The characteristic abnormality in amyloidosis is an accumulation of an abnormal folding of a protein, rendering it to be insoluble.
Amyloid light chain amyloidosis is the second most common type of systemic amyloidosis after wild type transthyretin amyloidosis and is caused by overproduction of mono clonal free light chains by a plasma cell clone
Accumulation of amyloid fibrils composed of misfolded transthyretin protein in the heart leads to transthyretin amyloid cardiomyopathy and heart failure.
ATT or amyloid deposition in the heart drives the progression of infiltrative cardiomyopathy, leading to worsening heart failure, arrhythmias, and conduction disease.
The median survival for ATTR cardiac amyloidosis ranges from 2 to 6 years depending on the disease, stage at diagnosis.
This abnormality may be a result of genetic mutations or excess formation.
Biventricular wall thickling can be associated with cardiac amyloidosis with either light chain amyloidosis or transthyretin amyloidosis.
There is a discrepancy between the wall thickness observed on echocardiographic studies and the QRS voltage observed on electrocardiography; the voltage is classically reduced.
Light chain amyloidosis (AL) is the most common type of systemic amyloidosis.
Amyloid deposition in the tissues causes disruption of architecture, induces oxidant stress, and results in organ dysfunction.
Cardiac involvement with amyloidosis is diagnosed using imaging techniques, such as echocardiogram with strain assessment to examine longitudinal strain, and cardiovascular MRI in certain circumstances.
Cardiac MRI enhancement shows abnormal myocardial and blood pool gadolinium kinetics.
Cardiac MRI in amyloidosis, demonstrates late gadolinium enhancement secondary to the disruption of tight junctions between the myocytes from expanding interstitial amyloid.
Cardiac amyloidosis symptoms include edema, ascites, and dyspnea due to restrictive cardiomyopathy, fatigue due to low cardiac output, and bradyarrhythmias and heart block.
Heart failure, electromechanical dissociation, and ventricular. arrhythmias are a common cause of cardiac mortality in patients with AL amyloidosis, especially sudden cardiac death.
Heart failure progresses rapidly, especially in patients with cardiac AL amyloidosis.
Multiorgan involvement is common.
Cardiac deposition is, in many patients, the most serious complication of ATTR.
Echocardiography enables visualization of increased ventricular wall thickness, increased septal thickness, valvular thickening, valvular insufficiency, atrial enlargement and appearance of granular sparkling.
Echocardiography findings are not sensitive nor specific enough to be diagnostic but is highly suggestive when present.
Amyloid deposits in the heart occur in the ventricular interstitium.
Amyloid deposits lead to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume.
Doppler echocardiography diastolic evaluation reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration.
The cardiac ejection fraction is preserved until late in disease.
Bone scintigraphy using technetium-provides very high diagnostic accuracy in the noninvasive assessment of cardiac ATTR.
Electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material.
The loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy.
Various arrhythmias may be seen and can be life threatening.
Light chain amyloidosis (AL) results from the proliferation of plasma cells in the bone marrow.
The plasma cell burden in AL is about 5-10%.
The plasma cell level is a marker of poor prognosis.
Lambda light chains are 3 times more likely involved than kappa chains.
Most cases of AL are associated with a benign monoclonal gammopathy.
AL is rarely seen with multiple myeloma, lymphoma, or macroglobulinemia.
Cardiac involvement is most common in the AL variety of amyloidosis, but is also seen in secondary, hereditary, and senile amyloidosis.
Cardiac amyloid deposition is most common in the myocardium but is also seen in the atria, pericardium, endocardium, and vasculature of the heart.
Cardiac deposition is, in many patients, the most serious complication of ATTR.
Echocardiography enables visualization of increased ventricular wall thickness, increased septal thickness, valvular thickening, valvular insufficiency, atrial enlargement and appearance of granular sparkling.
Echocardiography findings are not sensitive nor specific enough to be diagnostic but is highly suggestive when present.
Amyloid deposits in the heart occur in the ventricular interstitium.
Amyloid deposits lead to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume.
Doppler echocardiography diastolic evaluation reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration.
The cardiac ejection fraction is preserved until late in disease.
Bone scintigraphy using technetium-provides very high diagnostic accuracy in the noninvasive assessment of cardiac ATTR.
Electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material.
The loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy.
Various arrhythmias may be seen and can be life threatening.
Atrial arrhythmias or conduction system disease may occur due to to amyloid fibril deposition within areas responsible for electrical impulse conduction.
The myocardium becomes thick with amyloid deposition with a rubbery consistency.
More than 50% of myocardial infiltration occurs in AL variety of amyloid, and 90% of cases have vascular involvement.
Epicardial vessels are typically spared.
Mirovascular involvement is common, which can result in tissue ischemia and infarction.
Myocardial fibrosis results in myocardial dysfunction, leading to heart failure and cardiac arrhythmias.
The cardiac ventricles are typically normal in size.
The cardiac ventricles are, however, stiff causing restrictive ventricular filling and biatrial enlargement.
Pericardial involvement is common in cardiac amyloid and leads to pericardial effusion.
Endocardial involvement in amyloid may result in atrioventricular valve dysfunction.
Intracardiac thrombosis is common in cardiac amyloidosis and seen in about 33% cases in autopsy specimens.
The thickening of the left heart valves is also common in patients with AL.
Thickening of the left heart valves is associated with advanced age, poor functional class and worse systolic and diastolic function, and increases in all-cause mortality.
Conduction system abnormalities are frequent in amyloidosis, and include bundle branch block and atrioventricular block.
Severe sinoatrial node fibrosis was seen in 30% cases. In a small study.
Primary amyloidosis (AL) is the type of plasma cell dyscrasia that is most common type involving the heart.
Secondary systemic amyloidosis due to chronic inflammatory conditions rarely involves the heart, and organ dysfunction is usually reversible with resolution of the underlying inflammatory disorder.
Senile amyloidosis is common in people over 80 years of age and is associated with a better prognosis
Senile amyloidosis, in which wild-type transthyretin (TTR) accumulates in tissue and leads to the development of cardiac dysfunction.
Senile amyloidosis, in which wild-type transthyretin (TTR) accumulates is 3 times more common in elderly black patients compared to white patients (8.2% vs 2.7%, respectively).
Hereditary cardiac amyloidosis from a TTR mutation variants is more common in blacks than white persons; 23% of the patients have this variant.
AL type is usually seen in persons older than age 50 years.
AL can occur as early as the third decade of life.
Senile amyloidosis is seen in elderly patients and has a better prognosis than primary amyloidosis.
Cardiac involvement is a marker of poor prognosis.
Poor prognosis factors include:
Congestive heart failure
Syncope
Complex arrhythmia
Degree of left ventricular (LV) hypertrophy.
Low LV ejection fraction (LVEF)
Restrictive hemodynamic Right ventricular dilatation
Pulmonary hypertension
Low voltage on electrocardiography (ECG)
High brain natriuretic peptide (BNP) levels
High troponin levels
Gadolinium-enhanced magnetic resonance imaging (MRI) demonstrating extent of myocardial involvement.
Median survival of cardiac amyloidosis, without treatment is only 13 months.
Cardiac involvement has the worst prognosis and results in death in about 6 months after onset of CHF.
Only 5% of the patients with primary amyloidosis survive beyond 10 years.
Complications of cardiac amyloid include:
Atrial fibrillation
Congestive heart failure
Embolism and stroke
Ventricular arrhythmias
Heart block requiring pacemaker implantation
Pericardial tamponade
Death
Approximately half of the patients with cardiac involvement present with right-sided heart failure.
The patients may present with the following signs and symptoms:
Fatigue and weakness are the most common
Abnormal voice quality
Leg edema
Dyspnea
Dizziness
Presyncope/syncope
Postural hypotension
Easy bruising
Angina
Pulmonary edema
Sudden cardiac death
Cardiac tamponade
Heart block
Ischemic stroke (in 30% cases, cardioembolic in the remaining 70%)
Painful polyneuropathy (10-20% cases)
Carpal tunnel syndrome (20%)
Bilateral carpal tunnel syndrome and spinal canal stenosis occur frequently in transthyretin cardiac amyloidosis, both in the variant and the wild type form.
Pulmonary amyloid infiltration pulmonary hypertension, and cor pulmonale.
Clinical findings in primary amyloidosis are consistent with features of right-sided heart failure, elevated jugular venous pressure, right-sided third heart sound, lower extremity edema., and a fourth heart sound is present in patients without atrial fibrillation.
Periorbital purpura and macroglossia have poor sensitivity (10-20%) of diagnosing amyloidosis, but are specific for the diagnosis.
Altered speech quality may be an early manifestation of systemic amyloidosis, and is seen in most cases.
When visceral involvement occurs hepatomegaly and enlarged kidneys may occur.
Patients may experience hypotension due to low cardiac output or autonomic neuropathy.
If the tricuspid or mitral valve is infiltrated with amyloid, regurgitation murmurs may be heard.
Diagnostic evaluation to provide early diagnosis includes: findings on physical examination, cardiac biomarker studies, noninvasive tests, and myocardial biopsy and genetic studies.
Differential diagnosis: infiltrative cardiomyopathy of glycogen storage disease, Fabry disease, Hurler disease, Hypertensive Heart Disease and hypertrophic cardiomyopathy.
Laboratory tests include:
Elevated levels of troponin T have been seen patients with familial amyloid polyneuropathy (FAP), systolic dysfunction, and left ventricular (LV) hypertrophy (LVH).
High plasma BNP levels may be useful as prognostic markers of cardiac function in patients with senile systemic amyloidosis.
BNP levels are not useful is a cardiac prognostic marker for cardiac functions in patients with FAP.
Elevated NT-pro-BNP levels are noted in patients with FAP.
NT-proBNP has high sensitivity for cardiac involvement in patients with systemic light chain amyloidosis.
NT-proBNP in combination with echocardiography appears to make the diagnosis of cardiac amyloidosis without the need for endomyocardial biopsy.
Two-dimensional transthoracic echocardiography is most commonly used in the initial assessment and may reveal left ventricular (LV) thickening
Left ventricular (LV) thickening in the absence of hypertension is highly suggestive of an infiltrative heart disease .
Infiltrative heart disease is not specific for amyloidosis: other conditions, such as sarcoidosis, hemochromatosis, and glycogen storage diseases are considered.
Lack of LV hypertrophy (LVH) and septal thickness greater than 1.98 cm had a sensitivity of 72% and specificity of 91% to detect amyloidosis.
Preserved LV ejection fraction (LVEF) is common.
Reduced LV systolic function is seen late in the course of the disease.
Early impairment of long axis contraction is seen .
The major finding in cardiac amyloid disease is diastolic dysfunction that progresses over time.
Restrictive mitral in-flow filling pattern on Doppler evaluation is the result of diastolic dysfunction.
Doppler imaging of the mitral annulus shows reduced diastolic velocities with cardiac amyloidosis.
RV dilatation is a a marker of poor prognosis, and RV dysfunction is common in cardiac amyloidosis, and a tricuspid annular plane systolic excursion below 14 mm is an independent predictor of adverse cardiac events.
Left atrial size is an independent predictor of overall survival in patients with primary systemic amyloidosis.
The extent of left atrial enlargement on CMRI is highly predictive for cardiac amyloidosis.
Late gadolinium-enhanced (LGE) cardiovascular magnetic resonance imaging (CMRI) is of a great diagnostic value in the diagnosis of cardiac amyloidosis.
Amyloid infiltration of the myocardium leads to the expansion of extracellular space that retains the gadolinium.
As a result the signal enhances in comparison with normal myocardium, which can be detected in the late washout phase during delayed enhanced imaging.
On magnetic resonance imaging global subendocardial enhancement is the most common pattern.
Cardiac MRI is the most accurate predictor of biopsy positive cardiac amyloidosis, with a sensitivity and specificity of 88% and 95%, respectively.
Lower epicardial gadolinium uptake is a marker of better survival in patients with amyloidosis.
The cardiac extracellular volume was significantly greater in patients with amyloidosis than in control individuals.
There is a correlation between extracellular volume and a patient’s LVEF and LV diastolic function, the mean wall thickness of the left ventricle, RVEF, cardiac troponin level, and N-terminal fragments of proBNPs.
Extracellular volume could be used to distinguish between patients with amyloidosis and control individuals with a 79% sensitivity and 97% specificity.
Patients with cardiac amyloidosis may have extensive late gadolinium-enhanced (LGE) of the left atrial myocardium, associated with markedly reduced left atrial emptying function.
The extent of the left atrial LGE was highly predictive for cardiac amyloidosis.
On late gadolinium-enhanced (LGE) MRI global subendocardial enhancement is the most common pattern.
CMRI is the most accurate predictor of biopsy positive cardiac amyloidosis, with a sensitivity and specificity of 88% and 95%, respectively.
The measurement of myocardial extracellular volume with CMRI with or without gadolinium enhancement can be used in the diagnosis and monitoring of cardiac amyloidosis.
The cardiac extracellular volume was significantly greater in patients with amyloidosis than in control individuals.
There is a correlation between extracellular volume and a patient’s LVEF and LV diastolic function and with the mean wall thickness of the left ventricle, as well as with the RVEF, cardiac troponin level, and N-terminal fragments of proBNPs.
Extracellular volume could be used to distinguish between patients with amyloidosis and control individuals with a 79% sensitivity and 97% specificity.
Using CMRI and echocardiographic evaluation patients with cardiac amyloidosis may have extensive late-gadolinium enhanced (LGE) of the left atrial myocardium, associated with markedly reduced left atrial emptying function.
Left atrial LGE is highly predictive for cardiac amyloidosis.
ECG abnormalities seen in cardiac amyloidosis include:
Low voltage complexes seen in 46% of cases.
Atrial fibrillation.
Pseudo-infarct pattern is seen in 46% of cases
Both low voltage complexes and pseudo-infarct pattern are seen in 25% of cases.
Left ventricular hypertrophy is an unusual finding.
Atrial fibrillation and flutter are most common arrhythmias.
Intraventricular conduction delay may be seen, but high-degree atrioventricular (AV) block is unusual at about 3%.
ECG Low-voltage complexes on ECG and increased mass on echocardiography are predictors of infiltrative cardiomyopathy.
Late ECG potentials and are predictive of sudden cardiac death.
Lack of heart rate variability due to autonomic dysfunction, is an important predictor of 1-year mortality.
Sinus and atrioventricular node functions are preserved in most patients.
The Infra-His conduction interval is usually prolonged (> –55 ms), and
may be an independent predictor of sudden death.
Electromyocardia biopsy (EMB) is the standard for diagnosis.
Amyloid tissue with Congo red stain, appears as a amorphous pink deposit under light microscopy and has a green-apple birefringence under polarized microscopy.
As an alternate stain Sulfated Alcian blue can be used with a high specificity for the diagnosis of amyloidosis.
EMB has almost 100% sensitivity due to the diffuse cardiac involvement and allows differentiating cardiac amyloidosis from other infiltrative myocardial conditions.
Rectal submucosal biopsy has a sensitivity of greater than 75% for detecting amyloidosis but carries a risk of bleeding and rectal perforation.
Abdominal fat needle aspiration biopsy has a sensitivity of approximately 75%, and can obviate the need for a cardiac biopsy.
Bone marrow biopsy can evaluate
plasma cell burden and to exclude myeloma and other plasma cell disorders like Waldenstrom macroglobulinemia.
Management of amyloidosis includes: supportive measures for symptomatic problems, andmanagement of congestive heart failure.
Agents tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax) for cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM) in adults in May 2019.
Each drug has the same active moiety, tafamidis, but their recommended doses differ.
All-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo.
After an average of 30 months, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire.
Tafamidis stabilizes the tetrameric transthyretin proteins and is associated with the reductions in death from any cause and cardiovascular related hospitalization after 30 months, compared with placebo, but on average, functional capacity and quality of life declined among patients treated with tafamidis.
No preventive strategies are effective for primary amyloidosis.
Secondary amyloidosis improves after treatment of its underlying condition.
Negative inotropic effects that are rate-limiting calcium channel blocking agents (ie, verapamil, diltiazem) are contraindicated, as they can precipitate congestive heart failure.
Melphalan and prednisone have been used with limited benefit in cardiac amyloidosis.
Cyclophosphamide and thalidomide have also been used as an alternative therapy.
Colchicine has also been used sometimes.
Autologous stem cell transplantation and high-dose chemotherapy have shown promise in patients with limited cardiac involvement, with increased survival and better quality of life.
In a combination of cyclophosphamide/bortezomib/dexamethasone the overall hematologic response rate was 60%.
In another study, use of triple therapy (bortezomib, dexamethasone, and an alkylating agent) in the treatment of patients with AL who presented with symptomatic heart failure resulted in improved survival after adjustment of clinical variables.
Cardiac transplantation with cardiac involvement is associated with increased mortality.
A Mayo Clinic study showed a median overall survival of 3.5 years in 23 patients with AL who received orthotopic heart transplantation.
Among patients who achieve a complete hematologic response to either chemotherapy or autologous stem cell transplantation have a median survival of 10.8 years.
Loop diuretics relieve peripheral and pulmonary congestion, and are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites.
Calcium channel blockers and digoxin may lead to symptom exacerbation because they bind to amyloid fibrils.
Patients with evidence of heart failure require diuretic therapy.
Inotropic agents are used in patients who need hemodynamic-directed treatment during acute decompensation, those refractory to maximal standard therapy, as palliation for end-stage heart failure, or as a bridge to transplantation for appropriate candidates.
Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system.
Digoxin acts directly on cardiac muscle, increasing myocardial systolic contractions.
Digoxin indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
Digoxin binds to amyloid fibrils and predisposes these patients to digoxin toxicity.
A low dose of digoxin is used, when indicated, as toxicity can occur even when serum digoxin level is in the therapeutic range.
Patients receiving digoxin should be closely monitored for electrocardiographic evidence of digoxin toxicity .
Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are poorly tolerated in cardiac amyloidosis.
Digoxin binds to amyloid fibrils and can lead to locally high levels, therefore is used with caution.
There is high incidence of sudden death in patients with TTR cardiac amyloidosis, and prophylactic placement of an implantable cardioverter defibrillator (ICD)should be considered.
Antiarrhythmic drugs are useful in patients with supraventricular and nonsustained ventricular tachycardias.
Amiodarone may improve mortality rates in patients with cardiomyopathy.
It is better tolerated and should be used in patients with atrial fibrillation.
Dose of warfarin should be reduced, and digoxin should not be administered concurrently with amiodarone in patients with amyloidosis.
Anticoagulation therapy is indicated in patients with atrial fibrillation or documented cardiac thrombi.
Drugs that stabilize the amyloidogenic process may slow disease progression.
Tafamidis a selective stabilizer of TTR, is indicated for cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.
Tafamidis binds to TTR at thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
Tafamidis and tafamidis meglumine are not interchangeable on a mg-per-mg basis.
Tafamidis meglumine is indicated for cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.