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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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

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

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., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

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.

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 -1 (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.

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.

Obstructive sleep apnoea syndrome (OSAS) is a frequent sleep disorder that is known to be an independent risk factor for arterial hypertension (AHT). Potential confounding factors associated with both OSAS and AHT, such as age, diabetes mellitus and obesity, have been explored extensively, and are considered as independent but additive factors. However, these factors are also contributors to left ventricular (LV) hypertrophy (LVH) and LV diastolic dysfunction, both of which are important causes of cardiovascular morbidity, and have been reported to be associated with OSAS for decades. In this review, we present an overview of how OSAS may promote changes in LV geometry and diastolic dysfunction through its best-known cardiovascular complication, arterial hypertension. We also summarize the epidemiological links between OSAS and LVH, outline diastolic dysfunction in OSAS patients, and try to highlight the mechanisms responsible, focusing on the effect of confounding factors., (Copyright © 2016. Published by Elsevier Masson SAS.)

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., (© 2016 Associated Professional Sleep Societies, LLC.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

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., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sleep disordered breathing (SDB) is common in patients with heart failure with reduced ejection fraction (HFrEF). An increased apnea-hypopnea index (AHI) is associated with poor outcomes. We examined whether an analysis of nocturnal desaturations (NDs) can improve the risk stratification., Methods: Three-hundred seventy-six consecutive patients with stable chronic HFrEF and LVEF ≤ 45% were prospectively screened using polygraphy. Sleep apnea (SA) was defined as an AHI ≥ 15. The mean age was 59 ± 13 years, the mean LVEF was 30 ± 6%, and the median AHI was 18 [IQR: 9.33). The composite end-point of death, heart transplantation or LV assistance occurred in 98 patients (26%) within 3 years. Minimal oxygen saturation (MOS) during sleep, the number of desaturations <90%/h and the time spent with oxygen saturation <90% were significantly associated with adverse events (adjusted HR 1.25 [1.03-1.52], 1.25 [1.03-1.53], and 1.28 [1.04-1.59]), whereas the AHI was not (1.10 [0.86-1.39]). The best MOS cut-off value for poor outcomes was ≤ 88%. The patients with an MOS ≤ 88% had a significantly higher event rate (31.9%) than those with an MOS >88% (15.6%; p<0.01). The risk assessment using an MOS of ≤ 88% in addition to established prognostic markers yielded a net reclassification index (NRI) of nearly 6% and was particularly useful in the subgroup of patients with events (NRI: 8.4%)., Conclusions: In HFrEF patients, ND ≤ 88% appears to be predictive of adverse events, independent of the presence of SA. This suggests that the risk assessment in HFrEF should also include ND in top of AHI., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The association between obstructive sleep apnoea syndrome (OSAS), left ventricular (LV) diastolic dysfunction and LV geometry remains controversial because of coexisting disorders., Aims: To evaluate LV diastolic dysfunction and its independent predictors in a real-life cohort of OSAS patients, by a standardized approach., Methods: We consecutively included 188 OSAS patients after an overnight polysomnography to undergo clinical evaluation, ambulatory blood pressure measurement and complete echocardiography, combining M-mode, two-dimensional Doppler and tissue Doppler imaging modes. Correlations between OSAS severity and clinical and echocardiographical variables were assessed, and logistic regression models were used to identify possible determining factors of LV diastolic dysfunction., Results: Most patients were hypertensive (n=148, 78.7%) and already receiving treatment by continuous positive airway pressure (n=158, 84.5%). The prevalence of LV hypertrophy, defined by LV mass index (LVMi) normalized by height (2.7), was 12.4%, with a significant correlation with hypertension (P=0.004). The apnoea-hypopnoea index was correlated with body mass index (P<0.0001), 24-hour systolic blood pressure (P=0.01) and LVMi normalized by height (2.7) (P=0.03). Diastolic function assessed by a global approach was impaired for 70 patients (37.2%) and none of the OSAS severity variables was a determining factor after multivariable analysis with adjustment for age and sex., Conclusion: Diastolic dysfunction assessed by a standardized approach is common in OSAS and should be routinely evaluated; it is independently predicted by none of the respiratory severity variables., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2013. Published by Elsevier Masson SAS.)