2023 ACC Expert Consensus Decision Pathway on Cardiac Amyloidosis

What's New

Major Advances Since Previous Guidance

• Tafamidis FDA Approval (2019): Transthyretin stabilizer approved for ATTR-CM; reduces mortality and hospitalizations.
• Acoramidis: Newer TTR stabilizer in clinical development for ATTR.
• Daratumumab-based therapy: Now standard of care for newly diagnosed AL amyloidosis; offers superior outcomes to older regimens.
• Improved diagnostic accuracy: Technetium-99m (Tc-99m) pyrophosphate/DPD scintigraphy and advanced CMR allow noninvasive ATTR-CM diagnosis without biopsy.
• Gene silencing agents: Small interfering RNAs (patisiran, inotersen) approved for ATTR-associated polyneuropathy; cardiac applications evolving.
• Heart transplantation outcomes: Improved survival with modern protocols; now a viable option for selected advanced ATTR-CM and AL-CM patients.
• Multidisciplinary care imperative: Coordination between cardiology, hematology, neurology, genetics, and palliative care essential for optimal outcomes.

Cardiac Amyloidosis Types

AL Amyloidosis (Light Chain)

• Composed of misfolded immunoglobulin light chains (kappa or lambda)
• Most common amyloidosis; approximately 75% of all cardiac amyloidosis cases
• Results from clonal plasma cell proliferation
• Can affect heart, kidneys, GI tract, nervous system, and soft tissues
• Diagnosis requires demonstration of monoclonal protein AND amyloid tissue deposits

ATTR Amyloidosis (Transthyretin)

ATTR Wild-Type (ATTRwt)

• Previously called "senile" amyloidosis
• More common in elderly men (greater than 60 years old)
• Results from aggregation of normal (wild-type) TTR protein
• Primarily affects heart; GI and neurologic involvement rare
• Prevalence increasingly recognized; approximately 3.5% in Val122Ile carriers

ATTR Hereditary (ATTRv or ATTRv-CM)

• Caused by TTR gene mutations; greater than 100 variants identified
• Autosomal-dominant inheritance; one mutant allele sufficient to cause disease
• V30M: most common globally (Portugal, Japan, Sweden)
• Val122Ile (V122I): predominant in African Americans (approximately 3.5% of Black population)
• Wide phenotypic variability: cardiac, neuropathic, or mixed presentations
• Typically earlier onset and more aggressive than wild-type

Red Flag Recognition: "When to Suspect" Cardiac Amyloidosis

Cardiac Clues

• Heart failure with preserved ejection fraction (HFpEF) + increased LV wall thickness (in absence of hypertension)
• Restrictive cardiomyopathy pattern on echocardiography
• Low-voltage QRS on ECG (despite thick LV walls on echo) — pathognomonic finding
• Atrial fibrillation (especially if new-onset, younger patients, or disproportionate to structural disease)
• Conduction abnormalities or pacemaker dependence
• Dilated longitudinal strain despite preserved ejection fraction

Extracardiacs Clues

• Musculoskeletal: Bilateral carpal tunnel syndrome (CTS), lumbar/cervical spinal stenosis, spontaneous biceps tendon rupture, shoulder surgery history
• Neurologic: Polyneuropathy (small-fiber or mixed), family history of neuropathy, autonomic dysfunction (orthostatic hypotension, erectile dysfunction)
• Renal: Nephrotic syndrome (proteinuria, hypoalbuminemia)
• Gastrointestinal: Early satiety, nausea, weight loss, chronic diarrhea/constipation
• Other: Elevated troponin/NT-proBNP, macroglossia, periorbital ecchymosis, acquired factor X deficiency

Diagnostic Algorithm for Cardiac Amyloidosis

Step 1: Suspicion to Screening

1. Establish clinical suspicion via history, exam, ECG, and echocardiography
2. Monoclonal protein screen (first-line):
   • Serum kappa and lambda free light chains (FLC)
   • Serum immunofixation electrophoresis (IFE)
   • Urine immunofixation electrophoresis (UIFE)
3. Sensitivity and Specificity: If monoclonal protein absent AND serum FLC ratio normal, AL amyloidosis essentially excluded. If abnormal, proceed to genetic testing and/or scintigraphy.

Step 2: ATTR vs AL Differentiation

Step 3: Confirmatory Testing

• ATTR-CM confirmed: Genetic testing (TTR gene sequencing) to distinguish wild-type from hereditary
• AL-CM suspected: Tissue biopsy (cardiac preferred if cardiac involvement confirmed; otherwise fat pad, bone marrow) with Congo red staining and mass spectrometry-based proteomic analysis

Cardiac Imaging in Amyloidosis

Echocardiography

• Increased LV wall thickness (often greater than 11 mm in absence of hypertension)
• Restrictive filling pattern: restrictive mitral/tricuspid inflow, elevated E/e' ratio
• Strain pattern: Apical sparing (longitudinal strain preserved at apex, reduced elsewhere) — highly suggestive of ATTR
• Atrial enlargement, diastolic dysfunction, reduced global longitudinal strain

Cardiac Magnetic Resonance (CMR)

• Gold standard for tissue characterization
• Late gadolinium enhancement (LGE): Diffuse subendocardial or transmural pattern
• Extracellular volume (ECV): Elevated ECV fraction (greater than 40% abnormal; normal approximately 27%)
• Useful to exclude other causes (myocarditis, Fabry disease, sarcoidosis)
• Can differentiate AL from ATTR-CM based on patterns

Nuclear Imaging (Tc-99m PYP/DPD)

• Tc-99m pyrophosphate (PYP): Predominant agent in US
• Tc-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD): Preferred in Europe
• Grade 0 = no cardiac uptake; Grade 3 = intense cardiac uptake (Perugini scoring)
• Grade 2–3 uptake (without blood pool) virtually diagnostic of ATTR-CM
• Noninvasive diagnosis possible without biopsy if high clinical suspicion + typical imaging

Genetic Testing and Variant Stratification

Indications for TTR Gene Sequencing

• All patients with confirmed or suspected ATTR-CM
• First-degree relatives of known TTR mutation carriers
• Asymptomatic carriers with family history of amyloidosis

Common TTR Variants Causing Cardiac Amyloidosis

Cascade Genetic Testing

• All first-degree relatives should be offered testing
• Age-dependent penetrance: TTR variants show incomplete penetrance and variable expressivity
• Clinical assessment important even in asymptomatic carriers; baseline echocardiography and biomarkers recommended

ATTR Treatment

Tafamidis: TTR Stabilizer

Mechanism: Binds to tetrameric TTR, preventing dissociation and fibril formation.

• Dosing: Tafamidis 61 mg daily OR Tafamidis meglumine 80 mg daily
• Key Trial: ATTR-ACT showed reduction in mortality and cardiovascular hospitalizations
• Indication: Symptomatic ATTR-CM (both wild-type and hereditary)
• GDMT tolerance: Avoid beta-blockers, calcium channel blockers, and ACE inhibitors if possible (narrow hemodynamic margin)
• Side Effects: Generally mild; mild-to-moderate elevation of liver enzymes possible

Acoramidis

• Newer TTR stabilizer; smaller study cohorts suggest efficacy
• Still in development; not yet FDA-approved for cardiac indication

AL Amyloidosis: Treatment Overview

Backbone: Plasma Cell-Directed Therapy

Goal is to eradicate pathogenic plasma cell clone and reduce circulating light chains.

Standard of Care: Daratumumab-Based Induction

• Daratumumab + CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone): Now preferred induction for newly diagnosed AL
• Superior hematologic response rates vs. older regimens
• Improved cardiac biomarkers (troponin, NT-proBNP) in responders
• Recent FDA approval and European Medicines Agency endorsement

Alternative Regimens

• Bortezomib-based regimens (e.g., CyBorD without daratumumab) for high-risk patients
• Melphalan-based therapy if transplant ineligible
• Proteasome inhibitors, immunomodulatory agents, and novel agents in development

Stem Cell Transplantation (SCT)

• Role: High-dose melphalan with autologous stem cell rescue; considered for transplant-eligible patients after induction therapy
• Eligibility: Age less than 70 years (relative), adequate organ function, deep hematologic response to induction
• Outcomes: Can achieve durable complete hematologic remission and organ response
• Monitor cardiotoxicity: Cardiology evaluation essential before and after SCT

Heart Failure Management in Cardiac Amyloidosis

General Approach: Narrow Hemodynamic Margin

Amyloid hearts are exquisitely sensitive to changes in preload, afterload, and contractility. Aggressive diuresis and guideline-directed medical therapy often poorly tolerated.

Diuretics (First-Line)

• Loop diuretics: primary therapy for volume overload
• Thiazide agents for maintenance
• Use cautiously: over-diuresis leads to hypotension and azotemia
• Mineralocorticoid receptor antagonist (spironolactone) may be considered carefully

AVOID or Use with Caution

• Beta-blockers: Can precipitate cardiogenic shock; only if atrial fibrillation rate control essential and close monitoring available
• Calcium channel blockers (verapamil, diltiazem): Directly toxic to amyloid heart; contraindicated
• ACE inhibitors and ARBs: Narrow therapeutic window; can worsen renal function due to glomerular filtration dependence
• Digoxin: Binds amyloid fibrils; no benefit; risk of toxicity

SGLT2 Inhibitors and Novel HF Therapies

• Limited data in amyloidosis; use cautiously pending more evidence
• May have benefit in HFpEF phenotype (emerging data)

Arrhythmia Management

Atrial Fibrillation (AF)

• Prevalence: 50–70% in ATTR-CM; variable in AL-CM
• Anticoagulation: Recommended even in paroxysmal AF (high thromboembolism risk)
• Rate vs. Rhythm Control: Symptom-directed; rhythm control with amiodarone considered in some cases
• Catheter Ablation: Can be effective in select cases; early ablation may prevent heart failure progression

Bradyarrhythmias and Conduction Abnormalities

• Pacemaker indications: Standard indications apply; amyloid-infiltrated conduction system may necessitate pacing earlier than expected
• Close ECG and Holter monitoring to detect progression

Ventricular Arrhythmias

• Prevalence: Uncommon despite extensive infiltration; fibrosis may isolate damaged tissue
• ICD considerations: Limited data on efficacy; reserved for secondary prevention or high-risk AL

Prognosis and Staging

AL Amyloidosis: Mayo Staging (2004)

Based on cardiac biomarkers (troponin, NT-proBNP):

• Stage I: Both TnI and NT-proBNP below thresholds; median survival approximately 26 months
• Stage II: One abnormal biomarker; median survival approximately 10 months
• Stage III: Both abnormal; median survival approximately 2 months (untreated)

With modern therapy, survival has improved substantially but stratification remains useful.

ATTR-CM: NAC Staging

• Based on NT-proBNP, estimated glomerular filtration rate, and cardiac biomarkers
• Identifies candidates for advanced heart failure therapies and transplantation

Boston University Staging (AL)

• Incorporates BNP, troponin, and differences between involved and uninvolved free light chains
• Prognostic even in transplant candidates

Advanced Therapies: Transplantation and Mechanical Support

Heart Transplantation

• Indication: Select patients with advanced heart failure refractory to medical and device therapy
• AL-CM: Transplant alone adequate if excellent hematologic response (or after stem cell transplantation) achieved
• ATTRv-CM (hereditary): Heart and liver transplantation preferred (removes source of TTR production); heart alone considered if acceptable hematologic response on tafamidis pre-transplant
• Outcomes: Improved survival vs. historical controls; mean survival approximately 10 years post-transplant

Contraindications to Transplantation

• Severe extracardiacs (severe neuropathy, GI dysfunction, renal failure)
• High-grade albuminuria in AL (suggests aggressive systemic disease)
• Uncontrolled disease in AL (inadequate plasma cell response)

Mechanical Circulatory Support (MCS)

• Left ventricular assist device (LVAD): Limited role due to small left ventricular cavity and biventricular involvement; carefully selected cases as bridge to transplant
• Extracorporeal membrane oxygenation (ECMO): Bridge therapy in acute cardiogenic shock

Palliative Care

• Essential component for all advanced disease, regardless of transplant candidacy
• Goals of care discussions, symptom management, psychosocial support
• Integrates geriatric principles and caregiver support

Multidisciplinary Care Model

Essential Team Members

• Cardiologists (general and amyloidosis specialist): Diagnosis, cardiac imaging, heart failure management, transplant candidacy
• Hematologists and Oncologists: Monoclonal protein assessment, plasma cell-directed therapy, stem cell transplantation
• Geneticists: Variant interpretation, cascade testing counseling, management of asymptomatic carriers
• Nephrologists: Kidney manifestations, proteinuria, glomerular filtration rate monitoring, dialysis planning
• Neurologists: Polyneuropathy evaluation, autonomic dysfunction, neuropathic pain management
• Gastroenterologists: Gastrointestinal involvement assessment, nutritional optimization
• Palliative care specialists: Goals of care, symptom management, end-of-life planning
• Nurses, dietitians, pharmacists: Education, coordination, medication management

Communication and Coordination

• Regular case conferences to coordinate care
• Shared decision-making with patients and families
• Single point of contact (care coordinator) to streamline communication

Key Do's and Don'ts

Useful Calculators and Risk Assessment Tools

The following calculators help stratify risk, assess heart failure severity, and guide clinical decision-making in cardiac amyloidosis patients: