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Background: Although atrial fibrillation (AF) is a known complication of amyloidotic cardiomyopathy (AC), a precise pathophysiological and prognostic characterization is not available. We therefore aimed to assess prevalence, incidence, risk factors and prognostic significance of AF in light-chain (AL), hereditary transthyretin-related (m-ATTR) and non-mutant transthyretin-related (wt-ATTR) AC. Methods: Retrospective study of 262 patients with AC (123 AL, 94 m-ATTR, 45 wt-ATTR) from a single center. Results: AF prevalence was 15% (AL 9%, m-ATTR 11%, wt-ATTR 40%). During a median follow-up of 1.2 years 11 patients developed AF (2.1% person-years). Age, heart failure (HF), left ventricular (LV) ejection fraction, renal involvement, left atrial size and right atrial pressure were independently associated with AF. AF was associated with incident HF but not with increased mortality. All AF patients were prescribed warfarin and none suffered thromboembolic events. Conclusions: In AC the prevalence of AF varies widely according to etiology with a mean value of 15% that reaches 40% in wt-ATTR amyloidosis. Age, HF, LV ejection fraction, left atrial size and right atrial pressure were the main independent risk factors, while wall thickness and etiology were not the main independent risk factors. AF does not seem to impact all-cause mortality but was strongly associated with prevalent and incident HF. [ABSTRACT FROM AUTHOR]

The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients. [ABSTRACT FROM AUTHOR]

Background: Knowledge of the patterns of myocardial amyloid accumulation could improve the interpretation of electrocardiographic, echocardiographic and magnetic resonance imaging findings of amyloidosis. We assessed the extent and pattern of myocardial amyloid infiltration in explanted or autopsied hearts of patients with cardiomyopathy related to acquired monoclonal immunoglobulin light-chain (AL) or hereditary transthyretin (TTR) related amyloidosis (ATTR). Methods: We analyzed nine explanted/autopsied hearts from patients with AL ( n = 4) and ATTR ( n = 5) cardiac amyloidosis. For each heart, a biventricular histological macrosection was obtained at mid-ventricular level and analyzed with both inspective and computer-assisted histologic and histomorphometric analysis aimed in particular at quantifying muscle cells, fibrosis and amyloid infiltration. Results: The extent of amyloid infiltration of the left ventricle (LV) ranged from 45 to 76% (median [interquartile range (IQR)] = 57% [51-64]) of the overall surface. Although LV trabecular and subendocardial were the most infiltrated layers (45-94%, median [IQR] = 73% [67-84] and from 44 to 71%, median [IQR] = 57% [49-59], respectively), intra- and inter-patient heterogeneity was high. Three main patterns of amyloid infiltration of the LV were identified: diffuse (five cases), mainly subendocardial (two cases), and mainly segmental (two cases). The extent of amyloid infiltration of the right ventricle ranged from 48 to 93% (median [IQR] = 61% [59-83]); contributions of parietal and trabecular layers ranged from 32 to 99% (median [IQR] = 63% [47-88]) and from 49 to 93% (median [IQR] = 74% [64-79]), respectively. Conclusions: In amyloidotic cardiomyopathy, amyloid deposition is highly heterogeneous. Different patterns of infiltration are identifiable, including diffuse, mainly segmental and mainly subendocardial. Awareness of this variability can help the interpretation of ECGs, echocardiograms and magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin-related amyloidosis remains a widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non-endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular "hypertrophy". Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: In a cohort of patients with hereditary transthyretin-related amyloidosis (ATTR), we aimed to assess the role of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in detecting myocardial amyloid infiltration across a wide spectrum of cardiac involvement and in predicting major adverse cardiac events (MACE). Background: Hereditary transthyretin-related amyloidosis is a challenging and underdiagnosed condition where both early diagnosis and prognosis remain problematic. Methods: We evaluated 63 patients with ATTR: 40 with and 23 without echocardiographically diagnosed amyloidotic cardiomyopathy (AC). Myocardial uptake of 99mTc-DPD scintigraphy was semiquantitatively and visually assessed at 5 min and 3 h. Results: All patients with AC showed moderate-to-severe myocardial tracer uptake (i.e., visual score ≥2). Within the subgroup without AC, only 4 patients (with Ala36Pro, Gly47Ala, Thr49Ala, and Glu89Gln transthyretin mutations) showed myocardial tracer uptake and abnormal heart/whole body retention (H/WB) values: in all these cases endomyocardial biopsies showed amyloidotic infiltration. The H/WB was positively correlated with left ventricular (LV) mean wall thickness (Pearson''s r = 0.695, p < 0.001) and negatively with LV ejection fraction (r = −0.368, p = 0.004). The H/WB was an unfavorable predictor of MACE-free survival at Cox univariate analysis and contributed to the multivariate model. Notably, LV wall thickness >12 mm in combination with H/WB >7.5 was associated with the highest event rate. Conclusions: In ATTR, 99mTc-DPD scintigraphy can identify myocardial infiltration across a wide spectrum of morphologic/functional cardiac involvement, allowing an early diagnosis of the disease (even before the appearance of echocardiographic abnormalities). The 99mTc-DPD myocardial uptake is a prognostic determinant of “cardiac” outcome in ATTR, either alone or in combination with LV wall thickness. [Copyright &y& Elsevier]

Purpose: We previously reported in a small series of patients that Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) scintigraphy tested positive in transthyretin-related (TTR) (both mutant and wild-type) but not in primary (AL) amyloidotic cardiomyopathy (AC). We extended our study to a larger cohort of patients with AC. Methods: We evaluated (1) 45 patients with TTR-related AC (28 mutant and 17 wild-type), (2) 34 with AL-related AC and (3) 15 non-affected controls. Myocardial uptake of Tc-DPD (740 MBq i.v.) was semiquantitatively and visually assessed at 5 min and at 3 h. Results: Heart retention (HR) and heart to whole-body retention ratio (H/WB) of late Tc-DPD uptake were higher among TTR-related AC (HR 7.8%; H/WB 10.4) compared with both unaffected controls (HR 3.5%; H/WB 5.7; p < 0.0001) and AL-related AC (HR 4.0%; H/WB 6.1; p < 0.0001). For the diagnosis of TTR-related AC, positive and negative predictive accuracy of visual scoring of cardiac retention were: 80 and 100% (visual score ≥1); 88 and 100% (visual score ≥2); and 100 and 68% (visual score = 3). At adjusted linear regression analysis, TTR aetiology turned out to be the only positive predictor of increasing Tc-DPD uptake in terms of both HR [β 2.5, 95% confidence interval (CI) 1.5-3.5; p < 0.0001] and H/WB (β 3.5, 95% CI 2.1-4.9; p < 0.0001). Conclusion: While Tc-DPD scintigraphy was confirmed to be useful for differentiating TTR from AL-related AC, diagnostic accuracy was lower than previously reported due to a mild degree of tracer uptake in about one third of AL patients. Tc-DPD scintigraphy can provide an accurate differential diagnosis in cases of absent or intense uptake evaluated by visual score. [ABSTRACT FROM AUTHOR]

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8–120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart–liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy. [ABSTRACT FROM AUTHOR]