How do amyloid proteins deposit in the heart muscle?

How Amyloid Proteins Deposit in the Heart Muscle

Amyloid proteins deposit in the heart through a protein misfolding process where abnormal proteins accumulate in the extracellular space of the myocardium, causing architectural disruption, direct cytotoxicity to myocytes, and progressive organ dysfunction. 1

Mechanisms of Cardiac Amyloid Deposition

AL Amyloidosis Pathway

• Misfolded immunoglobulin light chains produced by clonal plasma cells or B-cell lymphoproliferative disorders form the amyloid deposits 1
• Lambda light chain isotype accounts for 75-80% of cases, with kappa isotype comprising the remainder 1
• These misfolded light chains circulate systemically and deposit in the cardiac extracellular space 2
• The deposits cause both architectural disruption and direct cytotoxicity to cardiac myocytes, leading to organ dysfunction and death 1

ATTR Amyloidosis Pathway

• Transthyretin (TTR) protein, normally produced by the liver to transport thyroid hormone and retinol, misfolds and forms amyloid fibrils 3
• In wild-type ATTR, normal TTR protein misfolds due to aging-related processes 1
• In hereditary ATTR, genetic mutations (over 130 variants exist) cause the TTR protein to become amyloidogenic and unstable 3, 4
• These misfolded TTR proteins aggregate and deposit in the myocardial extracellular space 2, 3

Pathophysiologic Consequences of Deposition

Myocardial Effects

• Amyloid infiltration in the myocardial interstitium disrupts myocyte function, increasing myocardial stiffness and impairing relaxation 5
• The deposits cause increased ventricular wall thickness with reduced chamber size, resulting in restrictive physiology 5
• Amyloid can also cause myocyte necrosis through oxidative stress, contributing to systolic dysfunction in advanced stages 6

Organ Tropism Mystery

• The mechanisms underlying why amyloid deposits preferentially in certain organs (organ tropism) remain poorly understood 1
• The heart and kidneys are the two most frequently affected organs in systemic AL amyloidosis 1
• ATTR amyloidosis more commonly affects the heart, peripheral nerves, and musculoskeletal system 7

Clinical Implications of Deposition Patterns

Cardiac-Specific Manifestations

• Amyloid deposits throughout the myocardium cause restrictive cardiomyopathy with diastolic dysfunction 5, 6
• Deposits in cardiac valves can lead to aortic stenosis, mitral regurgitation, and tricuspid regurgitation 8
• Infiltration of the conduction system causes heart block and arrhythmias including atrial fibrillation 3

Prognostic Impact

• Median survival in AL amyloidosis with cardiac involvement is only 13 months, dropping to 4 months once heart failure symptoms develop 7, 5
• Without treatment, ATTR amyloidosis with heart failure has a median survival of approximately 5 years 3
• The extent of cardiac disease independently predicts mortality in all forms of cardiac amyloidosis 9

Key Clinical Pitfall

A critical caveat: While the deposition process involves extracellular accumulation, the resulting damage includes both mechanical disruption from the physical presence of amyloid AND direct toxic effects on myocytes 1. This dual mechanism explains why cardiac dysfunction can progress even with relatively modest amyloid burden and why early treatment targeting the precursor protein is essential before irreversible myocyte damage occurs.