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Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis

Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement
Originally publishedhttps://doi.org/10.1161/CIRCIMAGING.116.005066Circulation: Cardiovascular Imaging. 2016;9:e005066

    Abstract

    Background—

    Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance.

    Methods and Results—

    A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75±6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and 99mTC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and >65 years (prevalence 5.6% in cAS >65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69–85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age >65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5–35.8]; P=0.001).

    Conclusions—

    Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged >65 years undergoing surgical aortic valve replacement and was associated with a poor outcome.

    Introduction

    Severe degenerative calcific aortic stenosis (cAS) is common, affecting 3% of individuals aged >75 years and leads to heart failure and death unless the valve is replaced.1,2 Its coexistence with cardiac amyloidosis has been reported, but this has not been studied systematically and the prognostic significance is unknown.3 Cardiac amyloidosis is a progressive infiltrative cardiomyopathy in which deposits of amyloid, almost always of either immunoglobulin light-chain (AL) or transthyretin amyloidosis (ATTR) type,46 accumulate in the ventricular myocardium; ATTR amyloid is usually wild-type (wtATTR) and acquired, but it may also be hereditary and associated with mutant forms of transthyretin. Wild-type cardiac ATTR amyloid has a male preponderance and was formerly known as senile amyloid reflecting its first appearance beyond 60 to 70 years of age and prevalence at autopsy of up to 25% among octogenarians.7,8 Its natural history and the prevalence of clinically significant ATTR amyloid deposition in the heart are unknown. In a recent small cohort of patients with AS who underwent transcatheter aortic valve replacement (TAVR) but subsequently died, cardiac amyloid deposits were identified at autopsy in one third of cases.9 It has been suggested that occult amyloid might account for the frequent need for pacemakers among TAVR patients, and the high prevalence of cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE),10 but this has not been studied systematically.

    See Editorial by Koyama

    See Clinical Perspective

    It has not hitherto been possible to reliably detect the presence of cardiac amyloidosis without recourse to biopsy, but this is now possible in most patients using a combination of multiparametric CMR incorporating native T1 mapping,11 estimation of the extracellular volume fraction (ECV),12 and the Phase Sensitive Inversion Recovery LGE technique,13 coupled with bone scintigraphy.14 This is all more important, given that several specific drug therapies for ATTR amyloidosis are now in clinical trial.15,16 We hypothesized that unrecognized ATTR amyloid deposits may act as a disease modifier in AS and report here a cohort of 146 severe AS patients requiring surgery who were investigated as a part of the RELIEF-AS study (Regression in Left Ventricular Interstitial Expansion and Fibrosis After Aortic Stenosis Surgery), in which myocardial biopsy and comprehensive multimodality imaging were performed. We aimed to (1) assess the prevalence of occult cardiac amyloid in AS, (2) identify the amyloid subtype, (3) determine the role of comprehensive imaging, and (4) elucidate its clinical and prognostic significance.

    Methods

    Research was performed in a single center (University College London Hospital NHS Trust, London, United Kingdom) between January 2011 and March 2015. Study approval was granted by the ethical committee of UK National Research Ethics Service and conformed to the principles of the Helsinki Declaration (UK NRES 07/H0715/101). A total of 181 patients with severe AS awaiting surgical AVR (sAVR) underwent echocardiography and multiparametric CMR (76% of all sAVR) as a part of the RELIEF-AS study (NCT 02174471). A total of 146 patients (81%) also underwent intraoperative myocardial biopsies. The echocardiography was performed as a clinical test and the CMR as a research study preoperatively, whereas 3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy was conducted during subsequent specialist clinical evaluation of subjects found to have amyloid on biopsy (see later). Exclusion criteria comprised contraindications to CMR including glomerular filtration rate <30 mL/min and CMR-incompatible devices. Assessment of patients with amyloid was performed at the UK National Amyloidosis Centre, London, UK.

    Diagnosis of Severe AS by Echocardiography

    Before AVR, all patients underwent a clinical transthoracic echocardiogram, primarily to assess aortic valve mean gradient, peak jet velocity, and effective orifice area, ie, assessment of AS severity, as well as systolic and diastolic functions.17 Global longitudinal strain was not performed routinely and was, therefore, not available before AVR. Analysis was performed retrospectively in patients with adequate endocardial border definitions as previously described.18

    CMR Scanning

    All subjects underwent CMR at 1.5 Tesla (Magnetom Avanto; Siemens Medical Solutions) using a standard clinical protocol with LGE imaging using Phase Sensitive Inversion Recovery 19 and T1 mapping before and after a bolus of 0.1 mmol/kg of gadoterate meglumine (gadolinium-DOTA, marketed as Dotarem, Guerbet S.A., Paris, France) for ECV quantification. Postcontrast LGE imaging was performed at 5 to 15 minutes. T1 mapping for ECV quantification was performed using Shortened Modified Look-Locker Inversion recovery,20 providing single-section T1 map in 1 breath-hold at 15 minutes (bolus only, pseudoequilibrium technique).21 Two amyloid-specific indices, myocardial contraction fraction (the ratio of stroke to myocardial volume) and ECG-voltage/left ventricular (LV) mass ratio, were calculated.22,23

    Histological Analysis

    An intraoperative septal biopsy (typically tubular, measuring 1.6×1.6×10 mm) was harvested from the basal LV septum under direct vision by the surgical team using a 14-gauge coaxial needle. Histological analysis was performed by Congo red staining on 6-µm formalin-fixed and paraffin-embedded sections and viewed in brightfield and cross-polarized light.24 When amyloid was confirmed by displaying apple green birefringence under cross-polars, immunohistochemistry was performed on the Shandon Sequenza system using a panel of monospecific antibodies against known amyloid-forming proteins, in an attempt to identify the amyloid fibril. Antigen retrieval was not performed with the exception for TTR antibodies which uses oxidation with 1% aqueous Na-m-periodate (10 minutes) and 0.1% di-NA borohydride (10 minutes) followed by 6 M guanidine (4 hours). Sections were blocked for endogenous peroxidases and with normal serum, incubated overnight at 4°C with the primary antibodies. Antibodies were detected with the appropriate species-specific IMMPRESS (Vector Laboratories) polymer detection kit and labeled using metal-enhanced 3,30-diaminobenzidine chromagen (Thermo Scientific). Interpretation was performed initially without any clinical information by 2 people independently using a Leica DMLB with and without crossed polars. Diagnosis was confirmed by laser microdissection and mass spectroscopy.25,26

    Clinical Assessment of Patients With Amyloid on Myocardial Biopsy

    Patients found to have amyloid were referred for full clinical assessment at the National Amyloidosis Centre, London, United Kingdom. A particular focus was to exclude AL amyloid, which can be treated with chemotherapy. Clinical work-up included serum and urine immunofixation, serum-free light chain analysis, comprehensive transthoracic echocardiogram, 123I-labeled serum amyloid P component scintigraphy, sequencing of the transthyretin gene, and cardiac scintigraphy using the 99mTc-labeled DPD bone tracer. This was graded on the Perugini scale—grade 0: no myocardial uptake; grade 1: minor cardiac uptake of less intensity than uptake in the bony skeleton; grade 2: moderate cardiac uptake with greater signal intensity than the bone; grade 3: strong cardiac uptake with little or no bone uptake visible.14,27

    Statistical Analysis

    A statistical package (SPSS, version 22) was used for all data analysis. Continuous variables were normally distributed (Shapiro–Wilk), other than N-terminal pro-brain natriuretic peptide (NT-proBNP), which was therefore natural log transformed for bivariate testing; these are presented as mean±SD with nontransformed NT-proBNP presented as median and Q1–Q3. Comparisons between groups were performed by 1-way ANOVA with post hoc Bonferroni correction. The χ2 test or Fisher exact test was used to compare discrete data as appropriate. Statistical significance was defined as P<0.05. Survival was evaluated using Cox proportional hazards analysis, providing estimated hazard ratios with 95% confidence intervals and Kaplan–Meier curves. Because of the low number of events (deaths), multivariable Cox regression models were not tested.

    Results

    A total of 146 patients with severe AS awaiting AVR were recruited. All patients had echocardiography, CMR with LGE, and T1/ECV mapping, as well as intraoperative myocardial biopsy. A total of 112 patients had cAS (75±6 years; 58% men); 32 patients had bicuspid AS (59±6 years; 66% men], 1 patient had rheumatic AS (65 years, female), and 1 had unicuspid AS (35 years, female). The treatment received was either a tissue or mechanical aortic valve in 71% and 29%, respectively, with additional bypass grafting in 23%, aortic intervention in 6% (interposition graft, reduction aortoplasty, and replacement of the ascending aorta), and mitral valve replacement in 1.4%. Baseline characteristics are shown in Table 1.

    Table 1. Baseline Characteristics

    Calcific ASOther Causes*P Value
    n11234
     Men, n (%)64 (58)21 (58)0.9
     Age, y75±659±7<0.001
     BMI, kg/m228±527±70.2
    Cardiovascular MR
     Indexed EDV, mL/m264±2174±210.02
     Indexed ESV, ml/m221±1725±200.6
     Indexed LV mass, g/m285±2494±240.2
     LVEF, %69±1570±150.5
     Myocardial contraction fraction, %0.53±0.160.55±0.140.5
     Voltage-mass ratio0.13±0.060.11±0.040.3
     Indexed LA area, cm2/m214±413±30.08
    Echocardiography
     Aortic valve peak velocity4.3±0.64.4±0.50.8
     Aortic valve mean gradient46±1547±150.8
     Aortic valve area, indexed0.41±0.170.42±0.150.2
     E-wave0.84±0.290.89±0.290.4
     E-deceleration time, ms240±79224±630.3
     E/A0.92±0.421.18±0.650.06
     E/E′ (mean septum/lateral wall)13±615±70.3
    Clinical parameters
     Hypertension (%)87 (78%)31(90%)0.1
     Diabetes mellitus (%)26 (23%)6 (18%)0.5
     Atrial fibrillation (%)18 (16%)2 (6%)0.2
     Coronary artery disease (%)37 (33%)9 (27%)0.6
     STS score1.9±1.41.6±0.90.3
     EURoScore II2.3±2.11.6±0.90.02
    Bloods
     NT-proBNP, pmol/L186 (5–1307)177 (8–1400)0.7
     eGFR, mL/min per 1.73 m272±1888±200.03
    Surgery
     Tissue AVR82 (73%)21 (62%)
     Mechanical AVR30 (27%)13 (38%)
     CABG29 (26%)5 (17%)
     Aortic intervention4 (3.6%)4 (11.8%)

    Values are mean±SD or %. AS indicates aortic stenosis; AVR, aortic valve replacement ; BMI, body mass index; CABG, coronary artery bypass grafting; EDV, end-diastolic volume; eGFR, estimated glomerular filtration rate; ESV, end-systolic volume; EuroScore II, European System for Cardiac Operative Risk Evaluation II; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; MR, magnetic resonance; NT-proBNP, N-terminal probrain natriuretic peptide; and STS score, Society of Thoracic Surgeons Adult Cardiac Surgery Risk Score.

    *Bicuspid AS n=32; unicuspid AS n=1; rheumatic AS n=1.

    P<0.05.

    Histological and Genetic Analysis

    Of the 146 biopsies, 6 contained amyloid (prevalence 4.1% all-comers). All 6 were cAS aged >65 years (prevalence 5.4% for cAS and 5.6% for >65 years). Typing by immunohistochemistry, supported by laser microdissection and mass spectroscopy, confirmed ATTR amyloid type in all 6 cases (Figures 1 and 2). Genetic sequencing confirmed nonhereditary wild-type transthyretin sequence in each case.

    Figure 1.

    Figure 1. Myocardial biopsy of patient with severe aortic stenosis and widespread overt myocardial transthyretin amyloidosis (ATTR) amyloid deposits. Histological slides stained with Congo red under brightfield light (Congo Red), under cross-polars with typical apple green birefringence (AGB) and under fluorescent (FL) microscopy. Separate slide prepared by transthyretin-specific immunohistochemistry (TTR) showing widespread ATTR amyloid staining (brown).

    Figure 2.

    Figure 2. Myocardial biopsy of patient with severe aortic stenosis without clinical evidence of cardiac amyloid. Histological slides stained with Congo red under brightfield light (Congo Red), under cross-polars with typical apple green birefringence (AGB) and under fluorescent (FL) microscopy. Separate slide prepared by transthyretin-specific immunohistochemistry (TTR). All showing patchy transthyretin (ATTR) amyloid deposits.

    Clinical Assessment of Patients With Amyloid

    Clinical evaluation of the 6 patients with amyloid was scheduled at the National Amyloidosis Center, United Kingdom, but 2 patients died before their appointment. Assessment revealed carpal tunnel syndrome in 1 patient but no other extracardiac manifestations typically seen in amyloidosis. AL amyloidosis was excluded in all cases. Summary findings are shown in Table 2.

    Table 2. Summary of Findings in Patients With Severe Aortic Stenosis and Wild-Type Transthyretin Amyloid on Myocardial Biopsy

    Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6
    Age/sex73 female69 male80 female85 male84 male71 male
    StatusAliveDeadDeadAliveDeadAlive
    Biopsy/genotypeTTR/wild-typeTTR/wild-typeTTR/wild-typeTTR/wild-typeTTR/wild-typeTTR/wild-type
    DPD scintigraphyGrade 2Grade 2Not attendedGrade 1Not attendedGrade 1
    SAP scanNegativeNegativeNot attendedNegativeNot attendedNegative
    Clinical
     Red flagsCarpel tunnelNo neuropathyNo neuropathyNo neuropathyNo neuropathyNo neuropathy
     NT-proBNP, pmol/L43145851051188201
     Light chainsNegativeNegativeNANegativeNANegative
     6-min-walk test, m432244510276150264
    ECG voltageLVH criteriaLVH criteriaNormalNormalNormalNormal
     Voltage-mass ratio0.130.120.140.180.160.07
    Echocardiogram
     AVAi, cm2/m20.360.520.60.340.350.24
     AoV peak gradient, mm Hg74457011061116
     Global longitudinal strain, %−6.4−11.6NA−19.6−12.7NA
    CMR
     LGE patternAmyloidosisAmyloidosisASASASAS
     LV ejection fraction, %616867776764
     LV mass index, g/m213715011710193132
     Myocardial contraction fraction, %253344645043
     Maximal wall thickness, mm182115121519
     Extracellular volume fraction, %605231253232

    AVAi indicates indexed aortic valve area; AoV, aortic valve; CMR, cardiovascular magnetic resonance; DPD scintigraphy, 3,3-diphosphono-1,2-propanodicarboxylic-acid scintigraphy; LGE, late gadolinium enhancement; LV, left ventricular; LVH, left ventricular hypertrophy; NT-proBNP, N-terminal probrain natriuretic peptide; and SAP, serum amyloid-P.

    Multimodality Imaging

    Figures 3 and 4 summarize the findings of multimodality imaging.

    Figure 3.

    Figure 3. Multimodality imaging of a patient with clinical features of cardiac amyloidosis. Although the echocardiogram showed left ventricular hypertrophy (A), this was attributed to the myocardial response to severe aortic stenosis. 3,3-diphosphono-1,2-propanodicarboxylic-acid scintigraphy showed Perugini Grade 2 cardiac uptake on bone scan (C) and single-photon emission computed tomography (B). Cardiac magnetic resonance showed overt left ventricular hypertrophy and impaired systolic function on cine imaging (D), and transmural late gadolinium enhancement with higher signal from the myocardium then the blood pool (E).

    Figure 4.

    Figure 4. Multimodality imaging of a patient with amyloid deposits on biopsy but no clinical features of amyloidosis. Neither preoperative echocardiogram (A) nor cardiovascular magnetic resonance (CMR) highlighted any features consistent with cardiac amyloidosis. 3,3-diphosphono-1,2-propanodicarboxylic-acid scintigraphy showed Perugini grade 1 cardiac uptake on bone scan (C, there is subtle uptake in the basal third of the left ventricle [see arrows]), which is more obvious on single-photon emission computed tomography (B). There was no left ventricular (LV) hypertrophy and good LV systolic function on CMR cine imaging (D), and only subtle patchy, nonischemic late gadolinium enhancement in the basal lateral wall (E).

    Echocardiography

    Preoperative routine transthoracic echocardiography did not raise any suspicion of amyloid among the 6 patients in whom amyloid was identified histologically and were consistent with severe AS by indexed valve area (mean aortic valve area index 0.41±0.17 cm2/m2) and transvalvular peak velocity (4.3±0.6 m/s). Clinical reporting identified significant concentric LV hypertrophy with impaired longitudinal shortening and diastolic dysfunction in 3 of 6 patients, but this was attributed to AS afterload. No suspicion of a dual pathology was raised. Retrospective analysis of global longitudinal strain (not performed routinely in our clinical AS work-up) was markedly reduced global longitudinal strain in patients 1 and 2 (−6.4% and −11.6%, respectively), but could only be obtained in a minority of patients in our cohort because of poor endocardial wall definition in many patients (Table 2).

    Cardiovascular Magnetic Resonance

    In 2 patients, the preoperative research multiparametric CMR study identified the dual pathology of AS and cardiac amyloidosis. This was based on the combination of severe LV hypertrophy out of proportion for the degree of AS, and (more definitively) tissue characterization findings of cardiac amyloid (global transmural LGE with blood pool nulling after the myocardium on the TI scout, elevated native myocardial T1 [here >5 SD above normal] and ECV >50%). These research findings were communicated to the surgical team, but a multidisciplinary decision was made to proceed with AVR and to conduct further evaluation of amyloidosis afterward (patients 1 and 2, Table 2). The myocardial contraction fraction was also markedly reduced in both these patients (25% and 33%, respectively), despite preserved LV ejection fraction; in the other 4 patients, myocardial contraction fraction fell within 1 SD of the overall AS cohort (53±13%; Table 2).

    Cardiac Scintigraphy With DPD Bone Tracer

    DPD bone scintigraphy was performed in the 4 surviving patients during the postoperative amyloid evaluation and was positive in all cases, with Perugini grade 2 uptake in both patients with features of amyloidosis on CMR, and Perugini grade 1 uptake in the 2 without.

    Outcome

    At median follow-up of 2.3 years (0.02–4.7 years), 11 patients with cAS had died whereas all of the patients with bicuspid AS were alive. Three of 6 cAS with wtATTR (50%; 1 cardiac death and 2 noncardiac death) died compared with 8 of 106 (7.5%) in the remaining cAS cohort, 7 of 101 (6.9%) in those over the age of 65 years, and 8 of 140 (5.7%) in overall cohort (Figure 5). Of all variables assessed, the presence of ATTR amyloid had the highest hazard ratio for all-cause mortality (hazard ratio, 9.5 [2.5–35.8]; P=0.001, univariable Cox regression analysis; Table 3).

    Table 3. Univariable Correlates of Outcome

    cAS and bAS (n=146), HR (95% CI)P ValuecAS only (n=112), HR (95% CI)P Value
    ATTR amyloid deposits9.5 (2.5–35.8)0.001*6.5 (1.7–24.7)0.006
    Age, y1.1 (1.02–1.23)0.02*1.1 (1.0–1.2)0.18
    Sex1.8 (0.5–6.9)0.371.9 (0.5–7.2)0.34
    Aortic valve
     Peak velocity, m/s0.5 (0.2–1.1)0.090.5 (0.2–1.2)0.11
     Mean gradient, mm Hg0.96 (0.92–1.00)0.060.96 (0.92–1.00)0.07
     Area, indexed, cm/m20.42 (0.01–23.2)0.70.6 (0.01–39.7)0.8
    CMR parameters
     LVEF, %0.97 (0.94–1.00)0.070.97 (0.94–1.01)0.1
     LV mass, indexed, g/m21.03 (1.00–1.52)0.05*1.03 (1.01–1.06)0.02*
     Myocardial contraction fraction, %0.04 (0.001–1.74)0.100.07 (0.002–2.45)0.14
    Blood parameters
     NT-proBNP, pmol/L2.1 (1.3–3.6)0.004*2.2 (1.2–4.0)0.006*
     eGFR, mL/min per 1.73 m20.99 (0.97–1.03)0.81.0 (0.9–1.0)0.7

    At median follow-up of 2.3 years (0.02–4.7 years), 11 calcific aortic stenosis (cAS) patients had died, whereas all of the bicuspid aortic stenosis (bAS) patients were alive. Of all variables assessed, the presence of transthyretin amyloidosis (ATTR) amyloid had the highest hazard ratio for death (HR, 9.5 [95% confidence interval (CI), 2.5–35.8], P=0.001, univariable Cox regression analysis). CMR indicates cardiovascular magnetic resonance; eGFR, estimated glomerular filtration rate; LV, left ventricular; LVEF, left ventricular ejection fraction; and NT-proBNP, N-terminal probrain natriuretic peptide.

    Figure 5.

    Figure 5. Kaplan–Meier plot of cumulative survival comparing aortic stenosis patients (n=146) with transthyretin amyloidosis (ATTR) amyloid on myocardial biopsy and those without. At median follow-up of 2.3 years (0.02–4.7), 11 patients with calcific aortic stenosis (cAS) had died, whereas all patients with bicuspid AS were alive. Three of 6 cAS with wild-type ATTR amyloid (50%) died compared with 8 of 106 (7.5%) in the remaining calcific AS cohort. AVR indicates surgical aortic valve replacement.

    Discussion

    In this single-center study of 146 severe AS undergoing surgery, to which 70% of all patients undergoing surgery were recruited, cardiac amyloid deposits were found at biopsy in 6 cases. All had wtATTR (formerly senile systemic) amyloidosis. The youngest was 69 years, and all had calcific AS indicating a 6% prevalence of amyloid among this latter group. Comprehensive imaging was performed, which showed a diagnostic hierarchy with noncontributory echocardiography, CMR detecting one third of cases, and cardiac DPD scintigraphy positive in all 4 patients who had this latter investigation. Biopsy showing wtATTR amyloid deposits was prognostic, and its presence was the strongest univariate predictor of adverse outcome after sAVR, suggesting that the presence of cardiac amyloid is a disease modifier in AS.

    Two aspects of the coexistence of wtATTR and AS stand out: incorrect interpretation of the severity of AS and modification of outcome. First, wtATTR amyloid in patients with moderate AS may cause severe hypertrophy and LV impairment, which can be misdiagnosed as severe AS (as low-flow-low-gradient). This was highlighted by Longhi et al3 in a recent communication, who presented data on 43 elderly cAS patient with at least one red flag for cardiac amyloidosis on echocardiography, performed DPD scintigraphy on 5 patients identified in this way (all positive), and confirmed diagnosis of wtATTR amyloid through biopsy and genotyping. Second, rather than leading to a misdiagnosis of severe AS, wtATTR amyloid may be a disease modifier, exhibiting a more severe phenotype with more heart failure and arrhythmias, and possibly amyloid involvement of other organ systems. Whether joint comorbidities increase the prevalence or progression of AS and wtATTR is unknown but should be explored in future studies.

    Implications for Management of AS

    Identification of cardiac amyloid is important for many reasons. The presentation of amyloid (LV hypertrophy and diastolic then systolic function dysfunction) has substantial overlap with the changes of AS, particularly as systemic features are limited with only carpal tunnel syndrome as a common red flag.28 Other traditional red flags (pericardial effusion, aortic valve thickening, and concentric hypertrophy) are common in severe, symptomatic AS. Although it is possible that minor cardiac amyloid deposits might have no significant consequences in many individuals, the clinical syndromes caused by cardiac amyloid deposition of sufficient magnitude, ie, overt cardiac amyloidosis of both ATTR and AL types, have a very poor prognosis from just months to a few years. Accurate typing of amyloid is essential because chemotherapy directed toward the plasma cell dyscrasias underlying AL amyloidosis can prolong life, and several specific therapies for ATTR amyloidosis are now at late stage of clinical development.15,16 The consequences of isolated subclinical cardiac wtATTR amyloid deposits are unknown; in our study, those patients with wtATTR and severe AS had 50% all-cause mortality. Although only one patient with overt cardiac amyloidosis died of a cardiac cause, all-cause death is a more objective, unbiased end point that is of primary interest, and suggests that amyloid deposits are an important frailty marker.

    Possible changes in clinical management could include minimizing bypass time during open valve surgery (eg, by using rapid deployment valves), switching to TAVR and influence the fundamental decision on medical management versus intervention.29 Interestingly, perioperative mortality was not affected by the presence of wtATTR. In addition, although there are few systematic data, clinical experience has suggested avoiding calcium channel blockers and digoxin in the presence of cardiac amyloid.

    ATTR Amyloid and Heart Failure

    wtATTR amyloid is emerging as an unrecognized, important bystander and potential disease modifier not only in AS but also in hypertrophic cardiomyopathy and heart failure with preserved ejection fraction. Historically, the requirement for histology has been a major obstacle to elucidating the significance of cardiac ATTR amyloid, but the remarkable diagnostic capability of noninvasive bone scintigraphy has lately yielded much new information. A large Italian nonselective endomyocardial biopsy study (n=4221, >28 years) found amyloid 4% of cases.30 More specific studies investigated autopsy specimens in a TAVR cohort in which amyloid was present in 5 of 17 cases and thought to have contributed to progressive heart failure and the deaths of 3 patients,9 and examination of 95 specimens obtained at septal myectomy for LV outflow tract obstruction with congenital or acquired AS in which 7% contained ATTR amyloid deposits.31 Cardiac amyloidosis is also a differential diagnosis for hypertrophic cardiomyopathy, especially in patients with predominantly basal involvement and outflow tract obstruction. Incidental deposits of amyloid have been reported in 1% of surgical septal myectomy specimens from patients with hypertrophic cardiomyopathy.32,33 Mohammed et al34 reported 17% prevalence of ATTR amyloid in patients with heart failure with preserved ejection fraction on autopsy with a substantial (80%) male predominance. In contrast to this series and the wider clinical impression, half of the patients with amyloid in our cohort were women; this was also a finding in a recent cohort of patients with heart failure with preserved ejection fraction who were studied with DPD scintigraphy,35 suggesting that the incidence may be underestimated in women generally, possibly because of a lower frequency of extreme hypertrophy that serves as the main red flag.

    Relative Strength of Imaging Modalities to Identify Amyloid

    Comprehensive imaging here showed a diagnostic hierarchy comprising noncontributory echocardiography, CMR detecting one third of cases, and bone scintigraphy being diagnostic in all 4 patients studied. Bone scintigraphy (DPD or technetium-99m stannous pyrophosphate scintigraphy in North America)27,36 is an attractive, low-cost modality with high sensitivity and specificity for cardiac ATTR amyloid. It is more practicable than cardiac biopsy for exclusion of ATTR amyloid in hypertrophic cardiomyopathy, heart failure with preserved ejection fraction, and AS, and its sensitivity for occult ATTR amyloid seems to be greater than CMR. Focal myocardial uptake of these tracers may occur transiently after myocardial infarction, and diffuse uptake does occur in a small proportion of patients with cardiac amyloid of AL type.

    Limitations

    Our study has limitations: patients were recruited from a single cardiothoracic center. The entry criterion was surgical AVR with no CMR contraindications leading to some under-representation of patients with advanced age (undergoing TAVR instead of sAVR), renal impairment, and cardiac pacemakers (although in reality, only 18 patients were excluded because of pacemaker [n=8] or estimated glomerular filtration rate <30 [n=10]). With a recruitment rate of 76% of all sAVR performed for AS (81% had myocardial biopsy), the RELIEF-AS study was indeed representative of a surgical AVR cohort in a major UK cardiothoracic center. Because of the low number of deaths, it was not possible to adjust hazard ratio for confounders (like age, sex, and comorbidities) using multivariable regression models; only univariate analysis was performed. Bone scintigraphy was not performed in all-comers because of limited availability at our center at the start of the study, but should be a part of any future studies. It is possible that other patients with wtATTR amyloid may have died before their AS had been considered severe enough to warrant intervention. Our echocardiographic analysis did not include strain rate imaging consistently (apically spared impaired longitudinal strain is characteristic of amyloid)—the markedly reduced global longitudinal strain in 2 patients could have raised red flags at time of echocardiography. Finally, the study did not include a large proportion of Afro-Caribbean individuals, 3% to 4% of whom possess the transthyretin V122I variant37 that causes hereditary cardiac ATTR amyloidosis and up to 10% of hospital admissions for heart failure in this ethnic group in South London.38

    Future Outlook

    Myocardial wtATTR amyloid seems to be an important prognosticator in elderly individuals with AS, but more work is needed. Myocardial wtATTR should, therefore, be considered relevant when assessing the prognosis in AS—perhaps even more so in the more elderly TAVR population, where there is greater risk, worse renal function, and more heart failure (reflected by higher European System for Cardiac Operative Risk Evaluation Score II and Society of Thoracic Surgeons Adult Cardiac Surgery Risk Score). Biopsy for amyloid is not practicable, but bone tracer scintigraphy could be used. The data here suggest that it could have a routine role in selected patients by influencing their management in terms of decisions surrounding intervention, procedure performance, and specific amyloid therapies. Wider use of cardiac scintigraphy with bone tracers, by detecting early amyloid, is likely also to improve our understanding of conventional testing, such as echocardiography.

    Conclusion

    Six percent of patients over the age of 65 years undergoing surgical AVR for cAS had wtATTR amyloid deposits on cardiac biopsy, which was associated with poor outcome. There seems to be a hierarchy of imaging diagnostic performance for identification of wtATTR amyloid, with DPD bone tracer scintigraphy superior to CMR, which was superior to echocardiography.

    Acknowledgments

    We gratefully acknowledge the contributions of the administrative and nursing staff, echocardiographers, radiographers, and biomedical scientists at the National Amyloidosis Centre, Great Ormond Street Hospital, and the Heart Hospital.

    Footnotes

    Correspondence to Thomas Treibel, MBBS, Barts Heart Centre, St Bartholomew’s Hospital, 2nd Floor, King George V Block, London EC1A 7BE, United Kingdom. E-mail

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    CLINICAL PERSPECTIVE

    Six percent of patients over the age of 65 years undergoing surgical aortic valve replacement for calcific aortic stenosis had wild-type transthyretin amyloid (wtATTR) deposits on cardiac biopsy, which was associated with worse outcome. There seems to be a hierarchy of imaging diagnostic performance for identification of wtATTR amyloid, with 3,3-diphosphono-1,2-propanodicarboxylic-acid bone tracer scintigraphy superior to cardiovascular magnetic resonance, which was superior to echocardiography. The prevalence and adverse clinical outcomes in this study suggest that wtATTR amyloid may be important in elderly individuals with calcific aortic stenosis. More work needs to be done to more fully characterize the impact of wtATTR amyloid in elderly patients with calcific aortic stenosis. Transcatheter aortic valve replacement is mostly performed in older age, where there is greater risk, worse renal function, and more heart failure. Biopsy for amyloid is not practicable, but bone tracer scintigraphy could be used and could contribute to decision making and clinical management of such patients around intervention, procedure performance, and specific amyloid therapies. Wider use of cardiac bone tracer scintigraphy, by detecting early amyloid, may be an important component of the imaging modalities used to stratify patients with wtATTR amyloid.