Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis.: Cardiac biomarkers in FAP

International audienceBACKGROUND: Familial amyloid polyneuropathy (FAP) mainly targets the peripheral nervous system and heart. Early noninvasive detection of cardiac impairment is critical for therapeutic management. AIM: To assess if amino-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (cTnT) can predict echocardiographic left-ventricle (LV) impairment in FAP. METHODS: Thirty-six asymptomatic carriers and patients with FAP had echocardiographic measurement of left-ventricular (LV) systolic function, hypertrophy (LVH) and estimation of filling pressure (FP). RESULTS: Overall, median age, NT-proBNP, and LV ejection fraction were, respectively, 59 years (41-74), 323 pg/ml (58-1960), and 60% (51-66). Twelve patients had increased cTnT. Prevalence of ATTR gene mutations was 53% for Val30Met. Four individuals were asymptomatic, 6 patients had isolated neurological clinical signs, and 26 had echo-LV abnormalities. The ROC curve identified NT-proBNP patients with echo-LV abnormalities (area: 0.92; (0.83-0.99), p = 0.001) at a threshold >82 pg/ml with a sensitivity of 92%, and a specificity of 90%. Increased in NT-proBNP occurred in patients with SD and/or LVH with or without increase in FP. Elevated cTnT (>0.01 ng/ml) was only observed in patients with LVH and systolic dysfunction, with or without FP. CONCLUSION: In FAP, NT-proBNP was associated with cardiac impairment suggesting that NT-proBNP could be used in carriers or in FAP patients with only neurologic symptoms for identifying the appropriate time to start cardiac echocardiographic assessment and follow-up. cTnT identified patients with severe cardiac disease

Prognostic significance and normal values of 2D strain to assess right ventricular systolic function in chronic heart failure.

International audienceBACKGROUND: Normal values and the prognostic significance of right ventricle (RV)-2D strain in chronic heart failure (CHF) patients are unknown. METHODS AND RESULTS: Between 2005 and 2010, we prospectively enrolled 43 controls and 118 stable CHF patients. Standard echocardiographic variables, tricuspid annular plane systolic excursion, peak systolic velocity of tricuspid annular motion using tissue Doppler imaging, and RV and left ventricle (LV) 2D-strain were measured. The primary outcome was death or emergency transplantation or emergency ventricular assist device implantation or acute heart failure. RV-2D strain was measurable in 39 controls (58±17 years, 50% men), whose median value was 30% (95% confidence interval [95%CI], 39%; 20%); and in 104 CHF patients (80% men, mean age 57±11 years, and mean LV ejection fraction 29%±8%), whose median value was 19% (95%CI, 34%; 9%). During the mean follow-up of 37±14 months, 44 experienced the primary outcome. By Cox proportional hazards multivariate analysis, only RV-2D strain and log B-type natriuretic peptide independently predicted experiencing the primary outcome within the first year. The best RV-2D strain cut-off by receiver-operating characteristics analysis was 21%, and patients with values >21% were at greatest risk (χ(2)-log-rank test=14.1, P<0.0001). CONCLUSIONS: RV-2D strain is a strong independent predictor of severe adverse events in patients with CHF and may be superior to other systolic RV or LV echocardiographic variables

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system

International audienceIn vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We previously described that node‐like clusters can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these clusters prior to myelination. We first demonstrated that their components can partially preassemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Nav for node‐like clustering initiation. We further assessed the fate of these clusters when myelination proceeds. Our results shed light on the intrinsic mechanisms involved in node‐like clustering prior to myelination and unravel a potential role of these clusters in node of Ranvier formation and in guiding myelination onset

0353: Prevalence of hereditary transthyretin cardiac amyloidosis in patients with increase in LV thickness in France

International audienceBackground Hereditary transthyretin cardiac amyloidosis (mTTR-CA) is a hypertrophic cardiomyopathy with challenging diagnosis and poor prognosis. The prevalence of m-TTR in patients with increased left ventricular wall thickness (LVWT) is unknown. Methods Prospective and consecutive multicenter study with systematic genetic screening for mTTR in adult patients with LVWT ≥15mm included in cardiology primary clinics. Results 298 patients were genotyped of whom 23% were African descendant. The median (IQR) age was 62(50,74), 74% were men and 36% were in NYHA class III-IV. The median of maximal LV thickness was 18 (16, 21)mm.17 patients had TTR mutation (5.7%) of whom 15 (5.0) had confirmed mTTR-CA. All the mTTR-CA were ≥55years meaning that the prevalence of mTTR-CA was 8.3% above this age. Of the 15 with mTTR-CA, 8 were Africans and 6 Caucasians. In Africans ≥55 years, the prevalence was 22% and reached 35% in those over 65 years. The most frequent mutations were V142I (8), V50M (2) and I127V (2). When adjusted to age, neuropathy (OR=20.1; 95%-CI, 5.86-69.4; P&lt;0.001), carpal tunnel syndrome (OR=15.31; 95%-CI, 4.32-54.3; P&lt;0.001), ECG low voltage (OR=8.8; 95%-CI, 2.67-29.1; P&lt;0.001), symmetric hyper-trophy (OR=10.9; 95%-CI, 1.97-59.8; P=0.006), LVEF impairment (OR=10.9; 95%-CI, 1.62-15.5; P=0.005), and late gadolinium enhancement at MRI (OR=42.9; 95%-CI, 2.38-772; P=0.011) were all associated with increased odds of CA. Conclusions mTTR-CA is frequent in HCM, particularly in African descendant and patients ≥55 years. mTTR genetic screening may be warranted for patients with increased LVWT, especially with neuropathy or carpal tunnel syndrome or LGE at MR

Role of a Contactin multi‐molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS

International audienceThe fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage-gated sodium channels at nodes of Ranvier. Axo-glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM-induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin-1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin-R). We show that Contactin-1 combined with RPTP/Phosphacan or Tenascin-R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin-1-immunodepleted OCM or OCM from Cntn1-null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin-1. Altogether, our results identify Contactin-1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations

[Senile systemic amyloidosis: definition, diagnosis, why thinking about?].

International audienceSenile systemic amyloidosis (SSA) is characterized by infiltration of amyloid transthyretin fibrils in the myocardium. SSA occurs mainly (but not always) in elderly men. SSA leads to hypertrophic and/or restrictive cardiomyopathy complicated by conduction disturbances, atrial arrhythmia and systemic embolization (stroke...). That is why SSA needs a special care and to be diagnosed. Cardiac SSA diagnosis needs to exclude two other forms of cardiac amyloidosis: AL amyloidosis (light chain) and hereditary transthyretin amyloidosis (genetic testing). Scintigraphic 99mTc-DPD heart retention is observed in cardiac amyloidosis. DPD heart retention is more frequent in cardiac transthyretin amyloidosis than in cardiac AL amyloidosis. Specific treatments of cardiac TTR amyloidosis are in development

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

International audienceAIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT 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. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. 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 \textless 0.001). 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. CONCLUSION: 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 LG