Ventricular Fractional Shortening Research Articles

0053 : Short-term moderate diet restriction in adulthood can reverse alterations of cardiac function induced by postnatal overfeeding in mice

Postnatal overfeeding (OF) in rodents induces early programming of cardio-metabolic risk: permanent moderate increase in body weight, metabolic disorders and progressive alterations of cardiac function in adulthood. Our aim was to determine whether moderate diet restriction, performed at the time where these disorders are acquired, could restore cardiac function and ameliorate post-ischemic recovery. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet ad libitum (AL). At 6 months of age, half of the NF mice and OF mice were assigned to a moderate 20% calorie restriction (CR, NF-CR, OF-CR) for one month, while the other half of mice continued to eat AL (NF-AL, OF-AL). Cardiac function was followed using echocardiography and, at 7 months, the sensitivity to ischemia-reperfusion injury was evaluated in isolated perfused hearts. Six-month-old OF mice weighed 19.3% more than NF mice. Left ventricular fractional shortening (LVFS) and ejection fraction (LVEF, 51.4% vs. 57.6%, p<0.001) were decreased in OF mice. Left ventricular internal diameter in diastole (LVIDd) was significantly greater in OF mice. After one month of moderate CR, body weight of NF-CR and OF-CR was reduced by 12.6% as compared to their respective AL-group. LVEF increased in OF-CR (60.2% vs. 49.4%, p<0.001) and became comparable to this of NF-AL, while LVIDd was also normalized, whereas no difference between NF-CR and NFAL were observed. After 30min of global ischemia, hearts isolated from OFCR mice showed smaller infarct size than this of others groups. Our study suggests that while short-term moderate CR could diminish body weight in both NF and OF groups of mice, CR was able to improve cardiac function and susceptibility to myocardial ischemia-reperfusion injury only in OF, reversing the deleterious influence of postnatal programming by early overnutrition.

0209 : Cardiovascular exploration integrated in International Mouse Phenotyping Consortium of new mutants for enhancer genes

A primary goal of mouse research is its application to human pathophysiology. Genetically engineered mouse model phenotyping has an increasing pivotal role in bridging preclinical and clinical development. Mouse Clinical Institute is involved in the International Mouse Phenotyping Consortium (IMPC), which comprises major mouse genetic research institutions. Its aim is to address the challenge of developing an encyclopedia of mammalian genes function. After knockout generation, each mutant line undergoes a standardized pipeline of high-throughput tests to identify developmental, anatomical, physiological, behavioral or potentially pathological phenotypes in order to determine the function of every gene. In the last 2 years, we have generated and characterized 60 mutants for enhancer genes. Some of them (NOL8, Yipf5, Setbp1, NTF5) have revealed interesting phenotypes regarding cardiovascular functions. E.g. NOL8 gene that encodes the nuclear protein 8 plays a role in cell growth and regulation of gene expression. The Knockout mice of NOL8 gene have disturbances in the ventricular systolic function and electrical activity in males and females related to heart degeneration detected histologically by the presence of a large number of Anitschkow cells. Setbp1 (SET binding protein) mutation showed a decrease in left ventricular mass, shortening fraction and heart weight, an increase in wall thickness and disturbances in electrical activity of the heart; aiming this line as a model for a human disease (Schinzel-Giedion Midface Retraction Syndrome). All these phenotypes were detected by performing first-line tests in electrocardiogram and echocardiography. Second line tests (tissue Doppler, hemodynamics assessment, color-flow contrast imaging) with a high resolution in vivo micro imaging system are envisioned for a more in depth cardiac (valvular heart disease, congenital heart disease, cardiomyopathies) and vascular (malformation and stenosis) evaluation to detect more subtle phenotypes.

Evaluation of right atrial function in patients with dilated cardiomyopathy and ischemic cardiomyopathy using two-dimensional speckle tracking imaging

Objective To evaluate right atrial function in patients with idiopathic dilated cardiomyopathy (IDCM) and ischemic cardiomyopathy (ICM) by using two-dimensional speckle tracking imaging (2D-STI). Methods Study population consisted of 31 patients with IDCM, 30 with ICM and 30 healthy subjects. High frame rate two-dimensional images were recorded from the apical four chamber view. Right atrial global longitudinal strain (GLS) was measured using two-dimensional strain soft ware. Results Compared with the controls, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC), right ventricular fractional shortening (RVFS) and tricuspid annular peak systolic velocity(S') decreased (P<0.05), while right ventricular myocardial performance index(MPI) increased in IDCM and ICM group. There were no significant differences for all above echocardiographic parameters between IDCM and ICM patients. Compared with the controls, right atrial GLS decreased significantly in patients with IDCM and ICM, even much lower in patients with IDCM (P<0.001). Conclusions Measurement of right atrial strain using 2D-STI could be used for the assessment of right atrial dysfunction in patients with ICDM and ICM. Key words: Echocardiography; Cardiomyopathy, dilated; Atrial function, right; Speckle tracking imaging

The value of cardiac MRI versus echocardiography in the pre-operative assessment of patients with Duchenne muscular dystrophy.

Duchenne Mmuscular Ddystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment. Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010 and 2013. Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29/% (range: 7-44). 37% of boys (13/35) had abnormal SF <25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF <55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p = 0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs = 0.67; p < 0.001), three-quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR. Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment.

Clinical characteristics and cardiac hemodynamic changes of patent ductus ateriosus in preterm infants

To study clinical characteristics and evaluate cardiac hemodynamic changes in premature infants with patent ductus ateriosus (PDA). One hundred and five infants born at ≤ 34 weeks' gestational age (GA) and ≤2 000 g birth weight (BW) were prospectively enrolled, including 63 males and 42 females, and the mean GA was (31. 1 ± 1.9) weeks and BW (1 401 ± 314) g. Echocardiography was done to detect hemodynamically significant PDA (hsPDA) and to evaluate left ventricular function at 2, 3, 5 and 7 d respectively after birth. On the basis of clinical symptoms and echocardiographic outcome, all the cases were divided into 3 groups: hsPDA group (n = 34), non-hsPDA (nhsPDA) group (n = 44) and non-PDA (nPDA) group (n = 27) to survey and compare general conditions, DA diameter, shunt direction, left ventricular function and complications. The hsPDA group had smaller GA ((30. 5 ± 2. 1) vs. (31. 6 ± 1. 6) weeks, P = 0. 01) and greater proportion of pulmonary surfactant use and mechanical ventilation (2, 3, 5 d of birth) than the nhsPDA and the nPDA group (χ2 = 11. 62, 14. 95, 12. 73, 1:1. 59, P = 0. 00; 0. 00, 0. 01, 0. 01). Univariate and multivariate Logistic regression analysis indicated that the average length of stay (ALOS) was correlated with hsPDA (F =3. 52 and P =0. 03, OR 1. 03 and P =0. 02). The ALOS was longer in the hsPDA group than in the nhsPDA and the nPDA group ((39 ±23)vs. (30 ± 16)and(29 ±13) d, P =0.02, 0.03). There was no significant.difference in rates of mortality/giving-up of treatment among the three groups (5. 9% (2/34)vs. 0 (0/44) and 3. 7% (1/27), χ2 = 5. 26, P = 0. 06). Diastolic blood pressure and mean blood pressure were significantly lower in the hsPDA group than in the other two groups (P all <0. 05) at 2, 3 and 5 days after birth and the pulse pressure was found significantly higher in the hsPDA group than in the nPDA group at 2 d after birth. Univariate and multivariate Logistic regression analysis demonstrated that hsPDA was correlated significantly with neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD) (χ2 =7. 34 and 7. 39, P = 0. 02 and 0. 02; OR = 3. 46 and 4. 01, P = 0. 04 and 0. 02). Premature infants with hsPDA had normal left ventricular fractional shortening (FS) and left ventricular ejection fraction (LVEF), although the cardiac output (CO) of left ventricle increased significantly(F = 6. 93, P <0. 01) within seven days of birth. There was no significant difference in cardiac hemodynamic parameters among closed group of hsPDA group, nhsPDA group and nPDA group simutaneously reexamined at 7th day after birth. The CO was extremely significantly different among premature infants who had different GAs and BWs. The lower the GAs and the BWs, the lower the value of CO(F =5. 16 and 14. 87, P all <0. 01). The DA diameter was reduced much more dramatically after ibuprofen treatment than before in hsPDA group(t = 5. 58, P <0. 01). The GA, PS use and mechanical ventilation were probably associated with hsPDA. The mean blood pressure and diastolic blood pressure were decreased and pulse pressure was increased in preterm infants with hsPDA that correlated significantly with ALOS, NRDS and BPD. In addition, increased CO values were found in hsPDA group. Oral ibuprofen administered to preterm infants for hsPDA at > 24 h of life promoted ductal closure.

2-Methylthio-adenosine-5'-triphosphate inhibits ventricular arrhythmogenesis in rabbits with chronic heart failure

To investigate the effects and related mechanisms of 2-methylthio-adenosine-5'-triphosphate (2-MeSATP), an important extracellular agonist that activates receptors for purine nucleotides (P2XR), on ventricular arrhythmias in rabbits with chronic heart failure (CHF). The male New Zealand rabbits were divide into control (n=12), CHF (n=12) and CHF+2-MeSATP groups (2-MeSATP, n=12). CHF was induced by isoproterenol injection (0.3 mg·kg⁻¹·d⁻¹ for 3 weeks) and rabbits were observed 6 months later. The main cardioelectrophysiological parameters and ventricular arrhythmias were tested by recording monophasic action potential (MAP) with burst-pacing (BCL) in rabbits in vivo. The transient outward potassium current (Ito) was recorded via whole-cell patch clamp technique and the fluorescence intensity of intracellular free Ca²⁺ was detected with Flup-3/AM loading by the laser scanning confocal microscope in enzymatically dissociated single rabbet ventricular myocytes. CHF rabbits developed severely clinical CHF signs and symptoms, reduced left ventricular ejection fraction and fractional shortening as well as enlarged end-diastolic dimension. Compared with CHF group, APA and MaxdV/dt were significantly increased, while APD20, APD50 and APD90 were significantly reduced in 2-MeSATP group (all P<0.01). Moreover, 2-MeSATP could obviously shorten BCL induced ventricular arrhythmias, and decrease deducibility and persistence time of ventricular arrhythmias with burst-pacing in 2-MeSATP group in vivo (all P<0.05). With voltage clamp model, 2-MeSATP could significantly increase the current density of Ito in different command potential in CHF ventricular myocytes (all P<0.01). When holding potential was set at -50 mV and command potential was set at +50 mV, the current densities of Ito increase was more significant in 2-MeSATP group than that in CHF group ((11.79 ± 4.51) pA/pF vs. (7.94 ± 3.53) pA/pF, P<0.01). 2-MeSATP could completely change the I-V curve upward without changing the I-V curve direction in CHF ventricular myocytes. The fluorescence intensities of intracellular free Ca²⁺ increase was more significant in 2-MeSATP group compared to CHF group ((1 291.98 ± 123.31) µmol/L vs. (793.59 ± 114.65) µmol/L, P<0.01). 2-MeSATP as a potent agonist acting on P2XR could significantly shorten APD, increase heart rate and improve cardiac performance as well as decrease the susceptibility of ventricular arrhythmias in this rabbit CHF model. Our results suggest that Ito increase and sarcoplasmic reticulum uptake Ca²⁺ enhancement as well as dynamic balance of intracellular Ca²⁺ cycling sustenance might linked to the beneficial effects of 2-MeSATP in this CHF model.

Blood pressure, left ventricular geometry, and systolic function in children exposed to inorganic arsenic.

Background:Inorganic arsenic (iAs) is a ubiquitous element present in the groundwater worldwide. Cardiovascular effects related to iAs exposure have been studied extensively in adult populations. Few epidemiological studies have been focused on iAs exposure–related cardiovascular disease in children.Objective:In this study we investigated the association between iAs exposure, blood pressure (BP), and functional and anatomical echocardiographic parameters in children.Methods:A cross-sectional study of 161 children between 3 and 8 years was conducted in Central Mexico. The total concentration of arsenic (As) species in urine (U-tAs) was determined by hydride generation–cryotrapping–atomic absorption spectrometry and lifetime iAs exposure was estimated by multiplying As concentrations measured in drinking water by the duration of water consumption in years (LAsE). BP was measured by standard protocols, and M-mode echocardiographic parameters were determined by ultrasonography.Results:U-tAs concentration and LAsE were significantly associated with diastolic (DBP) and systolic blood pressure (SBP) in multivariable linear regression models: DBP and SBP were 0.013 (95% CI: 0.002, 0.024) and 0.021 (95% CI: 0.004, 0.037) mmHg higher in association with each 1-ng/mL increase in U-tAs (p < 0.025), respectively. Left ventricular mass (LVM) was significantly associated with LAsE [5.5 g higher (95% CI: 0.65, 10.26) in children with LAsE > 620 compared with < 382 μg/L-year; p = 0.03] in an adjusted multivariable model. The systolic function parameters left ventricular ejection fraction (EF) and shortening fraction were 3.67% (95% CI: –7.14, –0.20) and 3.41% (95% CI: –6.44, –0.37) lower, respectively, in children with U-tAs > 70 ng/mL compared with < 35 ng/mL.Conclusion:Early-life exposure to iAs was significantly associated with higher BP and LVM and with lower EF in our study population of Mexican children.Citation:Osorio-Yáñez C, Ayllon-Vergara JC, Arreola-Mendoza L, Aguilar-Madrid G, Hernández-Castellanos E, Sánchez-Peña LC, Del Razo LM. 2015. Blood pressure, left ventricular geometry, and systolic function in children exposed to inorganic arsenic. Environ Health Perspect 123:629–635; http://dx.doi.org/10.1289/ehp.1307327

Tricuspid annular plane systolic excursion in evaluation of right heart systolic function of fetuses in second and late trimester with conventional M-mode and free angle M-mode echocardiography

Objective To evaluate the usefulness of free angle M-mode echocardiography (FAM) in obtaining tricuspid annular plane systolic excursion (TAPSE) for assessing the fetal right ventricular function, and to compare the results of measurements of TAPSE by conventional M-mode(CM) and FAM. Methods Two hundred and forty-three normal fetuses in second and late trimester were divided into 5 groups by gestational age(GA): 20-24 weeks, 24+ 1-28 weeks, 28+ 1-32 weeks, 32+ 1-36 weeks, 36+ 1-40 weeks. The TAPSE were measured by CM and FAM echocardiography, meanwhile multiple parameters for evaluating right ventricular function were obtained by using myocardial tissue Doppler imaging (TDI), and the correlation between TAPSE and other parameters were analyzed by linear correlation. ANOVA was used to compare CM-TAPSE, FAM-TAPSE, Em, Sm and right ventricular fractional shortening(RVFS) with different GA. Regression equation estimate was used to compare the relationship of FAM-TAPSE with GA. Independent sample t test was used to compare CM-TAPSE with FAM-TAPSE. Results There were significant differences in CM-TAPSE, FAM-TAPSE, Em, and Sm among 5 groups (P=0.000), the measured value of FAM-TAPSE was higher than that of CM-TAPSE (P=0.000). Both FAM-TPASE and CM-TAPSE showed significant positive correlations with GA, Em and Sm, but FAM-TAPSE demonstrated better correlation than CM-TAPSE. Conclusions By adjusting sample line of FAM, measuring the maximum displacement of tricuspid annular plane is feasible, and FAM may evaluate fetal right ventricular function more accurately and effectively. Key words: Ultrasonography, prenatal; Tricuspid annular plane systolic excursion; Ventricular function, right; Free angle M-mode echocardiography

Effects of enzyme replacement therapy started late in a murine model of mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don’t receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6–8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.

Overexpression of cyclic adenosine monophosphate effluent protein MRP4 induces an altered response to β-adrenergic stimulation in the senescent rat heart.

In the senescent heart, the positive inotropic response to β-adrenoceptor stimulation is reduced, partly by dysregulation of β1- and β3-adrenoceptors. The multidrug resistance protein 4 (MRP4) takes part in the control of intracellular cyclic adenosine monophosphate concentration by controlling its efflux but the role of MRP4 in the β-adrenergic dysfunction of the senescent heart remains unknown. The β-adrenergic responses to isoproterenol were investigated in vivo (stress echocardiography) and in vitro (isolated cardiomyocyte by Ionoptix with sarcomere shortening and calcium transient) in young (3 months old) and senescent (24 months old) rats pretreated or not with MK571, a specific MRP4 inhibitor. MRP4 was quantified in left ventricular homogenates by Western blotting. Data are mean ± SD expressed as percent of baseline value. The positive inotropic effect of isoproterenol was reduced in senescent rats in vivo (left ventricular shortening fraction 120 ± 16% vs. 158 ± 20%, P < 0.001, n = 16 rats) and in vitro (sarcomere shortening 129 ± 37% vs. 148 ± 35%, P = 0.004, n = 41 or 43 cells) as compared to young rats. MRP4 expression increased 3.6-fold in senescent compared to young rat myocardium (P = 0.012, n = 8 rats per group). In senescent rats, inhibition of MRP4 by MK571 restored the positive inotropic effect of isoproterenol in vivo (143 ± 11%, n = 8 rats). In vitro in senescent cardiomyocytes pretreated with MK571, both sarcomere shortening (161 ± 45% vs. 129 ± 37%, P = 0.007, n = 41 cells per group) and calcium transient amplitude (132 ± 25% vs. 113 ± 27%, P = 0.007) increased significantly. MRP4 overexpression contributes to the reduction of the positive inotropic response to β-adrenoceptor stimulation in the senescent heart.

Prospective cardiac MRI for the analysis of biventricular function in children undergoing cancer treatments.

Cardiotoxicity is one of the most serious long-term complications in childhood cancer survivors. Measurement of the left ventricular ejection and shortening fraction remains the most common screening tool for cardiac systolic dysfunction. However, M-mode echocardiography can be viewed as a crude approach as refined strategies are now available. The aim of this prospective study was to determine the role of cardiac MRI in the detection of subclinical left or right ventricular dysfunction as well as the prevalence of myocardial scaring in patients undergoing cancer treatments. Eighty-one children were enrolled in a pre-chemotherapy and then in a yearly protocol including a: (i) clinical evaluation; (ii) laboratory evaluation; (iii) electrocardiogram; (iv) echocardiogram; and (v) a cardiac magnetic resonance imaging (cMRI). Early left ventricular systolic dysfunction was only detected in two patients. The entire cohort presented a significant increase of the left atrial volume as measured by cMRI. This finding correlated with the total cumulative dose of anthracyclines (r = 0.34; P < 0.05) and the mean left ventricular radiation dose (r = 0.86; P < 0.05). We also observed a mild increase of myocardial scaring, similarly correlated to the radiation dose (r = 0.85; P < 0.05). Screening tools for late-onset cardiomyopathy secondary to cancer treatment are lacking. Our findings support the use of cMRI for the evaluation of the left atrial volume, as an early marker of diastolic dysfunction, and myocardial delayed enhancement, as a marker of myocardial fibrosis and scaring. Longer follow-up and larger studies are still needed to better define the role of cMRI in the evaluation of childhood cancer survivors.

Rosuvastatin Attenuates Atrial Structural Remodelling in Rats with Myocardial Infarction through the Inhibition of the p38 MAPK Signalling Pathway

The purpose of this study was to verify the hypothesis that rosuvastatin attenuates atrial structural remodelling in rats with myocardial infarction (MI) through the regulation of the p38 mitogen-activated protein kinase (MAPK) signalling pathway. A total of 66 rats were used in this study to establish a model of MI. The 56 rats that survived the first 24h after surgery were randomly divided into four groups: the control group (C group), the rosuvastatin group (R group), the low-dose torasemide group (T1 group), and the high-dose torasemide group (T2 group). The four groups of rats received daily intragastric administration of normal saline, rosuvastatin, or torasemide (T1: 1mg/kg body weight; T2: 2mg/kg body weight) for a total of four weeks. The rats in the sham-operated group (n=14) also received daily intragastric administration of normal saline for four weeks. After four weeks of intervention, the left ventricular end-diastolic pressure (LVEDP) was measured in all groups of rats by haemodynamic methods. The rats were then sacrificed, and the left atrial tissues were collected. The collagen volume fractions (CVFs) in the left atrial tissues were determined using Masson's trichrome staining. The expression of phosphorylated p38 (P-p38) MAPK in the left atrial tissues was examined by immunohistochemistry and western blot analysis. The results showed that LVEDP, CVF, and P-p38 MAPK expression were drastically elevated in the four MI groups in comparison to the sham-operated group (p<0.001). Rosuvastatin elevated the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF). Both rosuvastatin and torasemide improved the haemodynamic parameters. No significant difference was detected in LVEDP between the R group and the T1 group (p=0.37). In contrast, LVEDP was significantly higher in the R group than in the T2 group (p <0.05). CVF (%) was markedly decreased in the R group compared to the C, T1, and T2 groups (decreased by 47.4%, 28%, and 20.1%, respectively). Immunohistochemical analysis showed that the indices of P-p38 MAPK positive cells were significantly decreased in the R group in comparison with the C, T1, and T2 groups (decreased by 44.6%, 36.6%, and 21.4%, respectively). Western blot analysis demonstrated that P-p38 MAPK expression was markedly reduced in the R group compared with the C and T1 groups (reduced by 67% and 40.5%, respectively). The level of P-p38 MAPK in the R group was slightly higher than in the T2 group. However, the difference was not statistically significant (p>0.05). Rosuvastatin attenuates atrial structural remodelling in rats with MI. The mechanism underlying this phenomenon may be associated with the downregulation of P-p38 MAPK by rosuvastatin.

Values of high sensitive troponin T in long-term survivors of childhood cancer treated with anthracyclines

BackgroundCardiac biomarkers can play an important role in the early detection of subclinical heart failure. Our aims are to 1) obtain values of high sensitive cardiac troponin T (hs-cTnT) in long-term survivors of childhood cancer and 2) investigate the potential role of hs-cTnT in the detection of subclinical late-onset cardiotoxicity. MethodsHs-cTnT and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) were measured in 64 survivors. Electrocardiography and echocardiography were performed to evaluate cardiac function. ResultsMean follow-up period was 8.3years (range of 4.5 to 34.1). All survivors were clinically asymptomatic and had no history of clinical heart failure during or immediately after anthracycline treatment. Electrocardiography (available in 59 of 64 survivors) showed no signs of myocardial injury related to ischemia or abnormal QTc. Echocardiography was performed in all survivors. Mean left ventricular shortening fraction (SF) was 34% (range of 28 to 43%); mean ejection fraction (EF) was 61% (range of 48 to 74%). Seven survivors had a mildly decreased EF between 48% and 55%. Normal hs-cTnT levels were found in all 64 survivors (range of 3 to 13ng/L) and did not differ among different anthracycline dosage groups: ≤120, 120–300 and ≥300mg/m2. Yet, 5/64 survivors had elevated NT-pro-BNP levels (range of 7 to 25pg/ml) with normal SF and ECG findings and only one mildly abnormal EF of 51%. ConclusionsHs-cTnT concentrations are normal in long-term survivors of childhood cancer, even in the subpopulations with elevated NT-pro-BNP and/or a mildly decreased EF, indicating that it is not a sensitive marker for late onset subclinical anthracycline induced cardiotoxicity.

Abstract 12358: Abnormal Left Ventricular Midwall Fractional Shortening and Elevated Circulating Biomarkers Predict High Mortality in Elderly Individuals in the General Population

Background: Individuals in the general population with a minimal elevation of cardiac biomarkers and left ventricular hypertrophy are at high cardiovascular risk and may be candidate for early strategies of prevention and treatment. We investigated the combination of several circulating biomarkers with abnormal midwall fractional shortening (MFS), an early echocardiographic indicator of preclinical systolic dysfunction, with adverse outcomes. Methods: Circulating levels of N-terminal probrain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT), and intercellular adhesion molecule-1 (ICAM-1) were measured in 550 elderly community-dwelling individuals (65-84 years) from the PREDICTOR study. Participants were referred to cardiology centers for clinical examination and Doppler echocardiography with centrally-measured MFS. Causes of death or hospitalization were available after a median follow-up of 46 [39-54] months from record-linkage of administrative data. Results: Individuals with LV midwall dysfunction (MFS&lt;15%, n= 204 (38%)) had higher levels of NT-proBNP (148 [57-311] ng/L), hs-cTnT (7.3 [3.9-11.6] ng/L)and ICAM-1 (211 [177-261] ng/mL) than those with normal function (82 [42-171] and 5.0 [3.0-8.3] ng/L, 193 [165-230], respectively, p&lt;0.001). The cumulative incidence of total mortality (n=36) among individuals with abnormal MFS and elevated NT-proBNP (&gt;75th age- and sex-specific percentile) was 14% vs. 2% (abnormal MFS, low NT-proBNP), 6% (normal MFS, high NT-proBNP) and 1% (normal MFS, low NT-proBNP). Corresponding values for hs-cTnT (&gt; 3ng/L) were 14, 0, 5 and 3% (p&lt;0.0001) and 15, 5, 7 and 2% for ICAM-1 above median concentration (all p&lt;0.0001). After adjustment for sex, age, eGFR and hypertension, subjects with abnormal MFS and an elevated biomarker had a higher risk of total mortality compared to those with normal MFS and low biomarker: HR = 11.4 [1.5-87.7] (p=0.02) for NT-proBNP and 7.4 [2.1-25.6] (p=0.002) for ICAM-1, but not for hs-cTnT. Similar trends were seen for GDF-15. Conclusions: Elevation of circulating biomarkers combined with early alterations in LV systolic function with MFS identifies a subgroup of individuals in the general population aged 65 or more at higher risk for mortality.

Abstract 11940: Mineralocorticoid Receptor Dysregulation by MicroRNA-135a in Bradycardic Arrhythmogenic Remodeling

Introduction: Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of Torsades de Pointes (TdP) arrhythmias. MicroRNAs (miRs) are key regulators of gene expression that contribute to cardiac remodeling. Here, we assess microRNA changes after CAVB and their potential significance in arrhythmogenic cardiac remodeling. Methods: CAVB was induced in mice via His bundle ablation. Expression of miRs was evaluated by pan-microRNA microarray with qPCR confirmation on samples from controls and at 24 hrs and 4 wks post-CAVB. Arrhythmias were detected by continuous monitoring. MicroRNA target prediction algorithms were used to identify potential target genes. Biological confirmation of targets was by luciferase assay and overexpression (OE) studies in HEK and H9c2 cells respectively. Results: TdP occurred within 24 hrs in 6/17 CAVB mice, vs no controls. Ventricular tachyarrhythmia episodes were frequent at 4 wks CAVB (212±83 per 24 hrs) and were not seen in controls. CAVB was followed by increased left ventricular (LV) dimension (by 31%, ***p&lt;.001), LV mass (by 33%, *p&lt;.05) and LV fractional shortening (by 33%*) at 4 wks. Of &gt;400 miRs assayed, only miR-135a was altered at 24 hrs (downregulated by 96%***, Fig. A), with 70% decrease at 4 wks. TargetScan predicted miR-135a regulation of the mineralocorticoid receptor (MCR), encoded by the NR3C2 gene. miR-135a OE suppressed NR3C2 3’UTR reporter activity 3.2-fold* (n=5, Fig. B). miR-135a OE did not affect NR3C2 mRNA (Fig. C) but significantly reduced NR3C2 protein expression (n=4, Fig. D). Coexpression with anti-miR-135a eliminated the NR3C2 downregulating effect of miR-135a OE. Conclusions: The mineralocorticoid receptor, encoded by the NR3C2 gene, is translationally regulated by miR-135a, a microRNA that is downregulated in the heart following CAVB in mice. These results implicate miR-135a/mineralocorticoid modulation in arrhythmogenic ventricular remodeling caused by CAVB.

Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis

Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p&lt;0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p&lt;0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: &amp;#64258;]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p&lt;0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h). Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.

Abstract 19684: Abnormal Aortic Wall Properties in Children with Isolated Bicuspid Aortic Valve

Introduction: Abnormal aortic wall properties have been reported in patients with isolated bicuspid aortic valve (IBAV) even in the absence of significant aortic stenosis or regurgitation. Hypothesis: We sought to assess aortic distensibility (DIS) and stiffness index (SI) in children with IBAV compared to age group-matched subjects with normal tricuspid aortic valves (TAV) and to determine whether these abnormalities in the aortic wall properties correlate with bicuspid valve morphology or left ventricular systolic or diastolic function. Methods: Children ages 8-18 years with an IBAV and age group-matched controls with a TAV were prospectively enrolled. Subjects with greater than mild stenosis or mild regurgitation were excluded. Using echo, aortic valve morphology, aortic root (AoR) and ascending aorta (AAo) diameters and z-scores were determined. Left ventricular shortening fraction (LVSF), DIS and SI were measured using M-mode echo. Diastolic function was determined using mitral valve septal E/Ea. Blood pressure (BP) was measured at the time of echo. Results: Nineteen had IBAV and 17 had TAV. There were no significant differences in age, weight, height or BP between the two groups. In the IBAV group, 11 had right-left type (R/L) and 8 had right-non type (R/N). There was no significant difference in AoR z-scores between groups. The IBAV group had larger AAo z-scores (2.48±1.9 vs. -0.02±0.98, p&lt;0.0001), decreased DIS (9.6±4 vs. 12.3±3.1 cm2 dynes-1 x 10-6, p&lt;0.05) and increased SI (21.4±9.2 vs. 14.4±3.8, p=0.007) compared to the TAV group. There were no differences in these variables between the R/L or R/N subgroups. No correlation was seen between aortic wall properties and ventricular function in the IBAV group. By multivariate regression, presence of an IBAV (coefficient = -2.4, p=0.03), LVSF (coefficient = -0.35, p=0.01) and age-adjusted systolic BP (coefficient = -0.13, p=0.03) were independently associated with DIS. Similarly, presence of an IBAV (coefficient = 6.7, p=0.005) and age (coefficient=0.85, p=0.02) were independently associated with SI. Conclusions: Children with IBAV have decreased DIS and SI even without hemodynamic abnormalities. Long-term studies to determine the impact of these findings on cardiovascular risk are needed.

Right ventricular outflow tract systolic excursion: a useful method for determining right ventricular systolic function.

Assessment of right ventricular (RV) systolic function is not an easy task. Although RV fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) are useful in the assessment of RV function, their use can be sometimes limited. Right ventricular outflow tract systolic excursion (RVOT_SE) is a new way to evaluate RV systolic function. The aim of this study was to assess the correlation between RVOT_SE and other RV systolic function assessment methods. RVOT_SE was defined as the systolic excursion of the RV outflow tract anterior wall endocardium. A total of 104 patients with a wide range of RV systolic function, ejection fraction, and pulmonary artery systolic pressure were studied. We also measured another four ways to evaluate RV systolic function, FAC, TAPSE, right ventricular outflow tract fractional shortening (RVOT_FS), and tricuspid annular systolic excursion velocity S' (Tissue S'). There was a strong correlation between RVOT_SE and each one of the four studied ways to evaluate RV systolic function. Multivariate regression analysis showed that the independent variables correlated with RVOT_SE were RVOT_FS (p<0.0001), FAC (p=0.005) and TAPSE (p=0.023). RVOT_SE diagnosed patients with reduced RV systolic function with 98% sensitivity and 96% specificity. There was no correlation between RVOT_SE and ejection fraction, or between RVOT_SE and pulmonary artery systolic pressure in patients with reduced RV systolic function. Intra-observer and inter-observer reproducibility were favorable for RVOT_SE and all four studied ways. RVOT_SE is a simple, accurate, and promising method for evaluating RV systolic function.

CMR-derived TAPSE measurement: a semi-quantitative method of right ventricular function assessment in patients with hypertrophic cardiomyopathy

AimTo compare cardiovascular magnetic resonance (CMR)-derived right ventricular fractional shortening (RVFS), tricuspid annular plane systolic excursion with a reference point within the right ventricular apex (TAPSEin) and with one outside the ventricle (TAPSEout) with the standard volumetric approach in patients with hypertrophic cardiomyopathy (HCM).Methods and results105 patients with HCM and 20 healthy subjects underwent CMR. In patients with HCM, TAPSEin (r = 0.31, p = 0.001) and RVFS (r = 0.35, p = 0.0002) revealed a significant but weak correlation with right ventricular ejection fraction (RVEF), whereas TAPSEout (r = 0.57, p < 0.0001) showed a moderate correlation with RVEF. The ability to predict RVEF < 45 % in HCM patients was best for TAPSEout. In patients with hypertrophic obstructive cardiomyopathy (HOCM), RVEF showed a significant but weak correlation with TAPSEout (r = 0.36, p = 0.02) and no correlation with TAPSEin (r = 0.05, p = 0.07) and RVFS (r = 0.02, p = 0.2). In patients with hypertrophic non-obstructive cardiomyopathy (HNCM), there was a moderate correlation between RVEF and TAPSEout (r = 0.57, p < 0.0001) and a weak correlation with TAPSEin (r = 0.39, p = 0.001) and RVFS (r = 0.38, p = 0.002). In the 20 healthy controls, there was a strong correlation between RVEF and all semi-quantitative measurements.ConclusionCMR-derived TAPSEin is not suitable to determine right ventricular function in HCM patients. TAPSEout showed a good correlation with RVEF in HNCM patients but only a weak correlation in HOCM patients. TAPSEout might be used for screening but the detection of subtle changes in RV function requires the 3D volumetric approach.

PREMATURE VENTRICULAR CONTRACTIONS IN HEALTHY CHILDREN: DOES THE BURDEN OF ECTOPY MATTER?

age 15.1 3.7) and 2 patients died suddenly (mean age 17.5 1.9), corresponding to an event-free survival rate of 98 % at 7.2 years. All of these patients had abnormal ECG findings but, in univariate analyses, only the width of QRS was associated with arrhythmic events (110.3 8.2 ms in the event group vs. 98.1 1.7ms in the no-event group, p1⁄40.03). 71.4 % (n1⁄45) were diagnosed in their first year of life. CONCLUSION: During a follow up nearly 16 years, more than 85% of pediatric patients who suffered from MD1 had ECG abnormalities, which increased over time. Rhythmic events in pediatric population are rare but exist, and occured in patients with conduction abnormalities on basal ECG.