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Transthyretin-related amyloidoses and the heart: a clinical overview

Nature Reviews Cardiology volume 7, pages 398–408 (2010)Cite this article

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Abstract

A nonhereditary form of systemic amyloidosis associated with wild-type transthyretin causes heart involvement predominantly in elderly men (systemic senile amyloidosis, or SSA). However, hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis, a group of severe diseases with variable neurological and organ involvement. ATTR remains a challenging and widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. Such heterogeneity principally results from differential effects of the various reported transthyretin mutations, the geographic region the patient is from and, in the case of the most common mutation, Val30Met, whether or not large foci of cases occur (endemic versus nonendemic aggregation). Genetic or environmental factors (such as age, sex, and amyloid fibril composition) also contribute to the heterogeneity of ATTR, albeit to a lesser extent. The existence of exclusively or predominantly cardiac phenotypes should lead clinicians to consider the possibility of ATTR in all patients who present with an unexplained increase in left ventricular wall thickness at echocardiography. Assessment of such patients should include an active search for possible red flags that can point to the correct final diagnosis.

Key Points

  • Amyloidotic cardiomyopathy is a challenging condition that can mimic many other diseases, such as hypertrophic cardiomyopathy or coronary artery disease

  • Hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis

  • The clinical spectrum of ATTR ranges from almost exclusive neurologic involvement within a clearly familial context, to apparently sporadic cases with a strictly cardiac presentation

  • Phenotypic heterogeneity is linked to at least three different factors: the type of transthyretin mutation, geographic region, and the type of Val30Met aggregation (endemic or nonendemic)

  • Diagnosis of ATTR-related amyloidotic cardiomyopathy generally involves electrocardiography and echocardiography; the specific clinical signs can be very mild and may be missed by the patient

  • Orthotopic liver transplantation or combined heart–liver transplantation can provide surgical 'gene therapy' for amyloidotic cardiomyopathy; the combined procedure can be offered to patients with severe heart failure

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Figure 1: Representative findings in ATTR cardiomyopathy.
Figure 2: Main known determinants of phenotypic variability in ATTR.

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Acknowledgements

We thank Robin M. T. Cooke for editorial advice and writing assistance, which was indirectly funded by a 1-year contract with the Fondazione Maugeri, a not-for-profit organization providing evidence-based medical services within the framework of the Italian National Health Service.

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Authors and Affiliations

  1. Institute of Cardiology, University of Bologna and S. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, 40138, Italy

    Claudio Rapezzi, Candida Cristina Quarta, Letizia Riva, Simone Longhi, Ilaria Gallelli, Massimiliano Lorenzini, Paolo Ciliberti, Elena Biagini & Angelo Branzi

  2. Department of Neurology, Bellaria Hospital via Altura 3, Bologna, 40139, Italy

    Fabrizio Salvi

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Rapezzi, C., Quarta, C., Riva, L. et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 7, 398–408 (2010). https://doi.org/10.1038/nrcardio.2010.67

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