How to recognize amyloidosis as a cause of heart failure?

New ESC Recommendations

Patients with heart impairment caused by amyloid deposits have long been underdiagnosed. New, increasingly available diagnostic approaches and therapeutic options, however, can improve the bleak state of patients with amyloidosis. In 2021, a working group of the European Society of Cardiology (ESC) created a detailed document aimed at helping cardiologists correctly recognize and treat patients with cardiac amyloidosis.

What type of amyloid can be expected in cardiac amyloidosis?

Cardiac amyloidosis most often arises on the basis of light chain immunoglobulin (AL) amyloidosis or in the form of transthyretin amyloidosis (ATTR). Transthyretin amyloidosis is further divided into wild-type (>90% of cases) and hereditary, caused by mutated transthyretin. Both types of amyloid deposits are deposited in the extracellular space of the myocardium and in the walls of blood vessels.

Ejection fraction in heart failure due to amyloidosis

In the diagnosis of patients with cardiac amyloidosis, we typically find ourselves in the preserved left ventricular ejection fraction (LVEF) band, that is, >50%. LVEF values can even be very high (>65-70%), which is pathognomonic for cardiac amyloidosis and hypertrophic cardiomyopathy due to a decrease in the end-diastolic volume of the left ventricle.

In which patients does suspicion of cardiac amyloidosis arise?

The main criterion raising suspicion of cardiac amyloidosis in patients with heart failure is a left ventricular wall thickness >12 mm upon echocardiographic examination, accompanied by one or more of the following factors:

• Heart failure at age ≥65 years
• Aortic stenosis at age ≥65 years
• Newly developed arterial hypotension or normotension after a previous period of hypertension
• Autonomic and sensory nervous system dysfunction
• Peripheral polyneuropathy
• Proteinuria
• Increased formation of subcutaneous hematomas
• Bilateral carpal tunnel syndrome
• Biceps tendon rupture
• Abnormalities in cardiac magnetic resonance imaging (MRI): delayed gadolinium enhancement (LGE)
• Abnormalities in ECG examination
• Positive family history

These warning signs, red flags, should prompt doctors to further targeted search for symptoms of amyloidosis.

How to differentiate the various subtypes of amyloidosis?

Some hematological laboratory tests and special diagnostic methods can help us in determining the specific subtype of amyloid.

To diagnose AL amyloidosis, it is necessary to examine serum levels of free light chains kappa and lambda and perform serum and urine electrophoresis with immunofixation. Further diagnostic methods such as heart MRI and DPD (^99mTc-3,3-diphosfono-1,2-propanodicarboxylic acid) or HMDP (^99mTc-hydroxymethylenediphosphonate) scintigraphy with single-photon emission computed tomography (SPECT) are essential in recognizing transthyretin-based amyloidosis.

The gold standard in diagnosis is a biopsy proof of amyloid in the myocardium. Nowadays, it may be omitted if scintigraphy shows positivity of the 2nd-3rd degree, hematological tests are normal, and genetic testing confirms an amyloidogenic mutation of the transthyretin gene.

Basic recommendations for the treatment of cardiac amyloidosis

The main goal of treatment for patients with heart failure caused by amyloidosis is the maintenance of euvolemia. If patients are symptomatic, we administer loop diuretics, possibly together with mineralocorticoid receptor antagonists. On the contrary, calcium channel blockers are not indicated in patients with cardiac amyloidosis since they can cause severe hypotension and fatigue or form complexes with amyloid. Amyloid deposits can also be stored in the myocardium of the atria, leading to electromechanical dissociation with an increased risk of embolic events; therefore, patients should be secured with anticoagulant therapy.

Treatment of the underlying cause, namely amyloidosis, significantly depends on the type of amyloid. Treatment of AL amyloidosis is aimed at eliminating the pathological plasma cell clone through chemotherapy or autologous stem cell transplantation. In contrast, in the treatment of ATTR, stabilization of the transthyretin protein tetramer and reduction of its production is dominant, which is currently feasible with pharmacotherapy.

Conclusion

The growing population, aging population, and increasing number of comorbidities lead to expectations of up to a 50% increase in the number of hospitalized patients with heart failure in the next 25 years. Therefore, it is essential to consider rare causes of heart failure, as their treatment options are continually expanding.

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Sources:
1. Garcia-Pavia P., Rapezzi C., Adler Y. et al. Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur J Heart Fail 2021 Apr; 23(4): 512-526, doi: 10.1002/ejhf.2140.
2. McDonagh T. A., Metra M., Adamo M. et al.; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021 Sep 21; 42(36): 3599-3726, doi: 10.1093/eurheartj/ehab368.