Transthyretin cardiac amyloidosis: an update on treatment

Transthyretin Cardiac Amyloidosis: Overview

Misfolded liver-made transthyretin protein forms amyloid deposits in the heart muscle, causing stiffness, poor relaxation, and heart failure in transthyretin cardiac amyloidosis (ATTR-CM), a progressive and generally underdiagnosed heart ailment. It is inherited (owing to genetic changes) or wild-type (age-related, mainly in men over 70).

Progressive, incurable, and life-threatening ATTR-CM can occur randomly or run in families. Fortunately, new diagnostics and potential treatments are increasing outcomes and life expectancies.

Transthyretin Cardiac Amyloidosis

ATTR-CM types

Hereditary TTR gene mutations. Symptoms may appear in the 30s–50s. It affects the heart and nerves, is hereditary, and is more prevalent among individuals of African descent, as well as those from Portugal, Brazil, Sweden, and Japan.

Wild-type (wtATTR-CM): Normal TTR misfolds are age-related, usually in men over 70. Mostly heart-related, with associations to carpal tunnel syndrome, spinal stenosis, and tendon ruptures.

Common Cardiac Amyloidosis Symptoms

Symptoms of Heart

• Shortness of breath (active or resting)
• Edema in legs, ankles, or abdomen from fluid buildup
• Multiple-day fatigue and weakness
• Abnormal heartbeat (atrial fibrillation, bradycardia, ventricular tachycardia)

Pain in the chest like angina

• Conduction anomalies cause syncope or dizziness.

Red Flag and Systemic Symptoms

• Carpal tunnel syndrome (often precedes heart symptoms)
• Hand/foot tingling, numbness, discomfort
• Autonomic neuropathy (dizziness, low blood pressure when standing)
• Lumbar spinal stenosis or biceps tendon tear
• Kidney-related protein in urine
• Cachexia or weight loss without explanation

Complications

• Restrictive cardiomyopathy (stiff heart muscle limits filling)
• Conduction blockages, atrial fibrillation
• Combined heart-kidney dysfunction
• Atrial fibrillation/clot risk stroke
• Untreated progressive heart failure reduces survival.

Progressing symptoms

• Early weariness, slight breathlessness, and carpal tunnel. Misdiagnosed as hypertension or ageing.
• Intermediate: Swelling, palpitations, neuropathy. Conduction illness, arrhythmias
• Advanced. Cachexia, fainting, and severe breathlessness. Heart failure, stroke, sudden death

Diagnosis

• Early suspicion: ECG or echocardiography revealing thicker heart walls.
• Tests to confirm:
• Nuclear scintigraphy or cardiac MRI (for amyloid deposits).
• A heart or fat pad biopsy.
• Genetic testing (hereditary vs. wild-type).

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An ATTR therapy

Key Treatment Guidelines

• Disease-Changing Therapies:
• Tafamidis (Vyndamax/Vyndaqel) is the conventional ATTR-CM treatment, lowering mortality and hospitalizations. Acoramidis (Attruby) is ATTR-CM-approved.
• Vutrisiran, Patisiran, Inotersen, and Eplontersen are approved for hereditary ATTR (hATTR) with polyneuropathy.

Supportive/Symptomatic Care:

• Heart Failure (ATTR-CM): Volume control requires diuretics. Many beta-blockers are poorly tolerated.
• Arrhythmias: Atrial fibrillation requires anticoagulation; Amiodarone is preferred over Digoxin.
• Polyneuropathy (hATTR): Painkillers, PT, and nutrition help.
• Gene silencers have replaced liver transplantation as the main treatment for hATTR to reduce mutant TTR production.
• Genetic counseling: All ATTR patients should be screened for hereditary (hATTR) or wild-type (wtATTR).
• Light Chain (AL) amyloidosis requires different treatment, so it must be ruled out first.

Key Risks and Considerations

• Underdiagnosis: Elderly heart failure patients sometimes mistake ATTR-CM for other heart diseases.
• The median survival time after cardiac symptoms is 3–5 years without treatment.
• Early detection is key to effective treatment.

ATTR-CM causes

1. Wild-type ATTR

• Cause: Age-related protein homeostasis failure.
• Mechanism: As people get older, normal TTR protein becomes unstable, dissociates into monomers, and misfolds into amyloid fibrils.
• Carpal tunnel syndrome, spinal stenosis, and tendon ruptures
• Progressive cardiac muscle amyloid deposition causes restrictive cardiomyopathy.

It grows spontaneously with age, not inherited.

2. ATTRv variant

• Protein instability is caused by TTR gene mutations.
• Mutations make TTR tetramers unstable and subject to dissociation and misfolding.
• Family-based autosomal dominant inheritance.
• Common Mutations:
• Val122Ile (V142I): Found in ~3.4% of African Americans; highly associated to cardiac amyloidosis.
• Neuropathy and cardiac involvement are common in Portugal, Sweden, and Japan with Val30Met (V50M).
• Amyloid deposits in the heart and nerves cause cardiomyopathy and polyneuropathy.

Pathophysiology

• Normal TTR is a stable tetramer.
• Health Issue:
• Age or mutation makes the tetramer unstable.
• Splits monomerically.
• Amyloid fibrils form from monomers.
• The heart muscle stiffens and functions poorly due to fibrils.

How is transthyretin cardiac amyloidosis diagnosed?

The video understanding of ATTR-CM

Diagnostics for ATTR

1. Clinical Suspicion

• Warning signs: Unexplained thickening of heart walls, HFpEF, carpal tunnel syndrome, spinal stenosis, tendon ruptures, and neuropathy.
• For wild-type ATTR, elderly males (>70 years) are at risk; for hereditary ATTR, a family history or genetic risk is present.

2. Initial Tests

• ECG: Low voltage despite thicker heart walls.
• Echocardiogram: Concentric left ventricular thickness, diastolic dysfunction, “sparkling” myocardium.
• Eliminate AL amyloidosis with serum/urine immunofixation and free light chain testing.

3. Advanced Imaging

• Amyloid infiltration is detected by a late gadolinium enhancement on a cardiac MRI.
• Radionuclide bone scintigraphy (technetium-99m pyrophosphate scan): ATTR-specific and sensitive. Uptake in the heart without monoclonal proteins strongly implies ATTR.

4. Biopsy if needed

• Heart, stomach fat pad, salivary gland, or rectal tissue.
• To confirm and type amyloid deposits (ATTR vs AL).
• Note: Rarely needed if imaging and lab tests are positive.

5. Genetic Testing

• Detects TTR gene mutations for hereditary ATTR (ATTRv).
• Differentiates wild-type ATTR (age-related, non-hereditary) from variant ATTR (genetic).
• Mutation-related family screening: Recommended.

Age of Onset by Amyloidosis Type

ATTRv is a highly varied condition that can affect individuals from late teens to very old age. The severity of the condition varies depending on factors such as mutation, family history, and genetics. Mutations like Val30Met cause symptoms in the 20s–40s, whereas others show later. Non-penetrance allows family members to carry the mutation without symptoms.

AtTRwt: Usually beyond 70, particularly in men. Misfolding of normal transthyretin protein with age. Before cardiac symptoms, it is frequently associated with conditions, including carpal tunnel syndrome or spinal stenosis.

AL Light Chain Amyloidosis: Median age ~64 years. Caused by plasma cell issues. Young patients rarely start before 40, with a median age of 37.

AA Amyloidosis: Any age, generally younger. This is secondary to chronic inflammatory illnesses, such as rheumatoid arthritis and infections. Condition determines onset.

Important Considerations

• Genetic variability matters: Genetic modifiers, gender, and parent of origin might vary onset in hereditary ATTR even within the same family.
• Uninherited wild-type ATTR occurs spontaneously in older adults.
• Though rare, examples under 40 show the necessity of investigating AL amyloidosis in younger patients with unexplained organ failure.
• Surveillance carriers: Experts urge clinical surveillance for hereditary ATTR 10 years before the estimated age of onset based on family history.

What are the warning signs of cardiac amyloidosis?

Heart failure symptoms that don't fit the norm may indicate cardiac amyloidosis. Doctors seek cardiac and systemic indications that suggest amyloid accumulation rather than heart disease.

• Key Warning Signs
• Cardiac clues
• HFpEF despite thicker heart walls.
• Low ECG voltage is present despite echocardiography showing left ventricular hypertrophy.
• Arrhythmias or conduction disorders (atrial fibrillation, AV block) without explanation.
• Beta-blocker or ACE inhibitor intolerance for heart failure.

Systemic Hints

• Carpal tunnel syndrome (years before cardiac symptoms).
• Biceps tendon rupture or lumbar stenosis.
• Neuropathy (numbness, tingling, pain in hands/feet).
• Orthostatic hypotension, gastric motility difficulties.
• Kidney dysfunction or proteinuria (particularly in AL amyloidosis).

Clinical Patterns

• An elderly man with thicker heart walls and unexplained cardiac failure.
• The patient has HFpEF and carpal tunnel surgery.
• A history of neuropathy or cardiomyopathy suggests inherited ATTR.

What doctors treat amyloidosis?

• Common Specialists
• Haematologist/Oncologist
• Treats light-chain AL amyloidosis, which is connected to aberrant plasma cells.
• Manages chemotherapy and stem cell transplants.
• Cardiologist
• Cardiovascular amyloidosis requires ATTR-CM or AL.
• Treats heart failure, arrhythmias, and advanced therapy like tafamidis and transplant.
• Neurologist
• This condition is often associated with nervous system amyloidosis, also known as hereditary ATTR.
• Treats neuropathy, autonomic dysfunction, and symptoms.
• Nephrologist
• Treats renal disease, notably AL/AA amyloidosis.
• Treats proteinuria, renal failure, and dialysis.
• Geneticist

Important for hereditary ATTR amyloidosis.

• Offers genetic counselling, family screening, and mutation analysis.
• Amyloidosis multidisciplinary centres
• Specialised centres, including haematologists, cardiologists, neurologists, and nephrologists, help many patients.

Final stages of amyloidosis?

• Amyloidosis causes end-stage cardiac failure, renal failure, and systemic decline by damaging several organs, usually the heart and kidneys. Since organ loss is usually irreparable, treatment focuses on palliative care and symptom management.

Final Stages

1. Heart Involvement

• Severe heart failure with resting breathlessness.
• Arrhythmias and conduction blockages cause fainting or cardiac death.
• Pulmonary edema, limb swelling, and abdominal swelling result from fluid excess.
• Cardiogenic shock or circulatory collapse often kills.
• Studies suggest that two-thirds of cardiac amyloidosis deaths are cardiovascular, mostly from heart failure or sudden cardiac death.

2. Renal Involvement

• End-stage renal failure results in an inability to filter waste.
• Uremia or dialysis dependency.
• Proteinuria and edema lower life quality.

3. Liver, Nervous System

• Liver failure with jaundice, ascites, or portal hypertension.
• Pain, numbness, and autonomic dysfunction (low blood pressure, digestive difficulties) from severe neuropathy.

End-Stage Disease Symptoms

• Extreme weariness and weakness.
• Severe leg, abdominal, and lung swelling.
• Breathing issues even when resting.
• Vertigo, fainting, or bewilderment.
• Weight loss, cachexia.
• Standard heart or kidney medicine intolerance.

Important Considerations

• Prognosis: Untreated AL amyloidosis with cardiac involvement has a median life of less than 1 year; ATTR has a longer survival rate but is still limited by severe heart failure.
• Most patients die from progressive heart failure or sudden cardiac death, but renal and systemic problems also contribute.
• Palliative care, symptom alleviation, and comfort are the goals. Disease-modifying medicines lose their effectiveness when organs suffer severe damage.

Conclusion 

Misfolded proteins produce organ amyloid deposits in amyloidosis, a dangerous, degenerative illness. Impact varies by type:Misdiagnosis is common because symptoms resemble heart failure or neuropathy. Early detection is crucial. AL is treated with chemotherapy, ATTR with TTR stabilisers like tafamidis or gene-silencing treatments, and AA with anti-inflammatory management. After end-organ failure (heart, kidneys, liver, nerves), palliation and quality of life are prioritized.