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Cardiac amyloidosis

March 5, 2024 — published by Pyramidale Communication

Key numbers on cardiac amyloidosis

Cardiac amyloidosis is now the leading cause of restrictive cardiomyopathy in Western countries. Autopsy studies have revealed the presence of fibrillar transthyretin deposits in the hearts of 25% of elderly individuals.^1,2

What is cardiac amyloidosis?

Cardiac amyloidosis is a heterogeneous group of rare diseases characterized by the extracellular accumulation of insoluble amyloid fibrils. The location and type of amyloid deposits determine the clinical manifestations and organ damage, affecting the heart, kidneys, peripheral nervous system, and digestive tract. Amyloid infiltration of the heart leads to myocardial thickening, often described as “hypertrophy”, which can result in heart failure and conduction abnormalities.^3-5

Two proteins are responsible for the three types of cardiac amyloidosis:
The most common form, primary AL amyloidosis, accounts for more than 60% of cases of cardiac amyloidosis and affects approximately 10% of individuals over the age of 60. It is caused by the acquired overproduction of immunoglobulin light chains, LC (kappa or lambda) in the context of monoclonal gammopathy or multiple myeloma.
Hereditary transthyretin (hATTR) amyloidosis, also known as familial amyloidosis, is caused by a mutation in the transthyretin (TTR) gene. The resulted protein TTR is mainly synthesized by the liver that transports thyroxine and vitamin A. This form is characterized by misfolding of the protein.
ATTRwt or wild type, formerly known as senile amyloidosis, is caused by the misfolding and aggregation of wild-type TTR. The underlying pathophysiological mechanisms are not yet fully understood.^4-5
Secondary AA amyloidosis, a less common form, arises from infectious, inflammatory, or malignant diseases and results from the aggregation of acute-phase reactants such as serum amyloid A.^3-8

Although AL amyloidosis has long been considered the most prevalent form of cardiac amyloidosis, ATTR forms have been underestimated. Systemic AL amyloidosis remains the most frequently observed form in Western countries. For example, in France, the incidence is estimated at 500 to 700 new cases per year. However, the ePACT study estimated that 4,815 patients were diagnosed with transthyretin amyloid cardiomyopathy between 2011 and 2017.^2-3,9

The prognosis of cardiac amyloidosis is poor, making early diagnosis and management essential. In ATTR amyloidosis, median survival after the first episode of heart failure is less than 4 years without treatment. In AL amyloidosis, median survival is approximately 6 months after cardiac diagnosis in the absence of treatment.^4,10

Diagnostic criteria and medical care

The clinical manifestations of cardiac amyloidosis are heterogeneous and nonspecific, which makes diagnosis challenging. Common symptoms include those of heart failure summarized as EPOF: Exertional dyspnea, Physical weight gain, Oedema, and Fatigue, as well as rhythm and conduction disorders (palpitations, dizziness, syncope).
In wild-type amyloidosis, progressive renal failure and a history of carpal tunnel syndrome preceding the onset of heart failure symptoms have been reported. In hereditary ATTR amyloidosis, ophthalmologic manifestations, such as amyloid vitreous opacities, have also been described.
Macroglossia is a characteristic manifestation of AL amyloidosis, and periorbital ecchymoses caused by amyloid deposits in blood vessels may also be observed.^2–3,8

The diagnosis of cardiac amyloidosis follows the Gillmore algorithm, which includes biological tests, particularly cardiac and renal biomarkers, imaging tests (cardiac MRI, bone scintigraphy), screening for gammopathy, tissue biopsy to detect amyloid deposits, and genetic testing to confirm the presence of a transthyretin gene mutation.^3,10–12

“The clinical presentation is often misleading. In at least one-third of cases, the initial diagnosis is incorrect. Examples include hypertensive heart disease, heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, ischemic heart disease, and common aortic stenosis. These diagnostic errors are regrettable because, in the meantime, the amyloidosis process continues, causing irreversible damage.”

Interview with Dr. J.-C. Eicher, cardiologist

To learn more about cardiac amyloidosis, listen to Dr. Eicher’s explanations on RARE à l’écoute, the podcast dedicated to rare diseases, by clicking here.

The therapeutic management of cardiac amyloidosis depends on the type of amyloidosis (AL or ATTR) and the severity of organ involvement. In AL amyloidosis, chemotherapy aims to suppress the plasma cells responsible for overproducing immunoglobulin light chains, which aggregate into amyloid fibrils. In ATTR amyloidosis, transthyretin stabilizers are prescribed to limit fibril formation by maintaining the protein’s physiological conformation, while therapies that suppress amyloidogenic TTR synthesis are under investigation.^2-4,8

Heart failure treatment in amyloidosis focuses on relieving congestive symptoms, primarily through diuretics. Fluid and salt intake must be carefully controlled. Standard heart failure guidelines are not fully applicable in amyloidosis: beta-blockers are contraindicated as they reduce cardiac output and may worsen conduction disorders. The high risk of thromboembolic events justifies anticoagulation in severe amyloidosis and in the presence of arrhythmias. Given the progressive and infiltrative nature of the disease, regular monitoring for rhythm and conduction disorders is required. When appropriate, implantation of a pacemaker or defibrillator should be discussed with expert center. Finally, heart transplantation may be considered in selected patients under the age of 65 with cardiac amyloidosis and severe heart failure.^3-4,11

Management is multidisciplinary and involves various specialists depending on the organs affected. Therapeutic education is also essential and is available in centers dedicated to amyloidosis.^3-5,9

“The term ‘amyloidosis’ is still little known, even among cardiologists. We need to raise awareness among physicians and general practitioners (who are usually the first to make a diagnosis) that this disease exists and is not rare. The earlier it is detected, the better the prognosis.”

Interview with Mr. Houlot, member of the French Association Against Amyloidosis

To learn more about patient initiatives and associations, listen to Mr. Houlot’s testimony on RARE à l’écoute, the podcast dedicated to rare diseases. Click here to listen.

Would you like to learn more about cardiac amyloidosis?

Click here to listen to the season dedicated to cardiac amyloidosis on our RARE medical Podcast – RARE à l’écoute.

Listen to interviews with experts (Dr. J.-C. Eicher, Prof. T. Damy, Prof. O. Lairez, and Dr. F. Le Bras), as well as a testimony from Mr. Houlot, a patient and active member of the French Association Against Amyloidosis (AFCA).

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