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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 164-170

Review of cardiac amyloidosis

Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication11-Jan-2019

Correspondence Address:
Dr. Srikant Shivan
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcs.jpcs_68_18

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Cardiac amyloidosis is characterized by clinically significant extracellular amyloid infiltration of the heart that is commonly associated with multiorgan involvement depending on the type of amyloid. The deposits are derived from one of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Cardiac involvement represents the most important prognostic factor and thus an early diagnosis of amyloid heart disease is of utmost importance influencing further prognosis and management of the patients. The last decade has seen considerable progress in the understanding of amyloidosis. This review broadly aims to discuss clinical manifestations and diagnostics of amyloidosis with the main focus on treatment of amyloid cardiomyopathy.

Keywords: Amyloidosis, infiltrative, multisystem

How to cite this article:
Shivan S, Seth S. Review of cardiac amyloidosis. J Pract Cardiovasc Sci 2018;4:164-70

How to cite this URL:
Shivan S, Seth S. Review of cardiac amyloidosis. J Pract Cardiovasc Sci [serial online] 2018 [cited 2022 Jan 23];4:164-70. Available from: https://www.j-pcs.org/text.asp?2018/4/3/164/249948

  Introduction Top

Amyloidosis is a rare, infiltrative multisystem disease caused by extracellular deposition of fibrils in tissue that involves the major organ systems such as the kidney, heart, liver, autonomic nervous system, and others,[1],[2] leading to the loss of normal tissue architecture. Based on the type of amyloid protein, it may be systemic or localized. Amyloid fibrils are randomly oriented with a diameter of 7.5–10 nm which are arranged in the beta-pleated structure on electron microscopy and show apple-green birefringence under polarized light with Congo-red or Thioflavin-T staining. More than 30 different proteins have been implicated in the pathogenesis of formation of amyloid fibrils.[2] Diagnosis at an early stage may facilitate therapy before there is irreversible damage. In systemic amyloidosis cardiac involvement is the cause of death in nearly 50% of patients.[1] In this article, we will discuss the selected clinical and diagnostic aspects of cardiac amyloidosis and review the recent advances in the treatment of amyloidosis.[1],[2],[3],[4],[5]

  Types of Amyloidosis and Cardiac Involvement Top

Based on the type of amyloid precursor protein, cardiac involvement in amyloidosis can be divided into the following as shown in [Table 1]:
Table 1: Common systemic amyloidosis affecting the heart

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  • Amyloid light chain (AL) or primary amyloidosis
  • Transthyretin (TTR) or familial/hereditary amyloidosis
  • Systemic senile amyloidosis (SSA)
  • Isolated atrial amyloidosis (IAA)
  • Serum amyloid A (SAA) or secondary amyloidosis.[3]

Clinical outcome depends on the extent of tissue involvement and on the type of amyloid fibril deposits.

Primary amyloidosis

AL amyloidosis is the most commonly diagnosed form of the amyloid disease. It is slightly more commonly seen in men and is usually diagnosed after the fifth decade. AL amyloidosis is associated with lymphoproliferative disorders, including multiple myeloma–MGUS spectrum and occasionally, lymphomas.

Multiple myeloma coexists with AL amyloidosis in around 5%–10% of cases and which confers poorer prognosis.[4] In AL amyloidosis, monoclonal plasma cell population produces abnormal monoclonal light chains or fragments which misfold to form amyloid. In the majority of cases, there is a systemic organ involvement in 70% of AL amyloidosis. Apart from the heart, kidneys are most commonly affected in approximately 75%, liver in 25%, and peripheral and autonomic nerves in 20% of cases. Macroglossia and periorbital purpura (“panda” or “raccoon eyes”) are quite specific and almost pathognomonic for AL amyloidosis, however, are seen rarely in 10% of cases. Isolated cardiac involvement is seen in <5% of cases.[1],[2] Approximately 20% of patients have symptomatic cardiac involvement at the time of diagnosis.

Familial or hereditary systemic amyloidosis

Familial systemic amyloidosis is inherited in an autosomal dominant manner which has a variable penetrance. The clinically apparent disease usually presents in the middle-to-old age depending on the type of mutation. The majority of amyloidosis TTR (ATTR) mutations are associated with cardiac and nervous system involvement. Apart from carpal tunnel syndrome, other organ manifestations are rare. Onset and severity vary with specific mutation type. Some mutations may result in predominant cardiac amyloidosis. Neuropathy can present as a progressive sensorimotor and/or autonomic system involvement. Most common ATTR mutations are methionine for valine at position 30 (Val 30 Met) and isoleucine for valine at position 122 (Val 122 Ile).[5] Val 30 Met is commonly seen worldwide and Val 122 Ile is commonly found in about 4% of the African American/Caribbean population. Val 122 Ile mutation results in predominant cardiomyopathy with minimal or no neuropathy with onset in the late sixth decade in affected individuals.

Senile systemic amyloidosis

Wild-type TTR represents the precursor protein of this type of amyloidosis. It is a disease affecting almost exclusively men older than 75 years, about 20% of them presenting with symptoms of congestive heart failure and the final diagnosis is based on endomyocardial biopsy. Atrial fibrillation is a common feature, often developing several years before heart failure. SSA is the diagnosis of exclusion after ruling out AL and mutant ATTR.[2]

Isolated atrial amyloidosis

In IAA, the atrial natriuretic peptide is a precursor protein for amyloid formation and deposition. It is more commonly seen in elderly women over 80 years of age. IAA is thus usually diagnosed after autopsy study. IAA may play a role in the etiopathogenesis of idiopathic AF in the elderly. Despite the high prevalence, IAA does not lead to clinically significant heart failure.

Serum amyloid A amyloidosis

AA amyloidosis, formerly known as secondary amyloidosis, is usually found in chronic inflammatory states. The amyloid fibrils are made of SAA, an acute-phase reactant protein which is synthesized by the liver. It can be seen in familial Mediterranean fever, rheumatoid arthritis, inflammatory bowel diseases, or chronic infections such as tuberculosis. Renal involvement is the most common clinical feature of AA amyloidosis presenting with massive proteinuria. Clinically, apparent cardiac involvement is quite rare, occurring in about 1%–2% of the affected patients.

  Clinical Features and Diagnosis of Amyloid Heart Disease Top

Making an early diagnosis of amyloid heart disease and its type is of paramount importance in the successful management of affected individuals, including the choice of therapeutic strategy, especially in AL amyloidosis. Diagnosis of amyloidosis at an earlier stage with a milder degree of cardiac involvement, more aggressive treatment can be initiated resulting in better long-term outcomes for the patient.


The spectrum of organ involvement in AL amyloidosis is widespread, but cardiac involvement occurs in 50% of the cases and is sometimes only manifested with isolated cardiac involvement in 5% cases. Cardiac amyloidosis usually presents as restrictive cardiomyopathy characterized by rapidly progressing diastolic and subsequently systolic ventricular dysfunction and associated arrhythmias. AL amyloidosis usually, without appropriate treatment progresses rapidly and has very high mortality.[6],[7],[8],[9],[10],[11],[12],[13]

Macroglossia is almost pathognomonic for primary amyloidosis but is seen rarely, in only in about 10% of cases.[1],[2] Periorbital purpura (Raccoon eyes) is also quite specific for AL amyloidosis. It is seen as a result of vascular fragility. Weight loss, diarrhea, and general weakness and fatigue represent other typical, although nonspecific systemic symptoms. Renal and liver involvement is common in AL amyloidosis. Nephrotic range proteinuria should raise suspicion for renal involvement. Orthostatic hypotension due to autonomic neuropathy is fairly common and occurs in 30% of patients. Carpal tunnel syndrome and peripheral neuropathy are quite common, but there is a characteristic absence of central nervous system involvement in AL amyloidosis. The most common cause of death in patients with cardiac AL amyloidosis are refractory heart failure and sudden cardiac death.[6] Sudden cardiac death occurs in almost 30%–40% cases and is usually due to electromechanical dissociation rather than ventricular tachyarrhythmia.

The clinical features of ATTR amyloidosis differ from that of AL amyloidosis. In ATTR amyloidosis, cardiomyopathy and neuropathy are predominant manifestations as mutated TTR preferentially affects the heart and nervous system. Peripheral nervous system involvement results in a progressive sensorimotor neuropathy, sometimes associated with autonomic neuropathy. Onset and severity of manifestations vary with specific mutation type.[5] Some mutations may result mainly in cardiac amyloidosis. In senile systemic amyloidosis apart from cardiac involvement in the seventh decade, carpal tunnel syndrome biceps tendon rupture and spinal stenosis are the extracardiac manifestations. Renal and pulmonary involvement is quite rare.

Secondary AA amyloidosis is usually seen with chronic inflammatory conditions. Renal involvement with proteinuria is the predominant manifestation in AA amyloidosis, and cardiac failure is rarely seen.

Physical examination

Careful examination reveals prominent neck pulsations with an elevated JVP. Apex is generally not shifted and could be barely palpable or impalpable in advanced stages. Right-sided S3 can be seen in advanced cases of right-sided ventricular dysfunction. Despite being restrictive cardiomyopathy, the fourth heart sound is an exceedingly rare finding secondary to loss of atrial kick due to atrial amyloid infiltration. Hypotension is commonly seen because of low cardiac output and hypoadrenalism. Orthostatic hypotension may be present in patients secondary to autonomic neuropathy. Extracardiac manifestations include purpura, bruising, macroglossia, or periorbital ecchymosis. Hepatomegaly and ascites are seen in advanced cases of the right heart HF.

  Diagnostic Modalities for Cardiac Amyloidosis Top


Typical ECG findings[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] in amyloidosis include low QRS voltage (≤5 mV), better seen in limb leads and a pseudo-infarct pattern as shown in [Figure 1]. Low-voltage QRS complex occurs in approximately 40%–45% of patients with AL amyloidosis and is more common as compared to ATTR amyloidosis, but a pseudo-infarct pattern can be seen in both the types. Left bundle branch block and atrioventricular conduction defects are more commonly seen in ATTR Amyloidosis.[7] QRS fragmentation is a commonly seen in AL amyloidosis and is associated with worse prognosis
Figure 1: An electrocardiogram from the patient, shows low voltage with left-axis deviation with a pseudo-infarct pattern in leads V1–V3.

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Echocardiography plays an important role in diagnosis and shows several characteristic features for cardiac amyloidosis. On echocardiography, the characteristic features of the amyloid heart include increased biventricular wall thickness with myocardial “speckled” appearance (granular sparkling), normal or slightly reduced left ventricle (LV) volume, enlarged atria, and restrictive diastolic physiology with a restrictive pattern (Grade II–IV diastolic dysfunction) as shown in [Figure 2].[8],[12] A characteristic strain pattern by speckle tracking shows a significant decrease of longitudinal strain in the mid and basal wall regions with relative preservation of the apical region leading to a bull's eye pattern.[9] Atrial thrombi are common in AL amyloidosis even when patients are in sinus rhythm. Although most patients of cardiac AL amyloidosis have LV wall hypertrophy, heart failure can occur in even in patients with normal wall thickness.
Figure 2: Two dimensional echocardiography showing myocardial “speckled appearance” with (A-i) interatrial septal (IAS) thickening in apical 4 chamber view (A-ii) Left ventricular posterior wall (PW)/Interventricular septum(IVS) thickening in PLAX view (B) Tissue Doppler imaging shows restrictive inflow patterns.

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Cardiac Magnetic Resonance and Nuclear Imaging

Cardiac magnetic resonance (CMR) provides better characterization of myocardial borders and help in the quantification of wall thickness and ventricular volumes. The key finding in CMR is delayed gadolinium enhancement and reversal of normal myocardial nulling pattern [Figure 3]. In normal myocardium, gadolinium is not retained after administration, a phenomenon known as “nulling of myocardium.” In the amyloid heart, the distribution kinetics of gadolinium are changed due to extracellular deposition of amyloid, leading to retained contrast which produces the characteristic late gadolinium enhancement and inversion of the normal myocardial nulling pattern.[14],[15],[16]
Figure 3: Magnetic resonance of the heart showing (a) gadolinium enhanced cardiac magnetic resonance imaging showing inability to suppress (null) myocardial signal (myocardium appears similar to blood pool) {blue arrow} despite changing the inversion time; and (b) post-gadolinium delayed enhancement image (short axis chamber view) showing diffuse heterogeneous enhancement (yellow arrow).

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Use of radiotracers has been used to diagnose amyloidosis. Most commonly, 99 mTc-propanodicarboxylic acid (DPD) or 99 mTc-pyrophosphate (PYP) are used. A strongly positive DPD or PYP scan can differentiate TTR from AL amyloid[11] and can establish the diagnosis of ATTR amyloidosis without the need for tissue biopsy.

Laboratory examination and biomarkers

Laboratory evaluation includes the assessment of complete blood counts, urea and creatinine levels, liver function test, erythrocyte sedimentation rate, and C-reactive protein. After the clinical suspicion, the most appropriate initial screening test would be immunofixation of serum and urine for monoclonal protein spikes. Immunofixation is more sensitive than plain electrophoresis and should be a method of choice.[1],[2]

Serum immunoglobulin free light chain (FLC) assay used for prognostic staging and treatment follow-up of AL amyloidosis. The quantitative analysis of kappa (K) and lambda (L) FLCs levels is ten times more sensitive as compared to immunofixation electrophoresis for the detection of abnormal paraprotein.[5],[20],[22] In AL amyloidosis, lambda chains predominate over kappa chains in a ratio of 3:1 as compared to multiple myeloma where the ratio is reversed to 2:3.

Cardiac biomarkers troponins and N-terminal of B-type natriuretic peptide (BNP) (NT-proBNP) are elevated in patients with cardiac amyloidosis. In AL amyloidosis, NT-proBNP levels are elevated disproportionately to the clinical severity of heart failure.[6],[19],[21] Troponins and NT-proBNP or provide important prognostic information in AL amyloidosis and are currently used for staging the severity of organ involvement for example in mayo staging system. It is used for risk stratification of patients regarding their suitability and risk for high-dose chemotherapy and autologous stem cell transplantation (ASCT). NT-proBNP levels are also used for monitoring of disease progression and treatment response.

Histopathological diagnosis

The confirmation of amyloidosis requires some form of tissue diagnosis (fat pad aspirate or other tissues). Abdominal fat pad biopsy may reveal the diagnosis in about 60%–70% of patients. A bone marrow biopsy is required to characterize the monoclonal gammopathy, and usually, more than 5%–10% plasma cells are found in primary amyloidosis. Bone marrow biopsy along with Fat pad aspiration together can identify amyloid in 80%–90% of AL amyloidosis patients.[1],[2] Endomyocardial biopsy is considered gold standard and is extremely sensitive, but is often not required.[13] However, in isolated cardiac involvement seen rarely in 4% of cases with AL amyloidosis endomyocardial biopsy is always needed and more frequently with senile or familial amyloidosis. Histopathological detection of amorphous deposits by Congo red staining and classic apple-green birefringence under polarized light confirms the diagnosis of amyloidosis. A diagnostic algorithm for approach to cardiac amyloidosis is shown in [Figure 4].
Figure 4: Diagnostic algorithm for cardiac amyloidosis. +: Positive test result, –: Negative test result, AL: Amyloid light chain amyloidosis, ATTRm: Hereditary transthyretin amyloidosis, ATTRwt: Wild-type transthyretin amyloidosis, CMR: Cardiac MR, DPD: 99m3, 3diphosphono-1, 2-propanodicarboxylic acid, ECHO: Echocardiography, NT-proBNP: N-terminal fragment of pro-brain natriuretic peptide, PYP: 99mTc-pyrophosphate.

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  Prognosis Top

The prognosis[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] of the amyloidosis varies, but it is generally extremely poor if left untreated. Patients with AL amyloidosis have the worst prognosis, with a median survival of 6 months to 2 years. In patients with AL amyloidosis, the prognosis varies depending on the extent of organ involvement. Symptomatic heart involvement is associated with a median survival of 6 months, whereas median survival is 20 months when there is predominant renal involvement.[2] Multisystem involvement, especially if the heart and bowel are affected, has a very poor prognosis.

The prognosis in ATTR amyloidosis varies with the specific mutation and the time of diagnosis. Patients with ATTR amyloidosis may survive up to 15 years. In general, TTR mutations associated with a younger age at the onset of disease (20–30 years) involve more rapidly progressing neuropathy and cardiomyopathy and thus have a shorter survival. Various staging systems have been used for AL amyloidosis, with the primary focus on the degree of cardiac involvement. A widely utilized Mayo staging system was revised in 2012.[20],[21],[22],[23],[24] This staging system assigns patients a score of 1 for each, cTnT ≥0.025 ng/mL, differential FLC ≥18 mg/dL and NT-proBNP ≥1800 pg/mL, forming stages I (no points) to IV (three points) with median survival of 94.1, 40.3, 14, and 5.8 months for Stages I, II, III, and IV, respectively.

  Management Top

Cardiac amyloidosis has a rapid course and poor prognosis.[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] Therapeutic approach to cardiac amyloidosis has two components: supportive care including treatment of congestive heart failure and treatment to supress the amyloid precursor protein with the aim to prevent further deposition of amyloid.[1],[5] Standard heart failure therapy like beta blockers and angiotensin converting enzyme inhibitors may be of limited benefit or even detrimental due to low blood pressure or bradyarrhythmia hence should be avoided. Digoxin and calcium channel blockers bind to amyloid fibrils, thereby increasing toxicity and leading to negative inotropic effects there by worsening heart failure. Amiodarone used for rhythm control usually well tolerated. Reduced salt intake and loop diuretics together with aldosterone antagonists (spironolactone, eplerenone) are cornerstones of heart failure therapy.[2],[3] Anticoagulation therapy is given in patients with atrial flutter/fibrillation irrespective of CHADS2-VSAC score after cardioembolic stroke.

Patients with symptomatic bradyarrhythmia require permanent pacemaker implantation. The atrial and ventricular pacing threshold may be higher as compared to usual patients. In cases of high-degree AV block, biventricular pacing is better option because isolated RV pacing in the stiff small-cavity ventricle shall worsen AV synchrony. Most cases of sudden cardiac death in amyloidosis are due to electromechanical dissociation and thus role of implantation of cardioverter-defibrillator in prevention of fatal arrhythmic events is not very clear.[2],[30]

  Specific Treatment of Systemic Amyloidosis Top

Amyloid light amyoidosis

Specific treatment of systemic amyloidosis includes chemotherapy that eradicates pathologic plasma cells there by stopping the production of misfolded light chains. Chemotherapy typically involves the combination of antineoplastic, including alkylators (e.g., melphalan or cyclophosphamide), proteasome inhibitors (e.g., bortezomib or carfilzomib), and/or immunomodulators (e.g., lenalidomide or thalidomide) with steroids (e.g., dexamethasone). Hematologic responses have ranged between 40% and 45%. Bortezomib along with dexamethasone and cyclophosphamide is thefirst-line treatment in these patients. Using Mayo staging as stratification, an analysis of 230 patients treated with bortezomib, dexamethasone, and cyclophosphamide demonstrated better response and benefit in patients with stage I and II.[33] A matched case–control study revealed higher hematological response of 42% to bortezomib along with oral melphalan and dexamethasone as compared to 19% response to melphalan and dexamethasone alone.[34] Standard dose melphalan with high dose dexamethasone (MDex) is associated with favorable long-term outcomes in patients with low or intermediate risk disease; however, in patients at high risk, the results of treatment with MDex are poor.[33],[35] High-dose melphalan (HDM) followed by ASCT represent therapeutic option for only who are suitable candidates for this aggressive treatment. However, unfortunately, patients with cardiac amyloidosis do not tolerate HDM with ASCT therapy. A procedural mortality of 10% or more is reported, and the mortality rises to almost 90% in patients with advanced symptomatic cardiac amyloidosis.[3] Hence, this line of therapy is now reserved for patients who do not respond to standard frontline Bortezomib-based therapy.

Transthyretin amyloidosis

New drugs are being developed with small molecule ligands which act as silencers, stabilizers, or degraders of tetrameric structure of TTR.[36] Diflunisal is a nonsteroidal antiinflammatory drug type of stabilizer which reduces tetramer dissociation and subsequent misfolding and amyloid formation. Another stabilizer drug is Tafamidis. Maurer et al.[37] recently reported the results of the phase 3 TTR amyloidosis. Cardiomyopathy Clinical Trial, in which tafamidis was compared with placebo in the treatment of patients with ATTR cardiomyopathy. Treatment with Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations as well improved the functional capacity and quality of life as compared with placebo. A recently conducted clinical trial showed its beneficial role in neuropathy demonstrating the slowing of progression of neuropathyin ATTR amyloidosis.[39]

Small interfering RNA[37],[38],[39],[40] molecule Patisiran and the anti-sense oligonucleotide inotersen act as silencers which interfere with TTR production, reduced the progression of neuropathy among patients with stage1 ATTR amyloidosis. Combination of Doxycycline- tauroursodeoxycholic acid and anti serum amyloid protein (SAP) have also been recently tried as degrading agents of TTR in phase 1 trials. Hence, these multiple experimental agents offer hope for TTR amyloid patients in future and suggest new ways forward in developing therapies for this rare disease.

Secondary amyloidosis

Treatment is primarily directed to control the underlying chronic inflammatory state. Immunomodulating agents like tumor necrosis factor Alpha-inhibitors or interleukin 1 inhibitors have been tried. In a recent randomized study, eprodisate, a molecule that binds to SAA and inhibits fibril polymerization, was found beneficial in reducing the progression of renal failure in patients with AA amyloidosis.[41]

  Transplant Therapy Top

Most patients with AL amyloidosis have significant multi system involvement excluding them from routine cardiac transplantation. Cardiac transplantation alone does not address the underlying plasma cell dyscrasia and the deposition of amyloid thus continues unless hematologic disorder is treated. Cardiac transplantation with high intensity chemotherapy and ASCT performed within 6–12 months of heart transplant to prevent further amyloid deposition is currently recommended in highly selected patients.[25],[26],[27],[28] Combined heart and liver transplantation should be considered for patients with familial TTR amyloidosis with cardiac involvement.

  Conclusions Top

In the last decade, advances in molecular biology, immunology, and chemotherapy have greatly improved our understanding of the amyloidosis. It is important to diagnose the individual cardiac amyloidosis as treatment options vary. In general, supportive therapy for HF, chemotherapy, stem cell, and organ transplant are the currently available treatment options, whereas the newer therapies are in developmental phase. An increased clinical awareness of the disease on the part of treating physicians is critical for early diagnosis and timely access to new therapies for this otherwise uniformly fatal disease. Even with recent advances in the treatment, the overall prognosis remains quite dismal.

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Conflicts of interest

There are no conflicts of interest.

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ENDEAVOUR: Phase 3 Multicenter Study of Revusiran (ALN-TTRSC) in Patients with Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC). (National Institutes of Health Website); 2016. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02319005?term=NCT02319005&rank=1. [Last accessed on 2015 Dec 22].  Back to cited text no. 38
Efficacy and Safety of IONIS-TTR Rx in Familial Amyloid Polyneuropathy. (National Institutes of Health Website); 2016. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01737398?term=NCT01737398&rank=1. [Last accessed on 2015 Dec 22].  Back to cited text no. 39
APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis. (National Institutes of Health Website); 2016. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01960348?term=NCT01960348&rank=1. [Last accessed on 2015 Dec 22].  Back to cited text no. 40
Dember LM, Hawkins PN, Hazenberg BP, Gorevic PD, Merlini G, Butrimiene I, et al. Eprodisate for AA Amyloidosis Trial Group. Eprodisate for the treatment of renal disease in AA amyloidosis. The New England Journal of Medicine 2007; 356:2349-60.  Back to cited text no. 41


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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