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Hypertrophic Cardiomyopathy and Hereditary Transthyretin Amyloid Etiology

Paper presented by the Working Group on Myocardial and Pericardial Diseases

“Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness”

Presented by: Pr Philippe Charron, Referral center for cardiac hereditary diseases, Ambroise Paré Hospital and Versailles Saint Quentin University, Paris Ouest, France

Authors: Damy T, Costes B, Hagège AA, Donal E, Eicher JC, Slama M, Guellich A, Rappeneau S, Gueffet JP, Logeart D, Planté-Bordeneuve V, Bouvaist H, Huttin O, Mulak G, Dubois-Randé JL, Goossens M, Canoui-Poitrine F, Buxbaum JN.

Eur Heart J. 2015 Nov 3. pii: ehv583. [Epub ahead of print]


A part from common genetic causes related to sarcomeric genes mutations, Hypertrophic cardiomyopathy (HCM) encompasses a heterogenous group of disorders that are associated with left ventricular hypertrophy, yet genetically and mechanistically distinct. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for HCM. The issue is important because (mTTR-FAC) carries a particularly poor prognosis since usually diagnosed late in the disease course and with an important risk of congestive heart failure that require specific care management and avoidance of some pharmacological agents. In addition several new therapeutic modalities for mTTR-FAC are currently under evaluation in clinical trials, which make useful to know the prevalence of this etiology in HCM.


To establish the prevalence of TTR mutations (mTTR) in a population of HCM patients and study the clinical characteristics of the patients with mTTR-FAC.


The authors performed a prospective multicentre, cross-sectional study. The TTR gene was sequenced in 298 consecutive patients >18 years diagnosed with HCM (>15 mm in sporadic cases or >13 mm in familial forms) in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III-IV. Median LVWT was 18 (16-21) mm. Hypertension was present in 50% of patients.


Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had a mutation in TTR gene of whom 15 (5.0%; 95% CI [2.9;8.2]) were considered to have familial amyloid cardiomyopathy (mTTR-FAC) because of consistent findings (based on histology or biphosphonate scintigraphy and cardiac MRI). The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79].

Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P < 0.001). No intra left ventricular obstruction nor systolic anterior motion was observed in the 15 patients. In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. Age >73 years and LV EF < 40% were associated with mTTR-FAC after univariate analysis but not after multivariate analysis.


The authors observed that five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR-FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE on MRI.


This is the first prospective study to determine the prevalence of mTTR in patients with HCM and the figure of 5% of mTTR with amyloid cardiomyopathy is well above expected prevalence. Several factors may contribute to this result. First, mean age of patients in the total cohort was 62 years old in contrast with younger age in studies related to sarcomeric genes analysis. Second, patients with amyloid cardiomyopathy are older and often seen in centers specialized in neuropathies and may not be referred to cardiac centers specialized in HCM. Third, TTR gene is usually not systematically analyzed so that the exact prevalence of TTR mutations could not be evaluated until this study. The authors however did not mention in which centers the mTTR patients were identified and an hypothesis is that most patients were identified in the leading author centre that is a referral center for amyloidosis in France, which may have led to an inclusion bias and a potential overestimation of the prevalence. To know the number of patients included by center and the number of TTR mutations identified by center would have permit to answer the question.

The authors showed that several clinical features were associated with mTTR-FAC, and this may have important clinical implications for the better selection of patients that are at high risk of being TTR mutation carrier and therefore need to be screened by appropriate molecular sequencing. Results suggest to screen HCM patients of African descent and older than 65 years, or in patients with HCM and neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, or late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging. The remaining question is to know the precise role for genetic screening in the general diagnostic algorithm of amyloid cardiomyopathy. Should it be performed after confirming amyloid cardiomyopathy by histology, and no AL etiology, or should it be performed earlier and at which stage?


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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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