Cardiac Amyloidosis

Cardiac amyloidosis is an infiltrative disease characterized by amyloid deposition in the extracellular spaces of the myocardium. It can be part of a systemic amyloid disease or develop independently. The clinical picture is heterogeneous and depends on which organ is affected. In the case of the heart, symptoms are mainly those of unilateral or even biventricular heart failure. Diagnosis is based on the results of biochemical tests, imaging and biopsy methods.

Etiopathogenesis
Amyloidosis is a systemic infiltrative disease associated with the deposition of insoluble forms of proteins (amyloids) in the extracellular spaces of tissues of various organs, including the heart. It is one of the most common causes of restrictive cardiomyopathy. Amyloidoses are classified into several types according to the amyloid precursor proteins. The most common types are AL and TTR amyloidosis.

In AL amyloidosis deposition of monoclonal kappa or lambda light chain occurs. Amyloid precursor proteins are produced by defective plasma cells. It may be accompanied by multiple myeloma. In each case, some type of monoclonal gammopathy is present in these patients.

TTR amyloidosis (TTR protein is produced primarily in the liver) is divided into senile, where the precursor is wild-type transthyretin, and familial, where the precursor is mutant TTR protein. Transthyretion physiologically serves as a transporter of thyroid hormones and vitamin A derivatives.

Clinical picture
The clinical picture of the different types of cardiac amyloidosis is heterogeneous. In general, the predominant symptoms are signs of biventricular heart failure, reduced exercise tolerance and low blood pressure. Pleural effusion, hepatomegaly and ascites are often observed on physical examination. In some cases, a history of bilateral carpal tunnel syndrome or rupture of the musculus biceps brachii tendon may point to amyloidosis.

AL amyloidosis most commonly manifests after the age of 50 and affects all organ systems except the CNS. The heart is affected in 50% of cases. Clinically, this type manifests as rapidly progressive bilateral heart failure with predominance of right-sided manifestations. Patients also describe angiosis symptoms (due to amyloid deposition in the vessel walls).

Senile TTR amyloidosis in turn primarily affects the heart. In the familial form, the heart is also predominantly affected, along with the peripheral and autonomic nervous systems. Senile TTR amyloidosis manifests mainly after the age of 70 (but a diagnosis around the age of 40 is not uncommon).

Familial amyloidosis is an autosomal dominant disease with high penetrance. The gene encoding the TTR protein is mutated. The primary manifestation is neuropathy and very often cardiac involvement, which is influenced by the specific type of mutation (in some mutations the primary involvement is cardiovascular or neurological, or mixed). The disease first appears in patients in a wide range of ages from 20 to 70+ years.

Diagnostics
The diagnosis of amyloidosis is based on the clinical picture and the analysis of blood and biopsy samples. Serum levels of free kappa or lambda light chain (AL amyloidosis) are important in distinguishing the type of amyloidosis. Definitive diagnosis is based on the evaluation of the biopsy specimen. In the case of cardiac muscle involvement, it is not always necessary for the patient to undergo an endomyocardial biopsy. According to the current diagnostic criteria, biopsy verification in extracardiac tissue (in the presence of signs of cardiac involvement clinically, on imaging, or in the laboratory) is sufficient. Thus Endomyocardial biopsy is used more when isolated cardiac amyloidosis is suspected or in other specific situations.

The specific type of amyloidosis is determined by immunohistochemistry, which is important for specific treatment. However, the typing of amyloidosis is not always straightforward due to various factors, e.g. the presence of other physiologically occurring structures (glycosaminoglycans, etc. In addition to immunohistochemical methods, mass spectrometry is also used to distinguish between familial and senile forms of amyloidosis. Genetic testing is also used in TTR amyloidosis.

AL amyloidosis has a rather specific pattern on ECG, unfortunately not always present. It is low voltages in the limb leads, an anterior wall infarct pattern and grade I AV block. Echocardiography usually reveals a size-normal to small left ventricle, ventricular wall hypertrophy and increased myocardial echogenicity due to extracellularly deposited amyloid. Because amyloidosis is a common cause of restrictive cardiomyopathy, an increase in left ventricular filling pressures is also detected. The diagnosis includes magnetic resonance imaging. This reveals diffuse subendocardial late gadolinium enhancement (LGE) associated with myocardial tissue changes in most cases.

In contrast to AL amyloidosis, voltages in the limb leads are often normal in TTR amyloidosis. Nonspecific conduction disturbances, ST-T segment changes and atrial fibrillation are more likely to be present in up to 50%. There is also a higher incidence of left bundle branch block and higher grade AV block. The echocardiographic picture of TTR amyloidosis is similar to that of AL amyloidosis.

Treatment and prognosis
In cardiac amyloidosis, treatment is aimed at treating both the heart failure and the cause of the amyloid itself. In AL amyloidosis diuretics and aldosterone antagonists are primarily used in the treatment of heart failure. ACE inhibitors are often poorly tolerated (due to a combination of autonomic dysfunction and low cardiac output). In contrast, in TTR amyloidosis without autonomic neuropathy, low doses of ACE inhibitors are usually well tolerated. Due to arrhythmic manifestations, a pacemaker is sometimes indicated.

Specific treatment of AL amyloidosis targets plasma cells, including the use of chemotherapeutic agents and specific monoclonal antibodies. Reduction of serum light chain protein levels correlates with marked modification of heart failure manifestations. Autologous stem cell transplantationmay also be considered, but has limitations.

In TTR amyloidosis, the transthyretin tetramer stabilizer Tafamidis is already beginning to be used in clinical practice. Other agents are in the research phase. In both AL and TTR amyloidosis, heart transplantation is indicated in some cases.

Without treatment, the prognosis of AL amyloidosis is least favourable, especially in patients with heart failure, where survival is less than 9 months.

Related articles

 * Cardiomyopathy
 * Restrictive cardiomyopathy

Used literature

 * cited = 2021-12-27
 * cited = 2021-12-27
 * cited = 2021-12-27
 * cited = 2021-12-27