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Transthyretin (TTR) Cardiac Amyloidosis

2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 10 Linguagem: Inglês

10.1161/circulationaha.111.078915

1524-4539

Frederick L. Ruberg, John L. Berk,

Eosinophilic Disorders and Syndromes

HomeCirculationVol. 126, No. 10Transthyretin (TTR) Cardiac Amyloidosis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBTransthyretin (TTR) Cardiac Amyloidosis Frederick L. Ruberg, MD and John L. Berk, MD Frederick L. RubergFrederick L. Ruberg From the Amyloid Treatment and Research Program (F.L.R., J.L.B.) and Section of Cardiovascular Medicine (F.L.R.), Boston University School of Medicine and Boston Medical Center, Boston MA. and John L. BerkJohn L. Berk From the Amyloid Treatment and Research Program (F.L.R., J.L.B.) and Section of Cardiovascular Medicine (F.L.R.), Boston University School of Medicine and Boston Medical Center, Boston MA. Originally published4 Sep 2012https://doi.org/10.1161/CIRCULATIONAHA.111.078915Circulation. 2012;126:1286–1300IntroductionThe systemic amyloidoses are a family of diseases induced by misfolded or misassembled proteins. Extracellular deposition of these proteins as soluble or insoluble cross β-sheets disrupts vital organ function.1 More than 27 different precursor proteins have the propensity to form amyloid fibrils.2 The particular precursor protein that misfolds to form amyloid fibrils defines the amyloid type and predicts the patient's clinical course. Several types of amyloid can infiltrate the heart, resulting in progressive diastolic and systolic dysfunction, congestive heart failure, and death. Treatment of cardiac amyloidosis is dictated by the amyloid type and degree of involvement. Consequently, early recognition and accurate classification are essential.3The diagnosis of amyloidosis requires histological identification of amyloid deposits. Congo Red staining renders amyloid deposits salmon pink by light microscopy, with a characteristic apple green birefringence under polarized light conditions (Figure 1). Additional immunohistochemical staining for precursor proteins identifies the type of amyloidosis (Figure 2).4 Ultimately, immunogold electron microscopy and mass spectrometry confer the greatest sensitivity and specificity for amyloid typing.5,6Download figureDownload PowerPointFigure 1. Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy. A, Light microscopy; B, polarized light microscopy, 400× magnification.Download figureDownload PowerPointFigure 2. Transthyretin amyloid cardiomyopathy by immunohistochemical staining. Endomyocardial biopsy samples were stained with antibodies to (A) kappa light chain, (B) lambda light-chain, (C) serum amyloid A, and (D) transthyretin amyloid. Bright-light micrographs at 400× magnification.Two types of amyloid commonly infiltrate the heart: (1) Immunoglobulin light-chain (AL or primary systemic) amyloid and (2) transthyretin (TTR) amyloid. Transthyretin-related amyloidoses, in turn, encompass 2 forms of disease: Familial disease arising from misfolding of a mutated or variant TTR (familial amyloid cardiomyopathy or familial amyloidotic polyneuropathy [FAP]) and a sporadic, nongenetic disease caused by misaggregation of wild-type transthyretin (senile systemic amyloidosis [SSA]). Cardiac amyloidosis can also be caused by other precursor proteins such as apolipoprotein A1, but the prevalence of disease is low and beyond the scope of this review.3 In contrast, AL amyloidosis has an estimated incidence approaching ≈2500 new cases annually,7 with cardiac involvement in ≈50% of cases.8–10 Untreated, prognosis with AL disease is poor, with median survival after diagnosis of <1 year in the presence of heart failure symptoms.8 Unlike AL heart disease, transthyretin-related amyloid cardiomyopathy is slowly progressive and clinically well tolerated, often defying diagnosis until marked ventricular wall thickening, profound diastolic dysfunction, and conduction disease have occurred. Untreated, survival with transthyretin-related cardiac amyloidosis is measured in years to decades. Secondary or AA amyloidosis results from misfolding of serum amyloid A, an acute phase reactant induced by chronic inflammation. Echocardiographic evaluations in 3 studies involving 48, 30, and 224 patients, respectively, with AA amyloidosis identified features of amyloid cardiomyopathy in only 1.3% of the aggregate cohort, and 80 years of age and 50% in those >90 years of age.18 A study of 85 consecutive autopsies in patients ≥80 years of age found amyloid deposits with prealbumin immunohistochemical staining (TTR) in the atria or left ventricle of 21 hearts, a 25% prevalence for age-related TTR amyloid in this elderly population.19 On closer review, however, only two thirds of the TTR amyloid–staining hearts had left ventricular involvement, described as "small and widely scattered" in >50% of cases. These data suggest histologically significant cardiac TTR amyloid occurs in 8% to 16% of people >80 years of age. A prospective study of Finnish octogenarians (the Vantaa 85+ Study) also identified TTR amyloid deposits in 25% of hearts from 256 autopsies.20 Once again, moderate or severe cardiac amyloid deposition occurred in only 5.5% of the total autopsy population.Prevalence of SSA indisputably increases with advancing age, and virtually all patients are >60 years of age when diagnosed. SSA is a remarkably sex-specific disease, exhibiting ≈25 to 50:1 male:female expression.21 Although the Finnish autopsy study did not report a male predominance for amyloid deposition, male patients had more pronounced amyloid staining (greater amyloid burden) than did female SSA cases. By unclear aging mechanisms, aggregation and cardiac deposition of genetically normal TTR increase over time. Aggregate autopsy data suggest wild-type TTR, although histologically present in the hearts of 25% to 30% of septuagenarians and octogenarians, drives cardiac dysfunction in a smaller but significant elderly cohort. Projections of octogenarian population growth over the next 20 years predict SSA will become the most common form of cardiac amyloidosis.Familial Amyloid CardiomyopathyThe TTR gene is located on chromosome 18q12.1 and spans 4 exons and 5 introns. There are >100 single nucleotide polymorphisms encoding variant TTR, with 80 confirmed pathogenic mutations.22 These mutations tend to cluster into geographic or ethnic groupings and exhibit an autosomal dominant pattern of inheritance. The clinical phenotype of variant TTR amyloidosis varies greatly by mutation, the age of onset, disease penetrance, clinical course, and prognosis. Most FAP patients develop nervous system involvement with or without cardiac amyloidosis.23 The mutations that most commonly induce variant TTR cardiac amyloidosis are summarized in Table 1. The most prevalent and best described mutation associated with amyloid neuropathy is V30M (Met 30), which predominantly affects patients originating from Japan, Portugal, or Sweden. People with the Met30 genotype have variable disease penetrance influenced by the place of origin, sex, parental gene transmission, and age affecting disease expression.24 The T60A (Ala 60) TTR mutation is also a frequent cause of amyloid neuropathy and cardiomyopathy, affecting 1% of the population in northwest Ireland (County Donegal).25 Although the UK National Amyloidosis Centre reports cardiac involvement in nearly 100% of T60A patients with familial amyloid cardiomyopathy referred with neuropathy,26 the US experience is more heterogeneous.Table 1. Characteristics of Wild-Type and Common Variant Transthyretin Cardiac AmyloidosisMutationOriginPrevalenceMale:Female RatioOnsetOrgansSSAWorldwide25% >85 y25:1 to 50:1>60 yHeart, STV122IUnited States, Caribbean, Africa4% Black1:1 Gene (+) 3:1 Disease>65 yHeart, PNS, STV30MPortugal, Sweden, Japan1:10002:1>50 yPN/ANS, heartT60AUnited Kingdom, Ireland1% Northwest Ireland2:1>45 yHeart, PNS/ANSSSA indicates senile systemic amyloidosis, wild-type (no mutation); ST, soft tissue; PNS, peripheral nervous system; and ANS, autonomic nervous system.Among the variant TTRs that predominantly target the heart, the valine-to-isoleucine substitution at position 122 (V122I or Ile122) affects the greatest world population.27 First described in 1989 by Gorevic et al,28 Jacobson et al29,30 reported V122I TTR genopositivity in roughly 3% to 4% of the US black population, with virtually undetectable prevalence in the white population.31 The V122I founder appears to have originated in West Africa, which explains clinical expression of V122I TTR in the Caribbean islands (Haiti, Jamaica, and Bermuda; D. Jacobson, personal communication). Although penetrance of this particular allele is unknown, there appears to be a strong association between carrier status, the development of heart failure (relative risk 2.6),32 and echocardiographic features of cardiac amyloidosis.33 Examining stored samples from the Beta-Blocker Evaluation in Survival Trial (BEST), Buxbaum et al34 demonstrated that ≈10% of black study participants with heart failure who were >60 years of age carried V122I, which suggests that unrecognized cardiac amyloidosis may be a contributor to the development of heart failure. This trial enrolled patients with systolic dysfunction (left ventricular ejection fraction 65 years of age carrying V122I constitute the population at immediate risk for clinical expression of TTR cardiomyopathy, and they number ≈99 600 to 132 800 according to the 2010 census figure (3%–4% of 3 320 000 blacks), rendering V122I a potentially important cause of heart failure in the elderly black community.PathogenesisTransthyretin, a 127-amino acid protein, is encoded by 7 kb of DNA spanning exons 1 to 4 of a single gene on chromosome 18.38 In its native state, transthyretin circulates as a tetramer with 2 C2 symmetrical funnel-shaped thyroxine-binding sites at its dimer-dimer interface.39 Elegant thermodynamic studies demonstrate that tetramer dissociation is the rate-limiting step in misfolding of monomeric transthyretin to amyloid fibrils.16 In SSA, incompletely described age-related events such as posttranslational biochemical alterations in wild-type TTR or its chaperones appear to contribute to amyloid fibril formation. Data from transgenic mice overexpressing human SSA suggest that alterations in hepatic chaperone production or proteasome clearance of unfolded protein may determine which aging heart develops amyloidosis.40 In FAP, 1 amino acid substitution in native TTR (variant TTR) destabilizes the tetramer, promoting disaggregation of monomeric protein. Ultimately, the amyloidogenicity of a particular variant transthyretin is determined by the capacity of a specific amino acid substitution to destabilize circulating TTR tetramers, releasing monomeric TTR to permit misfolding to occur. To date, >100 variant TTRs have been described. Many amino acid substitutions associate with patterns of organ involvement, predicting distinct clinical courses. Typically, variant transthyretin is induced by a single-nucleotide substitution; however, 2-nucleotide changes or complete codon deletion have been shown to produce 1 amino acid change in transthyretin.41Affected organs invariably harbor extracellular amyloid deposits. Whether these deposits induce organ dysfunction or represent epiphenomena (disease markers) is debated. Review of sural nerve biopsy samples in 31 V30M ATTR patients described epineural amyloid deposits and nerve degeneration in half of the cohort. No correlation between the presence of amyloid deposits and histological nerve damage could be assigned,42 which suggests an alternative mechanism of injury. In the kidney, the degree of functional disruption is not predicted by the extent of amyloid deposits.43,44 Moreover, serial kidney biopsies in patients with AL amyloidosis before and after clinically successful treatments revealed unchanging amyloid burden despite significant improvement in proteinuria.45,46Increasingly, data support a central role for circulating or prefibrillar amyloidogenic proteins in the disruption of cardiac function in AL and TTR-mediated amyloid disease. Murine hearts perfused with clonal immunoglobulin light chain (AL-LC) isolated from patients with AL amyloid cardiomyopathy rapidly induced diastolic dysfunction. In contrast, light chain isolated from patients without AL amyloidosis did not alter ex vivo heart function.47 In vitro, exposure of cultured cardiomyocytes to physiological levels of AL-LC stimulated production of reactive oxygen species and upregulated heme oxygenase-1, a redox-sensitive protein that identifies cell injury.48 In addition to altering the cardiomyocyte intracellular redox state, AL-LC reduced intracellular calcium levels and cardiomyocyte contractility, in the absence of amyloid fibril formation.48 Recent data indicate AL-LC alters cardiomyocyte ion fluxes, contractility, and programmed cell death through a noncanonical p38α mitogen-activated protein kinase pathway.49Similar evidence of end-organ damage by prefibrillar TTR amyloid exists in FAP. Nerve biopsies from asymptomatic V30M ATTR carriers revealed prefibrillar/Congo Red stain–negative protein aggregates by anti-TTR immunohistochemistry and immunogold electron microscopy.50 Upregulation of nuclear factor-κB and proinflammatory cytokines in these nerve biopsy samples signaled cell toxicity affected by these nonfibrillar TTR aggregates, well before the onset of clinical disease. Exposure of neuronal cell cultures to L55P ATTR nonfibrillar aggregates induced caspase-3 generation and expression of programmed cell death. In contrast, mature L55P ATTR amyloid fibrils did not stimulate caspase-3 expression, which suggests that prefibrillar TTR aggregates are the neurotoxic mediator of disease. Additional data support a role for receptors of advanced glycosylation end products (RAGE) in mediating ATTR organ injury.51 Initial studies of V30M versus L55P ATTR transgenic mouse models of FAP did not detect differences in nerve toxicity mediated by the nonfibrillar forms of these variant TTR species. Taken together, data generated in AL and ATTR models of disease provide evidence that prefibrillar protein aggregates, and not mature amyloid fibrils, contribute to organ toxicity.DiagnosisDiagnosis of systemic amyloidosis requires histological identification of amyloid deposition by Congo red staining. Unlike light-chain (AL) amyloid disease, kidneys and tongue are rarely involved in clinically significant fashion, and thus, biopsy of these organs is usually not pursued.36 Abdominal fat aspirate is a simple, office-based biopsy procedure that identifies amyloid deposits in ≈70% of those with variant TTR such as V122I ATTR disease.35 Cardiac biopsy remains the gold standard for amyloid cardiomyopathy and is not complicated by sampling artifact (yielding false-positive or -negative findings) as occurs with other infiltrative processes such as sarcoidosis. Once amyloid is identified by Congo red staining, immunohistochemical stains for κ and γ light chains, AA, and TTR can be performed to determine the precursor protein. Confirmation of histology and identification of the amyloidogenic protein may be aided by review by pathologists at international amyloidosis referral centers. Immunohistochemistry demonstrating TTR protein in amyloid deposits requires further analysis to distinguish variant from wild-type TTR. Isoelectric focusing electrophoresis in most cases permits separation of variant from wild-type TTR by charge (Figure 3). In our experience, isoelectric focusing reveals distinct electrophoretic mobility differences for ≈95% of the variant TTRs tested. Polymerase chain reaction amplification and sequencing of TTR exons 1 to 4 validates the isoelectric focusing findings and definitively establishes variant from wild-type TTR genotype. Alternatively, biopsy tissue can be processed by laser dissection/liquid chromatography–tandem mass spectrometry to identify the precursor protein with 98% sensitivity.6 Occasionally, TTR cardiac amyloidosis can be diagnosed without cardiac biopsy; when variant TTR genopositivity is established, tissue biopsy from another site documents TTR amyloid deposits, and noninvasive data (see below) support cardiac involvement.Download figureDownload PowerPointFigure 3. Isoelectric focusing gel electrophoresis. Sera from patients with V122I, wild-type (WT), and L58H transthyretin amyloidosis (ATTR). Arrow indicates wild-type transthyretin migration. Note presence of 2 distinct bands in V122I and L58H lanes.In many international amyloid centers, AL amyloidosis and monoclonal gammopathy of unknown significance dominate the clinic population, occasionally obscuring recognition of variant or wild-type TTR amyloidosis. Lachmann et al52 identified TTR mutations among 4% of referrals to a national amyloid center for evaluation and treatment of presumed AL disease. None of these TTR amyloid patients had family histories that suggested genetic disease. Interestingly, all of the ATTR patients presented with cardiomyopathy. Immunohistochemical staining of tissue sections ultimately identified TTR as the amyloid subunit protein.52 Similarly, Connors et al35 reported biopsy-proven AL amyloidosis in 12% of V122I gene–positive patients. These data from large amyloid referral centers illustrate the importance of establishing the correct subunit protein that forms the amyloid tissue deposits, particularly in patients with ATTR genopositivity.Noninvasive TestingDiagnosis of cardiac amyloidosis can be based on invasive heart biopsies or a noninvasive approach, given the proper clinical context, supportive noninvasive testing, and identification of amyloid tissue deposits from a noncardiac source such as abdominal fat aspirate (Figure 4). A contemporary approach to noninvasive diagnosis of TTR cardiac amyloidosis includes echocardiography with strain imaging, cardiac magnetic resonance (CMR), electrocardiography (ECG), and serum biomarker testing, including B-type natriuretic peptide (BNP or N-terminal pro-BNP) and cardiac troponin (T or I). Physical examination does not typically assist in differentiation of amyloid type, with the notable exceptions of macroglossia and periorbital ecchymoses, which herald AL amyloidosis.36 Physical findings vary significantly depending on the severity of heart dysfunction, ranging from a relatively normal examination in early-stage disease to extensive signs of congestive heart failure, including pleural effusions, elevated jugular venous pressure, and peripheral edema. In many cases of TTR amyloid, isolated cardiac involvement or inconclusive biopsy samples from other sites (fat pad aspirate, gastric or rectal biopsies, extensor retinaculum sampling at carpal tunnel surgery, or salivary gland biopsies) warrant direct endomyocardial sampling.Download figureDownload PowerPointFigure 4. Diagnostic algorithm for diagnosis of transthyretin (TTR) cardiac amyloidosis. CMR indicates cardiac magnetic resonance imaging; AL, light-chain amyloidosis; LC/MS, laser dissection/liquid chromatography/tandem mass spectrometry; SSA, senile systemic amyloidosis; PCR, polymerase chain reaction; and ATTR, TTR amyloidosis.EchocardiographyEchocardiography remains the most useful imaging modality for identifying and monitoring cardiac amyloid disease. Ease of image acquisition and interpretation, relatively low cost, unparalleled diastolic functional assessment, and capacity for serial studies despite technical differences in data acquisition or disease progression make echocardiography the universal instrument for cardiac amyloid assessment. Recent reports validate detection of subtle systolic dysfunction by tissue Doppler imaging and speckle tracking technology.53By classic echocardiographic teaching, the cardiac amyloid phenotype is a thick-walled ventricle with a speckling appearance of the myocardium, small left ventricular chamber volume, valve thickening, atrial enlargement, and signs of elevated filling pressures (pericardial effusion, pleural effusions, dilated vena cava) caused by restrictive diastolic filling (Figure 5; online-only Data Supplement Movie I).54 Although the preponderance of data on which these echocardiographic features are based are derived from the AL population, similar findings have been reported in TTR cardiomyopathy.21 Wall-thickness increase remains the principal feature on which cardiac amyloidosis is diagnosed. According to an international consensus panel of experts in amyloid disease, interventricular septal thickness of >12 mm, in the absence of aortic valve disease or significant systemic hypertension, is the echocardiographic criterion that identifies cardiac involvement in patients with AL systemic amyloidosis (there are no established criteria for TTR disease).55 This single threshold fails to account for sex-specific differences in normal wall thickness56 and confers a high degree of specificity but low sensitivity for identification of cardiac involvement. The continuum of cardiac involvement makes early disease recognition challenging when wall thickness and diastolic function are only mildly abnormal. The perceived rarity of amyloid disease compared with other, more common entities that produce ventricular thickening, such as hypertensive remodeling and hypertrophic cardiomyopathy, likely lowers cardiologists' recognition of new cases. Echocardiography alone is often unable to differentiate these very different processes, prompting multimodality assessment. However, the presence of prominent right ventricular wall thickening, interatrial septal thickening, and restrictive (grade 3) diastolic dysfunction are uncommon in hypertensive remodeling or hypertrophic cardiomyopathy and can suggest that TTR amyloidosis may be present.24,33Download figureDownload PowerPointFigure 5. Echocardiographic appearance of V122I transthyretin cardiac amyloidosis (ATTR). Parasternal long-axis (A) and short-axis (B) views are illustrated, demonstrating increased ventricular wall thickness and pleural and pericardial effusions. C, Restrictive transmitral Doppler pattern. D, Tissue Doppler velocities consistent with reduced longitudinal systolic shortening (reduced S′ velocity) and diastolic dysfunction (reduced e′ velocity).The challenges of amyloid diagnosis coupled with mimicry of hypertensive and hypertrophic cardiomyopathy result in late recognition of TTR cardiac disease. Consequently, advanced remodeling changes are more often present on diagnosis of TTR cardiomyopathy than in AL heart disease. Patients with SSA cardiac amyloidosis tend to have the largest wall thickness and myocardial mass compared with AL21 and variant TTR disease.36 Although systolic dysfunction is frequently a manifestation of more advanced disease in light-chain and variant TTR cardiac amyloidosis, it is fairly common in SSA disease, again likely because of delayed recognition. Among patients with ATTR, a lower left ventricular ejection fraction (<50%) is associated with reduced survival.57Longitudinal strain measurement by tissue Doppler and echocardiographic speckle tracking have emerged as useful clinical tools for the identification of cardiac involvement in AL disease53 and can assist in differentiation of cardiac amyloidosis from other causes of wall thickening, including hypertension and hypertrophic cardiomyopathy.58 TTR cardiac amyloidosis also results in reduction in longitudinal shortening, although its prognostic significance has not been established.Cardiac Magnetic Resonance ImagingCompared with echocardiography, CMR offers superior myocardial border delineation and a 3-dimensional approach to quantify ventricular volumes, wall thickness, and mass (online-only Data Supplement Movie II). It is more precise and reproducible than echocardiography but also more expensive, less widely available, and limited by the inability to image patients with pacemakers or implanted cardioverter-defibrillator devices. At present, echocardiography provides the best imaging technique for assessment of ventricular diastolic function, conferring better temporal resolution than CMR. However, the principal advantage of CMR over echocardiography is the capacity to directly identify amyloid infiltration by means of late gadolinium enhancement (LGE) imaging. Gadolinium is an extracellular contrast agent, and under normal conditions, it is not retained in the myocardium after administration. Amyloid infiltration results in expansion of the extracellular space and abnormal myocardial gadolinium distribution kinetics, which result in contrast retained in the heart. Signal from normal myocardium is nulled or suppressed in LGE imaging, but because of diffusely retained contrast, this is difficult to achieve in cardiac amyloidosis. An important limitation of the application of contrast-enhanced CMR in TTR cardiac amyloidosis is coexistent chronic kidney disease and the risk of nephrogenic systemic fibrosis.59 If the creatinine clearance is <30 mL/min, gadolinium contrast cannot be administered safely, and LGE imaging cannot be performed.Maceira et al60 first reported a CMR profile that identified cardiac amyloidosis, but with an imaging technique that required an unusually short delay after contrast administration to obtain optimal LGE images. Subsequent studies, in mixed AL and TTR cohorts, have determined that the sensitivity and specificity of CMR for the identification of cardiac amyloidosis compared with endomyocardial biopsy approaches 90%.61–63 Unlike LGE abnormalities associated with myocardial infarction, in which focal regions of high-signal-intensity LGE are seen, patterns in cardiac amyloidosis are variable, with global subendocardial, diffuse, and focal foci noted (Figure 6).64 Furthermore, the retained gadolinium greatly shortens myocardial T1,65 a fundamental magnetic resonance characteristic on which LGE contrast is founded. Because of retained contrast, myocardial T1 approaches that of the ventricular blood pool, rendering a distinct pattern of early myocardial signal suppression (coincident to the blood pool) representative of diffuse amyloid infiltration.Download figureDownload PowerPointFigure 6. Cardiac magnetic resonance imaging of transthyretin amyloidosis. Late gadolinium enhancement (LGE) images from midventricular short-axis slices are depicted illustrating the different LGE patterns observed. A, LGE is evident (arrows) in a characteristic, diffuse subendocardial pattern (patient with wild-type transthyretin). B, Diffuse transmural low-intensity signal is seen with poor contrast between the blood pool and myocardium (patient with V122I variant transthyretin). C, High-signal-intensity, patchy LGE is evident involving the subendocardium in the lateral wall but transmurally involving the septum as well (arrows; patient with wild-type transthyretin).The majority of published reports of CMR in cardiac amyloidosis involve mixed cohorts of patients with relatively advanced AL and TTR disease, with the notable exception of the report by Di Bella et al,66 wherein CMR and nuclear scintigraphy were used to identify cardiac involvement in patients with FAP. Although precursor proteins differ, the LGE findings in TTR and AL cardiac amyloidosis appear relatively similar. As reported in the echocardiographic literature, CMR-determined wall thickness and mass are greater in TTR cardiac amyloidosis than in light-chain disease.67ElectrocardiographyClassically, cardiac amyloidosis is electrocardiographically typified by low QRS voltage and a pseudoinfarct pattern of Q-wave or T-wave changes on ECG. The presence of low QRS voltage and increased left ventricular wall thickness by echocardiography should prompt consideration of cardiac amyloidosis. Notably, certain ECG features support TTR cardiac disease more than AL heart disease. In different case series, low QRS voltage has been reproducibly identified in approximately 46% to 60% of AL patients but only 25% to 40% of those with TTR disease.36,68,69 However, a "pseudoinfarct" pattern is also equally seen in AL disease (47%–69%) and TTR disease (66%–69%).36,68,69 The presence of conduction system disease is more common in SSA disease, particularly left bundle-branch block. Finally, although most patients present with sinus rhythm, atrial fibrillation is more commonly observed in SS