Amyloidosis of the heart
Author Ольга Кияница
A myaloidosis is a general definition for a group of diseases that are united by deposition of amyloid protein in various tissues and organs. Today, more than 20 amyloid precursors are known, which, under favorable circumstances, are deposited in various parts of the body.
Amyloid has a fibrillar structure, which was determined by studying the protein under an electron microscope.
Heart amyloidosis is characterized by rapid progression, so treatment is most effective in the early stage of the disease. If adequate therapy is not carried out, then in one month the wall of the heart may thicken by 1.5 mm or more, and this threatens with very fast heart failure and death (after about 6 months).
Video: What is amyloidosis, how is it dangerous, how to deal with it?
Description of amyloidosis
The term “amyloidosis” refers not to a single pathology, but to the totality of diseases in which protein-based infiltration is deposited in the tissues as beta-pleated sheets. The subtype of the disease is determined by which protein is precipitated, although dozens of subtypes are described, most of them are incredibly rare or have trivial significance.
The correct nomenclature uses the letter “A” for amyloid, followed by the letter (s) related to the main deposited protein.For example, light chain amyloidosis is “AL” (“A” for amyloid and “L” for light chain). Transthyretin amyloidosis is defined as “ATTR” (“A” for amyloid and “TTR” for transthyretin). Terms such as “primary amyloidosis,” “secondary amyloidosis,” “senile amyloidosis,” and “familial amyloid cardiomyopathy” often lead to confusion, so they are best avoided.
Overwhelmingly, cardiac amyloidosis is caused by one of two proteins: light chains or transthyretin. The clinical manifestations and treatment of these two subtypes are different.
Light chain amyloidosis (AL-amyloidosis)
It is the most commonly diagnosed form of systemic amyloidosis. Also previously defined as “primary amyloidosis,” but for the reasons given above, this name will not be used.
Plasma cells are found primarily in the bone marrow and produce large amounts of antibodies. Antibodies consist of heavy chains and light chains. When a plasma cell becomes clonal (essentially becomes malignant), it and its clones usually produce a clonal antibody and a clonal excess of the light chain associated with this antibody. In this process there are three possible outcomes:
- A plasma cell clone takes over a small portion of the bone marrow, and the light chain is harmlessly excreted in the urine.This condition is called monoclonal gammapathy of indeterminate significance.
- A plasma cell clone absorbs most of the bone marrow, which potentially leads to hypercalcemia, anemia, lytic lesions and / or renal dysfunction. This condition is called myeloma.
- A plasma cell clone produces a light chain that is prone to improper replacement with beta-pleated sheets (β-folded layer). These light chains circulate in the bloodstream and precipitate in one or more tissues. This condition is called AL amyloidosis.
AL amyloid deposits can occur in almost any tissue, and the nature of organ involvement varies from patient to patient (Table 1).
Common non-lethal lesions and associated manifestations are as follows:
- kidneys (albuminuria and potential renal failure);
- liver (increased alkaline phosphatase and potential liver failure);
- gastrointestinal tract (dysphagia, constipation, malabsorption and bleeding);
- language (macroglossia);
- nervous system (peripheral neuropathy and autonomic dysfunction).
In extremely rare cases, the clinical participation of all these organs and systems is determined in one patient.
Table 1: Amyloid Subtypes and Clinical Characteristics
|Subtype||Demography||Organ involvement||Left ventricular hypertrophy||Therapy|
|AL||M ≈ F Age 40-80||Any (heart, kidney, GM, tongue, nerves, liver, soft tissue)||+||Chemotherapy or stem cell transplantation|
|Wild type (wild type) ATTR M||>>> F Age 65-95||Heart (carpal tunnel syndrome)||+++||Supportive therapy, clinical trials underway.|
|Mutant ATTR||M >> F Age 55-75||Heart and Nerves (Carpal Tunnel Syndrome)||+++||Supportive therapy, clinical trials underway.|
Cardiac manifestations in amyloidosis are as follows:
- Heart failure (HF), which can be diastolic and systolic.
- Arrhythmias (tachyarrhythmias / bradyarrhythmias).
The main symptom is ventricular hypertrophy , observed during echocardiography with a very low voltage electrocardiogram (ECG).
Natriuretic peptides usually increase with cardiac amyloidosis, and troponin assays are often chronically positive at low levels (0.1-1 ng / ml) due to the continued gradual destruction of cardiomyocytes.
Transthyretin amyloidosis (ATTR-amyloidosis)
Transthyretin (prealbumin) is a protein produced by the liver that functions as a transporter of thyroxine and retinol. It predominantly circulates as a homotetramer with a small amount of transthyretin, which is in monomeric form. This form of transthyretin is susceptible to improper replacement and is gradually deposited in the form of amyloid deposits.
There are two main subtypes of ATTR amyloidosis:
- Wild type ATTR
- Mutant ATTR.
In the case of wild-type ATTR, transthyretin protein is normal ( non-mutated ). Over the decades, it is gradually deposited in the form of amyloid accumulations. Although a small amount of deposits can occur in soft tissues (causing carpal tunnel syndrome) and the vascular network, the primary pathological deposits are determined in the heart.
Mutant type ATTR of amyloidosis of the heart is a hereditary disease. When it is determined by pathological mutations in transthyretin gene, which leads to accelerated deposition of amyloid. Mutant ATTR most often affects nerve fibers, and the pattern of deposition largely depends on the mutation.
Diagnosis of heart amyloidosis
The final diagnosis of amyloidosis requires a biopsy . The abdominal fat is often chosen for the procedure, since this place is characterized by easy accessibility and low morbidity. However, this part of the body has a relatively low sensitivity, so even in positive cases, inadequate amyloid deposits are typical for the final subtype of the disease (ATTR, AL, etc.). Thus, biopsy of the organ involved in the pathological process is practiced (i.e. the heart if cardiac amyloidosis is suspected).
When conducting an endomyocardial biopsy, almost 100% reliable results are given on the presence or absence of amyloidosis of the heart.
Determining the subtype of amyloidosis of the heart can be performed by immunofluorescence or samples are sent to the laboratory for mass spectrometry. If there is any doubt about the diagnosis based on immunofluorescence staining, mass spectrometry should be performed.
Additional laboratory tests for AL-amyloidosis can determine another organ dysfunction:
- alkaline phosphatase concentration;
- the number of circulating light chains.
Light chain concentration tests may be useful as a presumptive diagnosis before a biopsy is performed. In particular, the normal value of circulating light chains makes the diagnosis of AL-amyloidosis unlikely. So similar studies are needed to control the response to chemotherapy.
With ATTR-amyloidosis, genetic testing is performed to determine the transthyretin gene. The presence of a pathological mutation can affect the options for clinical trials, the prediction of organ involvement, and indicate a putative relationship with family members.
Electrocardiography is an important study in any form of cardiac amyloidosis. With its help, ventricular hypertrophy is detected. Hypertrophy in amyloidosis is the deposition of amyloid fibrils, not the hypertrophy / hyperplasia of myocytes.This explains the reduced ECG voltage, and not increased, as is the case with typical hypertrophy.
Magnetic resonance imaging of the heart is also performed if amyloidosis is suspected. In particular, the global transmural or subendocardial distribution of cardiac tissue can be determined.
Echocardiography - deformations and basal, apical-dominant disturbances are often determined.
Video: Heart in amyloidosis
Heart amyloidosis treatment
Treatment of AL-amyloidosis is carried out according to two parallel strategies:
- Elimination of the effects of organ dysfunction, that is, symptomatic therapy.
- Slowing the progression of the disease, for which clonal plasma cells are killed (and, consequently, the number of circulating pathological light chains is reduced). Chemotherapy is used for this.
It is practiced in all forms of amyloidosis, taking into account a number of important points:
- The emphasis is on regulating the volume of fluid in the body. Diuretics are used for this and salt is restricted.
- Digoxin binds to amyloid fibrils, which leads to potential digoxin toxicity, even at normal circulating levels, so this drug is usually avoided.
- If necessary, control over arrhythmia. At the same time, neurohormonal antagonists commonly used for HF are often poorly tolerated and are counterproductive.
- Beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers often lead to hypotension (due to autonomic dysfunction and the presence of a small cavity of the left ventricle with the impossibility of increasing the volume).
- Additionally, beta-blockers often aggravate the course of bradyarrhythmias.
Pacemakers are necessary with a high prevalence of the disease and a decrease in the quality of conductivity (especially with ATTR-amyloidosis). Atrial fibrillation is quite common among patients with cardiac amyloidosis and is often poorly tolerated. Such a condition requires cardioversion and / or antiarrhythmic therapy (most often amiodarone).Ventricular arrhythmias and sudden cardiac death are common among this category of patients.
Historically, the implantation of a cardioverter-defibrillator (CVD) has not gained universal acceptance because of the poor prognosis associated with cardiac amyloidosis. More recent evidence suggests that ARCs can be an effective part of the management strategy for patients with amyloidosis of the heart. In particular, the implantation of the device prolongs life for 1 year or more.
Since cardiac amyloidosis is an irreversible disease and can often be associated with severe symptoms and high mortality rates, heart transplantation is considered as a treatment for individual patients. Additionally, the following are taken into account:
- In the treatment of patients with AL amyloidosis, the possibility of significant involvement of other vital organs is excluded. In addition, cardiac transplantation must be accompanied by a strategy based on chemotherapy to control the production of light chains.
- With ATTR-amyloidosis, significant neurological involvement of patients with familial forms should be excluded.
In all cases, it is recommended to perform transplantation only in centers that have a practice of heart transplantation in patients with amyloidosis.
Over the past decade, the possibilities of chemotherapy for the treatment of AL-amyloidosis have noticeably improved, so that in most patients a significant reduction (and sometimes complete normalization) of the number of circulating pathological light chains is achieved.
Chemotherapy usually consists of a combination of several classes of antineoplastics. In particular, it is used:
- alkylators (e.g. melphalan or cyclophosphamide);
- steroids (for example, dexamethasone);
- proteasome inhibitors (for example, bortezomib or carfilzomib);
- immunomodulators (for example, lenalidomide or pomalidomide).
An alternative strategy involves stem cell transplantation (stem-cell transplant) against the background of high-dose chemotherapy with an alkylating agent. A stem cell transplant can be an effective method for reducing light chains, and is therefore used by many centers.
It is important to note that the only randomized trial comparing stem cell therapy with standard chemotherapy showed that the graft produced lower results. Also, when using standard chemotherapy methods, faster improvements are noted, therefore stem cell transplantation is rarely performed, only in some cases.
Since ATTR-amyloidosis is not a malignant process, chemotherapy does not play such an important role as in the case of AL-amyloidosis. Although the disease modifying drugs have not been approved yet, some drugs have been studied for the treatment of ATTR-amyloidosis, some of which are in the late stages of clinical evaluation. These include the following:
- Diflunisal . This nonsteroidal anti-inflammatory drug, which is approved for the treatment of arthritis, stabilizes the tetrameric form of transthyretin. A randomized study demonstrated a slower progression of the disease among patients with polyneuropathy due to mutant ATTR-amyloidosis. Since nonsteroidal anti-inflammatory drugs are relatively contraindicated in CH, this medicine is hardly a good option in the presence of amyloid cardiomyopathy.
- Tafamidis (Tafamidis). This drug is approved in some countries of the world (Europe and Japan) for the treatment of mutant ATTR-amyloidosis, causing polyneuropathy, but it is not approved in the United States.
- RNA interference . Two drugs that work through interfering RNA or RNA interference (reduction of transthyretin production by the liver) are in phase 3 studies of ATTR-amyloidosis, complicated by both polyneuropathy and cardiomyopathy.
The prognostic conclusion for amyloidosis depends primarily on the severity of heart damage. In AL-amyloidosis, the level of circulating light chains is also important. Since the possibilities of chemotherapy have expanded significantly in recent years, the prognosis for AL-amyloidosis has improved markedly. Also, the average life expectancy of most patients, including many of those who have significant heart damage, is already measured not in months, as before, but in years.
The prognosis for ATTR-amyloidosis is usually better than for AL-amyloidosis, although both forms of the disease still have a high annual mortality rate.
For AL amyloidosis, various prognostic decision systems have been proposed, with a focus on the extent of heart damage. A widely used forecasting system, published in 2004, was based solely on two cardiac biomarkers:
- troponin (T or I);
- pro-natriuretic N-terminal peptide b-type.
Thus, the continuous improvement of chemotherapy regimens from the period of the initiated studies of the pathological condition will increase the survival of patients with cardiac amyloidosis.
- Attitudes to amyloidosis of the heart have changed markedly over the past decade, with a greater number of patients being diagnosed, and the therapeutic capabilities have markedly improved.
- Diagnostic signs of cardiac amyloidosis include atypical ventricular hypertrophy with a low ECG voltage, unexplained HF and characteristic dysfunction of other organs.
- The final diagnosis is based on a biopsy of the affected organ, and this study is also crucial for the final subtyping of amyloid deposits (for example, AL and ATTR).
- In AL-amyloidosis, treatment should begin immediately, using the principles of chemotherapy or stem cell transplantation.
- With ATTR-amyloidosis, patients are often registered to participate in one of the ongoing clinical trials.
- Treatment of the heart in amyloidosis is primarily based on the use of diuretics and arrhythmic drugs.
- In some cases, the possibility of implantation of CVD or heart transplantation is considered.
Since cardiac amyloidosis often requires the participation of doctors of various specialties, the patient is usually recommended to contact an amyloidosis center.
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