Infiltration of the heart from insoluble protein deposits in amyloidosis often results in restrictive cardiomyopathy that manifests late in its course with heart failure and conduction abnormalities. While the rare primary amyloidosis–related heart disease has been well characterized, senile amyloidosis occurring in the seventh decade of life most frequently affects the heart. Early diagnosis of cardiac amyloidosis may improve outcomes but requires heightened suspicion and a systematic clinical approach to evaluation. Demonstration of tissue infiltration of biopsy specimens using special stains, followed by immunohistochemical studies and genetic testing, is essential in defining the specific protein involved. The therapeutic strategy depends on the characterization of the type of amyloid protein and extent of disease and may include chemotherapy, stem cell transplantation, and liver transplantation. Heart transplantation is controversial and is generally performed only at isolated centers.
Matthias Schleiden, a German botanist and co-creator of the cell theory, fashioned the word amyloid in 1834 to describe the waxy starch in plants. Today, amyloidosis describes the infiltration of multiple organs by insoluble deposits composed of fibrillar protein that arise from a diverse group of disease processes. To date, 24 heterogeneous proteins prone to misfolding have been discovered that comprise amyloid deposits.1 The misfolded proteins arise secondary to genetic mutations or excess production and form a β-pleated sheet that aligns in an antiparallel manner. The sheets form insoluble amyloid fibrils that resist proteolysis and cause mechanical disruption and local oxidative stress in various organs.2
Regardless of which precursor protein causes disease, the deposits are virtually indistinguishable with light microscopy. The amorphous proteinacous substance stains pink with Congo red staining, with apple-green birefringence under polarizing light microscopy. The spectrum of organ involvement can include the kidneys, heart, blood vessels, central and peripheral nervous systems, liver, intestines, lungs, eyes, skin, and bones.3 Amyloid deposition in the heart is a devastating and progressive process that leads to congestive heart failure, angina, and arrhythmias. For patients with amyloidosis, infiltration of the heart confers the worst prognosis. In this systematic review, we discuss the clinical features of cardiac amyloidosis, present a diagnostic approach, and describe potential therapies.
Cardiac amyloidosis is classified by the protein precursor as primary, secondary (reactive), senile systemic, hereditary, isolated atrial, and hemodialysis-associated amyloidosis. These distinct forms are differentiated by means of immunohistochemical and genetic testing, and prognosis and therapeutic strategies differ among these subtypes (Table).
In primary amyloidosis (AL), a plasma cell defect produces amyloidogenic immunoglobulin light-chain proteins, resulting in an aggressive form of amyloidosis. Primary amyloidosis is rare, with an incidence of 8.9 per million population.4 The mean survival has improved from 4.9 months in 1961 to 13.2 months in 1995.5,6 Primary amyloidosis affects more men than women (3:2), usually around the sixth decade of life.7
Cardiac involvement in AL is common, and 60% of patients demonstrate electrocardiographic or echocardiographic abnormalities. Clinical manifestations of heart failure identify a more aggressive natural history (median survival, 4 months). Death is attributed to cardiac causes in at least half of the patients with primary amyloidosis, who die of either heart failure or an arrhythmia.6
Light-chain amyloidosis affects several organs, and extracardiac manifestations often lead to the initial diagnosis. Early in the disease, nonspecific systemic complaints including weakness, fatigue, and weight loss dominate. Hepatomegaly results from infiltration of the liver or from hepatic congestion. Renal involvement causes profound proteinuria and nephrotic syndrome. Purpura and easy bruising, especially of the face and neck, occur from clotting factor deficiencies and fragile venules. Carpal tunnel syndrome, peripheral neuropathy, and macroglossia may also be present.6
Laboratory data reveal excess light-chain protein production. In one case series, 89% of patients with biopsy-confirmed primary amyloidosis had monoclonal light chains present at urine or serum protein immunofixation electrophoresis. The M protein type was primarily λ with a 2:1 predominance over κ. Bone marrow biopsy can reveal an increased fraction of plasma cells with proliferation of a clonal line and excessive λ and κ light-chain staining.6
Secondary amyloidosis (AA) results from the accumulation of amyloid A fibrils formed from an acute-phase reactant, serum amyloid A protein. Secondary amyloidosis may be associated with rheumatoid arthritis, familial Mediterranean fever, chronic infections, and inflammatory bowel disease.
Secondary amyloidosis of the heart is typically clinically insignificant.8,9 The primary pathologic findings involve the kidney, with development of proteinuria and renal failure. Treatment of the underlying process can reverse the disease.10
Senile Systemic Amyloidosis
Senile systemic amyloidosis, an age-related disease, occurs in the aorta, heart tissue, brain, pancreas, lung, liver, kidney, and a number of other tissues.11 Wild-type transthyretin (TTR), a transport protein synthesized in the liver and choroid plexus, forms the amyloid deposits.12 Senile systemic amyloidosis affects men predominantly, usually after age 70 years, and affects the heart in 25% of persons older than 80 years.13 The disease is often unrecognized; however, extensive amyloid deposition leads to clinically significant heart failure. The disease course is less aggressive than AL, with a median survival of 75 months.14
Hereditary (familial) amyloidosis is an autosomal dominant disease in which genetically mutated proteins form the amyloid fibrils. Mutations in both apolipoprotein I and TTR (ATTR) are known to lead to cardiac involvement, but our focus here is on TTR mutations, which are more prevalent.
Variant forms of TTR caused by more than 80 point mutations in the DNA predispose the protein to misfolding and to amyloid formation.15 The prominent feature is peripheral and autonomic neuropathy, a clinical entity referred to as familial amyloid polyneuropathy. Mutations causing significant cardiac disease are methionine-for-valine substitution at position 30, serine-for-isoleucine substitution at position 84, and alanine-for-threonine substitution at position 60.16 While less aggressive than AL disease, ATTR-related cardiac amyloidosis also results in clinically significant heart failure.
Familial amyloid polyneuropathy is generally classified by ancestral affiliation.17 Over years, patients develop progressive peripheral and autonomic neuropathy. Hyperesthesia to pain and temperature, motor weakness, and a diminished deep tendon reflex ascend from the lower extremities, and patients often become wheelchair dependent. Inactivity masks exertional symptoms from the underlying cardiomyopathy. Autonomic dysfunction includes impotence, decreased bowel motility, incontinence, and orthostatic hypotension.16
An isoleucine 122 gene mutation of the TTR DNA causes a familial amyloidosis primarily involving the heart without neurologic symptoms and is unique to elderly black persons. It is estimated that 1.3 million black persons are heterozygous for isoleucine 122.18 Presentation of the phenotype is variable, and the penetrance of the disease has yet to be defined.19
If tissue sampling confirms the presence of TTR in the amyloid deposits, isoelectric focusing of the patient's serum can differentiate mutant from normal TTR.20 Genetic testing by restriction fragment length polymorphism analysis can identify the type of mutation.
Isolated Atrial Amyloidosis
Isolated atrial amyloidosis (AANF) is composed of atrial natriuretic peptide, a protein secreted by atrial myocytes in response to increased wall stretch.21-23 The incidence of AANF increases with age (>90% in the ninth decade of life) and in females.24 The disease also occurs in young patients with valvular disease and in patients with chronic atrial fibrillation.25-27 AANF is limited to the heart as thin, linear deposits along and underneath the endocardium. It is unclear whether the disease process has any clinical significance.28
Hemodialysis-Related Amyloidosis
Patients receiving long-term dialysis can develop cardiac amyloidosis with accumulation of β2-microglobulin from long-standing uremia.29,30 The protein accumulates with declining renal function and is ineffectively cleared with hemodialysis. The clinical effect of deposits occurring in the myocardium, pericardium, and cardiac valves is minimal, and the predominant symptoms are from joint involvement.31,32 Renal transplantation normalizes β2-microglobulin concentrations and improves joint pain.33
While several types of amyloid infiltrate the heart, only senile, hereditary, and primary amyloidosis commonly cause clinically significant disease. Amyloid infiltration of the heart interrupts contractile function and electrical conduction and influences coronary flow. Amyloid penetrates the myocardial interstitium in the form of nodular deposits and branching filaments interlacing individual myocytes. Early mild diastolic dysfunction can be noted at echocardiography, but late disease produces a thickened heart wall with a firm and rubbery consistency, worsening cardiac relaxation and compliance. The stiff heart wall elevates filling pressures, resulting in restrictive cardiomyopathy.34,35 Increased diastolic filling pressures lead to dilation of the atrial chambers. The less compliant left ventricle remains of normal chamber diameter with thickening of the free wall and septum.36,37 With progression, myocyte necrosis and local interstitial fibrosis result in systolic ventricular dysfunction. The deposition into the atrial walls is extensive and in rare cases can cause mechanical failure and conduction standstill.38,39 Endocardial deposition may cause valvular insufficiency and worsen congestive heart failure. In rare cases, pericardial involvement occurs with high-grade disease and can lead to constrictive physiologic findings.36 There are reports of pulmonary amyloid infiltration resulting in pulmonary hypertension and cor pulmonale.40
In addition to mechanical disruption, amyloid deposits induce oxidant stress that depresses myocyte contractile function.41 Amyloid also modulates interstitial matrix composition and tissue remodeling by disabling the balance of matrix metalloproteinases and their inhibitors.42
Myocardial ischemia results from microvasculature disease. Amyloid deposits spare the epicardial vessels, while involvement of the intramural vasculature is present in 90% of patients with AL amyloidosis.36,43 Although severe obstruction is rare, diffuse involvement leads to numerous endocardial foci of ischemia, microinfarction, and eventual fibrosis, contributing to further myocardial dysfunction.44
Direct invasion of the conduction system is rare. However, perivascular fibrosis secondary to microvascular ischemia commonly involves the sinus node and bundle of His.45,46
While systemic symptoms of amyloidosis are variable, cardiac findings are dominated by diastolic heart failure resulting from restrictive cardiomyopathy. Findings of right-sided heart failure predominate, including lower extremity edema, hepatomegaly, ascites, and elevated jugular pressure.7 A murmur may be present from valvular insufficiency, and atrial fibrillation is common.
Anginal chest pain secondary to microvascular involvement with amyloid can also occur. Rare cases of amyloid manifesting as chest pain from intramural obstruction without evidence of myocardial deposition have been reported.47-51
Patients often have syncope and light-headedness resulting from autonomic dysfunction or arrhythmia in the setting of poor cardiac reserve. Amyloid deposition leads to obliteration of adrenergic input into the heart and alters baseline and compensatory neurohormonal cardiac stimulation.52 Often, autocorrection of hypertension is observed as relative hypotension develops.7
Diagnosis of amyloidosis must be established by histologic analysis of tissue. Congo red staining identifies amorphous pink deposits at light microscopy, which exhibit apple-green birefringence at examination under polarized microscopy (Figures 1, 2, and 3). If disease is limited to the heart, as in isoleucine 122 hereditary amyloidosis, examination of endomyocardial biopsy tissue is the only method of diagnosing the disease. Four endomyocardial biopsy samples ensure near 100% sensitivity for detecting disease.53 Less invasive tissue sampling methods are available for diagnosing systemic amyloid disease. The rectal submucosa has been the traditional biopsy site, with a reported sensitivity of 75% to 85%, but can be complicated by bleeding or perforation.54,55 Abdominal fat aspiration is without serious complications and is more sensitive (84%-88%) for diagnosing systemic amyloidosis.56-58 Endomyocardial biopsy specimens should be analyzed if less invasive methods fail to enable diagnosis of amyloidosis.
Cardiac nonamyloidotic immunoglobulin deposition disease describes the nonfibrillary deposition of monoclonal immunoglobulin light chain in the setting of a plasma cell dyscrasia that mimics cardiac amyloidosis. Unlike amyloidosis, the biopsy specimen appears normal at microscopy with negative Congo red staining, and the disease usually improves with resolution of the blood disorder.59
Serum markers of cardiac injury or stress are often elevated in cardiac amyloidosis. Cardiac-specific troponin serum concentrations may rise because of myocyte necrosis from amyloid deposits and ischemia related to intramural vessel obstruction.60 Natriuretic peptide levels are also elevated secondary to elevated filling pressures and possibly myocyte necrosis.61,62 Elevations in the troponin and natriuretic peptide levels portend a poor prognosis; however, their usefulness in monitoring disease progression is unknown.63,64
Low-voltage QRS amplitudes in the precordial leads (≤10 mV in all leads) or limb leads (≤5 mV in all leads), a pseudoinfarction pattern (QS waves in consecutive leads), and conduction delays are common. The low-voltage amplitudes in relation to wall thickness result from the displacement of viable myocardium with amyloid deposits; however, they also occur in other conditions, including obesity, emphysema, hypothyroidism, effusion, myocardial fibrosis, and adrenal insufficiency.
Dubrey et al7 reported that electrocardiograms for 75% of patients with cardiac amyloidosis demonstrated a pseudoinfarction pattern, and more than 70% exhibited low-voltage amplitudes. In another series, Murtagh et al65 challenged these findings and found that only 47% of electrocardiograms demonstrated a pseudoinfarction pattern and that 46% exhibited low-voltage amplitudes. Numerous arrhythmias have been described, including atrial fibrillation, atrial flutter, ventricular tachycardia, atrioventricular block, prolonged QT interval, and junctional rhythm.7
Echocardiography offers a noninvasive diagnostic approach for monitoring progression of disease. To our knowledge, Siqueira-Filho et al66 first described the “granular sparkling” refractile myocardium pathognomonic for the disease. Similar studies in patients with symptomatic disease revealed increased ventricular mass with thickening of the ventricular septal and free walls. Increasing wall thickness is inversely correlated with survival.67 Septal thickening can often imitate hypertrophic obstructive cardiomyopathy.68,69 Increased atrial septal wall thickening and granular sparkling myocardium are highly specific for differentiating cardiac amyloidosis from other causes of left ventricular hypertrophy.70 Both atria are typically dilated and the ventricular chamber dimensions are normal. Systolic function can be depressed with extensive disease.66
Doppler echocardiography provides useful information characterizing the progression of cardiac dysfunction. Early amyloid deposition impairs isovolumetric relaxation, resulting in decreased early diastolic flow velocity across the mitral valve (E) and increased dependence on atrial contraction for ventricular filling, leading to increased late diastolic filling velocities (A).71 The decreased E:A ratio of flow velocities is an earlier sign of amyloid involvement. As the heart wall becomes less compliant, left atrial pressures increase, as does early diastolic filling across the mitral valve, thus pseudonormalizing the E:A ratio.72
The echocardiographic findings of cardiac amyloidosis mimic other causes of left ventricular hypertrophy; thus, it is helpful to combine diagnostic methods to identify cardiac amyloidosis.70 Specifically, comparing the voltage on the electrocardiogram with the wall thickness on the echocardiogram can identify patients with infiltrative cardiomyopathy (Figure 4). Recent advances in echocardiography, including strain and strain rate Doppler imaging, may further improve the sensitivity of detecting cardiac amyloidosis.73
The coronary angiogram is usually normal because only in rare cases does amyloid involve the epicardial vessels. Right-sided heart catheterization enables measurement of intracardiac pressures for diagnosis of restrictive cardiomyopathy. Characteristic findings on the hemodynamic profile of extensive amyloid deposition in the myocardium are indistinguishable from other causes of restrictive cardiomyopathy. Diastolic pressure is elevated in both ventricles and right-sided pressure tracings reveal a dip and plateau or square root sign.
Scintigraphic evaluation of the heart for uptake of radiolabeled phosphonates by amyloid was first explored more than 20 years ago.74,75 Sensitivity for diagnosis has been variable; thus, the test has not been incorporated into the routine workup for cardiac amyloidosis.76 A recent study, however, indicates that technetium Tc 99m–3,3,-diphosphono-1,2-propanodicarboxylic acid may be capable of differentiating TTR-associated amyloidosis from AL amyloidosis.77
Cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging enables high-resolution 3-dimensional imaging of the myocardium and evaluation of chamber diameters, wall thickness and consistency, and regional wall motion.78 In addition, decreased tissue signal intensity along with late subendocardium tissue enhancement by gadolinium are a result of myocardial amyloid deposits and can help differentiate cardiac amyloidosis from other causes of cardiomyopathy.79,80Figure 5 shows the clinical and diagnostic findings that should raise suspicion for cardiac amyloidosis.
The primary goal of medical therapy is relief of symptoms, and decongestion is achieved by cautious diuresis. Orthostatic hypotension and obliteration of sympathetic input preclude use of negative inotropic agents. Reports describe clinical deterioration when cardiac amyloidosis is treated with calcium channel blockers.81,82 Similar reasoning extends to β-adrenergic receptor blockers, but this has not been demonstrated in the available literature. Digoxin binds to amyloid fibrils in vivo, and digoxin toxic effects have been reported.83,84 The binding properties of digoxin to amyloid deposits may disrupt safe administration of the medication. Patients should be instructed to monitor their weight and their fluid and salt intake daily.
Permanent pacemaker implantation is indicated in patients meeting guidelines for device placement.85 While cardiac pacing improves symptoms, it has not been shown to improve survival.86 No data are available on biventricular pacing or automatic implantable cardioverter-defibrillators in this population.
Chemotherapy and Stem Cell Transplantation
Treatment for AL includes oral chemotherapy (melphalan and prednisone) or high-dose chemotherapy with autologous stem cell transplantation. The benefit of oral chemotherapy is inadequate, and the greatest survival benefits are limited to patients without cardiac involvement.87,88
Stem cell transplantation has shown promising results for the treatment of primary amyloidosis.89,90 Compared with other hematologic malignancies, transplant-related mortality is increased 5-fold in amyloidosis. The increased mortality has been attributed to extensive and diffuse systemic end-organ damage from amyloid deposits, and patients with extensive cardiac disease are not optimal candidates for therapy.89,91
Solid Organ Transplantation
Heart transplantation is not generally accepted as a viable treatment for cardiac amyloidosis because limited case series have suggested poor long-term survival as a result of disease recurrence in the allograft; however, extracardiac amyloid disease and sepsis are common modes of death.92,93 Adjuvant chemotherapy with transplantation has not been shown to improve mortality, but only limited data are available for modern regimens.94,95 Newer mechanical circulatory support ventricular assist devices may offer an alternative palliative therapy in end-stage heart failure as destination therapy, but no specific use of such devices in amyloidosis has been reported.96
Liver transplantation removes the source of mutant TTR and is the onlyknown curative treatment for hereditary amyloidosis. More than 500 patients with here ditary amyloidosis have undergone transplantation surgery.97,98 Five-year survival is reportedly 60% to 77%, with substantial improvement in neuropathy.99-102 If extensive cardiac infiltration is also present, combined heart and liver transplantation has been successfully performed in selected patients.103 Early identification of candidates for transplantation is critical because those with less severe manifestations of disease burden tolerate surgery better.104
Cardiac amyloidosis is a rare disorder that poses a diagnostic challenge because its clinical characteristics overlap with common causes of cardiac disease. Heightened clinical suspicion coupled with classic findings, including low-voltage amplitudes on electrocardiograms and hyperrefractile myocardium on echocardiograms, typically help in the diagnosis of late-stage disease. While successful therapeutic interventions are limited, early diagnosis portends a better response to current therapy and prolonged survival. Thus, awareness and understanding of amyloidosis is important for cardiologists and general practitioners alike.
Correspondence: Mandeep R. Mehra, MD, Division of Cardiology, University of Maryland, 22 S Greene St, Room S3BO6, Baltimore, MD 21201 (mmehra@medicine.umaryland.edu).
Accepted for Publication: May 30, 2006.
Financial Disclosure: None reported.
Acknowledgment: We thank Allen Burke, MD, for providing the microscopy images.
4.Kyle
RALinos
ABeard
CM
et al. Incidence and natural history of primary systemic amyloidosis in Olmstead County, Minnesota, 1950 through 1989.
Blood 1992;791817- 1822
PubMedGoogle Scholar 5.Kyle
RABayrd
ED “Primary” systemic amyloidosis and myeloma: discussion of relationship and review of 81 cases.
Arch Intern Med 1961;107344- 353
PubMedGoogle ScholarCrossref 6.Kyle
RAGertz
MA Primary systemic amyloidosis: clinical and laboratory features in 474 cases.
Semin Hematol 1995;3245- 59
PubMedGoogle Scholar 7.Dubrey
SWCha
KAnderson
J
et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement.
QJM 1998;91141- 157
PubMedGoogle ScholarCrossref 8.Dubrey
SWCha
KSimms
RWSkinner
MFalk
RH Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis.
Am J Cardiol 1996;77313- 315
PubMedGoogle ScholarCrossref 9.Gertz
MAKyle
RA Secondary systemic amyloidosis: response and survival in 64 patients.
Medicine (Baltimore) 1991;70246- 256
PubMedGoogle ScholarCrossref 10.Gillmore
JDLovat
LBPersey
MRPepys
MBHawkins
PN Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein.
Lancet 2001;35824- 29
PubMedGoogle ScholarCrossref 11.Pitkanen
PWestermark
PCornwell
GG
III Senile systemic amyloidosis.
Am J Pathol 1984;117391- 399
PubMedGoogle Scholar 12.Westermark
PSletten
KJohansson
BCornwell
GG
III Fibril in senile systemic amyloidosis is derived from normal transthyretin.
Proc Natl Acad Sci U S A 1990;872843- 2845
PubMedGoogle ScholarCrossref 13.Cornwell
GG
IIIMurdoch
WLKyle
RAWestermark
PPitkanen
P Frequency and distribution of senile cardiovascular amyloid: a clinicopathologic correlation.
Am J Med 1983;75618- 623
PubMedGoogle ScholarCrossref 14.Ng
BConnors
LHDavidoff
RSkinner
MFalk
RH Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated (AL) amyloidosis.
Arch Intern Med 2005;1651425- 1429
PubMedGoogle ScholarCrossref 15.Connors
LHRichardson
AMTheberge
RCostello
CE Tabulation of transthyretin (TTR) variants as of 1/1/2000.
Amyloid 2000;754- 69
PubMedGoogle ScholarCrossref 17.Benson
MDWallace
MRTejada
EBaumann
HPage
B Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy: Appalachian amyloid.
Arthritis Rheum 1987;30195- 200
PubMedGoogle ScholarCrossref 18.Jacobson
DRPastore
RPool
S
et al. Revised transthyretin Ile 122 allele frequency in African-Americans.
Hum Genet 1996;98236- 238
PubMedGoogle ScholarCrossref 19.Jacobson
DRPastore
DRYaghoubian
R
et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.
N Engl J Med 1997;336466- 473
PubMedGoogle ScholarCrossref 20.Altland
KBanzhoff
A Separation by hybrid isoelectric focusing of normal human plasma transthyretin (prealbumin) and a variant with a methionine for valine substitution associated with familial amyloidotic polyneuropathy.
Electrophoresis 1986;7529- 533
Google ScholarCrossref 21.Kaye
GCButler
MGd’Ardenne
AJEdmondson
SJCamm
AJSlavin
G Isolated atrial amyloid contains atrial natriuretic peptide: a report of six cases.
Br Heart J 1986;56317- 320
PubMedGoogle ScholarCrossref 22.Johansson
BWernstedt
CWestermark
P Atrial natriuretic peptide deposited as atrial amyloid fibrils.
Biochem Biophys Res Commun 1987;1481087- 1092
PubMedGoogle ScholarCrossref 24.Kawamura
STakahashi
MIshihara
TUchino
F Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts.
Pathol Int 1995;45335- 342
PubMedGoogle ScholarCrossref 25.Looi
LM Isolated atrial amyloidosis: a clinicopathologic study indicating increased prevalence in chronic heart disease.
Hum Pathol 1993;24602- 607
PubMedGoogle ScholarCrossref 26.Röcken
CPeters
BJuenemann
G
et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
Circulation 2002;1062091- 2097
PubMedGoogle ScholarCrossref 27.Leone
OBoriani
GChiappini
B
et al. Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation.
Eur Heart J 2004;251237- 1241
PubMedGoogle ScholarCrossref 28.Westermark
PJohansson
BNatvig
JB Senile cardiac amyloidosis: evidence of two different amyloid substances in the ageing heart.
Scand J Immunol 1979;10303- 308
PubMedGoogle ScholarCrossref 29.Gejyo
FYamada
TOdani
S
et al. A new form of amyloid protein associated with chronic hemodialysis was identified as beta 2-microglobulin.
Biochem Biophys Res Commun 1985;129701- 706
PubMedGoogle ScholarCrossref 30.Gorevic
PDCasey
TTStone
WJDiRaimondo
CRPrelli
FCFrangione
B Beta-2 microglobulin is an amyloidogenic protein in man.
J Clin Invest 1985;762425- 2429
PubMedGoogle ScholarCrossref 31.Noel
LHZingraff
JBardin
TAtienza
CKuntz
DDrueke
T Tissue distribution of dialysis amyloidosis.
Clin Nephrol 1987;27175- 178
PubMedGoogle Scholar 32.Gal
RKorzets
ASchwartz
ARath-Wolfson
LGafter
U Systemic distribution of beta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysis: report of seven cases and review of the literature.
Arch Pathol Lab Med 1994;118718- 721
PubMedGoogle Scholar 33.Tan
SYIrish
AWinearls
CG
et al. Long term effect of renal transplantation on dialysis-related amyloid deposits and symptomatology.
Kidney Int 1996;50282- 289
PubMedGoogle ScholarCrossref 34.Chew
CZiady
GMRaphael
MJOakley
CM The functional defect in amyloid heart disease: the stiff heart syndrome.
Am J Cardiol 1975;36438- 444
PubMedGoogle ScholarCrossref 35.Swanton
RHBrooksby
IADavies
MJColtart
DJJenkins
BSWebb-Peploe
MM Systolic and diastolic ventricular function in cardiac amyloidosis: studies in six cases diagnosed with endomyocardial biopsy.
Am J Cardiol 1977;39658- 664
PubMedGoogle ScholarCrossref 36.Smith
TJKyle
RALie
JT Clinical significance of histopathologic patterns of cardiac amyloidosis.
Mayo Clin Proc 1984;59547- 555
PubMedGoogle ScholarCrossref 37.Roberts
WCWaller
BF Cardiac amyloidosis causing cardiac dysfunction: analysis of 54 necropsy patients.
Am J Cardiol 1983;52137- 146
PubMedGoogle ScholarCrossref 39.Plehn
JFSouthworth
JCornwell
GG
III Brief report: atrial systolic failure in primary amyloidosis.
N Engl J Med 1992;3271570- 1573
PubMedGoogle ScholarCrossref 41.Brenner
DAJain
MPimentel
DR
et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.
Circ Res 2004;941008- 1010
PubMedGoogle ScholarCrossref 42.Muller
DRoessner
ARocken
C Distribution pattern of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors of matrix metalloproteinases 1 and 2, and α2-macroglobulin in cases of generalized AA- and AL amyloidosis.
Virchows Arch 2000;437521- 527
PubMedGoogle ScholarCrossref 43.Crotty
TBLi
CYEdwards
WDSuman
VJ Amyloidosis and endomyocardial biopsy: correlation of extent and pattern of deposition with amyloid immunophenotype in 100 cases.
Cardiovasc Pathol 1995;439- 42
Google ScholarCrossref 44.Smith
RRHutchins
GM Ischemic heart disease secondary to amyloidosis of intramyocardial arteries.
Am J Cardiol 1979;44413- 417
PubMedGoogle ScholarCrossref 46.Ridolfi
RLBulkley
BHHutchins
GM The conduction system in cardiac amyloidosis: clinical and pathologic features of 23 patients.
Am J Med 1977;62677- 686
PubMedGoogle ScholarCrossref 47.Ishikawa
YIshii
TMasuda
S
et al. Myocardial ischemia due to vascular systemic amyloidosis: a quantitative analysis of autopsy findings on stenosis of the intramural coronary arteries.
Pathol Int 1996;46189- 194
PubMedGoogle ScholarCrossref 48.Schafer
SSchardt
CBurkhard-Meier
UKlein
RMHeintzen
MPStrauer
BE Angina pectoris and progressive fatigue in a 61-year-old man.
Circulation 1996;943376- 3381
PubMedGoogle ScholarCrossref 49.Saffitz
JESazama
KRoberts
WC Amyloidosis limited to small arteries causing angina pectoris and sudden death.
Am J Cardiol 1983;511234- 1235
PubMedGoogle ScholarCrossref 50.Narang
RChopra
PWasir
HS Cardiac amyloidosis presenting as ischemic heart disease: a case report and review of literature.
Cardiology 1993;82294- 300
PubMedGoogle ScholarCrossref 51.Mueller
PSEdwards
WDGertz
MA Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis.
Am J Med 2000;109181- 188
PubMedGoogle ScholarCrossref 52.Volpi
ACavalli
AMaggioni
APMatturri
LRossi
L Cardiac amyloidosis involving the conduction system and the aortocoronary neuroreceptors: clinicopathologic correlates.
Chest 1986;90619- 621
PubMedGoogle ScholarCrossref 53.Pellikka
PAHolmes
DR
JrEdwards
WDNishimura
RATajik
AJKyle
RA Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement.
Arch Intern Med 1988;148662- 666
PubMedGoogle ScholarCrossref 54.Kyle
RASpencer
RJDahlin
DC Value of rectal biopsy in the diagnosis of primary systemic amyloidosis.
Am J Med Sci 1966;251501- 506
PubMedGoogle ScholarCrossref 57.Libbey
CASkinner
MCohen
AS Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis.
Arch Intern Med 1983;1431549- 1552
PubMedGoogle ScholarCrossref 59.Buxbaum
JNGenega
EMLazowski
P
et al. Infiltrative nonamyloidotic monoclonal immunoglobulin light chain cardiomyopathy: an underappreciated manifestation of plasma cell dyscrasias.
Cardiology 2000;93220- 228
PubMedGoogle ScholarCrossref 60.Miller
WLWright
RSMcGregor
CG
et al. Troponin levels in patients with amyloid cardiomyopathy undergoing cardiac transplantation.
Am J Cardiol 2001;88813- 815
PubMedGoogle ScholarCrossref 61.Takemura
GTakatsu
YDoyama
K
et al. Expression of atrial and brain natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis.
J Am Coll Cardiol 1998;31754- 765
Google ScholarCrossref 62.Nordlinger
MMagnani
BSkinner
MFalk
RH Is elevated plasma B-natriuretic peptide in amyloidosis simply a function of the presence of heart failure?
Am J Cardiol 2005;96982- 984
PubMedGoogle ScholarCrossref 63.Palladini
GCampana
CKlersy
C
et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis.
Circulation 2003;1072440- 2445
PubMedGoogle ScholarCrossref 64.Dispenzieri
AKyle
RAGertz
MA
et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins.
Lancet 2003;3611787- 1789
PubMedGoogle ScholarCrossref 65.Murtagh
BHammill
SCGertz
MAKyle
RATajik
AJGrogan
M Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement.
Am J Cardiol 2005;95535- 537
PubMedGoogle ScholarCrossref 66.Siqueira-Filho
AGCunha
CLTajik
AJSeward
JBSchattenberg
TGiuliani
ER M-mode and two-dimensional echocardiographic features in cardiac amyloidosis.
Circulation 1981;63188- 196
PubMedGoogle ScholarCrossref 67.Cueto-Garcia
LReeder
GSKyle
RA
et al. Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival.
J Am Coll Cardiol 1985;6737- 743
PubMedGoogle ScholarCrossref 68.Presti
CFWaller
BFArmstrong
WF Cardiac amyloidosis mimicking the echocardiographic appearance of obstructive hypertrophic myopathy.
Chest 1988;93881- 883
PubMedGoogle ScholarCrossref 69.Sedlis
SPSaffitz
JESchwob
VSJaffe
AS Cardiac amyloidosis simulating hypertrophic cardiomyopathy.
Am J Cardiol 1984;53969- 970
PubMedGoogle ScholarCrossref 70.Falk
RHPlehn
JFDeering
T
et al. Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis.
Am J Cardiol 1987;59418- 422
PubMedGoogle ScholarCrossref 71.Klein
ALHatle
LKBurstow
DJ
et al. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis.
J Am Coll Cardiol 1989;131017- 1026
PubMedGoogle ScholarCrossref 72.Klein
ALHatle
LKTaliercio
CP
et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis.
J Am Coll Cardiol 1990;161135- 1141
PubMedGoogle ScholarCrossref 73.Koyama
JRay-Sequin
PAFalk
RH Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis.
Circulation 2003;1072446- 2452
PubMedGoogle ScholarCrossref 74.Wizenberg
TAMuz
JSohn
YHSamlowski
WWeissler
AM Value of positive myocardial technetium-99m-pyrophosphate scintigraphy in the noninvasive diagnosis of cardiac amyloidosis.
Am Heart J 1982;103468- 473
PubMedGoogle ScholarCrossref 75.Falk
RHLee
VWRubinow
AHood
WB
JrCohen
AS Sensitivity of technetium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloid.
Am J Cardiol 1983;51826- 830
PubMedGoogle ScholarCrossref 76.Gertz
MABrown
MLHauser
MFKyle
RA Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis.
Arch Intern Med 1987;1471039- 1044
PubMedGoogle ScholarCrossref 77.Perugini
EGuidalotti
PLSalvi
F
et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using
99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy.
J Am Coll Cardiol 2005;461076- 1084
PubMedGoogle ScholarCrossref 78.Fattori
RRocchi
GCelletti
FBertaccini
PRapezzi
CGavelli
G Contribution of magnetic resonance imaging in the differential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy.
Am Heart J 1998;136824- 830
PubMedGoogle ScholarCrossref 80.Celletti
FFattori
RNapoli
G
et al. Assessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging.
Am J Cardiol 1999;83798- 801
PubMedGoogle ScholarCrossref 81.Gertz
MAFalk
RHSkinner
MCohen
ASKyle
RA Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents.
Am J Cardiol 1985;55(13) (pt 1)1645
PubMedGoogle ScholarCrossref 82.Griffiths
BEHughes
PDowdle
RStephens
MR Cardiac amyloidosis with asymmetrical septal hypertrophy and deterioration after nifedipine.
Thorax 1982;37711- 712
PubMedGoogle ScholarCrossref 85.Gregoratos
GAbrams
JEpstein
AE
et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines).
J Am Coll Cardiol 2002;401703- 1719
PubMedGoogle ScholarCrossref 86.Mathew
VOlson
LJGertz
MAHayes
DL Symptomatic conduction system disease in cardiac amyloidosis.
Am J Cardiol 1997;801491- 1492
PubMedGoogle ScholarCrossref 87.Skinner
MAnderson
JSimms
R
et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only.
Am J Med 1996;100290- 298
PubMedGoogle ScholarCrossref 88.Kyle
RAGertz
MAGreipp
PR
et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.
N Engl J Med 1997;3361202- 1207
PubMedGoogle ScholarCrossref 89.Comenzo
RLVosburgh
ESimms
RW
et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.
Blood 1996;882801- 2806
PubMedGoogle Scholar 90.Gertz
MABlood
EVesole
DHLazarus
HMGreipp
PR Amyloidosis: a multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study.
Bone Marrow Transplant 2004;34149- 154
PubMedGoogle ScholarCrossref 91.Moreau
PLeblond
VBourquelot
P
et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients.
Br J Haematol 1998;101766- 769
PubMedGoogle ScholarCrossref 92.Hosenpud
JDDeMarco
TFrazier
OH
et al. Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation: follow-up results of a multicenter survey.
Circulation 1991;84
((5) (suppl III))
III338- III343
PubMedGoogle Scholar 93.Kpodonu
JMassad
MGCaines
AGeha
AS Outcome of heart transplantation in patients with amyloid cardiomyopathy.
J Heart Lung Transplant 2005;241763- 1765
PubMedGoogle ScholarCrossref 94.Dubrey
SWBurke
MMKhaghani
AHawkins
PNYacoub
MHBanner
NR Long term results of heart transplantation in patients with amyloid heart disease.
Heart 2001;85202- 207
PubMedGoogle ScholarCrossref 95.Dubrey
SWBurke
MMHawkins
PNBanner
NR Cardiac transplantation for amyloid heart disease: the United Kingdom experience.
J Heart Lung Transplant 2004;231142- 1153
PubMedGoogle ScholarCrossref 96.Rose
EAGelijns
ACMoskowitz
AJ
et al. Long-term mechanical left ventricular assistance for end-stage heart failure.
N Engl J Med 2001;3451435- 1443
PubMedGoogle ScholarCrossref 97.Holmgren
GSteen
LEkstedt
J
et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30).
Clin Genet 1991;40242- 246
PubMedGoogle ScholarCrossref 98.Herlenius
GWilczek
HELarsson
MEriczon
BGFamilial Amyloidotic Polyneuropathy World Transplant Registry, Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry.
Transplantation 2004;7764- 71
PubMedGoogle ScholarCrossref 99.Lewis
WDSkinner
MSimms
RWJones
LACohen
ASJenkins
RL Orthotopic liver transplantation for familial amyloidotic polyneuropathy.
Clin Transplant 1994;8107- 110
PubMedGoogle Scholar 100.Adams
DSamuel
DGoulon-Goeau
C
et al. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation.
Brain 2000;123(pt 7)1495- 1504
PubMedGoogle ScholarCrossref 101.Bergethon
PRSabin
TDLewis
DSimms
RWCohen
ASSkinner
M Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation.
Neurology 1996;47944- 951
PubMedGoogle ScholarCrossref 102.Parrilla
PRamirez
PAndreu
LF
et al. Long-term results of liver transplantation in familial amyloidotic polyneuropathy type I.
Transplantation 1997;64646- 649
PubMedGoogle ScholarCrossref 103.Nardo
BBeltempo
PBertelli
R
et al. Combined heart and liver transplantation in four adults with familial amyloidosis: experience of a single center.
Transplant Proc 2004;36645- 647
PubMedGoogle ScholarCrossref 104.Jonsen
ESuhr
OBTashima
KAthlin
E Early liver transplantation is essential for familial amyloidotic polyneuropathy patients' quality of life.
Amyloid 2001;852- 57
PubMedGoogle ScholarCrossref