Cardiac Amyloidosis: Symptoms, Types, Causes and Treatment

Cardiac amyloidosis is a complex and often underdiagnosed condition where misfolded proteins—known as amyloid—accumulate in the heart, leading to serious consequences for cardiac structure and function. As advances in imaging and targeted therapies emerge, understanding the spectrum of symptoms, diverse types, underlying causes, and modern treatments is crucial for both clinicians and patients. This comprehensive article aims to demystify cardiac amyloidosis, providing clear, evidence-based information in an accessible format.

Symptoms of Cardiac Amyloidosis

Cardiac amyloidosis often presents subtly, and its symptoms can mimic those of more common heart conditions, making early detection challenging. Recognizing the hallmark and associated features is vital for timely intervention and improved outcomes.

Key Symptom	Description	Associated Features	Sources
Heart failure	Shortness of breath, fatigue, edema	Worse on exertion or lying down	2 3 5
Arrhythmias	Irregular heartbeat, palpitations	Atrial fibrillation, conduction issues	4 5
Chest discomfort	Pressure or angina-like pain	Often during exertion	2 3
Peripheral signs	Leg/abdominal swelling, foamy urine, bruising	Tingling/numbness, carpal tunnel	2 5 8

Table 1: Key Symptoms

Heart Failure and Fluid Retention

The most prominent symptom of cardiac amyloidosis is heart failure, especially with preserved ejection fraction. Patients often notice progressive shortness of breath, which worsens with physical activity or when lying flat. Swelling of the legs and abdomen is common due to fluid retention, and weight gain may be masked by this fluid buildup. These symptoms reflect the heart's increasing stiffness, as amyloid deposits thicken the cardiac walls and restrict the heart's ability to fill and pump efficiently 2 3 8.

Arrhythmias and Conduction Disorders

Irregular heartbeats are common, with atrial fibrillation affecting up to 70% of patients at diagnosis. Conduction abnormalities, including atrioventricular (AV) block and sinus node dysfunction, may require pacemaker implantation. Patients are also at heightened risk for thromboembolic events, sometimes even without obvious arrhythmias 4 5.

Chest Discomfort and Angina

Many individuals with cardiac amyloidosis experience chest pressure or discomfort, particularly during exertion. This can be due to amyloid infiltration of the small blood vessels supplying the heart (microvascular angina) 2 3.

Peripheral and Systemic Features

The systemic nature of amyloidosis means symptoms may extend beyond the heart. These can include:

• Carpal tunnel syndrome (often preceding cardiac symptoms)
• Tingling, numbness, or weakness in hands and feet (peripheral neuropathy)
• Orthostatic hypotension (dizziness upon standing)
• Proteinuria causing foamy urine
• Unexplained bruising, especially around the eyes
• Weight loss masked by fluid retention 2 5 8

Being aware of these diverse features is critical, as they can serve as early warning signs—so-called "red flags"—for the diagnosis of cardiac amyloidosis.

Types of Cardiac Amyloidosis

The type of amyloid protein determines not only the clinical presentation but also the prognosis and approach to treatment. Accurate identification of the amyloid type is essential for effective management.

Type	Origin Protein	Typical Age/Onset	Sources
AL (Light-Chain)	Immunoglobulin light chains	Adults, any age	3 6 7
ATTRwt	Wild-type transthyretin (TTR)	Elderly (esp. >70–80 yrs)	1 3 12
ATTRv/m	Mutant/variant transthyretin	Middle age, hereditary	3 9 12

Table 2: Major Types of Cardiac Amyloidosis

AL (Light-Chain) Amyloidosis

AL amyloidosis is caused by an abnormal proliferation of plasma cells that produce excess immunoglobulin light chains. These misfolded light chains deposit as amyloid, frequently affecting the heart and kidneys. AL amyloidosis can occur at any adult age and typically has a rapid, aggressive course with poor prognosis if untreated 3 6 7.

ATTR (Transthyretin) Amyloidosis

ATTR amyloidosis stems from misfolded transthyretin, a transport protein produced by the liver. There are two main forms:

• Wild-type ATTR (ATTRwt): Formerly called "senile systemic amyloidosis," this variant affects mainly older adults (often men over 70). It tends to progress slowly, with the heart as the primary organ involved 1 3 12.

• Variant or Mutant ATTR (ATTRv/m): Caused by inherited mutations (over 100 identified) in the TTR gene, this form can present in younger or middle-aged individuals, with a strong hereditary component. Certain mutations, such as Val122Ile, are particularly prevalent in specific populations (e.g., up to 4% of African Americans) 3 9 12.

Other Rare Forms

Cardiac involvement is extremely rare in secondary (AA) amyloidosis and other uncommon amyloid types, and these are typically not the focus in cardiac presentations 6 10.

Causes of Cardiac Amyloidosis

Understanding the root causes of cardiac amyloidosis helps clarify why and how the disease develops, as well as who is most at risk.

Cause	Underlying Mechanism	At-Risk Groups	Sources
Plasma cell dyscrasia	Overproduction of light chains	AL amyloidosis patients	3 7 8
TTR gene mutation	Misfolded transthyretin protein	Hereditary ATTR	1 12
Aging/liver production	Instability of wild-type TTR	Elderly (esp. men)	9 12

Table 3: Causes of Cardiac Amyloidosis

Plasma Cell Disorders (AL Amyloidosis)

AL amyloidosis is driven by an abnormal clone of plasma cells in the bone marrow, which secrete excess immunoglobulin light chains. These light chains misfold and aggregate, depositing in various organs, especially the heart and kidneys. The underlying plasma cell disorder is often similar to multiple myeloma, but with a typically lower tumor burden 3 7 8.

Transthyretin Protein Instability (ATTR Amyloidosis)

Transthyretin is a normal blood protein produced by the liver. In ATTR amyloidosis:

• Wild-type ATTR (ATTRwt): In older individuals, the normal TTR protein becomes unstable, misfolds, and forms amyloid fibrils. This is a non-hereditary, age-related process 9 12.
• Variant ATTR (ATTRv): Inherited mutations in the TTR gene result in a structurally abnormal, unstable protein that is more prone to misfolding and aggregation. Disease onset and severity depend on the specific mutation. Some mutations are strongly associated with cardiac involvement, while others may cause neurologic symptoms 1 12.

Additional Triggers and Factors

• Genetic susceptibility: Certain populations, such as African Americans, have a higher prevalence of the Val122Ile TTR mutation, increasing their risk for hereditary ATTR amyloidosis 12.
• Other forms: Secondary (AA) amyloidosis, associated with chronic inflammation, almost never affects the heart in a clinically significant way 6.

Treatment of Cardiac Amyloidosis

Treatment strategies for cardiac amyloidosis have advanced rapidly in recent years, transforming what was once considered a uniformly fatal disease into a condition with meaningful therapeutic options. The approach depends on the amyloid type and the organs affected.

Therapy Type	Approach/Medication	Target Amyloid Type	Sources
Supportive	Diuretics, standard HF care	All types	3 8 14
Anti-plasma cell	Chemotherapy, stem cell transplant	AL	7 8 9
TTR stabilizers	Tafamidis, diflunisal	ATTR	8 9 11
TTR silencers	Patisiran, inotersen	ATTR	8 9 11
Cardiac devices	Pacemakers, ICDs	Severe conduction issues	4 5 14
Transplant	Heart ± bone marrow/liver tx	Select cases	8 14

Table 4: Treatment Approaches

Supportive and Symptom-Directed Therapy

All patients benefit from symptom management:

• Diuretics are used to control fluid overload, but doses must be carefully balanced to avoid low blood pressure and kidney dysfunction.
• Standard heart failure medications (like beta-blockers and ACE inhibitors) require caution and are often poorly tolerated due to low blood pressure or conduction disease 3 8 14.

Disease-Modifying Therapies

For AL Amyloidosis:

• Anti-plasma cell therapy is the cornerstone of treatment. Options include chemotherapy regimens (e.g., bortezomib, cyclophosphamide, dexamethasone) and, in eligible patients, autologous stem cell transplant.
• Early diagnosis and prompt initiation of therapy are critical, as cardiac involvement predicts poorer outcomes 7 8 9.

For ATTR Amyloidosis:

• Transthyretin stabilizers (e.g., tafamidis, diflunisal) bind to the TTR protein, preventing its dissociation and subsequent misfolding. Tafamidis, in particular, has demonstrated a mortality benefit in ATTR-CA.
• TTR gene silencers (e.g., patisiran, inotersen) are RNA-based therapies that reduce hepatic production of both mutant and wild-type TTR. These are especially beneficial for patients with neuropathic symptoms but are emerging for cardiac disease as well 8 9 11.
• Investigational therapies including monoclonal antibodies aim to directly clear amyloid deposits and are under active study 3.

Device Therapy and Advanced Options

• Pacemakers may be required for severe conduction system disease or AV block.
• Implantable cardioverter-defibrillators (ICDs) are controversial; their benefit is less established in amyloidosis compared to other forms of heart disease 4 5 14.
• Transplantation: In select patients, heart transplantation (sometimes combined with bone marrow or liver transplantation, depending on amyloid type) can be considered, but patient selection is stringent 8 14.

Multidisciplinary Care and Monitoring

Optimal management requires a team approach, including cardiologists, hematologists, neurologists, and genetic counselors. Ongoing monitoring for progression and treatment side effects is essential, as is genetic counseling for families affected by hereditary forms 13 14.

Conclusion

Cardiac amyloidosis is an increasingly recognized cause of heart failure and arrhythmia, often masquerading as more common conditions. Early detection, precise typing, and tailored therapy are critical to improving patient outcomes. Advances in both diagnosis and treatment are transforming the landscape for those affected by this once-intractable disease.

Key Takeaways:

• Cardiac amyloidosis presents with heart failure, arrhythmias, and systemic symptoms that require a high index of suspicion for diagnosis.
• The two major types—AL and ATTR—differ in underlying cause, affected populations, and treatment approach.
• Timely, accurate typing (AL vs. ATTR) is essential, as therapy is protein-specific.
• Disease-modifying therapies, especially tafamidis and plasma cell-directed regimens, have improved outcomes, but early intervention remains critical.
• Multidisciplinary care and ongoing research offer hope for continued progress in the management of this challenging disease.