Rodney H Falk
Diagnosis and management of the cardiac amyloidoses.
Circulation. 2005 Sep 27;112(13):2047-60. doi: 10.1161/CIRCULATIONAHA.104.489187.
Abstract/Text
R A Kyle, A Linos, C M Beard, R P Linke, M A Gertz, W M O'Fallon, L T Kurland
Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989.
Blood. 1992 Apr 1;79(7):1817-22.
Abstract/Text
No reports of the incidence rates for primary systemic amyloidosis (AL) have come to our attention. Records of all residents of Olmstead County, Minnesota, with a diagnosis of amyloidosis were obtained from the Mayo Clinic and its affiliated hospitals, as well as other medical groups that might have seen local patients for the period January 1, 1950 to December 31, 1989. Twenty-one patients fulfilled the criteria for the diagnosis of AL. The median age was 73.5 years, and 62% were men. In all but one patient the diagnosis was made ante mortem. The clinical data of the 21 patients were similar to those referral patients with AL seen at Mayo Clinic. Immunohistochemical stains were positive for monoclonal light chains in the amyloid deposits in 15 of the 21 cases. In six cases, tissue was not available for immunohistochemical studies. Three of the six patients without immunohistochemical stains had a free monoclonal lambda light chain in the urine, and the other three had a monoclonal serum protein. Immunoelectrophoresis/immunofixation detected a monoclonal (M)-protein in the serum of 16 of 17 patients tested. A monoclonal light chain was found in the urine of 10 of 15 patients. The overall sex- and age-adjusted rate per million person-years was 6.1 from 1950 to 1969 and 10.5 from 1970 to 1989. The similarity of these rates suggests no significant increase over time.
S W Dubrey, K Cha, R W Simms, M Skinner, R H Falk
Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis.
Am J Cardiol. 1996 Feb 1;77(4):313-5.
Abstract/Text
The fibrils in AL and AA amyloidosis, although similar in appearance, have different biochemical composition and staining characteristics. Whereas electrocardiographic and echocardiographic features of heart involvement in AA amyloidosis resemble those for AL amyloidosis, our findings support the concept that the constituent amyloid fibrils may play a decisive role in the clinical pattern and significance of heart infiltration.
R H Falk, R L Comenzo, M Skinner
The systemic amyloidoses.
N Engl J Med. 1997 Sep 25;337(13):898-909. doi: 10.1056/NEJM199709253371306.
Abstract/Text
Frederick L Ruberg, John L Berk
Transthyretin (TTR) cardiac amyloidosis.
Circulation. 2012 Sep 4;126(10):1286-300. doi: 10.1161/CIRCULATIONAHA.111.078915.
Abstract/Text
Rodney H Falk
Cardiac amyloidosis: a treatable disease, often overlooked.
Circulation. 2011 Aug 30;124(9):1079-85. doi: 10.1161/CIRCULATIONAHA.110.010447.
Abstract/Text
Masatoshi Minamisawa, Jun Koyama, Yoshiki Sekijima, Shu-ichi Ikeda, Ayako Kozuka, Soichiro Ebisawa, Takashi Miura, Hirohiko Motoki, Ayako Okada, Atsushi Izawa, Uichi Ikeda
Comparison of the standard and speckle tracking echocardiographic features of wild-type and mutated transthyretin cardiac amyloidoses.
Eur Heart J Cardiovasc Imaging. 2016 Apr;17(4):402-10. doi: 10.1093/ehjci/jew003. Epub 2016 Feb 11.
Abstract/Text
AIMS: To compare cardiac function in patients with the two types of transthyretin (TTR)-related amyloidoses [wild-type (wt) and mutated (m) TTR amyloidoses (ATTR)] using standard and speckle tracking echocardiography (STE).
METHODS AND RESULTS: Twenty-one consecutive patients with biopsy-proved ATTRwt were compared with 21 patients with ATTRm from the database, matched by age and left ventricular (LV) wall thickness (n = 135, ATTRm). All patients were examined using 2D echocardiography. Apical four- and two-chamber, and long-axis views and basal, mid, and apical short-axis views were used to examine LV longitudinal, circumferential, and radial strains. LV ejection fraction (EF), LV basal circumferential/radial strain, and mid-radial strain were significantly lower in patients with ATTRwt compared with patients with ATTRm. There was no significant difference between the two groups in the other parameters. In the receiver-operating characteristic curve analysis, LVEF and LV basal mean radial strain were the best parameters for distinguishing between the two groups.
CONCLUSION: Patients with ATTRwt are characterized by lower LVEF, LV basal, and LV mid-radial strains compared with patients with ATTRm. LVEF and LV radial strain are useful in distinguishing between ATTRwt and ATTRm when TTR has been proved in biopsy specimens.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.
Yoshiki Sekijima, Masahide Yazaki, Mitsuharu Ueda, Haruki Koike, Masahito Yamada, Yukio Ando
First nationwide survey on systemic wild-type ATTR amyloidosis in Japan.
Amyloid. 2018 Mar;25(1):8-10. doi: 10.1080/13506129.2017.1409706. Epub 2017 Nov 28.
Abstract/Text
OBJECTIVE: A nationwide survey on systemic wild-type ATTR (ATTRwt) amyloidosis was conducted to elucidate the frequency, clinical picture and possible diagnostic issues of ATTRwt amyloidosis in Japan.
METHODS: A questionnaire was sent to 4629 clinical departments across Japan. A total of 2341 (50.6%) responses were returned completed for further analysis.
RESULTS: Fifty-one patients with ATTRwt amyloidosis (82% male) were identified between January 2012 and December 2014. The study subjects were identified in 11 departments at 10 institutes. The mean age of onset and diagnosis were 71.6 and 73.6 years, respectively. The main clinical findings were cardiac failure (76%), cardiac conduction defects/arrhythmia (59%), renal dysfunction (49%), carpal tunnel syndrome (45%) and spinal canal stenosis (22%).
CONCLUSIONS: ATTRwt amyloidosis is diagnosed in a limited number of institutes in Japan and is therefore considered to be underdiagnosed.
S W Dubrey, K Cha, J Anderson, B Chamarthi, J Reisinger, M Skinner, R H Falk
The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement.
QJM. 1998 Feb;91(2):141-57.
Abstract/Text
We reviewed clinical presentation, investigations, therapy, prognosis and outcome of 232 patients with primary (AL) cardiac amyloidosis. There were 142 men and 90 women. Median age at presentation was 59 years (range 29-85). AL heart disease was unusual both in patients under the age of 40 (3.0%) and in non-Caucasians (6.5%). Fatigue and weakness were the commonest presenting symptoms. Hallmark features of periorbital ecchymoses and macroglossia were present in 12.5% and 27.2%, respectively. AL cardiac amyloidosis was unusual in isolation (3.9%), and most frequently patients had features of multiorgan dysfunction; heavy proteinuria and features of malabsorption predominating in this respect. Heart involvement represents the worst prognostic indicator, with a median survival from diagnosis of 1.08 years, falling to 0.75 years with the onset of heart failure. Current therapeutic procedures appear to prolong survival, with left ventricular wall thickness, mass and ejection fraction on echocardiography and late potentials on signal averaged electrocardiography of use in prognostic stratification. Cardiac involvement from AL amyloidosis is rapidly fatal. It should be suspected in all patients with heart failure who have wall thickening on echo, normal chamber sizes, low EKG voltages and evidence suggesting a multisystem disease.
R A Kyle, M A Gertz
Primary systemic amyloidosis: clinical and laboratory features in 474 cases.
Semin Hematol. 1995 Jan;32(1):45-59.
Abstract/Text
Haruki Koike, Yukio Ando, Mitsuharu Ueda, Yuichi Kawagashira, Masahiro Iijima, Junko Fujitake, Michiyuki Hayashi, Masahiko Yamamoto, Eiichiro Mukai, Tomohiko Nakamura, Masahisa Katsuno, Naoki Hattori, Gen Sobue
Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy.
J Neurol Sci. 2009 Dec 15;287(1-2):178-84. doi: 10.1016/j.jns.2009.07.028. Epub 2009 Aug 25.
Abstract/Text
Late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) cases unrelated to endemic foci in Japan show different clinicopathological features from the conventional early-onset cases in endemic foci. We compared the characteristics of amyloid deposits in early-onset FAP ATTR Val30Met cases in endemic foci and late-onset cases in non-endemic areas. Amyloid deposits in three early-onset cases from endemic foci and five late-onset cases from non-endemic areas were systematically examined post-mortem. Amyloid deposits in early-onset cases were highly congophilic and showed strong apple-green birefringence with Congo red staining and had long, parallel fibrils in most organs. On the other hand, those in late-onset cases were generally weakly congophilic and showed faint apple-green birefringence with Congo red staining and had short, haphazard fibrils. In the renal glomus and adrenal gland of early-onset cases, the characteristics of amyloid deposits were similar to those observed in late-onset cases. Analysis of cardiac amyloid using surface enhanced desorption/ionization time-of-flight mass spectrometry indicated that most transthyretin (TTR) was variant in early-onset cases, while more than half was composed of wild-type TTR in late-onset cases. Although characteristics of amyloid deposits may differ among individual organs of respective cases, especially in early-onset cases, the pattern was distinct between early- and late-onset cases. Amyloid deposition in late-onset cases may be similar to that observed in senile systemic amyloidosis with wild-type TTR deposition, suggesting that aging may play an important role in these cases.
S W Dubrey, K Cha, M Skinner, M LaValley, R H Falk
Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.
Heart. 1997 Jul;78(1):74-82.
Abstract/Text
OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings.
DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis.
SETTING: International referral centre for amyloid research and treatment.
PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis.
RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes.
CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases.
S Dubrey, A Pollak, M Skinner, R H Falk
Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation.
Br Heart J. 1995 Nov;74(5):541-4.
Abstract/Text
Thrombus formation in the left atrium is rare in patients in sinus rhythm. In three patients with extensive cardiac amyloidosis transthoracic echocardiography showed large atrial thrombi in or protruding into the body of the left atrium during sinus rhythm. Doppler studies showed no A wave on mitral inflow. Severe atrial and ventricular infiltration by amyloid may have resulted in mechanical atrial standstill with resultant thrombus formation. These findings suggest that patients with severe cardiac amyloidosis may require anticoagulation when atrial function is impaired.
M Santarone, G Corrado, L M Tagliagambe, G F Manzillo, G Tadeo, M Spata, M Longhi
Atrial thrombosis in cardiac amyloidosis: diagnostic contribution of transesophageal echocardiography.
J Am Soc Echocardiogr. 1999 Jun;12(6):533-6.
Abstract/Text
Few cases of atrial thrombosis detected by transesophageal echocardiography (TEE) in cardiac amyloidosis have been reported recently. We present the cases of 3 consecutive patients affected by AL-type cardiac amyloidosis, symptomatic for heart failure and in sinus rhythm. All patients had a cardiac restrictive pattern at Doppler examination. TEE showed left atrial thrombus in 2 patients and biatrial thrombi in 1 patient; conventional transthoracic echocardiography detected only 1 left atrial thrombus. Our experience confirms the association between cardiac amyloidosis and atrial thrombosis, even in sinus rhythm. TEE should be considered to assess thromboembolic risk in all cases of cardiac amyloidosis with severe diastolic dysfunction.
DaLi Feng, William D Edwards, Jae K Oh, Krishnaswamy Chandrasekaran, Martha Grogan, Matthew W Martinez, Imran S Syed, Imran I Syed, Deborah A Hughes, John A Lust, Allan S Jaffe, Morie A Gertz, Kyle W Klarich
Intracardiac thrombosis and embolism in patients with cardiac amyloidosis.
Circulation. 2007 Nov 20;116(21):2420-6. doi: 10.1161/CIRCULATIONAHA.107.697763. Epub 2007 Nov 5.
Abstract/Text
BACKGROUND: Patients with primary amyloidosis (AL type) have a poor prognosis, in part due to frequent cardiac involvement. Although intracardiac thrombus has been reported in anecdotal cases, neither its frequency nor its role in causing mortality is known. Furthermore, the clinical and echocardiographic variables that may be associated with thromboembolism in cardiac amyloidosis have not been defined.
METHODS AND RESULTS: A total of 116 autopsy or explanted cases of cardiac amyloidosis (55 AL and 61 other type) were identified in the Mayo Clinic. Forty-six fatal nonamyloid trauma cases served as controls. Each heart was examined for intracardiac thrombus. The cause of death was determined from autopsy and clinical notes. Intracardiac thrombosis was identified in 38 hearts (33%). Twenty-three had 1 thrombus, whereas 15 had 2 to 5 thrombi. Although subjects in the AL group were younger and had less atrial fibrillation than those with other types of amyloidosis, the AL group had significantly more intracardiac thrombus (51% versus 16%, P<0.001) and more fatal embolic events (26% versus 8%, P<0.03). Control hearts had no intracardiac thrombus. The presence of both atrial fibrillation and AL was associated with an extremely high risk for thromboembolism (odds ratio 55.0 [95% confidence interval 8.1 to 1131.4]). By multivariate analysis, AL type (odds ratio 8.4 [95% confidence interval 1.8 to 51.2]) and left ventricular diastolic dysfunction (odds ratio 12.2 [95% confidence interval 2.7 to 72.7]) were independently associated with thromboembolism.
CONCLUSIONS: A high frequency of intracardiac thrombosis was present in cardiac amyloidosis. Furthermore, thromboembolism caused significant fatality. Several risk factors for thromboembolism were identified. Early screening, especially in high-risk patients, and early anticoagulation might reduce morbidity and mortality.
DaLi Feng, Imran S Syed, Matthew Martinez, Jae K Oh, Allan S Jaffe, Martha Grogan, William D Edwards, Morie A Gertz, Kyle W Klarich
Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis.
Circulation. 2009 May 12;119(18):2490-7. doi: 10.1161/CIRCULATIONAHA.108.785014. Epub 2009 May 4.
Abstract/Text
BACKGROUND: Primary amyloidosis has a poor prognosis as a result of frequent cardiac involvement. We recently reported a high prevalence of intracardiac thrombus in cardiac amyloid patients at autopsy. However, neither the prevalence nor the effect of anticoagulation on intracardiac thrombus has been evaluated antemortem.
METHODS AND RESULTS: We studied all transthoracic and transesophageal echocardiograms of cardiac amyloid patients at the Mayo Clinic. The prevalence of intracardiac thrombosis, clinical and transthoracic/transesophageal echocardiographic risks for intracardiac thrombosis, and effect of anticoagulation were investigated. We identified 156 patients with cardiac amyloidosis who underwent transesophageal echocardiograms. Amyloidosis was the primary type (AL) in 80; other types occurred in 76 patients, including 56 with the wild transthyretin type, 17 with the mutant transthyretin type, and 3 with the secondary type. Fifth-eight intracardiac thrombi were identified in 42 patients (27%). AL amyloid had more frequent intracardiac thrombus than the other types (35% versus 18%; P=0.02), although the AL patients were younger and had less atrial fibrillation. Multivariate analysis showed that atrial fibrillation, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis, whereas anticoagulation was associated with a significantly decreased risk (odds ratio, 0.09; 95% CI, 0.01 to 0.51; P<0.006).
CONCLUSIONS: Intracardiac thrombosis occurs frequently in cardiac amyloid patients, especially in the AL type and in those with atrial fibrillation. Risk for thrombosis increased if left ventricular diastolic dysfunction and atrial mechanical dysfunction were present. Anticoagulation therapy appears protective. Timely screening in high-risk patients may allow early detection of intracardiac thrombus. Anticoagulation should be carefully considered.
Jun Koyama, Masatoshi Minamisawa, Yoshiki Sekijima, Shu-Ichi Ikeda, Ayako Kozuka, Soichirou Ebisawa, Takashi Miura, Hirohiko Motoki, Ayako Okada, Atsushi Izawa, Uichi Ikeda
Left ventricular deformation and torsion assessed by speckle-tracking echocardiography in patients with mutated transthyretin-associated cardiac amyloidosis and the effect of diflunisal on myocardial function.
Int J Cardiol Heart Vasc. 2015 Dec 7;9:1-10. doi: 10.1016/j.ijcha.2015.07.010. Epub 2015 Aug 4.
Abstract/Text
BACKGROUND: Mutated transthyretin-associated (ATTRm) amyloidosis with heart failure is associated with decreased longitudinal left ventricular (LV) myocardial contraction, as measured by strain Doppler echocardiography. We sought to clarify whether speckle-tracking echocardiography (STE) would provide useful information in patients with ATTRm cardiac amyloidosis.
METHODS: One hundred twenty-three consecutive patients with ATTRm amyloidosis were divided into 3 groups. Group 1 had no evidence of cardiac involvement (n = 47), group 2 had heart involvement but no congestive heart failure (CHF) and/or serum brain natriuretic peptide (BNP) levels < 100 pg/mL (n = 35), and group 3 had heart involvement and CHF and/or serum BNP levels ≥ 100 pg/mL (n = 41). All patients underwent standard 2-dimensional (2D), Doppler echo, and STE.
RESULTS: By standard 2D and Doppler echo, differences in parameters were only apparent between group 3 and groups 1 and 2. Global circumferential strains by STE at each LV level and LV torsion were different between group 1 and groups 2 and 3, but not between group 2 and group 3. In contrast, global longitudinal LV strain showed significant intergroup differences (- 17.3 ± 2.3%, - 13.3 ± 2.3%, - 9.9 ± 3.3% for groups 1 to 3, respectively, P < 0.0001). Radial strain also showed significant intergroup differences for each basal LV segment. Among 41 patients who could have been followed up after 1 year, 34 patients with diflunisal treatment had shown improvement in apical rotation and torsion without deterioration in multidirectional strains.
CONCLUSION: ATTRm cardiac amyloidosis is characterized by progressive impairment in longitudinal and basal LV radial function when global circumferential shortening and torsion remain unchanged.
Falk RH. Response to Letter Regarding Article, “Cardiac Amyloidosis: A Treatable Disease Often Overlooked.” Circulation [Internet]. Lippincott Williams & WilkinsHagerstown, MD; 2012 Apr 3 [cited 2019 Feb 27];125(13). Available from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.078386
Sebastian J Buss, Mostafa Emami, Derliz Mereles, Grigorios Korosoglou, Arnt V Kristen, Andreas Voss, Dieter Schellberg, Christian Zugck, Christian Galuschky, Evangelos Giannitsis, Ute Hegenbart, Anthony D Ho, Hugo A Katus, Stefan O Schonland, Stefan E Hardt
Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers.
J Am Coll Cardiol. 2012 Sep 18;60(12):1067-76. doi: 10.1016/j.jacc.2012.04.043. Epub 2012 Aug 8.
Abstract/Text
OBJECTIVES: The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) amyloidosis.
BACKGROUND: AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease.
METHODS: Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation.
RESULTS: After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were -10.65% for LS and -11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers.
CONCLUSIONS: In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters.
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
P S Mueller, W D Edwards, M A Gertz
Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis.
Am J Med. 2000 Aug 15;109(3):181-8.
Abstract/Text
PURPOSE: Obstructive intramural coronary amyloidosis is an unusual complication of systemic amyloidosis.
SUBJECTS AND METHODS: We review the characteristics of 11 patients seen at the Mayo Clinic (Rochester, Minnesota) from January 1, 1960, to June 1, 1999, with intramural cardiac amyloidosis diagnosed at autopsy or after examination of an explanted heart.
RESULTS: Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis was found in 11 patients (8 men, 3 women). The mean (+/-SD) age at the diagnosis of primary amyloidosis was 62 +/- 12 years. All patients had angina pectoris; angina was the presenting symptom of primary amyloidosis in 6 patients. Unstable coronary syndromes occurred in 7 patients and congestive heart failure in 8. New electrocardiographic abnormalities after the development of angina were common and included ischemic changes, bundle branch block, and dysrhythmias. Low voltage was seen in only 2 patients. All 7 patients who underwent coronary angiography had normal or clinically insignificant findings. Endomyocardial biopsy was performed on 4 patients; amyloid was found in 3 patients, none of whom had obstructive intramural coronary amyloidosis. The diagnosis of obstructive intramural coronary amyloidosis with associated myocardial injury was established only at autopsy or after examination of the explanted heart after cardiac transplantation. The mean time to death or cardiac transplantation after symptoms of cardiac ischemia developed was 18 +/- 20 months.
CONCLUSIONS: The diagnosis of ischemic heart disease resulting from obstructive intramural coronary amyloidosis is difficult to establish before death or cardiac transplantation. Although the condition has a poor prognosis, its accurate recognition may have therapeutic implications, because some patients may benefit from treatment, including systemic chemotherapy or cardiac transplantation.
Claudio Rapezzi, Giampaolo Merlini, Candida C Quarta, Letizia Riva, Simone Longhi, Ornella Leone, Fabrizio Salvi, Paolo Ciliberti, Francesca Pastorelli, Elena Biagini, Fabio Coccolo, Robin M T Cooke, Letizia Bacchi-Reggiani, Diego Sangiorgi, Alessandra Ferlini, Michele Cavo, Elena Zamagni, Maria Luisa Fonte, Giovanni Palladini, Francesco Salinaro, Francesco Musca, Laura Obici, Angelo Branzi, Stefano Perlini
Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.
Circulation. 2009 Sep 29;120(13):1203-12. doi: 10.1161/CIRCULATIONAHA.108.843334. Epub 2009 Sep 14.
Abstract/Text
BACKGROUND: Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis.
METHODS AND RESULTS: We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1+/-0.5 versus 0.9+/-0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events.
CONCLUSIONS: AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.
Joseph E Rahman, Emelie F Helou, Ramona Gelzer-Bell, Richard E Thompson, Chih Kuo, E Rene Rodriguez, Joshua M Hare, Kenneth L Baughman, Edward K Kasper
Noninvasive diagnosis of biopsy-proven cardiac amyloidosis.
J Am Coll Cardiol. 2004 Feb 4;43(3):410-5. doi: 10.1016/j.jacc.2003.08.043.
Abstract/Text
OBJECTIVES: This study analyzed the utility of electrocardiographic (ECG) and echocardiographic findings in the diagnosis of amyloidosis proven by endomyocardial biopsy.
BACKGROUND: Cardiac amyloidosis is associated with characteristic ECG and echocardiographic changes, yet each finding alone is relatively nonspecific. A combination of noninvasive prognostic parameters would be desirable for this tissue-based diagnosis.
METHODS: We performed an analysis of 196 consecutive patients referred for endomyocardial biopsy because of clinical suspicion of cardiac amyloidosis. The diagnosis was confirmed in 58 patients (29%). The ECGs, echocardiograms, and right heart hemodynamic data were reviewed to determine which findings strongly correlate with the diagnosis. These findings were then used to build multivariate logistic regression models that predict the log-odds of having cardiac amyloidosis.
RESULTS: The univariate analysis showed that low-voltage and pseudo-infarction patterns on the ECG and increased myocardial thickness and speckled-appearing myocardium on the echocardiogram were associated with biopsy-proven cardiac amyloidosis (each p < 0.01). In multivariate logistic regression models, a combination of a low voltage and measures of myocardial thickness produced the most statistically useful models. For instance, one model showed that if a low voltage was present and interventricular septal thickness is >1.98 cm, the diagnosis of cardiac amyloidosis could be made with a sensitivity of 72% and a specificity of 91%. In this model, the positive predictive and negative predictive values were 79% and 88%, respectively.
CONCLUSIONS: In patients with suspected cardiac amyloidosis, a combination of noninvasive parameters-namely, a low voltage and increased intraventricular septal thickness-is a useful diagnostic tool.
Jun Koyama, Patricia A Ray-Sequin, Rodney H Falk
Prognostic significance of ultrasound myocardial tissue characterization in patients with cardiac amyloidosis.
Circulation. 2002 Jul 30;106(5):556-61.
Abstract/Text
BACKGROUND: Cycle-dependent variation of myocardial integrated backscatter (CV-IB) is an objective measurement that may detect myocardial abnormalities. However, no data exist about the prognostic value of CV-IB in primary cardiac amyloidosis.
METHODS AND RESULTS: We prospectively examined 208 consecutive biopsy-proven patients with primary amyloidosis. The magnitude of CV-IB was analyzed at the interventricular septum and left ventricular (LV) posterior wall and its prognostic value was compared with standard Doppler measurements with to the Tei index (isovolumic contraction time plus isovolumic relaxation time divided by ejection time). One hundred thirty-three patients had cardiac involvement (mean LV thickness > 12 mm). Forty-one patients (20%) (32 cardiac deaths) died during a mean follow-up of period of 307+/-156 days. Univariate analysis showed that the CV-IB at the LV posterior wall was the best predictor of cardiac death (P<0.0001) and all-cause death (P< 0.0001). The Tei index did not identify patients at risk of death. Multivariate analysis showed that CV-IB at the LV posterior wall was the only independent predictor of both cardiac and overall deaths.
CONCLUSIONS: Among patients with cardiac amyloidosis, CV-IB at the LV posterior wall is a powerful predictor of clinical outcome and is superior to standard echocardiographic/Doppler flow indexes.
Jun Koyama, Patricia A Ray-Sequin, Rodney H Falk
Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis.
Circulation. 2003 May 20;107(19):2446-52. doi: 10.1161/01.CIR.0000068313.67758.4F. Epub 2003 May 12.
Abstract/Text
BACKGROUND: AL amyloidosis with heart failure is associated with decreased longitudinal myocardial contraction measured by pulsed tissue Doppler imaging. We sought to clarify whether new modalities of myocardial strain Doppler (change in length per unit length) or strain rate (the temporal derivative of strain) were more sensitive than tissue Doppler and could detect early regional myocardial dysfunction before the onset of congestive heart failure (CHF) in patients with AL (primary) amyloidosis.
METHODS AND RESULTS: Ninety-seven biopsy-proven patients with AL amyloidosis were divided into 3 groups. Group 1 patients had no cardiac involvement (n=36), group 2 had heart involvement but no CHF (n=32), and group 3 had heart involvement and CHF (n=29). All patients underwent tissue velocity (TV) imaging, strain, and strain rate imaging (SR) at the basal, mid, and apical ventricle in 2 apical views. With the use of TV, differences in systolic function were only apparent between group 3 (basal mean value, 3.0+/-1.1 cm/s) and groups 1 and 2 (5.0+/-1.3 and 4.6+/-1.2 cm/s, respectively). In contrast, basal peak systolic SR (l/s) showed significant differences among all 3 groups (-2.0+/-0.4, -1.55+/-0.6, and -0.76+/-0.3 for groups 1 to 3, respectively. P<0.01). Basal strain also demonstrated statistically significant differences among the groups (-19+/-4%, -15+/-4.5%, and -8.0+/-5%; P<0.01).
CONCLUSIONS: Cardiac amyloidosis is characterized by an early impairment in systolic function at a time when fractional shortening remains normal. This abnormality precedes the onset of CHF and can be detected by strain and SR but is not apparent by TV imaging.
Angela Dispenzieri, Morie A Gertz, Robert A Kyle, Martha Q Lacy, Mary F Burritt, Terry M Therneau, Joseph P McConnell, Mark R Litzow, Dennis A Gastineau, Ayalew Tefferi, David J Inwards, Ivana N Micallef, Stephen M Ansell, Luis F Porrata, Michelle A Elliott, William J Hogan, S Vincent Rajkumar, Rafael Fonseca, Philip R Greipp, Thomas E Witzig, John A Lust, Steven R Zeldenrust, Denise S Snow, Susan R Hayman, Christopher G A McGregor, Allan S Jaffe
Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.
Blood. 2004 Sep 15;104(6):1881-7. doi: 10.1182/blood-2004-01-0390. Epub 2004 Mar 25.
Abstract/Text
Primary systemic amyloidosis (AL) is a fatal plasma cell disorder. Pilot data suggest survival is better in patients undergoing peripheral blood stem cell transplantation (PBSCT), but the selection process makes the apparent benefit suspect. We have reported that circulating cardiac biomarkers are the best predictors of survival outside of the transplantation setting. We now test whether cardiac troponins (cTnT and cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are prognostic in transplant recipients. In 98 patients with AL undergoing PBSCT, serum cardiac biomarkers were measured (cTnT, 98 patients; cTnI, 65 patients; and NT-proBNP, 63 patients). Elevated levels of cTnT, cTnI, and NT-proBNP were present in 14%, 43%, and 48% of patients, respectively. At 20 months median follow-up, median survival has not been reached for patients with values below the thresholds; in patients with values above the thresholds, median survival is 26.1 months, 66.1 months, and 66.1 months, respectively. Our previously reported risk systems incorporating these markers were also prognostic, notably the cTnT/NT-proBNP staging. Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT.
Giovanni Palladini, Carlo Campana, Catherine Klersy, Alessandra Balduini, Giovanbattista Vadacca, Vittorio Perfetti, Stefano Perlini, Laura Obici, Edoardo Ascari, Gianvico Melzi d'Eril, Remigio Moratti, Giampaolo Merlini
Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis.
Circulation. 2003 May 20;107(19):2440-5. doi: 10.1161/01.CIR.0000068314.02595.B2. Epub 2003 Apr 28.
Abstract/Text
BACKGROUND: Brain natriuretic peptide (BNP) is a marker of ventricular dysfunction and can be used to assess prognosis in heart failure and after myocardial infarction. Heart involvement is the most important prognostic factor and causes death in almost all patients with light-chain amyloidosis (AL). We investigated the prognostic value of NT-proBNP and its utility in monitoring amyloid heart dysfunction.
METHODS AND RESULTS: NT-proBNP was quantified at diagnosis in 152 consecutive patients seen at the coordinating center of the Italian Amyloidosis Study Group (Pavia) from 1999 throughout 2001. Heart involvement was estimated on the basis of clinical signs, electrocardiography, and echocardiography. NT-proBNP concentrations differed in patients with (n=90, 59%) and without (n=62, 41%) heart involvement (median: 507.8 pmol/L versus 22.1 pmol/L, P=10(-7)). The best cutoff for heart involvement was at 152 pmol/L (sensitivity: 93.33%, specificity: 90.16%, accuracy: 92.05%) and distinguished two groups with different survival (P<0.001). The Cox multivariate model including NT-proBNP was better than models including echocardiographic and clinical signs of heart involvement. NT-proBNP appeared to be more sensitive than conventional echocardiographic parameters in detecting clinical improvement or worsening of amyloid cardiomyopathy during follow-up.
CONCLUSIONS: NT-proBNP appeared to be the most sensitive index of myocardial dysfunction and the most powerful prognostic determinant in AL amyloidosis. It adds prognostic information for newly diagnosed patients and can be useful in designing therapeutic strategies and monitoring response. NT-proBNP is a sensitive marker of heart toxicity caused by amyloidogenic light chains.
Roshini S Abraham, Jerry A Katzmann, Raynell J Clark, A R Bradwell, Robert A Kyle, Morie A Gertz
Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis.
Am J Clin Pathol. 2003 Feb;119(2):274-8. doi: 10.1309/LYWM-47K2-L8XY-FFB3.
Abstract/Text
Primary systemic amyloidosis is a plasma cell dyscrasia characterized by the accumulation of excess free immunoglobulin light chains (FLCs) as amyloid. One of the diagnostic features of amyloidosis is the presence of circulating monoclonal FLCs in the serum and urine of the patients. The FLC usually is present in small amounts, and immunofixation is required for detection. A nephelometric method for quantitating FLCs in serum has been described using antibodies that recognize only FLC not bound to heavy chain. We describe a retrospective study using this quantitative FLC method for assessing monoclonal FLCs in 95 patients with amyloidosis. The sensitivity of nephelometric serum FLC measurements is particularly useful in patients with negative immunofixation results for serum, urine, or both. In addition, the FLC assay can be used for follow-up of patients with amyloidosis who have undergone stem cell transplantation.
Jerry A Katzmann, Raynell J Clark, Roshini S Abraham, Sandra Bryant, James F Lymp, Arthur R Bradwell, Robert A Kyle
Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.
Clin Chem. 2002 Sep;48(9):1437-44.
Abstract/Text
BACKGROUND: The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors.
METHODS: We used an automated immunoassay for FLCs and sera from a population 21-90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal kappa and lambda FLCs in the sera of patients with monoclonal gammopathies.
RESULTS: Serum kappa and lambda FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of kappa FLC to lambda FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26-1.65. The 95% reference interval for kappa FLC was 3.3-19.4 mg/L, and that for lambda FLC was 5.7-26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease.
CONCLUSIONS: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.
J S Borer, W L Henry, S E Epstein
Echocardiographic observations in patients with systemic infiltrative disease involving the heart.
Am J Cardiol. 1977 Feb;39(2):184-8.
Abstract/Text
Echocardiography was used to evaluate the heart in 19 patients with one of various systemic diseases known to be associated with infiltrative cardiomyopathy. Four patients had systemic amyloidosis, 10 had idiopathic hypereosinophilia and 5 had iron overload caused by multiple blood transfusions. Although 10 patients (53 percent) had no clinical evidence of cardiac disease, all 19 had echocardiographic abnormalities; the left ventricle was symmetrically thickened (more than 11 mm) and left ventricular mass was increased (more than 275 g) in all; the left ventricular transverse dimension was modestly increased (more than 52 mm) in 5 patients (26 percent) and the velocity of mitral valve closure in early diastole was reduced (less that 60 mm/sec) in 5 patients. Systolic function, as evidenced by ejection fraction, was well maintained (greater than 60 percent) in 18 of 19 patients. Thus, it appears that echocardiographic abnormalities can be detected in many patients with a systemic disease associated with infiltrative cardiomyopathy even before clinically evident heart disease develops.
J S Child, J Krivokapich, A S Abbasi
Increased right ventricular wall thickness on echocardiography in amyloid infiltrative cardiomyopathy.
Am J Cardiol. 1979 Dec;44(7):1391-5.
Abstract/Text
In six patients with clinically significant amyloid infiltrative cardiomyopathy, echocardiographic right ventricular anterior wall thickness was significantly increased (mean 7.5 +/- 2.3 mm; range 5 to 10 mm). This finding in conjunction with the previously described abnormalities of the left ventricle (symmetric increase in wall thickness, diffuse hypokinesia, and small to normal left ventricular diastolic dimension) is consistent with the findings of a diffuse myocardial infiltrative process and should minimize confusion with constrictive pericarditis.
A G Siqueira-Filho, C L Cunha, A J Tajik, J B Seward, T T Schattenberg, E R Giuliani
M-mode and two-dimensional echocardiographic features in cardiac amyloidosis.
Circulation. 1981 Jan;63(1):188-96.
Abstract/Text
Twenty-eight patients with cardiac amyloidosis were studied by echocardiography -- 26 by M-mode and 13 by two-dimensional (2D) studies. All had heart failure and biopsy-proved amyloidosis, M-mode features included (1) normal left ventricular (LV) dimension in all; (2) thickened ventricular septum (88%), LV posterior wall (77%), and right ventricular (RV) anterior wall (79%); (3) decreased thickening of ventricular septum (96%) and of LV posterior wall (65%) and reduced LV global function (62%); (4) left atrial enlargement (50%); and (5) pericardial effusion (58%). Two-dimensional echocardiography provided additional features: (1) thickened papillary muscles (five of 13); (2) thickened valves (four of 13); (3) better appreciation of thickened RV wall; and (4) a characteristic "granular sparkling" appearance of thickened cardiac walls -- presumably secondary to the amyloid deposit -- which was noted in 12 of 13 patients. Thus, M-mode echocardiography is helpful in the recognition of cardiac amyloidosis. However, the better appreciation with 2D echocardiography of thickened cardiac walls with a "granular sparkling" appearance in patients with unexplained cardiac failure is virtually diagnostic of cardiac amyloidosis.
A K Bhandari, N C Nanda
Myocardial texture characterization by two-dimensional echocardiography.
Am J Cardiol. 1983 Mar 1;51(5):817-25.
Abstract/Text
Twenty-four normal subjects and 181 patients with various cardiac disorders (36 autopsies) were studied by 2-dimensional echocardiography. In vitro echocardiographic studies were performed on 26 of 36 autopsied hearts utilizing an ultrasonically visible metallic probe to correlate myocardial echo patterns with histopathologic features. All normal subjects and the majority of patients with ventricular hypertrophy due to valvular or hypertensive lesions showed a uniformly speckled or an echolucent appearance of the myocardium (type I texture). No autopsied heart with this texture had gross fibrosis (visible to the naked eye) or infiltrative disease. All patients with infiltrative disorders (amyloidosis, 7 of 7; Pompe's disease, 4 of 4) had multiple, discrete, and small (3 to 5 mm) highly refractile echoes (HREs) in the myocardium involving the ventricle or ventricles completely (type IIA texture) or partly (type IIB texture). However, this finding was non-specific and was observed in many other conditions such as left heart hypoplastic syndrome (10 of 10), hypertrophic cardiomyopathy (19 of 26), and chronic renal failure (4 of 9). In the noninfiltrative group, HREs in the autopsied cases were shown to result from gross fibrosis or endocardiofibroelastosis utilizing in vitro echocardiographic studies and metallic probe-guided biopsies, while HREs in the autopsied cases with cardiac amyloidosis could be correlated only with amyloid deposits since fibrosis was absent. Larger HREs (greater than 5 mm) presenting as broad patches or long linear echoes in the myocardium (type IIC texture) was seen in old myocardial infarctions (9 of 21) and congestive cardiomyopathy (4 of 26) and were correlated with large areas of myocardial fibrosis. Two-dimensional echocardiographic studies of myocardial texture help identify various infiltrative and degenerative processes in the heart.
A L Klein, L K Hatle, D J Burstow, J B Seward, R A Kyle, K R Bailey, T F Luscher, M A Gertz, A J Tajik
Doppler characterization of left ventricular diastolic function in cardiac amyloidosis.
J Am Coll Cardiol. 1989 Apr;13(5):1017-26.
Abstract/Text
Sixty-four patients with primary systemic amyloidosis-53 with two-dimensional echocardiographic features of cardiac involvement (Group I) and 11 without cardiac involvement (Group II)--underwent Doppler echocardiographic assessment of left ventricular diastolic function. Pulsed wave Doppler recordings of left ventricular inflow velocities and pulmonary vein flow velocities with respiratory monitoring in these patients were compared with findings in a normal group. Patients in Group I showed striking abnormalities of left ventricular diastolic filling when classified into subgroups by mean left ventricular wall thickness: early greater than 12 but less than 15 mm; advanced greater than or equal to 15 mm. In early amyloidosis, relaxation was abnormal, with decreased peak early velocity (75 +/- 20 versus 86 +/- 16 cm/s; p less than 0.01), increased late velocity (71 +/- 22 versus 56 +/- 13 cm/s; p less than 0.01), decreased early to late velocity ratio (1.2 +/- 0.6 versus 1.6 +/- 0.5; p less than 0.01) and prolonged isovolumic relaxation time (87 +/- 15 versus 73 +/- 13 ms; p less than 0.01) compared with normal values. In advanced amyloidosis, there was a restrictive filling pattern with a markedly shortened deceleration time (148 +/- 50 versus 199 +/- 32 ms; p less than 0.001), decreased pulmonary vein peak systolic flow velocity (34 +/- 16 versus 54 +/- 12 cm/s; p less than 0.01) and increased diastolic flow velocity (55 +/- 20 versus 44 +/- 12 cm/s; p less than 0.01) compared with normal values. Group and the subgroup with early amyloidosis had similar flow velocity patterns. Thus, this study documents that in cardiac amyloidosis, a spectrum of diastolic filling abnormalities exists; the restrictive filling pattern is seen only in the advanced stages.
Dan Liu, Kai Hu, Markus Niemann, Sebastian Herrmann, Maja Cikes, Stefan Störk, Philipp Daniel Gaudron, Stefan Knop, Georg Ertl, Bart Bijnens, Frank Weidemann
Effect of combined systolic and diastolic functional parameter assessment for differentiation of cardiac amyloidosis from other causes of concentric left ventricular hypertrophy.
Circ Cardiovasc Imaging. 2013 Nov;6(6):1066-72. doi: 10.1161/CIRCIMAGING.113.000683. Epub 2013 Oct 7.
Abstract/Text
BACKGROUND: Differentiation of cardiac amyloidosis (CA) from other causes of concentric left ventricular hypertrophy remains a clinical challenge, especially in patients with preserved ejection fraction at the early disease stages.
METHODS AND RESULTS: Consecutive hypertrophic patients with CA, isolated arterial hypertension, Fabry disease, and Friedreich ataxia (n=25 per group) were investigated; 25 healthy volunteers served as a control group. Standard echocardiography was performed, and segmental longitudinal peak systolic strain (LSsys) in the septum was assessed by 2-dimensional speckle tracking imaging. Indices of left ventricular hypertrophy and ejection fraction were similar among all patient groups. Deceleration time of early filling was significantly lower in patients with CA (147±46 milliseconds) compared with those with isolated arterial hypertension, Fabry disease, or control subjects (all P<0.0125). Septal basal LSsys (-6±2%) was significantly lower in patients with CA compared with those with isolated arterial hypertension (-14±6%), Fabry disease (-12±5%), Friedreich ataxia (-16±2%), or control subjects (-17±3%; all P<0.001), whereas septal apical LSsys was similar among all patient groups and control subjects (all P>0.05). A data-driven cutoff value for the ratio of septal apical to basal LSsys ratio >2.1 differentiated CA from other causes of left ventricular hypertrophy (sensitivity, 88%; specificity, 85%; positive predictive value, 67%; negative predictive value, 96%). The prevalence of septal apical to basal LSsys ratio >2.1 plus deceleration time of early filling <200 milliseconds was 88% in CA but 0% in all other groups.
CONCLUSIONS: A systolic septal longitudinal base-to-apex strain gradient (septal apical to basal LSsys ratio >2.1), combined with a shortened diastolic deceleration time of early filling (deceleration time of early filling <200 milliseconds), aids in differentiating CA from other causes of concentric left ventricular hypertrophy.
Holger Vogelsberg, Heiko Mahrholdt, Claudia C Deluigi, Ali Yilmaz, Eva M Kispert, Simon Greulich, Karin Klingel, Reinhard Kandolf, Udo Sechtem
Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy.
J Am Coll Cardiol. 2008 Mar 11;51(10):1022-30. doi: 10.1016/j.jacc.2007.10.049.
Abstract/Text
OBJECTIVES: We sought to evaluate the diagnostic performance of cardiovascular magnetic resonance imaging (CMRI) for detection of cardiac amyloidosis compared with endomyocardial biopsy (EMB) in a clinical routine setting.
BACKGROUND: For the clinical workup of heart failure with restrictive filling, pattern cardiac amyloidosis is an important differential diagnosis that is difficult to verify with current noninvasive techniques, especially in the presence of myocardial hypertrophy.
METHODS: A total of 33 consecutive patients underwent both CMRI and EMB for workup of heart failure with restrictive filling pattern in combination with myocardial hypertrophy (n = 24) and/or clinical conditions often associated with cardiac amyloidosis (n = 18).
RESULTS: Cardiac amyloidosis was detected by EMB in 15 of the 33 patients. In patients with biopsy-proven cardiac amyloidosis, CMRI revealed a distinct pattern of late gadolinium enhancement, which was distributed over the entire subendocardial circumference, extending in various degrees into the neighboring myocardium. This pattern was found in 12 of the 15 patients diagnosed with cardiac amyloidosis by EMB, compared with only 1 individual in the group of 18 patients diagnosed with other myocardial diseases. Consequently, using this pattern as a diagnostic criterion, the sensitivity of CMRI for diagnosing cardiac amyloidosis was 80%, yielding a specificity of 94%. The positive predictive value was 92%, and the negative predictive value was 85%.
CONCLUSIONS: In patients with biopsy-proven cardiac amyloidosis, late gadolinium enhancement frequently occurs in a peculiar pattern. On the basis of the gold standard, EMB, noninvasive CMRI can be used to diagnose or rule out cardiac amyloidosis with good sensitivity and excellent specificity in a clinical routine setting.
Marianna Fontana, Silvia Pica, Patricia Reant, Amna Abdel-Gadir, Thomas A Treibel, Sanjay M Banypersad, Viviana Maestrini, William Barcella, Stefania Rosmini, Heerajnarain Bulluck, Rabya H Sayed, Ketna Patel, Shameem Mamhood, Chiara Bucciarelli-Ducci, Carol J Whelan, Anna S Herrey, Helen J Lachmann, Ashutosh D Wechalekar, Charlotte H Manisty, Eric B Schelbert, Peter Kellman, Julian D Gillmore, Philip N Hawkins, James C Moon
Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis.
Circulation. 2015 Oct 20;132(16):1570-9. doi: 10.1161/CIRCULATIONAHA.115.016567. Epub 2015 Sep 11.
Abstract/Text
BACKGROUND: The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown.
METHODS AND RESULTS: Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3-13.1; P<0.05).
CONCLUSIONS: There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.
© 2015 The Authors.
Eloisa Arbustini, Laura Verga, Monica Concardi, Giovanni Palladini, Laura Obici, Giampaolo Merlini
Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis.
Amyloid. 2002 Jun;9(2):108-14.
Abstract/Text
We evaluated the role of electron microscopy and immuno-electron microscopy studies on abdominal fat fine-needle biopsy samples in diagnosis and characterization of cardiac amyloidosis. The series consists of 15 patients with echocardiographic evidence of "restrictive cardiomyopathy" suspected to be due to amyloidosis. Patients underwent: clinical examination, electrocardiography, 2-D and Doppler echocardiography, immunofixation of serum and urine for detection of monoclonal immunoglobulins, and abdominalfat biopsies that were investigated with polarized light (Congo red), electron and immuno-electron microscopy using specific antibodies to kappa and lambda light chains, apolipoprotein A1, serum amyloid A (SAA), and transthyretin (TTR). Ultrastructural study of abdominal fat samples identified amyloid deposits in 15/15 cases. Immuno-electron microscopy specifically stained amyloid fibrils with antibodies anti-lambda (n = 8), -kappa (n = 2), -apolipoprotein A1 (n = 2) and -TTR (n = 3). Immuno-electron microscopy revealed TTR immuno-labelling in 2 patients with accidental monoclonal components, and a A reaction in I patient without monoclonal components. TTR and apolipoprotein A1 positive cases carried missense mutations in the corresponding genes. Our results demonstrate that amyloid deposits are present in the abdominalfat of patients suspected to have cardiac amyloidosis and that immuno-electron microscopy was able to characterize the amyloid protein in all cases.
Sabahat Bokhari, Adam Castaño, Ted Pozniakoff, Susan Deslisle, Farhana Latif, Mathew S Maurer
(99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses.
Circ Cardiovasc Imaging. 2013 Mar 1;6(2):195-201. doi: 10.1161/CIRCIMAGING.112.000132. Epub 2013 Feb 11.
Abstract/Text
BACKGROUND: Differentiating immunoglobulin light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of (99m)Tc-pyrophosphate ((99m)Tc-PYP) scintigraphy in AL versus ATTR.
METHODS AND RESULTS: Forty-five subjects (12 AL, 16 ATTR wild type, and 17 ATTR mutants) underwent (99m)Tc-PYP planar and single-photon positive emission computed tomography cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects' cohort assignment. Cardiac retention was assessed with both a semiquantitative visual score (range, 0; no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score than the AL cohort (2.9±0.06 versus 0.8±0.27; P<0.0001) as well as a higher quantitative score (1.80±0.04 versus 1.21±0.04; P<0.0001). Using a heart-to-contralateral ratio >1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, P<0.0001 for identifying ATTR cardiac amyloidosis.
CONCLUSIONS: (99m)Tc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis, which should be studied in a larger prospective manner.
C A Libbey, M Skinner, A S Cohen
Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis.
Arch Intern Med. 1983 Aug;143(8):1549-52.
Abstract/Text
The needle aspirate of abdominal fat was investigated for its sensitivity in giving a tissue diagnosis in 32 consecutive patients with systemic amyloidosis. The fat tissue aspirate was stained with Congo red and examined with a polarizing microscope. Positive results were obtained in 95% (18/19) of patients with primary (AL) amyloidosis, 66% (4/6) of patients with secondary (AA) amyloidosis, and 86% (6/7) of patients with the heredofamilial (AF) form. The overall positive yield was 88% (28/32). Abdominal fat tissue aspiration is proposed as a simple, rapid, and effective technique for the diagnosis of amyloidosis. The prevalence of positive results in known amyloid disease are comparable with the rectal biopsy specimen and are more frequent than gingival or skin biopsy specimens.
Shu-ichi Ikeda, Yoshiki Sekijima, Kana Tojo, Jun Koyama
Diagnostic value of abdominal wall fat pad biopsy in senile systemic amyloidosis.
Amyloid. 2011 Dec;18(4):211-5. doi: 10.3109/13506129.2011.623199. Epub 2011 Oct 17.
Abstract/Text
Senile systemic amyloidosis (SSA) is a main cause of intractable heart failure in elderly individuals. To demonstrate transthyretin (TTR)-derived amyloid deposition endomyocardial biopsy has been commonly carried out in the patients with SSA, but this invasive biopsy technique cannot always be performed in aged patients with severe cardiac dysfunction. During the past 3 years, 11 patients with SSA (6 males and 5 females; ages from 70 to 97 years) were examined. All underwent skin biopsy from the abdominal wall and 8 showed TTR-immunoreactive amyloid deposition (sensitivity: 73%): amyloid deposits were seen mainly in the deep layer of subcutaneous fat tissue and showed a patchy distribution. They were weakly Congophilic, but were strongly immunolabeled by an anti-TTR antibody. The severity and pattern of amyloid deposition in this biopsy of SSA patients were considerably different from those obtained from age-matched patients with TTR-related familial amyloid polyneuropathy. Surgical skin biopsy including the deep subcutaneous fat pad can be performed safely at the bedside and is useful for the histopathological diagnosis of SSA.
Katsutoshi Furukawa, Shu-Ichi Ikeda, Nobuyuki Okamura, Manabu Tashiro, Naoki Tomita, Shozo Furumoto, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Hiroyuki Arai
Cardiac positron-emission tomography images with an amyloid-specific tracer in familial transthyretin-related systemic amyloidosis.
Circulation. 2012 Jan 24;125(3):556-7. doi: 10.1161/CIRCULATIONAHA.111.045237.
Abstract/Text
Jun Koyama, Rodney H Falk
Prognostic significance of strain Doppler imaging in light-chain amyloidosis.
JACC Cardiovasc Imaging. 2010 Apr;3(4):333-42. doi: 10.1016/j.jcmg.2009.11.013.
Abstract/Text
OBJECTIVES: To clarify the prognostic value of strain and strain rate imaging in light-chain (AL) amyloidosis.
BACKGROUND: Myocardial strain and strain rate Doppler imaging are objective measurements that may detect regional subtle myocardial functional abnormalities in patients with amyloidosis.
METHODS: We prospectively examined 119 consecutive, untreated patients with biopsy-proven AL amyloidosis. The mean values of tissue velocity, strain, and strain rate were calculated from the basal, mid, and apical left ventricular (LV) multiple walls in apical 2- and 4-chamber views. The prognostic value of these parameters was compared with standard 2-dimensional echocardiographic and Doppler measurements of transmitral and pulmonary venous flow.
RESULTS: Seventy patients had cardiac involvement defined as the mean value of LV wall thickness greater than 12 mm. Thirty-two patients (27%) (including 22 proven cardiac deaths) died during a mean follow-up period of 285 +/- 136 days. No echocardiographic or Doppler features differentiated patients with cardiac involvement without congestive heart failure (CHF) from noncardiac amyloid group other than the pre-defined wall thickness and LV end-diastolic and end-systolic diameters. On the other hand, strain rate and strain imaging clearly detected differences of longitudinal LV myocardial deformation among 3 groups (noncardiac involvement group, cardiac amyloidosis without CHF group, and cardiac amyloidosis with CHF group). Univariate analysis showed that strain rate, strain, and tissue velocity values were statistically significant predictors of outcome at most of the sites. Multivariate analysis showed that the mean LV basal strain was the only independent predictor of both cardiac and overall deaths.
CONCLUSIONS: Among patients with AL amyloidosis, the mean basal strain, a measure of longitudinal LV function, was a powerful predictor of clinical outcome and was superior to standard 2-dimensional echocardiographic, Doppler flow measurements, and simple tissue velocity indexes.
Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Candida Cristina Quarta, Scott D Solomon, Imran Uraizee, Jenna Kruger, Simone Longhi, Marinella Ferlito, Christian Gagliardi, Agnese Milandri, Claudio Rapezzi, Rodney H Falk
Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis.
Circulation. 2014 May 6;129(18):1840-9. doi: 10.1161/CIRCULATIONAHA.113.006242. Epub 2014 Feb 21.
Abstract/Text
BACKGROUND: Immunoglobulin amyloid light-chain (AL)-related cardiac amyloidosis (CA) has a worse prognosis than either wild-type (ATTRwt) or mutant (ATTRm) transthyretin (TTR) CA. Detailed echocardiographic studies have been performed in AL amyloidosis but not in TTR amyloidosis and might give insight into this difference. We assessed cardiac structure and function and outcome in a large population of patients with CA and compared findings in TTR and AL-related disease.
METHODS AND RESULTS: We analyzed 172 patients with CA (AL amyloidosis, n=80; ATTRm, n=36; ATTRwt, n=56) by standard echocardiography and 2-dimensional speckle-tracking imaging-derived left ventricular (LV) longitudinal (LS), radial, and circumferential strains. Despite a preserved LV ejection fraction (55±12%), LS was severely impaired in CA. Standard measures of LV function and speckle-tracking imaging worsened as wall thickness increased, whereas apical LS was preserved regardless of the pathogenesis of CA and the degree of wall thickening. Compared with ATTRm and AL amyloidosis, ATTRwt was characterized by greater LV wall thickness and lower ejection fraction. LS was more depressed in both ATTRwt and AL amyloidosis (-11±3% and -12±4%, respectively, P=0.54) than in ATTRm (-15±4%, P<0.01 versus AL amyloidosis and ATTRwt). TTR-related causes were favorable predictors of survival, whereas LS and advanced New York Heart Association class were negative predictors.
CONCLUSIONS: In patients with CA, worsening LV function correlated with increasing wall thickness regardless of pathogenesis. Patients with ATTRwt had a statistically greater wall thickness but lesser mortality than those with AL amyloidosis, despite very similar degrees of LS impairment. This paradox suggests an additional mechanism for LV dysfunction in AL amyloidosis, such as previously demonstrated light-chain toxicity.
Belinda Ng, Lawreen H Connors, Ravin Davidoff, Martha Skinner, Rodney H Falk
Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis.
Arch Intern Med. 2005 Jun 27;165(12):1425-9. doi: 10.1001/archinte.165.12.1425.
Abstract/Text
BACKGROUND: Small deposits of amyloid are often found in the hearts of elderly patients. However, extensive deposition of transthyretin-derived amyloid fibrils in the heart (senile systemic amyloidosis [SSA]) can cause heart failure. The clinical features of SSA that involve the heart are ill defined, and the condition may be overlooked as a cause of heart failure. We sought to better define the clinical, echocardiographic, and electrocardiographic features of cardiac involvement in SSA and to compare them with the findings in patients with light chain-associated (AL) amyloidosis that affects the heart.
METHODS: Eighteen consecutive patients with SSA and heart failure evaluated at a tertiary referral center for the diagnosis and treatment of amyloidosis were compared with 18 randomly selected patients with AL amyloidosis that involved the heart. All patients underwent a complete clinical and biochemical evaluation. Echocardiograms and electrocardiograms were interpreted by blinded investigators.
RESULTS: Patients with SSA were older than those with AL amyloidosis and were all male. Proteinuria (protein output of >1 g per 24 hours) was common in AL amyloidosis but was not present in SSA. Left ventricular wall thickness was greater in patients with SSA than those with AL amyloidosis, but despite thicker walls and older age, the severity of heart failure was less in the SSA group and the median survival was much longer (75 vs 11 months; P = .003).
CONCLUSIONS: Senile systemic amyloidosis is a disorder of elderly men and is characterized by amyloidosis clinically limited to the heart. In contrast to the rapid progression of heart failure in AL amyloidosis, SSA results in slowly progressive heart failure. The difference in survival, despite evidence of more myocardial disease in the senile group, suggests that heart failure in AL amyloidosis may have a toxic component, possibly related to the circulating monoclonal light chain.
Diego Bellavia, Patricia A Pellikka, Ghormallah B Al-Zahrani, Theodore P Abraham, Angela Dispenzieri, Chinami Miyazaki, Martha Lacy, Christopher G Scott, Jae K Oh, Fletcher A Miller
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. 2010 Jun;23(6):643-52. doi: 10.1016/j.echo.2010.03.027.
Abstract/Text
BACKGROUND: The prognostic value of Doppler myocardial imaging, including myocardial velocity imaging, strain, and strain rate imaging, in patients with primary (AL) amyloidosis is uncertain. The aim of this longitudinal study was to identify independent predictors of survival, comparing clinical data, hematologic and cardiac biomarkers, and standard echocardiographic and Doppler myocardial imaging measures in a cohort of patients with AL amyloidosis.
METHODS: A total of 249 consecutive patients with AL amyloidosis were prospectively enrolled. The primary end point was all-cause mortality, and during a median follow-up period of 18 months, 75 patients (30%) died. Clinical and electrocardiographic data, biomarkers (brain natriuretic peptide and cardiac troponin T) and standard echocardiographic and longitudinal systolic and diastolic Doppler myocardial imaging measurements for 16 left ventricular segments were tested as potential independent predictors of survival.
RESULTS: Age (hazard ratio [HR], 1.03; P = .03), New York Heart Association class III or IV (HR, 2.47; P = .01), the presence of pleural effusion (HR, 1.79; P = .08), brain natriuretic peptide level (HR, 1.29; P = .01), ejection time (HR, 0.99; P = .13), and peak longitudinal systolic strain of the basal anteroseptal segment (HR, 1.05; P = .02) were independent predictors in the final model.
CONCLUSIONS: Multivariate survival analysis identified independent predictors of clinical outcome in patients with AL amyloidosis: New York Heart Association class III or IV, presence of pleural effusion, brain natriuretic peptide level > 493 pg/mL, ejection time < 273 ms, and peak longitudinal systolic basal anteroseptal strain less negative than or equal to -7.5% defined a high-risk group of patients.
Copyright 2010 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.
S Perlini, F Musca, F Salinaro, I Fracchioni, G Palladini, L Obici, R Albertini, R Moratti, F Lavatelli, G Palladini, C Rapezzi, G Merlini
Functional correlates of N-terminal natriuretic peptide type B (NT-proBNP) response to therapy in cardiac light chain (AL) amyloidosis.
Amyloid. 2011 Jun;18 Suppl 1:96-7. doi: 10.3109/13506129.2011.574354035.
Abstract/Text
Nobuhiro Kotani, Takeshi Hattori, Shingo Yamagata, Takahiko Tokuda, Akira Shirasawa, Shuhei Yamaguchi, Shotai Kobayashi, Shu-ichi Ikeda
Transthyretin Thr60Ala Appalachian-type mutation in a Japanese family with familial amyloidotic polyneuropathy.
Amyloid. 2002 Mar;9(1):31-4.
Abstract/Text
A Japanese case with familial amyloidotic polyneuropathy (FAP) associated with the transthyretin mutation Thr60Ala (Appalachian-type mutation) is described This is the first reported case of a non-Caucasian harboring this type of TTR mutation. The patient developed severe late-onset restrictive cardiomyopathy as well as sensorimotor and autonomic polyneuropathy, which were essentially similar to the previously reported clinical pictures of Appalachian-type FAP.
Yoshiki Sekijima, Kana Tojo, Hiroshi Morita, Jun Koyama, Shu-ichi Ikeda
Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis.
Amyloid. 2015;22(2):79-83. doi: 10.3109/13506129.2014.997872. Epub 2015 May 27.
Abstract/Text
BACKGROUND: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis.
METHODS: Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 months).
RESULTS: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment.
CONCLUSIONS: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.
M A Gertz, R H Falk, M Skinner, A S Cohen, R A Kyle
Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents.
Am J Cardiol. 1985 Jun 1;55(13 Pt 1):1645.
Abstract/Text
A Pollak, R H Falk
Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis.
Chest. 1993 Aug;104(2):618-20.
Abstract/Text
Cardiac amyloidosis produces a restrictive cardiomyopathy with impaired diastolic function. We report a case in which low-dose verapamil resulted in marked worsening of congestive heart failure, as a result of a profound negative inotropic effect. Withdrawal of verapamil therapy demonstrated a return of systolic function to normal with improvement in heart failure. We postulate that patients with cardiac amyloidosis may be exceptionally sensitive to the negative inotropic effects of calcium-channel blockers either because of abnormal binding to amyloid fibrils or because their usual vasodilator effects are blunted.
A Rubinow, M Skinner, A S Cohen
Digoxin sensitivity in amyloid cardiomyopathy.
Circulation. 1981 Jun;63(6):1285-8.
Abstract/Text
Digoxin (5 mg/ml) was added to 10-mg and 20-mg pellets of purified primary and secondary amyloid fibrils, a normal human liver and heart homogenate and a homogenate from the heart of a patient with amyloid cardiomyopathy who had not received digitalis. After centrifugation, the supernatants were recovered and assayed for digoxin concentrations. Aliquots from the sediments were studied for the presence of digoxin, using rabbits antidigoxin antiserum and an indirect immunofluorescent technique. The results showed that 0.11--0.13 ng/ml of digoxin bound per milligram of fibrils and could not be separated by repeated washings. Elution with citrate or changes in the pH of the buffer. Immunofluorescent studies demonstrated diffusely bright immunofluorescence with the fibril preparation and amyloid heart homogenate when reacted with digoxin and digoxin-specific antiserum. These studies demonstrate that isolated amyloid fibrils bind digoxin and suggest that this interaction may play some role in the sensitivity to digitalis that has been observed in some patients with amyloid cardiomyopathy.
John L Berk, Joseph Keane, David C Seldin, Vaishali Sanchorawala, Jun Koyama, Laura M Dember, Rodney H Falk
Persistent pleural effusions in primary systemic amyloidosis: etiology and prognosis.
Chest. 2003 Sep;124(3):969-77.
Abstract/Text
BACKGROUND: Restrictive cardiomyopathy frequently complicates primary systemic amyloidosis (AL), yet only a small number of these patients develop large pleural effusions refractory to diuretic therapy and thoracentesis. We hypothesized that disruption of pleural function by amyloid deposits underlies persistent pleural effusions (PPEs) in patients with AL disease.
METHODS: We performed a retrospective study of AL patients with and without PPEs who had been referred to Boston University between 1994 and 2001. The presence of PPEs was defined by a failure to resolve the condition with thoracentesis and aggressive diuresis. AL cardiomyopathy patients without pleural effusions constituted the control (cardiac) group. Indexes of plasma cell dyscrasia, nephrotic syndrome, thyroid function, and echocardiographic measures of left and right ventricle performance were compared between groups. When available, closed needle biopsies and autopsy specimens of parietal pleura were examined for amyloid deposits.
RESULTS: Among 636 patients with AL, 35 PPE patients underwent a median of three thoracenteses each. No statistical differences were found between the PPE and cardiac groups in echocardiographic measures of septal thickness, left ventricular systolic function, or diastolic compliance. Right ventricular (RV) hypokinesis occurred more often in PPE patients; however, nearly half of this group had normal RV systolic function. Renal function, plasma protein levels, and thyroid function were the same between groups. Nephrotic range proteinuria (ie, > 3 g/d) was more prevalent in the cardiac group than in the PPE group (44% vs 26%, respectively; p = 0.057). All pleural biopsies in the PPE group (six biopsies) revealed amyloid deposits. Autopsy samples of parietal pleura were negative for disease in two cardiac patients. Eighteen patients had chest tubes placed, and 11 underwent pleurodesis. PPE signaled limited survival among patients who were ineligible for treatment. Untreated PPE patients lived a median 1.8 months vs 6 months for untreated cardiac patients (p = 0.031). Survival after intensive chemotherapy and autologous stem cell transplantation was comparable in the PPE and cardiac groups (21.8 vs 15.6 months, respectively; p = 0.405).
CONCLUSION: In AL patients with cardiac amyloid, neither echocardiographic measures of ventricular function nor the degree of nephrosis distinguished those patients with PPEs. We conclude that pleural amyloid infiltration plays a central role in the creation and persistence of pleural effusions among patients with AL.
Efstathios Kastritis, Giovanni Palladini, Monique C Minnema, Ashutosh D Wechalekar, Arnaud Jaccard, Hans C Lee, Vaishali Sanchorawala, Simon Gibbs, Peter Mollee, Christopher P Venner, Jin Lu, Stefan Schönland, Moshe E Gatt, Kenshi Suzuki, Kihyun Kim, M Teresa Cibeira, Meral Beksac, Edward Libby, Jason Valent, Vania Hungria, Sandy W Wong, Michael Rosenzweig, Naresh Bumma, Antoine Huart, Meletios A Dimopoulos, Divaya Bhutani, Adam J Waxman, Stacey A Goodman, Jeffrey A Zonder, Selay Lam, Kevin Song, Timon Hansen, Salomon Manier, Wilfried Roeloffzen, Krzysztof Jamroziak, Fiona Kwok, Chihiro Shimazaki, Jin-Seok Kim, Edvan Crusoe, Tahamtan Ahmadi, NamPhuong Tran, Xiang Qin, Sandra Y Vasey, Brenda Tromp, Jordan M Schecter, Brendan M Weiss, Sen H Zhuang, Jessica Vermeulen, Giampaolo Merlini, Raymond L Comenzo, ANDROMEDA Trial Investigators
Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
N Engl J Med. 2021 Jul 1;385(1):46-58. doi: 10.1056/NEJMoa2028631.
Abstract/Text
BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.
METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.
RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.
CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
Copyright © 2021 Massachusetts Medical Society.
John L Berk, Ole B Suhr, Laura Obici, Yoshiki Sekijima, Steven R Zeldenrust, Taro Yamashita, Michael A Heneghan, Peter D Gorevic, William J Litchy, Janice F Wiesman, Erik Nordh, Manuel Corato, Alessandro Lozza, Andrea Cortese, Jessica Robinson-Papp, Theodore Colton, Denis V Rybin, Alice B Bisbee, Yukio Ando, Shu-ichi Ikeda, David C Seldin, Giampaolo Merlini, Martha Skinner, Jeffery W Kelly, Peter J Dyck, Diflunisal Trial Consortium
Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
JAMA. 2013 Dec 25;310(24):2658-67. doi: 10.1001/jama.2013.283815.
Abstract/Text
IMPORTANCE: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.
OBJECTIVE: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.
DESIGN, SETTING, AND PARTICIPANTS: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.
INTERVENTION: Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.
MAIN OUTCOMES AND MEASURES: The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.
RESULTS: By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007).
CONCLUSIONS AND RELEVANCE: Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294671.
Mathew S Maurer, Donna R Grogan, Daniel P Judge, Rajiv Mundayat, Jeff Packman, Ilise Lombardo, Arshed A Quyyumi, Janske Aarts, Rodney H Falk
Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.
Circ Heart Fail. 2015 May;8(3):519-26. doi: 10.1161/CIRCHEARTFAILURE.113.000890. Epub 2015 Apr 14.
Abstract/Text
BACKGROUND: Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid.
METHODS AND RESULTS: This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I-II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea.
CONCLUSIONS: Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.
© 2015 American Heart Association, Inc.
Vincent Algalarrondo, Teresa Antonini, Marie Théaudin, Béatrice Ducot, Pierre Lozeron, Denis Chemla, Anouar Benmalek, Catherine Lacroix, Daniel Azoulay, Denis Castaing, Cécile Cauquil, François Rouzet, Sylvie Dinanian, Ludivine Eliahou, Dominique Le Guludec, Didier Samuel, Michel S Slama, David Adams
Prediction of long-term survival after liver transplantation for familial transthyretin amyloidosis.
J Am Coll Cardiol. 2015 Nov 10;66(19):2154-6. doi: 10.1016/j.jacc.2015.08.870.
Abstract/Text
Ole B Suhr, Marie Larsson, Bo-Göran Ericzon, Henryk E Wilczek, FAPWTRʼs investigators
Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry.
Transplantation. 2016 Feb;100(2):373-81. doi: 10.1097/TP.0000000000001021.
Abstract/Text
BACKGROUND: Liver transplantation (LTx) has been performed for hereditary transthyretin amyloidosis (ATTR) since 1990. Outcomes for a relatively large series of LTx ATTR patients with the Val30Met (mutation are available, but for non-Val30Met patients, only a few reports with a small number of patients exist. Here, we present outcomes for non-Val30Met ATTR patients after LTx, as reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR).
METHODS: Data regarding outcome were extracted for all non-Val30Met patients reported to the registry. Survival rates were analyzed by the Kaplan-Meier method and log-rank test.
RESULTS: The total number of patients with a non-Val30Met mutation in the registry was 264 (174 men and 90 women), representing 57 mutations. The 10-year survival varied markedly for the 9 most common mutations, ranging from 21% for Ser50Arg to 85% for Val71Ala. Poor survival was noted for all mutations with leptomeningeal complications except for those with the Tyr114Cys mutation.
CONCLUSIONS: Large differences in survival were observed relative to different mutations and between mutations with similar phenotypes. Excellent survival was noted for mutations, such as Leu111Met, Val71Ala, and Leu58His. Patients with mutations other than Val30Met are not a homogeneous group, and the term non-Val30Met should be used with caution or avoided. Moreover, for several mutations, data are too limited to allow evaluation of the efficacy of LTx, and continuous international collaboration is important for obtaining treatment guidance.
Takahisa Gono, Masayuki Matsuda, Yasuhiro Shimojima, Wataru Ishii, Jun Koyama, Kazuo Sakashita, Kenichi Koike, Yoshinobu Hoshii, Shu-ichi Ikeda
VAD with or without subsequent high-dose melphalan followed by autologous stem cell support in AL amyloidosis: Japanese experience and criteria for patient selection.
Amyloid. 2004 Dec;11(4):245-56.
Abstract/Text
Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.
