Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition

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Abstract

Purpose

Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.

Material and Methods

Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.

Results

There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.

Conclusion

This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

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Most cited references 17

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Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.

Richard Devereux, Daniel R. Alonso, Elizabeth M. Lutas … (1986)

To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)

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Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology.

Joakim Bergström, Asa Gustavsson, Ulf Hellman … (2005)

The pathological fibrillar deposits found in the heart and other organs of patients with senile systemic amyloidosis (SSA) and Swedish familial amyloidotic polyneuropathy (FAP) contain wild-type (wt) and a mutant form of transthyretin (TTR), respectively. Previously, it was reported that these two forms of amyloid have different molecular features and it was thus postulated that the mechanism responsible for TTR fibrillogenesis in SSA and FAP may differ. To document further the nature of the amyloid in these entities, detailed morphological, histochemical, immunological, and structural analyses of specimens obtained from 14 individuals with SSA and 11 Swedish FAP patients have been performed. Two distinct patterns of amyloid deposition (designated A and B) were evident. In pattern A, found in all SSA and five of 11 FAP cases, the amyloid had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and was composed of tightly packed, short, unorientated fibrils. This material contained mainly approximately 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen in the six other FAP patients, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. These findings provide substantive evidence for the morphological and structural heterogeneity of TTR fibrils and suggest that the two types of deposition may reflect fundamental differences in the pathogenesis of the TTR-associated amyloidoses. Copyright 2005 Pathological Society of Great Britain and Ireland

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Gender differences and aging: effects on the human heart.

M Melissari, G Giordano, C A Lagrasta … (1995)

This study investigated the changes in myocyte size and number in the left and right ventricles that occur with aging in the female and male heart. Differences in life span between women and men may be related to a better preservation of myocardial structure in the female heart with aging. On this basis, the hypothesis was advanced that the aging process has a different impact on the integrity of the myocardium in the two genders. Morphometric methodologies were applied to analyze the changes in number and size of ventricular myocytes in the hearts of 53 women and 53 men. The changes in mononucleated and binucleated myocytes with age were determined in enzymatically dissociated cells. The age interval examined varied from 17 to 95 years. Aging was associated with a preservation of ventricular myocardial mass, aggregate number of mononucleated and binucleated myocytes, average cell diameter and volume in the female heart. In contrast, nearly 1 g/year of myocardium was lost in the male heart, and this phenomenon accounted for the loss of approximately 64 million cells. This detrimental effect involved the left and right sides of the heart. In the remaining cells, myocyte cell volume increased at a rate of 158 microns3/year in the left and 167 microns3/year in the right ventricle. Aging does not lead to myocyte cell loss and myocyte cellular reactive hypertrophy in women, indicating that gender differences may play a significant role in the detrimental effects of the aging process on the heart.

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Author and article information

Contributors

Maria Gasset: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 23 November 2015

Publication date Collection: 2015

Volume: 10

Issue: 11

Electronic Location Identifier: e0143456

Affiliations

[1 ]Department of Clinical Physiology, Heart Centre, Umeå University, Umeå, Sweden

[2 ]Department of Cardiology, Heart Centre, Umeå University, Umeå, Sweden

[3 ]Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

[4 ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

[5 ]Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden

Consejo Superior de Investigaciones Cientificas, SPAIN

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: OBS PL SA BP. Performed the experiments: SA BP PW. Analyzed the data: SA BP PL OBS. Contributed reagents/materials/analysis tools: SA PL PW. Wrote the paper: SA BP PW PL OBS.

* E-mail: sandra.gustavsson@ 123456umu.se

Article

Publisher ID: PONE-D-15-40179

DOI: 10.1371/journal.pone.0143456

PMC ID: 4658178

PubMed ID: 26600306

SO-VID: 3c8c6137-a933-46e0-a77d-d89c8f64b070

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 11 September 2015

Date accepted : 4 November 2015

Page count

Figures: 2, Tables: 3, Pages: 11

Funding

This study was supported by grants from the Swedish Heart-Lung Foundation ( http://www.hjart-lungfonden.se/) [PL, OBS], from a regional agreement between Umeå University and Västerbotten County Council/ALF [VLL 365301 for funding of SA], the Heart Foundation of Northern Sweden ( http://www.hjartfonden.com/) [SA], and a spearhead grant from Umeå County [OBS]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information file.

Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition

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Abstract

Purpose

Material and Methods

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PLOS Global Public Health

Most cited references 17

Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.

Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology.

Gender differences and aging: effects on the human heart.

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