Cardiac amyloidosis is a subcategory of
amyloidosis where there is depositing of the protein
amyloid
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...
in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the
heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased
cardiac function.
The overall decrease in cardiac function leads to a plethora of symptoms.
This multisystem disease was often misdiagnosed, with diagnosis previously occurring after death during autopsy. However, recent advancements of technologies have increased the diagnosis of the disease. Cardiac amyloidosis has multiple sub-types including
light chain,
familial, and
senile
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
.
One of the most studied types is light chain cardiac amyloidosis.
Prognosis depends on the extent of the deposits in the body and the type of amyloidosis.
New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.
Types
The multiple subtypes of cardiac amyloidosis have varying epidemiological, diagnostic, and prognostic characteristics.
Light chain (AL-CM)
This relatively rare form of cardiac amyloidosis occurs in an estimated six to ten cases per 1,000,000 people.
This sub- type usually affects males over the age of 60
and is rapidly progressive. Pathogenesis of this form is due to the aggregation of
immunoglobulin lambda light chains.
These chains are created by an abnormal expansion of
plasma cells.
Over time, these light chains deposit into the
interstitial tissue
An interstitial space or interstice is a space between structures or objects.
In particular, interstitial may refer to:
Biology
* Interstitial cell tumor
* Interstitial cell, any cell that lies between other cells
* Interstitial collagenase, ...
within the myocardium.
Diagnostic tests includes serum and urine
electrophoresis,
laboratory testing for the determination of elevated levels of
troponin
image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL
Troponin, ...
and
BNP, and ECGs showing low QRS voltages.
Familial (ATTRm-CM)
This type is caused by mutations of proteins involved in amyloid formation, including
transthyretin
Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol' ...
(TTR),
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
,
apolipoprotein A1
Apolipoprotein AI (ApoA-I) is a protein that in humans is encoded by the ''APOA1'' gene. As the major component of HDL particles, it has a specific role in lipid metabolism.
Structure
''APOA1'' is located on chromosome 11, with its specific lo ...
, or
apolipoprotein A2. Due to the multiple number of potential genetic causes the incidence of this form is variable. The vast majority of familial cardiac amyloidosis still present after the age of 60.
A common mutation is the
TTR gene mutation Val122Ile.
It is estimated that 3.5–4% of African Americans in The United States have the Val 122lle mutation.
This type of amyloidosis can be identified by
genetic testing for protein mutation.
For the diagnosis of familial cardiac amyloidosis to be made a biopsy with histological evaluation must be obtained.
In this histological evaluation special stains are utilized to visualize the
amyloid deposits.
One such stain is
Congo Red
Congo red is an organic compound, the sodium salt of 3,3′-( ,1′-biphenyl4,4′-diyl)bis(4-aminonaphthalene-1-sulfonic acid). It is an azo dye. Congo red is water-soluble, yielding a red colloidal solution; its solubility is greater in organic ...
, which binds specifically to the amyloid deposit and can be characterized by various lighting methods.
Under polarized light, the amyloid deposits while show pathognomonic apple green birefringence, and under plain light the deposits will appear a light salmon pink color.
Familial amyloidosis symptoms are centered around neuropathological and cardiac problems.
Cardiac manifestations of the TTR mutation present more often in The United States.
Wild-type (ATTRwt-CM)
This type is considered the wild-type mutation which leads to the development of
TTR deposits.
It usually affects males over 70 years with the manifestation of
carpal tunnel syndrome
Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparen ...
.
Similar to the other subtypes of cardiac amyloidosis, a biopsy is required for diagnosis.
However, formal diagnosis of Senile cardiac amyloidosis is a diagnosis of exclusion.
Biopsy with histological evaluation can rule out Light chain and Familial subtypes, leaving the diagnosis of Senile.
This type is often misdiagnosed, however, greater use of
cardiac magnetic resonance has increased the rate of diagnosis
The severity of the disease tends to be less than the Light chain and Familial variants.
This is due to the amount of time that it takes to accumulate the amyloid depositions being longer in the Senile variant.
Symptoms and signs
Symptoms of cardiac amyloidosis are a combination of heart failure and amyloid deposition in various other organs.
Amyloid deposition in the heart causes restrictive diastolic
heart failure that progresses to systolic heart failure.
Cardiac manifestations include:
*
Dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
on exertion
*
Peripheral edema
Peripheral edema is edema (accumulation of fluid causing swelling) in tissues perfused by the peripheral vascular system, usually in the lower limbs. In the most dependent parts of the body (those hanging distally), it may be called dependent ede ...
and
ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, a ...
*
Pericardial effusion
A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...
* Arrhythmias (secondary to disruption of the normal electrical system of the heart)
** Atrial arrhythmias (such as
atrial fibrillation)
** First/second degree
heart block
Heart block (HB) is a disorder in the heart's rhythm due to a fault in the natural pacemaker. This is caused by an obstruction – a block – in the electrical conduction system of the heart. Sometimes a disorder can be inherited. Despite the se ...
s
*
Syncope
* Elevated neck veins and
jugular venous pressure
*
Myocardial ischemia
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
/
Angina (secondary to amyloid deposition in the small arteries of the heart)
** Myocardial oxygen demand is increased in patients with cardiac amyloidosis, regardless of changes to coronary perfusion.
For patients with light-chain amyloidosis, there can be depositions of amyloid into numerous different organs.
Deposition of amyloid into other organs makes the diagnosis of cardiac amyloidosis difficult as these extracardiac manifestations mask the diagnosis.
Extracardiac manifestations include:
*
Macroglossia
Macroglossia is the medical term for an unusually large tongue. Severe enlargement of the tongue can cause cosmetic and functional difficulties in speaking, eating, swallowing and sleeping. Macroglossia is uncommon, and usually occurs in children. ...
*
Periorbital bruising
* Loss of the third and fourth heart sound
*
Thromboembolism
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
s
* Symmetric
sensory neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
(such as bilateral carpal tunnel)
*
Postural hypotension
Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...
(secondary to autonomic neuropathy)
*
Nephrotic syndrome (secondary to free light chain damage to the kidneys/deposition of amyloid in the kidneys)
Cause
The general cause of cardiac amyloidosis is the misfolding of a specific protein precursor depending on the amyloidosis type. Protein precursors include immunoglobulin-derived light chains and
transthyretin
Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol' ...
mutations.
The misfolding of the protein causes it to have insoluble beta-pleated sheets,
creating an amyloid. Amyloid, the aggregation, or clumping, of proteins, is resistant to degradation by the body. Amyloids are mostly
fibril
Fibrils (from the Latin ''fibra'') are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10-100 nanometers (whereas fibers are micro ...
s, while also containing a P component,
apolipoprotein
Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.
The lipid components of lipoproteins ...
,
collagen,
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
, and
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
.
The P component, a
pentameric protein A pentameric protein is a quaternary protein structure that consists of five protein subunits.
Examples
Ligand-gated ion channels
Five sub-units come together to form a channel. Each channel consist of two alpha chain, one beta, one gamma and ...
, stabilizes the fibrils of the amyloid, which reduces their clearance from the body.
Deposits of the amyloids can occur throughout the body, including the heart, liver, kidneys, spleen, adrenal glands, and bones. Deposits in the extracellular cardiac space can stiffen the heart, resulting in restriction of the ventricles.
This restriction in ventricular motion results in a decreased ability for the heart to pump efficiently, leading to the various symptoms associated with cardiac amyloidosis.
Diagnosis
Echocardiography
Echocardiography is a safe and non-invasive method that can be used to assess the structural and functional disease of the heart.
Amyloidosis presents with ventricle and valvular thickening, biatrial enlargement,
restrictive filling pattern, with normal to mildly reduced systolic function
and decreased
diastolic filling.
An echo can be used to evaluate for prognosis of the disease, measuring the different strains within the heart.
Cardiac amyloidosis produces specific alterations to the functionality of the heart. Echocardiography can be utilized to detect this specific pattern (relative preservation of the apical myocardium with decreased longitudinal strain in the mid and basal sections), which is 90–95% sensitive and 80–85% specific for cardiac amyloidosis.
Echocardiography can be used to help physicians with diagnosis, however, it can only be used for the suggestion of the disease, not the confirmation, unless it is late stage amyloidosis.
ECG/EKG
ECGs of patients with cardiac amyloidosis usually show a low voltage in the limb leads, with an unusual extreme right axis. There is usually a normal
P-wave, however, it can be slightly prolonged. For patients with light-chain amyloidosis, the
QRS complex pattern is skewed,
with poor R-waves of the chest leads.
Holter ECGs can be used to identify asymptomatic
arrhythmias
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
.
EKG
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
changes may be present, showing low voltage and conduction abnormalities like
atrioventricular block
Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatr ...
or
sinus node
The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approxima ...
dysfunction.
Laboratory Tests
Laboratory tests including
urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important ...
and
creatinine levels,
liver enzymes
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...
, glucose,
thyroid function,
full blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and plat ...
, and clotting tests. The analysis of serum and urine for presence of
monoclonal immunoglobulin is also done through
immunofixation Immunofixation permits the detection and typing of monoclonal antibodies or immunoglobulins in Blood serum, serum or urine. It is of great importance for the diagnosis and monitoring of certain blood related diseases such as myeloma.
Principle
T ...
for detection of the monoclonal band. Presence of the monoclonal band would be consistent with light chain amyloidosis. For light chain amyloidosis,
serum immunoglobulin free light chain assay can be used for diagnosis and following of the amyloidosis.
In light-chain amyloidosis, a low
paraprotein level can be present.
Cardiac biomarkers
There are two main cardiac biomarkers used in the assessment of cardiac amyloidosis,
troponin
image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL
Troponin, ...
and
N-terminal proBNP. As expected, with cardiac damage and dysfunction, there can be an elevation of these markers in patients with cardiac amyloidosis. These markers have been incorporated into the various staging/scoring systems used by physicians to determine severity of the disease and prognosis.
Biopsies
Extracardiac biopsies of tissues of the kidney, liver, peripheral nerve, or abdominal fat can be used to confirm the presence of amyloid deposits. Amyloid deposits in biopsy samples are confirmed through the use of
Congo red dye, which produces a green birefringence when viewed under polarized light.
Sirius red staining or
electron microscopy examination can also be done. The determination of the type of amyloid can be done by
immunohisto-labeling techniques as well as
immunofluorescence staining.
For light-chain amyloidosis patients, bone marrow biopsies could be conducted to determine the baseline percentage of plasma cells and to rule out
multiple myeloma.
Catheterization
Right heart catheterization is the test used to test for elevated diastolic
ventricular pressures. This test is more invasive and would be performed after inconclusive
endomyocardial biopsy
Endomyocardial biopsy (EMB) is an invasive procedure used routinely to obtain small samples of heart muscle, primarily for detecting rejection of a donor heart following heart transplantation. It is also used as a diagnostic tool in some hea ...
samples.
Cardiac magnetic resonance imaging
Cardiac magnetic resonance (CMR) is capable of measuring the thickness of different areas of the heart. This can be used for quantification of the deposits in the heart.
CMR also shows the characterization of
myocardial tissue through patterns of
gadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is only slightly malleable and is a ductile rare-earth element. Gadolinium reacts with atmospheric oxygen ...
enhancements.
However, none of the CMR technique is able to differentiate ATTR-CM and AL-CM definitely.
For AL-CM, 68% of them have symmetrical and concentric
left ventricular hypertrophy
Left ventricular hypertrophy (LVH) is thickening of the heart muscle of the left ventricle of the heart, that is, left-sided ventricular hypertrophy and resulting increased left ventricular mass.
Causes
While ventricular hypertrophy occurs ...
. On the other hand, for ATTR-CM, 79% of them have asymmetrical left ventricular hypertrophy and 18% of them have symmetrical and concentric left ventricular hypertrophy.
In
T1-weighted imaging, edema in the heart can be detected with a high T1 signal. Meanwhile, enlargement of heart cells will reduce the T1 signal. Using T1 signal, Extracellular volume (ECV) is useful to determine the degree of amyloid deposition around the heart cells and detect the regression of amyloid deposits after treatment. ECV is higher in ATTR-CM than in AL-CM.
In T2-weighted imaging, the T2 signal is increased in acute myocarditis (inflammation of heart muscles), and
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
(heart attack). T2 signal is also increased in AL-CM and ATTR-CM but the signal is greater in AL-CM before starting chemotherapy.
Late gadolinum enhancement (LGE) can determine the severity of deposition of amyloid in heart tissue. The higher the LGE signal, the more severe the heart involvement. It can be divided into three stages: no LGE, sub
endocardial
The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides protection to the val ...
LGE, and full-thickness (transmural) LGE.
Scintigraphy/radionuclide imaging
Scintigraphy
Scintigraphy (from Latin ''scintilla'', "spark"), also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally and ...
can be used to measure the extent and distribution of the amyloid throughout the body, including the liver, kidney, spleen, and heart.
A
radiolabelled
Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope (an atom with a detectable variation in neutron count) through a reaction, metabolic pathway, or cell. The reactant is 'labeled' by replacing specific ...
serum amyloid P component can be administered to a patient
intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
and the P component pools to the amyloid deposit proportional to the size of the deposit. The labeling of the P component can then be pictured by a
gamma camera
A gamma camera (γ-camera), also called a scintillation camera or Anger camera, is a device used to image gamma radiation emitting radioisotopes, a technique known as scintigraphy. The applications of scintigraphy include early drug development ...
.
Technetium
Technetium is a chemical element with the symbol Tc and atomic number 43. It is the lightest element whose isotopes are all radioactive. All available technetium is produced as a synthetic element. Naturally occurring technetium is a spontaneous ...
radionuclide scans can now reliably diagnosis cardiac amyloidosis, with certain scanning methods having greater than 99% sensitivity (but only 91% specific for amyloidosis).
In this method of imaging, radiolabeled technetium is injected into the body where it binds to cardiac amyloid deposits.
A subsequent scan is taken to determine where the tracer stays, therefore highlighting the amyloid deposition in the heart.
This method allows for a noninvasive definitive diagnosis of cardiac amyloidosis (as in the past an endomyocardial biopsy was required)
Mass spectrometry
Mass spectrometry can be used to determine whether the protein is light-chain or familial amyloidosis by identifying the
protein subunit.
Treatments
Treatments differ according to the type of amyloidosis present.
The majority of treatment is aimed at preserving heart function and treating heart failure symptoms.
Light chain (AL-CM) Treatment: Since the cause of this subtype of cardiac amyloidosis is the excessive production of free light chains, the major goal of treatment is the reduction in concentration of light chains.
For light-chain amyloidosis, the use of FLC assays and NT-proBNP levels can be used to monitor the progression of amyloidosis and any response to treatments.
One of the major routes to decrease the production of these excess light chains is to kill the abnormal cells that are producing them.
Chemotherapeutic agents such as
melphalan
Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is taken by mouth or by injection into a vein.
Common side effects incl ...
or
bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
can be used to kill off the abnormal cell line that is producing the free light chains.
Following chemotherapy, a
bone marrow transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
can be utilized to restore the normal cell lines.
There are newer medications (
ixazomib
Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.
Common side effects include diarrhea, constipation a ...
,
carfilzomib
Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.
The U. ...
,
daratumumab
Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly de ...
,
elotuzumab
Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone, for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma ...
) under research for the treatment of multiple myeloma that can help to decrease the production of free light chains.
New data suggests that orthotopic heart transplant followed by melphalan and stem cell transplant produces results similar to non cardiac amyloidosis indicated heart transplant.
To treat complications, medications can be prescribed including
midodrine
Midodrine is a vasopressor/ antihypotensive agent (it raises the blood pressure). Midodrine was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension. In A ...
for
autonomic neuropathy
Autonomic neuropathy (AN or AAN) is a form of polyneuropathy that affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system), affecting mostly the internal organs such as the bladder muscles, the cardiovascular s ...
,
amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibril ...
for patients with
atrial fibrillation to prevent
arrhythmias
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
, and
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
used after a cardioembolic episode.
Beta-blockers should be avoided due to the usual symptom of
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
.
Familial (ATTR
m-CM) Treatment: In recent years there have been developments in the treatment of Familial/Transthyretin cardiac amyloidosis including methods to suppress transthyretin production, stabilize amyloid fibrils, and medications that can destroy already existing fibrils.
For familial amyloidosis,
ACE-inhibitors and beta-blockers can be prescribed if there is no autonomic neuropathy.
* Suppression of transthyretin production: liver transplantation and medications that decreases the activity of the transthyretin genes (
patisiran
Patisiran, sold under the brand name Onpattro, is a medication used for the treatment of polyneuropathy in people with hereditary transthyretin-mediated amyloidosis, a fatal rare disease that is estimated to affect 50,000 people worldwide.
It is ...
and
inotersen).
In patients with familial transthyretin mutations, liver transplantation can provide the body with a source of normal transthyretin.
By changing the source of transthyretin from the original liver that contains the mutated transthyretin to a healthy liver, there will be no more production of the abnormal protein.
However, liver transplant does not reverse the disease.
The goal of liver transplant is to prevent additional amyloid deposition and prevent new symptoms/complications from happening.
These medications bind to the mRNA of transthyretin and prevent the production of the transthyretin protein, thus decreasing the overall amount of transthyretin that can accumulate in the body.
* Stabilization of abnormal transthyretin: There are medications that can stabilize the normally folded transthyretin, preventing misfolding and subsequent amyloid deposition.
These medications include
Tafamidis
Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyo ...
, the
NSAID
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
Diflunisal
Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It wa ...
, and AG
10.
Tafamidis is a medication that binds to transthyretin and keeps it in its normal shape, stopping it from aggregating into amyloid fibrils.
Diflunisal and AG
10 work in a similar manner to Tafamidis in their ability to bind to and stabilize Transthyretin.
* Destruction of existing amyloid fibrils: There are multiple medications that show amyloid destroying properties,
Doxycycline,
Tauro-ursodeoxy-cholic acid (TUDCA), and monoclonal antibodies.
The use of
pacemakers
An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eit ...
(both right ventricular pacing and biventricular pacing) or
implantable cardioverter defibrillators remains questionable in cardiac amyloidosis.
In 2012, Craig Lewis, a 55 year old Texan, presented at the Texas Heart Institute with a severe case of amyloidosis. He was given an experimental continuous-flow artificial heart transplant which saved his life. Lewis died 5 weeks later of liver failure after slipping into a coma due to the amyloidosis.
Prognosis
Overall prognosis is dependent on the extent of
cardiac dysfunction. Worse outcomes have been seen when echocardiography shows left ventricular wall thickness, poor systolic function and severe diastolic dysfunction.
Light chain (AL-CM) Prognosis: For light-chain amyloidosis early detection leads to best possibility of therapies prolonging the period of remission.
Well treated light chain cardiac amyloidosis has a 4-year survival rate of around 90%.
In patients that undergo stem cell transplant the average survival time increases to 10 years.
Staging systems have been developed to stratify severity of the disease, including the Mayo Biomarker Stage, which utilizes various biomarkers such as
troponin I
Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to ac ...
,
troponin T
Troponin T (shortened TnT or TropT) is a part of the troponin complex, which are proteins integral to the contraction of skeletal and heart muscles. They are expressed in skeletal and cardiac myocytes. Troponin T binds to tropomyosin and help ...
,
BNP, and
NT-proBNP, and Free light chain concentrations.
Familial (ATTR
m-CM) Prognosis: Due to the extensive number of variables involved in this subtype, prognosis varies depending on the specific type of familial cardiac amyloidosis.
Variables involve mutant vs wild type transthyretin mutation and age of onset of symptoms.
In comparison to light chain amyloidosis, the familial subtype is slower to progress and has a more favorable prognosis.
However, the Val 122lle mutation (most common cause of familial cardiac amyloidosis) has a 4-year survival rate of 16% with an average length of 26 months.
A delay in recognition plays a major factor in this reduced survival rate.
References
{{Medicine
Amyloidosis
Heart diseases