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BACKGROUND: Signs of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking. OBJECTIVES: To identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR. METHODS: Analysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe). RESULTS: 425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15?mm (14, 16) (moderate) and 20?mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ?55?years of age; 81% were men; 86% had blood pressure

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.

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

Prevalence, predictors, and prognostic value of right ventricular (RV) function measured by the tricuspid annular plane systolic excursion (TAPSE) in patients with chronic heart failure (CHF) symptoms with a broad range of left ventricular ejection fraction (LVEF) are unknown.Of 1,547 patients, mean (±SD) age was 71 ± 11 years, 48% were women, median (interquartile range [IQR]) TAPSE was 18.5 (14.0-22.7) mm, mean LVEF was 47 ± 16%, 47% had LVEF ≤45% and 67% were diagnosed with CHF, defined as systolic (S-HF) if LVEF was ≤45% and as heart failure with preserved ejection fraction (HFPEF) if LVEF was45% and treated with a loop diuretic. During a median (IQR) follow-up of 63 (41-75) months, mortality was 34%. In multivariable analysis, increasing age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, right atrial volume index, and transtricuspid pressure gradient; lower TAPSE, diastolic blood pressure, and hemoglobin; and atrial fibrillation (AF) or COPD were associated with an adverse prognosis. Receiver operating characteristic curve analysis identified a TAPSE of 15.9 mm as the best prognostic threshold (P = .0001); 47% of S-HF and 20% of HFPEF had a TAPSE of15.9 mm. The main associations with a TAPSE15.9 mm were higher NT-proBNP, presence of atrial fibrillation and presence of LV systolic dysfunction.In patients with CHF, low values for TAPSE are common, especially in those with reduced LVEF. TAPSE, unlike LVEF, was an independent predictor of outcome.

La Presse Medicale - In Press.Proof corrected by the author Available online since jeudi 3 juillet 2014

Background Patients with Fabry disease (FD) show left ventricular hypertrophy (LVH) mimicking hypertrophic cardiomyopathy (HCM) of sarcomeric origin and might benefit, if detected early, from specific enzyme replacement therapy. The prevalence of FD in patients with LVH of 13 mm or greater, screened using the leucocyte alpha-galactosidase A (a-gal A) activity test, a technique that is difficult to apply routinely, ranged from 0% to 6%. Objective To screen systematically for FD in patients with a diagnosis of HCM (LVH $15 mm) in primary cardiology practice, a validated, physician-friendly a-gal A assay was used on dried blood spots using a filter paper test. Design and patients A cohort of 392 adults (278 men) followed for HCM were screened for FD. A standard blood test was used for confirmation in nine men in whom the a-gal A result was 40% or less. Results Four men (1.5%; 1.8% of men $40 years vs 0%

The epidemiology of pulmonary arterial hypertension (PAH) in patients with heart failure (HF) is poorly described. Our aim was to investigate the determinants and prognostic significance of PAH in a large representative outpatient population with HF.Routine measurement of right ventricular tricuspid pressure gradient (RVTG) was attempted among unselected, consecutive referrals to an HF clinic. The diagnosis of HF was based on symptoms, signs, echocardiography, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Of 2100 patients referred, 1380 were diagnosed as HF, of whom 1026 had left ventricular systolic dysfunction (LVSD) and 354 did not. Right ventricular tricuspid pressure gradient could be measured in 270 (26%) patients with and 143 (40%) without LVSD. The highest RVTG quartile [RVTG35 mmHg equivalent to an estimated PA systolic pressure (PASP)45 mmHg] constituted 7% of all those with HF and was associated with higher LV filling pressures, LV end-diastolic volume, LVSD, and more severe mitral regurgitation (MR). During a median (inter-quartile range) follow-up of 66 (56-74) months, mortality was 40.3%. Mortality was similar in the lowest quartile of RVTG and in those in whom RVTG could not be measured and rose with increasing RVTG quartile (log-rank: 26.9; P0.0001). The highest RVTG quartile, age, blood pressure, and log NT-proBNP independently predicted mortality. Right ventricular tricuspid pressure gradient35 mmHg had a 96% specificity to discriminate between those with and without HF in patients without LVSD.Using a definition of PASP45 mmHg, 7% of the patients with HF have PAH, which is associated with worse LV function, MR, and prognosis. Whether PAH is a target for therapy in this population remains to be elucidated.

[Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4][![Graphic][5] ][5] A 28-year-old woman, who had malignant teratoma treated by chemotherapy v(cisplatin, anthracycline, and vincristine) at 2 years of age, was referred for heart transplantation (HT). She had clinical signs

Sleep-disordered breathing (SDB) is associated with left ventricle (LV) remodelling in patients with normal LV function. Sleep-disordered breathing is common in chronic heart failure (CHF) with systolic LV dysfunction, and may contribute to LV remodelling and CHF progression. Our aim was to determine the consequence of SDB on LV geometry in patients with CHF. We hypothesised that SDB severity was correlated with the degree of LV hypertrophy (LVH). One-hundred and sixty patients with CHF with a non-ischaemic systolic LV dysfunction were assessed by overnight polygraphy and echocardiography. Patients were classified in four groups according to their apnoea-hypopnoea index (AHI):5 (no-SDB); 5-14 (mild); 15-29 (moderate); ≥30 (severe). Left ventricular mass index (LVM Ind) was calculated using the usual echocardiographic M-Mode parameters. Their mean age, New York Heart Association and left ventricular ejection fraction were, respectively: 56 ± 13 years, 2.4 ± 0.8 and 30 ± 10%, and 77% were men. Body mass index, interventricular septal and posterior LV wall thicknesses, and LVM Ind were significantly increased in severe SDB versus no-SDB. LVM Ind was correlated to the AHI (R = 0.27, P = 0.0006) and, using logistic regression, AHI was the unique independent factor of LVH in this population. In non-ischaemic CHF, SDB severity is associated with LV remodelling.

International audience; Frequency domain analysis of heart rate variation has been suggested as an effective screening tool for sleep-disordered breathing (SDB) in the general population. The aim of this study was to assess this method in patients with chronic congestive heart failure (CHF). We included prospectively 84 patients with stable CHF, left ventricular ejection fraction (LVEF) or =15 h(-1) was diagnosed in 57.4% of patients. Percent VLFI was not correlated with AHI (r = 0.12). Receiver-operating characteristic curves constructed using various AHI cut-offs (5-30 h(-1)) failed to identify a %VLFI cut-off associated with SDB. The 2.4% VLFI cut-off recommended for the general population of patients with suspected SDB had low specificity (35%) and low positive and negative predictive values (35% and 54%, respectively). Heart rate increment analysis has several limitations in CHF patients and cannot be recommended as an SDB screening tool in the CHF population.

IntroductionLatest generation continuous flow left ventricular assist devices (LVADs) have been proposed as an alternative to heart transplantation for end-stage heart failure. However, postoperative right ventricle (RV) dysfunction remains common and has a negative impact on prognosis. Purpose of our study was to identify echocardiographic or hemodynamic parameters that could predict early RV failure after LVAD implantation in patients with biventricular dysfunction.MethodsFourteen patients with biventricular dysfunction who have been evaluated for LVAD implantation were included. Right and left ventricular dysfunction were respectively defined as: tricuspid annular plane excursion < 16 mm (TAPSE) and LV ejection fraction < 35%. In all patients, preoperative measurements were obtained at rest. In 7 patients, right heart catheterization was performed simultaneously with increasing doses of dobutamine (15γ/Kg/min). Primary endpoint was death caused by right ventricle systolic dysfunction or need for right ventricle mechanical support within 30 days after surgery (RVSD+).ResultsMean recipient age was 58±7 years. Primary end-point (RVSD+) was noted in five patients. Preoperative demographic, echocardiographic and hemodynamic data were similar between RVSD+ and RVSD- patients (Table). Percent increase of TAPSE and systolic PAP between basal and high dobutamine dose was significantly lower in RVSD+ than in RVSD- patients.ConclusionPercent increase of TAPSE and systolic PAP induced by high dose dobutamine infusion might be two interesting criteria to assess RV contractile reserve and predict RV outcome after LVAD implantation in patient with biventricular dysfunction.Baseline Measurement (n=14)Change after Dobutamine infusion,% (n=7)RVSD-RVSD+pRVSD-RVSD+pN95TAPSE, mm14±214±20.955±526±20.03Systolic PAP, mmHg51±753±60.842±84±70.05Cardiac Output, l/min3.3±0.53.5±0.50.987±1093±470.7Pulm Vasc Res, Wood3.9±14.3±10.62±41-36±70.8

International audience; AIMS: Heart failure (HF) has a poor prognosis. Several right ventricular (RV) echocardiographic parameters have been proposed as sensitive markers to detect patients at risk. Our objective was to compare the predictive value of four RV systolic echocardiographic parameters for outcomes in patients with HF. METHODS AND RESULTS: One hundred and thirty-six patients with stable HF and a left ventricular ejection fraction

Pulmonary Hypertension (PAH) is frequent in patient with advanced Heart Failure (HF). One of the underlying mechanisms of this pathogenic pathway could be a reduced ability of the arteriolar vascular smooth muscle to relax. The cGMP plays an important in the regulation of pulmonary vascular tone and its clearance is dependant of phosphodiesterase 5 (PDE 5). The aim of this study was to investigate whether or not the PDE 5 G(-1142)T genotype was associated with PAH and could affect the NO-inhaled response in HF. Methods HF patients underwent VO2, echocardiography 24h before the right side cardiac catheterization. Hemodynamic parameters, cGMP plasma level (n=12) were made after Air and 20ppm NO gas breathing. The PCR-restriction fragment length polymorphism method was used to determine the PDE5 G/T gene. Subjects: We included 72 HF patients. Most of the patients had a ischemic cardiomyopathy (54 %). The mean LVEF was 29±1 and age was 53±1. The mean pulmonary artery pressure was 25.5±1.3mmHg. The genotype TT, GT, GG and G(-1142) allele frequency distribution was respectively 38.9 %, 41.7 %, 19.4 % and 40.3 %. Results Baseline characteristics were similar between the three genotypes except for the cGMP which was significantly decrease in TT genotype versus GG-GT group (p=0.02) Furthermore the pulmonary capillary wedge pressure (PCWP) trend to decrease in TT genotype (p=0.09). These results suggested that PDE 5 activity is increase in patient with TT genotype and may increase the pulmonary artery tone. NO-inhaled PVR was significantly different between the three subgroups (Anova for repeated measures: p=0.002) and was more important in the TT group with a decrease of PVR of 33 % versus 1.6 % in GG and 0 % in GT subgroups. The PVR decrease is explained by a superior increase in PCWP in TT genotype after NO inhalation. Our hypothesis is that the greatest NO-inhaled response in TT genotype is due to a greater degree of pulmonary vasoconstriction tone at baseline. Conclusion We first demonstrate that G(-1142) polymorphism of PDE 5 is functional and may regulate the basal pulmonary artery tone at baseline and increase the NO-inhaled response in Heart Failure.

Summary Background Heart failure with systolic dysfunction occurs frequently. Studies in North America and Germany have shown a high prevalence of sleep-disordered breathing in patients with heart failure. Aims To assess the prevalence of sleep-disordered breathing and its associated risk factors in French patients with heart failure. Methods A total of 316 patients with stable heart failure and a left ventricular ejection fraction less or equal to 45% underwent polygraphy prospectively to diagnose sleep apnoea syndrome, defined as an apnoea-hypopnoea index greater or equal to 10 events/h. Results Mean age, left ventricular ejection fraction, and body mass index were 59 ± 13 years, 30 ± 11% and 28 ± 6 kg/m2, respectively. The prevalence of sleep breathing disorder was 81% (n = 256); 30% of syndromes were classified as central and 70% as obstructive. The mean apnoea-hypopnoea index was high (30 ± 3 events/h) and a large proportion (41%) of syndromes had an apnoea-hypopnoea index greater or equal to 30 events/h. A central sleep apnoea syndrome pattern was associated with more severe heart failure and a more elevated apnoea-hypopnoea index than an obstructive pattern. The prevalence of sleep-disordered breathing was lower in women than in men (64% versus 85%; χ2 = 0.0003) as was its severity (mean apnoea-hypopnoea index 15 ± 13 events/h versus 27 ± 19 events/h, p = 0.0001). Conclusion The prevalence of sleep-disordered breathing was high in a French heart failure population, with most syndromes having an obstructive pattern. Prevalence and severity were higher in men than in women.

International audience; BACKGROUND: The tripeptide glutathione (L-gamma-glutamyl-cysteinyl-glycine) is essential to cell survival, and deficiency in cardiac and systemic glutathione relates to heart failure progression and cardiac remodelling in animal models. Accordingly, we investigated cardiac and blood glutathione levels in patients of different functional classes and with different structural heart diseases. METHODS: Glutathione was measured using standard enzymatic recycling method in venous blood samples obtained from 91 individuals, including 15 healthy volunteers and 76 patients of New York Heart Association (NYHA) functional class I to IV, undergoing cardiac surgery for coronary artery disease, aortic stenosis or terminal cardiomyopathy. Glutathione was also quantified in right atrial appendages obtained at the time of surgery. RESULTS: In atrial tissue, glutathione was severely depleted (-58%) in NYHA class IV patients compared to NYHA class I patients (P = 0.002). In patients with coronary artery disease, this depletion was related to the severity of left ventricular dysfunction (P = 0.006). Compared to healthy controls, blood glutathione was decreased by 21% in NYHA class I patients with structural cardiac disease (P

Estrogens [E(2)] exert direct and indirect effects that can modulate the development of cardiac disease. However, the precise mechanisms that are involved remain undefined. Our objective was to investigate whether E(2) affected the activity and expression of constitutive nitric oxide synthase (NOS) isoforms (NOS3 and NOS1) in cardiac hypertrophy induced by thoracic aortic constriction (TAC). Ovariectomized (Ovx) and nonovariectomized Wistar rats were subjected to TAC. Ovx animals received E(2) or placebo 3 wk after surgery for 11 wk. Afterward cardiac function and degree of left ventricular hypertrophy were assessed by echocardiography. NOS activity and expression were studied by biochemical techniques. TAC led to significant left ventricular hypertrophy (>90%) irrespective of hormonal status. Cardiac performance declined more in TAC+Ovx (−20%, P < 0.015) than in the two other TAC groups [TAC and TAC+Ovx+E(2)]. Total NOS activity decreased significantly in the Ovx groups. In response to TAC, total NOS activity increased whatever the E(2) status. Specific NOS3 activity dramatically decreased in the Ovx groups (−55%, P < 0.009) and was unaltered by TAC. By using coimmunoprecipitation assays, we showed that NOS3/caveolin-1 complexes negatively regulated NOS3 activity as a function of E(2) status. On the other hand, NOS1 expression and activity were markedly increased in hypertrophied myocardium (P < 0.003), irrespective of E(2) status. This study demonstrates a differential regulation of NOS expression and activity in response to pressure overload and E(2) status, the former being mainly involved in the induction of NOS1, whereas the latter regulated NOS3 activity and in turn cardiac function.

Deficiency in cellular thiol tripeptide glutathione (l-gamma glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle.

This study was designed to determine the effects of PPARα lack on cardiac mechanical performance and to identify potential intracellular mechanisms linking PPARα pathway deficiency to cardiac contractile dysfunction. Echocardiography, ex vivo papillary muscle assays, and in vitro motility assays were used to assess global, intrinsic ventricular muscle performance and myosin mechanical properties, respectively, in PPARα−/−and age-matched wild-type mice. Three-nitrotyrosine formation and 4-hydroxy-2-nonenal protein-adducts, both markers of oxidative damage, were analyzed by Western blot analysis and immunolabeling. Radical scavenging capacity was analyzed by measuring protein levels and/or activities of the main antioxidant enzymes, including catalase, glutathione peroxidase, and manganese and copper-zinc superoxide dismutases. Echocardiographic left ventricular fractional shortening in PPARα−/−was 16% lower than that in wild-type. Ex vivo left ventricular papillary muscle exhibited reduced shortening velocity and isometric tension (three- and twofold, respectively). In vitro myosin-based velocity was ≈20% slower in PPARα−/−, indicating that myosin itself was involved in the contractile dysfunction. Staining of 3-nitrotyrosine was more pronounced in PPARα−/−, and myosin heavy chain was the main nitrated protein. Formation of 3-nitrotyrosine myosin heavy chain was twofold higher in PPARα−/−and 4-hydroxy-2-nonenal protein-adducts were threefold higher. The expression and activity of manganese superoxide dismutase were respectively 33% and 50% lower in PPARα−/−, with no changes in copper-zinc superoxide dismutase, catalase, or glutathione peroxidase. These findings demonstrate that PPARα pathway deficiency impairs cardiac function and also identify oxidative damage to myosin as a link between PPARα deficiency and contractile dysfunction.

Background Cardiac amyloidosis (CA) is a condition of poor prognosis. The three major forms of amyloidosis are light chain (AL), hereditary transthyretin (M-TTR), and wildtype transthyretin (WT-TTR). Two-dimensional (2D) echocardiography measurement of longitudinal strain (LS) has been reported to be useful in the diagnosis of CA. Regional distribution of LS in CA and its diagnostic value in detecting early left-ventricular systolic dysfunction is unclear.

Background Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of either immunoglobulin light-chain (AL) or transthyretin (ATTR) fibrils. Two forms of ATTR CA cause life-threatening cardiomyopathy: an inherited form arising from misfolding of mutated ATTR (familial amyloid cardiomyopathy [FAC]) and a sporadic form caused by wild-type ATTR (senile systemic amyloidosis [SSA]). More than half of over 100 reported ATTR mutations are associated with FAC. The most common mutation in the US is Val122Ile found in 3-4% of African Americans (AA). FAC can be difficult to recognize clinically and is likely under diagnosed. The DISCOVERY study aims to determine the prevalence of TTR mutations and FAC diagnosis in a cohort of patients (pts) with clinical features suggestive of CA.

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. 99mTc-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.

Background Cardiac involvement in systemic light-chain amyloidosis (AL) is characterized by slightly decreased systolic left ventricular function (LV) function and typically a diastolic dysfunction including left atrial (LA) enlargement. Cardiac magnetic resonance (CMR) is often performed in AL to accurately assess chambers size and function. We aimed to compare features of LV systolic and diastolic function obtained by 2D transthoracic echocardiography (TTE), with morphological and functional myocardial LV (presence of late gadolinium enhancement: LGE) and LA (volume and emptying fraction) parameters as assessed by CMR in a consecutive series of patients with cardiac AL.

Background Transthyretin (TTR) familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant neurodegenerative disease characterized by deposition of transthyretin targeting mainly the peripheral nervous system and the heart. Early noninvasive detection of cardiac impairment is of importance for the therapeutic management. Aim Assess if natriuretic peptide (NT-proBNP) or troponin T (cTnT) are reliable biomarkers to predict echocardiographic left ventricle (LV) impairment in a wide variety of TTR patients. Methods 36 asymptomatic carriers and patients with proven FAP genetic mutation had clinical, biological and echocardiography assessment of left ventricle (LV) systolic function (SD), filling pressure (FP) and hypertrophy (LVH) as marker of amyloid deposition Results In the all cohort, the median (IQR) age, NT-proBNP, LV ejection fraction were respectively 59 (41-74), 323pg/ml (58-1960) and 60% (51-66). 64% were men and 12 had an increased in cTnT. TTR gene mutations prevalence was 50% for Val30Met. 4 patients were asymptomatic, 6 had only neurologic clinical signs and 26 had echo-LV abnormalities with or without neurologic disorders. Their median NT-proBNP value were respectively: 33 (19-50), 54 (37-154) and 747 (253;2840). Using received-operator curve, NTproBNP identified significantly patients with echo-LV abnormalities (Area: 0.92;(0.83-0.99), p=0.001) with a threshold above 82pg/ml and a sensitivity of 92% and specificity of 90%. Elevated cTnT (superior to 0.01ng/ml) was only observed in patients combining impairment of LVH and SD or LVH, SD and FP. Conclusion In TTR amyloidosis, NTproBNP and troponin T are associated with LV impairment measured by echocardiography suggesting that NTproBNP could be useful in FAP carriers to start echocardiographic follow-up whereas troponin would identify patients with severe cardiac disease.

Background— An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined. Methods and Results— Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats ( P P es ) was significantly reduced in HF rats ( P P es by 33±3% and τ by 17±2% ( P es increased by 163±42% ( P P P es to β-adrenergic stimulation in HF rats but had no effect in shams. Conclusions— These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.

Experimental data suggest that nitric oxide (NO) generated from neuronal NO synthase (nNOS) modulates the myocardial inotropic state. To assess the contribution of NO, derived from endothelial and neuronal isoforms, to the pathophysiology of congestive heart failure in human beings, we compared expression, localisation, and specific activity of NOS isoforms in myocardium from patients with dilated cardiomyopathy with those in controls who had died from head trauma or intracranial bleeds. Diseased hearts had a significant increase in nNOS mRNA and protein expression, and activity associated with the translocation of nNOS to the sarcolemma through interactions with caveolin 3. Enhanced nNOS activity counteracted a decrease in eNOS expression and activity. Our results provide evidence of increased nNOS-derived NO in the failing human heart. Such altered regulation may be important in the pathophysiology of cardiac dysfunction in human congestive heart failure.

International audience; OBJECTIVE: Caveolins, the structural proteins of caveolae, modulate numerous signaling pathways including Nitric Oxide (NO) production. Among the caveolin family, caveolin-1 and -3 are mainly expressed in endothelial and muscle cells, respectively. In this study, we investigate whether (i) changes in caveolin abundance and/or distribution occur during cardiac aging and failure in rat, and (ii) the process could influence NO synthase (NOS) activity. METHODS: Using immunohistolabelling and Western blot approaches, expression and distribution of caveolins were analysed in adult (Ad), senescent (S-Sh) and myocardial infarction-induced failing (S-MI) hearts. NOS3/caveolin-1 interactions were evaluated by immunoprecipitation assays. RESULTS: At the microscope level, caveolin-1 distribution in the endothelial cells was unchanged between the groups. Conversely the typical distribution of caveolin-3 in myocyte sarcolemma was dramatically altered in S-MI rats, resulting in a heterogeneous pattern throughout the septum. Total abundance of caveolin-1 and -3 remained stable whatever the group. In the fractions free of caveolae (Triton X-100 soluble), the levels of caveolin-1 alpha and -3 increased with aging (+20%, and +104%, P

BackgroundPulmonary hypertension (PH) is common in patients with heart failure (HF) but, its relationship to symptoms and prognosis in a broad representative population of patients with HF has rarely been investigated.MethodsWe interrogated a large database of consecutive referral to a HF clinic serving a population of 600,000 people. Systolic HF (S-HF) was defined as a LVEF≤45% and Preserved systolic LV HF (PS-HF) was defined as LVEF >45% with an NT-proBNP value >400pg/mL. Right Ventricle Systolic Pressure (RVSP) was assessed by the measurement of the tricuspid regurgitation (TR) peak systolic velocity.ResultsOf 2135 patients referred, 1026 had S-HF, 354 had PS-HF and 533 had an accurate TR velocity measurement. Median (IQR) calculated RVSP for HF patients was 25 (18-35mmHg). Amongst these patients, 270 had S-HF and 143 had PS-HF. Mean age, prevalence of ischaemic heart disease and arrhythmia were 74+/-10, 52% and 44%. The maximal follow up was 88 months and the median follow up was 65 months. Amongst 1,380 patients with HF, the 413 with RVSP measurement had a worse prognosis than those who did not (log Rank=0.0001). Patients in the lowest quartile of RVSP (

Background: In patients with cardiac symptoms, echocardiography is the first examination to be performed where interventricular septal thickness (IVST) is measured. Transthyretin amyloidosis (TTR) is one of the causes leading to increase in IVST due to amyloid cardiac infiltration. Two different forms of TTR are known: hereditary transthyretin amyloids (TTR-FAP) and wild type (TTR-WT). Cardiologists are under informed of clinical and echocardiographic signs associated with TTR amyloidosis. Aim: Define the clinical and echocardiographic characteristics associated with increased IVST due to TTR amyloidosis to raise cardiologist's awareness of TTR related amyloidosis. Methods: We analyzed the baseline characteristics of 363 patients with echocardiographic-IVST measurement included in the global multicenter observational Transthyretin Amyloidosis Outcomes Survey (THAOS), representing 24% of the 1488 patients included. Patients were divided in four classes (normal, mild, moderated and severe) of IVST according to the American Society of Echocardiography adapted to gender. Results: Increase in IVST was frequent (≥moderate in 57%), correlated to age (R=0.35) and was more frequent in male. IVST was normal in 71 patients, of whom most had TTR-FAP Val30Met mutation (77%). Their median[IQR] age was 37yrs[33,53]. 86 had mild abnormal IVST (11mm [10,12]) with a median[IQR] age of 47yrs[38,63] of whom 1% were TTR-WT. Moderate increase in IVST (15mm[14,16]) was observed in 64 patients, their median age was 67yrs[57,76] and 73% were male and 38% were TTR-WT. 31% had symptomatic motor neuropathy,64% sensory neuropathy and 53% autonomic neuropathy. Systolic blood pressure, ejection fraction and cardiac out-put were normal as well as the E/A ratio. Of the 142 patients with severely abnormal IVST (20mm[18,22]), the median age was 70yrs[61,75], 85% were male, 30% were TTR-WT. 44% of these patients had symptomatic motor neuropathy, 54% a sensory neuropathy and 56% autonomic neuropathy. Systolic blood pressure was normal: 112mmHg[100,130]. Ejection fraction and cardiac out-put were 44%[35-60] and 4.1L/min[3.8,5.4]. Increased in Right ventricle free wall thickness and prevalence of aortic and mitral thickening were more important in moderated and severe IVST class than in mild and normal (each with overall p

Differences in transthyretin amyloidosis between the United States and the rest of the world : a report from the Transthyretin Amyloid Outcome Survey (THAOS)

IntroductionIvabradine is a selective heart-rate-lowering agent that acts on the sinoatrial node without influence on myocardial contractility and cardiac output. Physiological effects of ivabradine during dobutamine infusion have never been studied.MethodsThe study included 11 healthy subjects (82% men, aged 29.1± 4.7 years). All underwent dobutamine transthoracic echocardiography before and after ivabradine (3 hours after 5mg of ivabradine). Baseline left ventricular longitudinal global strain by speckle tracking and stroke volume at rest and during low dose of dobutamine (when heart rate increased by more than 10 points from baseline) were compared to those obtained under ivabradine.ResultsBaseline heart rate (64±8bpm) decreased in 7 subjects (68±7bpm vs. 60±6bpm, P=0.009) but paradoxically increased in 3. Dobutamine rate required to increase the heart rate by 10 points was similar with and without ivabradine (11±2γ/kg/min vs. 12±3 γ/kg/min, P=0.4). Overall, global strain increased under low dose dobutamine before (−20±2% vs. −23±2%, P=0.008) and after ivabradine (−21±2% vs. −23±3%, P< 0.001). Interestingly, in the 7 subjects that responded to ivabradine, global strain (−23±2% vs. −25±1%, P=0.006) and stroke volume (102±17ml vs. 110±20ml, P=0.05) more increased under dobutamine with ivabradine.ConclusionIn healthy subjects, heart rate reduction obtained by ivabradine allows to increase myocardial contractility and stroke volume for a similar rate of dobutamine. This propriety may be useful in decompensate heart failure patients with rapid tachycardia induced by catecholamine infusion.

Background Cardiac resynchronization therapy (CRT) prolongs survival in appropriately selected patients with heart failure. Right ventricular (RV) dysfunction is associated with a worse prognosis in this setting but it is not clear whether it influences the clinical response to CRT. Method and Results Of 813 patients enrolled in the Cardiac Resynchronization-Heart Failure (CARE-HF) study, 688 had tricuspid plane systolic excursion (TAPSE) measured at baseline and 345 of these were assigned to CRT. Their median (IQR) age was 66 (58-71) years, left ventricular (LV) ejection fraction was 24 (21-28)% and TAPSE was 19 (16-22)mm. Baseline LV function and size and QRS duration were similar amongst TAPSE tertiles but those in the worst tertile (TAPSE Conclusion RV dysfunction is a powerful determinant of prognosis amongst candidates for CRT, regardless of treatment assigned: CRT improved prognostic in patients with RV dysfunction despite less improvement in LV remodelling.

ObjectiveDefine the prognosis value of the congestive clinical signs of heart failure (CHF) in an out-patient clinic compared to other clinical variables.BackgroundClinical examination is non-specific to diagnose CHF. However the prognosis value of the clinic signs of CHF is unknow.MethodsAnalysis of referrals to a community clinic of suspected chronic heart failure with a clinical examination. Clinical signs of CHF were defined as no sign, fluid retention (FR; oedema, ascitis, hepatomegaly, jugular vein distension), lung crackles (LC) and their combination (FR+LC). Systolic heart failure was defined as LVEF50pmol.l−1 (HeFNEF), others were defined as No-HF.ResultsOf 1881 patients referred, 853 patients had S-HF, 321 had HeFNEF and 707 No-HF. Their median (IQR) age was 72yrs (64–78), LVEF was 47% (35–59) and 40% were women. 1207 patients had no clinical signs of CHF of whom 41% were SHF and 16% HeFNEF, 85 had LC of whom 43% were S-HF and 20% HeFNEF, 417 had FR of whom 49% had S-HF and 21% HeFNEF and 172 had LC+Frof whom 43% had S-HF and 16% HeFNEF. Patients with LC+RF were more breathless, had more frequently an ischaemic heart disease and had a lower ejection fraction and a lower right ventricle function measured by the tricupsid annular plane systolic excursion. During a median (IQR) follow up of 64 (44–76) months, mortality was 40%. In multivariable analysis, increasing age, NYHA class, heart rate, LC+FR, FR, ischaemic heart disease and chronic obstructive pulmonary disease predicted an adverse prognosis; increasing diastolic blood pressure and female sex predicted a better outcome. Using Kaplan Meier curves, LC and FR indicated a similar bad prognosis, LC+FR indicated the worse prognosis when all the patients were considered (log Rank=185, p

ObjectiveTo assess and compare cognitive levels and profiles of five cognitive functions according to hypertensive and heart failure status.Methods111 hypertensive patients (24h-Ambulatory Blood Pressure Monitoring: day-systolic BP >135mmHg, day-diastolic BP >85mmHg, night-systolic BP > 120mmHg or night-diastolic BP > 70mmHg), 56 normotensive patients and 51 stable heart failure patients (Left Ventricular Ejection Fraction 21) or recent stroke, underwent a computerized cognitive test: the CogRT-Kit. This new neuropsychological test evaluates globally and specifically 5 cognitive functions (visuospatial abilities, language, executive functions, recent and delayed memory) with the same paradigm. Therefore this test enhances comparison between functions to determine a cognitive profile. Comparison between function in profile used the Student t-test.ResultsHeart failure was significantly associated with global cognition (β=−0.65, p=0.04, R2=0.27), language, (β=−0.56, p=0.002, R2=0.26) executive functions (β=−0.96, p=0.007, R2=0.34) recent (β=−0.75, p