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Systemic Cardiac Amyloidoses. Disease Profiles and Clinical Courses of the 3 Main Types

The term amyloidoses describes a group of diseases characterized by extracellular accumulation of fibrillary proteins, leading to loss of normal tissue architecture. Amyloidosis may be systemic or localized, and is currently classified according to the type of precursor protein. The three most frequent and clinically challenging types of systemic amyloidosis are: 1) acquired monoclonal immunoglobulin light-chain amyloidosis (AL), characterized by clonal plasma cells in the bone marrow which produce the immunoglobulin lights chains of the fibrillary deposits; 2) the hereditary, transthyretin-related form (ATTRm), which can be caused by over 100 mutations of transthyretin (TTR), a transport protein mainly synthesized by the liver; 3) wild-type (non-mutant) transthyretin-related amyloidosis (ATTRwt) or systemic “senile” amyloidosis, which mainly affects the hearts of elderly men. In all three forms, myocardial involvement is frequent and has major clinical implications. Despite the intrinsic, etiologic heterogeneity of cardiac amyloidosis, most available clinical/instrumental studies address the disease as a single entity.

In this study, the Authors  compare the diagnostic and clinical profiles of these three types of systemic cardiac amyloidosis in search of clinical and instrumental aspects specific for the three etiologies, beyond the shared anatomical substrate.

Myocardial Disease

The paper presents a multicenter longitudinal study of 233 consecutive patients with clear-cut diagnosis by type of the three main forms of cardiac amyloidosis, seen at 2 large Italian centers (Bologna and Pavia) providing coordinated amyloidosis diagnosis/management facilities since 1990. The study enrolled 157 patients with (AL), 61 patients with ATTRm, 15 patients ATTRwt. The three groups of patients were compared in terms of clinical and instrumental (echocardiographic and electrocardiographic) profiles at baseline and in term of clinical outcome. In about 40% of study population hemodynamic data and endomyocardial biopsy data were also available for comparisons. Diagnosis of amyloidosis was defined by histological documentation of Congo Red staining and apple-green birefringence under cross-polarized light in at least 1 involved organ. Amyloidotic cardiomyopathy was defined echocardiographically as end-diastolic thickness of the interventricular septum >1.2 cm in the absence of any other cause of ventricular hypertrophy. Clear-cut distinction between TTR-related and AL amyloidosis was based on genotyping and/or immunohistochemistry.

In about 65% of cases, amyloidotic cardiomyopathy was detected at routine echocardiographic screening after diagnosis of systemic amyloidosis. In <2% of cases (2 AL; 1 ATTRwt) diagnosis of cardiac systemic amyloidosis was incidental. In the remaining 34% of cases, patients were initially diagnosed as having hypertrophic cardiomyopathy, heart failure, or arrhythmia at a secondary or tertiary cardiological center.

At presentation, the 3 groups of patients showed some expected clinical differences, including high prevalence of neurological impairment and carpal tunnel syndrome in ATTRm, kidney involvement in AL, and heart failure in both AL and ATTRwt (a disease thought to be confined to elderly men).
Regarding ECG, at univariate analysis left bundle branch block was more frequent in ATTRwt; 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). At multivariate analysis low QRS voltages were negatively associated with ATTRm.
Highly significant differences were apparent for most echocardiographic morphological and functional descriptors: morphologically, ATTRwt group showed the highest average values, with 3 to 4 mm greater mean LV wall thickness (diastolic interventricular septum thickness 19.7±4 mm) than in ATTRm (16.6±3.8 mm) or AL (15.8±2.8 mm), p <0.0001; LV ejection fraction values varied considerably, tending to be normal in ATTRm (58±13%), around lower normal limits in AL (52.5±13%), and abnormally low in ATTRwt (44.2±15.4, p<0.0001).
The different etiologies showed relevant hemodynamic differences, with AL patients most often displaying abnormal values in the different measures of diastolic function.
With regard to clinical outcome, in terms of both overall and MACE-free survival, the group with the least morphological impairment— AL— had a rather aggressive clinical course; the group that showed the greatest LV wall thickness— ATTRwt —  showed a less aggressive course despite the patients’ higher average age. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events.


The paper regards the largest available follow-up study of cardiac amyloidosis and represents a relevant contribution at different levels ranging from disease classification to diagnosis and clinical management.

From a nosographic point of view, this study supports the concept that cardiomyopathies due to AL, ATTRm and ATTRwt should be considered three different cardiac diseases with different pathophysiologic substrates and clinical courses. Cardiac amyloidosis is commonly considered a form of restrictive cardiomyopathy (i.e., a myocardial disease with increased parietal stiffness, causing precipitous rises in ventricular pressure accompanied by only small increases in volume). Nevertheless, as many as one-fifth of the hemodynamically evaluated patients did not display any abnormal finding, and the majority of the overall patients did not display restrictive filling pattern, which is traditionally considered the key non-invasive marker of restrictive pathophysiology. Sub analysis of baseline hemodynamic data highlights the differences among the three etiologic forms, with only AL patients displaying abnormal values in the different measures of diastolic function in the vast majority of cases.  The higher frequency of hemodynamic impairment in the AL patients contrasts with their lesser morphological involvement. So, within a group of infiltrative cardiomyopathies that are traditionally considered “restrictive”, the degree of infiltration (assessed by increased wall thickness) does not seem to be associated with the severity of restrictive hemodynamic impairment.  This mismatch could plausibly be attributed to the well-documented direct toxicity of the immunoglobulin circulating immunoglobulin light-chains in AL, along with other plausible contributory factors.

For instance, it is reasonable to hypothesize that a higher frequency of vascular localization of amyloid deposition in AL could be responsible for myocardial ischemia, contributing to ventricular dysfunction. Furthermore, gradual deposition in the TTR-related forms might allow the organism time to develop local compensatory mechanisms (a rather less likely scenario in the rapidly developing amyloidotic cardiomyopathy of AL patients). Different types of amyloid substance could also lead to different degrees of myocardial damage (unfortunately, the study did not explore this aspect). Taken together, these observations may also explain why the clinical outcome of the three groups of patients, in terms of both overall and MACE-free survival, appeared to contrast with the degree of morphological involvement, where the group with the least morphological derangement (AL) had a rather aggressive clinical course. In contrast, the group that showed the greatest LV wall thickness values (ATTRwt) seemed to have a less aggressive course.

From a clinical point of view, a particularly important observation of the study regards standard ECG. Although the presence of low QRS voltages is considered a key player to orient diagnostic suspicion of cardiac amyloidosis,  the prevalence of low QRS voltages at the time of diagnosis was lower than in other reports (~45% overall) and particularly low in the ATTRm subset (25%), despite a greater myocardial infiltration (as indicated by mean ventricular wall thickness values). A possible explanation for this finding could be greater myocardial cellular damage (regardless of wall thickness) induced by light-chain toxicity in AL. Interestingly the occurrence of left bundle-branch block was relatively frequent in ATTRwt type (up to 40% of cases).  Appropriately, the study underscores the importance of not excluding a diagnosis of amyloidotic cardiomyopathy (especially of TTR-related forms) on the grounds of normal QRS voltage or left bundle-branch block.



To sum up, the paper underscores the profound differences between the three most frequent etiological types of cardiac amyloidosis in terms of disease profile and long-term outcome. Awareness of this heterogeneity may help orient aspects of the diagnostic workup of patients with suspected cardiac amyloidosis and subsequent clinical management.



Selected references on the topic of this paper I

Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon A, Grateau G. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol 2005;79:319–328.

Arbustini E, Verga L, Concardi M, Palladini G, Obici L, Merlini G. Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis. Amyloid 2002;9:108–114.

Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins PN. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;6:346:1786–1791.

Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.

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Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chainassociated amyloidosis. Arch Intern Med 2005;165:1425–1429.

Selected references on the topic of this paper II

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Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol 2005;62:1057–1062.

Johansson B, Westermark P. Senile systemic amyloidosis: a clinicopathological study of twelve patients with massive amyloid infiltration. Int J Cardiol 1991;32:83–92.

Dubrey SW, Cha K, Skinner M, LaValley M, Falk RH. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes. Heart 1997;78:74–82.

Rahman JE, Helou EF, Gelzer-Bell R, Thompson RE, Kuo C, Rodriguez ER, Hare JM, Baughman KL, Kasper EK. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol 2004;43:410–415.

Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res 2004;94:1008–1010.


Notes to editor

Claudio Rapezzi, MD;Giampaolo Merlini, MD; Candida C. Quarta, MD; Letizia Riva, MD; Simone Longhi, MD; Ornella Leone, MD; Fabrizio Salvi, MD; Paolo Ciliberti, MD; Francesca Pastorelli, MD;  Elena Biagini, MD; Fabio Coccolo, MD; Robin M.T. Cooke, MA; Letizia Bacchi-Reggiani, MSc MStat; Diego Sangiorgi, MStat; Alessandra Ferlini, MD; Michele Cavo, MD; Elena Zamagni, MD; Maria Luisa Fonte, MD; Giovanni Palladini, MD; Francesco Salinaro, MD; Francesco Musca, MD; Laura Obici, MD; Angelo Branzi, MD; Stefano Perlini, MD. Circulation 2009;120:1203-12.

Presented by Candida C. Quarta and Luigi Tavazzi. Institute of Cardiology, University of Bologna and S.Orsola-Malpighi Hospital, Bologna, Italy and GVM Hospitals of Care and Research, Villa Maria Cecilia Hospital, Cotignola, Italy

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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