Expert Analysis and Opinion—Understanding Cardiac Amyloidosis

Part 1: Nomenclature and Epidemiology

  1. Cardiac amyloidosis (CA) is a protein-folding disorder nearly exclusively caused by misfolded amyloid transthyretin (ATTR) and amyloid light chain (AL) proteins.
    • Name derives from Latin "amylum" (starch like).
    • Nomenclature: "A" for amyloid, followed by precursor protein abbreviation (e.g., AL = amyloid light chain amyloidosis).
    • Histologic diagnosis: Aggregates of beta-sheets that stain with Congo red (green birefringence under polarized light). Congo red staining does not identify the type of amyloidosis.
    • Systemic amyloidoses classified by precursor protein:
      • Light chain and transthyretin (TTR) are the most common types.
      • Immunoglobulin light chains are produced by the bone marrow plasma cell; circulating TTR (formerly known as "prealbumin") is produced by the liver.
      • TTR can be genetically normal (transthyretin amyloidosis wild-type [ATTRwt]) or variant (transthyretin amyloidosis variant [ATTRv] or hereditary transthyretin amyloidosis [hATTR]).
      • Single-nucleotide polymorphisms in the transthyretin (TTR) gene induce TTR instability and misfolding.
  2. CA causes symptoms of heart failure (HF) and arrythmia as well as other extracardiac signs/symptoms.
    • Both AL and ATTR can cause:
      • HF manifesting as left- or right-sided symptoms with dyspnea, lower extremity edema, elevated jugular venous pressure, hepatomegaly, fatigue, or hypotension.
      • Arrythmia manifesting as conduction disease and heart block, atrial fibrillation (AF) or atrial flutter (AFL), and ventricular arrhythmias.
      • Autonomic neuropathy manifesting as orthostasis, dyshidrosis, erectile dysfunction, or gastrointestinal motility problems.
    • AL is associated with periorbital ecchymosis and macroglossia in a minority of cases. Carpal tunnel syndrome is common.
    • ATTR is associated with tendinopathies including carpal tunnel syndrome (bilateral), spinal stenosis, and spontaneous tendon ruptures.
    • ATTRv is associated with a length-dependent, peripheral sensory neuropathy and autonomic neuropathy.
    • The pathophysiology of CA involves extracellular deposition of misfolded protein amyloid fibrils in both AL and ATTR, causing compromise of ventricular compliance and reduced longitudinal systolic function early in the disease course followed by global systolic dysfunction later in the disease course.
    • A component of direct toxicity of prefibrillary light-chain fragments causing cell injury is well recognized in AL, and a similar mechanism is likely present in ATTR.
  3. AL amyloidosis is a rare disease, ATTR may not be.
    • AL incidence is 1:50,000-100,000, with 5,000-7,000 new cases identified annually in the United States. The prevalence is increasing, as survival has improved dramatically.
    • ATTR demonstrates an age-dependent clinical penetrance.
    • ATTRv has unknown incidence and prevalence, and varies by the actual TTR variant, but the most common variant associated with ATTRv is Val122Ile (pV142I), which is found in 3.4% of self-identified African Americans. The proportion of those who carry this allele who have or will develop ATTRv-CA is not known.
    • ATTRwt is the most common type of amyloidosis. Estimates place the prevalence as >100,000 persons; described in older (>60 years of age, generally) and predominantly white, male cohorts.
    • Specific populations merit increased scrutiny; ATTRwt is noted in approximately 10% of patients with severe aortic stenosis.
    • ATTRwt is likely present in approximately 10-15% of men >60 years of age with heart failure with preserved ejection fraction (HFpEF).
  4. The clinical presentation and course of AL and ATTR are variable, but early diagnosis remains essential with specific populations that merit consideration of screening.
    • Therapies for AL amyloidosis have dramatically improved survival over the prior decade.
      • Treatments for AL are derived from approved therapies for multiple myeloma (see Part 4, later).
      • Hematologic response is determined by measuring the change in the amyloid-causing light chain with therapy, as well as changes in bone marrow plasma cell populations.
      • A cardiac response is defined as a 30% reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP), or a decline of >300 pg/mL for NT-proBNP or >50 pg/mL for BNP (whichever is greater), that generally occurs 6 months (but can be seen 3-12 months) after evidence of a hematologic response.
      • Survival in AL amyloidosis is determined in large part by cardiac involvement and response to treatment. The cardiac biomarkers NT-proBNP or BNP and troponins can be used together in scoring systems to establish survival prognosis. The median survival for all patients exceeds 10 years in the majority of cases, with some living >15 years. Those with varying degrees of cardiac involvement experience reduced survival, generally with a median survival of approximately 5 years or less.
      • That said, those with the most advanced disease (stage 3b or stage 4) still experience dismal outcomes, with 1-year survival of 50%, underscoring the need to identify patients early in the disease course.
    • In ATTR amyloidosis, survival is also largely determined by the severity of cardiac involvement.
      • Survival estimates can be derived from staging systems using cardiac biomarkers (NT-proBNP) and estimated glomerular filtration rate.
      • Survival in ATTRwt after diagnosis without treatment is a median of approximately 4 years.
      • Survival in ATTRv Val122Ile without treatment is worse than ATTRwt for a given biomarker stage, but whether this is related to biology of TTR,  comorbidities, or systemic barriers to health is unclear. Generally, median survival for ATTRv Val122Ile is 2-3 years without treatment.
      • Treatments now involve therapies to stabilize TTR or suppress/silence TTR synthesis and improve survival and symptoms in ATTR (see Part 4, later).
    • Populations that merit enhanced consideration of ATTR amyloidosis include:
      • Severe aortic stenosis, particularly the low-flow, low-gradient phenotype.
      • Older patients with HFpEF, particularly those with bilateral carpal tunnel syndrome, spinal stenosis, or tendon rupture.
      • Autonomic or peripheral neuropathy and HF.
      • Presumed new diagnosis of hypertrophic cardiomyopathy (HCM) in an older patient.

Part 2: Diagnosis of Cardiac Amyloidosis

  1. Endomyocardial biopsy (EMBx) remains the "gold standard" but is not necessary in the majority of cases of AL and ATTR.
    • EMBx remains necessary in cases of high clinical suspicion and equivocal noninvasive testing or to confirm cardiac AL amyloidosis in the absence of an extracardiac biopsy.
    • EMBx is not subject to sampling error, as is the case with other cardiomyopathies (e.g., sarcoidosis). Tissue processing for Congo red staining to confirm amyloid deposits followed by liquid chromatography tandem mass spectrometry is the preferred method to identify the misfolded protein precursor.
  2. Echocardiography with strain imaging and cardiovascular magnetic resonance (CMR) can identify patterns strongly suggestive of CA.
    • A multisocietal consensus document was published detailing the proper method for performance and reporting of cardiac imaging techniques.
    • Echocardiographic imaging is considered standard of care in cases of suspected CA.
      • Amyloid deposition increases wall thickness and impairs diastolic compliance initially. Right ventricular (RV) wall thickening is also a common feature.
      • Impairment of longitudinal contraction as determined by longitudinal strain is also an early feature of CA; reduction in global measures of systolic function, such as left ventricular (LV) ejection fraction, are late manifestations of advanced disease.
      • An apical sparing longitudinal strain pattern is typical of CA, wherein the apical strain is greater than two times the basal strain segments. Recognition of this pattern is helpful to differentiate amyloidosis from other wall-thickening processes.
      • Global longitudinal strain (GLS) is reduced and associated with survival in both AL and ATTR. Improvement in GLS is associated with hematologic response in AL amyloidosis.
      • AL and ATTR have overlapping echocardiographic features, although in general ATTR is characterized by thicker walls, likely owing to the more insidious nature of deposition and the toxic aspect of light chains in AL facilitating earlier recognition.
    • CMR is an indispensable tool for differentiation of CA from other nonamyloid disease processes (hypertension or HCM).
      • The strength of CMR is the capacity to characterize tissue by means of parametric mapping techniques and late gadolinium enhancement (LGE).
      • Amyloidosis is characterized by increased native (noncontrast) T1 and increased extracellular volume fraction.
      • The LGE pattern observed in amyloidosis is a diffuse pattern that progresses from subendocardial to transmural and does not follow a specific coronary distribution.
      • Amyloid deposition increases the extracellular space, resulting in retention of gadolinium contrast, thereby creating shortening postcontrast T1.
      • The inability to suppress myocardial signal on LGE imaging (using the phase sensitive inversion recovery technique) is a typical feature of amyloidosis.
      • As in echocardiography, features of AL and ATTR overlap, although ATTR tends to have increased wall thickness and LV mass compared with AL.
  3. Nuclear imaging with bone-seeking radiotracers (pyrophosphate [PYP] and 3,3-diphosphono-1,2-propanodicarboxylicacid [DPD]) can diagnose ATTR amyloidosis with diagnostic uptake and no evidence of a plasma cell disorder (PCD) by blood and urine testing.
    • The technetium-labelled radiotracer PYP (technetium-99m [99mTc]–PYP) is available in the United States, whereas the tracers DPD (99mTc-DPD) and hydroxymethylene diphosphonate (HMDP; 99mTc-HMDP) are available in Europe.
    • These are bone-seeking radiotracers that accumulate in the bony structures of the thorax and are retained in the heart if ATTR deposits are present.
    • Nuclear imaging can only be interpreted as diagnostic of ATTR amyloidosis if there is no evidence of a PCD or monoclonal gammopathy by serum and urine testing.
      • The correct tests to order are serum free light chains (FLCs) and serum and urine immunofixation electrophoresis (serum protein electrophoresis [SPEP] is insensitive and should not be ordered without immunofixation).
      • Many patients with biopsy-proven ATTR amyloidosis will have abnormal PCD testing given that chronic kidney disease results in elevated kappa FLC above the normal range.
      • Hematology consultation should be obtained if there is any uncertainty in testing result interpretation.
      • A lambda light chain abnormality is always abnormal and merits hematology consultation.
    • Tracer injection is followed by a 1- or 3-hour incubation before imaging.
    • Interpretation of planar scans requires comparison of cardiac uptake to that of the rib (the semiquantitative or Perugini score) or determination of mean counts from a region of interest (ROI) placed over the heart and compared with an identically sized ROI placed over the contralateral chest (heart/contralateral chest [H/CL] ratio).
    • A test is considered consistent with ATTR amyloidosis when there is uptake in the heart equal to or greater than that of the rib (semiquantitative grade 2 or 3) or the H/CL ratio is >1.5 at 1 hour.
    • Single photon emission computed tomography (SPECT) is essential to confirm that the uptake seen on the plan scan is indeed myocardial and not related to the blood pool, and that extracardiac uptake (e.g., bone or breast) is not confounding interpretation.
    • Blood pool uptake is a major confounder and must be excluded by SPECT imaging to avoid false-positive scan interpretations.
    • False-negative scans are uncommon and reported in rare TTR variants.
  4. Genotyping of TTR is essential in cases of confirmed ATTR.
    • ATTRwt is a disease of older individuals, nearly all >65 years of age, although some cases have been observed among patients in their 50s.
    • ATTRv-CA will generally be caused by one of two principal variants in the United States—Val122Ile and Thr60Ala. Other variants that cause dominant cardiac involvement are well recognized in specific countries and regions.
    • Genotyping is essential to determine treatment and predict disease course.
    • Identification of a variant is important because the carrier's children and siblings (of the same parentage) have a 50% chance of also inheriting the allele.
    • A genotype-first approach will not identify ATTRwt amyloidosis cases. Additionally, as phenotypic penetrance is variable, it is not clear whether an inherited variant will result in clinical amyloidosis or when onset will occur.

Part 3: Symptom Management

  1. Congestive HF symptoms are managed by volume control (bioavailable loop diuretic/mineralocorticoid-receptor antagonists [MRAs]) with no guideline-based recommendations for renin-angiotensin system (RAS) antagonists and beta-blockers.
    • Volume management is critical and often challenging in patients with CA because they have a low blood pressure from a reduced and fixed stroke volume along with concomitant autonomic dysfunction in some patients.
    • Bioavailable loop diuretics (torsemide or bumetanide) are preferred in the presence of right HF.
    • MRAs are often used in conjunction with loop diuretics to augment the effect of the loop diuretic and maintain a normal serum potassium.
    • There are no guideline-based recommendations for HF therapies (angiotensin-converting enzyme, angiotensin-receptor blockers, angiotensin receptor–neprilysin inhibitors, and beta-blockers) in patients with CA.
    • Often, antagonists of the RAS are not well tolerated, especially in high doses given the reduced systemic blood pressure from either a low stroke volume/cardiac output or from concomitant autonomic dysfunction.
    • Beta-blockers, especially in high doses, should be avoided because patients with CA are usually reliant on a high heart rate to maintain their cardiac output in the face of a low and fixed stroke volume.
    • Nondihydropyridine calcium channel blockers (e.g., verapamil) should not be given to patients with CA because they can avidly bind to amyloid fibrils and cause high-degree heart block and shock.
    • The role of digoxin in the management of CA remains controversial but low-dose digoxin with close monitoring is a reasonable alternative for rate control, especially in patients prone to hypotension.
  2. Arrythmia (particularly AF) is common in ATTR, with a high rate of intracardiac thrombi.
    • Atrial arrhythmias (AF and AFL) are very common in patients with CA and are more common in ATTRwt than AL or ATTRv disease.
    • Among patients with ATTRwt, ≥30% present with AF and nearly 90% develop AF over the course of their disease.
    • Intracardiac thrombi are very common in CA.
    • Patients with CA and AF should be anticoagulated irrespective of their CHADS-VASC2 score.
    • Due to the high prevalence of AF and the risk of systemic embolism, screening with long-term monitoring should be considered in those without clinically evident AF or AFL.
    • Transesophageal echocardiography–guided direct-current cardioversion has been recommended regardless of anticoagulation status given the high rate of intracardiac thrombi.
    • There are insufficient data to inform whether vitamin K antagonists or direct oral anticoagulants are preferred for oral anticoagulation in patients with CA; however, both appear equally tolerated and effective.
    • Ventricular arrhythmias, especially nonsustained ventricular tachycardia, are very common with long-term heart rate monitoring; whether their presence confers an increased risk for adverse outcomes is not clear.
  3. Permanent pacing is often needed, especially in ATTR-CA, and the role of defibrillators, especially for primary prevention, is not well defined.
    • Conduction disease is quite common in patients with ATTRwt-CA and ATTRv-CA more so than in those with AL-CA.
    • Standard indications for pacing are recommended in patients with CA.
    • There are insufficient data to suggest that automated implantable cardioverter-defibrillators (ICDs) have a role for primary prevention of sudden death in CA.
    • The European Society of Cardiology (ESC) guidelines note that there are insufficient data to provide recommendations for the use of ICDs for primary prevention in CA, and the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline recommends individualized decision making for both primary and secondary prevention with ICDs in CA.
    • Given that patients with CA have very low stroke volumes and often become pacer dependent, RV pacing may be associated with a decline in cardiac output and biventricular pacing may be useful.
  4. Heart transplantation has been performed with outcomes similar to nonamyloid cardiomyopathy in patients with class D HF.
    • For selected patients with isolated CA, heart transplantation has been successfully performed in specialized centers with appropriate expertise, with recent outcomes not differing from patients with HF but not amyloid.
    • Patients with isolated AL-CA may be considered for heart transplantation in experienced centers with established collaborations between cardiovascular and hematology teams.
    • Patients with ATTRwt-CA can be considered for isolated heart transplantation.
    • Patients with ATTRv-CA were previously considered for combined heart and liver transplantation (as the liver is the source of TTR production), but advances in TTR therapies have resulted in concomitant liver transplantation rarely being performed.
    • Amyloid involvement of extracardiac organs must be carefully evaluated for when considering patients with CA for heart transplantation.
    • Significant extracardiac amyloid organ dysfunction should be considered a contraindication to proceeding with heart transplantation.

Part 4: Amyloid-Specific Therapy

  1. There are many highly effective antiplasma cell therapies. Daratumumab is the first and only Food and Drug Administration (FDA)–approved therapy for AL amyloidosis. The role of stem cell transplantation is evolving.
    • Antiplasma cell therapy is pursued with the goal of attaining complete response (CR), defined as normalization of serum kappa and lambda FLCs and FLC ratio.
    • Those who do not achieve CR may be classified as having very good partial response (PR), defined as a difference in FLC <40 mg/dL, PR (decrease in difference in FLC >50%), or no response.
    • Antiplasma cell therapies for AL amyloidosis are approved for the treatment of multiple myeloma and used "off-label" for AL amyloidosis, including several different classes of medications (alkylating agents [melphalan, cyclophosphamide, bendamustine], steroids, immunomodulatory drugs [IMiDs; lenalidomide and pomalidomide], and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).
    • Daratumumab (a monoclonal Ab against cluster of differentiation 38, which is expressed on plasma cells) has been shown to be highly effective in the treatment of patients with AL-CA who are either newly diagnosed or with relapsing or progression of AL amyloidosis, inducing rapid and strong hematologic response rates with few toxicities, resulting in its approval by the FDA as the first and only therapy specifically indicated for AL amyloidosis.
    • Proteosome inhibitors, developed in 2008, have dramatically improved outcomes for patients with AL-CA, resulting in hematologic response defined by a reduction in involved serum FLC.
    • IMiDs (lenalidomide and pomalidomide) tend to raise NT-proBNP in patients with AL amyloidosis.
  2. In ATTR, pharmacologic treatment includes both TTR silencers and stabilizers.
    • Proven effective therapeutic options involve two different mechanisms, one that involves stabilization of the TTR tetramer with tafamidis or diflunisal (or others in development, such as Acoramidis [AG10; BridgeBio Pharma Inc., Palo Alto, California]) and therapies aimed at silencing or knocking down TTR production such as the agents inotersen or patisiran (or others in development, including Vutrisiran [Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts] and ligand-conjugated antisense or LICA/TTR-LRx [Ionis Pharmaceuticals Inc., Carlsbad, California]; see later).
    • Tafamidis is the only therapy currently approved by the FDA for ATTR-CA. It has been shown to reduce mortality and morbidity compared with placebo and to slow the decline in health-related quality of life and submaximal functional capacity as measured by the 6-min hall walk.
    • Tafamidis is available in two formulations: tafamidis meglumine (20 mg pills), in which the FDA recommended daily dose is 80 mg a day; or tafamidis free salt (61 mg a day). Although they are not equivalent on a milligram-to-milligram basis, both achieve a similar blood level of tafamidis at higher dosages.
  3. Selection of treatment is dependent on the phenotype (cardiac vs. neurologic), hereditary versus sporadic, cost, and patient preference.
    • Tafamidis is currently approved by the FDA for the treatment of ATTR-CA due to either wild type or hereditary disease.
    • Patisiran and inotersen are approved by the FDA for the treatment of ATTR polyneuropathy from a TTR variant (e.g., hereditary disease) with or without a concomitant cardiomyopathy, but are not approved for ATTRwt disease or ATTRv disease with only cardiomyopathy.
    • The cost of such therapies is very high, and the cost-effectiveness based on standard quality of life years has been questioned.
    • Tafamidis is an oral therapy taken daily, inotersen is administered subcutaneously on a weekly basis, and patisiran is given intravenously every 3 weeks.
    • Both silencers (inotersen and patisiran) require supplementation of vitamin A (3000 U daily) because the silencing of TTR production can impair vitamin A delivery.
    • Inotersen has been associated with rare but serious side effects (thrombocytopenia and glomerulonephritis) and needs to be administered as part of an FDA risk evaluation and mitigation strategy procedure with monitoring of renal function and platelet counts every 2 weeks.
  4. Current and future randomized controlled trials include different silencing/stabilizing agents as well as novel approaches to facilitate degradation of amyloid deposits.
    • Based on a biologic understanding of amyloidogenesis, there has been an explosion of new therapeutic approaches now under evaluation, in particular for ATTR-CA.
    • There are four phase 3 randomized controlled trials that are either fully enrolled or actively recruiting that are evaluating the safety and efficacy of novel TTR stabilizers (AG10) or silencers including patisiran, Vutrisiran, or AKCEA-TTR-LRx/ION-682884 (Ionis Pharmaceuticals Inc., Carlsbad, California) for ATTR-CA.
    • In addition, CRISPR associated protein 9, a gene-editing approach in which target DNA can be permanently modified or repaired, is being developed for permanent TTR silencing as a means of treating hATTR.
    • Finally, there are several compounds that target the removal of amyloid fibrils from the myocardium that are being tested, including NEOD001 (Prothena Corporation PLC, Dublin, Ireland), targeted at AL amyloidosis, and PRX-004 (Prothena Corporation PLC, Dublin, Ireland), targeted at ATTR amyloidosis.
    • It is envisioned that clinicians will be in the enviable position of choosing along with their patients from a wide range of therapies for ATTR-CA.

Educational grant support provided by Janssen Oncology.

To visit the hub for the Raising Awareness and Understanding of Cardiac Amyloidosis Grant, click here!


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Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Valvular Heart Disease, Implantable Devices, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Heart Failure, Amyloidosis, Prealbumin, Amyloid, Natriuretic Peptide, Brain, Immunoglobulin Light Chains, Macroglossia, African Americans, Carpal Tunnel Syndrome, Protein Structure, Secondary, Troponin, Atrial Fibrillation, Atrial Flutter, Multiple Myeloma, Ecchymosis, Hepatomegaly, Rare Diseases, Spinal Stenosis, Glomerular Filtration Rate, Polymorphism, Single Nucleotide, Dizziness, Tumor Necrosis Factor Ligand Superfamily Member 14, Birefringence, Plasma Cells, Stroke Volume, Edema, Heart Block, Biomarkers, Cardiomyopathy, Hypertrophic, Early Diagnosis, Hypotension, Dyspnea, Tendinopathy, Staining and Labeling, Fatigue, Aortic Valve Stenosis, Gastrointestinal Motility, Venous Pressure, Lower Extremity

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