Systemic Cardiac Amyloidoses
Disease Profiles and Clinical Courses of the 3 Main Types
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.
Received December 23, 2008; accepted July 17, 2009.
The term amyloidosis describes a group of rare diseases characterized by extracellular accumulation of fibrillary proteins, leading to loss of normal tissue architecture.1 Amyloidosis may be systemic or localized and is currently classified according to the type of precursor protein.2 The 3 most frequent and clinically challenging types of systemic amyloidosis are acquired monoclonal immunoglobulin light-chain amyloidosis (AL), characterized by clonal plasma cells in the bone marrow that produce the immunoglobulin lights chains of the fibrillary deposits; the hereditary, transthyretin (TTR)-related form (ATTRm), which can be caused by >100 mutations of TTR, a transport protein synthesized mainly by the liver; and wild-type (nonmutant) TTR-related amyloidosis (ATTRwt) systemic “senile” amyloidosis, which affects mainly the hearts of elderly men. In all 3 forms, myocardial involvement is frequent and has major clinical implications.3,4 Despite the intrinsic pathogenic heterogeneity of cardiac amyloidosis, most available clinical/instrumental studies address the disease as a single entity. Comparative studies are hampered by the wide variety of specialty settings in which amyloidosis patients can present. Correct recognition of cardiac amyloidosis and its various types remains a challenge, and the condition may be vastly underdiagnosed.3 The aim of this study was to compare the diagnostic/clinical profiles of different types of systemic cardiac amyloidosis.
Clinical Perspective on p 1212
Setting and Study Design
We conducted a multicenter longitudinal study of cardiac amyloidosis based on data pooled from 2 large Italian centers. Since 1990, the cardiology, hematology, nephrology, neurology, and genetics departments at our hospitals have provided coordinated centers for the diagnosis and management of systemic amyloidosis. All data are collated in centralized databases. Family screening is recommended to all ATTRm patients.
We screened all patients diagnosed with systemic amyloidosis who presented to the Bologna center from 1990 to May 2008 and to the Pavia center from 2003 to June 2004. Consecutive patients with echocardiographically defined amyloidotic cardiomyopathy5 were considered eligible for analysis.
We compared the 3 groups of patients (AL, ATTRwt, and ATTRm) in terms of clinical/instrumental profiles at baseline (ie, first evaluation at either center) and clinical outcome. At presentation, all patients provided informed consent for anonymous publication of scientific data. In our country, formal ethics approval was not applicable for this observational study involving only routinely performed procedures.
Diagnosis of systemic amyloidosis was defined by histological documentation of Congo Red staining and apple-green birefringence under cross-polarized light in at least 1 involved organ.6 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.5 Clear-cut distinction between TTR-related and AL amyloidosis was based on genotyping and/or immunohistochemistry.7,8 Diagnosis of familial ATTRm was defined by a documented TTR mutation at DNA analysis following procedures described elsewhere,9 ATTRwt by positive immunohistochemistry for TTR in the absence of any TTR mutation at DNA analysis,10 and AL by the presence of monoclonal plasma cells in the bone marrow, plus both negative immunohistochemistry for TTR and the absence of any TTR mutation on DNA analysis.11,12 Kidney involvement was defined as the presence of 24-hour urine protein excretion ≥0.5 g/d,5 and renal insufficiency was defined as glomerular filtration rate <60 mL/min. The definition of peripheral nervous system involvement was based on characteristic neurological signs and symptoms (typical symmetric ascending sensorimotor peripheral neuropathy). Autonomic impairment was defined by the presence of orthostatic hypotension, gastric-emptying disorder, pseudoobstruction, and voiding dysfunction not related to direct organ infiltration.5
ECG and echocardiographic measures were based on standard definitions.13,14 Left ventricular (LV) mass was calculated according to the method of Devereux et al15 and was classified as raised when >130 g/m2 in men and >110 g/m2 in women. LV restrictive filling pattern was defined in terms of E-wave deceleration time <150 ms accompanied by E/A wave ratio >2.5 on pulsed Doppler echocardiography.16 Voltage-to-mass ratio was calculated as Sokolow index divided by the cross-sectional area of the LV wall with the formula defined by Carroll et al.17
At 1 center (Bologna), systematically collected hemodynamic data were available for patients routinely submitted to myocardial biopsy for pathogenic diagnosis or clinical evaluation at baseline. Available data included mean right atrial pressure (normal, ≤5 mm Hg), mean pulmonary capillary wedge pressure (normal, ≤12 mm Hg), cardiac index (normal, between 2.5 and 4.2 L · min−1 · m−2), and dip-plateau morphology of the right ventricle pressure tracing.
Histology and Immunohistochemistry
Histological documentation of amyloid deposition was obtained either from subcutaneous adipose tissue from abdominal fat or from endomyocardial biopsies. All samples (5 per patient) were microwave fixed and processed, and multiple 2-μm sections were tested for the presence of amyloid by Congo Red staining and apple-green birefringence under cross-polarized light microscopy. Amyloid localization was described in terms of interstitial, vascular, and endocardial involvement.18 Immunohistochemical analysis was performed by the labeled streptavidin-biotin method with an antibody against TTR (R.P. Linke, Max Plank Institute of Biochemistry, Germany) or by immunoelectron microscopy with specific antibody proteins (DAKO, Ely, UK).
Follow-up visits were planned for every 6 months (or more frequently if clinically appropriate). Follow-up was closed in November 2008; for patients who had not attended a visit in the last 6 months, vital status was ascertained by telephone and/or by contacting referring physicians.
Summary statistics are expressed as mean±SD, median (interquartile range), or numbers (percentages). We used 1-way ANOVA or the Pearson χ2 test for comparisons of baseline data between AL, ATTRwt, and ATTRm. The Bonferroni test was used to perform pairwise comparisons for variables that reached global significance. We tested selected variables chosen for their potential pathophysiological relevance in a series of multivariate models constructed to assess independent associations with the type (reference category, AL). Dependent variables were treated continuously (with multivariate linear regression), except low QRS voltage, which was treated as a binary variable (in a logistic regression model) because of its diagnostic relevance. Analyses of hemodynamic and histological data were restricted to the Bologna subpopulation. To explore factors that could be associated with total mortality and major adverse cardiac events (MACEs), we conducted multivariate analysis of a set of variables that were selected a priori on the basis of their potential clinical or pathophysiological relevance. Analyses were conducted with SPSS version 13 (SPSS Inc, Chicago, Ill) or STATA version 9 (Stata Corp, College Station, Tex). Values of P<0.05 were considered significant.
Of the 500 patients diagnosed with systemic amyloidosis in our centers during the study period, 233 (47%: AL, n=157; ATTRm, n=61; ATTRwt, n=15) had echocardiographic evidence of cardiac amyloidosis and were included in this analysis. Of note, these patients represented 51% of all 307 AL patients seen in the 2 centers during the study period (69 patients first evaluated in Bologna, 88 seen in Pavia); 34% of 178 ATTRm patients (Bologna, n=54; Pavia, n=7); and 100% of 15 ATTRwt patients (Bologna, n=14; Pavia, n=1). All patients except 1 were of Italian descent (the family of 1 ATTRm patient comes from the Republic of Macedonia). Except for 1 ATTRm patient (with a Val30Met mutation recognized 8 months before referral), amyloidosis was always diagnosed within our centers. In 150 cases, amyloidotic cardiomyopathy was detected at routine echocardiographic screening after diagnosis of systemic amyloidosis (AL, n=102; ATTRm, n=48). In 3 cases (2 AL; 1 ATTRwt) diagnosis of cardiac systemic amyloidosis was incidental. All the remaining 80 patients were initially diagnosed as having hypertrophic cardiomyopathy, heart failure, or arrhythmia at a secondary or tertiary cardiological center. In these cases, suspicion of amyloidotic cardiomyopathy always stemmed from critical appraisal of echocardiography and ECG (and sometimes clinical findings) before the final diagnosis of AL (n=53), ATTRm (n=13), or ATTRwt (n=14). In particular, echocardiographic signs suggesting possible cardiac amyloidosis (in addition to increased LV wall thickness) were granular sparkling appearance of ventricular myocardium, increased thickness of atrioventricular valves or interatrial septum, and pericardial effusion.
TTR mutations were Glu89Gln (17 patients, 10 families, 5 from Sicily), Val30Met (11 patients, 7 families, 5 from central Italy), Ile68Leu (10 patients, 10 families, all from central eastern/northeastern Italy), Thr49Ala (7 patients, 4 families), Glu54Lys (2 patients, 1 family), Ala36Pro (2 patients, 1 family), Arg34Thr (2 patients, 1 family), Ser23Asn (2 patients, 2 families), Thr59Lys (1 patient), His88Arg (1 patient), Phe64Leu (1 patient), Gly47Ala (1 patient), Val30Ala (1 patient), Ser50Arg (1 patient), Phe33Val (1 patient), and Val14Leu (1 patient), a novel TTR mutation not previously described. Table 1 summarizes patients’ individual profiles at baseline according to pathogenic type. Unsurprisingly,3,12 all but 1 of the 15 ATTRwt patients were men ≥59 years of age. Average age was higher in AL than in ATTRm. Most cases of AL were referred to hematologists and cardiologists, whereas all but 1 of the ATTRwt patients were first seen by cardiologists. About two fifths of the AL and ATTRwt patients had severe heart failure. Most ATTRm patients had neurological involvement; kidney involvement was frequent only in AL.
Instrumental Characteristics at Baseline
On univariate analysis (Table 2), highly significant differences among the 3 groups were apparent for left bundle-branch block, low QRS voltage, and total QRS score. On multivariate analysis, low QRS voltage turned out to be negatively associated with ATTRm pathogenesis independently of age, gender, mean LV wall thickness, and pericardial effusion (Tables 3 and 4⇓). Of note, left bundle-branch block was found in 6 of the ATTRwt patients (40%) and was an occasional finding in AL and ATTRm patients (Table 2).
On univariate analysis (Table 2), highly significant differences were apparent for the following morphological/functional LV descriptors: diastolic interventricular septum and posterior wall thicknesses, LV mass (in men), left atrial diameter, LV end-systolic diameter, LV ejection fraction, and voltage-to-mass ratio; differences in E-wave deceleration time reached borderline significance. Frequency of increased atrioventricular valve thickness ranged from 47% for AL to as much as 67% for ATTRm (P=0.08). Independent associations involving pathogenesis were recorded during multivariate analysis (Tables 3 and 4⇑); increasing LV wall thickness was associated with ATTRwt, whereas voltage-to-mass ratio was strongly associated with ATTRm.
Analysis of baseline hemodynamic measures was restricted to a single center (Bologna), where data were available for 43 AL patients (62%), 38 ATTRm patients (70%), and 12 ATTRwt patients (86%). Differences on univariate analysis (Table 2) among the 3 groups were apparent for mean and raised right atrial pressure and mean and raised pulmonary capillary wedge pressure. Figure 1 reports frequencies of abnormal diastolic function measures (increased filling pressures, dip-plateau morphology, restrictive filling pattern at Doppler echocardiography). Frequency of the various abnormal findings varied considerably, ranging from 78% for at least 1 filling pressure abnormality to 3% for dip-plateau morphology of the right ventricular pressure tracing (Figure 1A). Comparisons of the 3 pathogenic types (Figure 1B) showed differences for most of the single and combined pressure measures; remarkably, abnormal values were always most frequent in AL.
Clinically driven biopsy findings were available for the subpopulation of patients with available hemodynamic data (see above). Frequency of vascular localization varied between pathogenic subtypes (AL, 34 of 43 [79%]; ATTRm, 8 of 38 [21%]; ATTRwt, 0 of 12 [0%]; P=0.0001), being more common in AL. Frequency of inflammation also appeared to vary (AL, 6 of 43 [14%]; ATTRm, 1 of 38 [3%]; ATTRwt, 4 of 12 [33%]; P=0.014), being more common in ATTRwt.
Median duration of follow-up was 19 months (interquartile range, 4 to 46 months) in AL, 26 months (interquartile range, 13 to 62 months) in ATTRm, and 19 months (interquartile range, 10 to 40 months) in ATTRwt. All AL patients received melphalan and/or desametazone, and 8 (5%) had high-dose chemotherapy with stem cell reperfusion; another patient received heart transplantation followed by stem cell reperfusion. Twenty-nine ATTRm patients (49%) had solid organ transplantation (orthotopic liver transplantation, n=20; planned heart-liver transplantation, n=9). The first recorded MACEs were as follows: death resulting from cardiovascular causes in 31 AL patients (20%), 3 ATTRm patients (5%), and 2 ATTRwt patients (13%); hospitalization for heart failure in 48 AL patients (31%), 10 ATTRm patients (16%), and 4 ATTRwt patients (27%); complete atrioventricular block in 5 AL patients (3%), 3 ATTRm patients (5%), and 1 ATTRwt patient (7%); stroke in 5 AL patients (3%); and atrial fibrillation/flutter in 17 AL patients (11%), 2 ATTRm patients (3%), and 1 ATTRwt patient (7%).
Unadjusted overall survival at 2 years was 63% for AL, 98% for ATTRm, and 100% for ATTRwt patients. Freedom from MACEs at 2 years was 51% for AL, 77% for ATTRm, and 69% for ATTRwt patients (Figures 2 and 3⇓).
Table 5 reports the results of multivariate analysis. ATTRm and ATTRwt types were favorable predictors of overall survival, whereas severe heart failure (New York Heart Association class III to IV), increasing age, and mean LV wall thickness were unfavorable. With regard to freedom from MACEs, ATTRwt turned out to be a strongly favorable predictor, whereas severe heart failure (New York Heart Association class III to IV), mean LV wall thickness, severe renal insufficiency, and increasing age were unfavorable (restrictive filling pattern did not reach significance, P=0.08).
To the best of our knowledge, this is the largest available follow-up study of cardiac amyloidosis. The results underscore profound differences between the 3 most frequent pathogenic types 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.
Relatively little is known about the relation between causes of amyloidosis and types and severity of cardiac involvement. Two studies from a single center focused on differences between ATTRm and AL19 and between AL and ATTRwt.12 In both comparisons, AL was associated with worse prognosis and more rapid progression of heart failure (despite greater myocardial involvement in ATTRwt and lack of apparent differences in involvement between AL and ATTRm). In an independent study focusing on survival analysis of patients with amyloidotic cardiomyopathy, the few ATTRm patients included in the series had a better outcome than the AL patients.20 The present work describes patients with all 3 main forms of systemic cardiac amyloidosis. The particular setting—2 large centers with coordinated facilities for diagnosis and management of systemic amyloidosis—facilitates the study of patients with each of the 3 main types of systemic amyloidosis satisfying a strict echocardiographic definition of amyloidotic cardiomyopathy.
At presentation, the 3 groups of patients showed expected8 clinical differences (Table 1), including high prevalence of neurological impairment in ATTRm, kidney involvement in AL, and heart failure in both AL and ATTRwt (a disease thought to be confined to elderly men).10,12,21 The high prevalence of carpal tunnel syndrome in ATTRm supports the concept that this condition frequently precedes diagnosis of cardiomyopathy in these patients.22,23
Severity of cardiac amyloidosis is commonly described in terms of ventricular wall thickness and systolic and diastolic function. Remarkably, alterations in these 3 indicators of cardiac involvement did not seem to go hand in hand in the 3 subtypes (Table 2). Morphologically, LV wall thickness measures varied widely between the 3 groups, with the ATTRwt group showing the highest average values (3 to 4 mm greater mean LV wall thickness than in AL or ATTRm). All patients had nondilated LV, but LV ejection fraction values varied considerably, tending to be normal in ATTRm, around lower normal limits in AL, and abnormally low in ATTRwt. In parallel, mean left atrial diameter values tended to be normal in ATTRm, slightly increased in AL, and high in ATTRwt. Interestingly, increased AV valve thickness appeared to be particularly frequent in the 2 TTR-related forms. A plausible explanation for these morphological observations regards the duration of amyloid deposition, which seems to be much more protracted in the 2 TTR-related forms.
Cardiac amyloidosis is commonly considered a form of restrictive cardiomyopathy18 (ie, a myocardial disease with increased parietal stiffness, causing precipitous rises in ventricular pressure accompanied by only small increases in volume).18 Nevertheless, the majority of patients in each of the 3 groups did not display restrictive filling pattern, which is traditionally considered the key noninvasive marker of restrictive pathophysiology. Subanalysis of baseline hemodynamic data (one of the largest such data sets currently available) suggests further insights into ventricular function in the 3 pathogenic forms. As many as one fifth of the hemodynamically evaluated patients did not display any abnormal findings (Figure 1). Furthermore, the 3 groups showed relevant hemodynamic differences, with AL patients most often displaying abnormal values in the different measures of diastolic function. The higher frequency of hemodynamic impairment in the AL patients contrasts with their lesser morphological involvement (in terms of LV wall thickness values). This mismatch could plausibly be attributed to the well-documented direct toxicity of the immunoglobulin circulating immunoglobulin light chains in AL,8,24 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 substances could also lead to different degrees of myocardial damage. Measurement of biochemical markers such as brain natriuretic protein and troponin, which have provided useful insights into myocardial involvement in systemic amyloidosis,25–27 could shed light on this possibility (number considerations precluded a meaningful analysis in the present study). Interestingly, the single currently available study comparing these biomarkers in different forms of amyloidotic cardiomyopathy suggested that brain natriuretic protein and troponin values are lower in ATTRm than in AL.27,28
ECG is considered a key player to orient diagnostic suspicion of cardiac amyloidosis, with low QRS voltages providing a particularly valuable noninvasive clue. Most biopsy-proven studies of diagnostic accuracy have been based on series characterized either by incomplete pathogenic diagnosis or by small numbers of ATTRm patients.29 The present study regarded patients with clear-cut diagnosis by type, including appreciable numbers with TTR-related disease (both ATTRm and ATTRwt); in this context, the prevalence of low QRS voltages at the time of diagnosis was somewhat lower than in other reports (≈45% overall) and was particularly low in the ATTRm subset (25%) despite greater myocardial infiltration (as indicated by mean ventricular wall thickness values). Consequently, voltage-to-mass ratios were higher in TTR-related disease than in AL. Moreover, on multivariate analysis, ATTRm actually turned out to be negatively associated with low QRS voltage. Pathophysiologically, these findings depict an intriguing scenario for an infiltrative disease: higher QRS voltages in patients with greater wall thickness (ie, in the 2 TTR-related forms). A possible explanation for this finding could be greater myocardial cellular damage (regardless of wall thickness) induced by light-chain toxicity in AL. Another interesting finding regards the relatively frequent occurrence of left bundle-branch block in our patients, especially those with TTR-related disease (up to 40% in ATTRwt). Taken together, these observations underscore 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.
With regard to clinical outcome, we recorded substantial differences in overall and MACE-free survival between the 3 groups that appear to contrast with degree of morphological involvement. In particular, the group with the least morphological derangement (ie, AL) had a rather aggressive clinical course. In contrast, the group that showed the greatest LV wall thickness (ie, ATTRwt) seemed to have a less aggressive course despite the patients’ higher average age. These possible discrepancies may depend on both cardiological and noncardiological factors. Patients with AL may be penalized by the apparently greater severity of hemodynamic impairment, as well as by disease burden in other organs. Of note, on multivariate analysis, LV wall thickness appeared to be a predictor of survival, along with age and severity of heart failure (remarkably, only weak associations were apparent for restrictive filling pattern and LVEF).
Differences in patients’ characteristics may have been influenced by diagnosis in different phases of disease (lead-time bias). Nevertheless, we believe that the findings, when considered together, support the underlying hypothesis that the 3 entities should be considered distinct forms of amyloidotic cardiomyopathy. For example, the key cross-sectional finding that AL patients appear to have greater functional impairment at diagnosis despite less morphological involvement cannot be explained in terms of lead-time bias alone.
It should be stressed that this study was primarily descriptive. We did not attempt to take into account correlated data from the various families. Furthermore, P values were not adjusted for multiple comparisons, and some detected differences may be fortuitous.
Referral bias is another potential concern. However, despite the different characteristics of the 2 centers (eg, greater focus on AL in Pavia and on the TTR-related forms in Bologna), stratification by center did not reveal substantial differences in the main study findings (data not shown). Availability of baseline hemodynamic data in many patients from 1 center was an important feature of this study. Although relevant minorities of AL and ATTRm patients did not receive routine hemodynamic evaluation, it seems unlikely that the direction of the recorded differences between AL and the other 2 groups could be wholly attributed to selection bias. When we looked at the baseline clinical, ECG, and echocardiographic characteristics of patients with available hemodynamic data, ATTRm (but not AL) patients appeared to have more severe heart failure compared with patients lacking hemodynamic data (data not shown).
ATTRm is characterized by considerable allelic genetic heterogeneity linked to several factors, including specific mutation, geographic area, and type of aggregation (endemic/nonendemic).30–33 Our data on ATTRm derive from a nonendemic area with a high prevalence of mutations other than Val30Met, and the results cannot automatically be generalized to other geographic settings or genotype mixes.
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 study also supports the concept that cardiomyopathies resulting from AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases with different pathophysiological substrates and clinical courses. In particular, AL cardiomyopathy seems to be associated with only slightly increased wall thickness, but it appears to show the highest frequencies of hemodynamic derangement (mainly because of diastolic dysfunction) and low QRS voltages on ECG, and its clinical course may be rather aggressive. ATTRm and especially ATTRwt seem to be associated with markedly increased wall thickness but less frequently with hemodynamic alterations; their clinical course appears to be less aggressive than that of AL despite the patients’ higher average age and greater morphological abnormalities. In the 2 TTR-related cardiomyopathies, voltage-to-mass ratio tends to be higher than in AL patients (with the possibility of left bundle-branch block), and increased atrioventricular valve thickness appears to be particularly frequent. Awareness of the diversity underlying the shared label of cardiac amyloidosis is important on several levels, ranging from disease classification to diagnosis and clinical management.
Sources of Funding
The contributions of G.M., G.P., L.O. and S.P. were partially supported by: the EURAMY (“Systemic Amyloidoses in Europe”) project partially funded by the European Community’s Sixth Framework Program; CARIPLO (Fondazione Cassa di Risparmio delle Provincie Lombarde); NOBEL Project “Transcriptomics and Proteomics Approaches to Diseases of High Sociomedical Impact: A Technology-Integrated Network”; Ricerca Finalizzata Malattie Rare, Ministero della Salute - Istituto Superiore di Sanità (526D/63); Ministero dell’Istruzione, dell’Università e della Ricerca, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale 2007, Project No 2007XY59ZJ_005 and No 2007AE8FX2_003. F.S. was partially supported by an investigator fellowship from Collegio Ghislieri, Pavia. C.R. was partially supported by Università di Bologna, RFO (Ricerca Fondamentale Orientata) 2008.
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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). 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) to compare clinical, morphological, and pathophysiological profiles of these different types. Our results support the concept that cardiomyopathies resulting from AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases with different pathophysiological substrates and clinical courses. In particular, AL cardiomyopathy is associated with only slightly increased wall thickness, whereas it appears to show the highest frequencies of hemodynamic derangement (mainly resulting from diastolic dysfunction) and low QRS voltages on ECG. The clinical course appears rather aggressive. In contrast, ATTRm and especially ATTRwt are associated with markedly increased wall thickness but less frequently with hemodynamic alterations. In these 2 transthyretin-related cardiomyopathies, the clinical course appears to be less aggressive than in AL despite the patients’ higher average age and greater morphological abnormalities. Furthermore, the voltage-to-mass ratio tends to be higher than in AL (with the possibility of left bundle-branch block), and increased AV valve thickness appears to be particularly frequent. Awareness of the diversity underlying the shared label of cardiac amyloidosis is important on several levels, ranging from disease classification to diagnosis and clinical management.
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