What are the signs and symptoms of cardiac amyloidosis?

Signs and Symptoms of Cardiac Amyloidosis

The cardinal signs and symptoms of cardiac amyloidosis include heart failure symptoms (dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, exercise intolerance), syncope/presyncope, arrhythmias, and extracardiac manifestations such as carpal tunnel syndrome, peripheral neuropathy, and autonomic dysfunction. 1

Cardiac Manifestations

Heart Failure Symptoms

• Dyspnea (shortness of breath)
• Orthopnea (difficulty breathing when lying flat)
• Paroxysmal nocturnal dyspnea
• Exercise intolerance
• Fatigue
• Peripheral edema (leg swelling)
• Bloating 1

Cardiovascular Signs

• Hypotension or normotension in previously hypertensive patients
• Intolerance to standard heart failure medications (ACE inhibitors, ARBs, beta blockers)
• Dizziness/lightheadedness
• Syncope (fainting)
• Palpitations 1

Arrhythmias and Conduction Abnormalities

• Atrial fibrillation
• AV blocks
• Bundle branch blocks
• Ventricular arrhythmias 1

Extracardiac Manifestations

Neurological

• Peripheral sensorimotor polyneuropathy (paresthesias and weakness)
• Autonomic dysfunction:
  • Orthostatic hypotension
  • Erectile dysfunction
  • Sweating abnormalities
  • Postprandial diarrhea alternating with constipation
  • Gastroparesis
  • Urinary retention and incontinence 1, 2

Musculoskeletal/Soft Tissue

• Bilateral carpal tunnel syndrome (particularly common in males with ATTR)
• Lumbar spinal stenosis
• Spontaneous biceps tendon rupture
• History of orthopedic procedures
• Macroglossia (enlarged tongue)
• Periorbital purpura (bruising around eyes)
• Submandibular gland enlargement 1, 2

Gastrointestinal

• Early satiety
• Weight loss
• Abdominal pain
• Nausea
• Constipation
• Diarrhea 2

Laboratory and Diagnostic Findings

Electrocardiographic Abnormalities

• Low voltage in limb leads (less common in ATTR than AL amyloidosis)
• Pseudoinfarct pattern (QS waves in V1-V3)
• Poor R-wave progression
• Conduction abnormalities
• Discordance between QRS voltage and wall thickness on imaging 1

Biomarkers

• Elevated cardiac troponins (persistent low-level elevation)
• Elevated NT-proBNP (disproportionately high compared to degree of heart failure)
• Abnormal free light chains ratio (in AL amyloidosis) 1

Echocardiographic Features

• Left ventricular wall thickening with normal cavity size
• Right ventricular thickening
• Atrial wall thickening
• Valve thickening
• "Sparkling" or granular appearance of myocardium
• Restrictive filling pattern
• Reduced longitudinal strain with apical sparing pattern
• Pericardial effusion 1, 3

Important Clinical Considerations

1. Red Flags for Early Detection:

   • Heart failure with preserved ejection fraction in patients ≥65 years
   • Aortic stenosis in patients ≥65 years (particularly low-flow, low-gradient type)
   • Unexplained increased left ventricular wall thickness
   • Resolution of previously documented hypertension 1

2. Diagnostic Pitfalls:

   • Cardiac amyloidosis is frequently misdiagnosed as:
     • Hypertrophic cardiomyopathy
     • Generic heart failure with preserved ejection fraction
     • Acute coronary syndrome (due to elevated troponins and ECG changes) 1, 4

3. Population Considerations:

   • Wild-type ATTR amyloidosis: More common in older males
   • Variant ATTR amyloidosis: Consider in patients with family history of polyneuropathy or cardiomyopathy
   • AL amyloidosis: Consider in patients with monoclonal gammopathy or multiple myeloma 1

Early recognition of these signs and symptoms is critical, as treatment effectiveness depends on initiating therapy before irreversible organ damage occurs 2. The combination of cardiac and extracardiac manifestations should raise suspicion for cardiac amyloidosis, particularly in older patients with heart failure with preserved ejection fraction.