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

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.

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

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.

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

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-ß(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.

Apnea-hypopnea and desaturations in heart failure with reduced ejection fraction: Are we aiming at the right target?

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.

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

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.

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

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.

Noninvasive detection of cardiac amyloidosis using delayed enhanced MDCT: a pilot study.

OBJECTIVES: To evaluate myocardial enhancement of patients with cardiac amyloidosis (CA) using computed tomography (CT). METHODS: Thirteen patients with CA and 11 control patients were examined with first-pass and delayed CT acquisition. A qualitative and quantitative analysis of images was performed. Myocardial attenuation, myocardial signal-to-noise ratio (SNRmyoc), blood pool SNR (SNRblood), contrast-to-noise ratio between blood pool and myocardium (CNRblood-myoc) and relative attenuation index (RAI) defined as variation of myocardial attenuation between delayed and first-pass acquisitions were calculated. RESULTS: Two false negative cases (15 %) and three false positive cases (27 %) were detected on qualitative analysis. SNRmyoc of patients with CA was significantly (p < 0.05) lower on first-pass (4.08 ± 1.9) and higher on delayed acquisition (7.10 ± 2.7) than control patients (6.1 ± 2.2 and 5.03 ± 1.8, respectively). Myocardial attenuation was higher in CA (121 ± 39 HU) than control patients (81 ± 17 HU) on delayed acquisition. CNRblood-myoc was significantly (p < 0.05) lower in CA (1.51 ± 0.7) than control patients (2.85 ± 1.2) on delayed acquisition. The RAI was significantly (p < 0.05) higher in CA (0.12 ± 0.25) than in control patients (-0.56 ± 0.21). CONCLUSION: Dual phase MDCT can detect abnormal myocardial enhancement in patients with CA. KEY POINTS: • CT can detect abnormal first-pass and delayed enhancement in cardiac amyloidosis. • Measurement of relative myocardial enhancement between acquisitions helps to detect cardiac amyloidosis. • CT may provide useful data to diagnose cardiac amyloidosis.

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

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.

[Senile systemic amyloidosis: definition, diagnosis, why thinking about?]. / Amylose systémique sénile : définition, diagnostic, pourquoi y penser ?

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.

Prognostic impact of sleep-disordered breathing and its treatment with nocturnal ventilation for chronic heart failure.

AIMS: To determine whether severity patterns or nocturnal ventilation to treat sleep-disordered breathing (SDB) during chronic heart failure (CHF) is associated with adverse outcomes. Although SDB is frequent during CHF, the relationships between SDB and CHF outcomes are unknown. METHODS AND RESULTS: A total of 384 CHF patients (82% men, mean age 59 ± 13 years) with a left ventricular ejection fraction (LVEF) of ≤45% (mean LVEF 29 ± 9%) were assessed by polygraphy in our clinic between 2001 and 2009. Nocturnal ventilation was started according to the severity of SDB. Combined endpoints were death, heart transplant, and implant of a ventricular assist device. The prevalence of obstructive sleep apnoea (OSA), central sleep apnoea (CSA), and Cheyne-Stokes respiration (CSR) was 62, 26, and 29%, respectively. A primary endpoint occurred in 31%. Mean follow-up for survivors was 47 ± 25 months. Those with moderate [apnoea-hypopnoea index (AHI) ≤5-20/h] and severe SDB (AHI ≥20/h), and OSA and CSA, had poor prognoses compared with patients without SDB (P = 0.036, P = 0.003, respectively). A total of 31% of SDB patients were treated with nocturnal ventilation. Treated SDB had a better outcome than untreated severe SDB after adjustment for confounding factors [P = 0.031; hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.33-0.95]. Subgroup analysis that included only OSA showed a similar result after adjustment (P = 0.017; HR 0.40; 95% CI 0.19-0.95). CONCLUSIONS: In CHF, SDB is associated with a poor prognosis whatever the SDB pattern, and nocturnal ventilation is associated with a better outcome.

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

BACKGROUND: 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.