Cardiac amyloidosis: recognition, diagnosis and management

SUMMARY

Cardiac amyloidosis is an under-recognised but treatable condition characterised by insoluble protein deposition in the heart and is associated with high morbidity and mortality. It is most commonly caused by transthyretin (known as transthyretin [ATTR] amyloidosis) but may also be caused by a plasma cell dyscrasia (known as light chain [AL] amyloidosis).

Cardiac amyloidosis should be suspected in patients with heart failure and other suggestive features (e.g. carpal tunnel syndrome, peripheral and/or autonomic neuropathy), particularly in those aged over 65 years. Findings from a standard work-up for heart failure may raise the possibility of cardiac amyloidosis, such as unexplained cardiac biomarker elevation or left ventricular wall thickening on an echocardiogram.

Early investigation can begin in primary care. Monoclonal protein testing is essential to exclude AL amyloidosis, which requires urgent haematology review and treatment. Standard heart failure assessment should also be undertaken if not already performed. Patients with suspected cardiac amyloidosis should be promptly referred to a cardiologist or amyloidosis centre for confirmatory testing, which, in most cases, can be done noninvasively.

Treatment of ATTR includes disease-modifying therapies (tafamidis, vutrisiran) and heart failure management, predominantly with diuretics and sodium-glucose co-transporter 2 inhibitors. All patients with atrial fibrillation or atrial flutter should be anticoagulated regardless of CHA₂DS₂-VA score.

Early recognition, timely referral and multidisciplinary care are essential to improve outcomes.

 

Introduction

Amyloidosis is an umbrella term describing conditions characterised by insoluble protein deposition in tissues and organs.¹ Although localised amyloidosis can occur, systemic involvement is more common and often results in multiorgan disease, requiring specialised multidisciplinary care for diagnosis and management. Clinical features, severity and prognosis vary depending on the type of amyloid and the organs involved. Although multiple organs may be affected (heart, peripheral nerves, kidneys, musculoskeletal and gastrointestinal systems), cardiac involvement has the highest morbidity and mortality among all amyloidosis types.²

Amyloid diseases are named after the causative protein, with more than 35 different types identified in humans.³ In cardiac amyloidosis, 98% of cases are caused by either transthyretin, a predominantly liver-produced transport protein (transthyretin [ATTR] amyloidosis), or abnormal immunoglobulin light chains from a plasma cell dyscrasia (light chain [AL] amyloidosis).⁴ AA amyloidosis (serum amyloid A or secondary amyloidosis) is associated with chronic inflammatory conditions and infections but is now less prevalent with specific treatment of the underlying conditions and rarely causes cardiac amyloidosis.³

The subtypes of cardiac amyloidosis cannot be distinguished based on clinical presentation, organ involvement or nonspecific cardiac imaging (i.e. echocardiography or cardiac magnetic resonance imaging). Formal diagnostic assessment is required to confirm amyloidosis and accurately identify the subtype.

Although the diagnosis of cardiac amyloidosis, particularly ATTR amyloidosis, has increased significantly in the past decade, many cases remain unrecognised because of nonspecific presentation, with diagnostic delays often exceeding a year.^1,5,6 ATTR amyloidosis is now the most common form of cardiac amyloidosis, but its true prevalence remains unknown. ATTR amyloidosis is present in up to 1 in 6 patients with either heart failure with preserved ejection fraction (HFpEF) or degenerative aortic stenosis.⁷ AL amyloidosis is uncommon (10 cases per million and increasing in an ageing population),^3,8 but can present as rapidly progressive severe heart failure requiring urgent diagnosis and treatment.

Disease-modifying therapies in cardiac amyloidosis have dramatically improved survival, with earlier initiation associated with better outcomes. General practitioners (GPs) play an integral role in early recognition, timely referral, ongoing treatment and care coordination.

This article focuses on the recognition, diagnosis and management of ATTR amyloidosis.

 

Subtypes of ATTR amyloidosis

There are 2 subtypes of ATTR amyloidosis: variant or hereditary (ATTRv), caused by destabilising gene variants (mutations) in the transthyretin (TTR) gene; and wild-type (ATTRwt), which, although poorly understood, is likely due to age-related changes resulting in misfolding of the normal TTR protein and predominantly affects older adults but can present in midlife.⁹ Australian estimates suggest 10% of people with ATTR carry a gene mutation, but international studies show higher rates.^10,11

 

Clinical presentation of ATTR amyloidosis

The clinical presentation of ATTR amyloidosis is variable and nonspecific. The commonest presentation is dyspnoea and fatigue, often associated with heart failure.¹² ATTR-related heart failure is usually with preserved ejection fraction (HFpEF), but one-third of patients have heart failure with reduced ejection fraction (HFrEF). ATTR amyloidosis may also manifest as atrial fibrillation, exercise intolerance or symptomatic bradycardia (Box 1).¹

Noncardiac features include polyneuropathy, gastrointestinal tract symptoms and autonomic dysfunction (Box 1).^13-15 Notably, ATTR amyloidosis is often preceded by musculoskeletal manifestations (e.g. carpal tunnel syndrome, spinal canal stenosis) up to a decade prior to a diagnosis of heart failure.⁷

 

Diagnosis of cardiac amyloidosis

Cardiac amyloidosis cannot easily be distinguished from other more common cardiac pathologies, so a high degree of clinical suspicion is required to make a timely diagnosis. The steps to diagnosing cardiac amyloidosis are as follows:

1.    Identify patients who may have cardiac amyloidosis (GP or non-GP specialist led).

2.    Initiate initial investigations (GP or non-GP specialist led).

3.    Confirm diagnosis of amyloidosis (non-GP specialist led).

Identify patients who may have cardiac amyloidosis

Clinicians should suspect cardiac amyloidosis in patients with heart failure, especially HFpEF (either newly diagnosed or established), who have any additional features of amyloidosis (Box 1), following a thorough history and assessment.¹⁶ The majority of patients with cardiac amyloidosis (particularly ATTRwt) are over 65 years of age, so suspicion should be particularly high in this group.

Findings from a standard work-up for heart failure may raise the possibility of cardiac amyloidosis (Box 2). These include unexplained increased left ventricular wall thickness or atrial enlargement on echocardiography and persistently elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin concentrations without an identifiable cause. Low QRS voltage on electrocardiography that is disproportionate to the degree of left ventricular wall thickening further supports the diagnosis, although it is more common in AL amyloidosis. Importantly, the presence or absence of these findings does not confirm or exclude cardiac amyloidosis.

Initiate initial investigations

Once cardiac amyloidosis is suspected, the first and most critical step, which should be initiated by the clinician who first suspects cardiac amyloidosis, is to exclude AL amyloidosis by assessing for a monoclonal protein (Figure 1). This is because management is different for AL and ATTR amyloidosis, and cardiac involvement in AL amyloidosis has a poor prognosis (as little as 6 months in advanced disease), requiring urgent haematological review.¹⁷ AL amyloidosis is confirmed by the presence of a circulating monoclonal protein (a precursor of AL amyloid), which requires serum and urine electrophoresis with immunofixation and testing of serum free light chains. It is only when all of these tests have been performed and are negative for monoclonal protein that AL amyloidosis can be excluded with 98% certainty.¹⁸ These tests attract a Medicare rebate.

Concurrently, patients should undergo standard cardiac assessment for heart failure if not already performed, including NT-proBNP and troponin testing, electrocardiography and transthoracic echocardiography.

Patients should also be referred for cardiology review when cardiac amyloidosis is suspected, and referral should not be delayed while awaiting completion of investigations. Early cardiology review can expedite further diagnostic assessment while investigations to distinguish AL from ATTR amyloidosis are underway.

Confirm diagnosis of amyloidosis

Because confirmation of cardiac amyloidosis requires specific testing, patients with suspected disease should be referred promptly to a cardiologist or amyloidosis centre. Confirmatory testing includes a monoclonal protein assessment (if not yet performed) and cardiac bone scintigraphy (Figure 2). Cardiac bone scintigraphy is a noninvasive nuclear imaging test that detects tracer uptake in the myocardium, which is highly suggestive of ATTR amyloid deposition, although positive findings can also occur in other forms of amyloidosis (including AL amyloidosis).¹⁹

In most cases, a noninvasive diagnosis of ATTR cardiomyopathy can be made with a positive bone scan and negative monoclonal protein studies (Figure 2). However, up to 30% of patients will have both a positive bone scan and a monoclonal protein (often monoclonal gammopathy of undetermined significance [MGUS], which is common in older adults).²⁰ In these patients, AL amyloidosis cannot be excluded without tissue biopsy, and urgent haematology referral is required. Importantly, an abnormal or positive monoclonal protein assessment warrants urgent haematology review, regardless of bone scan results.

Biopsy may include the heart, bone marrow or tenosynovial tissue (e.g. carpal tunnel). Fat pad biopsy has low sensitivity, particularly in ATTRwt, and has a limited role.³ Amyloidosis is confirmed with Congo red staining of biopsied tissue, with further testing required (immunohistochemistry or mass spectroscopy) to definitively identify the amyloid subtype.³

ATTRv and ATTRwt cannot be distinguished clinically; therefore, guidelines recommend genetic testing for all patients with confirmed ATTR amyloidosis, regardless of age.³

Incidental cardiac uptake on bone scintigraphy performed for other indications (e.g. fractures, arthritis, metastatic malignancy) and using other bone scintigraphy tracers (see Figure 2 footnote) is suggestive but not diagnostic of ATTR amyloidosis.²¹ Patients require complete assessment, including dedicated cardiac bone scintigraphy and laboratory testing to exclude AL amyloidosis, as discussed above.

 

Management of ATTR amyloidosis

Once the diagnosis and subtype of cardiac amyloidosis are confirmed, timely initiation of disease-modifying therapy is critical and is initiated by either a cardiologist or an amyloidosis centre. Long-term care has 3 pillars (Figure 3): disease-modifying therapy, heart failure management and multidisciplinary supportive care.

Disease-modifying therapy

Disease-modifying therapy should be commenced by a cardiologist or an amyloidosis centre as soon as possible following diagnosis, because earlier treatment initiation is associated with greater benefit. Notably, these therapies slow disease progression rather than reverse established disease, so patients should expect stabilisation of symptoms rather than improvement. At the time of writing, 2 therapies are subsidised on the Pharmaceutical Benefits Scheme (PBS) for ATTRv (tafamidis and vutrisiran), whereas tafamidis is the only therapy subsidised for ATTRwt; however, vutrisiran was recommended for PBS listing for ATTRwt in July 2026.²²

Tafamidis stabilises the transthyretin protein, reducing further amyloid fibril formation and deposition.²³ Tafamidis has been shown to reduce cardiovascular hospitalisations and mortality, with greater survival benefit with earlier initiation.^23,24 It is taken orally and is usually well tolerated, but there is a risk of rhabdomyolysis with some concomitant statin therapy (atorvastatin above 40 mg or rosuvastatin above 20 mg); alternative statin therapy or statin dose reduction may be required.⁷

Vutrisiran is approved for ATTRv patients with polyneuropathy and, after recent approval by the Australian Therapeutic Goods Administration, a patient access program is available for patients with ATTR cardiomyopathy (both ATTRwt and ATTRv). This small interfering RNA acts in the liver to silence the TTR gene and reduce transthyretin production. Trials have demonstrated a reduction in neuropathy progression, cardiovascular events and mortality, as well as an improvement in quality of life.^25,26 Vutrisiran requires subcutaneous administration every 3 months, and patients require daily vitamin A supplementation because of the risk of vitamin A deficiency. Patisiran, a closely related intravenous drug, is planned for Australian market withdrawal.

Many disease-modifying therapies for ATTR are on the horizon, with several in or having completed phase 3 trials, including monoclonal antibodies that target the removal of transthyretin deposits and gene-editing therapy that aims to permanently silence the TTR gene using CRISPR (clustered regularly interspaced short palindromic repeat) technology.⁷

Heart failure management

Cardiac amyloidosis typically causes restrictive, low-output heart failure regardless of ejection fraction.⁷ Importantly, heart failure therapy for amyloidosis differs from standard guideline-directed therapy and is not differentiated by ejection fraction. Patients with cardiac amyloidosis have a narrow euvolaemic window and are susceptible to both fluid overload and dehydration, requiring careful diuretic titration and regular review with a GP or heart failure services.

Diuretics are the cornerstone of therapy. Loop diuretics (e.g. furosemide) are typically first line; bumetanide may be required at higher doses or with diuretic resistance. Mineralocorticoid receptor antagonists (e.g. spironolactone) are often used, with a signal towards mortality benefit in retrospective analyses.²⁷ Thiazide diuretics may be necessary for refractory congestion but carry risks of renal impairment, over-diuresis and hypokalaemia.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are commonly used in ATTR cardiomyopathy. These are well tolerated, reduce diuretic requirements and have been shown to improve survival, as well as cardiovascular and renal outcomes, in nonrandomised studies.^7,28

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have not shown a benefit in ATTR, and their use is frequently limited by hypotension and the risk of renal injury.⁷ There are limited data on angiotensin receptor–neprilysin inhibitors (ARNIs), with similar limiting complications.

Beta blockers can be problematic due to chronotropic incompetence (clinically seen as exertional intolerance) and autonomic dysfunction, but may be tolerated at a low dose, particularly for rate control in atrial fibrillation or in patients with reduced ejection fraction.^7,27

Calcium channel blockers are relatively contraindicated due to their negative inotropic effect and affinity to bind amyloid fibrils.¹⁶

Cardiac amyloidosis is associated with high rates of atrial arrhythmias, intracardiac thrombi and stroke, with studies demonstrating that clinical risk scores are poor predictors of thromboembolic events.²⁹ Anticoagulation is recommended for all patients with atrial arrhythmias, regardless of CHA₂DS₂-VA score. Yearly Holter monitoring is recommended because bradyarrhythmias and tachyarrhythmias are common, and cardiac devices are often required.³

Select patients under 70 years of age without significant extracardiac involvement may be considered for heart transplant after amyloidosis multidisciplinary review.¹⁶

Ongoing shared care with heart failure services is recommended to support diuretic titration, rehabilitation, patient education and multidisciplinary follow-up, with telehealth where appropriate to improve access and reduce hospitalisations. Patient education should cover medication adherence, symptom monitoring and lifestyle modification strategies.

Multidisciplinary supportive care

Given the multisystem, chronic nature of cardiac amyloidosis, GPs are central to management, including symptomatic care and care coordination. Multidisciplinary amyloidosis care can optimise symptoms and quality of life.

 

Conclusion

ATTR amyloidosis is the most common form of cardiac amyloidosis but remains under-recognised and under-diagnosed. GPs play a central role in identifying at-risk individuals who require timely assessment and referral. Early diagnosis and treatment, including multidisciplinary supportive care, are critical to improving patient outcomes.

 

Key practice points

This article was finalised on 28 August 2026.

Conflicts of interest: Natasha Gorrie has received speaker fees from Pfizer and Novartis, and travel and accommodation support from Pfizer. Natasha is a member of the Cardiac Society of Australia and New Zealand (CSANZ) Education Committee and the Australian Amyloidosis Network (AAN) Advocacy and Research Subcommittee.

Elyn Montgomery is a recipient of a St Vincent’s Clinic Research Foundation Grant.

Georgia McCaughan has received honoraria from Johnson & Johnson, Pfizer and Arrotex.

Antonia Carroll has received honoraria for educational lectures from Pfizer and Medison, as well as advisory fees from Pfizer, Alnylam and Medison. Antonia was involved in the development of the American Society of Haematology 2026 guidelines on diagnosis of light chain amyloidosis and the 2025 International Society of Amyloidosis expert panel guidelines on supportive care for systemic amyloidosis. Antonia is a member of the AAN Communications and Membership Subcommittees.

Nicole Bart has received advisory fees and/or speaker fees from Pfizer, BridgeBio, Novo Nordisk, Bristol Myers Squibb and Medison. Nicole has received research funding from Pfizer via the Victor Chang Cardiac Research Institute and from BridgeBio. Nicole was an author on the 2023 World Heart Federation consensus on transthyretin amyloidosis cardiomyopathy, the 2020 CSANZ position statement on COVID-19 and acute heart failure, and the 2025 Journal of the American College of Cardiology expert consensus statement on cardiac amyloidosis in older adults with a focus on frailty. Nicole is the CSANZ Heart Failure Stream Lead and a member of the AAN and CSANZ cardiac amyloidosis subcommittees.

This article is peer reviewed.

 

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