Publications by authors named "Aziz Guellich"

38 Publications

Association between hearing loss and hereditary ATTR amyloidosis.

Amyloid 2019 Dec 10;26(4):234-242. Epub 2019 Sep 10.

Department of Oto-Rhino-Laryngo Surgery, Centre Hospitalier Intercommunal de Créteil , Créteil , France.

Hereditary transthyretin (TTR) related amyloidosis (ATTRv) is a life-threatening condition, which can potentially affect all organs. The objective was to identify the hearing status of patients with cardiac ATTRv and describe their audiological pattern. Nineteen patients with confirmed diagnosis of ATTRv cardiac amyloidosis (CA) underwent otoscopy and audiological tests, including pure tone and speech audiometry. 74% were male, with a mean age of 72 ± 1.8 years. The main mutations were Val122Ile ( 7) and Val30Met ( 6). Objective hearing loss was detected in 17 patients (89%), whereas only 37% complained of hearing loss. ATTRv patients presented a different audiometric profile compared to patients of the same age with presbycusis: a higher prevalence and worse hearing thresholds compared to age-related expectations (ISO). Hearing loss affected all frequencies with, unexpectedly, mixed or conductive hearing loss (35%). According to the type of mutation, there was an increased rate of sensorineural or mixed/conductive hearing loss. the present study indicates that hearing loss is more prevalent and worse in patients with ATTRv amyloidosis than in the general population, while mostly clinically under-estimated. It suggests that ATTRv deposits could infiltrate the various anatomical structures of the inner and mild ear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13506129.2019.1663814DOI Listing
December 2019

Causes and consequences of cardiac fibrosis in patients referred for surgical aortic valve replacement.

ESC Heart Fail 2019 08 21;6(4):649-657. Epub 2019 May 21.

UPEC, AP-HP, Henri-Mondor Teaching Hospital, Créteil, France.

Aims: Cardiac fibrosis is associated with left ventricular (LV) remodelling and contractile dysfunction in aortic stenosis (AS). The fibrotic process in this condition is still unclear. The aim of this study was to determine the role of both local and systemic inflammation as underlying mechanisms of LV fibrosis and contractile dysfunction. The diagnostic values of 2D-strain echocardiography and serum biomarkers in the evaluation of cardiac fibrosis in this condition were assessed through correlation analyses.

Methods And Results: Patients with AS referred for surgical valve replacement were prospectively and consecutively included. They all had a comprehensive echocardiography including 2D strain. Blood samples were collected to measure cytokines and inflammatory biomarkers using Luminex bead-based assays. A per-surgical myocardial biopsy of the basal antero-septal segment (S1) was performed. Serial sections of each biopsy were stained with Sirius red. Digital image analysis was used to quantify fibrosis. Immunostainings using specific antibodies against macrophage, glycoprotein (gp) 130, and interleukin 6 (IL-6) were also performed. Patients were divided into tertiles reflecting the severity of fibrosis: mild, moderate, and severe load (TF1 to TF3). The mean age of the 58 included patients was 73 ± 11 years. Twenty-four (43%) were in New York Heart Association III-IV. Mean aortic valve area was 0.8 ± 0.2 cm . Mean aortic stenosis peak velocity and mean gradient were respectively 4.5 ± 0.8 m/s and 54 ± 15 mmHg. The mean LV ejection fraction was 54 ± 12%, and the global LV longitudinal strain was -15 ± 4%. The mean S1 strain, corresponding to the biopsied region, was -10 ± 6% and was strongly correlated to fibrosis load (R = 0.83, P < 0.0001). TF3 was associated with higher mortality (P = 0.009), higher serum C-reactive protein and IL-6, and lower gp130 compared with the other tertiles (P < 0.05). IL-6 and gp130 were expressed in the heart and respectively in the plasma membrane of macrophages and in the cytoplasm of both macrophages and cardiomyocytes. During follow-up, three patients died and were all in the third fibrosis tertile.

Conclusions: We found a positive correlation between elevated inflammatory markers and degree of fibrosis load. These two parameters were associated with worse outcomes in patients with severe AS. Our results may be of interest especially in patients for whom a transcatheter aortic valve implantation is indicated and myocardial biopsy is not possible. Strategies aiming at preventing inflammation might be considered to decrease or limit the progression of cardiac fibrosis in patients followed for AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676299PMC
August 2019

Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction.

Cardiovasc Res 2019 10;115(12):1778-1790

INSERM, U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU ATVB, Créteil, France.

Aims: Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of β-adrenergic/cAMP signalling. Our objective was to evaluate cardiac cAMP signalling as age increases between 2 months and 12 months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age.

Methods And Results: Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2- and 12 months old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased phosphodiesterase and PKA activity, and increased phosphorylation of several PKA targets including sarco(endo)plasmic-reticulum-calcium-ATPase (SERCA2a) cofactor phospholamban (PLN) and GSK3α/β a main regulator of hypertrophic growth and ageing. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2-month-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-month-old NTG and AC8TG, PLN and GSK3α/β phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Haemodynamics demonstrated an increased contractile function in 2- and 12-month-old AC8TG, but not in NTG. In contrast, echocardiography and tissue Doppler imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-month-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to heart failure (HF) and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG when compared with NTG.

Conclusion: Our data demonstrated an early and accelerated cardiac remodelling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signalling can accelerate cardiac ageing, partly through GSK3α/β phosphorylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvy306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755357PMC
October 2019

Development and Validation of a New Tool to Assess Burden of Dietary Sodium Restriction in Patients with Chronic Heart Failure: The BIRD Questionnaire.

Nutrients 2018 Oct 7;10(10). Epub 2018 Oct 7.

Heart Failure Unit, Department of Cardiology, INSERM U955, ARI, DHU ATVB, AP-HP Henri Mondor Hospital, University Paris Est Créteil (UPEC), 94000 Créteil, France.

(1) Background: Burden scales are useful in estimating the impact of interventions from patients' perspectives. This is overlooked in sodium diet/heart failure (HF). The aim of this study is to develop and validate a specific tool to assess the burden associated with low-sodium diets in HF: the Burden scale In Restricted Diets (BIRD). (2) Methods: Based on the literature and reports from patients, 14 candidate items were identified for the following dietary-related domains: organization, pleasure, leisure, social life, vitality, and self-rated health. The validation study was conducted prospectively. The questionnaire was refined via item reduction according to inter-item correlations and exploratory factor analysis. Internal consistency was determined using Cronbach's alpha (Cα) and convergent validity by assessing correlations between BIRD and the health-related quality of life (HRQoL) Minnesota Living with HF questionnaire (MLHF). (3) Results: Of the 152 invited patients, 96 (63%) returned the questionnaire. The median score was 6.5 (IQR 2.0⁻14.0). The results showed good acceptability (non-response rates/item from 2.0% to 12.1%), an excellent internal consistency (Cα = 0.903) and a good convergent validity (rhos = 0.37 (physical), 0.4 (mental), and 0.45 (global); all < 0.05). (4) Conclusions: BIRD demonstrates good psychometric properties and is useful to quantify the burden associated with sodium restriction. It may help optimize dietary interventions and improve the overall management of patients with HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu10101453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213449PMC
October 2018

How your ears can tell what is hidden in your heart: wild-type transthyretin amyloidosis as potential cause of sensorineural hearing loss inelderly-AmyloDEAFNESS pilot study.

Amyloid 2017 06 9;24(2):96-100. Epub 2017 Jun 9.

a School of Medicine , University Paris-Est Creteil (UPEC) , Créteil , France.

Background: Wild-type transthyretin amyloidosis (ATTRwt) is an age-related life-threatening condition. Prognosis is mainly dependent on cardiac involvement. Other organs and tissues may be affected. Their early recognition may increase awareness of physicians and positively affects the prognosis. Presbycusis is another age-related disorder. Whether this disease is associated to ATTRwt amyloidosis is unknown.

Methods: Sixteen consecutive patients with confirmed diagnosis of ATTRwt amyloidosis at the Mondor Amyloidosis Network, France, underwent otoscopy and audiological tests including pure tone audiometry, speech reception threshold and speech discrimination score.

Results: The mean age was 79 ± 5 years. All were male with an NYHA average of 2.5 ± 0.8. All the patients had sensorineural hearing loss that seemed to preexist to cardiac disorder with greater severity than expected for their age. For speech discrimination test, the mean speech reception threshold was 28 ± 15 dB and the mean speech discrimination score was 68 ± 16 at 40 dB. Ten patients (62.5%) failed to recognize 100% of the words. Compared to age-related expectations according to statistical distribution (ISO), hearing loss included all frequencies and was more severe in patients with ATTRwt amyloidosis.

Conclusions: These findings suggest that amyloid deposits could infiltrate the various anatomical structures of the inner ear. Description of specific audiologic pattern of ATTRwt amyloidosis might be proposed as a "red flag" and could help for early identification of patients who may be at high risk of ATTRwt amyloidosis as specific treatments are available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13506129.2017.1330744DOI Listing
June 2017

Apical sparing pattern of left ventricular myocardial Tc-HMDP uptake in patients with transthyretin cardiac amyloidosis.

J Nucl Cardiol 2018 12 26;25(6):2072-2079. Epub 2017 Apr 26.

Mondor Amyloidosis Network, Créteil, France.

Background: A decreased longitudinal strain in basal segments with a base-to-apex gradient has been described in patients with cardiac amyloidosis (CA).

Objectives: Aim was to investigate the left ventricular (LV) regional distribution of early-phase Tc-Hydroxymethylene diphosphonate (Tc-HMDP) uptake in patients with transthyretin-related cardiac amyloidosis (TTR-CA).

Methods: All patients underwent a whole-body planar Tc-HMDP scintigraphy acquired at 10-min post-injection (early-phase) followed by a thorax SPECT/CT. The segmental uptake (expressed as % of maximal myocardial HMDP uptake) was investigated on the AHA 17-segment model and 3-segment model (basal, mid-cavity, apical).

Results: Sixty-one TTR-CA patients were included of whom 29 were wild-type (wt-TTR-CA) and 32 had hereditary TTR-CA (m-TTR-CA). Early myocardial Tc-HMDP uptake occurred in all TTR-CA. In all patients, segmental analysis of the LV myocardial distribution of Tc-HMDP uptake showed an increased median uptake (interquartile range) in basal/mid-cavity segments compared to the lowest median uptake of apical segments (respectively, 79% [72%-86%] vs. 72% [64%-81%]; P < 10). This pattern was similar in wt-TTR-CA group (78% [70%-84%] vs. 70% [61%-81%]; P < 10), in m-TTR-CA group (80% [74%-86%] vs. 73 [66%-82%]; P < 10) and remained constant independently of the TTR mutation subtype with P ranging 10 to 0.03.

Conclusions: Early-phase myocardial scintigraphy identified regional distribution of Tc-HMDP uptake characterized by a base-to-apex gradient, corroborating echocardiographic, and cardiac magnetic resonance findings. This apical sparing pattern was similar across TTR-CA and TTR mutation subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-017-0894-zDOI Listing
December 2018

Sequential cyclophosphamide-bortezomib-dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.

Eur J Cancer 2017 05 20;76:183-187. Epub 2017 Mar 20.

Paris XII University, UPEC, Créteil, France; GRC Amyloid Research Institute, IMRB-INSERM U955, and Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, AP-HP, Henri-Mondor Hospital, Créteil, France; DHU ATVB, Créteil, France; Inserm Clinical Investigation Center 1430, Créteil, F-94000, France. Electronic address:

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2017.02.004DOI Listing
May 2017

Isolated Pericardial Infiltration Without Myocardial Involvement in Light-Chain-Related Amyloidosis.

Ann Thorac Surg 2017 Mar;103(3):e255-e257

University Paris-Est Créteil, Créteil, France; Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, Henri-Mondor Teaching Hospital, Créteil, France; GRC Amyloid Research Institute, Créteil, France. Electronic address:

Light-chain-related amyloidosis is a systemic disease characterized by continuous accumulation of insoluble fibrillar proteins in different organs. Cardiac involvement is frequent in this condition. However, atypical presentations and unusual amyloid deposits localization may be encountered making the diagnosis challenging. We present here a case of a light-chain-related pericardial amyloidosis without evidence of myocardial involvement and emphasize the difficulty and importance of amyloidosis typing before starting treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2016.08.108DOI Listing
March 2017

Myocardial Gene Expression Profiling to Predict and Identify Cardiac Allograft Acute Cellular Rejection: The GET-Study.

PLoS One 2016 29;11(11):e0167213. Epub 2016 Nov 29.

AP-HP, Department of Cardiology, Henri Mondor Teaching Hospital, Créteil, France.

Aims: Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR.

Methods: A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or ≥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n = 13); rejection ≥3A (RISHLT, n = 13); 0 one month before ACR (BRISHLT, n = 10).

Results: We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples.

Conclusion: Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipients' care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167213PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127573PMC
July 2017

Early-phase myocardial uptake intensity of Tc-HMDP vs Tc-DPD in patients with hereditary transthyretin-related cardiac amyloidosis.

J Nucl Cardiol 2018 02 1;25(1):217-222. Epub 2016 Nov 1.

Mondor Amyloidosis Network, 94000, Créteil, France.

Background: This study sought to compare the intensity of early-phase myocardial uptake of two phosphonate-based radiotracers, Tc-hydroxymethylene diphosphonate (HMDP) and Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), in patients with hereditary transthyretin-related cardiac amyloidosis (TTR-CA).

Methods: Six patients with biopsy-proven diagnosis of TTR-CA and characteristic amyloid fibril composition underwent early-phase Tc-HMDP myocardial scintigraphy as part of their routine workup; they were later assessed by Tc-DPD scintigraphy after having signed informed written consent. Heart-to-mediastinum-ratio was measured at both time points as well as regional distribution on 17-segment analysis.

Results: All patients had an H/M ratio >1.28 on both imaging. Tc-DPD uptake was slightly higher than Tc-HMDP uptake in 3 patients, but no statistical difference was found (P = 0.13). Regional distribution of the two radiotracers was well correlated on bull's eyes analysis, with only slight underestimation of Tc-DPD uptake in the anterior/apical segments, compared with Tc-HMDP.

Conclusion: Tc-HMDP and Tc-DPD show comparable myocardial uptake intensity on early-phase scintigraphy and can be used alternatively for the diagnosis of TTR-CA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-016-0707-9DOI Listing
February 2018

[Cardiac amyloidosis: How to recognize them and manage them?]

Presse Med 2016 Oct 1;45(10):845-855. Epub 2016 Aug 1.

CHU Henri-Mondor, service de cardiologie, 94010 Créteil cedex, France; CHU Henri-Mondor, réseau Amylose Mondor, 94010 Créteil cedex, France; Université Paris-Est-Créteil, faculté de médecine, 94010 Créteil cedex, France; CHU Henri-Mondor, GRC-ARI, DHU-ATVB, Inserm U955, IMRB, 94010 Créteil cedex, France.

Cardiac amyloidosis must be suspected in all cases of hypertrophic cardiomyopathy with preserved left ventricular ejection fraction to allow specific management. Final diagnosis needs pathological evidence, but bone scintigraphy may be an alternative for TTR amyloidosis. Invasive samplings are limited by new tools. Amyloidosis typing is required to start specific therapies if possible. Main specific treatments that are available are chemotherapy for AL; transthyretin stabilizer or gene therapy, studied for TTR-related cardiac amyloidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lpm.2016.07.001DOI Listing
October 2016

Identification of prognostic markers in transthyretin and AL cardiac amyloidosis.

Amyloid 2016 Sep 20;23(3):194-202. Epub 2016 Sep 20.

g Department of Cardiology , Dupuytren Teaching Hospital , Limoges , France.

Background: The prognosis of amyloidosis is known to depend heavily on cardiac function and may be improved by identifying patients at highest risk for adverse cardiac events.

Aims: Identify predictors of mortality in patients with cardiac light-chain amyloidosis (AL), hereditary transthyretin amyloidosis (m-TTR), or wild-type transthyretin amyloidosis (WT-TTR) to prompt physician to refer these patients to dedicated centers.

Methods And Results: Observational study. About 266 patients referred for suspected cardiac amyloidosis (CA) in two French university centers were included. About 198 patients had CA (AL = 118, m-TTR = 57, and WT-TTR = 23). Their median (25th-75th percentile) age, NT-proBNP left ventricular ejection fraction were, respectively, 68 years (59-76), 2339 pg mL (424-5974), and 60% (48-66). About 31% were in NYHA class III-IV. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (p < 0.0001). Median follow-up in survivor was 26 months (15-44) and 87 (44%) patients died. By multivariate analysis, independent predictors of mortality for AL amyloidosis were the following: age, cardiac output and NT-proBNP; for TTR amyloidosis was: NT-proBNP. When all amyloidosis were combined NT-proBNP, low cardiac output and pericardial effusion were independently associated with mortality.

Conclusion: NT-proBNP is a strong prognosticator in the three types of cardiac amyloidosis. High NT-proBNP, low cardiac output, and pericardial effusion at the time of screening should prompt physician to refer the patients to amyloidosis referral center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13506129.2016.1221815DOI Listing
September 2016

Prognostic value of right ventricular systolic function in cardiac amyloidosis.

Amyloid 2016 Sep 27;23(3):158-167. Epub 2016 Jun 27.

a Department of Cardiology.

Background: Right ventricular (RV) dysfunction is a strong predictor of poor outcomes in heart failure. Its prognostic meaning in cardiac amyloidosis (CA) is under-investigated.

Methods: Hundred and twenty nine patients with suspected CA and an interventricular septum thickness (IVST) ≥ 12 mm underwent echocardiography with measurement of left ventricular (LV) and RV longitudinal strain (LS), late gadolinium-enhancement (LGE) cardiac MRI, and standard evaluation.

Results: Among 82 confirmed CA, types were immunoglobulin light chain (AL, n = 26), hereditary transthyretin (m-TTR, n = 37) and senile (WT-TTR, n = 19). Compared to those without, CA patients had significantly lower RV fractional shortening (RV-FS), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler systolic velocity, and global RV-LS, without any difference among the CA types. RV-LGE, observed in 62% of CA patients, was associated with lower global and basal RV-FS. Median follow-up was 8(2; 16) months. Using multivariate analysis, NYHA-class and low TAPSE independently predicted major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure. Independent determinants of TAPSE < 14 mm, the best cut-off value, were LV ejection fraction (LVEF), estimated filling pressure (E/E'), NT-proBNP and pulmonary artery pressure, but not RV-LGE.

Conclusions: RV dysfunction is common in CA. Its routine evaluation by a simple TAPSE may be an aid in assessing the prognosis of CA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13506129.2016.1194264DOI Listing
September 2016

Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis.

Sleep 2016 Jul 1;39(7):1333-41. Epub 2016 Jul 1.

Cardiology Department, AP-HP Henri Mondor Teaching Hospital, Créteil, France.

Study Objectives: To assess prevalence, severity, and prognostic value of sleep-disordered breathing (SDB), in the three main cardiac amyloidosis (CA) types, i.e., light-chain (AL), transthyretin-related familial (m-TTR), or senile (WT-TTR).

Methods: Patients consecutively referred for CA diagnosis work-up underwent cardiac assessment and nocturnal polygraphy. SDB was defined as apnea-hypopnea index (AHI) ≥ 5/h. Multivariate analysis was used to identify predictors of a major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure.

Results: Seventy CA patients were included (31 AL, 22 m-TTR, 17 WT-TTR). The mean ± standard deviation age and left ventricular ejection fraction were 71 ± 12 years and 49% ± 13% and median (interquartile range) N terminal pro brain natriuretic peptide (NT-proBNP) was 3,932 (1,607; 7,028) pg/mL. The prevalence of SDB was 90% without difference between amyloidosis types. SDB was central in 27% and obstructive in 73%. AL had less frequent severe SDB compared to m-TTR and WT-TTR (P = 0.015) but longer time with peripheral capillary oxygen saturation (SpO2) < 90% (P = 0.037). After a median follow-up of 7.5 (2.8; 14.9) months, 49% patients experienced MACE. Time with nocturnal SpO2 < 90% was the only independent predictor of MACE. The best-identified threshold was 30 min. Values > 30 min were associated with bad prognosis (Log-rank χ(2): 8.01, P value = 0.005). Using binomial logistic regression, determinants of time with nocturnal SpO2 < 90% were New York Heart Association class (P = 0.011), and log-NT-proBNP (P = 0.04) but not AHI.

Conclusions: In CA population, prevalence of SDB is high (90%) and dominated by the obstructive pattern. Bad prognosis in this population was driven by nocturnal desaturation, reflecting heart failure severity and respiratory involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5665/sleep.5958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909615PMC
July 2016

Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?

Eur Heart J 2016 Dec 22;37(47):3525-3531. Epub 2016 Feb 22.

UPEC, Créteil F-94000, France

Background: Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated.

Aims: To describe patients with concomitant AS and TTR-CA.

Methods: Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years.

Results: Sixteen patients were included. Mean ± SD age was 79 ± 6 years, 81% were men. Sixty per cent were NYHA III-IV, 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n = 14/16), of whom 86% (n = 12) had low-gradient AS. Mean ± SD interventricular septum thickness was 18 ± 4 mm. Mean left ventricular ejection fraction and global LS were 50 ± 13% and -7 ± 4%, respectively. Diagnosis of TTR-CA was histologically proven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n = 13), one had mutated Val122I and 19% did not had genetic test (n = 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months. Mortality was of 44% (n = 7) during the whole follow-up period.

Conclusions: Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehw033DOI Listing
December 2016

Causes and Consequences of Longitudinal LV Dysfunction Assessed by 2D Strain Echocardiography in Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2016 Feb 6;9(2):126-38. Epub 2016 Jan 6.

UPEC, Créteil, France; Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, AP-HP, Henri-Mondor Teaching Hospital, Créteil, France; INSERM U955, GRC Amyloid Research Institute, Créteil, France; DHU ATVB, Créteil, France; INSERM Clinical Investigation Center 006, Créteil, France. Electronic address:

Objectives: The aim of this study was to compare left ventricular longitudinal strain (LS) evaluated by 2-dimensional echocardiography with cardiac magnetic resonance (CMR) in cardiac amyloidosis (CA), establish correlations between histological and imaging findings, and assess the prognostic usefulness of LS measurement and CMR.

Background: CA is a condition with a poor prognosis due chiefly to 3 forms of amyloidosis: light-chain amyloidosis (AL), hereditary transthyretin (M-TTR), and wild-type transthyretin (WT-TTR). Two-dimensional echocardiography measurement of LS has been reported to detect early left ventricular systolic dysfunction. The pathophysiological underpinnings, regional distribution, and prognostic significance of LS in CA are unclear.

Methods: All patients underwent echocardiography, and 53 underwent CMR. The native hearts of the 3 patients who received heart transplants were subjected to histological examination. For each of the 17 left ventricular segments in the American Heart Association model, we evaluated LS, late gadolinium enhancement (LGE) by CMR, and cardiac amyloid deposition. Univariate and multivariate analyses were performed at 6 months to identify variables associated with major adverse cardiac events (MACE).

Results: We studied 79 patients with CA; 26 had AL, 36 M-TTR, and 17 WT-TTR. Mean LS was -10 ± 4%. Both LS and amyloid deposits showed a basal-to-apical gradient. The mean LS and number of segments with LGE were similar across the 3 CA types. LS correlated with LGE and amyloid burden (r = 0.72). LGE was seen in the 6 basal segments in all WT-TTR patients. During the median follow-up of 11 months (range 4 to 17 months), 36 (46%) patients experienced MACE. Independent predictors of MACE were apical LS (cutoff, -14.5%), N-terminal pro-B-type natriuretic peptide (cutoff, 4,000 ng/l), and New York Heart Association functional class III to IV heart failure.

Conclusions: Basal-to-apical LS abnormalities are similar across CA types and reflect the amyloid burden. Apical LS independently predicts MACE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmg.2015.05.014DOI Listing
February 2016

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

Eur Heart J 2016 06 3;37(23):1826-34. Epub 2015 Nov 3.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Aims: 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 < 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 LGE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehv583DOI Listing
June 2016

Haematological determinants of cardiac involvement in adults with sickle cell disease.

Eur Heart J 2016 Apr 29;37(14):1158-1167. Epub 2015 Oct 29.

School of Medicine, Paris-Est University (UPEC), 61 avenue du Général de Gaulle, Créteil F-94000, France.

Aims: Cardiac involvement is common in sickle cell disease (SCD). Studies are needed to establish haematological determinants of this involvement and prognostic markers. The aim of the study was to identify haematological factors associated with cardiac involvement in SCD and their impact on prognosis.

Methods And Results: This longitudinal observational study was performed on 1780 SCD patients with SS or S-β(0)-thalassemia referred to our centre. Six hundred fifty-six met our inclusion criteria (availability of a blood-workup and echocardiogram obtained <1 year apart, no heart valve surgery and no current pregnancy). Median age was 31 (interquartile range, 25-40) years, and median haemoglobin (Hb) was 87 (80-95)g/L. Left ventricular (LV) dilation, left atrial dilation, cardiac index (CI) >4 L/min/m(2), LV ejection fraction <55%, and tricuspid regurgitant velocity (TRV) ≥2.5 m/s were found in 35, 78, 23, 8.5, and 17% of patients, respectively. Compared with other patients, those in the fourth quartiles (Q4) of LV end-diastolic dimension index (LVEDDind) and left atrial dimension index (LADind) and those with high CI had significantly lower Hb, % foetal Hb (HbF), and red blood cell (RBC) counts; and significantly higher lactate dehydrogenase, bilirubin, and %dense RBCs. Independent haematologic determinants of Q4 LVEDDind and LADind were low RBC count and %HbF; high %dense RBCs were associated with LADind. Low %HbF and RBC count were associated with high CI. High %dense RBCs or no α-thalassemia gene deletion was associated with greater severity of anaemia and cardiac dilation and with higher CI. During the median follow-up of 48 (32-59) months, 50 (7.6%) patients died. Tricuspid regurgitant velocity ≥ 2.5 m/s was a predictor of mortality. The risk of death increased four-fold when left ventricular ejection fraction <55% was present also (P = 0.0001).

Conclusion: Cardiac dilation and CI elevation in patients with SCD are associated with haematologic variables reflecting haemolysis, RBC rigidity, and blood viscosity. Tricuspid regurgitant velocity ≥ 2.5 and LV dysfunction (even mild) predict mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehv555DOI Listing
April 2016

Usefulness of (99m)Tc-HMDP scintigraphy for the etiologic diagnosis and prognosis of cardiac amyloidosis.

Amyloid 2015 14;22(4):210-20. Epub 2015 Oct 14.

a UPEC , Créteil , France .

Background: Amyloidosis is characterized by extracellular deposits of insoluble proteins that cause tissue damage. The three main types are monoclonal light chain (AL), wild-type transthyretin (wt-TTR) and mutated transthyretin (m-TTR) amyloidosis. Cardiac amyloidosis (CA) raises diagnostic challenges.

Objective: To assess the diagnostic accuracy of (99m)Tc-HMDP-scintigraphy for typing CA, differentiating CA from non-amyloid left ventricle hypertrophy (LVH), and predicting outcomes.

Methods: 121 patients with suspected CA underwent (99m)Tc-HMDP-scintigraphy in addition to standard investigations.

Results: CA was diagnosed in all AL (n = 14) and wt-TTR (n = 21). Among m-TTR (n = 34), 26 had CA, 4 neuropathy without CA and 4 were asymptomatic carriers. Of the 52 patients with non-amyloid heart disease, 37 had LVH and served as controls. (99m)Tc-HMDP cardiac uptake occurred in all wt-TTR, in m-TTR with CA except two and in one AL. A visual score ≥ 2 was 100% specific for diagnosing TTR-CA. Among TTR-CA, heart-to-skull retention (HR/SR) correlated with CA severity (LVEF and NT-proBNP). Median follow-up was 111 days (50;343). In a multivariate Cox model including clinical, echocardiographic and scintigraphic variables, NYHA III-IV and HR/SR > 1.94 predicted acute heart failure and/or death.

Conclusions: This preliminary study suggests that (99m)Tc-HMDP-scintigraphy may aid differentiation between transthyretin and AL-CA as well as CA from other LVHs. (99m)Tc-HMDP-scintigraphy appears to provide prognostic information in CA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13506129.2015.1072089DOI Listing
October 2016

[18F]-NaF PET/CT imaging in cardiac amyloidosis.

J Nucl Cardiol 2016 08 24;23(4):846-9. Epub 2015 Sep 24.

UPEC, AP-HP Henri-Mondor Teaching Hospital, 94000, Créteil, France.

Cardiac amyloidosis (CA) is recognized as a common cause of restrictive cardiomyopathy and heart failure due to the deposition of insoluble proteins in the myocardial interstitium. We emphasize the role of [18F]-sodium fluoride (NaF) PET/CT as a potential noninvasive tool to identify and differentiate the transthyretin-related cardiac amyloidosis from the light-chain cardiac amyloidosis. We report cases of a 73-year-old man and a 75-year-old woman followed in our center for congestive heart failure with marked alteration of the left ventricular ejection fraction due to familial transthyretin Val122Ile cardiac amyloidosis and light-chain cardiac amyloidosis, respectively, confirmed on endomyocardial biopsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-015-0287-0DOI Listing
August 2016

Sleep-disordered breathing in chronic heart failure: development and validation of a clinical screening score.

Sleep Med 2015 Sep 30;16(9):1094-101. Epub 2015 Mar 30.

Public Health Department, APHP, Henri-Mondor Teaching Hospital, Créteil, F-94000, France; UPEC, Laboratoire d'Investigation Clinique (LIC), EA 4393, Créteil F-94000, France; INSERM Clinical Investigation Centre 006, Paris F-75000, France; Department of Clinical research and Public Health, Clinical Investigation Centre 006, Paris F-75000, France.

Aims: Sleep-disordered breathing (SDB) is highly prevalent and of adverse prognostic significance in patients with chronic heart failure (CHF). Polygraphy is used for diagnosing SDB but polygraphy resources fall short of needs. Here, our aim was to develop a score for SDB screening in patients with CHF.

Methods And Results: Consecutive patients with stable chronic CHF referred to our CHF clinic for a scheduled follow-up evaluation were included prospectively between 2000 and 2012. SDB was defined as an apnoea-hypopnoea index ≥ 5/h as assessed by routine polygraphy. A screening score was developed as a linear combination of factors independently associated with SDB by multivariate logistic regression. Calibration and discrimination were evaluated using the Hosmer-Lemeshow (HL) test and area under the receiver-operating characteristics curve (AUC), respectively. Bootstrapping was performed to assess internal validity. Of 450 included patients (mean age, 59.5 ± 13.7 years), 397 (88%) had SDB. An easy-to-use score was based on age (2 points if ≥65 years), body mass index (2 points if ≥25 kg/m(2)), New York Heart Association (NYHA) class (2 points if ≥3 or 4) and male gender (3 points). A score cut-off of 5 was 78.9% sensitive and 61.5% specific for SDB. The final model exhibited adequate calibration (pHL ≥ 0.3) and discrimination (AUC, 0.737; 95% confidence interval, 0.663; 0.810).

Conclusion: An easy-to-use clinical score combining age, body mass index, NYHA class, and gender may help to identify those CHF patients most likely to have SDB, thereby improving the allocation of scarce polygraphy resources and early diagnosis of SDB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2014.11.022DOI Listing
September 2015

(99m)Tc-HMDP scintigraphy rectifies wrong diagnosis of AL amyloidosis.

J Nucl Cardiol 2015 Aug 22;22(4):853-7. Epub 2015 May 22.

UPEC, 94000, Créteil, France,

A 71-year-old African man without history of cardiac disease was referred to our center for dyspnea. Transthoracic echocardiogram and cardiac MRI were suggestive of cardiac amyloidosis (CA). The diagnosis of the light-chain cardiac amyloidosis (AL-CA) was made after a first endomyocardial biopsy. Accordingly chemotherapy was started. Systematic 99mTc-HMDP scintigraphy showed moderate cardiac uptake (visual score of 2), unusual for AL-CA, and permitted to rectify the diagnosis. Hereditary transthyretin cardiac amyloidosis was confirmed by a second endomyocardial biopsy with a positive Congo-red and anti-transthyretin antibody stainings, mass spectrometry and genetic analysis (Val122Ile mutation).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-015-0176-6DOI Listing
August 2015

Development of a Human Model for the Study of Effects of Hypoxia, Exercise, and Sildenafil on Cardiac and Vascular Function in Chronic Heart Failure.

J Cardiovasc Pharmacol 2015 Sep;66(3):229-38

*Department of Cardiology, University of Hull, Castle Hill Hospital, Kingston upon Hull, United Kingdom; †Department of Cardiology, AP-HP Groupe, Henri-Mondor Albert-Chenevier, Créteil, France; ‡INSERM, Unité U955, Créteil, France; §Université Paris Est, Faculté de Médecine and DHU ATVB and INSERM Clinical Investigation Center 006, Créteil, France; and ¶National Heart & Lung Institute, Imperial College, London, United Kingdom.

Background: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects.

Methods And Results: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.

Conclusions: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000262DOI Listing
September 2015

Altered cross-bridge properties in skeletal muscle dystrophies.

Front Physiol 2014 14;5:393. Epub 2014 Oct 14.

UMRS 974, Institut National de la Santé et de la Recherche Médicale Paris, France ; UM 76, Université Pierre et Marie Curie, Sorbonne Universités Paris, France ; UMR 7215, Centre National de la Recherche Scientifique Paris, France ; Institut de Myologie Paris, France.

Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca(2+) through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies (MDs) have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2014.00393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196474PMC
October 2014

[Answer to the letter from Mrs Aurélie Daumas about our article "senile systemic amyloidosis: definition, diagnosis, why thinking about?"].

Presse Med 2014 Sep 2;43(9):1027-8. Epub 2014 Jul 2.

CHU Henri-Mondor, service de cardiologie, 94000 Créteil, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lpm.2014.04.013DOI Listing
September 2014

Cyclic AMP synthesis and hydrolysis in the normal and failing heart.

Pflugers Arch 2014 Jun 24;466(6):1163-75. Epub 2014 Apr 24.

INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France.

Cyclic AMP regulates a multitude of cellular responses and orchestrates a network of intracellular events. In the heart, cAMP is the main second messenger of the β-adrenergic receptor (β-AR) pathway producing positive chronotropic, inotropic, and lusitropic effects during sympathetic stimulation. Whereas short-term stimulation of β-AR/cAMP is beneficial for the heart, chronic activation of this pathway triggers pathological cardiac remodeling, which may ultimately lead to heart failure (HF). Cyclic AMP is controlled by two families of enzymes with opposite actions: adenylyl cyclases, which control cAMP production and phosphodiesterases, which control its degradation. The large number of families and isoforms of these enzymes, their different localization within the cell, and their organization in macromolecular complexes leads to a high level of compartmentation, both in space and time, of cAMP signaling in cardiac myocytes. Here, we review the expression level, molecular characteristics, functional properties, and roles of the different adenylyl cyclase and phosphodiesterase families expressed in heart muscle and the changes that occur in cardiac hypertrophy and failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00424-014-1515-1DOI Listing
June 2014

Inactivation of the Carney complex gene 1 (PRKAR1A) alters spatiotemporal regulation of cAMP and cAMP-dependent protein kinase: a study using genetically encoded FRET-based reporters.

Hum Mol Genet 2014 Mar 10;23(5):1163-74. Epub 2013 Oct 10.

INSERM U1016, Paris F-75014, France.

Carney complex (CNC) is a hereditary disease associating cardiac myxoma, spotty skin pigmentation and endocrine overactivity. CNC is caused by inactivating mutations in the PRKAR1A gene encoding PKA type I alpha regulatory subunit (RIα). Although PKA activity is enhanced in CNC, the mechanisms linking PKA dysregulation to endocrine tumorigenesis are poorly understood. In this study, we used Förster resonance energy transfer (FRET)-based sensors for cAMP and PKA activity to define the role of RIα in the spatiotemporal organization of the cAMP/PKA pathway. RIα knockdown in HEK293 cells increased basal as well as forskolin or prostaglandin E1 (PGE1)-stimulated total cellular PKA activity as reported by western blots of endogenous PKA targets and the FRET-based global PKA activity reporter, AKAR3. Using variants of AKAR3 targeted to subcellular compartments, we identified similar increases in the response to PGE1 in the cytoplasm and at the outer mitochondrial membrane. In contrast, at the plasma membrane, the response to PGE1 was decreased along with an increase in basal FRET ratio. These results were confirmed by western blot analysis of basal and PGE1-induced phosphorylation of membrane-associated vasodilator-stimulated phosphoprotein. Similar differences were observed between the cytoplasm and the plasma membrane in human adrenal cells carrying a RIα inactivating mutation. RIα inactivation also increased cAMP in the cytoplasm, at the outer mitochondrial membrane and at the plasma membrane, as reported by targeted versions of the cAMP indicator Epac1-camps. These results show that RIα inactivation leads to multiple, compartment-specific alterations of the cAMP/PKA pathway revealing new aspects of signaling dysregulation in tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddt510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919008PMC
March 2014

Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis.

Amyloid 2013 Dec 21;20(4):212-20. Epub 2013 Aug 21.

Department of cardiology .

Background: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13506129.2013.825240DOI Listing
December 2013

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

Presse Med 2013 Jun 11;42(6 Pt 1):1003-14. Epub 2013 May 11.

CHU Henri-Mondor, fédération de cardiologie, 94000 Créteil, France.

Senile 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lpm.2013.03.004DOI Listing
June 2013