84% for AL-CM, 45% for ATTRv-CM and 15% for ATTRwt-CM,125 and is thus useful in positive cases but does not exclude CA when it is negative.125,126 Minor salivary gland biopsy has also shown amyloid deposition in 91% of cases of ATTRv and polyneuropathy.127

The presence of TTR fibrils in extracardiac tissue associated with imaging characteristics suggestive of cardiac involvement by amyloidosis enables a diagnosis of ATTR-CM8,14,120 (Figure 4 and Table 10), as the type of CA is generally assumed to correspond to the type of amyloid identified in extracardiac biopsy. However, endomyocardial biopsy should still be performed in older individuals with cardiac uptake at 99mTc-DPD/HMDP/PYP scintigraphy and AL deposits in extracardiac biopsy, given the possibility of a combination of ATTR-CM and extracardiac AL amyloidosis.128–130

On light microscopy, under routine hematoxylin and eosin staining, amyloid deposits have a nonspecific appearance of amorphous extracellular eosinophilic deposits. However, this staining is not specific for amyloid and its presence must be confirmed by thioflavin dyes, most commonly Congo red. Under Congo red staining, the presence of amyloid fibrils is confirmed by the detection of the typical apple-green birefringence under cross-polarized light.8,14,124 As early amyloid deposits may be inconspicuous under hematoxylin and eosin staining, Congo red staining should always be performed to rule out early amyloidosis and not just to confirm a suspicion of amyloid based on hematoxylin and eosin staining.124 Notably, the sensitivity of Congo red stain for amyloid may be further enhanced by combining it with fluorescence microscopy.131

For the diagnosis of amyloid type, several methods are available, with antibody-based techniques being the most used.

Immunohistochemistry involves using antibodies against protein epitopes within amyloid. In a study by the UK National Amyloidosis Centre and the Mayo Clinic, 142 biopsies from different tissues were assessed by immunohistochemistry and mass spectrometry. Immunohistochemistry was diagnostic and correctly identified the amyloid type in 108 (76%) cases, and showed 100% agreement with mass spectrometry results.132 However, outside specialized centers, the diagnostic performance of immunohistochemistry is lower, being subject to pitfalls and frequently leading to inconclusive or false results.124

Immunofluorescence is similar to immunohistochemistry, but uses antibodies labeled with fluorescent dyes against target epitopes, with the resultant staining pattern in tissue viewed by a fluorescence microscope.124 This technique is mostly used for kidney samples because it usually requires fresh or frozen tissue.128 A study on kidney biopsies evaluated the performance of immunofluorescence for amyloid typing, using the results of mass spectrometry as a reference standard.125 In this study, sensitivity for the diagnosis of immunoglobulin-derived amyloidosis was 84.6% and specificity was 92.4%.133

Immunoelectron microscopy is a technique that combines immunohistochemistry using gold-labeled antibodies against amyloid protein epitopes and electron microscopy. In a study of 423 cases of systemic amyloidosis diagnosed at a specialized amyloidosis center in Italy, correct classification of the amyloid type was achieved in 99.5% of cases.134 In another study that included 106 Congo red-positive biopsies from different organs, immunoelectron microscopy identified specific staining of amyloid fibrils in 91.6% of cases.135

Mass spectrometry is the gold standard method for diagnosing the type of amyloid fibrils8,14,120,136 (Table 10). In a study from the Mayo Clinic, mass spectrometry correctly identified the amyloid type in 100% of cases in the training set and in 98% of cases in the validation set, whereas immunohistochemistry was informative in only 42% of cases.136 In the study by the National Amyloidosis Centre and the Mayo Clinic that included 142 consecutive biopsy specimens, accurate typing was achieved using mass spectrometry in 94% of cases, compared to 76% with immunohistochemistry.132

Technetium (Tc) scintigraphy labels of phosphate derivatives, commonly used in bone assessment, have been increasingly used in recent years for the non-invasive diagnosis of ATTR-CM.8,14,120

Currently, the radiotracers most commonly used for the diagnosis of ATTR-CM are 99mTc-DPD, 99mTc-HMDP and 99mTc-PYP. Of those, 99mTc-DPD is the most used in Europe, and 99mTc-PYP is the most used in the USA.126 The Perugini visual score of cardiac retention should be routinely used (score 0: absence of cardiac uptake and normal bone uptake; score 1: mild cardiac uptake lower than bone uptake; score 2: moderate cardiac uptake and attenuated bone uptake; score 3: strong cardiac uptake and mild/absent bone uptake) (Figure 6).137

Figure 6.

99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy in a patient with wild-type transthyretin amyloid cardiomyopathy, showing whole-body anterior and posterior planar views, performed three hours post injection of 99mTc labeled DPD. The image shows a Perugini score of 3, as there is strong cardiac uptake with slight bone uptake. pi: post injection.

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99mTc-DPD/HMDP/PYP scintigraphy is recommended in patients with suspected ATTR-CM (Table 10), as it has high diagnostic accuracy against the gold standard endomyocardial biopsy. A large multicenter study, including 1217 patients with suspected CA based on echocardiographic or CMR findings, showed that 99mTc-DPD/HMDP/PYP scintigraphy with grade 2 or 3 myocardial uptake had specificity and positive predictive value of 100% for the diagnosis of ATTR-CM, after exclusion of a monoclonal protein in serum and urine.138 This study was groundbreaking, as it provided the evidence for the use of the non-invasive diagnostic algorithm for ATTR-CM (Table 10).

A systematic review and meta-analysis confirmed the high diagnostic accuracy of grade 2 or 3 99mTc-DPD/HMDP/PYP scintigraphy, against endomyocardial biopsy, in differentiating ATTR-CM from AL-CA (sensitivity of 91.5% and specificity of 88.6%).139 Nevertheless, false positive and false negative results can occur in 99mTc-DPD/HMDP/PYP scintigraphy. Table 11 lists the leading causes of false positive and false negative results, how to suspect them, and how to proceed with the differential diagnosis of ATTR-CM.8,121

Single-photon emission computed tomography (SPECT) can add three-dimensional visualization to planar scintigraphy and more detailed and accurate assessment of radiotracer uptake in the myocardial wall as opposed to the blood pool, valvular or annular calcifications, rib fractures, or recent myocardial infarction.140,141 Therefore, SPECT is recommended over planar scintigraphy for the diagnosis of ATTR-CM.

Notably, cardiac uptake consistent with ATTR-CM (grade 2 or 3) may be present in more than 10% of patients with AL-CM.14,141,142 Thus, bone scintigraphy alone, without properly ruling out the presence of a monoclonal protein, is not suitable to distinguish ATTR-CM from AL-CM.8,14,120

Finally, false negative results may occur with some TTR variants that do not bind the radiotracer, such as the Val50Met variant.14,141,142 TTR amyloid fibrils may consist of a mixture of full-length and fragmented short haphazard and weakly congophilic fibrils (type A fibrils), or only full-length long parallel and highly congophilic fibrils (type B fibrils).143 In one study, 97% of patients with type A amyloid fibrils had significant 99mTc-DPD cardiac uptake at scintigraphy, while none of those with type B fibrils displayed detectable cardiac radiotracer retention.144 Notably, type B fibrils have been found in some TTR variants, including Phe84Leu, Glu94Asp, Ser97Tyr, Tyr134Cys and Val50Met,145–148 especially in early onset disease.146,147

In Portugal, 99mTc-DPD/HMDP scintigraphy is available at low cost, making it usually more accessible than tissue biopsy.

Hematological tests are essential to exclude AL amyloidosis and thus establish a non-invasive diagnosis of ATTR-CM.8,14,80,120

Several tests are available to detect a monoclonal protein. Serum-free light chain assay quantifies kappa and lambda light chains, assuming clonality when the kappa/lambda (K/L) ratio deviates from normal. In turn, serum immunofixation confirms the clonal production of immunoglobulins, and urine immunofixation confirms the clonal production of light chains.8,14

Combining serum free light chain quantification/ratio and serum and urine immunofixation of immunoglobulins is recommended, as this combination has been reported to be 100% sensitive for detecting AL amyloidosis8,149 (Table 10). In another study, the performance of different tests was evaluated in 592 patients with AL amyloidosis confirmed by mass spectrometry in tissue biopsy.150 Serum immunofixation was positive in 80% of cases, and urine immunofixation in 88%.150 Notably, 94% of patients had at least one positive result on one of the two immunofixation tests (serum or urine).150 The serum free light chain ratio was positive in 91% of cases.150 When these three tests were combined, only one patient was not detected, resulting in a detection rate of 99.8%.150

Due to certain limitations of the test,14 the K/L ratio of free light chains should be preferred over absolute levels.

Bone marrow typically produces twice as many kappa as lambda chains.14 Clearance of light chains occurs through the kidney and the reticuloendothelial system. The clearance rate by the reticuloendothelial system can be assumed to be stable.14 As glomerular filtration rate (GFR) decreases, renal clearance of light chains is also reduced, with a smaller contribution from the kidney to the overall clearance of light chains.151 Because the kidneys are more efficient at eliminating kappa than lambda chains, in chronic kidney disease there are higher K/L ratios.151 The iStopMM study, which reported data from 75422 participants, aimed to define reference ranges for light chain K/L ratios, considering different estimated GFR (eGFR) levels.152 This study showed that the normal K/L ratio is 0.26–1.65 when renal function is normal.152 Reference intervals for the free light chain ratio are 0.46–2.62 for eGFR 45–59, 0.48–3.38 for eGFR 30–44, and 0.54–3.30 for eGFR <30 ml/min/1.73 m2 groups, respectively.152 These results are valid for the most commonly used assay (Freelite®). When the free light-chain ratio is within these ranges, and serum and urine immunofixation are normal, AL amyloidosis is uncommon.152 By contrast, a low K/L ratio is never normal because it indicates a lambda monoclonal protein and always needs further investigation.153

When hematological tests are positive, a joint assessment with hematology specialists is mandatory, and a biopsy is usually necessary to establish the diagnosis and type of amyloidosis.8,14,120

Echocardiography should be performed in all patients suspected of having ATTR-CM8,14,120 (Table 10).

Several echocardiographic characteristics are suggestive of CA8,14,154 (Table 5 and Figure 7). However, echocardiography alone cannot establish the diagnosis of CA. Instead, it is useful to provide evidence of cardiac involvement by ATTR amyloidosis when extracardiac biopsy or 99mTc-DPD/HMDP/PYP scintigraphy is used for the diagnosis8,120 (Figure 4).

Figure 7.

Transthoracic echocardiogram in a patient with transthyretin amyloid cardiomyopathy. (A–C) Left ventricular (LV) hypertrophy with a sparkling pattern of the myocardium on the two-dimensional transthoracic echocardiogram in 4-chamber (Video 1) (A), 3-chamber (Video 2) (B) and parasternal short-axis (Video 3) (C) views; (D) mitral annular tissue Doppler imaging, showing LV diastolic dysfunction with reduced septal e′ velocity (5 cm/s) and increased E/e′ ratio (20.9); (E) LV bullseye plot with peak systolic global longitudinal strain, showing an apical sparing pattern.

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Nevertheless, the proposed echocardiographic criteria of cardiac involvement by ATTR amyloidosis differ significantly between medical societies8,120 (Table 12). The 2021 US expert consensus recommendations propose as evidence of cardiac involvement by amyloidosis any of the following: LVWT >12 mm, apical sparing, or grade 2 or 3 diastolic dysfunction.120 By contrast, the 2021 European position statement proposed a combination of unexplained LVH (≥12 mm) with at least two additional echocardiographic findings (grade 2 or 3 diastolic dysfunction, 5-5-5 sign or GLS <−15%) or a multiparametric echocardiographic score of ≥8.8

The 2016 study by Gillmore et al., which provided the basis for the non-invasive diagnostic algorithm, tested the diagnostic performance of 99mTc-DPD/HMDP/PYP scintigraphy, alone and together with monoclonal protein studies, against endomyocardial biopsy and other organ biopsy, in patients with suspected amyloidosis based on echocardiography or CMR findings.138 Notably, in this study, echocardiographic features characteristic of amyloid were defined as the combined findings of thickened LV walls, impaired GLS with relative sparing of the apical region, and abnormal diastolic physiology. Therefore, the high diagnostic accuracy of 99mTc-DPD/HMDP/PYP scintigraphy was demonstrated in patients who simultaneously present these three echocardiographic criteria. A subsequent study including patients with the same echocardiographic and CMR features showed that the non-invasive diagnostic algorithm proposed by Gillmore et al. presented a high specificity (97%).142

Based on this evidence, this Task Force considers that the combination of these three echocardiographic characteristics is an adequate criterion of cardiac involvement by amyloidosis, when applying the non-invasive diagnostic algorithm (Table 10).

Nevertheless, unexplained LVH, measured as end-diastolic interventricular septal wall thickness >12 mm, has been used in the inclusion criteria of clinical trials of ATTR-CM therapies1,4 as stand-alone evidence of cardiac involvement by amyloidosis in the context of the non-invasive diagnosis of ATTR-CM. Therefore, it seems appropriate to use LVH with LVWT >12 mm as a stand-alone criterion of cardiac involvement by amyloidosis, when applying the non-invasive diagnostic algorithm in clinical practice, although the performance of this algorithm has never been tested in patients presenting with LVH only (Table 10).

The diagnostic accuracy of the non-invasive diagnostic algorithm was also not assessed specifically in patients presenting apical sparing or grade 2 or 3 diastolic dysfunction as stand-alone criteria, in the absence of LVH. Still, considering that these characteristics are suggestive of CA, this Task Force proposes that they should be considered as echocardiographic evidence of cardiac involvement by amyloidosis, in the context of the non-invasive diagnostic algorithm, if there is no other reasonable explanation for their presence (Table 10).

CMR should be performed with morphological and functional assessment and gadolinium administration.121 Diffuse subendocardial and transmural LGE patterns predominate in CA. Both patterns are present in AL-CA and ATTR-CM.8,14,121,154 A study reported that the presence of a diffuse LGE pattern had a high sensitivity of 93%, but a moderate specificity of 70% for the diagnosis of CA.155 Myocardial nulling before blood pool nulling or at the same inversion time as the blood pool is another typical finding in CA (Figure 8).156

Figure 8.

Cardiac magnetic resonance (1.5 T) in a patient with transthyretin amyloid cardiomyopathy. (A) Cine image in horizontal long-axis view (Video 4) and (B) cine image at the basal slice of short-axis view of the left ventricle (balanced steady-state free precession sequences), showing left ventricular hypertrophy with a maximum left ventricular wall thickness of 19 mm at the mid inferoseptal wall and mild pericardial effusion; (C) Look-Locker sequence, revealing abnormal gadolinium kinetics with myocardial signal nulling occurring before blood pool signal nulling; (D) diffuse transmural late gadolinium enhancement, observed in 4-chamber view and basal and mid left ventricular (LV) short-axis slices (phase sensitive inversion recovery sequence); (E) native T1 mapping (left) and post-contrast T1 mapping (right), performed using a modified Look-Locker inversion recovery sequence at the basal LV short-axis slice, showing high native T1 (1179 ms) and expanded extracellular volume (44%); the resulting pixel-by-pixel T1 color maps regarding native T1 are displayed using a customized lookup table, in which normal myocardium is in blue-purple and increasing T1 is represented in more orange and yellowish colors.

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Native myocardial T1 is increased in ATTR-CM (Figure 8).157,158 One study showed that native myocardial T1 mapping achieved a sensitivity of 92% and specificity of 91% for the diagnosis of CA.159 Furthermore, another study showed that native T1 less than 1036 ms had a negative predictive value of 98%, while native T1 more than 1164 ms had a positive predictive value of 98% for the diagnosis of CA.160 Notably, native T1 mapping accuracy was also high in patients with normal LV mass, highlighting the role of native T1 as an early disease marker.160 Native T1 mapping is also useful in patients with severe renal failure, in whom gadolinium administration is not desirable due to safety issues.160 However, care must be taken in the interpretation of different T1 cutoffs because T1 varies with different vendors, magnetic field strength and different sequences.158

Native T1, however, is a composite signal from the extra- and intracellular space. The administration of gadolinium with ECV measurement allows assessment of the extracellular space.158 Since amyloidosis is an example of interstitial disease, it is associated with increased ECV158 (Figure 8). In addition, ECV may be elevated even when assessment of cardiac morphology and function and LGE suggest no cardiac involvement, highlighting a potential role of ECV as an early disease marker.158,161

Nevertheless, the performance of CMR is worse than that of 99mTc-DPD/HMDP/PYP scintigraphy in the diagnosis of ATTR-CM. In a systematic review and meta-analysis, CMR had a sensitivity of 85.7% and specificity of 92.0% against endomyocardial biopsy for the diagnosis of CA.162 Even so, it could not reliably differentiate ATTR-CM from AL-CA (sensitivity 28.1–99.0% and specificity 11.0–60.0%).162 However, when a positive CMR (indicative of CA) is combined with negative monoclonal protein tests, the specificity reaches 98% and the positive predictive value reaches 99% for the diagnosis of ATTR-CM (compared to biopsy findings).163

Although CMR is not mandatory for the diagnosis of ATTR-CM, some CMR features are highly suggestive of CA, providing evidence of cardiac involvement by ATTR amyloidosis, when extracardiac biopsy or 99mTc-DPD/HMDP/PYP scintigraphy is used to establish the diagnosis8,120,154 (Figure 4).

However, the CMR criteria used for this purpose differ between European and US recommendations8,120 (Table 12). The 2021 European position statement defined CMR evidence of cardiac involvement by amyloidosis as the combination of diffuse subendocardial/transmural LGE and abnormal gadolinium kinetics,8 while the 2021 US expert consensus considered any of the following findings: LVWT above the upper limit of normal for sex, global ECV >0.40, diffuse LGE, or abnormal gadolinium kinetics.120

Notably, the 2016 study by Gillmore et al., which provided the basis for the non-invasive diagnostic algorithm, considered as CMR features characteristic of amyloid the presence of diffuse subendocardial or transmural LGE coupled with abnormal myocardial and blood-pool gadolinium kinetics.138

Since then, this subject has been an active field of investigation and the focus of several recent publications.

In a recent meta-analysis of 11 studies, diffuse subendocardial LGE showed sensitivity for the diagnosis of CA of 85.7% and specificity of 92.0% against endomyocardial biopsy, and sensitivity of 78.9% and specificity of 93.9% against any organ biopsy.139 This meta-analysis supported the high specificity of diffuse LGE in the diagnosis of CA. Therefore, this Task Force considers that diffuse LGE is an adequate stand-alone CMR criterion of cardiac involvement by amyloidosis and recommends its use in the context of the non-invasive diagnostic algorithm of CA (Table 10).

Abnormal myocardial nulling has also shown high specificity for the diagnosis of CA. A study including 144 patients with suspected CA showed that abnormal myocardial nulling had a sensitivity of 40.6% and specificity of 100% for the diagnosis of CA.164 Therefore, this Task Force considers that abnormal gadolinium kinetics typical for amyloidosis with myocardial nulling occurring prior to blood pool nulling is an adequate stand-alone CMR criterion of cardiac involvement by amyloidosis and recommends its use in the context of the non-invasive diagnostic algorithm of CA (Table 10).

ECV >0.40 has also been shown to be an adequate cutoff to differentiate individuals with CA from those without amyloidosis. A meta-analysis showed that ECV had an area under the curve (AUC) of 0.96 (95% confidence interval [CI]: 0.93–1.00) for the diagnosis of CA. The mean ECV was 47.6% (95% CI: 43.6–51.6) for CA, 51.7% (49.1–54.2) for ATTR-CM and 27.5% (25.7–29.3) for controls. Notably, the pooled ECV upper boundary for controls was 33.4% (95% CI: 31.0–35.7), thus below 40%.165

Furthermore, a very recent study, including 70 patients with CA and 32 patients with non-amyloid cardiac hypertrophy, showed that global ECV achieved an AUC of 0.957 (95% CI: 0.916–0.999) for the diagnosis of CA and basal ECV achieved the best performance for the diagnosis (AUC=0.975; 95% CI: 0.947–1). Median ECV in CA patients was 47% (Q1–Q3: 41–55), ranging from 29 to 72%, which was significantly higher than in non-amyloid patients, in whom the median ECV was 28% (Q1–Q3: 26–30), ranging from a minimum of 22% and a maximum of 37%, thus below 40%.166

Finally, a recent study, including 352 patients with known or suspected HF or cardiomyopathy, 136 of whom had CA, showed that ECV presented a sensitivity of 89.0% (95% CI: 82–94%) and a specificity of 98.6% (95% CI: 96–100%) for the detection of CA. Notably, the cutoff of 40% achieved an AUC of 0.99 (95% CI: 0.97–1.00).167

Taken together, the accumulated evidence so far suggests that ECV >0.40 is an adequate stand-alone CMR criterion of cardiac involvement by amyloidosis. Therefore, this Task Force recommends its use in the context of the non-invasive diagnostic algorithm of CA (Table 10).

LVH, as mentioned previously, has been used in the inclusion criteria of clinical trials of ATTR-CM therapies as evidence of cardiac involvement by amyloidosis in the context of the non-invasive diagnosis of ATTR-CM.1,4 Accordingly, as CMR is the gold-standard method for assessing LVH, it seems appropriate to accept LVH also as a stand-alone CMR criterion of cardiac involvement by amyloidosis. Therefore, this Task Force recommends its use in the context of the non-invasive diagnostic algorithm of CA (Table 10).

The value of positron emission tomography (PET) for the diagnosis of ATTR-CM is still based on limited evidence.

To date, various PET tracers have been proposed to discriminate ATTR-CM from controls, including carbon-11 Pittsburgh compound B (11C-PIB),168–170 fluorine-18 florbetapir (18F-FBP),171,172 fluorine-18 florbetaben (18F-FBB),173 fluorine-18 sodium fluoride (18F-NaF),174,175 fluorine-18 flutemetamol (18F-FMM)176 and 124I-evuzamitide.177

In ATTRv due to the Val50Met variant, the PET myocardial uptake of 11C-PIB was shown to be increased, positively identifying patients with ATTR-CM, with both type A and type B fibrils, unlike bone scintigraphy, which is usually associated with false negative results in patients with early-onset disease and type B fibrils.178

Some of these PET tracers have also been proposed to distinguish between ATTR-CM and AL-CA. 18F-NaF has been shown to distinguish ATTR-CM from AL-CA,174,175,179–181 with a tissue to background ratio threshold >1.14 in areas of LGE, demonstrating 100% sensitivity and 100% specificity for ATTR-CM.17911C-PIB uptake was shown to be significantly higher in AL-CA than in ATTR-CM.182 This tracer retention index was also found to be elevated in patients with CA (AL and ATTR) without increased wall thickness, suggesting potential value for detection of early cardiac involvement.182 Other studies also suggested that 18F-florbetaben183,184 and 18F-florbetapir185 are able to distinguish ATTR-CM from AL-CA.

However, more recently, a systematic review on PET tracers in ATTR-CM, including 21 studies and 211 patients, found that 11C-PIB, 18F-FBP and 18F-NaF can distinguish ATTR-CM from controls. 11C-PIB and 18F-NaF were able to distinguish between ATTR-CM and AL-CA. Evidence on the diagnostic performance of 18F-FBB and 18F-FMM was contradictory.186

Although US medical societies provide recommendations for typical imaging features of PET regarding the diagnosis of CA120 (Table 12), this Task Force, given the limited data on this subject, proposes that the use of PET may be considered for the diagnosis of ATTR-CM when other imaging methods are not available or conclusive (Table 10).

In cases with an established diagnosis of ATTR-CM, even when the diagnosis of ATTRwt is probable, it is mandatory to sequence the TTR gene for a definite differential diagnosis between wild-type and variant forms of ATTR amyloidosis (Table 10). Identifying a pathogenic/likely pathogenic TTR variant has a significant impact on patients’ treatment and prognosis and allows family screening and early detection and follow-up of affected family members.14

Genetic counseling is essential in asymptomatic relatives, considering the variable penetrance and expressivity of ATTRv amyloidosis.14

The diagnostic algorithm recommended in previous expert consensuses8,14,80,120,154 was based on the study by Gillmore et al., which showed that, against endomyocardial biopsy, grade 2 or 3 99mTc-DPD/HMDP/PYP scintigraphy, in the absence of a monoclonal protein, had a sensitivity of 70% and negative predictive value of 59%, but a very high specificity and a positive predictive value of 100% for the diagnosis of ATTR-CM.138 This diagnostic algorithm was recently validated in a large international multicenter study of 3354 suspected or biopsy-confirmed CA cases, which reported a very high specificity of 97% (95% CI: 91–99%) for the diagnosis of ATTR-CM.142 Based on this evidence, this expert consensus recommends the use of this non-invasive diagnostic algorithm in clinical practice (Figure 9).

Figure 9.

Non-invasive diagnostic algorithm for transthyretin amyloid cardiomyopathy. 99mTc: 99mtechnetium; ATTR-CM: transthyretin amyloid cardiomyopathy; ATTRv-CM: hereditary transthyretin amyloid cardiomyopathy; ATTRwt-CM: wild-type transthyretin amyloid cardiomyopathy; CMR: cardiac magnetic resonance; DPD: 3,3-diphosphono-1,2-propanodicarboxylic acid; HMDP: hydroxymethylene diphosphonate; PYP: pyrophosphate; SPECT: single-photon emission computed tomography.

*Considering the endemic presence of the Val50Met variant in Portugal, in the presence of grade 0 scintigraphy associated with negative hematological tests, the diagnosis of ATTR-CM should still be pursued if there is a high clinical suspicion.

(0.19MB).

Biopsy may be necessary when non-invasive diagnostic workup is inconclusive, including in patients with (i) positive hematological tests, grade 0 99mTc-DPD/HMDP/PYP scintigraphy and CMR suggestive of CA; (ii) grade 1 99mTc-DPD/HMDP/PYP scintigraphy and negative hematological tests; and (iii) grades 1–3 99mTc-DPD/HMDP/PYP scintigraphy and positive hematological tests8,14,120 (Figure 9).

Diuretics are the mainstay of therapy in patients with CA and congestive symptoms, with furosemide used as the first line. The combination of furosemide and spironolactone is usually well tolerated, and spironolactone may have prognostic benefit.187 A subanalysis of the TOPCAT trial, including patients with echocardiographic features suggestive of ATTR-CM (s′ velocity ≤6 cm/s and IVS thickness ≥1.2 cm), showed benefit in survival with treatment with spironolactone.187 Furthermore, a retrospective analysis of all consecutive patients diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2000 and September 2022 demonstrated that the use of mineralocorticoid receptor antagonists was associated with a significant reduction in mortality in the overall population as well as in patients with LVEF >40%.119

In cases of persistent congestive symptoms despite high doses of furosemide and spironolactone, metolazone may be considered. However, this entails an additional risk of electrolyte imbalance, particularly in elderly patients. Likely reflecting the progression of the disease and the impact of restrictive physiology on the decline in cardiac output and consequent worsening of the cardiorenal syndrome, a higher diuretic dose is an independent predictor of mortality in ATTR-CM.188

Sodium glucose cotransporter 2 inhibitors (SGLT2i) have been shown to be well tolerated and associated with favorable effects in patients with ATTR-CM.189–192

Preliminary studies showed that SGLT2i were well tolerated and resulted in reductions in New York Heart Association (NYHA) class, NT-proBNP levels and loop diuretic doses in some patients.189,190

In line with these results, a study based on a tertiary care center including ATTR-CM patients (87 treated with SGLT2i and 95 untreated) showed that SGLT2i treatment was associated with significantly greater reductions in weight, loop diuretic dose, and uric acid during a median follow-up of 5.6 (interquartile range [IQR] 5.2) and 8.4 (IQR 2.1) months in the SGLT2i and control cohorts, respectively. No significant difference was noted between groups in cardiac biomarkers; eGFR was reduced at one month in the SGLT2i subgroup, but no differences were noted at later timepoints. Some patients discontinued SGLT2i (11.5%), mainly due to genitourinary symptoms.191

More recently, in a multicenter longitudinal observational study performed in 14 referral centers in Europe and the USA, 220 patients under SGLT2i were compared with 220 propensity-matched control individuals. Patients treated with SGLT2i had less worsening of NYHA functional class, NT-proBNP and eGFR, and fewer new initiations of loop diuretic therapy at 12 months. Importantly, SGLT2i treatment showed an association with significantly lower all-cause mortality, cardiovascular mortality, HF hospitalizations and the composite outcome of cardiovascular mortality and HF hospitalizations at 28 months.192

Some of the current therapeutic pillars for HF are, however, poorly tolerated. Beta-blockers should be used with caution, as restrictive physiology makes these patients dependent on heart rate to maintain an appropriate cardiac output. Furthermore, these drugs may not be tolerated due to hypotension and may worsen cardiac conduction abnormalities. The tolerated dose in ATTR-CM patients is often ≤25% of the target dose for HF.119 An exception may be the subgroup of patients with LVEF ≤40% and chronic adrenergic overstimulation, in whom a low beta-blocker dose may have a beneficial effect on mortality.119

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sacubitril/valsartan may also be poorly tolerated due to hypotension, frequently leading to their discontinuation and limited benefit.119 The majority of patients are treated with ≤37.5% of the target dose, and nearly one-third discontinue these drugs.119 In a high-volume center, during a median follow-up of 27.8 months, the use of renin-angiotensin system blockers was not associated with improved survival.119

A study including 480 patients (242 ATTRwt and 238 ATTRv) showed that, in ATTRv patients, survival was significantly shorter in patients treated with beta-blockers as well as in patients treated with angiotensin-converting enzyme inhibitors. By contrast, in ATTRwt, no significant difference was observed in survival between patients with and without beta-blockers and between patients with and without angiotensin-converting enzyme inhibitors.193

A later publication from the same center, based on 403 patients with ATTR-CM (268 ATTRwt and 135 ATTRv) followed for a mean of 28 months, confirmed that survival was significantly shorter in ATTRv patients receiving HF therapy (beta-blockers or angiotensin-converting enzyme inhibitors). However, ATTRwt patients with comorbidities (coronary artery disease or hypertension) had significantly better survival when treated with HF therapy (beta-blockers or angiotensin-converting enzyme inhibitors). No significant differences in survival were observed with HF therapy in ATTRwt patients without comorbidities.194

Randomized clinical trials are needed to assess the effect of conventional HF drugs in ATTR-CM patients. Table 13 summarizes the recommendations for the medical treatment of heart failure in patients with ATTR-CM.

A study including 30 ATTR-CM patients who underwent cardiac resynchronization therapy (CRT) and 30 matched ATTR-CM patients who did not receive CRT (baseline LVEF 33±15 vs. 34±9%; 60 vs. 13% with left bundle branch block) showed that CRT was associated with a significant improvement in survival. At a mean follow-up of 30±24 months, 60% of the patients with CRT died against 83% of those without CRT. Furthermore, patients with CRT had significant improvement in mean LVEF at six months (38±14%), while patients without CRT suffered significant worsening (31±9%). Notably, 50% of the patients with CRT had ≥5% improvement in LVEF, 33% ≥10% improvement and 27% ≥15% improvement. At six months, improvement of NYHA class was observed in 47% of patients with CRT.195 Recommendations on CRT in patients with ATTR-CM are outlined in Table 14.

In cases of advanced HF, mechanical circulatory support (MCS) may be considered as a bridge to transplantation or as destination therapy in ATTR-CM patients. However, it remains uncertain whether durable MCS favorably modifies the long-term prognosis of carefully selected patients with advanced CA.

In patients with end-stage RCM and an LV assist device (LVAD), larger LV end-diastolic and end-systolic dimensions are associated with better survival, with survival being significantly shorter among patients with LV end-diastolic diameter (LVEDD) ≤46 mm.196 However, patients with CA frequently present smaller LV dimensions,196,197 which may represent a technical challenge for LVAD inflow cannula implantation and may result in suboptimal device placement and inadequate MCS.196 In addition, patients with smaller LV dimensions are at increased risk for suck-down events, as the septum encroaches upon the inflow cannula, which may lead to ventricular arrhythmias or reduction in LVAD preload. Finally, off-loading the small left ventricle by the assist device may cause shifting of the interventricular septum to the left, which may exacerbate right ventricular failure.196

Nevertheless, the survival rate at one year in patients with end-stage RCM with an LVAD was reported to be 64%, with no significant difference between amyloidosis and non-amyloidosis patients.196

However, the concomitant amyloid infiltration of the right ventricle makes right ventricular failure a frequent complication,196,198 and thus amyloid patients frequently need biventricular assist devices.

In a study based on the US Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), the need for biventricular devices was significantly greater in patients with CA (41.3%) than in those with non-amyloid RCM (19.4%) or dilated cardiomyopathy (DCM) (6.7%).197 In this study, compared to other cardiomyopathy types, patients with CA had a significantly higher frequency of early adverse events in the first three months after MCS, such as major bleeding, neurological dysfunction, hemorrhagic cerebrovascular accident, and renal dysfunction.197 Survival under MCS was worse in patients with CA than in non-amyloidosis patients, regardless of the therapeutic strategy (bridge to transplantation or destination therapy).197 When the cohort was divided by device type, the increased risk of death for patients with CA was observed for the LVAD alone cohort and not for patients who required biventricular MCS.197 Survival was worse in patients with CA than in patients with DCM, with a risk of death estimated at 2.5-fold higher under MCS and 3.4-fold higher specifically under LVAD alone.197

Recommendations on MCS in patients with ATTR-CM are outlined in Table 14.

Heart transplantation should be considered in patients with advanced HF, i.e. those with repeated hospitalizations or emergency department visits for HF in the past 12 months; need for intravenous inotropic therapy; NYHA functional class III–IV despite treatment; reduced exercise capacity, with peak oxygen uptake (VO2) <14 ml/kg/min or <50% predicted, 6-min walk test distance <300 m, or inability to walk one block on level ground because of dyspnea or fatigue; need to escalate diuretic agents to maintain volume status (daily furosemide equivalent dose >160 mg/d or use of supplemental metolazone therapy); refractory clinical congestion; or refractory or recurrent ventricular arrhythmias.14,199

The survival of ATTR-CM patients undergoing heart transplantation was reported as 75% at one-, two- and five-year follow-up,200 with no statistically significant difference in survival between amyloid and non-amyloid patients after heart transplantation in the modern era.200,201

Considering the systemic nature of amyloidosis, the contraindications for heart transplantation are closely related to the degree of extracardiac involvement and dysfunction of other organs, particularly the presence of significant gastrointestinal involvement, severe peripheral neuropathy with resulting inability to ambulate (stage 3 familial amyloid polyneuropathy), severe autonomic dysfunction (orthostatic hypotension requiring medication that cannot be weaned, urinary retention requiring catheterization, malnutrition and wasting with a modified body mass index <600 kg/ m2·g/l) and/or advanced age.14,199

In the presence of neuropathy and cardiomyopathy, depending on the stage of the disease, combined heart and liver transplantation may be considered, particularly in ATTRv amyloidosis. Combined liver/heart transplantation showed a survival rate of 62% at a median follow-up of 4.5 years.202 An Italian study with 14 patients undergoing combined liver/heart transplantation, 13 of whom had ATTR amyloidosis, reported one-year survival of 93% and five-year survival of 82%.203 However, the most recent International Society for Heart and Lung Transplantation guidelines for the evaluation and care of cardiac transplant candidates consider that the role of heart-liver transplantation is not well established, given the advent of TTR silencer therapy, which reduces the progression of amyloid neuropathy (class of recommendation 2b, level of evidence B).199

Recommendations on heart transplantation in patients with ATTR-CM are provided in Table 14.

ATTR-CM may occur after liver transplantation, and its diagnosis and management are thoroughly examined in a contemporary article.204

Valve intervention confers symptomatic improvement and increases survival, and therefore the presence of CA should not in itself be a contraindication for the procedure45,90 (Table 15).

A study including patients with severe AS undergoing TAVR showed that patients with concomitant ATTR-CM had similar rates of periprocedural cardiovascular death, stroke and pacemaker implantation, as well as similar cardiovascular death at one year, compared to patients with lone severe AS.43 In another study, the rate of TAVR periprocedural complications such as stroke, vascular complication, acute kidney injury and pacemaker implantation, was also similar between patients with concomitant ATTR-CM and patients with lone severe AS.45 Finally, another study including patients with severe AS undergoing TAVR confirmed similar rates of post-TAVR complications and mortality at a median follow-up of 19 months in patients with concomitant ATTR-CM compared to patients with lone severe AS.90

By contrast, one study including patients with severe AS undergoing SAVR showed that the presence of concomitant wild-type TTR cardiac amyloid deposits was associated with higher mortality at a median follow-up of 2.3 years compared to patients with isolated AS, with a hazard ratio for death of 9.5.46

In a study based on the US National Inpatient Sample database, between 2009 and 2014, TAVR was compared to SAVR in patients with AS and CA (amyloid type was not specified). In this study, TAVR was associated with lower in-hospital mortality and shorter length of stay than SAVR.205 In addition, acute myocardial infarction, acute kidney injury and major bleeding were more common in the SAVR group, while stroke, vascular complications and permanent pacemaker implantation were more common in the TAVR group.205

Taking into consideration all the above evidence, this Task Force considers TAVR as the treatment modality of choice in patients with concomitant ATTR-CM and AS (Table 15).

Atrial remodeling secondary to LV diastolic dysfunction, elevated filling pressures and amyloid infiltration contributes to the increased prevalence of AF in ATTR-CM, which is higher in wild-type (27–62%) than in hereditary forms (5–18%).206–209

Embolic events are frequent in patients with CA (16%). Their incidence was estimated as 1.64 events per 100 patient-years, and is particularly high in patients with AF without anticoagulation – 4.8 per 100 patient-years.59 Anticoagulation is therefore recommended for paroxysmal/persistent/permanent AF, in the absence of contraindications, regardless of the CHA2DS2-VA (congestive HF or left ventricular dysfunction, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease, age 65–74 years) score (Table 16). In a retrospective cohort study of 100 patients with ATTR-CM who underwent transesophageal echocardiography before cardioversion of AF, left atrial appendage thrombus was identified in 24 of 75 subjects (32%) with ATTRwt and 25 subjects (24%) with ATTRv. Similar CHA2DS2-VASc (congestive HF or left ventricular dysfunction, hypertension, age ≥75 [doubled], diabetes, stroke [doubled]-vascular disease, age 65–74, sex category [female]) scores were noted in patients with left atrial appendage thrombus (3±1.1) and in those without (4±1.4), demonstrating that this score is inaccurate for predicting embolic events in ATTR-CM patients with a history of AF.210 Anticoagulation should also be initiated in patients with a previous history of thromboembolic events or intracardiac thrombus211 (Table 16).

Although randomized trials are lacking in patients with ATTR-CM, observational studies have confirmed the safety and efficacy of direct oral anticoagulants in this population, showing similar time to the combined primary outcome of thromboembolism, major bleeding, or death.59,212,213 Therefore, in line with the current recommendations, this Task Force considers that direct oral anticoagulants should be preferred over vitamin K antagonists.214 Left atrial appendage closure devices may be considered in patients with contraindications for oral anticoagulation, although data are scarce14 (Table 16).

Left atrial thrombi are frequent, even in patients under anticoagulation or with less than 48 h of AF.215 In a study of 58 patients with CA (50% AL, 43% ATTRwt, 7% ATTRv) and atrial arrhythmia scheduled for direct-current cardioversion, 43 patients underwent transesophageal echocardiography before cardioversion. Left atrial/left atrial appendage thrombi were found in 28% of the patients, which was significantly more frequently than in matched controls (2.5%, p<0.001). In addition, left atrial appendage emptying velocity was significantly lower in amyloidosis patients than in controls (20.6±14.1 vs. 33.9±18.4 cm/s). Notably, 46% of patients with atrial thrombi were under anticoagulation for ≥3 weeks (31%) or had arrhythmia onset <48 h (15%) before the planned cardioversion.215 Therefore, transesophageal echocardiography is mandatory before cardioversion, regardless of the duration of the atrial arrhythmia or the previous use of anticoagulation.

The risk of atrial thrombus is increased even in patients in sinus rhythm, due to amyloid infiltration of the atria and consequent atrial standstill. The prevalence of intracardiac thrombi in ATTR-CM patients in sinus rhythm was documented as 1.1%.60 Intracardiac thrombi were found to be more frequent in patients with severe biventricular systolic dysfunction and atrial dilatation, and higher degree of amyloid infiltration (measured by ECV).60 The prevalence of systemic embolism in patients with ATTR-CM in sinus rhythm was reported as 2.4% and the incidence as 1.3 per 100 patient-years.59

As the risk of embolic events increases dramatically in the presence of AF,59 this Task Force suggests close rhythm monitoring in ATTR-CM patients with risk factors for AF, such as advanced ATTR-CM (National Amyloidosis Centre stage 3) and higher left atrial volume index.59,216,217 Application of the CHA2DS2-VASc score to 540 ATTR-CM patients without AF at baseline, not receiving anticoagulation, resulted in poor prediction of embolic events, as embolic events occurred similarly across all CHA2DS2-VASc scores.59 Therefore, this Task Force does not recommend the use of the CHA2DS2-VA score to predict embolic risk in ATTR-CM patients in sinus rhythm.

In a study performed in 906 ATTR-CM patients, 22% of patients in sinus rhythm showed no evidence of atrial mechanical contraction (atrial electromechanical dissociation).60 Interestingly, a study on 156 patients with CA (80 AL, 73 ATTR, 3 AA), 64% of whom had AF, showed that low left atrial appendage emptying velocity was associated with increased risk for intracardiac thrombosis. In this study, a left atrial appendage emptying velocity of ≤15 cm/s was shown to have a sensitivity of 70% and specificity of 73% for intracardiac thrombosis. In non-AF patients, the prevalence of intracardiac thrombosis was 0% if left atrial appendage emptying velocity was >15% and LV diastolic function grade was ≤2, 15% if one of these factors was absent and 50% if both these factors were absent.218

Despite the increased risk of thrombosis in ATTR-CM patients, the increased risk of bleeding must also be considered. The incidence of bleeding events in ATTR-CM patients under oral anticoagulation was reported as 3.8 per 100 patient-years,59 which is higher than the estimated incidence of thromboembolic events in ATTR-CM patients in sinus rhythm. Therefore, this Task Force considers that there is insufficient evidence to recommend systematic anticoagulation in ATTR-CM patients in sinus rhythm.

Amiodarone is usually the first-line treatment for rhythm control. Catheter ablation may also be considered. However, AF in CA is associated with large areas of electrical voltage attenuation and a multifocal nature, leading to a high recurrence rate after ablation (83%), with a hazard ratio for post-ablation atrial tachycardia/AF of 5.4, compared to non-amyloid patients.219

For heart rate control, beta-blockers are the most used drugs, but it should be borne in mind that, in the presence of restrictive physiology, a lower heart rate may significantly decrease cardiac output. Since digoxin binds to amyloid fibrils, this drug should be used with caution, at low doses and with close monitoring of digoxin levels and renal function220 (Table 16).

Ventricular arrhythmias are not the most frequent cause of death in patients with ATTR-CM, and the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death is uncertain.

Non-sustained ventricular tachycardia has not been consistently described as a predictor of sudden cardiac death.221,222

Furthermore, despite relatively frequent appropriate therapies, ICD implantation does not consistently increase survival, due to other non-cardiac and non-arrhythmic causes of death.223–225

According to the recent ESC guidelines, an ICD should be considered in patients with hemodynamically not tolerated ventricular tachycardia (class of recommendation IIa, level of evidence C).226 The American College of Cardiology (ACC) Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient with Cardiac Amyloidosis considers that there are insufficient data to provide recommendations for the use of an ICD for primary prevention of sudden cardiac death.14 Based on the available data, this Task Force agrees with this position of the current guidelines (Table 17).

Nevertheless, further studies are needed to determine whether the new therapies for ATTR amyloidosis, by delaying disease progression and increasing life expectancy, may enable ICDs to have an impact on survival.

In patients with CA, sudden cardiac death is frequently caused by bradyarrhythmia or pulseless electrical activity.58,227

A single-center study evaluated prophylactic pacemaker implantation in patients with ATTRv with polyneuropathy and any of the following criteria: His-ventricular interval ≥70 ms, His-ventricular interval >55 ms associated with fascicular block, first-degree atrioventricular block, or Wenckebach anterograde point ≤100 beats/min. In this study, during a mean follow-up of 45±35 months, 25% of patients developed high-degree atrioventricular block.228 Nevertheless, this evidence is limited to a single-center study on ATTRv patients with polyneuropathy and there are no data on prophylactic pacemaker implantation in patients with ATTRv and cardiomyopathy or ATTRwt.

Pacemaker implantation for conduction disease should therefore follow the current standard guidelines229 (Table 17). A study including patients with CA (29.4% AL, 14.6% ATTRv and 56% ATTRwt) showed that a history of AF, PR interval >200 ms and QRS interval >120 ms are predictors of future pacemaker implantation, independently of amyloid type.230

In a study of 78 patients with ATTR-CM, high right ventricular pacing burden (>40%) was associated with deleterious remodeling, including worsening of LVEF and mitral regurgitation, and congestive HF, with worsening of NYHA class and NT-proBNP levels. Furthermore, in a mean follow-up of 42 months, biventricular pacing was associated with improvement of LVEF, mitral regurgitation severity and NYHA class in 78%, 67% and 67% of patients, respectively. Death occurred in 92% of patients with high right ventricular pacing burden (>40%) versus 68% of those with pacing burden <40% and 67% of those with CRT.231 Therefore, for patients with an indication for a pacemaker and expected high pacing burden, CRT may be preferable (Table 17).

Novel therapies have emerged in recent years for the specific treatment of ATTR-CM.232Table 18 summarizes the recommendations for targeted disease-specific therapy in patients with ATTR-CM.

Tafamidis is an oral TTR stabilizer that selectively binds to the thyroxin-binding sites of TTR, stabilizing the TTR tetramer and slowing the dissociation of TTR into monomers, thereby preventing fibril formation and tissue deposition.233 Tafamidis has been shown to slow the progression of peripheral neurological impairment in transthyretin amyloid polyneuropathy.234,235

ATTR-ACT was a phase 3 double-blind randomized clinical trial, including 441 patients, 106 with ATTRv and 335 with ATTRwt (76.0%), that compared tafamidis meglumine 20 or 80 mg with placebo, for 30 months. This study hierarchically assessed all-cause mortality followed by frequency of cardiovascular-related hospitalizations, and demonstrated that tafamidis was associated with a significant reduction in all-cause mortality and cardiovascular-related hospitalizations at 30 months. Tafamidis also led to a reduction in decline of functional capacity, measured by 6-min walk distance, and quality of life, assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, and was associated with a smaller increase in NT-proBNP.1

In this trial, the benefit in quality of life was seen earlier (six vs. 12 months) with the 80 mg dose of tafamidis than with the 20 mg dose.1 Furthermore, long-term extension data from the ATTR-ACT trial showed a significantly greater survival benefit and a significantly lower increase in NT-proBNP with tafamidis 80 vs. 20 mg, thus supporting the use of the 80 mg dose in ATTR-CM.236

In the ATTR-ACT trial, greater benefit of tafamidis was noted in patients in NYHA class I and II.1 Long-term extension data also showed that patients under tafamidis since the beginning of the trial had better survival than those who were under placebo and then switched to tafamidis, further supporting the prognostic benefit of early treatment.98 Notably, in patients in NYHA class III at baseline, a survival benefit with continuous tafamidis treatment compared with delayed treatment (placebo then tafamidis) was also observed during the five-year follow-up.237

Tafamidis slows disease progression, but does not consistently contribute to disease regression, although in some cases it was reported to lead to a decrease in radiotracer cardiac uptake on 99mTc-DPD or 99mTc-PYP scintigraphy238,239 and to an increase in peak VO2 assessed by cardiopulmonary exercise testing.240

Tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) is the only targeted disease-specific therapy available in Portugal for ATTR-CM. Based on the above data, this Task Force agrees with the use of tafamidis in NYHA classes I–III, after careful assessment of the individual's clinical status and comorbidities, avoiding futility.

It remains to define the indication for tafamidis in asymptomatic TTR variant carriers, patients with ATTR-CM but without HF symptoms, and those with other clinical manifestations of amyloid deposition besides polyneuropathy and cardiomyopathy (for example carpal tunnel syndrome). In our opinion, treatment should also be considered in patients presenting ATTR-CM after liver transplantation.204

Acoramidis is another oral TTR stabilizer that binds to TTR, mimicking the specific disease-protective action of the variant T119M in stabilizing TTR.241 The ATTRibute-CM trial, a phase 3 double-blind randomized clinical trial using this drug, reinforced the evidence for the efficacy of TTR stabilizers in improving outcomes in patients with ATTR-CM. This trial enrolled 632 patients with ATTR-CM (571 with ATTRwt and 61 with ATTRv). The primary endpoint of 6-min walk distance at 12 months was not achieved; however, a significant benefit was seen in quality of life (assessed by the KCCQ) and NT-proBNP levels at 12 months. At 30 months, the four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, change from baseline in NT-proBNP level, and change from baseline in 6-min walk distance. Acoramidis had benefits in the primary outcome at 30 months compared to placebo and in cardiovascular hospitalizations, 6-min walk distance, quality of life, and NT-proBNP levels. The effect on mortality did not achieve statistical significance, likely related to the need for a larger sample and longer follow-up.2

Patisiran is a small interfering ribonucleic acid (RNA), which is administered intravenously every three weeks. In hepatocytes, it targets a genetically conserved sequence of the 3′ region of the messenger RNA of TTR, leading to the RNA-induced silencing complex (RISC)-mediated degradation of messenger RNA and the suppression of TTR synthesis.242 In the APOLLO phase 3 double-blind randomized clinical trial, patisiran showed benefit compared to placebo on the modified Neuropathy Impairment Score Plus 7 at 18 months in 225 ATTRv amyloidosis patients with polyneuropathy.243 This trial reported data from a prespecified analysis of the subpopulation of 126 patients with CA, showing that patisiran compared to placebo appeared to be associated with lower mortality and hospitalization rate, higher speed in the 10-m walk test, lower NT-proBNP, lower LVWT, and better cardiac output and GLS.244

APOLLO-B was a phase 3 double-blind randomized clinical trial that included 360 patients with ATTR-CM (ATTRwt or ATTRv), randomized to patisiran or placebo. The primary endpoint was 6-min walk distance at 12 months. Patisiran showed a statistically significant benefit compared to placebo in 6-min walk distance, quality of life as assessed by the KCCQ, and NT-proBNP levels. However, the secondary composite outcome of all cause-mortality, cardiovascular events and 6-min walk distance at 12 months was not achieved.3

Vutrisiran is a double-stranded small interfering RNA that specifically targets the messenger RNA of TTR. In hepatocytes, it induces the RISC-mediated degradation of the messenger RNA of TTR, inhibiting TTR production. HELIOS-A was a phase 3 open-label trial that enrolled 164 patients with ATTRv and polyneuropathy. Patients were randomized 3:1 to the subcutaneous administration of vutrisiran every three months (n=122) or the intravenous administration of patisiran every three weeks (n=42) for 18 months. Vutrisiran compared to an external placebo group (from the APOLLO trial) proved to be beneficial in the Neuropathy Impairment Score Plus 7 and quality of life.245 In the cardiac subgroup, vutrisiran7 (n=40) compared to the external placebo (n=36) showed benefit in NT-proBNP levels, LV stroke volume and cardiac output.246

HELIOS-B was a phase 3 multicenter double-blind randomized placebo-controlled trial that enrolled 655 patients with ATTR-CM, randomly assigned in a 1:1 ratio to receive vutrisiran (25 mg) or placebo subcutaneously every 12 weeks for up to 36 months. In the overall population, 88% of patients had ATTRwt amyloidosis, and 78% were in NYHA class II. Sixty per cent of the patients in the vutrisiran group and in the placebo group were not taking tafamidis at baseline, constituting the monotherapy population. Among this population, 22% in the vutrisiran group and 21% in the placebo group began tafamidis after randomization. Treatment with vutrisiran reduced the risk of death from any cause and recurrent cardiovascular events (hospitalizations for cardiovascular causes or urgent visits for HF) at 33-36 months compared to placebo, in both the overall and monotherapy populations. Furthermore, in both the overall and monotherapy populations, vutrisiran significantly reduced total mortality at 42 months and reduced decline in functional capacity assessed by the 6-min walk test and in quality of life assessed by the KCCQ overall summary score at 30 months. In addition, a higher proportion of patients had stable or improved NYHA class at 30 months under vutrisiran than under placebo.4

Inotersen is a second-generation 2′-O-methoxyethyl-modified antisense oligonucleotide that selectively binds to a region in the 3′-UTR of the messenger RNA of TTR, which leads to RNase H1-mediated degradation and consequent inhibition of TTR production.247 NEURO-TTR was a phase 3 double-blind randomized clinical trial that enrolled 172 patients with ATTRv and polyneuropathy. Compared to placebo, inotersen resulted in a statistically significant benefit in the Neuropathy Impairment Score Plus 7 and quality of life at 66 weeks.248 In the subset of 108 patients with CA, exploratory echocardiographic parameters, including LVWT, mass, ejection fraction, GLS and E/E′ lateral ratio, were not significantly affected by inotersen. The main serious adverse events associated with inotersen were glomerulonephritis and thrombocytopenia.248

Inotersen was also studied in a single-center open-label study that enrolled 33 patients with ATTR-CM (ATTRwt or ATTRv) in NYHA classes I-III. At two-year follow-up, mean LV mass had decreased by 8.4% measured by CMR, and LVEF remained stable in most patients. Distance in the 6-min walk test increased in ATTRv patients, whereas in ATTRwt patients it remained relatively stable.249

Eplontersen is an antisense oligonucleotide that shares the same nucleotide sequence as inotersen. However, eplontersen uses ligand-conjugated technology for delivery to hepatocytes and a triantennary N-acetylgalactosamine moiety (GalNAc3) that increases its potency, enabling a lower dose and frequency of administration compared to inotersen.250

NEURO-TTRansform was an open-label single-group phase 3 trial, enrolling 168 patients with stage 1 or 2 ATTRv polyneuropathy. Patients received a subcutaneous administration of eplontersen every four weeks (n=144) or inotersen every week (n=24). Eplontersen was compared to the historical placebo of the NEURO-TTR trial, showing a significant benefit in the Neuropathy Impairment Score Plus 7 and quality of life at 66 weeks.250 In the cardiac subgroup, eplontersen (n=49) compared to historical placebo (n=30) showed significant improvements in LVEF and stroke volume at 65 weeks.251

The CARDIO-TTRansform phase 3 double-blind randomized clinical trial (NCT04136171), testing eplontersen in patients with ATTR-CM (ATTRv and ATTRwt), is ongoing.252

Several monoclonal antibodies are currently being tested in phase 1, 2 or 3 trials.253 NI006 has been tested in a phase 1 trial that included 40 patients with wild-type or variant ATTR-CM and chronic HF, who were randomized in a 2:1 ratio for NI006 or placebo. NI006 was reported to reduce NT-proBNP, troponin levels, cardiac tracer uptake on scintigraphy, and ECV on CMR at 12 months.254

In a phase 1 open-label trial including six ATTRv patients with polyneuropathy, NTLA-2001, which uses gene editing mediated by clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-Cas9), was shown to be safe and to decrease serum TTR levels at 28 days.255 Subsequently, NTLA-2001 was also tested in a phase 1 open-label trial including 12 patients with ATTR-CM (ATTRwt or ATTRv) in NYHA class I-III, demonstrating safety and a significant reduction in serum TTR levels at 28 days.256