**Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management**

Glenn K. Lee, DaLi Feng, Martha Grogan, Cynthia Taub, Angela Dispenzieri and Kyle W. Klarich

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53763

## **1. Introduction**

Amyloidosis is uncommon, with age-adjusted incidences of between 6.1 and 10.5 per million person-years,[1] and an estimated 1275 to 3200 new cases occurring annually in the United States.[1, 2] The contemporary understanding of amyloidosis points to a group of complex sys‐ temic disorders involving the extracellular deposition of misfolded proteinaceous material in many organs, most commonly the kidneys, heart, liver, central and peripheral nervous sys‐ tems.[2-4] The normal function of tissues is altered, and end-organ dysfunction usually ensues. Cardiac amyloidosis can be isolated to the heart, but it often coexists with disease elsewhere in the body.[4, 5] Cardiac manifestations may predominate the clinical presentation or may be subclinical and detected on routine investigation of a patient presenting with non-cardiac com‐ plaints.[5] The presence and relative prominence of cardiac involvement in the clinical picture is dependent on the type of amyloidosis and severity of amyloid infiltration in the tissue.[5]

## **2. Classification of amyloidosis**

Amyloidosis refers to a group of unrelated diseases involving the extracellular deposition of proteinaceous material that demonstrates apple-green birefringence under polarized light on staining with Congo red.[5] In all forms of amyloidosis, abnormal and unstable protein is produced in response to a variety of stimuli and precipitates as amyloid in the extracellular matrix.[2, 3] The contemporary classification of amyloidosis is primarily based on the bio‐ chemistry of the disease process from the precursor amyloid proteins, and comprises several major subgroups. Table 1 describes the typical characteristics of each type of amyloidosis.

© 2013 Lee et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**2.1. Immunoglobulin light chain amyloidosis (AL)**

cardiographic imaging respectively.[13, 14]

**2.2. Familial amyloidosis (ATTR)**

**2.3. Senile systemic amyloidosis**

AL amyloidosis is a monoclonal plasma cell disorder in which the precursor protein is an immunoglobulin light chain or light chain fragment. It may occur as a primary disease or in association with multiple myeloma or other plasma cell dyscrasias.[3, 6], 7] The median num‐ ber of clonal plasma cells in AL amyloidosis is between 5% and 10%.[2] The extent of clonal plasma cell marrow infiltration is an important prognositic indicator, presumably because it reflects the degree of pathogenic light chain synthesis.[8] In primary amyloidosis, there is 2:1 preponderance for λ over κ light chain synthesis.[9] While in itself uncommon, with an inci‐ dence of 8.9 per million,[1] AL amyloidosis is the commonest type of amyloidosis, account‐ ing for about 85% of all newly diagnosed cases.[3, 10] The clinical picture of AL amyloidosis is the most varied, since it commonly affects a large number of organ systems including the heart, kidney, liver, peripheral and autonomic nervous systems, soft tissue and gastrointesti‐ nal systems.[3, 5] The heart is affected in over 50% of cases,[11] and symptomatic cardiac in‐ volvement portends a worse prognosis.[11, 12] Conversely, involvement limited to the heart constitutes <5% of patients with AL amyloidosis.[11] Cardiac involvement with resultant heart failure or arrhythmia accounts for >50% of the mortality in patients with AL amyloido‐ sis.[12] Furthermore, thromboembolism also contributes significantly to morbidity and mor‐ tality. Intracardiac thrombosis was found in 51% and 35% of subjects with AL amyloidosis in the Mayo amyloid autopsy study and in a group of patients undergoing follow up echo‐

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

35

Familial amyloidosis is a hereditary autosomal dominant disorder involving amyloidogenic mutations in most commonly the transthyretin gene.[15] The age of onset of familial amyloi‐ dosis appears to vary with ethnicity. Interestingly, about 10% of gene carriers remain asymptomatic (although the disease manifestation can be age dependent with variable pene‐ trance),[16-18] suggesting that the pathogenesis of these diseases may involve other genetic or environmental factors. Familial amyloidosis usually affects the peripheral and autonomic nervous systems and the heart.[5] While usually more slowly progressive than AL amyloi‐ dosis, the familial type may also cause clinically significant heart failure. Significant cardiac disease is associated with mutations at positions 30, 60 and 84 of the transthyretin gene.[17] A mutation involving isoleucine at position 122 which involves solely the heart has been de‐ scribed in elderly African-American persons.[19, 20] This form of amyloid is probably un‐ derdiagnosed since nearly 4% of newborn African Americans harbor this mutation.[19] The TranstHyretin Amyloidosis Outcome Survey (THAOS) registry is a global observational survey set up with the aim of furthering our understanding of hereditary amyloidosis.

Senile systemic amyloidosis is primarily a disease of the elderly, most commonly affecting men over the age of 70. It accounts for approximately 25% of patients over 80 years with amyloidosis.[21, 22] It is caused by wild-type transthyretin.[5, 21] Cardiac, particularly at‐

**Table 1.** Types of amyloidosis affecting the heart.

#### **2.1. Immunoglobulin light chain amyloidosis (AL)**

**Type of amyloidosis**

34 Amyloidosis

Immunoglobu‐ lin amyloidosis (AL)

Familial amyloi‐ dosis (ATTR)

Senile systemic amyloidosis

Reactive amyloi‐ dosis (SAA)

Hemodialysis-as‐ sociated amyloi‐

Isolated atrial amyloidosis

dosis

**Precursor protein**

Immunoglobulin light chain

Mutant transthyre‐

Wild-type trans‐ thyretin

Atrial natriuretic peptide

**Table 1.** Types of amyloidosis affecting the heart.

β2-microglobulin Musculoskeletal

tin

**Spectrum of organ involvement**

Heart, kidneys, liv‐ er, peripheral/ autonomic nervous systems, soft tissue, gastrointestinal system

Peripheral/auto‐ nomic nervous sys‐ tems, heart

Heart (predomi‐ nant, usually atrial)

system, rare in heart

**Frequency of cardiac involvement**

Up to 50% have clinical cardiac in‐ volvement

Variable, depend‐ ing on exact muta‐

tion

Serum amyloid A Kidney, heart Uncommon, <10% 24.5 Target organ bi‐

Unknown, asymp‐ tomatic

Heart Limited to heart Unclear clini‐

**Median survival, months**

13 (4 months if heart failure present at di‐ agnosis)

Common 75 ATTR antiserum

Unclear clini‐ cal signifi‐ cance

cal signifi‐ cance

**Diagnostic testing**

SPEP, UPEP, bone marrow biopsy tissue analysis re‐ vealing plasma cell dyscrasia, κ and λ light chain antiserum stain‐

ing

staining, serum TTR isoelectric fo‐ cusing, restriction fragment length polymorphism analysis

staining

opsy specimen analysis, AA anti‐ serum staining

Synovial and bone biopsy specimen analy‐ sis, β2-microglo‐ bulin antiserum, serum β2-micro‐ globulin concen‐ tration

Atrial natriuretic peptide antise‐ rum staining

70 ATTR antiserum

**Treatment**

Anti-plasma cell chemotherapy, autologous stem cell replacement, sequential heart and stem cell transplant

Liver transplanta‐ tion, combined liver and heart transplantation in certain cases, new pharmacological strategies to stabi‐

lize TTR

lize TTR

Supportive, new pharmacological strategies to stabi‐

Treat the underly‐ ing inflammatory process

Renal transplanta‐

None required

tion

AL amyloidosis is a monoclonal plasma cell disorder in which the precursor protein is an immunoglobulin light chain or light chain fragment. It may occur as a primary disease or in association with multiple myeloma or other plasma cell dyscrasias.[3, 6], 7] The median num‐ ber of clonal plasma cells in AL amyloidosis is between 5% and 10%.[2] The extent of clonal plasma cell marrow infiltration is an important prognositic indicator, presumably because it reflects the degree of pathogenic light chain synthesis.[8] In primary amyloidosis, there is 2:1 preponderance for λ over κ light chain synthesis.[9] While in itself uncommon, with an inci‐ dence of 8.9 per million,[1] AL amyloidosis is the commonest type of amyloidosis, account‐ ing for about 85% of all newly diagnosed cases.[3, 10] The clinical picture of AL amyloidosis is the most varied, since it commonly affects a large number of organ systems including the heart, kidney, liver, peripheral and autonomic nervous systems, soft tissue and gastrointesti‐ nal systems.[3, 5] The heart is affected in over 50% of cases,[11] and symptomatic cardiac in‐ volvement portends a worse prognosis.[11, 12] Conversely, involvement limited to the heart constitutes <5% of patients with AL amyloidosis.[11] Cardiac involvement with resultant heart failure or arrhythmia accounts for >50% of the mortality in patients with AL amyloido‐ sis.[12] Furthermore, thromboembolism also contributes significantly to morbidity and mor‐ tality. Intracardiac thrombosis was found in 51% and 35% of subjects with AL amyloidosis in the Mayo amyloid autopsy study and in a group of patients undergoing follow up echo‐ cardiographic imaging respectively.[13, 14]

#### **2.2. Familial amyloidosis (ATTR)**

Familial amyloidosis is a hereditary autosomal dominant disorder involving amyloidogenic mutations in most commonly the transthyretin gene.[15] The age of onset of familial amyloi‐ dosis appears to vary with ethnicity. Interestingly, about 10% of gene carriers remain asymptomatic (although the disease manifestation can be age dependent with variable pene‐ trance),[16-18] suggesting that the pathogenesis of these diseases may involve other genetic or environmental factors. Familial amyloidosis usually affects the peripheral and autonomic nervous systems and the heart.[5] While usually more slowly progressive than AL amyloi‐ dosis, the familial type may also cause clinically significant heart failure. Significant cardiac disease is associated with mutations at positions 30, 60 and 84 of the transthyretin gene.[17] A mutation involving isoleucine at position 122 which involves solely the heart has been de‐ scribed in elderly African-American persons.[19, 20] This form of amyloid is probably un‐ derdiagnosed since nearly 4% of newborn African Americans harbor this mutation.[19] The TranstHyretin Amyloidosis Outcome Survey (THAOS) registry is a global observational survey set up with the aim of furthering our understanding of hereditary amyloidosis.

#### **2.3. Senile systemic amyloidosis**

Senile systemic amyloidosis is primarily a disease of the elderly, most commonly affecting men over the age of 70. It accounts for approximately 25% of patients over 80 years with amyloidosis.[21, 22] It is caused by wild-type transthyretin.[5, 21] Cardiac, particularly at‐ rial, involvement is common,[23, 24] and may be associated with clinically significant heart failure, atrial fibrillation and conduction abnormalities.[25, 26]

further compromising cardiac contractility.[49] The resultant perivascular amyloid infiltra‐ tion commonly involves the conduction system, leading to conduction abnormalities.[50, 51]

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

37

**4. Clinical presentation – When should physicians suspect amyloidosis?**

Depending on the spectrum of organ involvement, a patient can present with a multitude of symptoms and signs which are often nonspecific and variable, especially in the early stages of disease.[12] This is particularly so in AL amyloidosis, in which many systems can be af‐ fected. Common constitutional complaints include weakness, fatigue, peripheral edema and weight loss.[9] Hepatomegaly is common and results from either direct hepatic infiltration or congestion secondary to cardiac failure.[52, 53] Renal involvement may cause profound pro‐ teinuria and the nephrotic syndrome.[5, 9] Easy bruising and periorbital purpura results from clotting factor deficiencies and fragile venules; the latter is virtually pathognomonic of the AL type disease.[54, 55] Soft tissue involvement may result in carpal tunnel syndrome[5, 9] and macroglossia,[56] while peripheral and/or autonomic neuropathy may be the hall‐ mark of neurological involvement.[5, 9, 12] The presence of complaints involving multiple organ systems without any other known cause should trigger a search for multisystem dis‐ ease, one of which being amyloidosis. Early diagnosis improves outcomes, given the irrever‐ sible damage caused by amyloidosis and that patients with advanced disease are often not candidates for definitive treatment options (some of which may be curative),[43] but this re‐

quires a high index of suspicion and a systematic algorithm for evaluation.[4, 9]

a poor prognosis and affects treatment strategies.[3]

**5. Diagnosis and evaluation of cardiac amyloidosis**

Cardiac findings are predominantly due to diastolic dysfunction, also known as heart failure with preserved ejection fraction.[3, 5, 9] The initial presentation is often that of progressive exertional dyspnea followed by worsening heart failure, pulmonary congestion, pleural ef‐ fusions, edema, and ascites.[11] Valvular insufficiency or stenosis due to endocardial in‐ volvement may result in a murmur,[9, 43, 57] and atrial fibrillation is common, although all manner of arrhythmias have been reported.[57, 58] Coronary flow abnormalities due to mi‐ crovascular involvement may present as angina chest pain;[59] rarely, this may be the only presenting complaint.[59-63] Patients may have syncope and lightheadedness, particularly postural, caused by autonomic dysfunction and arrhythmias in the face of declining cardiac functional reserve.[64] The heart should be screened in all patients with known or suspected amyloidosis even in the absence of cardiac symptoms, as involvement of the heart portends

Histologic examination remains the definitive diagnostic modality in cardiac amyloidosis.[9, 65] While not definitive, certain non-invasive imaging and laboratory findings may guide further diagnostic testing and management and assess the severity of the disease for prog‐ nostic purposes.[9, 43] Often, the diagnosis of cardiac amyloidosis and perhaps the type of

#### **2.4. Reactive amyloidosis (SAA)**

Reactive amyloidosis is characterized by the deposition of serum amyloid A protein (SAA), an acute phase reactant produced in response to chronic inflammatory processes such as chronic infections, rheumatologic disease and familial periodic fever syndromes.[27, 29] With efficacious treatment of chronic infections in patients in the developed world, the inci‐ dence of reactive amyloidosis has fallen.[29] The kidney is commonly involved, [5] and car‐ diac involvement, if present, is rarely clinically significant.[30, 31]

#### **2.5. Hemodialysis-associated amyloidosis (Aβ2M)**

Hemodialysis-associated amyloidosis occurs in chronic renal failure patients undergoing he‐ modialysis.[12] β2-microglobulin is the precursor protein.[32, 33] Musculoskeletal involve‐ ment is common, and the clinical effect from cardiac deposition is minimal and typically clinically insignificant.[34, 35]

#### **2.6. Isolated atrial amyloidosis (AANF)**

Isolated atrial amyloidosis is predominantly seen in those >80 years and in females,[23] but also occurs in younger patients with valvular abnormalities or chronic atrial fibrillation. [36-38] The precursor protein is atrial natriuretic peptide.[39-41] Involvement is usually lim‐ ited to the subendocardial region of the heart, and its clinical significance is unclear.[42]

## **3. Pathophysiology of cardiac amyloidosis**

In cardiac amyloidosis, the clinical presentation is typically heart failure with initially pre‐ served ejection fraction and restrictive diastolic physiology. This has led to its classification as a "restrictive" cardiomyopathy.[3, 5, 9, 43] This is defined by a high filling pressure that can lead classically to heart failure with preserved ejection fraction. Cardiac contractile func‐ tion and electrical conduction can be impaired with amyloid infiltration.[9] At a cellular lev‐ el, amyloid infiltration results in abnormal cellular metabolism, calcium transport and receptor regulation. [3] Adrenergic input is disrupted and the neurohormonal milieu is al‐ tered in cardiac amyloidosis.[44] Amyloid deposition induces oxidant stress[45] and modu‐ lates interstitial matrix composition and tissue remodeling,[46] leading to further depression of myocyte contractility. Furthermore, there is evidence of a direct toxic role of the monoclo‐ nal light chain extracted from the urine of AL patients on myocardial diastolic function in the mouse hearts; infusion of the monoclonal light chain caused a significant elevation in the LV end diastolic pressure in this animal model.[47] Involvement of the coronary microvas‐ culature may also result in coronary flow abnormalities; this is seen in 90% of patients with AL amyloidosis.[48] This global involvement leads to diffuse ischemia and microinfarction, further compromising cardiac contractility.[49] The resultant perivascular amyloid infiltra‐ tion commonly involves the conduction system, leading to conduction abnormalities.[50, 51]

rial, involvement is common,[23, 24] and may be associated with clinically significant heart

Reactive amyloidosis is characterized by the deposition of serum amyloid A protein (SAA), an acute phase reactant produced in response to chronic inflammatory processes such as chronic infections, rheumatologic disease and familial periodic fever syndromes.[27, 29] With efficacious treatment of chronic infections in patients in the developed world, the inci‐ dence of reactive amyloidosis has fallen.[29] The kidney is commonly involved, [5] and car‐

Hemodialysis-associated amyloidosis occurs in chronic renal failure patients undergoing he‐ modialysis.[12] β2-microglobulin is the precursor protein.[32, 33] Musculoskeletal involve‐ ment is common, and the clinical effect from cardiac deposition is minimal and typically

Isolated atrial amyloidosis is predominantly seen in those >80 years and in females,[23] but also occurs in younger patients with valvular abnormalities or chronic atrial fibrillation. [36-38] The precursor protein is atrial natriuretic peptide.[39-41] Involvement is usually lim‐ ited to the subendocardial region of the heart, and its clinical significance is unclear.[42]

In cardiac amyloidosis, the clinical presentation is typically heart failure with initially pre‐ served ejection fraction and restrictive diastolic physiology. This has led to its classification as a "restrictive" cardiomyopathy.[3, 5, 9, 43] This is defined by a high filling pressure that can lead classically to heart failure with preserved ejection fraction. Cardiac contractile func‐ tion and electrical conduction can be impaired with amyloid infiltration.[9] At a cellular lev‐ el, amyloid infiltration results in abnormal cellular metabolism, calcium transport and receptor regulation. [3] Adrenergic input is disrupted and the neurohormonal milieu is al‐ tered in cardiac amyloidosis.[44] Amyloid deposition induces oxidant stress[45] and modu‐ lates interstitial matrix composition and tissue remodeling,[46] leading to further depression of myocyte contractility. Furthermore, there is evidence of a direct toxic role of the monoclo‐ nal light chain extracted from the urine of AL patients on myocardial diastolic function in the mouse hearts; infusion of the monoclonal light chain caused a significant elevation in the LV end diastolic pressure in this animal model.[47] Involvement of the coronary microvas‐ culature may also result in coronary flow abnormalities; this is seen in 90% of patients with AL amyloidosis.[48] This global involvement leads to diffuse ischemia and microinfarction,

failure, atrial fibrillation and conduction abnormalities.[25, 26]

diac involvement, if present, is rarely clinically significant.[30, 31]

**2.5. Hemodialysis-associated amyloidosis (Aβ2M)**

**3. Pathophysiology of cardiac amyloidosis**

**2.4. Reactive amyloidosis (SAA)**

36 Amyloidosis

clinically insignificant.[34, 35]

**2.6. Isolated atrial amyloidosis (AANF)**

## **4. Clinical presentation – When should physicians suspect amyloidosis?**

Depending on the spectrum of organ involvement, a patient can present with a multitude of symptoms and signs which are often nonspecific and variable, especially in the early stages of disease.[12] This is particularly so in AL amyloidosis, in which many systems can be af‐ fected. Common constitutional complaints include weakness, fatigue, peripheral edema and weight loss.[9] Hepatomegaly is common and results from either direct hepatic infiltration or congestion secondary to cardiac failure.[52, 53] Renal involvement may cause profound pro‐ teinuria and the nephrotic syndrome.[5, 9] Easy bruising and periorbital purpura results from clotting factor deficiencies and fragile venules; the latter is virtually pathognomonic of the AL type disease.[54, 55] Soft tissue involvement may result in carpal tunnel syndrome[5, 9] and macroglossia,[56] while peripheral and/or autonomic neuropathy may be the hall‐ mark of neurological involvement.[5, 9, 12] The presence of complaints involving multiple organ systems without any other known cause should trigger a search for multisystem dis‐ ease, one of which being amyloidosis. Early diagnosis improves outcomes, given the irrever‐ sible damage caused by amyloidosis and that patients with advanced disease are often not candidates for definitive treatment options (some of which may be curative),[43] but this re‐ quires a high index of suspicion and a systematic algorithm for evaluation.[4, 9]

Cardiac findings are predominantly due to diastolic dysfunction, also known as heart failure with preserved ejection fraction.[3, 5, 9] The initial presentation is often that of progressive exertional dyspnea followed by worsening heart failure, pulmonary congestion, pleural ef‐ fusions, edema, and ascites.[11] Valvular insufficiency or stenosis due to endocardial in‐ volvement may result in a murmur,[9, 43, 57] and atrial fibrillation is common, although all manner of arrhythmias have been reported.[57, 58] Coronary flow abnormalities due to mi‐ crovascular involvement may present as angina chest pain;[59] rarely, this may be the only presenting complaint.[59-63] Patients may have syncope and lightheadedness, particularly postural, caused by autonomic dysfunction and arrhythmias in the face of declining cardiac functional reserve.[64] The heart should be screened in all patients with known or suspected amyloidosis even in the absence of cardiac symptoms, as involvement of the heart portends a poor prognosis and affects treatment strategies.[3]

#### **5. Diagnosis and evaluation of cardiac amyloidosis**

Histologic examination remains the definitive diagnostic modality in cardiac amyloidosis.[9, 65] While not definitive, certain non-invasive imaging and laboratory findings may guide further diagnostic testing and management and assess the severity of the disease for prog‐ nostic purposes.[9, 43] Often, the diagnosis of cardiac amyloidosis and perhaps the type of amyloidosis can be reasonably ascertained by employing one or more non-invasive imaging and laboratory modalities.

While pulmonary involvement is a harbinger of adverse outcome, it is often difficult to de‐ termine the exact extent to which pulmonary amyloid deposition contributes to symptoms

**Figure 1.** (A) Two-dimensional echocardiographic, (B) transmitral Doppler and (C) tissue Doppler images classical of

AL amyloidosis.

A

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

39

B

C

or outcome because cardiac deposition commonly coexists.[89]

#### **5.1. Echocardiography**

Echocardiography remains the most widely utilized noninvasive modality in the diagnosis of cardiac amyloidosis, in part because of its widespread availability and relatively low cost. [5, 66] In cases with characteristic echocardiographic findings, signs and symptoms of heart failure, and a positive biopsy of another organ, cardiac involvement is almost certain. How‐ ever, echocardiography cannot determine the type of amyloidosis and in some patients with early disease the findings may be subtle.[43]

Echocardiography may show mild diastolic dysfunction [9] as the only clue in early amyloid heart disease, but this is non-specific and may often be mistaken for more common conditions such as hypertensive or hypertrophic cardiomyopathy. Recently, it has been found that tissue Doppler imaging could identify abnormalities in both early and late-stage cardiac amyloidosis, affording the possibility for early diagnosis and disease-modifying intervention.[66, 67] Tissue Doppler imaging can also be helpful in differentiating restrictive cardiomyopathy from con‐ strictive pericarditis.[68, 69] Diastolic dysfunction is the predominant pathology in cardiac amyloidosis; the classic picture of a thick and stiff ventricle elevates diastolic filling pressures causing restrictive hemodynamics and atrial dilatation.[70, 71] Decreased ejection fraction typi‐ cally occurs only in late-stage disease as a result of loss of myocardial contractile function through myocyte necrosis and local interstitial amyloid infiltration;[5, 72-75] despite preserved ejection fraction, systolic function is not normal in cardiac amyloidosis. Techniques of myocar‐ dial deformation imaging have shown that abnormal strain and strain rate imaging occur in most cases of cardiac amyloidosis.[76-79] Amyloid cardiomyopathy seems to be associated with a marked dissociation between short and long-axis systolic function; tissue Doppler or strain rate imaging may show severe impairment in long-axis contraction even when the left ventricu‐ lar ejection fraction remains within the normal range.

The typical features of cardiac amyloidosis such as left ventricular wall thickening[66, 72-74, 80, 81] with myocardial hyperechogenicity,[74, 81-84] biatrial enlargement,[74, 75, 81] thick‐ ened atrial septum[81] and valve leaflets,[75, 81] as well as pericardial effusion [75, 81] are usually seen at a more advanced stage of the disease (Figure 1). A thickened left ventricular wall in the absence of high electrocardiographic voltages is suggestive of infiltrative cardiac disease. Deposition in the atria is usually extensive and may cause atrial mechanical failure and atrial standstill, i.e. atrial electro-mechanical dissociation even in patients who are in normal sinus rhythm. Atrial involvement may also result in atrial arrhythmias; in fact, atrial fibrillation can significantly affect the cardiac output from an already impaired ventricle.[85, 86] Heart failure can be further worsened by valvular insufficiency caused by subendocar‐ dial infiltration. [9] Rarely, pericardial involvement occurs in severe disease leading to peri‐ cardial effusion or constriction.[48] In some cases, pulmonary hypertension and cor pulmonale may occur in patients with amyloidosis.[87] Although usually caused by con‐ comitant and frequently more severe cardiac amyloidosis with left ventricular failure,[88] pulmonary hypertension may be the result of advanced pulmonary amyloid infiltration.[87] While pulmonary involvement is a harbinger of adverse outcome, it is often difficult to de‐ termine the exact extent to which pulmonary amyloid deposition contributes to symptoms or outcome because cardiac deposition commonly coexists.[89]

amyloidosis can be reasonably ascertained by employing one or more non-invasive imaging

Echocardiography remains the most widely utilized noninvasive modality in the diagnosis of cardiac amyloidosis, in part because of its widespread availability and relatively low cost. [5, 66] In cases with characteristic echocardiographic findings, signs and symptoms of heart failure, and a positive biopsy of another organ, cardiac involvement is almost certain. How‐ ever, echocardiography cannot determine the type of amyloidosis and in some patients with

Echocardiography may show mild diastolic dysfunction [9] as the only clue in early amyloid heart disease, but this is non-specific and may often be mistaken for more common conditions such as hypertensive or hypertrophic cardiomyopathy. Recently, it has been found that tissue Doppler imaging could identify abnormalities in both early and late-stage cardiac amyloidosis, affording the possibility for early diagnosis and disease-modifying intervention.[66, 67] Tissue Doppler imaging can also be helpful in differentiating restrictive cardiomyopathy from con‐ strictive pericarditis.[68, 69] Diastolic dysfunction is the predominant pathology in cardiac amyloidosis; the classic picture of a thick and stiff ventricle elevates diastolic filling pressures causing restrictive hemodynamics and atrial dilatation.[70, 71] Decreased ejection fraction typi‐ cally occurs only in late-stage disease as a result of loss of myocardial contractile function through myocyte necrosis and local interstitial amyloid infiltration;[5, 72-75] despite preserved ejection fraction, systolic function is not normal in cardiac amyloidosis. Techniques of myocar‐ dial deformation imaging have shown that abnormal strain and strain rate imaging occur in most cases of cardiac amyloidosis.[76-79] Amyloid cardiomyopathy seems to be associated with a marked dissociation between short and long-axis systolic function; tissue Doppler or strain rate imaging may show severe impairment in long-axis contraction even when the left ventricu‐

The typical features of cardiac amyloidosis such as left ventricular wall thickening[66, 72-74, 80, 81] with myocardial hyperechogenicity,[74, 81-84] biatrial enlargement,[74, 75, 81] thick‐ ened atrial septum[81] and valve leaflets,[75, 81] as well as pericardial effusion [75, 81] are usually seen at a more advanced stage of the disease (Figure 1). A thickened left ventricular wall in the absence of high electrocardiographic voltages is suggestive of infiltrative cardiac disease. Deposition in the atria is usually extensive and may cause atrial mechanical failure and atrial standstill, i.e. atrial electro-mechanical dissociation even in patients who are in normal sinus rhythm. Atrial involvement may also result in atrial arrhythmias; in fact, atrial fibrillation can significantly affect the cardiac output from an already impaired ventricle.[85, 86] Heart failure can be further worsened by valvular insufficiency caused by subendocar‐ dial infiltration. [9] Rarely, pericardial involvement occurs in severe disease leading to peri‐ cardial effusion or constriction.[48] In some cases, pulmonary hypertension and cor pulmonale may occur in patients with amyloidosis.[87] Although usually caused by con‐ comitant and frequently more severe cardiac amyloidosis with left ventricular failure,[88] pulmonary hypertension may be the result of advanced pulmonary amyloid infiltration.[87]

and laboratory modalities.

early disease the findings may be subtle.[43]

lar ejection fraction remains within the normal range.

**5.1. Echocardiography**

38 Amyloidosis

**Figure 1.** (A) Two-dimensional echocardiographic, (B) transmitral Doppler and (C) tissue Doppler images classical of AL amyloidosis.

Several other findings on echocardiography may have prognostic significance in cardiac amyloidosis, such as left ventricular ejection time,[90] wall motion abnormalities,[91, 92] dyssynchrony,[93] as well as increased right ventricular Tei index (which reflects right ven‐ tricular dysfunction).[94] Myocardial contrast echocardiography can reveal microvascular dysfunction, and may be a useful adjunct in echocardiographic assessment for the early di‐ agnosis of cardiac amyloidosis, although it is not typically utilized in day to day practice. [95] Transesophageal echocardiography (TEE) may be useful in characterizing atrial thrombi and assessing left atrial appendage dysfunction,[96] a common finding in cardiac amyloido‐ sis even in the absence of atrial fibrillation (Figure 2).[96, 97] Risk factors for intracardiac thrombosis include: AL type amyloidosis, atrial fibrillation, and diastolic dysfunction. In‐ creased right ventricular wall thickness is a marker of increased risk in intracardiac throm‐ bosis, probably due to the presence of advanced infiltrative cardiomyopathy.[14] Timely assessment for intracardiac thrombosis in high-risk patients is important for anticoagulation considerations.[13, 14, 98] Patients with amyloidosis should not be cardioverted without ad‐ equate anticoagulation and in some institutions, TEE imaging is routinely performed prior to cardioversion even in the presence of adequate anticoagulation.

Besides its diagnostic value, echocardiography is a useful adjunct during the endomyocar‐ dial biopsy procedure. It complements, and in some institutions has replaced, fluoroscopy as a method of bioptome guidance because of its superior resolution of the tricuspid valve

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

41

Electrocardiography (ECG) provides useful and complementary information in patients with cardiac amyloidosis. The classic findings of low voltages and pseudoinfarct patterns (Figure 3) are common occurrences,[11, 58, 100] and both findings may occur in 25% to 50% of patients.[43] Poor R wave progression is also often seen.[3, 101] Low voltage correlated with the presence of a pericardial effusion but not with decreased ejection fraction.[43] The combination of low voltage and an interventricular septum thickness >1.98 cm is very specif‐ ic for cardiac amyloidosis.[74] The finding of low voltage in a patient with echocardiograph‐ ic evidence of increased wall thickness should raise the clinical suspicion of infiltrative cardiomyopathy, but the reverse is not necessarily true – normal voltage does not exclude amyloidosis.[58] ECG criteria for left ventricular hypertrophy, especially limb lead ECG left ventricular hypertrophy, however, is rarely present in patients with cardiac biopsy proven

**Figure 3.** ECG changes classical of cardiac amyloidosis with sinus tachycardia, low voltage and pseudoinfarct patterns.

The conduction system can often be affected in cardiac amyloidosis.[11] Atrial fibrillation and flutter are the commonest arrhythmias seen,[58] but atrioventricular and bundle branch blocks may occur.[65] Sinus tachycardia seen in advanced cardiac amyloidosis is probably

anatomy, endocardial surface, and thin right ventricular free wall and apex.[99]

**5.2. Electrocardiography**

amyloidosis.[58]

Besides its diagnostic value, echocardiography is a useful adjunct during the endomyocar‐ dial biopsy procedure. It complements, and in some institutions has replaced, fluoroscopy as a method of bioptome guidance because of its superior resolution of the tricuspid valve anatomy, endocardial surface, and thin right ventricular free wall and apex.[99]

#### **5.2. Electrocardiography**

Several other findings on echocardiography may have prognostic significance in cardiac amyloidosis, such as left ventricular ejection time,[90] wall motion abnormalities,[91, 92] dyssynchrony,[93] as well as increased right ventricular Tei index (which reflects right ven‐ tricular dysfunction).[94] Myocardial contrast echocardiography can reveal microvascular dysfunction, and may be a useful adjunct in echocardiographic assessment for the early di‐ agnosis of cardiac amyloidosis, although it is not typically utilized in day to day practice. [95] Transesophageal echocardiography (TEE) may be useful in characterizing atrial thrombi and assessing left atrial appendage dysfunction,[96] a common finding in cardiac amyloido‐ sis even in the absence of atrial fibrillation (Figure 2).[96, 97] Risk factors for intracardiac thrombosis include: AL type amyloidosis, atrial fibrillation, and diastolic dysfunction. In‐ creased right ventricular wall thickness is a marker of increased risk in intracardiac throm‐ bosis, probably due to the presence of advanced infiltrative cardiomyopathy.[14] Timely assessment for intracardiac thrombosis in high-risk patients is important for anticoagulation considerations.[13, 14, 98] Patients with amyloidosis should not be cardioverted without ad‐ equate anticoagulation and in some institutions, TEE imaging is routinely performed prior

**Figure 2.** Left atrial appendage (LAA) thrombus in a patient with cardiac amyloidosis; the patient was known to be in

sinus rhythm. (With permission from Feng et al. *Circulation.* Nov 20 2007;116(21):2420-2426.)

to cardioversion even in the presence of adequate anticoagulation.

40 Amyloidosis

Electrocardiography (ECG) provides useful and complementary information in patients with cardiac amyloidosis. The classic findings of low voltages and pseudoinfarct patterns (Figure 3) are common occurrences,[11, 58, 100] and both findings may occur in 25% to 50% of patients.[43] Poor R wave progression is also often seen.[3, 101] Low voltage correlated with the presence of a pericardial effusion but not with decreased ejection fraction.[43] The combination of low voltage and an interventricular septum thickness >1.98 cm is very specif‐ ic for cardiac amyloidosis.[74] The finding of low voltage in a patient with echocardiograph‐ ic evidence of increased wall thickness should raise the clinical suspicion of infiltrative cardiomyopathy, but the reverse is not necessarily true – normal voltage does not exclude amyloidosis.[58] ECG criteria for left ventricular hypertrophy, especially limb lead ECG left ventricular hypertrophy, however, is rarely present in patients with cardiac biopsy proven amyloidosis.[58]

**Figure 3.** ECG changes classical of cardiac amyloidosis with sinus tachycardia, low voltage and pseudoinfarct patterns.

The conduction system can often be affected in cardiac amyloidosis.[11] Atrial fibrillation and flutter are the commonest arrhythmias seen,[58] but atrioventricular and bundle branch blocks may occur.[65] Sinus tachycardia seen in advanced cardiac amyloidosis is probably due to the restrictive filling leading to cardiac output adjustments based solely on heart rate; in one study this was a marker of increased risk for intracardiac thrombosis.[14] Prolonged QT intervals and junctional rhythms may be present. [9] Advanced ventricular arrhythmias such as sustained ventricular tachycardia are rarely seen (although frequent PVCs, couplets or triplets are common), which is likely due to poorly tolerance of the arrhythmia in the ad‐ vanced cardiac amyloid patients who would die suddenly from sustain VT.[58, 102] Sudden death in severe cardiac amyloidosis is commonly attributed to electromechanical dissocia‐ tion; a pattern similar to severe cardiac diseases of other etiologies.[64]

The largest reported ECG series consists of 127 patients with AL amyloidosis and biopsy proven cardiac involvement seen at the Mayo Clinic. The two most common abnormalities were low voltage and a pseudoinfarct pattern, which were seen in 46 and 47 percent of cas‐ es. Other findings included first degree AV block in 21 percent, nonspecific intraventricular conduction delay in 16 percent, second or third degree AV block in 3 percent, atrial fibrilla‐ tion or flutter in 20 percent, and ventricular tachycardia in 5 percent. ECG criteria for left ventricular hypertrophy were present in 16 percent, but some of these patients had a history of hypertension. The left ventricular hypertrophy criteria were limited almost exclusively to precordial leads, sometimes with low-voltage limb leads.[58] In patients with AL amyloido‐ sis, signal-averaged ECG may demonstrate delayed myocardial activation or "late poten‐ tials"; this is an independent predictor of sudden death.[43, 100] Reduced heart rate variability predicts mortality in the short-term in both AL and familial amyloidosis, and probably represents autonomic dysfunction.[103, 104]

Many of the ECG findings in cardiac amyloidosis are nonspecific, and other causes of such should be ruled out.[65] On the other hand, ECGs, especially if done serially, allows for ear‐ ly diagnosis and intervention in cardiac amyloidosis. Physicians should understand the characteristics and symptoms of amyloidosis, and be aware of subtle changes in the ECG, especially abnormalities that suggest disorders in the conduction system (such as prolonged PR interval, widened QRS, atrioventricular blocks, and bundle branch blocks) or decreased electromotive force (such as progressive R wave decrease).[105]

**Figure 4.** CMR findings of global transmural LGE classical of cardiac amyloidosis; this patient had histologically proven AL amyloidosis. Furthermore, three intracardiac thrombi (red arrows) were detected in the left atrial appendage, right

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

43

Maceira et al [108] first studied LGE in CMR in 29 patients with cardiac amyloidosis. They found that CMR shows a characteristic pattern of global subendocardial LGE coupled with abnormal myocardial and blood-pool gadolinium kinetics. In 22 of these, myocardial gado‐ linium kinetics with T1 mapping was compared with that in 16 hypertensive controls. Sub‐ endocardial T1 in amyloid patients was shorter than in controls (at 4 minutes: 427±73 vs. 579±75 ms; p<0.01), and was correlated with markers of increased myocardial amyloid load such as left ventricular mass, wall thickness, interatrial septal thickness and diastolic func‐ tion. Global subendocardial LGE was found in 20 amyloid patients (69%); these patients had greater left ventricular mass than unenhanced patients. Histological quantification showed substantial interstitial expansion with amyloid (30.5%) but only minor fibrosis (1.3%). Amyloid deposition was predominantly subendocardial (42%), compared with mid‐ wall (29%) and subepicardial (18%). The LGE findings agree with the transmural histologi‐ cal distribution of amyloid protein and the cardiac amyloid load. Using the difference between the T1 of subendomyocardium and blood, a cutoff value of 191 ms at 4 minutes had 90% sensitivity, 87% specificity and 88% of accuracy for the correct diagnosis of cardiac

atrial appendage and at the right atrial free wall close to tricuspid annulus.

#### **5.3. Cardiac magnetic resonance imaging**

Cardiac magnetic resonance imaging (CMR) is emerging as a useful tool in the diagnosis of cardiac amyloidosis. Its strength lies in its high three-dimensional spatial resolution and signal-to-noise ratio, permitting reproducible measurements of cardiac chamber vol‐ umes and mass, as well as left ventricular and atrial septal wall thickness.[106] Addition‐ ally, it can characterize pericardial and pleural fluid.[106] Late gadolinium enhancement (LGE) is the cornerstone of detecting myocardial amyloid infiltrates and is seen in almost all cases.[107] Compared with normal myocardium which has no LGE because of little ga‐ dolinium accumulation on delayed imaging, contrast accumulates in the extracellular space in cardiac amyloidosis which is expanded by amyloid infiltration, resulting in LGE. [108] The predominant pattern of LGE seen in cardiac amyloidosis is global transmural (Figure 4) or subendocardial; [108, 109] other patterns including focal patchy LGE and dif‐ ficulty nulling can also be seen.

due to the restrictive filling leading to cardiac output adjustments based solely on heart rate; in one study this was a marker of increased risk for intracardiac thrombosis.[14] Prolonged QT intervals and junctional rhythms may be present. [9] Advanced ventricular arrhythmias such as sustained ventricular tachycardia are rarely seen (although frequent PVCs, couplets or triplets are common), which is likely due to poorly tolerance of the arrhythmia in the ad‐ vanced cardiac amyloid patients who would die suddenly from sustain VT.[58, 102] Sudden death in severe cardiac amyloidosis is commonly attributed to electromechanical dissocia‐

The largest reported ECG series consists of 127 patients with AL amyloidosis and biopsy proven cardiac involvement seen at the Mayo Clinic. The two most common abnormalities were low voltage and a pseudoinfarct pattern, which were seen in 46 and 47 percent of cas‐ es. Other findings included first degree AV block in 21 percent, nonspecific intraventricular conduction delay in 16 percent, second or third degree AV block in 3 percent, atrial fibrilla‐ tion or flutter in 20 percent, and ventricular tachycardia in 5 percent. ECG criteria for left ventricular hypertrophy were present in 16 percent, but some of these patients had a history of hypertension. The left ventricular hypertrophy criteria were limited almost exclusively to precordial leads, sometimes with low-voltage limb leads.[58] In patients with AL amyloido‐ sis, signal-averaged ECG may demonstrate delayed myocardial activation or "late poten‐ tials"; this is an independent predictor of sudden death.[43, 100] Reduced heart rate variability predicts mortality in the short-term in both AL and familial amyloidosis, and

Many of the ECG findings in cardiac amyloidosis are nonspecific, and other causes of such should be ruled out.[65] On the other hand, ECGs, especially if done serially, allows for ear‐ ly diagnosis and intervention in cardiac amyloidosis. Physicians should understand the characteristics and symptoms of amyloidosis, and be aware of subtle changes in the ECG, especially abnormalities that suggest disorders in the conduction system (such as prolonged PR interval, widened QRS, atrioventricular blocks, and bundle branch blocks) or decreased

Cardiac magnetic resonance imaging (CMR) is emerging as a useful tool in the diagnosis of cardiac amyloidosis. Its strength lies in its high three-dimensional spatial resolution and signal-to-noise ratio, permitting reproducible measurements of cardiac chamber vol‐ umes and mass, as well as left ventricular and atrial septal wall thickness.[106] Addition‐ ally, it can characterize pericardial and pleural fluid.[106] Late gadolinium enhancement (LGE) is the cornerstone of detecting myocardial amyloid infiltrates and is seen in almost all cases.[107] Compared with normal myocardium which has no LGE because of little ga‐ dolinium accumulation on delayed imaging, contrast accumulates in the extracellular space in cardiac amyloidosis which is expanded by amyloid infiltration, resulting in LGE. [108] The predominant pattern of LGE seen in cardiac amyloidosis is global transmural (Figure 4) or subendocardial; [108, 109] other patterns including focal patchy LGE and dif‐

tion; a pattern similar to severe cardiac diseases of other etiologies.[64]

probably represents autonomic dysfunction.[103, 104]

**5.3. Cardiac magnetic resonance imaging**

42 Amyloidosis

ficulty nulling can also be seen.

electromotive force (such as progressive R wave decrease).[105]

**Figure 4.** CMR findings of global transmural LGE classical of cardiac amyloidosis; this patient had histologically proven AL amyloidosis. Furthermore, three intracardiac thrombi (red arrows) were detected in the left atrial appendage, right atrial appendage and at the right atrial free wall close to tricuspid annulus.

Maceira et al [108] first studied LGE in CMR in 29 patients with cardiac amyloidosis. They found that CMR shows a characteristic pattern of global subendocardial LGE coupled with abnormal myocardial and blood-pool gadolinium kinetics. In 22 of these, myocardial gado‐ linium kinetics with T1 mapping was compared with that in 16 hypertensive controls. Sub‐ endocardial T1 in amyloid patients was shorter than in controls (at 4 minutes: 427±73 vs. 579±75 ms; p<0.01), and was correlated with markers of increased myocardial amyloid load such as left ventricular mass, wall thickness, interatrial septal thickness and diastolic func‐ tion. Global subendocardial LGE was found in 20 amyloid patients (69%); these patients had greater left ventricular mass than unenhanced patients. Histological quantification showed substantial interstitial expansion with amyloid (30.5%) but only minor fibrosis (1.3%). Amyloid deposition was predominantly subendocardial (42%), compared with mid‐ wall (29%) and subepicardial (18%). The LGE findings agree with the transmural histologi‐ cal distribution of amyloid protein and the cardiac amyloid load. Using the difference between the T1 of subendomyocardium and blood, a cutoff value of 191 ms at 4 minutes had 90% sensitivity, 87% specificity and 88% of accuracy for the correct diagnosis of cardiac amyloidosis. There was 97% concordance in diagnosis of cardiac amyloidosis by combining the presence of late gadolinium enhancement and an optimized T1 threshold between myo‐ cardium and blood.

≥1273 milliseconds was found to be both sensitive and specific for the diagnosis of cardiac

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

45

Based on these studies, it is apparent that gadolinium-enhanced CMR is the most accurate imaging modality to diagnose cardiac amyloidosis. LGE is common in cardiac amyloidosis and it is due to interstitial expansion from amyloid deposition and kinetic change of gadoli‐ nium in the blood pool and myocardium/interstitia. This modality may potentially detect early cardiac involvement in patients with amyloidosis and normal left ventricular wall thickness.[43, 107] It also affords global assessment of the heart, eliminating the sampling er‐ ror that endomyocardial biopsy may potentially carry.[111] Furthermore, it may be useful in detecting subclinical early cardiac involvement;[43] indeed studies have shown that even early cardiac involvement carried a significant mortality risk, in particular cardiac mortality. [112, 113] Serial CMR studies may have the potential to chart the progression or regression of the disease over time after the initiation of treatment.[114] However, despite the high sen‐ sitivity and specificity of CMR in the diagnosis of cardiac amyloidosis, similar patterns, while uncommon, have been occasionally reported in systemic sclerosis and post-heart transplant patients. The autopsy study by Syed et al suggests that rarely, gadolinium-en‐

hanced CMR may be falsely negative because the amyloid infiltrate is mild.[107]

which may preclude them from undergoing CMR.

**5.4. Nuclear scintigraphy**

CMR may be a reasonable adjuvant or even an alternative to endomyocardial biopsy, espe‐ cially in patients with a tissue diagnosis from a remote site and who are high-risk for inva‐ sive investigation. However, it is important to notice that the diagnosis of cardiac amyloidosis is confirmed by demonstrating amyloid deposits on endomyocardial biopsy. Cardiac amyloidosis may be presumably, but not conclusively, established in patients with appropriate cardiac imaging findings with demonstration of amyloid deposits on histologi‐ cal examination of a biopsy from other tissues (e.g., abdominal fat pad, rectum, or kidney). There are several limitations in the use of this modality. Firstly, it is incompatible with pa‐ tients with implanted devices such as pacemakers or implantable cardioverter-defibrillators. Nevertheless, pacemakers compatible with magnetic resonance imaging were recently ap‐ proved by the United States Food and Drug Administration for clinical use in the 1.5 tesla magnetic resonance imaging scanner. Secondly, gadolinium contrast administration is con‐ traindicated in patients whose creatinine clearance is less than 30 mL/minute given the risk of nephrogenic systemic fibrosis.[115] Many patients with cardiac amyloidosis have indica‐ tions for heart failure device therapy (e.g. pacemakers, implantable cardioverter-defibrilla‐ tors) as well as renal impairment as a result of amyloid deposition in the kidneys, both of

Several single-photon emission computed tomography tracers have been evaluated in the diagnosis of cardiac amyloidosis.[116] There is evidence that [123]I-metaiodobenzylguani‐ dine may be an indirect measure of cardiac amyloid deposition. The finding of intense up‐ take in the heart on [99]mTc-pyrophosphate scintigraphy, which was indicative of cardiac amyloidosis, was insufficiently sensitive to warrant routine use in the diagnosis of the dis‐ ease. While not routinely performed for diagnosing cardiac amyloidosis given its variable

amyloidosis.[110]

Mayo investigators further evaluated the mechanism of LGE in CMR in identifying cardiac involvement in a population of known amyloidosis patients and to investigate associations between LGE and clinical, morphological, functional, and biochemical features.[107] Gadoli‐ nium-enhanced CMR was performed in 120 patients with amyloidosis of which 100 had AL amyloidosis, 11 had familial amyloidosis and 9 had senile amyloidosis. Cardiac autopsy and/or histology was available in 35 patients. The remaining 85 patients were divided into those with and without echocardiographic evidence of cardiac amyloidosis. Abnormal LGE was present in 34 (97%) patients with histologically proven cardiac amyloidosis. Global transmural or subendocardial LGE (83%) was most common while suboptimal myocardial nulling (8%) and patchy focal LGE (6%) were also observed (Figure 5). Global LGE was as‐ sociated with a higher burden of interstitial amyloid quantified from histology. LGE distri‐ bution matched the deposition pattern of interstitial amyloid at autopsy. Importantly, the study found that LGE was present in 47% of patients without evidence of cardiac amyloido‐ sis by echocardiography. LGE presence and pattern was associated with New York Heart Association class, ECG voltages, left ventricular mass index and thickness, right ventricular thickness, troponin-T, and B-type natriuretic peptide levels. The global LGE patterns were associated with the worst clinical, ECG, echocardiographic and biomarker abnormalities compared to other types of LGE (focal or suboptimal nulling).

**Figure 5.** The different patterns of LGE on CMR in patients with cardiac amyloidosis. (With permission from Syed et al. *JACC Cardiovasc Imaging.* 2010;3:155-164.)

CMR relaxometry is a novel approach in the diagnosis of cardiac amyloidosis, showing ele‐ vated relaxation times in patients with the disease. A T1 relaxation time cutoff value of ≥1273 milliseconds was found to be both sensitive and specific for the diagnosis of cardiac amyloidosis.[110]

Based on these studies, it is apparent that gadolinium-enhanced CMR is the most accurate imaging modality to diagnose cardiac amyloidosis. LGE is common in cardiac amyloidosis and it is due to interstitial expansion from amyloid deposition and kinetic change of gadoli‐ nium in the blood pool and myocardium/interstitia. This modality may potentially detect early cardiac involvement in patients with amyloidosis and normal left ventricular wall thickness.[43, 107] It also affords global assessment of the heart, eliminating the sampling er‐ ror that endomyocardial biopsy may potentially carry.[111] Furthermore, it may be useful in detecting subclinical early cardiac involvement;[43] indeed studies have shown that even early cardiac involvement carried a significant mortality risk, in particular cardiac mortality. [112, 113] Serial CMR studies may have the potential to chart the progression or regression of the disease over time after the initiation of treatment.[114] However, despite the high sen‐ sitivity and specificity of CMR in the diagnosis of cardiac amyloidosis, similar patterns, while uncommon, have been occasionally reported in systemic sclerosis and post-heart transplant patients. The autopsy study by Syed et al suggests that rarely, gadolinium-en‐ hanced CMR may be falsely negative because the amyloid infiltrate is mild.[107]

CMR may be a reasonable adjuvant or even an alternative to endomyocardial biopsy, espe‐ cially in patients with a tissue diagnosis from a remote site and who are high-risk for inva‐ sive investigation. However, it is important to notice that the diagnosis of cardiac amyloidosis is confirmed by demonstrating amyloid deposits on endomyocardial biopsy. Cardiac amyloidosis may be presumably, but not conclusively, established in patients with appropriate cardiac imaging findings with demonstration of amyloid deposits on histologi‐ cal examination of a biopsy from other tissues (e.g., abdominal fat pad, rectum, or kidney).

There are several limitations in the use of this modality. Firstly, it is incompatible with pa‐ tients with implanted devices such as pacemakers or implantable cardioverter-defibrillators. Nevertheless, pacemakers compatible with magnetic resonance imaging were recently ap‐ proved by the United States Food and Drug Administration for clinical use in the 1.5 tesla magnetic resonance imaging scanner. Secondly, gadolinium contrast administration is con‐ traindicated in patients whose creatinine clearance is less than 30 mL/minute given the risk of nephrogenic systemic fibrosis.[115] Many patients with cardiac amyloidosis have indica‐ tions for heart failure device therapy (e.g. pacemakers, implantable cardioverter-defibrilla‐ tors) as well as renal impairment as a result of amyloid deposition in the kidneys, both of which may preclude them from undergoing CMR.

#### **5.4. Nuclear scintigraphy**

amyloidosis. There was 97% concordance in diagnosis of cardiac amyloidosis by combining the presence of late gadolinium enhancement and an optimized T1 threshold between myo‐

Mayo investigators further evaluated the mechanism of LGE in CMR in identifying cardiac involvement in a population of known amyloidosis patients and to investigate associations between LGE and clinical, morphological, functional, and biochemical features.[107] Gadoli‐ nium-enhanced CMR was performed in 120 patients with amyloidosis of which 100 had AL amyloidosis, 11 had familial amyloidosis and 9 had senile amyloidosis. Cardiac autopsy and/or histology was available in 35 patients. The remaining 85 patients were divided into those with and without echocardiographic evidence of cardiac amyloidosis. Abnormal LGE was present in 34 (97%) patients with histologically proven cardiac amyloidosis. Global transmural or subendocardial LGE (83%) was most common while suboptimal myocardial nulling (8%) and patchy focal LGE (6%) were also observed (Figure 5). Global LGE was as‐ sociated with a higher burden of interstitial amyloid quantified from histology. LGE distri‐ bution matched the deposition pattern of interstitial amyloid at autopsy. Importantly, the study found that LGE was present in 47% of patients without evidence of cardiac amyloido‐ sis by echocardiography. LGE presence and pattern was associated with New York Heart Association class, ECG voltages, left ventricular mass index and thickness, right ventricular thickness, troponin-T, and B-type natriuretic peptide levels. The global LGE patterns were associated with the worst clinical, ECG, echocardiographic and biomarker abnormalities

**Figure 5.** The different patterns of LGE on CMR in patients with cardiac amyloidosis. (With permission from Syed et al.

CMR relaxometry is a novel approach in the diagnosis of cardiac amyloidosis, showing ele‐ vated relaxation times in patients with the disease. A T1 relaxation time cutoff value of

compared to other types of LGE (focal or suboptimal nulling).

*JACC Cardiovasc Imaging.* 2010;3:155-164.)

cardium and blood.

44 Amyloidosis

Several single-photon emission computed tomography tracers have been evaluated in the diagnosis of cardiac amyloidosis.[116] There is evidence that [123]I-metaiodobenzylguani‐ dine may be an indirect measure of cardiac amyloid deposition. The finding of intense up‐ take in the heart on [99]mTc-pyrophosphate scintigraphy, which was indicative of cardiac amyloidosis, was insufficiently sensitive to warrant routine use in the diagnosis of the dis‐ ease. While not routinely performed for diagnosing cardiac amyloidosis given its variable sensitivity, a new technique, [99]mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintig‐ raphy, may be able to differentiate familial transthyretin-associated amyloidosis from AL amyloidosis, a clinically-relevant distinction; however, further study into this new technique is needed.[117]

**5.6. Biochemical markers and prognostication**

tide levels.[124]

tality.[132]

Cardiac biomarkers may be elevated in cardiac amyloidosis, often disproportionate to the clinical presentation.[122] Amyloid-induced myonecrosis and small vessel ischemia causes raised cardiac troponins,[123] while diastolic dysfunction and upregulation of na‐ triuretic peptide genes in diseased ventricles result in elevated B-type natriuretic pep‐

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

47

Cardiac troponins and N-terminal-pro-B-type natriuretic peptide are important prognos‐ tic indicators in cardiac amyloidosis, and also allow for monitoring progression of dis‐ ease or efficacy of therapy.[43, 77, 125-127] One study showed a significantly decreased median survival in patients with troponin elevation; this may even predict survival bet‐ ter than symptomatic congestive heart failure and two-dimensional echocardiographic findings.[128] A 30% decrease in N-terminal-pro-B-type natriuretic peptide after effec‐ tive chemotherapy correlates with increased event-free survival even without objective echocardiographic findings.[129] A combination of high-sensitivity cardiac troponin T at presentation and N-terminal-pro-B-type natriuretic peptide changes after chemotherapy had superior predictive value for survival.[130] Serum uric acid is a novel independent prognostic factor in AL amyloidosis. The median overall survival was lower in patients with uric acid levels ≥8 mg/dL.[131] A combination of uric acid, troponin T and N-ter‐ minal-pro-B-type natriuretic peptide provides a strong predictive model for early mor‐

The serum immunoglobulin free light chain assay enables quantification of aberrant cir‐ culating amyloidogenic fibril protein precursors.[129] It enables serial monitoring of amyloidogenic light chain production during chemotherapy.[133] A fall in aberrant free light chain production by half following chemotherapy was associated with reductions in N-terminal-pro-B-type natriuretic peptide but not in left ventricular wall thickness, and was associated with clinical improvement.[129] Further highly reproducible and quantifiable imaging studies such as CMR may assist in defining associations between

Although the management of cardiac amyloidosis is challenging, evolution of treatment options have improved prognosis. It is essential to determine the type of amyloidosis to guide treatment.[43] In general, the management aims can be broadly divided into the general supportive care of cardiac and extracardiac manifestations of the disease, as well as type-specific targeted therapy.[5, 43] Table 2 shows a general algorithm for the

cardiac function and alterations in light chain load.[43]

investigation and management of cardiac amyloidosis.

**6. Management of cardiac amyloidosis**

#### **5.5. Fat aspirate and endomyocardial biopsy for tissue diagnosis**

Even with current imaging technology, amyloidosis remains a histological diagnosis (Figure 6). The presence of serum or urine monoclonal paraprotein is suggestive of AL amyloidosis, but on its own does not firmly establish the diagnosis because low serum concentrations of a monoclonal protein (possibly from an unrelated monoclonal gammopathy of undetermined significance) can incorrectly suggest AL amyloid in some familial cardiac amyloidosis con‐ firmed later by cardiac biopsy.[118] For the diagnosis of systemic disease, less invasive tis‐ sue sampling methods are available.[9] Biopsies may be taken from the abdominal subcutaneous fat, with sensitivities of >80% for the latter in AL.[119-121]. Abdominal subcu‐ taneous fat aspiration is easily obtained with minimal risk and is now preferred over rectal biopsy. Endomyocardial biopsy should be considered if the diagnosis of amyloidosis cannot be made with noninvasive techniques and the suspicion of cardiac amyloidosis remains high, or in cases of isolated cardiac amyloidosis, for example in the isoleucine 122 form of familial amyloidosis and senile systemic amyloidosis.[9] The sensitivity of four endomyocar‐ dial biopsy samples for the disease is nearly 100%.[111] Mass spectrometry of the tissue bi‐ opsy is used to determine the type of amyloidosis.

**Figure 6.** Histologic findings classical of cardiac amyloidosis. Hematoxylin and eosin staining of an amyloid-infiltrated left ventricular myocardium is shown here. The amyloid protein stained an amorphic light pink color (arrows).

#### **5.6. Biochemical markers and prognostication**

sensitivity, a new technique, [99]mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintig‐ raphy, may be able to differentiate familial transthyretin-associated amyloidosis from AL amyloidosis, a clinically-relevant distinction; however, further study into this new technique

Even with current imaging technology, amyloidosis remains a histological diagnosis (Figure 6). The presence of serum or urine monoclonal paraprotein is suggestive of AL amyloidosis, but on its own does not firmly establish the diagnosis because low serum concentrations of a monoclonal protein (possibly from an unrelated monoclonal gammopathy of undetermined significance) can incorrectly suggest AL amyloid in some familial cardiac amyloidosis con‐ firmed later by cardiac biopsy.[118] For the diagnosis of systemic disease, less invasive tis‐ sue sampling methods are available.[9] Biopsies may be taken from the abdominal subcutaneous fat, with sensitivities of >80% for the latter in AL.[119-121]. Abdominal subcu‐ taneous fat aspiration is easily obtained with minimal risk and is now preferred over rectal biopsy. Endomyocardial biopsy should be considered if the diagnosis of amyloidosis cannot be made with noninvasive techniques and the suspicion of cardiac amyloidosis remains high, or in cases of isolated cardiac amyloidosis, for example in the isoleucine 122 form of familial amyloidosis and senile systemic amyloidosis.[9] The sensitivity of four endomyocar‐ dial biopsy samples for the disease is nearly 100%.[111] Mass spectrometry of the tissue bi‐

**Figure 6.** Histologic findings classical of cardiac amyloidosis. Hematoxylin and eosin staining of an amyloid-infiltrated left ventricular myocardium is shown here. The amyloid protein stained an amorphic light pink color (arrows).

**5.5. Fat aspirate and endomyocardial biopsy for tissue diagnosis**

opsy is used to determine the type of amyloidosis.

is needed.[117]

46 Amyloidosis

Cardiac biomarkers may be elevated in cardiac amyloidosis, often disproportionate to the clinical presentation.[122] Amyloid-induced myonecrosis and small vessel ischemia causes raised cardiac troponins,[123] while diastolic dysfunction and upregulation of na‐ triuretic peptide genes in diseased ventricles result in elevated B-type natriuretic pep‐ tide levels.[124]

Cardiac troponins and N-terminal-pro-B-type natriuretic peptide are important prognos‐ tic indicators in cardiac amyloidosis, and also allow for monitoring progression of dis‐ ease or efficacy of therapy.[43, 77, 125-127] One study showed a significantly decreased median survival in patients with troponin elevation; this may even predict survival bet‐ ter than symptomatic congestive heart failure and two-dimensional echocardiographic findings.[128] A 30% decrease in N-terminal-pro-B-type natriuretic peptide after effec‐ tive chemotherapy correlates with increased event-free survival even without objective echocardiographic findings.[129] A combination of high-sensitivity cardiac troponin T at presentation and N-terminal-pro-B-type natriuretic peptide changes after chemotherapy had superior predictive value for survival.[130] Serum uric acid is a novel independent prognostic factor in AL amyloidosis. The median overall survival was lower in patients with uric acid levels ≥8 mg/dL.[131] A combination of uric acid, troponin T and N-ter‐ minal-pro-B-type natriuretic peptide provides a strong predictive model for early mor‐ tality.[132]

The serum immunoglobulin free light chain assay enables quantification of aberrant cir‐ culating amyloidogenic fibril protein precursors.[129] It enables serial monitoring of amyloidogenic light chain production during chemotherapy.[133] A fall in aberrant free light chain production by half following chemotherapy was associated with reductions in N-terminal-pro-B-type natriuretic peptide but not in left ventricular wall thickness, and was associated with clinical improvement.[129] Further highly reproducible and quantifiable imaging studies such as CMR may assist in defining associations between cardiac function and alterations in light chain load.[43]

## **6. Management of cardiac amyloidosis**

Although the management of cardiac amyloidosis is challenging, evolution of treatment options have improved prognosis. It is essential to determine the type of amyloidosis to guide treatment.[43] In general, the management aims can be broadly divided into the general supportive care of cardiac and extracardiac manifestations of the disease, as well as type-specific targeted therapy.[5, 43] Table 2 shows a general algorithm for the investigation and management of cardiac amyloidosis.

#### **Step 1 – Identification of clinical scenarios suspicious for cardiac amyloidosis**

*Any one of the features below could trigger clinical suspicion – NOT all are required*

 •Dyspnea with exertion or heart failure of unknown etiology, often with thickening of the LV and/or RV walls, especially if associated with low voltages on ECG

**6.1. General supportive care**

these outcomes.

The traditional teaching that amyloidosis with cardiac involvement is universally fatal has dramatically changed in the last decade, largely due to chemotherapy and stem cell trans‐ plant therapies. However, important supportive care measures are necessary to achieve

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

49

Cardiac manifestations of amyloidosis primarily include heart failure and cardiac ar‐ rhythmias. The mainstay of heart failure treatment in cardiac amyloidosis is diuresis; pa‐ tients with hypoalbuminemia due to concomitant nephrotic syndrome require high doses. It is essential to monitor fluid balance meticulously with daily weighing and diu‐ retic dose adjustment.[5, 43] For a variety of reasons, beta-blockers, [9] renin-angiotensin system inhibitors,[5, 43] digoxin [134, 135] and calcium channel blockers[136]-[138] should be avoided where possible. In markedly impaired diastolic filling and reduced stroke volume, tachycardia is a compensatory mechanism that maintains cardiac output. Consequently, high doses of beta-adrenergic receptor blocking agents are often poorly tolerated. Calcium channel blockers and digitalis are considered contraindicated in car‐ diac amyloid disease due to potential binding of amyloid fibrils and potentiation of drug toxicity. Evidence for the use of vasodilator or inotropic agents in cardiac amyloidosis is lacking, but renal-dose dopamine may be helpful in the treatment of anasarca if renal function is unimpaired.[5] Recurrent large pleural effusions may represent pleural amy‐ loid and may require thoracentesis and occasionally, pleurodesis.[139] Placement of a pleural catheter can helpful for palliation of recurrent pleural effusions. Anticoagulation should be administered for standard indications such as intracardiac thrombus and atrial fibrillation, and an embolic event even in the absence of atrial fibrillation should trigger a search for intracardiac thrombosis.[14, 43, 97, 140] Appropriate selection of patients suitable for thromboembolic prophylaxis is difficult given the high anticoagulation-associ‐

ated bleeding risk due to vascular fragility and coagulopathy in amyloidosis.

Patient with cardiac amyloidosis are predisposed to many different types of arrhythmias, [57, 58] most commonly atrial fibrillation.[58] Given the atrial dilation from increased ven‐ tricular end-diastolic pressures as well as atrial amyloid infiltration, restoration of sinus rhythm is challenging and frequently unsuccessful in the long term.[14] It is reasonable, however, to attempt sinus rhythm restoration with DC cardioversion in highly symptomatic and medication refractory cases, provided no atrial thrombus is present by TEE. Atrial fibril‐ lation recurs in most patients, and as such a rate-control and anticoagulation strategy is war‐ ranted in most circumstances. Patients with AL amyloidosis with concomitant AF are at an extremely high risk of thromboembolism, and the thromboembolic risk in transthyretin-re‐ lated amyloidosis is also elevated above that of non-amyloid AF patients. Proper anticoagu‐ lation therapy reduces thromboembolic risk.[14] Amiodarone can be useful as both a rate controlling and rhythm maintaining agent. Amiodarone is presumed safe in cardiac amyloi‐ dosis although systemic study is lacking. Patients must be monitored for the known toxici‐ ties, and the drug should be avoided in the presence of significant conduction disease (e.g., left bundle branch block) without pacemaker placement. Dronedarone as well as many oth‐ er antiarrhythmic medications (typically of classes IA, IC and III) have not been well studied

•Unexplained fatigue and weight loss

 •Associated hepatomegaly, nephrotic-range proteinuria, peripheral or autonomic neuropathy, carpal tunnel syndrome, family history of amyloidosis

•Periorbital purpura (rare but almost pathognomonic) and macroglossia

#### **Step 2 – Cardiac diagnostic assessment**

 •Detailed echocardiographic examination including diastolic function analysis, tissue Doppler, strain imaging, assessment of RV wall thickness

•Cardiac MRI with late gadolinium enhancement

•Cardiac biomarkers: troponin T and NT-proBNP

#### **Step 3 – Further evaluation for the diagnosis of amyloidosis**

•Screening biopsy of abdominal subcutaneous fat aspirate or rectal mucosa with Congo red staining

•Screen serum and urine for monoclonal protein, serum free light chain assay

 •If clinical suspicion remains high despite the above being negative, consider endomyocardial biopsy (or other involved organ) with Congo red staining

#### **Step 4 – Determination of the amyloid fibril type (if the diagnosis of amyloidosis is made)**

*Tissue diagnosis and correct typing of amyloid is critical*

 •Mass spectrometry based proteomic analysis of tissue containing amyloid to determine specific type of amyloid protein

#### **Step 5 – Do specific testing based on type of amyloidosis**

 •Bone marrow aspirate and biopsy if diagnosis is AL amyloidosis or myeloma with associated amyloidosis •For TTR-related amyloidosis, genetic testing to distinguish between age-related and hereditary variant TTR types •For other hereditary amyloidoses, appropriate genetic testing for family counseling

#### **Step 6 – Type-specific treatment**

 •AL amyloidosis: quantify light chains (as baseline for follow-up), exclude concomitant myeloma, troponin and NTproBNP measurements for staging (if not done), supportive therapy, and determine which chemotherapy (including possible autologous stem cell transplant) and/or whether, sequential cardiac and autologous stem cell transplant is appropriate

•Familial amyloidosis: supportive therapy; assess for liver transplant with or without heart transplant

 •Reactive amyloidosis: treating the underlying chronic inflammatory state and anti-cytokines therapy (IL-6, TNFα) •Senile systemic amyloidosis: supportive therapy and possibly tafamidis in the future

AL, immunoglobulin light chain; ECG, electrocardiogram; LV, left ventricular; NT-proBNP, N-terminal prohormone brain natriuretic peptide; RV, right ventricular; TTR, transthyretin

**Table 2.** Evaluating a patient with suspected cardiac amyloidosis.

#### **6.1. General supportive care**

**Step 1 – Identification of clinical scenarios suspicious for cardiac amyloidosis** *Any one of the features below could trigger clinical suspicion – NOT all are required*

•Periorbital purpura (rare but almost pathognomonic) and macroglossia

especially if associated with low voltages on ECG

•Unexplained fatigue and weight loss

syndrome, family history of amyloidosis

**Step 2 – Cardiac diagnostic assessment**

involved organ) with Congo red staining

**Step 6 – Type-specific treatment**

protein

48 Amyloidosis

appropriate

*Tissue diagnosis and correct typing of amyloid is critical*

**Step 5 – Do specific testing based on type of amyloidosis**

 •Cardiac MRI with late gadolinium enhancement •Cardiac biomarkers: troponin T and NT-proBNP

**Step 3 – Further evaluation for the diagnosis of amyloidosis**

•Screen serum and urine for monoclonal protein, serum free light chain assay

assessment of RV wall thickness

•Dyspnea with exertion or heart failure of unknown etiology, often with thickening of the LV and/or RV walls,

•Associated hepatomegaly, nephrotic-range proteinuria, peripheral or autonomic neuropathy, carpal tunnel

•Detailed echocardiographic examination including diastolic function analysis, tissue Doppler, strain imaging,

•If clinical suspicion remains high despite the above being negative, consider endomyocardial biopsy (or other

•Mass spectrometry based proteomic analysis of tissue containing amyloid to determine specific type of amyloid

 •AL amyloidosis: quantify light chains (as baseline for follow-up), exclude concomitant myeloma, troponin and NTproBNP measurements for staging (if not done), supportive therapy, and determine which chemotherapy (including possible autologous stem cell transplant) and/or whether, sequential cardiac and autologous stem cell transplant is

•Reactive amyloidosis: treating the underlying chronic inflammatory state and anti-cytokines therapy (IL-6, TNFα)

AL, immunoglobulin light chain; ECG, electrocardiogram; LV, left ventricular; NT-proBNP, N-terminal prohormone

 •Bone marrow aspirate and biopsy if diagnosis is AL amyloidosis or myeloma with associated amyloidosis •For TTR-related amyloidosis, genetic testing to distinguish between age-related and hereditary variant TTR types

•Familial amyloidosis: supportive therapy; assess for liver transplant with or without heart transplant

•Screening biopsy of abdominal subcutaneous fat aspirate or rectal mucosa with Congo red staining

**Step 4 – Determination of the amyloid fibril type (if the diagnosis of amyloidosis is made)**

•For other hereditary amyloidoses, appropriate genetic testing for family counseling

•Senile systemic amyloidosis: supportive therapy and possibly tafamidis in the future

brain natriuretic peptide; RV, right ventricular; TTR, transthyretin

**Table 2.** Evaluating a patient with suspected cardiac amyloidosis.

The traditional teaching that amyloidosis with cardiac involvement is universally fatal has dramatically changed in the last decade, largely due to chemotherapy and stem cell trans‐ plant therapies. However, important supportive care measures are necessary to achieve these outcomes.

Cardiac manifestations of amyloidosis primarily include heart failure and cardiac ar‐ rhythmias. The mainstay of heart failure treatment in cardiac amyloidosis is diuresis; pa‐ tients with hypoalbuminemia due to concomitant nephrotic syndrome require high doses. It is essential to monitor fluid balance meticulously with daily weighing and diu‐ retic dose adjustment.[5, 43] For a variety of reasons, beta-blockers, [9] renin-angiotensin system inhibitors,[5, 43] digoxin [134, 135] and calcium channel blockers[136]-[138] should be avoided where possible. In markedly impaired diastolic filling and reduced stroke volume, tachycardia is a compensatory mechanism that maintains cardiac output. Consequently, high doses of beta-adrenergic receptor blocking agents are often poorly tolerated. Calcium channel blockers and digitalis are considered contraindicated in car‐ diac amyloid disease due to potential binding of amyloid fibrils and potentiation of drug toxicity. Evidence for the use of vasodilator or inotropic agents in cardiac amyloidosis is lacking, but renal-dose dopamine may be helpful in the treatment of anasarca if renal function is unimpaired.[5] Recurrent large pleural effusions may represent pleural amy‐ loid and may require thoracentesis and occasionally, pleurodesis.[139] Placement of a pleural catheter can helpful for palliation of recurrent pleural effusions. Anticoagulation should be administered for standard indications such as intracardiac thrombus and atrial fibrillation, and an embolic event even in the absence of atrial fibrillation should trigger a search for intracardiac thrombosis.[14, 43, 97, 140] Appropriate selection of patients suitable for thromboembolic prophylaxis is difficult given the high anticoagulation-associ‐ ated bleeding risk due to vascular fragility and coagulopathy in amyloidosis.

Patient with cardiac amyloidosis are predisposed to many different types of arrhythmias, [57, 58] most commonly atrial fibrillation.[58] Given the atrial dilation from increased ven‐ tricular end-diastolic pressures as well as atrial amyloid infiltration, restoration of sinus rhythm is challenging and frequently unsuccessful in the long term.[14] It is reasonable, however, to attempt sinus rhythm restoration with DC cardioversion in highly symptomatic and medication refractory cases, provided no atrial thrombus is present by TEE. Atrial fibril‐ lation recurs in most patients, and as such a rate-control and anticoagulation strategy is war‐ ranted in most circumstances. Patients with AL amyloidosis with concomitant AF are at an extremely high risk of thromboembolism, and the thromboembolic risk in transthyretin-re‐ lated amyloidosis is also elevated above that of non-amyloid AF patients. Proper anticoagu‐ lation therapy reduces thromboembolic risk.[14] Amiodarone can be useful as both a rate controlling and rhythm maintaining agent. Amiodarone is presumed safe in cardiac amyloi‐ dosis although systemic study is lacking. Patients must be monitored for the known toxici‐ ties, and the drug should be avoided in the presence of significant conduction disease (e.g., left bundle branch block) without pacemaker placement. Dronedarone as well as many oth‐ er antiarrhythmic medications (typically of classes IA, IC and III) have not been well studied in cardiac amyloidosis. However, based on studies in patients with structural heart disease and heart failure, they should be considered as contraindicated in advanced amyloid pa‐ tients at this time. Sudden death is often due to electromechanical dissociation; however, ventricular tachyarrhythmias are not infrequent.[102] The role of implantable cardioverterdefibrillator for primary prevention of sudden cardiac death in cardiac amyloid remains un‐ clear and controversial. Strategies to reduce the elevated defibrillation thresholds in cardiac amyloidosis such as a subcutaneous array lead system may improve the efficacy of implant‐ able cardioverter-defibrillator therapy.[141] The standard indications for pacing generally apply to cardiac amyloidosis,[142] but the threshold to introduce pacing is often lower in view of the propensity for the concomitant autonomic neuropathy and hypoalbuminemia to worsen any preexisting amyloidosis-related hemodynamic compromise.[43] Dual-chamber pacing may be particularly useful for optimizing the atrial filling component in this restric‐ tive cardiomyopathy.[43] However, there is no evidence that the symptomatic improvement from pacing translates into increased survival.[143] The generally accepted indications for cardiac resynchronization therapy apply in cardiac amyloidosis.[144] There are currently no prospective randomized controlled trials evaluating the use of continuous intra-axial cardiac flow pumps and left ventricular assist devices, but one patient received the former in a feasi‐ bility study with subsequent symptom relief.[145]

has been attempted, but significant cardiac involvement precludes it given the high peri‐ treatment mortality.[5, 153] Many patients are diagnosed at a stage at which such an ag‐ gressive therapeutic modality is too toxic; early studies in which patients were not carefully selected for high-dose chemotherapy with autologous stem cell transplant had transplant-related mortality of nearly 50%.[5, 158] The presence of symptomatic and structural features of cardiac amyloidosis strongly predicts poor outcomes from autolo‐ gous stem cell replacement,[159, 160] and the presence of clinical findings consistent with advanced disease, multiorgan involvement and poor functional status should preclude autologous stem cell therapy.[160, 161] Newer and investigational approaches include thalidomide or lenolidamide mono- or combination therapy,[151, 162, 163] rituximab to target CD20-positive plasma cell clones,[164] and the proteasome inhibitor bortezomib. [165-167] Heart transplantation is infrequently performed due to concerns about extracar‐ diac disease progression as well as amyloid deposition in the transplant heart. Indeed heart transplant survival rates were lower in cardiac amyloidosis compared with other indications.[168, 169] Sequential heart and stem cell transplant is promising in young pa‐ tients with cardiac failure and preserved extracardiac organ function, with a 1-year sur‐ vival of between 75% and 83%.[170-173] While there are several predictors of prognosis, it is at present difficult to select patients for the appropriate treatment regimen.[5, 43] In some patients high-intensity regimens may be excessive, but in others the disease re‐ mains refractory even to the most intense of regimens.[43] Therefore highly-individual‐

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

51

*Familial amyloidosis*. Because plasma transthyretin is mainly synthesized in the liver, defini‐ tive treatment for familial amyloidosis requires liver transplantation to arrest the synthesis of amyloidogenic proteins, as well as transplantation of failed organs.[174] Outcomes are generally favorable in young and fit patients with the methionine 30 mutation. However, in older patients of the non-methionine 30 variants, paradoxical acceleration of disease pro‐ gression has been reported, necessitating combined heart and liver transplants.[175-177] There is some evidence that transthyretin can be stabilized by certain nonsteroidal agents like diflunisal; clinical trials are necessary to investigate their efficacy in preventing disease progression.[178] These agents, however, may precipitate or aggravate congestive heart fail‐ ure by fluid retention, and other agents are actively being sought.[179] One promising thera‐ peutic candidate is tafamidis, a small-molecule transthyretin stabilizer which prevents transthyretin from forming amyloid fibrils. Tafamidis has demonstrated efficacy for the treatment of ATTR polyneuropathy, and has therefore been granted orphan drug status in the United States. Tafamidis is currently undergoing Phase II trials for the treatment of

*Reactive amyloidosis*. Definitive treatment involves treating the underlying inflammatory process and decreasing the serum amyloid A concentration, improving survival.[181] In‐ flammatory syndromes such as rheumatoid arthritis, Crohn's disease, seronegative spondy‐ loarthropathies, and several periodic fever syndromes can be effectively treated with tumor necrosis factor and interleukin-1 inhibitors.[182] Familial Mediterranean fever can be treated with colchicine,[183] while excision of interleukin-6-secreting masses is an effective treat‐

ized management of cardiac amyloidosis is essential.[43]

ATTR cardiomyopathy.[180]

#### **6.2. Targeting the underlying amyloid pathology**

This is an area of management that is specific to the type of amyloidosis, but the general aim is to decrease the formation new amyloid proteins and possibly facilitate the regres‐ sion of existing deposits.[5, 43] Recent advancements in both our ability to diagnose the type of amyloidosis and the treatment options for the various types have greatly im‐ proved outcome.[43]

*AL amyloidosis*. The mainstay of treatment in this type of amyloidosis is targeting the patho‐ genic light chain-producing clonal plasma cells with chemotherapy.[146-152] This minimiz‐ es amyloid production (potentially reversing the disease process), preserves organ function and enhances survival.[153, 154] Indeed, immunoassays for free light chains are useful in monitoring the disease process and responses to treatment, and halving the aberrant mono‐ clonal light chain on a sustained basis improves survival.[154] Reducing the circulating amyloidogenic precursor may result in some improvement in cardiac function even as the cardiac amyloid load found on echocardiography remains fairly constant.[129] These find‐ ings supports the direct toxic role of the aberrant monoclonal light chain on myocardial function that was shown in an animal model.[47] Moreover, similar findings were observed in other organs. For example, serial kidney biopsies in patients with AL amyloidosis before and after clinically successful treatments reveal unchanging amyloid burden despite signifi‐ cant improvement in proteinuria.[155, 156]

For patients who are fit for chemotherapy, several treatment regimens exist. The historic regimen of melphalan and prednisolone had responses that were few and much delayed; [157] more rapid responses are seen with intermediate-intensity regimens like melphalan and dexamethasone.[43] High-dose chemotherapy with autologous stem cell replacement has been attempted, but significant cardiac involvement precludes it given the high peri‐ treatment mortality.[5, 153] Many patients are diagnosed at a stage at which such an ag‐ gressive therapeutic modality is too toxic; early studies in which patients were not carefully selected for high-dose chemotherapy with autologous stem cell transplant had transplant-related mortality of nearly 50%.[5, 158] The presence of symptomatic and structural features of cardiac amyloidosis strongly predicts poor outcomes from autolo‐ gous stem cell replacement,[159, 160] and the presence of clinical findings consistent with advanced disease, multiorgan involvement and poor functional status should preclude autologous stem cell therapy.[160, 161] Newer and investigational approaches include thalidomide or lenolidamide mono- or combination therapy,[151, 162, 163] rituximab to target CD20-positive plasma cell clones,[164] and the proteasome inhibitor bortezomib. [165-167] Heart transplantation is infrequently performed due to concerns about extracar‐ diac disease progression as well as amyloid deposition in the transplant heart. Indeed heart transplant survival rates were lower in cardiac amyloidosis compared with other indications.[168, 169] Sequential heart and stem cell transplant is promising in young pa‐ tients with cardiac failure and preserved extracardiac organ function, with a 1-year sur‐ vival of between 75% and 83%.[170-173] While there are several predictors of prognosis, it is at present difficult to select patients for the appropriate treatment regimen.[5, 43] In some patients high-intensity regimens may be excessive, but in others the disease re‐ mains refractory even to the most intense of regimens.[43] Therefore highly-individual‐ ized management of cardiac amyloidosis is essential.[43]

in cardiac amyloidosis. However, based on studies in patients with structural heart disease and heart failure, they should be considered as contraindicated in advanced amyloid pa‐ tients at this time. Sudden death is often due to electromechanical dissociation; however, ventricular tachyarrhythmias are not infrequent.[102] The role of implantable cardioverterdefibrillator for primary prevention of sudden cardiac death in cardiac amyloid remains un‐ clear and controversial. Strategies to reduce the elevated defibrillation thresholds in cardiac amyloidosis such as a subcutaneous array lead system may improve the efficacy of implant‐ able cardioverter-defibrillator therapy.[141] The standard indications for pacing generally apply to cardiac amyloidosis,[142] but the threshold to introduce pacing is often lower in view of the propensity for the concomitant autonomic neuropathy and hypoalbuminemia to worsen any preexisting amyloidosis-related hemodynamic compromise.[43] Dual-chamber pacing may be particularly useful for optimizing the atrial filling component in this restric‐ tive cardiomyopathy.[43] However, there is no evidence that the symptomatic improvement from pacing translates into increased survival.[143] The generally accepted indications for cardiac resynchronization therapy apply in cardiac amyloidosis.[144] There are currently no prospective randomized controlled trials evaluating the use of continuous intra-axial cardiac flow pumps and left ventricular assist devices, but one patient received the former in a feasi‐

This is an area of management that is specific to the type of amyloidosis, but the general aim is to decrease the formation new amyloid proteins and possibly facilitate the regres‐ sion of existing deposits.[5, 43] Recent advancements in both our ability to diagnose the type of amyloidosis and the treatment options for the various types have greatly im‐

*AL amyloidosis*. The mainstay of treatment in this type of amyloidosis is targeting the patho‐ genic light chain-producing clonal plasma cells with chemotherapy.[146-152] This minimiz‐ es amyloid production (potentially reversing the disease process), preserves organ function and enhances survival.[153, 154] Indeed, immunoassays for free light chains are useful in monitoring the disease process and responses to treatment, and halving the aberrant mono‐ clonal light chain on a sustained basis improves survival.[154] Reducing the circulating amyloidogenic precursor may result in some improvement in cardiac function even as the cardiac amyloid load found on echocardiography remains fairly constant.[129] These find‐ ings supports the direct toxic role of the aberrant monoclonal light chain on myocardial function that was shown in an animal model.[47] Moreover, similar findings were observed in other organs. For example, serial kidney biopsies in patients with AL amyloidosis before and after clinically successful treatments reveal unchanging amyloid burden despite signifi‐

For patients who are fit for chemotherapy, several treatment regimens exist. The historic regimen of melphalan and prednisolone had responses that were few and much delayed; [157] more rapid responses are seen with intermediate-intensity regimens like melphalan and dexamethasone.[43] High-dose chemotherapy with autologous stem cell replacement

bility study with subsequent symptom relief.[145]

**6.2. Targeting the underlying amyloid pathology**

cant improvement in proteinuria.[155, 156]

proved outcome.[43]

50 Amyloidosis

*Familial amyloidosis*. Because plasma transthyretin is mainly synthesized in the liver, defini‐ tive treatment for familial amyloidosis requires liver transplantation to arrest the synthesis of amyloidogenic proteins, as well as transplantation of failed organs.[174] Outcomes are generally favorable in young and fit patients with the methionine 30 mutation. However, in older patients of the non-methionine 30 variants, paradoxical acceleration of disease pro‐ gression has been reported, necessitating combined heart and liver transplants.[175-177] There is some evidence that transthyretin can be stabilized by certain nonsteroidal agents like diflunisal; clinical trials are necessary to investigate their efficacy in preventing disease progression.[178] These agents, however, may precipitate or aggravate congestive heart fail‐ ure by fluid retention, and other agents are actively being sought.[179] One promising thera‐ peutic candidate is tafamidis, a small-molecule transthyretin stabilizer which prevents transthyretin from forming amyloid fibrils. Tafamidis has demonstrated efficacy for the treatment of ATTR polyneuropathy, and has therefore been granted orphan drug status in the United States. Tafamidis is currently undergoing Phase II trials for the treatment of ATTR cardiomyopathy.[180]

*Reactive amyloidosis*. Definitive treatment involves treating the underlying inflammatory process and decreasing the serum amyloid A concentration, improving survival.[181] In‐ flammatory syndromes such as rheumatoid arthritis, Crohn's disease, seronegative spondy‐ loarthropathies, and several periodic fever syndromes can be effectively treated with tumor necrosis factor and interleukin-1 inhibitors.[182] Familial Mediterranean fever can be treated with colchicine,[183] while excision of interleukin-6-secreting masses is an effective treat‐ ment for Castleman's disease.[184] A randomized controlled trial showed that eprodisate slows the decline of renal function in reactive amyloidosis, [185] and may have possible ap‐ plicability to other types of amyloidosis.[186]

**References**

1992;79(7):1817-1822.

1997;337(13):898-909.

2005;32(2):178-184.

2005;112(13):2047-2060.

J Hematol. Oct 2010;85(10):805-808.

Haematologica. Mar 1999;84(3):218-221.

Arch Intern Med. Sep 25 2006;166(17):1805-1813.

in 474 cases. Semin Hematol. Jan 1995;32(1):45-59.

Suppl 4:iv63-66.

2004;255(2):159-178.

[1] Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. Apr 1

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

53

[2] Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. Sep 25

[3] Hassan W, Al-Sergani H, Mourad W, Tabbaa R. Amyloid heart disease. New fron‐ tiers and insights in pathophysiology, diagnosis, and management. Tex Heart Inst J.

[4] Desai HV, Aronow WS, Peterson SJ, Frishman WH. Cardiac amyloidosis: approaches

[5] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. Sep 27

[6] Merlini G, Palladini G. Amyloidosis: is a cure possible? Ann Oncol. Jun 2008;19

[7] Telio D, Bailey D, Chen C, Crump M, Reece D, Kukreti V. Two distinct syndromes of lymphoma-associated AL amyloidosis: a case series and review of the literature. Am

[8] Perfetti V, Colli Vignarelli M, Anesi E, et al. The degrees of plasma cell clonality and marrow infiltration adversely influence the prognosis of AL amyloidosis patients.

[9] Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart: a comprehensive review.

[10] Chee CE, Lacy MQ, Dogan A, Zeldenrust SR, Gertz MA. Pitfalls in the diagnosis of primary amyloidosis. Clin Lymphoma Myeloma Leuk. Jun 2010;10(3):177-180. [11] Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin lightchain (AL) amyloidosis with heart involvement. QJM. Feb 1998;91(2):141-157. [12] Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features

[13] Feng D, Edwards WD, Oh JK, et al. Intracardiac thrombosis and embolism in patients

[14] Feng D, Syed IS, Martinez M, et al. Intracardiac thrombosis and anticoagulation ther‐

[15] Merlini G, Westermark P. The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies. J Intern Med. Feb

with cardiac amyloidosis. Circulation. Nov 20 2007;116(21):2420-2426.

apy in cardiac amyloidosis. Circulation. May 12 2009;119(18):2490-2497.

to diagnosis and management. Cardiol Rev. Jan-Feb 2010;18(1):1-11.

Currently, there is no known treatment that specifically targets senile amyloid, but research into this field is quickly evolving. Investigational approaches undergoing intensive research include targeted therapies that stabilize the soluble form of amyloidogenic proteins and re‐ verse preexisting deposits. A new therapy based on epigallocatechin gallate, a compound that binds to denatured protein thereby inhibiting the formation of insoluble amyloid, has been proposed.[65] These potential new therapies offer exciting prospects for improvements in treatment.[43, 65]

## **7. Conclusion**

Amyloidosis describes a heterogeneous group of several uncommon diseases by aberrant protein deposition in tissues throughout the body. Cardiac amyloidosis refers to clinically significant cardiac involvement, causing restrictive cardiomyopathy and its resultant effects, the most severe being congestive heart failure and arrhythmias. It is often underdiagnosed. However, recent advances in imaging have allowed us to accurately diagnose the condition and better characterize the degree of cardiac involvement. Cardiac biomarkers are useful in monitoring disease progression and response to therapy. The treatment of cardiac amyloi‐ dosis is rapidly evolving, and encompasses general supportive care of cardiac and extracar‐ diac manifestations of the disease, and in addition, the management of the underlying amyloid disease process. Importance must be attached to early diagnosis of the disease, par‐ ticularly in AL amyloidosis, because patients diagnosed late are often too ill to undergo dis‐ ease-modifying chemotherapy. Novel therapies are actively being investigated and may present exciting new frontiers in the treatment of the disease.

#### **Author details**

Glenn K. Lee1 , DaLi Feng2 , Martha Grogan3 , Cynthia Taub4 , Angela Dispenzieri3 and Kyle W. Klarich3

1 Department of Medicine, National University Health System, Singapore


## **References**

ment for Castleman's disease.[184] A randomized controlled trial showed that eprodisate slows the decline of renal function in reactive amyloidosis, [185] and may have possible ap‐

Currently, there is no known treatment that specifically targets senile amyloid, but research into this field is quickly evolving. Investigational approaches undergoing intensive research include targeted therapies that stabilize the soluble form of amyloidogenic proteins and re‐ verse preexisting deposits. A new therapy based on epigallocatechin gallate, a compound that binds to denatured protein thereby inhibiting the formation of insoluble amyloid, has been proposed.[65] These potential new therapies offer exciting prospects for improvements

Amyloidosis describes a heterogeneous group of several uncommon diseases by aberrant protein deposition in tissues throughout the body. Cardiac amyloidosis refers to clinically significant cardiac involvement, causing restrictive cardiomyopathy and its resultant effects, the most severe being congestive heart failure and arrhythmias. It is often underdiagnosed. However, recent advances in imaging have allowed us to accurately diagnose the condition and better characterize the degree of cardiac involvement. Cardiac biomarkers are useful in monitoring disease progression and response to therapy. The treatment of cardiac amyloi‐ dosis is rapidly evolving, and encompasses general supportive care of cardiac and extracar‐ diac manifestations of the disease, and in addition, the management of the underlying amyloid disease process. Importance must be attached to early diagnosis of the disease, par‐ ticularly in AL amyloidosis, because patients diagnosed late are often too ill to undergo dis‐ ease-modifying chemotherapy. Novel therapies are actively being investigated and may

, Cynthia Taub4

, Angela Dispenzieri3

and

present exciting new frontiers in the treatment of the disease.

, Martha Grogan3

2 Metropolitan Heart and Vascular Institute, Minneapolis, MN, USA

1 Department of Medicine, National University Health System, Singapore

3 Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

4 Division of Cardiology, Montefiore Medical Center, New York, NY, USA

plicability to other types of amyloidosis.[186]

in treatment.[43, 65]

52 Amyloidosis

**7. Conclusion**

**Author details**

, DaLi Feng2

Glenn K. Lee1

Kyle W. Klarich3


[16] Holmgren G, Holmberg E, Lindstrom A, et al. Diagnosis of familial amyloidotic pol‐ yneuropathy in Sweden by RFLP analysis. Clin Genet. Mar 1988;33(3):176-180.

[30] Dubrey SW, Cha K, Simms RW, Skinner M, Falk RH. Electrocardiography and Dop‐ pler echocardiography in secondary (AA) amyloidosis. Am J Cardiol. Feb 1

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

55

[31] Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64

[32] Gejyo F, Yamada T, Odani S, et al. A new form of amyloid protein associated with chronic hemodialysis was identified as beta 2-microglobulin. Biochem Biophys Res

[33] Gorevic PD, Casey TT, Stone WJ, DiRaimondo CR, Prelli FC, Frangione B. Beta-2 mi‐ croglobulin is an amyloidogenic protein in man. J Clin Invest. Dec 1985;76(6):

[34] Noel LH, Zingraff J, Bardin T, Atienza C, Kuntz D, Drueke T. Tissue distribution of

[35] Gal R, Korzets A, Schwartz A, Rath-Wolfson L, Gafter U. Systemic distribution of be‐ ta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemo‐ dialysis. Report of seven cases and review of the literature. Arch Pathol Lab Med. Jul

[36] Leone O, Boriani G, Chiappini B, et al. Amyloid deposition as a cause of atrial re‐ modelling in persistent valvular atrial fibrillation. Eur Heart J. Jul 2004;25(14):

[37] Looi LM. Isolated atrial amyloidosis: a clinicopathologic study indicating increased

[38] Rocken C, Peters B, Juenemann G, et al. Atrial amyloidosis: an arrhythmogenic sub‐ strate for persistent atrial fibrillation. Circulation. Oct 15 2002;106(16):2091-2097.

[39] Johansson B, Wernstedt C, Westermark P. Atrial natriuretic peptide deposited as at‐ rial amyloid fibrils. Biochem Biophys Res Commun. Nov 13 1987;148(3):1087-1092.

[40] Kaye GC, Butler MG, d'Ardenne AJ, Edmondson SJ, Camm AJ, Slavin G. Isolated at‐ rial amyloid contains atrial natriuretic peptide: a report of six cases. Br Heart J. Oct

[41] Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. Jul 30

[42] Westermark P, Johansson B, Natvig JB. Senile cardiac amyloidosis: evidence of two different amyloid substances in the ageing heart. Scand J Immunol. 1979;10(4):

[43] Selvanayagam JB, Hawkins PN, Paul B, Myerson SG, Neubauer S. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol. Nov 27 2007;50(22):

prevalence in chronic heart disease. Hum Pathol. Jun 1993;24(6):602-607.

patients. Medicine (Baltimore). Jul 1991;70(4):246-256.

dialysis amyloidosis. Clin Nephrol. Apr 1987;27(4):175-178.

Commun. Jun 28 1985;129(3):701-706.

1996;77(4):313-315.

2425-2429.

1237-1241.

1994;118(7):718-721.

1986;56(4):317-320.

1998;339(5):321-328.

303-308.

2101-2110.


[30] Dubrey SW, Cha K, Simms RW, Skinner M, Falk RH. Electrocardiography and Dop‐ pler echocardiography in secondary (AA) amyloidosis. Am J Cardiol. Feb 1 1996;77(4):313-315.

[16] Holmgren G, Holmberg E, Lindstrom A, et al. Diagnosis of familial amyloidotic pol‐ yneuropathy in Sweden by RFLP analysis. Clin Genet. Mar 1988;33(3):176-180.

[17] Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Adv Hum Genet.

[18] Skare J, Yazici H, Erken E, et al. Homozygosity for the met30 transthyretin gene in a Turkish kindred with familial amyloidotic polyneuropathy. Hum Genet. Nov

[19] Jacobson DR, Pastore R, Pool S, et al. Revised transthyretin Ile 122 allele frequency in

[20] Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (iso‐ leucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. Feb

[21] Westermark P, Sletten K, Johansson B, Cornwell GG, 3rd. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A. Apr

[22] Cornwell GG, 3rd, Murdoch WL, Kyle RA, Westermark P, Pitkanen P. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation.

[23] Kawamura S, Takahashi M, Ishihara T, Uchino F. Incidence and distribution of isolat‐ ed atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts.

[24] Olson LJ, Gertz MA, Edwards WD, et al. Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. N

[25] Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med. Oct 1996;101(4):395-400.

[26] Pitkanen P, Westermark P, Cornwell GG, 3rd. Senile systemic amyloidosis. Am J

[27] Dubrey SW, Davidoff R, Skinner M, Bergethon P, Lewis D, Falk RH. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis. Trans‐

[28] Kluve-Beckerman B, Dwulet FE, Benson MD. Human serum amyloid A. Three hepat‐ ic mRNAs and the corresponding proteins in one person. J Clin Invest. Nov

[29] Husby G. Amyloidosis and rheumatoid arthritis. Clin Exp Rheumatol. Apr-Jun

African-Americans. Hum Genet. Aug 1996;98(2):236-238.

1991;20:69-123, 309-111.

13 1997;336(7):466-473.

1990;87(7):2843-2845.

Am J Med. Oct 1983;75(4):618-623.

Pathol Int. May 1995;45(5):335-342.

Pathol. Dec 1984;117(3):391-399.

plantation. Jul 15 1997;64(1):74-80.

1988;82(5):1670-1675.

1985;3(2):173-180.

Engl J Med. Sep 17 1987;317(12):738-742.

1990;86(1):89-90.

54 Amyloidosis


[44] Volpi A, Cavalli A, Maggioni AP, Matturri L, Rossi L. Cardiac amyloidosis involving the conduction system and the aortocoronary neuroreceptors. Clinicopathologic cor‐ relates. Chest. Oct 1986;90(4):619-621.

[58] Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardio‐ graphic findings in primary systemic amyloidosis and biopsy-proven cardiac in‐

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

57

[59] Mueller PS, Edwards WD, Gertz MA. Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis. Am J Med. Aug 15 2000;109(3):

[60] Ishikawa Y, Ishii T, Masuda S, et al. Myocardial ischemia due to vascular systemic amyloidosis: a quantitative analysis of autopsy findings on stenosis of the intramural

[61] Narang R, Chopra P, Wasir HS. Cardiac amyloidosis presenting as ischemic heart disease. A case report and review of literature. Cardiology. 1993;82(4):294-300.

[62] Saffitz JE, Sazama K, Roberts WC. Amyloidosis limited to small arteries causing an‐

[63] Schafer S, Schardt C, Burkhard-Meier U, Klein RM, Heintzen MP, Strauer BE. Angina pectoris and progressive fatigue in a 61-year-old man. Circulation. Dec 15

[64] Chamarthi B, Dubrey SW, Cha K, Skinner M, Falk RH. Features and prognosis of ex‐ ertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. Nov

[65] Halwani O, Delgado DH. Cardiac amyloidosis: an approach to diagnosis and man‐

[66] Cueto-Garcia L, Tajik AJ, Kyle RA, et al. Serial echocardiographic observations in pa‐ tients with primary systemic amyloidosis: an introduction to the concept of early (asymptomatic) amyloid infiltration of the heart. Mayo Clin Proc. Sep 1984;59(9):

[67] Koyama J, Ray-Sequin PA, Davidoff R, Falk RH. Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with

[68] Ha JW, Ommen SR, Tajik AJ, et al. Differentiation of constrictive pericarditis from re‐ strictive cardiomyopathy using mitral annular velocity by tissue Doppler echocar‐

[69] Butz T, Piper C, Langer C, et al. Diagnostic superiority of a combined assessment of the systolic and early diastolic mitral annular velocities by tissue Doppler imaging for the differentiation of restrictive cardiomyopathy from constrictive pericarditis.

[70] Chew C, Ziady GM, Raphael MJ, Oakley CM. The functional defect in amyloid heart disease. The "stiff heart" syndrome. Am J Cardiol. Oct 6 1975;36(4):438-444.

AL (primary) amyloidosis. Am J Cardiol. May 1 2002;89(9):1067-1071.

diography. Am J Cardiol. Aug 1 2004;94(3):316-319.

Clin Res Cardiol. Apr 2010;99(4):207-215.

agement. Expert Rev Cardiovasc Ther. Jul 2010;8(7):1007-1013.

gina pectoris and sudden death. Am J Cardiol. Apr 1983;51(7):1234-1235.

volvement. Am J Cardiol. Feb 15 2005;95(4):535-537.

coronary arteries. Pathol Int. Mar 1996;46(3):189-194.

181-188.

1996;94(12):3376-3381.

1 1997;80(9):1242-1245.

589-597.


[58] Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardio‐ graphic findings in primary systemic amyloidosis and biopsy-proven cardiac in‐ volvement. Am J Cardiol. Feb 15 2005;95(4):535-537.

[44] Volpi A, Cavalli A, Maggioni AP, Matturri L, Rossi L. Cardiac amyloidosis involving the conduction system and the aortocoronary neuroreceptors. Clinicopathologic cor‐

[45] Brenner DA, Jain M, Pimentel DR, et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ

[46] Muller D, Roessner A, Rocken C. Distribution pattern of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors of matrix metalloproteinases 1 and 2, and alpha 2-macro‐ globulin in cases of generalized AA- and AL amyloidosis. Virchows Arch. Nov

[47] Liao R, Jain M, Teller P, et al. Infusion of light chains from patients with cardiac amy‐ loidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. Oct 2

[48] Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac

[49] Smith RR, Hutchins GM. Ischemic heart disease secondary to amyloidosis of intra‐

[50] James TN. Pathology of the cardiac conduction system in amyloidosis. Ann Intern

[51] Ridolfi RL, Bulkley BH, Hutchins GM. The conduction system in cardiac amyloido‐ sis. Clinical and pathologic features of 23 patients. Am J Med. May 1977;62(5):

[52] Gillmore JD, Lovat LB, Hawkins PN. Amyloidosis and the liver. J Hepatol. 1999;30

[53] Chopra S, Rubinow A, Koff RS, Cohen AS. Hepatic amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms. Am J Pathol. May 1984;115(2):

[54] Daoud MS, Lust JA, Kyle RA, Pittelkow MR. Monoclonal gammopathies and associ‐ ated skin disorders. J Am Acad Dermatol. Apr 1999;40(4):507-535; quiz 536-508.

[55] Rubinow A, Cohen AS. Skin involvement in generalized amyloidosis. A study of clinically involved and uninvolved skin in 50 patients with primary and secondary

[56] Burroughs EI, Aronson AE, Duffy JR, Kyle RA. Speech disorders in systemic amyloi‐

[57] McCarthy RE, 3rd, Kasper EK. A review of the amyloidoses that infiltrate the heart.

amyloidosis. Mayo Clin Proc. Aug 1984;59(8):547-555.

amyloidosis. Ann Intern Med. Jun 1978;88(6):781-785.

dosis. Br J Disord Commun. Aug 1991;26(2):201-206.

Clin Cardiol. Aug 1998;21(8):547-552.

myocardial arteries. Am J Cardiol. Sep 1979;44(3):413-417.

relates. Chest. Oct 1986;90(4):619-621.

Res. Apr 30 2004;94(8):1008-1010.

2000;437(5):521-527.

56 Amyloidosis

2001;104(14):1594-1597.

Med. Jul 1966;65(1):28-36.

677-686.

186-193.

Suppl 1:17-33.


[71] Swanton RH, Brooksby IA, Davies MJ, Coltart DJ, Jenkins BS, Webb-Peploe MM. Sys‐ tolic and diastolic ventricular function in cardiac amyloidosis. Studies in six cases di‐ agnosed with endomyocardial biopsy. Am J Cardiol. May 4 1977;39(5):658-664.

[83] Child JS, Levisman JA, Abbasi AS, MacAlpin RN. Echocardiographic manifestations of infiltrative cardiomyopathy. A report of seven cases due to amyloid. Chest. Dec

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

59

[84] Falk RH, Plehn JF, Deering T, et al. Sensitivity and specificity of the echocardiograph‐ ic features of cardiac amyloidosis. Am J Cardiol. Feb 15 1987;59(5):418-422.

[85] Maeda S, Tanaka T, Hayashi T. Familial atrial standstill caused by amyloidosis. Br

[86] Plehn JF, Southworth J, Cornwell GG, 3rd. Brief report: atrial systolic failure in pri‐

[87] Dingli D, Utz JP, Gertz MA. Pulmonary hypertension in patients with amyloidosis.

[88] Smith RR, Hutchins GM, Moore GW, Humphrey RL. Type and distribution of pul‐ monary parenchymal and vascular amyloid. Correlation with cardiac amyloid. Am J

[89] Utz JP, Swensen SJ, Gertz MA. Pulmonary amyloidosis. The Mayo Clinic experience

[90] Migrino RQ, Mareedu RK, Eastwood D, Bowers M, Harmann L, Hari P. Left ventric‐ ular ejection time on echocardiography predicts long-term mortality in light chain

[91] Belkin RN, Kupersmith AC, Khalique O, et al. A Novel Two-Dimensional Echocar‐ diographic Finding in Cardiac Amyloidosis. Echocardiography. Jun 24 2010.

[92] Porciani MC, Cappelli F, Perfetto F, et al. Rotational mechanics of the left ventricle in

[93] Migrino RQ, Harmann L, Woods T, Bright M, Truran S, Hari P. Intraventricular dys‐ synchrony in light chain amyloidosis: a new mechanism of systolic dysfunction as‐

sessed by 3-dimensional echocardiography. Cardiovasc Ultrasound. 2008;6:40.

[94] Kim WH, Otsuji Y, Yuasa T, Minagoe S, Seward JB, Tei C. Evaluation of right ventric‐ ular dysfunction in patients with cardiac amyloidosis using Tei index. J Am Soc

[95] Abdelmoneim SS, Bernier M, Bellavia D, et al. Myocardial contrast echocardiography in biopsy-proven primary cardiac amyloidosis. Eur J Echocardiogr. Mar 2008;9(2):

[96] Santarone M, Corrado G, Tagliagambe LM, et al. Atrial thrombosis in cardiac amyloi‐ dosis: diagnostic contribution of transesophageal echocardiography. J Am Soc Echo‐

mary amyloidosis. N Engl J Med. Nov 26 1992;327(22):1570-1573.

from 1980 to 1993. Ann Intern Med. Feb 15 1996;124(4):407-413.

amyloidosis. J Am Soc Echocardiogr. Dec 2009;22(12):1396-1402.

Al amyloidosis. Echocardiography. Oct 2010;27(9):1061-1068.

1976;70(6):726-731.

Heart J. Apr 1988;59(4):498-500.

Chest. Nov 2001;120(5):1735-1738.

Echocardiogr. Jan 2004;17(1):45-49.

cardiogr. Jun 1999;12(6):533-536.

338-341.

Med. Jan 1979;66(1):96-104.


[83] Child JS, Levisman JA, Abbasi AS, MacAlpin RN. Echocardiographic manifestations of infiltrative cardiomyopathy. A report of seven cases due to amyloid. Chest. Dec 1976;70(6):726-731.

[71] Swanton RH, Brooksby IA, Davies MJ, Coltart DJ, Jenkins BS, Webb-Peploe MM. Sys‐ tolic and diastolic ventricular function in cardiac amyloidosis. Studies in six cases di‐ agnosed with endomyocardial biopsy. Am J Cardiol. May 4 1977;39(5):658-664.

[72] Klein AL, Hatle LK, Taliercio CP, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. Nov

[73] Nishikawa H, Nishiyama S, Nishimura S, et al. Echocardiographic findings in nine patients with cardiac amyloidosis: their correlation with necropsy findings. J Cardiol.

[74] Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven

[75] Simons M, Isner JM. Assessment of relative sensitivities of noninvasive tests for car‐ diac amyloidosis in documented cardiac amyloidosis. Am J Cardiol. Feb 1 1992;69(4):

[76] Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular sys‐ tolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler

[77] Bellavia D, Pellikka PA, Al-Zahrani GB, et al. Independent predictors of survival in primary systemic (Al) amyloidosis, including cardiac biomarkers and left ventricular strain imaging: an observational cohort study. J Am Soc Echocardiogr. Jun 2010;23(6):

[78] Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain

[79] Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation. May 20 2003;107(19):2446-2452.

[80] Hamer JP, Janssen S, van Rijswijk MH, Lie KI. Amyloid cardiomyopathy in systemic non-hereditary amyloidosis. Clinical, echocardiographic and electrocardiographic findings in 30 patients with AA and 24 patients with AL amyloidosis. Eur Heart J.

[81] Siqueira-Filho AG, Cunha CL, Tajik AJ, Seward JB, Schattenberg TT, Giuliani ER. Mmode and two-dimensional echocardiographic features in cardiac amyloidosis. Cir‐

[82] Bhandari AK, Nanda NC. Myocardial texture characterization by two-dimensional

cardiac amyloidosis. J Am Coll Cardiol. Feb 4 2004;43(3):410-415.

echocardiography. Am J Cardiol. Apr 1 2008;101(7):1039-1045.

amyloidosis. JACC Cardiovasc Imaging. Apr 2010;3(4):333-342.

echocardiography. Am J Cardiol. Mar 1 1983;51(5):817-825.

1990;16(5):1135-1141.

Mar 1988;18(1):121-133.

425-427.

58 Amyloidosis

643-652.

May 1992;13(5):623-627.

culation. Jan 1981;63(1):188-196.


[97] Dubrey S, Pollak A, Skinner M, Falk RH. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J. Nov 1995;74(5):541-544.

[111] Pellikka PA, Holmes DR, Jr., Edwards WD, Nishimura RA, Tajik AJ, Kyle RA. Endo‐ myocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac in‐

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

61

[112] Mekinian A, Lions C, Leleu X, et al. Prognosis assessment of cardiac involvement in systemic AL amyloidosis by magnetic resonance imaging. Am J Med. Sep

[113] Austin BA, Tang WH, Rodriguez ER, et al. Delayed hyper-enhancement magnetic resonance imaging provides incremental diagnostic and prognostic utility in suspect‐

ed cardiac amyloidosis. JACC Cardiovasc Imaging. Dec 2009;2(12):1369-1377.

[114] Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. Jan-Feb

[115] Zou Z, Zhang HL, Roditi GH, Leiner T, Kucharczyk W, Prince MR. Nephrogenic sys‐ temic fibrosis: review of 370 biopsy-confirmed cases. JACC Cardiovasc Imaging. Nov

[116] Glaudemans AW, Slart RH, Zeebregts CJ, et al. Nuclear imaging in cardiac amyloi‐

[117] Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigra‐

[118] Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as

[119] Duston MA, Skinner M, Shirahama T, Cohen AS. Diagnosis of amyloidosis by ab‐ dominal fat aspiration. Analysis of four years' experience. Am J Med. Mar 1987;82(3):

[120] Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagno‐ sis of systemic amyloidosis. Arch Intern Med. Aug 1983;143(8):1549-1552.

[121] Westermark P, Stenkvist B. A new method for the diagnosis of systemic amyloidosis.

[122] Nordlinger M, Magnani B, Skinner M, Falk RH. Is elevated plasma B-natriuretic pep‐ tide in amyloidosis simply a function of the presence of heart failure? Am J Cardiol.

[123] Miller WL, Wright RS, McGregor CG, et al. Troponin levels in patients with amyloid cardiomyopathy undergoing cardiac transplantation. Am J Cardiol. Oct 1 2001;88(7):

[124] Takemura G, Takatsu Y, Doyama K, et al. Expression of atrial and brain natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis. J Am Coll

AL (primary) amyloidosis. N Engl J Med. Jun 6 2002;346(23):1786-1791.

dosis. Eur J Nucl Med Mol Imaging. Apr 2009;36(4):702-714.

phy. J Am Coll Cardiol. Sep 20 2005;46(6):1076-1084.

Arch Intern Med. Oct 1973;132(4):522-523.

Oct 1 2005;96(7):982-984.

Cardiol. Mar 15 1998;31(4):754-765.

volvement. Arch Intern Med. Mar 1988;148(3):662-666.

2010;123(9):864-868.

2010;52(4):347-361.

2011;4(11):1206-1216.

412-414.

813-815.


[111] Pellikka PA, Holmes DR, Jr., Edwards WD, Nishimura RA, Tajik AJ, Kyle RA. Endo‐ myocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac in‐ volvement. Arch Intern Med. Mar 1988;148(3):662-666.

[97] Dubrey S, Pollak A, Skinner M, Falk RH. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br

[98] Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac dysfunction: analysis of

[99] Sloan KP, Bruce CJ, Oh JK, Rihal CS. Complications of echocardiography-guided en‐ domyocardial biopsy. J Am Soc Echocardiogr. Mar 2009;22(3):324 e321-324.

[100] Dubrey SW, Bilazarian S, LaValley M, Reisinger J, Skinner M, Falk RH. Signal-aver‐ aged electrocardiography in patients with AL (primary) amyloidosis. Am Heart J.

[102] Falk RH, Rubinow A, Cohen AS. Cardiac arrhythmias in systemic amyloidosis: corre‐ lation with echocardiographic abnormalities. J Am Coll Cardiol. Jan 1984;3(1):

[103] Reyners AK, Hazenberg BP, Reitsma WD, Smit AJ. Heart rate variability as a predic‐ tor of mortality in patients with AA and AL amyloidosis. Eur Heart J. Jan 2002;23(2):

[104] Kinoshita O, Hongo M, Saikawa Y, et al. Heart rate variability in patients with fami‐ lial amyloid polyneuropathy. Pacing Clin Electrophysiol. Dec 1997;20(12 Pt 1):

[105] Takigawa M, Hashimura K, Ishibashi-Ueda H, et al. Annual electrocardiograms con‐ sistent with silent progression of cardiac involvement in sporadic familial amyloid

[106] Selvanayagam JB, Leong DP. MR Imaging and Cardiac Amyloidosis Where to Go

[107] Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. Feb 2010;3(2):155-164.

[108] Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac

[109] Vogelsberg H, Mahrholdt H, Deluigi CC, et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endo‐

[110] Hosch W, Bock M, Libicher M, et al. MR-relaxometry of myocardial tissue: significant elevation of T1 and T2 relaxation times in cardiac amyloidosis. Invest Radiol. Sep

myocardial biopsy. J Am Coll Cardiol. Mar 11 2008;51(10):1022-1030.

polyneuropathy: a case report. Intern Med. 2010;49(2):139-144.

From Here? JACC Cardiovasc Imaging. Feb 2010;3(2):165-167.

amyloidosis. Circulation. Jan 18 2005;111(2):186-193.

54 necropsy patients. Am J Cardiol. Jul 1983;52(1):137-146.

[101] Kyle RA. Amyloidosis. Circulation. Feb 15 1995;91(4):1269-1271.

Heart J. Nov 1995;74(5):541-544.

Dec 1997;134(6):994-1001.

107-113.

60 Amyloidosis

157-161.

2949-2953.

2007;42(9):636-642.


[125] Kristen AV, Giannitsis E, Lehrke S, et al. Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay. Blood. Oct 7 2010;116(14):2455-2461.

[137] Griffiths BE, Hughes P, Dowdle R, Stephens MR. Cardiac amyloidosis with asym‐ metrical septal hypertrophy and deterioration after nifedipine. Thorax. Sep

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

63

[138] Pollak A, Falk RH. Left ventricular systolic dysfunction precipitated by verapamil in

[139] Berk JL, Keane J, Seldin DC, et al. Persistent pleural effusions in primary systemic

[140] Modesto KM, Dispenzieri A, Cauduro SA, et al. Left atrial myopathy in cardiac amy‐ loidosis: implications of novel echocardiographic techniques. Eur Heart J. Jan

[141] Dhoble A, Khasnis A, Olomu A, Thakur R. Cardiac amyloidosis treated with an im‐ plantable cardioverter defibrillator and subcutaneous array lead system: report of a

[142] Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guide‐ lines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of

[143] Mathew V, Olson LJ, Gertz MA, Hayes DL. Symptomatic conduction system disease

[144] Strickberger SA, Conti J, Daoud EG, et al. Patient selection for cardiac resynchroniza‐ tion therapy: from the Council on Clinical Cardiology Subcommittee on Electrocar‐ diography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in collaboration with the Heart Rhythm Society.

[145] Siegenthaler MP, Westaby S, Frazier OH, et al. Advanced heart failure: feasibility study of long-term continuous axial flow pump support. Eur Heart J. May

[146] De Lorenzi E, Giorgetti S, Grossi S, Merlini G, Caccialanza G, Bellotti V. Pharmaceut‐ ical strategies against amyloidosis: old and new drugs in targeting a "protein mis‐

[147] Sanchorawala V, Wright DG, Seldin DC, et al. High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective random‐

[148] Gertz MA, Lacy MQ, Dispenzieri A. Therapy for immunoglobulin light chain amy‐

amyloidosis: etiology and prognosis. Chest. Sep 2003;124(3):969-977.

case and literature review. Clin Cardiol. Aug 2009;32(8):E63-65.

Thoracic Surgeons. J Am Coll Cardiol. May 27 2008;51(21):e1-62.

in cardiac amyloidosis. Am J Cardiol. Dec 1 1997;80(11):1491-1492.

folding disease". Curr Med Chem. Apr 2004;11(8):1065-1084.

ized trial. Bone Marrow Transplant. Feb 2004;33(4):381-388.

loidosis: the new and the old. Blood Rev. Mar 2004;18(1):17-37.

Circulation. Apr 26 2005;111(16):2146-2150.

2005;26(10):1031-1038.

cardiac amyloidosis. Chest. Aug 1993;104(2):618-620.

1982;37(9):711-712.

2005;26(2):173-179.


[137] Griffiths BE, Hughes P, Dowdle R, Stephens MR. Cardiac amyloidosis with asym‐ metrical septal hypertrophy and deterioration after nifedipine. Thorax. Sep 1982;37(9):711-712.

[125] Kristen AV, Giannitsis E, Lehrke S, et al. Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T

[126] Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J

[127] Dispenzieri A, Gertz MA, Kyle RA, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary sys‐ temic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. Sep

[128] Dispenzieri A, Kyle RA, Gertz MA, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet. May 24 2003;361(9371):

[129] Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in associa‐ tion with improvement of survival in AL. Blood. May 15 2006;107(10):3854-3858.

[130] Palladini G, Barassi A, Klersy C, et al. The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis.

[131] Kumar S, Dispenzieri A, Lacy MQ, et al. Serum uric acid: novel prognostic factor in

[132] Kumar SK, Gertz MA, Lacy MQ, et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin

[133] Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis under‐ going peripheral blood stem cell transplantation. Blood. Apr 15 2006;107(8):

[134] Cassidy JT. Cardiac amyloidosis. Two cases with digitalis sensitivity. Ann Intern

[135] Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy.

[136] Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J

primary systemic amyloidosis. Mayo Clin Proc. Mar 2008;83(3):297-303.

assay. Blood. Oct 7 2010;116(14):2455-2461.

Clin Oncol. Sep 15 2004;22(18):3751-3757.

Blood. Nov 4 2010;116(18):3426-3430.

Proc. Jan 2011;86(1):12-18.

Med. Dec 1961;55:989-994.

Circulation. Jun 1981;63(6):1285-1288.

Cardiol. Jun 1 1985;55(13 Pt 1):1645.

3378-3383.

15 2004;104(6):1881-1887.

1787-1789.

62 Amyloidosis


[149] Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexa‐ methasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. Apr 15 2004;103(8):2936-2938.

[162] Cohen AD, Zhou P, Chou J, et al. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis:

Cardiac Amyloidosis: Typing, Diagnosis, Prognosis and Management

http://dx.doi.org/10.5772/53763

65

[163] Palladini G, Russo P, Lavatelli F, et al. Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide. Ann Hema‐

[164] Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amy‐ loidosis: a French nationwide retrospective study of 72 patients. Medicine (Balti‐

[165] Lamm W, Willenbacher W, Lang A, et al. Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis. Ann Hematol. Sep 7 2010.

[166] Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or without dex‐ amethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. Feb 20

[167] Reece DE, Sanchorawala V, Hegenbart U, et al. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study.

[168] Kpodonu J, Massad MG, Caines A, Geha AS. Outcome of heart transplantation in pa‐ tients with amyloid cardiomyopathy. J Heart Lung Transplant. Nov 2005;24(11):

[169] Dubrey SW, Burke MM, Hawkins PN, Banner NR. Cardiac transplantation for amy‐ loid heart disease: the United Kingdom experience. J Heart Lung Transplant. Oct

[170] Gillmore JD, Goodman HJ, Lachmann HJ, et al. Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis. Blood. Feb 1 2006;107(3):

[171] Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-do‐ nor criteria organs for systemic amyloidosis complicated by heart failure. Transplan‐

[172] Dey BR, Chung SS, Spitzer TR, et al. Cardiac transplantation followed by dose-inten‐ sive melphalan and autologous stem-cell transplantation for light chain amyloidosis

[173] Kristen AV, Sack FU, Schonland SO, et al. Staged heart transplantation and chemo‐ therapy as a treatment option in patients with severe cardiac light-chain amyloidosis.

[174] Suhr OB, Herlenius G, Friman S, Ericzon BG. Liver transplantation for hereditary

and heart failure. Transplantation. Oct 27 2010;90(8):905-911.

transthyretin amyloidosis. Liver Transpl. May 2000;6(3):263-276.

results of a phase II trial. Br J Haematol. Oct 2007;139(2):224-233.

tol. Apr 2009;88(4):347-350.

more). Mar 2008;87(2):99-109.

Blood. Aug 20 2009;114(8):1489-1497.

2010;28(6):1031-1037.

2004;23(10):1142-1153.

tation. Mar 15 2007;83(5):539-545.

Eur J Heart Fail. Oct 2009;11(10):1014-1020.

1763-1765.

1227-1229.


[162] Cohen AD, Zhou P, Chou J, et al. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial. Br J Haematol. Oct 2007;139(2):224-233.

[149] Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexa‐ methasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. Apr 15 2004;103(8):2936-2938.

[150] Sanchorawala V, Wright DG, Seldin DC, et al. Low-dose continuous oral melphalan for the treatment of primary systemic (AL) amyloidosis. Br J Haematol. Jun

[151] Seldin DC, Choufani EB, Dember LM, et al. Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. Clin Lym‐

[152] Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann In‐

[153] Goodman HJ, Gillmore JD, Lachmann HJ, Wechalekar AD, Bradwell AR, Hawkins PN. Outcome of autologous stem cell transplantation for AL amyloidosis in the UK.

[154] Lachmann HJ, Gallimore R, Gillmore JD, et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light

[155] Kyle RA, Wagoner RD, Holley KE. Primary systemic amyloidosis: resolution of the nephrotic syndrome with melphalan and prednisone. Arch Intern Med. Aug

[156] Zeier M, Perz J, Linke RP, et al. No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and signifi‐ cant clinical improvement. Nephrol Dial Transplant. Dec 2003;18(12):2644-2647.

[157] Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloido‐ sis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and

[158] Moreau P. Autologous stem cell transplantation for AL amyloidosis: a standard ther‐

[159] Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and re‐ sponse after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. Jun 1998;101(4):766-769.

[160] Saba N, Sutton D, Ross H, et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant. Oct

[161] Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic

colchicine. N Engl J Med. Apr 24 1997;336(17):1202-1207.

apy? Leukemia. Dec 1999;13(12):1929-1931.

amyloidosis. Blood. Jun 15 2002;99(12):4276-4282.

chains following chemotherapy. Br J Haematol. Jul 2003;122(1):78-84.

2002;117(4):886-889.

64 Amyloidosis

1982;142(8):1445-1447.

1999;24(8):853-855.

phoma. Mar 2003;3(4):241-246.

tern Med. Jan 20 2004;140(2):85-93.

Br J Haematol. Aug 2006;134(4):417-425.


[175] Stangou AJ, Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr Opin Neurol. Oct 2004;17(5):615-620.

**Chapter 4**

**Dialysis-Related Amyloidosis: Pathogenesis and Clinical**

Amyloidosis is defined as an insoluble protein fibril that is deposited, mainly, in the extracel‐ lular spaces of organs and tissues as a result of a sequence of changes in protein folding. Precursor proteins change their conformation that forms amyloid fibrils, then deposited

To date, there are 27 types of amyloidosis known extracellular fibril proteins in human, and each amyloidosis is characterized amyloid protein precursor, systemic (S) or localized organ (L), and syndrome or involved tissues [1]. In the nomenclature, dialysis-related amyloidosis (DRA) is defined as β2-microglobulin-related (Aβ2M) amyloid which precursor protein is β2 microglobulin (β2-m). It is associated to dialysis, a kidney replacement therapy, and deposits

Long-term dialysis treatment for end-stage kidney disease often induces the Aβ2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as carpal tunnel syndrome (CTS), destructive spondyloarthropathy (DSA), and cystic bone lesions as well as in systemic organs such as heart and gastrointestinal tract when disease advances. Several biomolecules including β2-m as well as clinical risk factors are thought to relate with Aβ2M amyloidogenesis (Figure 1). Recent progress of dialysis therapy has improved survival of dialysis patients, however, older age and long-term dialysis treatment may increase the onset and acceleration of DRA. In this article, we described about DRA focused on pathogen‐ esis, clinical manifestations and treatment, and showed DRA is still one of serious complica‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Yamamoto et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Features in Patients Undergoing Dialysis Treatment**

Suguru Yamamoto, Junichiro James Kazama,

Additional information is available at the end of the chapter

amyloid induce organ damage with disease specific conditions.

tions for patients undergoing long-term dialysis treatment.

Hiroki Maruyama and Ichiei Narita

http://dx.doi.org/10.5772/53390

in systemic (S), mainly joint tissues [1].

**1. Introduction**

