Cardiac Amyloidosis

Updated: Mar 25, 2020
Author: Gyanendra K Sharma, MD, FACC, FASE; Chief Editor: Terrence X O'Brien, MD, MS, FACC 



Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble fibrils (approximately 7.5-10 nm wide) with beta-pleated sheet configuration.[1] The protein misfolding abnormalities result in amyloid fibrils and may manifest as primary, secondary, familial, or senile amyloidosis. Amyloid deposition can occur in multiple organs (eg, heart, liver, kidney, skin, eyes, lungs, nervous system) resulting in a variety of clinical manifestations.[2] Cardiac involvement is a progressive disorder resulting in early death due to congestive heart failure (CHF) and arrhythmias. Cardiac involvement can occur as part of a systemic disease or as a localized phenomenon.[3, 4]

Educating patients about dietary restrictions and medications is useful. Education about symptoms of heart failure and stroke would be helpful in guiding patients to seek early medical advice.

This article provides an overview of the primary systemic amyloidosis (AL) that predominantly affects the heart.[5] In the last few years amyloid transthyretin (ATTR) cardiomyopathy has been better defined with ease of diagnosis and newer therapeutic options.


The characteristic abnormality in amyloidosis is an abnormal folding of a protein, rendering it to be insoluble.[6] These abnormalities may be a result of genetic mutations or excess formation. Various proteins may form amyloid fibrils; light chain amyloidosis (AL) is the most common type of systemic amyloidosis that results from the proliferation of plasma cells in the bone marrow. The plasma cell burden in AL is about 5-10% and is a marker of poor prognosis.[7, 8] Lambda light chains are 3 times more likely involved than kappa chains.

Most cases of AL are associated with a benign monoclonal gammopathy. Only rarely is AL seen in patients with multiple myeloma, lymphoma, or macroglobulinemia. Amyloid deposition in the tissues causes disruption of architecture, induces oxidant stress, and results in organ dysfunction. Multiorgan involvement is common. Cardiac involvement is most common in the AL variety 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. The myocardium becomes thick (mean weight 500 g) with a rubbery consistency.[9] High-grade infiltration (>50%) of myocardium is most common in the AL variety, and 90% of cases have vascular involvement.[10] Epicardial vessels are typically spared, but microvascular involvement is common, resulting in tissue ischemia and infarction.[11, 12, 13] Resultant myocardial fibrosis adds to the myocardial dysfunction, causing heart failure and cardiac arrhythmias.

The ventricular cavities are typically normal in size, but the ventricles are stiff, which cause restrictive ventricular filling and biatrial enlargement. Pericardial involvement is common and leads to pericardial effusion.[14] Endocardial involvement may result in atrioventricular valve dysfunction. Intracardiac thrombosis is common and seen in about 33% cases in autopsy specimens.[15] The thickening of the left heart valves is common in patients with AL, is associated with advanced age, and increases all-cause mortality.[16] These patients have poor functional class and worse systolic and diastolic function.[16]

Conduction system abnormalities (ie, bundle branch block and atrioventricular block) are frequent in amyloidosis. In a small series, severe sinoatrial node fibrosis was seen in 30% cases.[17]


Primary amyloidosis (AL) is a type of plasma cell dyscrasia and is the most common type involving the heart.

Secondary systemic amyloidosis seen in chronic inflammatory conditions rarely involves the heart. Organ dysfunction is usually reversible with resolution of the underlying inflammatory disorder.

Familial or hereditary amyloidosis occurs because of a mutation in the transthyretin (TTR) gene located on the chromosome 18. Most patients with ATTR have heterozygous mutation and autosomal dominant inheritance.

Senile systemic amyloidosis, also known as wild-type transthyretin (wt-TTR), is common in people over 70 years of age and has a better prognosis.


United States statistics

Systemic amyloidosis (AL) is a rare disorder, and it is difficult to estimate the exact incidence due to changing diagnostic criteria. In Olmsted County, Minnesota, only 21 cases were diagnosed from Jan 1950 to Dec 1989. In this first population-based study, the incidence of AL was approximately 8.9 per million person years.[18] In the United States, approximately 2000-2500 cases of AL are diagnosed annually.[19]

International statistics

Amyloidosis is reported as a cause of death in 1 in 1000 of the British population.

Race, sex-, and age-related differences in incidence

AL is uncommon in non-white individuals and persons younger than 40 years,[20] and it affects men and women equally. Senile amyloidosis, in which wild-type transthyretin (wt-TTR) accumulates in tissue and leads to the development of cardiac dysfunction,[21] is 3 times more common in elderly black patients compared to white patients (8.2% vs 2.7%, respectively)[22] and is more common in males.[23] Hereditary cardiac amyloidosis resulting from a mutation in TTR (>100 TTR variants[24] ) is more common in black individuals than white persons; 23% of the patients have this variant.[25] .

AL type is usually seen in persons older than age 50 years. Although unusual, it can occur as early as the third decade of life. Late onset amyloidosis (senile) is seen in elderly patients and has a better prognosis than primary amyloidosis.


In general, cardiac involvement is a marker of poor prognosis.[26, 27] Therefore, any clinical, laboratory or imaging abnormality that suggests increased cardiac involvement will be indicative of a worse prognosis. No consensus has been reached about a single most important prognostic factor. The factors associated with a poor prognosis include the following:

  • Congestive heart failure

  • Syncope

  • Complex arrhythmia

  • Degree of left ventricular (LV) hypertrophy (More = worse prognosis)

  • 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

  • T1 kinetics on gadolinium-enhanced magnetic resonance imaging (MRI) (to demonstrate extent of myocardial involvement)


Amyloidosis has a poor prognosis, and the median survival without treatment is only 13 months. Cardiac involvement has the worst prognosis and results in death in about 6 months after onset of congestive heart failure. Only 5% of the patients with primary amyloidosis survive beyond 10 years.[28] Among 82 patients with cardiac amyloidosis, New York Heart Association (NYHA) class and right ventricular systolic dysfunction (tricuspid annular plane systolic excursion [TAPSE] < 14 mm) independently predicted major adverse cardiac events.[29]


Complications include the following:

  • Atrial fibrillation

  • Congestive heart failure

  • Embolism and stroke

  • Ventricular arrhythmias

  • Heart block requiring pacemaker implantation

  • Pericardial tamponade

  • Death




Systemic amyloidosis (AL) is a complex multisystem disorder, and symptoms depend on the organ involvement.[30] Symptoms occur because of infiltrative cardiomyopathy and diastolic dysfunction. Approximately half of the patients with cardiac involvement present with right-sided heart failure. Patients may present with the following signs and symptoms[20] :

  • Fatigue and weakness (most common symptoms)

  • Dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea

  • Leg edema

  • Dizziness

  • Presyncope/syncope[31]

  • Postural hypotension
  • Easy bruising

  • Angina[13, 32]

  • Pleural effusion, pulmonary edema (rare)

  • Sudden cardiac death

  • Pericardial effusion, cardiac tamponade (rare)[33]

  • Heart block[34]

  • Ischemic stroke (in 30% cases, cardioembolic in the remaining 70%)[35]

  • Painful polyneuropathy (10-20% cases)

  • Carpal tunnel syndrome (20%)[36]

  • Pulmonary amyloid infiltration, pulmonary hypertension, and cor pulmonale

  • Abnormal voice quality

Physical Examination

Physical examination findings in primary amyloidosis are consistent with features of right-sided heart failure and includes elevated jugular venous pressure, right-sided third heart sound, and lower extremity edema. A prominent fourth heart sound is present in patients without atrial fibrillation.

Periorbital purpura and macroglossia are specific for the presence of disease but have poor sensitivity (10-20%). Abnormal phonation resulting in a change in speech quality is seen in most cases and may be an early feature of systemic amyloidosis.[37] Visceral involvement may result in the enlargement of liver and kidneys. Ascites and pleural effusion may be present. The patient may present with bilateral carpel tunnel syndrome or painful peripheral neuropathy.

Hypotension may be from low cardiac output or autonomic neuropathy. Murmurs of tricuspid or mitral regurgitation may be present in patients with valvular infiltration of amyloid.



Diagnostic Considerations

Owing to the complexity of, and multisystem involvement in, cardiac amyloidosis, clinicians need to have a high index of suspicion for this condition and its varied presentation,[30] particularly in patients who present with heart failure and preserved ejection fraction.[38] Early recognition and treatment is essential in stopping the disease process before irreversible damage has occurred and improving survival.[38] Diagnostic evaluation includes findings on physical examination in conjunction with results of cardiac biomarker studies, noninvasive tests, and myocardial biopsy (as needed). Identification of the type of amyloidosis requires genetic studies.[30]

Clinicians should also consider infiltrative cardiomyopathy (ie, glycogen storage disease, Fabry disease, Hurler disease, and others) when evaluating patients with suspected cardiac amyloidosis.

Differential Diagnoses



Laboratory Studies

Laboratory tests include measurements of the following:

  • Troponin: Elevated levels of troponin T have been seen in patients with familial amyloid polyneuropathy (FAP), systolic dysfunction, and left ventricular (LV) hypertrophy (LVH).[39]

  • B-type natriuretic peptide (BNP): High plasma BNP levels may be useful as prognostic markers of cardiac function in patients with senile systemic amyloidosis (but not FAP).[21]

  • N-terminal pro-brain natriuretic peptide (NT-proBNP): Elevated NT-pro-BNP levels, whether or not accompanied by findings of increased LV filling pressures, have been noted in patients with FAP, systolic dysfunction, and/or LVH.[39] NT-proBNP has high sensitivity for cardiac involvement in patients with systemic light chain amyloidosis; the combination of NT-proBNP with echocardiography appears to make the diagnosis of cardiac amyloidosis without the need for endomyocardial biopsy.[40]  A negative NT-proBNP appears to exclude clinically meaningful cardiac involvement and may remove the need for routine use of TTE in patients at low clinical suspicion for cardiac amyloidosis.[40]

  • Urine for proteinuria

  • Serum and urine protein electrophoresis

  • Serum and urine immunofixation (more sensitive than electrophoresis)

  • Transthyretin protein (TTR): TTR has been found in patients with senile systemic amyloidosis[24] and TTR variants of familial systemic amyloidosis.[21]

  • Genetic studies: Identification of the specific type of amyloidosis is important.[30]


Two-dimensional transthoracic echocardiography (2D-TTE)[41, 42, 43] is most commonly used in the initial assessment[44] and may reveal the following abnormalities:

  • Left ventricular (LV) thickening (most common) in the absence of hypertension is highly suggestive of an infiltrative heart disease (not specific for amyloidosis and also seen in other conditions, such as sarcoidosis, hemochromatosis, and glycogen storage diseases). Lack of LV hypertrophy (LVH) on electrocardiography (ECG) and septal thickness greater than 1.98 cm had a sensitivity of 72% and specificity of 91% to detect amyloidosis.[45]

  • LV myocardium has granular or sparkling appearance (poor sensitivity: seen only in 26% cases; see the images below).

  • Long axis parasternal view: Left ventricular hypertrophy (LVH) with sparkling appearance, pericardial effusion.
  • Short axis view: Left ventricular hypertrophy (LVH), pericardial effusion, normal RV size.
  • Normal or small LV cavity dimensions is seen.

  • Preserved LV ejection fraction (LVEF) is common, and reduced LV systolic function is seen late in the course of the disease.

  • Impairment of long axis contraction is seen early. This can be shown on abnormalities of strain rate imaging.[46]

  • Diastolic dysfunction is the hallmark of the disease and progresses over time, resulting in restrictive mitral in-flow filling pattern on Doppler evaluation.[47, 48] Tissue Doppler imaging of the mitral annulus shows reduced diastolic velocities with cardiac amyloidosis and is useful to differentiate it from constrictive physiology, in which early diastolic mitral annular velocity (E') is above 8 cm/s.[49] Longitudinal strain of the LV basal segments and E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity) can help to differentiate primary cardiac amyloidosis from hypertensive LVH.[50] Investigators found that cardiac amyloidosis was predicted by basal longitudinal strain of -11.3% or below (63.3% sensitivity, 100% specificity) and an E/e' of 12.3 or greater (69.7% sensitivity, 83.3% specificity).[50] Longitudinal strain can also be used as a measure of pretreatment cardiac functional impairment in light chain cardiac amyloidosis; in addition, it can predict survival and early cardiac functional improvement following chemotherapy.[51]

  • Right ventricular (RV) hypertrophy (RVH)

  • RV dilatation (a marker of poor prognosis): RV dysfunction is common in cardiac amyloidosis, and a tricuspid annular plane systolic excursion (TAPSE) below 14 mm is an independent predictor of adverse cardiac events.[52] Independent determinants of TAPSE below 14 mm are LVEF, E/E', N-terminal pro b-type natriuretic peptide (NT-proBNP) levels, and pulmonary artery pressure, but not RV late gadolinium-enhancement (LGE) on cardiac magnetic resonance imaging (CMRI).[52]

  • Left atrial enlargement, biatrial enlargement (late): Left atrial size is an independent predictor of overall survival in patients with primary systemic amyloidosis[53] ; the extent of left atrial LGE on CMRI is highly predictive for cardiac amyloidosis.[54]

  • Thickened interatrial septum

  • Thickened atrioventricular valves

  • Small pericardial effusion

Three-dimensional speckle tracking TTE (3D-TTE) may allow earlier detection of LV systolic dysfunction in patients with systemic light-chain amyloidosis than 2D-TTE.[44] In a study of 58 patients with confirmed light chain amyloidosis and 21 healthy control subjects, investigators noted 3D-TTE demonstrated significantly worse LV systolic function in Mayo Clinic (MC) stage II and III patients compared to control subjects, and that MC III patients had significantly worse global circumferential strain and area tracking. In addition, although 2D-TTE revealed apparently preserved LVEF in patients with light chain amyloidosis in MC stage II and III, 3D-TTE showed evidence of LV systolic dysfunction using LVEF and strain analysis. Worse LV involvement by light chain amyloidosis was associated with more impaired 3D-TTE LV systolic parameters.[44]

Cardiovascular Magnetic Resonance Imaging

Late gadolinium-enhanced (LGE) cardiovascular magnetic resonance imaging (CMRI) is of a great diagnostic value in the evaluation of cardiac amyloidosis. Amyloid infiltration leads to the expansion of extracellular space that retains gadolinium, resulting in signal enhancement in comparison with normal myocardium, which can be detected in the late washout phase during delayed enhanced imaging. Global subendocardial enhancement is the most common pattern.[28, 55, 56, 57, 58]

Short axis left ventricle: Global subendocardial g Short axis left ventricle: Global subendocardial gadolinium enhancement.

The gadolinium wash-out time is increased, and the myocardium appears bright in contrast to normal myocardium that appears black. CMRI is the most accurate predictor of biopsy positive cardiac amyloidosis, with a sensitivity and specificity of 88% and 95%, respectively. T1 kinetics (intramyocardial T1 gradient) to denote lower epicardial gadolinium uptake is a marker of better survival in patients with amyloidosis.

A study by Barison et al indicated that the measurement of myocardial extracellular volume with CMRI with or without gadolinium enhancement can be used in the diagnosis and monitoring of cardiac amyloidosis.[59] Using a novel T1-mapping technique, the investigators found that the cardiac extracellular volume was significantly greater in patients with amyloidosis than in control individuals, with the volume difference being apparent whether or not LGE was used. They also found that a correlation existed 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. In addition, using an extracellular volume cutoff value of over 0.316, Barison et al found that extracellular volume could be used to distinguish between patients with amyloidosis and control individuals with a 79% sensitivity and 97% specificity.[59]

Using CMRI and echocardiographic evaluation to study 22 patients with biopsy-proven cardiac amyloidosis, 37 with systemic hypertension, and 22 with nonischemic dilated cardiomyopathy, Kwong et al found that patients with cardiac amyloidosis may have extensive LGE of the left atrial myocardium, associated with markedly reduced left atrial emptying function.[54] The extent of the left atrial LGE was highly predictive for cardiac amyloidosis.[54]

In patients with LGE-negative systemic amyloidosis on CMRI, CMR strain analysis appears to have the ability to detect early systolic and diastolic strain impairment.[60] In a study that evaluated 34 patients (17 each) with LGE-positive or LGE-negative light-chain amyloidosis and 17 healthy controls, Kuetting et al found that regardless of whether patients had LGE or not, their early diastolic strain rate (EDSR) and peak systolic longitudinal strain (PSLS) values were significantly lower than that of their healthy cohorts. Quantitative LGE-enhancement analysis showed increased enhancement in qualitative LGE-negative patients relative to the healthy control group.[60]

Other Imaging Studies

Nuclear imaging

Nuclear imaging was not typically used for the diagnosis of amyloidosis. Increased uptake of radio-labeled technetium has been reported in patients with cardiac amyloidosis and correlates well with cardiac involvement.[61, 62] Technetium-99m pyrophosphate scintigraphy (99mTc-PYP) is used to differentiate ATTR from AL with a sensitivity of 97% and specificity of 100%.[63]

Radiolabeled serum amyloid P (SAP) component scintigraphy

SAP component plasma glycoprotein is seen in all types of amyloid deposits. After intravenous injection of radiolabeled SAP, scanning is done to assess its distribution and extent of organ involvement. This method cannot be used for evaluation of cardiac amyloidosis because of the heart's movement, but it is of value in assessment of systemic amyloidosis.[64]

Electrocardiography and Holter Monitoring

Electrocardiography (ECG)

The following ECG abnormalities have been reported:[17, 45, 65]

  • Low voltage complexes (QRS amplitude ≤ 0.5 mV in limb leads or ≤ 1.0 mV in all precordial leads) are seen in 46% of cases (see image below).

    Low voltage complexes, atrial fibrillation. Low voltage complexes, atrial fibrillation.
  • Pseudo-infarct pattern is seen in 46% of cases (most common anteriorly).

  • Both low voltage complexes and pseudo-infarct pattern are seen in 25% of cases.

  • Left ventricular (LV) hypertrophy is unusual.

  • Atrial fibrillation and flutter are most common arrhythmias (20%).

  • Intraventricular conduction delay is seen.

  • High-degree atrioventricular (AV) block is unusual (3%).

  • Low-voltage complexes on ECG and increased mass on echocardiography are the best predictors of infiltrative cardiomyopathy.

Signal-averaged ECG

Late ECG potentials are seen in 31% patients with echocardiographic evidence of cardiac amyloidosis and are predictive of sudden cardiac death.[66]

Holter monitoring

Cardiac Holter monitoring may show lack of heart rate variability due to autonomic dysfunction. It is an important predictor of 1-year mortality.[67] Detecting ventricular arrhythmias and conduction abnormalities is also helpful.

Electrophysiologic Abnormalities

Electrophysiologic studies reveal the following feature:

  • Sinus and atrioventricular node functions are preserved in most patients.

  • Infra-His conduction interval is usually prolonged (> –55 ms).

  • In one study in which 23 patients who died during follow-up, infra-His prolongation was the sole independent predictor of sudden death by multivariate analysis (P = 0.05).[68]

Histologic Findings

Endomyocardial biopsy

Electromyocardia biopsy (EMB) is considered the criterion standard for diagnosis. Amyloid tissue, when stained with Congo red, appears as an amorphous pink deposit under light microscopy and has a green-apple birefringence under polarized microscopy. Sulfated Alcian blue can be used as an alternative stain with a high specificity for the diagnosis of amyloidosis. EMB has a great sensitivity (almost 100%) due to the diffuse cardiac involvement and is a safe procedure in experienced hands. EMB is also of a great value in differentiating cardiac amyloidosis from other infiltrative myocardial conditions.[69, 70, 71]

Rectal submucosal biopsy

Rectal submucosal biopsy has been a traditional site in the past. It has a sensitivity of greater than 75% for detecting amyloidosis but carries a risk of bleeding and rectal perforation.[72]

Abdominal fat biopsy

Needle aspiration biopsy of the abdominal fat is a simple and commonly performed procedure in the patient suspected of having amyloidosis with a sensitivity of approximately 75%. If positive, it obviates the need for a cardiac biopsy in the right clinical setting.[73]

Bone marrow biopsy

Bone marrow biopsy is useful to assess plasma cell burden and to exclude myeloma and other disorders like Waldenstrom macroglobulinemia.



Approach Considerations

Management of amyloidosis includes supportive measures for symptomatic relief, management of congestive heart failure, and specific measures toward underlying amyloid disease. Patients with large pleural effusions may need thoracentesis.

The US Food and Drug Administration (FDA) approved tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax) for cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM) in adults in May 2019.[74] These are the first FDA-approved treatments for ATTR-CM. Although each product has the same active moiety, tafamidis, they are not substitutable on a milligram-to milligram basis and their recommended doses differ.[74]

The efficacy of tafamidis was shown in a clinical trial of 441 patients randomized to receive tafamidis meglumine or a placebo.[74, 75] 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 (P< 0.001).[75] After an average of 30 months, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P < 0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (P< 0.001).[75]

Hospitalization may be needed for management of heart failure. Selected patients may require transfer to the centers where facilities for chemotherapy are available.

Patients should be advised to take a salt-restricted diet as well as check their weights on a regular basis to assess for volume status. Activity can be performed as tolerated

Waist-high elastic stockings may be useful in patients with orthostatic hypotension.

Follow-up is performed in the heart failure clinic. No preventive strategies are applicable to primary amyloidosis. Secondary amyloidosis improves after treatment of underlying condition.


Surgical consultation for abdominal fat pad or rectal biopsy is suggested. Other suggested consultations include the following:

  • Hematology/oncology specialists

  • Cardiology consultation for management of heart failure

  • Electrophysiology consultation for pacemaker implantation when clinically indicated



Guidelines Summary

In February 2020, the Canadian Cardiovascular Society (CCS) and Canadian Heart Failure Society (CHFS) released their recommendations on selected topics of high clinical relevance in the management of heart failure (HF).[76] These guidelines incorporate new evidence from randomized clinical trials published after 2017.

Percutaneous Mitral Valve Repair for HF and Reduced Ejection Fraction and Severe Functional Mitral Regurgitation

The CCS/CHFS recommends maximally tolerated guideline-directed medical therapy (GDMT), including cardiac resynchronization therapy and revascularization where appropriate, be implemented before consideration of percutaneous mitral valve repair (PMVR) for patients with HF and reduced ejection fraction (HFrEF) and severe functional mitral regurgitation (FMR) (strong recommendation).

It is suggested that patients with symptomatic HF (HFrEF) despite maximal GDMT and severe mitral regurgitation be evaluated for PMVR (weak recommendation).

The CCS/CHFS recommends that a multidisciplinary dedicated heart team (including interventionalists, cardiac surgeons, imaging specialists, and HF specialists) evaluate and manage the care of potential candidates for PMVR (strong recommendation).

Practical tips

Use caution when treating FMR in patients with HFrEF.

Patients with HFrEF and FMR who have severe left ventricular (LV) dilatation (typically LV end diastolic dimension >70 mm) and less than severe mitral regurgitation may be poor candidates for PMVR with MitraClip.

Patients with FMR should first receive maximally tolerated GDMT, including pharmacologic and nonpharmacologic HF therapies (eg, cardiac resynchronization therapy where applicable) for a reasonable minimum period (eg, 3 months), before PMVR is considered.

Refer patients considered for PMVR to centers experienced in evaluating patients with advanced HF, have high volumes of patients with valve disease managed medically and surgically, and have a high likelihood of achieving the volume of PMVR (eg, 2-4 per month) required for developing and maintaining competence in well-selected patients.

Treatment of Cardiac Amyloidosis

When cardiac amyloidosis (CA) is suspected, rule out light-chain amyloidosis (AL amyloidosis) using serum free light chains (kappa and lambda), and serum and urine protein electrophoresis with immunofixation. Accurate identification of the amyloid subtype is essential to initiate specific treatment and avoid inappropriate application of therapy.

Practical tips

In the setting of undifferentiated CA, the presence of light chains does not confirm the diagnosis of light chain cardiac amyloidosis (AL-CA) because monoclonal gammopathy of unknown significance and transthyretin cardiac amyloidosis (ATTR-CA) can coexist. In such settings, tissue biopsy is often necessary to exclude AL-CA.

Perform technetium-labeled scintigraphy, where available, to diagnose ATTR-CA when plasma cell dyscrasias have been ruled out.

Patient selection for tafamidis, a transthyretin tetramer stabilizer, should reflect the inclusion criteria for the Transthyretin Amyloidosis Cardiomyopathy Trial (ATTR-ACT) that showed clinical benefits of tafamidis over placebo with respect to mortality and cardiovascular hospitalization, including established ATTR-CA and objective evidence of HF (with elevated natriuretic peptides, where available).

Do not routinely consider treatment with tafamidis for patients with New York Heart Association (NYHA) class IV symptoms or severe functional disability, measured using a 6-minute walk test < 100 m. (These patient were excluded from ATTR-ACT.) Subgroup analysis from the ATTR-ACT trial suggested that the reduction in cardiovascular hospitalizations seen with tafamidis might be limited to patients with less severe symptoms (NYHA class I or II).

Because of the complexity in diagnosing CA and the potential for offering advanced or experimental treatment options, consider referring patients with CA to experienced centers. Other agents are currently under investigation, which might modify current treatment recommendations.

New Evidence for Angiotensin Receptor Neprilysin Inhibitors in HFpEF

The Prospective Comparison of ARNI (angiotensin receptor-neprilysin inhibitors) with ARB (angiotensin-receptor blockers) Global Outcomes in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) trial, which compared sacubitril/valsartan with valsartan in HFpEF patients, showed a modest but nonsignificant 13% reduction in the primary outcome of first and recurrent HF hospitalizations and cardiovascular death. A secondary end point analysis revealed improvement in quality of life and renal function, which suggested potential benefits with sacubitril/valsartan compared with valsartan. The data further suggest heterogeneity in the treatment response with greater benefit in women and in individuals with a lower LVEF.

The CCS/CHFS indicate that the statistically negative results of the primary end point analysis preclude any recommendation for the general use of sacubitril/valsartan in patients with HFpEF.

New Evidence for SGLT2 Inhibitors and HF

The CCS/CHFS recommend use of SGLT2 inhibitors (eg, empagliflozin, canagliflozin, dapagliflozin) for treatment of patients with type 2 diabetes and atherosclerotic cardiovascular disease to reduce the risk of HF hospitalization and death (strong recommendation).

SGLT2 inhibitors, such as dapagliflozin, are recommended for use in patients with the following features:

  • Type 2 diabetes, aged >50 years, with additional risk factors for atherosclerotic cardiovascular disease, to reduce the risk of HF hospitalization (strong recommendation)

  • Mild to moderate HF due to reduced LVEF (≤ 40%) and concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (strong recommendation)

  • Mild to moderate HF due to reduced LVEF (≤ 40%) and without concomitant diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (conditional recommendation)

The CCS/CHFS recommend SGLT2 inhibitors, such as canagliflozin, be used in patients aged >30 years with type 2 diabetes, and macroalbumineric renal disease, to reduce the risk of HF hospitalization and progression of renal disease (strong recommendation).

Practical tips

Note that SGLT2 inhibitors are currently contraindicated for patients with type 1 diabetes.

The most common adverse effects of SGLT2 inhibitors are genital mycotic infections (GMIs), with the highest risk in women (10%-15% risk), those with previous GMIs, and uncircumcised men. GMIs can generally be managed with antifungal drugs and do not require discontinuation of therapy.

SGLT2 inhibitors might result in an up to 15% temporary reduction of estimated glomerular filtration rate (eGFR) (usually resolves within 1-3 months). These drugs have also been associated with acute kidney injury, and increased monitoring is warranted in those at risk.

SGLT2 inhibitors do not cause hypoglycemia in the absence of concomitant insulin and/or secretagogue therapy. Background therapies might need adjustment to prevent hypoglycemia.

SGLT2 inhibitors should be held in the setting of concomitant dehydrating illness as part of “sick day” management. Patients should be educated on “sick day” management.

These agents have been associated with diabetic ketoacidosis (incidence 0.1%). Patients might present with normal or only modestly elevated blood glucose level (< 14 mmol/L). Rarely, SGLT2 inhibitors might be associated with normal anion gap acidosis (best detected with measurement of serum ketones). Nonspecific symptoms associated with diabetic ketoacidosis include dyspnea, nausea/vomiting, abdominal pain, confusion, anorexia, excessive thirst, and lethargy.

Exercise caution when combining SGLT2 inhibitors, ARNIs, and diuretics because of their concomitant effects to promote diuresis.

For more information, please go to Heart Failure, Transthyretin-Related Amyloidosis, and Risk Factors for Coronary Artery Disease.

For more Clinical Practice Guidelines, please go to Guidelines.



Medication Summary

The goals of pharmacotherapy include symptom relief, improved cardiac output, shortened hospital stay, fewer emergency department visits, and decreased mortality.

Tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax) are the first drugs approved by the FDA for cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM) in adults.[74, 75]

Because of their negative inotropic effects, 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. Better results may be obtained with the combination of melphalan and dexamethasone. 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 study that used a combination of cyclophosphamide/bortezomib/dexamethasone (CyBorD) to treat 230 patients with light chain (AL) amyloidosis, investigators found that the overall hematologic response rate was 60%.[77] Of the 201 patients with measurable disease, the overall hematologic response rate was 62%, with 43% achieving at least very good partial response (VGPR).[77] 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.[78]

Cardiac transplantation is not a good choice in patients with cardiac involvement because of increased mortality.[79, 80, 81, 82, 83, 84, 85] A 2016 Mayo Clinic study showed a median overall survival of 3.5 years in 23 patients (median age, 53 years) with AL who received orthotopic heart transplantation.[86] Seven patients who achieved a complete hematologic response to either chemotherapy or autologous stem cell transplantation had a median survival of 10.8 years.[86]

Diuretics, Loop

Class Summary

These agents relieve peripheral and pulmonary congestion. They promote excretion of water and electrolytes by the kidneys and are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites.

Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The bioavailability of oral furosemide is 50%. If a switch is made from IV to oral administration, an equivalent oral dose should be used. Doses vary depending on the patient's clinical condition.

Patients with evidence of heart failure require diuretic therapy. As these patients are preload dependent, such a therapy should be judiciously used to avoid hypotension and depletion of intravascular volume.

Inotropic Agents

Class Summary

Inotropic agents are reserved for 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 (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. 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.[62] A low dose of digoxin should be used when indicated, as toxicity can occur even when serum digoxin level is in the therapeutic range. No precise dose recommendation can be made due to lack of evidence. Patients receiving digoxin should be closely monitored for electrocardiographic evidence of digoxin toxicity (eg, heart block, ventricular arrhythmia, junctional rhythm).

Antidysrhythmics, III

Class Summary

Antiarrhythmics are useful in patients with supraventricular and nonsustained ventricular tachycardias. Not all antiarrhythmics are considered safe in patients with structural heart disease.

Amiodarone (Cordarone)

Amiodarone may inhibit atrioventricular conduction and sinus node function. It prolongs the action potential and refractory period in myocardium and inhibits adrenergic stimulation. Amiodarone may improve mortality rates in patients with cardiomyopathy.

It is better tolerated and should be used in patients with atrial fibrillation. Amiodarone can be used intravenously (150 mg IV bolus; then 1 mg/minute for 6 hrs followed by 0.5 mg/minute for 18 hrs or by mouth 400 mg 3 times daily for 7 days followed by 400 mg twice daily for 1 week as a loading dose. The usual maintenance dose is 200-400 mg daily. The patients should be closely followed for amiodarone toxicity, including QT prolongation, hepatic, and thyroid function abnormalities. Dose of warfarin should be reduced, and digoxin should not be administered concurrently with amiodarone in patients with amyloidosis.

Anticoagulants, Cardiovascular

Class Summary

The use of anticoagulants is restricted to patients in atrial fibrillation, with artificial valves, and with known mural thrombus. Some data support their use in patients with low ejection fractions.

Warfarin (Coumadin)

Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. Anticoagulation therapy is indicated in patients with atrial fibrillation or documented cardiac thrombi. It is also indicated in advanced amyloidosis with the loss of atrial function when thrombi can form even in presence of a sinus rhythm.[63] Usual starting dose of warfarin is 2.5-5 mg daily depending upon the age of the patient and comorbid conditions

Alpha-Adrenergic Agonists

Class Summary

These agents may reduce sympathetic outflow, which may reduce muscle tone.


Midodrine is a prodrug with activity as an alpha1-adrenoreceptor agonist. This agent is widely used to treat orthostatic hypotension. Midodrine acts directly on the vasculature to increase BP and avoids electrolyte abnormalities associated with fludrocortisone. Fludrocortisone should be avoided because of risk of salt and water retention. Midodrine has often caused an unpleasant sensation in the scalp (due to piloerection).

Usual recommended dose of Midodrine is 10 mg by mouth 3 times daily.

Transthyretin Binders

Class Summary

Accumulation of amyloid fibrils composed of misfolded transthyretin protein in the heart leads to transthyretin amyloid cardiomyopathy and heart failure. Drugs that stabilize the amyloidogenic process may slow disease progression.

Tafamidis (Vyndamax)

Tafamidis 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 is a selective stabilizer of TTR. Tafamidis binds to TTR at thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process. NOTE: Tafamidis and tafamidis meglumine are not interchangeable on a mg-per-mg basis.

Tafamidis meglumine (Vyndaqel)

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. Tafamidis is a selective stabilizer of TTR. Tafamidis binds to TTR at thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process. NOTE: Tafamidis and tafamidis meglumine are not interchangeable on a mg-per-mg basis.


Questions & Answers


What is cardiac amyloidosis?

What is the pathophysiology of cardiac amyloidosis?

What causes cardiac amyloidosis?

What is the prevalence of cardiac amyloidosis in the US?

What is the global prevalence of cardiac amyloidosis?

Which patient groups have the highest prevalence of cardiac amyloidosis?

What are the possible complications of cardiac amyloidosis?

What is the prognosis of cardiac amyloidosis?

What are the mortality rates of cardiac amyloidosis?


What are the signs and symptoms of cardiac amyloidosis?

Which physical findings are characteristic of cardiac amyloidosis?


How is cardiac amyloidosis diagnosed?

Which conditions are included in the differential diagnoses of cardiac amyloidosis?

What are the differential diagnoses for Cardiac Amyloidosis?


What is the role of lab testing in the workup of cardiac amyloidosis?

What is the role of echocardiography in the workup of cardiac amyloidosis?

What is the role of cardiovascular MRI in the workup of cardiac amyloidosis?

What is the role of nuclear imaging in the workup of cardiac amyloidosis?

What is the role of ECG in the workup of cardiac amyloidosis?

What is the role of cardiac Holter monitoring in the workup of cardiac amyloidosis?

What is the role of electrophysiologic studies in the workup of cardiac amyloidosis?

What is the role of endomyocardial biopsy (EMB) in the workup of cardiac amyloidosis?

What is the role of rectal submucosal biopsy in the workup of cardiac amyloidosis?

What is the role of abdominal fat biopsy in the workup of cardiac amyloidosis?

What is the role of bone marrow biopsy in the workup of cardiac amyloidosis?


How is cardiac amyloidosis treated?

Which specialist consultations are beneficial to patients with cardiac amyloidosis?


What is the role of medications in the treatment of cardiac amyloidosis?

Which medications in the drug class Alpha-Adrenergic Agonists are used in the treatment of Cardiac Amyloidosis?

Which medications in the drug class Anticoagulants, Cardiovascular are used in the treatment of Cardiac Amyloidosis?

Which medications in the drug class Antidysrhythmics, III are used in the treatment of Cardiac Amyloidosis?

Which medications in the drug class Inotropic Agents are used in the treatment of Cardiac Amyloidosis?

Which medications in the drug class Diuretics, Loop are used in the treatment of Cardiac Amyloidosis?

Which medications in the drug class Transthyretin Binders are used in the treatment of Cardiac Amyloidosis?