Cardiac amyloidosis may develop in various forms of systemic amyloidosis and implies deposition of inappropriately folded proteins in cardiac tissue. Symptoms depend on the underlying type and location of protein deposits, but in general, cardiomyopathy and heart failure are main manifestations. Accompanying symptoms related to kidneys, liver, nervous system and other organs are frequently present. The diagnosis is made exclusively by biopsy, while treatment mainly consists of supportive measures.
Patients with amyloidosis involving the heart may present with a plethora of symptoms and all systems should be thoroughly investigated to assess the scope of organ involvement, but also to exclude other more common conditions. Usually, fatigue and weakness associated with dyspnea and chest discomfort are frequently observed, together with weight loss, syncope, and dizziness. Because of progressive heart failure, reduced cardiac output usually leads to hypotension and arrhythmia may be noted as well, usually of atrial origin. Peripheral edema, as a result of protein deposition in the kidneys, frequently occurs, sometimes with severe proteinuria that may reach the criteria for nephrotic syndrome (>3 g/24h) . Pulmonary hypertension increased jugular venous pressure, and consequent hepatomegaly may be a common finding. Peripheral neuropathy, long-standing carpal tunnel syndrome, as well as sensory deficits and paresthesias of fingers and toes, can be seen in various percentages in patients with involvement of nervous tissue, most likely due to familial forms of amyloidosis. Macroglossia, dysphonia, and dysphagia are also reported , while skin manifestations such as increased rate of bruising and development of purpura in the periorbital area can also be seen in patients with systemic amyloidosis.
The first step in making a valid clinical suspicion toward amyloidosis that involves cardiac tissue is performing a full physical examination, which may reveal some key findings. A full cardiac examination together with electrocardiography (ECG) will reveal either a systolic rhythm without significant abnormalities, but atrial fibrillation, atrioventricular blocks and other forms of arrhythmia related to the atria may be encountered. Low voltage on the ECG is one of the hallmarks of cardiac amyloidosis, which can be seen in virtually all leads, most prominently on precordial . Heart sound is usually normal, without the appearance of S3 or S4. Apart from an examination of the heart, abdominal palpation may reveal a very large and hard liver, together with ascites and peripheral edema.
Guided by reported symptoms and findings during a physical examination, initial workup should comprise blood tests, urinalysis, with an emphasis on protein levels and levels of cardiac-specific enzymes. Levels of troponin should be measured in all patients complaining of progressive chest pain, dyspnea and showing signs of heart failure, and in most cases, mild elevations are observed, as a result of slowly progressive myocardial necrosis and ischemia of smaller blood vessels. In fact, elevated troponin levels have shown to be a factor of worse prognosis in several studies , together with brain natriuretic peptide (BNP), which may also be elevated.
Echocardiography is one of the key imaging studies in further differentiating cardiac amyloidosis from other conditions. Frequent observations are nondilated thickened ventricles, enlarged atria, thickened atrial septum and increased echogenicity of the myocardium . In severe forms of the disease, reduced ejection fraction, reduced cardiac output, and diastolic dysfunction are seen. In general, the patterns of a restrictive cardiomyopathy accompanied with valvular thickening is the main form of cardiac abnormality and may be accompanied with pericardial effusions in a significant number of patients. Doppler echocardiography may be useful in assessing impaired blood flow that is typically observed, with alterations in pulmonary and transmitral blood flow that influence ejection fraction and diastolic dysfunction.
To make a definite diagnosis of amyloidosis as the cause of cardiac lesions, it is necessary to perform a biopsy. Because amyloidosis is a systemic disease, and deposition of misfolded proteins occurs throughout the body, including the subcutaneous tissue and vessels in the GI tract, these are the initial sites where biopsy is done , but if appropriate specimens are not obtained, an endocardial biopsy is indicated. It is important to identify the exact type of amyloidosis, which is done by special staining. The use of Congo Red stain, and the appearance of apple-green birefringence, as well as the use of polarizing microscopy, are methods which confirm amyloidosis . Additionally, serum and urine immunofixation should be performed to identify the presence of abnormal light chains, as well as the kappa/lambda light chain ratio, to confirm light-chain amyloidosis , which may necessitate bone marrow biopsy as well, to identify possible blood cell dyscrasia. Other special staining and immunohistochemical techniques may be used to differentiate between other forms of amyloidosis .
Once the diagnosis of cardiac amyloidosis is made, primary interventions like alleviation of cardiac symptoms and symptomatic therapy should be done. If possible, cause-directed therapy can be used, which is the case with primary amyloidosis associated with plasma cell dyscrasia. The treatment modalities are:
- Use of diuretics, often intravenously, is the mainstay of alleviating congestive heart failure, while the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor antagonists are not indicated due to their poor effects. More importantly, calcium-channel blockers, β-blockers, and digoxin are contraindicated, as these groups of drugs can cause further progression of heart failure .
- Because of very high risk of thromboembolism, particularly in patients with atrial fibrillation, anticoagulant therapy, mainly warfarin is often used .
- Chemotherapy has shown significant results against AL amyloidosis, with melphalan, belonging to the group of alkylating agents, showing to be the most potent drug . Unfortunately, patients commonly present in very poor condition and high-dose chemotherapy may be rarely carried out, since high mortality rates have been documented, but its use has shown significant effects on reversing cardiac lesions. Thus, its use in high-risk patients, together with stem cell transplantation, is promoted. Various regimens exist and depend on the general condition of the patient.
- Organ transplantation - In patients with severe cardiac insufficiency, or liver failure, either heart or liver transplantation may be indicated. However, because of the nature of the disease, specific indications and appropriate follow-up chemotherapy regimens, especially in the AL amyloidosis forms, are necessary to ensure long-term benefit from this form of therapy.
- Other supportive treatment may include insertion of a permanent pacemaker, to stabilize cardiac conduction abnormalities.
The prognosis of cardiac amyloidosis significantly depends on the underlying type and the time of diagnosis. In patients with primary (AL) amyloidosis, the median survival rate of untreated patients after the development of congestive heart failure is < 6 months, which shows the importance of an early diagnosis and appropriate therapy . In comparison to primary amyloidosis, senile cardiac amyloidosis has a much better prognosis, with survival rates reaching up to 7 years from the onset of heart failure . It is established that patients appropriately treated with chemotherapy with underlying plasma cell dyscrasia may lead to significant improvement and even reversal of cardiomyopathy , further emphasizing the value of an early diagnosis.
Amyloidosis has several distinct types, including primary, secondary, familial and localized forms. Each is associated with different pathophysiologic mechanisms and features and cardiac involvement significantly varies among them :
- Amyloid light-chain (AL Amyloid) or primary amyloidosis - It is the most common form of amyloidosis, . It is associated with plasma cell dyscrasia, with the most likely candidate being multiple myelomas. AL amyloidosis is characterized by deposition of misfolded immunoglobulins, most commonly fragments of light chains and in some cases, components of heavy chains (AH amyloidosis) . Cardiac involvement is commonly observed in this type of amyloidosis .
- Amyloid A (AA form) or secondary amyloidosis - This form occurs due to degradation and subsequent deposition of serum amyloid A (SAA), which is produced in the setting of infections such as tuberculosis, autoimmune disorders such as juvenile rheumatoid arthritis (RA) and ankylosing spondylitis, and malignancies such as renal cell carcinoma . However, this form almost never targets cardiac tissue but has a predilection for the liver, kidneys and lymph nodes .
- Hereditary amyloidosis - The hallmark of this form are mutations in transthyretin (TTR), a plasma protein which serves as a transport molecule for thyroid hormones and retinol. Dozens of mutations have been discovered and depending on which mutation is responsible, cardiac involvement may be either absent or severe, but cardiomyopathy and heart failure almost always appear in later stages. The peripheral nervous system is the most common target of this form . A particular form of TTR mutation can lead to senile systemic amyloidosis (SSA), which always presents with protein deposition in cardiac tissue (for which is it also known as senile cardiac amyloidosis - SCA).
- Isolated atrial amyloidosis - Described as a separate entity, this form of amyloidosis implies localized atrial deposition of misfolded proteins and is associated with atrial natriuretic peptide (ANP) and atrial fibrillation, but its pathophysiologic mechanisms remain to be discovered.
- β2-microglobulin and β-protein amyloidosis open link, the two localized forms which are associated with dialysis and Alzheimer disease, respectively, virtually never affect cardiac tissue.
The exact rates of cardiac involvement in various types of amyloidosis are not known, but it is established that out of approximately 2500 cases of primary amyloidosis (AL) that occur annually in the United States, 50% of patients have cardiac involvement . Gender predilection has been established in hereditary amyloidosis, which exclusively develops in male patients only, for unknown reasons . The African-American population is shown to be at a significantly higher risk for development of hereditary amyloidosis, with much higher rates of specific TTR mutations observed in this population .
Extracellular accumulation and deposition of misfolded proteins is the hallmark of cardiac amyloidosis, but the exact etiology and pathogenesis remain unclear. It is established that some form of plasma cell dyscrasia is responsible for primary amyloidosis, but not all patients develop this phenomenon. Consequently, abnormal production of immunoglobulins in AL amyloidosis, transthyretin in familial forms and serum amyloid A in secondary amyloidosis lead to their deposition in the atria, ventricles, perivascular tissue, valves and the conduction system . The most common feature is thickening of the ventricular wall without accompanying dilation, which should occur as a compensatory mechanism. Usually, both ventricles, but also atria are enlarged, with thickening of the atrial septum being frequently noted. The valvular deposition may result in improper closure and lead to insufficiency. As a result, development of stiff ventricles, poor valvular function, and reduced cardiac output lead to significant impairment of proper cardiac function and progression to heart failure occurs invariably in all patients where the cardiac deposition is severe . In some cases, deposits may be found in the pericardium, which can further reduce inotropic functions of the heart through the development of pericardial effusions, while fibrosis of conduction system can give frequent rhythm disorders.
Current preventive strategies do not exist, as the actual cause of mutations and processes that lead to protein misfolding is not known. However, establishing an early diagnosis and appropriate treatment may significantly reduce the burden of this disease, which may have a significant impact on the quality of patient's life. Screening of families with members who have familial forms of amyloidosis could be a potential preventive measure.
Cardiac amyloidosis is a disorder that results from protein misfolding and subsequent deposition of protein fibrils derived from β-sheets in the extracellular cardiac tissue . These fibrils are very small, with their diameters ranging from 7.5-10 nm, and usually deposit in numerous other organs apart from the heart, including the liver, kidneys, lungs, nerves, skin, etc. Amyloidosis may present a significant challenge for physicians as numerous symptoms may develop . Regardless of the type of amyloidosis, cardiac involvement uniformly involves deposition of proteins in virtually any tissue in the heart, including the atria, ventricles, valves and small blood vessels, while the conduction system may also be a target. This process leads to ventricular thickening without adequate dilation, as well as atrial enlargement, which ultimately leads to patients presenting with heart failure open link and severe cardiac insufficiency. Depending on the type of amyloidosis, patients may present with rapidly progressing symptoms and a very poor prognosis, or a very slow and insidious onset of cardiac symptoms may be observed. Dyspnea, weakness, edema of the extremities, arrhythmias, and weight loss are some of the most common cardiac-related symptoms. Non-cardiac symptoms are frequently observed in patients with cardiac amyloidosis, as other organs and tissues are affected. Symptoms such as proteinuria, severe edema, hepatomegaly, ascites may be present in amyloidosis. Also, the involvement of lungs, nervous system, spleen and the gastrointestinal tract may be present. The initial diagnosis of cardiac amyloidosis can be made by echocardiography, in which typical wall thickening without accompanying dilation can be observed, together with slight elevations of troponin. Biopsy, however, is the tool for obtaining a definite diagnosis, which comprises staining of obtained tissues with Congo red dye and use of a polarizing microscope to confirm amyloidosis . Samples can be obtained from various tissues in the body, most preferably the abdominal subcutaneous tissue, but if appropriate samples are not obtained, an endocardial biopsy is indicated. Treatment principles are chemotherapy in the case of AL amyloidosis, liver, and potentially cardiac transplantation in hereditary forms (since nearly all mutated proteins are produced in the liver in this form), while supportive therapy is indicated in all forms.
Cardiac amyloidosis is a term that describes deposition of various abnormally formed proteins (amyloids) in the heart and it is often a component of systemic amyloidosis, which usually involves numerous parts of the body. There are several forms:
- Primary amyloidosis occurs on the grounds of plasma cell abnormalities and includes formation and deposition of abnormal components of antibodies, or immunoglobulins (known as light-chain amyloidosis - AL). In approximately 50% of patients with primary amyloidosis, the proteins are deposited in the heart and cause life-threatening symptoms.
- Secondary amyloidosis is associated with various infections, autoimmune diseases such as rheumatoid arthritis and malignant diseases, in which degradation of proteins activated in inflammation and their subsequent deposition throughout the body occurs. Heart-related symptoms are very rare in this type of amyloidosis.
- Familial or Hereditary amyloidosis is another form which occurs due to abnormal deposition of various mutated proteins, most commonly transthyretin and is exclusively seen in male patients. This disorder most commonly attacks the liver, as the majority of mutated proteins are synthesized in this organ, but the heart may be involved as well.
It is not known why or what are the exact mechanisms that lead to deposition of these abnormal proteins in various organs of the body, but the end-result in the case of cardiac amyloidosis is development of severe and life-threatening heart failure which manifests with symptoms such as chest pain, breathing difficulties, weakness, swelling of the extremities and weight loss. Because this disease affects many organs simultaneously, other symptoms are frequently present, including liver enlargement, numbness of fingers and toes, lowered blood pressure, enlarged tongue, voice changes, etc. Symptoms may appear within a short period of time, or they may be slowly progressive, depending on the underlying type of amyloidosis. Making the diagnosis of this disease may be difficult, but various diagnostic tools, such as electrocardiography, ultrasound of the heart and biopsy are used in differentiating this condition from various other that may present in similar fashion. Treatment depends on the subtype. Primary amyloidosis may be treated with chemotherapeutic drugs such as melphalan, which acts on plasma cells that are responsible for the production of abnormal proteins and has shown very good results in some patients. Management of heart failure is performed mainly through diuretics, but ultimately, heart transplantation may be indicated, as there is no cure for this condition. Because of the majority of patients with primary amyloidosis present in advanced stages of the disease and in poor general condition, the prognosis is very poor, as individuals rarely survive over 1 year without early aggressive therapy, while the significantly better prognosis is observed in patients with hereditary amyloidosis. In general, this disease involves multiple organs and is progressive in nature, which is why an early diagnosis may provide a significantly better quality of life, as sometimes cause-directed treatment may be initiated early on.
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