LncRNA H19 induces immune dysregulation of BMMSCs, at least partly, by inhibiting IL-2 production.

BACKGROUND: Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease. LncRNA H19 has been identified to participate in various biological processes in human diseases. However, the role of H19 in SLE remains unclear. METHODS: In this study, we first examined H19 expression in SLE patients by RT-qPCR and found that H19 expression was significantly upregulated in the serum and bone marrow-derived mesenchymal stem cells (BMMSCs) of SLE patients and positively associated with SLE disease activity index. We then performed gain-of-function and loss-of-function using mimic-H19 (H19-OE) and inhibitor-H19 (H19-KD) to examine the effects of H19 on BMMSC differentiation, proliferation, migration, and apoptosis using flow cytometry, DAPI staining, and migration and apoptosis assays. RESULTS: The results showed that H19 inhibited proliferation and migration but promoted apoptosis of BMMSCs, interfered with BMMSCs-mediated Treg cell proliferation and differentiation, and regulated BMMSCs-mediated Tfh/Treg cell balance. Dual-luciferase reporter assay confirmed the in silico prediction of interaction between H19 and IL-2. Furthermore, RT-qPCR showed that H19 directly inhibited IL-2 transcription in BMMSCs. ELISA showed that both active and total IL-2 protein levels were significantly lower in SLE BMMSCs. More importantly, we found that IL-2 significantly enhanced H19-OE-induced Treg cell differentiation and migration of BMMSCs, and these effects were reversed by anti-IL-2 antibody. CONCLUSION: Overall, our study indicates that LncRNA H19 induces immune dysregulation of BMMSCs, at least partly, by inhibiting IL-2 production and might be a novel therapeutic target for SLE.

Deterioration of left ventricular systolic function in extended Pacing to Avoid Cardiac Enlargement (PACE) trial: the predictive value of early systolic dyssynchrony.

AIMS: Biventricular (BiV) pacing was superior to right ventricular apical (RVA) pacing at extended follow-up in the Pacing to Avoid Cardiac Enlargement (PACE) trial. Early pacing-induced systolic dyssynchrony (DYS) might be related to mid-term result. However, it remains unknown whether early pacing-induced DYS can predict long-term reduction of left ventricular (LV) systolic function. METHODS AND RESULTS: Patients with standard pacing indications and normal LV ejection fraction (LVEF) were randomized either to BiV (n = 89) or RVA (n = 88) pacing. Seventy-four patients in the RVA group and 72 in the BiV pacing group completed follow-up longer than 2 years. Serial echocardiography was performed with DYS assessed by tissue Doppler imaging, and the early pacing-induced DYS was defined as >33 ms by using standard deviation of the time to peak systolic velocity (Dyssynchrony Index) in a 12-segment model of LV at 1 month. There were 46 (32%) patients having early pacing-induced DYS that was more prevalent in the RVA pacing group than that in the BiV pacing group (50.7 vs. 12.3%, χ(2) = 25.1, P < 0.001) despite the similar DYS between the two groups at baseline (30 ± 13 vs. 26 ± 11 ms, P = 0.051). At a median follow-up of 4.8 years, patients developing early DYS had lower LVEF (53.2 ± 9.4 vs. 60.9 ± 8.0%, P < 0.001) and larger LV end-systolic volume (40.3 ± 23.7 vs. 29.3 ± 13.4 mL, P < 0.001) than those without DYS. Significant EF reduction (defined as ≥5%) occurred in 71.7% (33 in 46) of patients with DYS, but only in 30% (30 in 100) in those without DYS (χ(2) = 22.4, P < 0.001). Further analysis showed that both DYS at 1 month [odds ratio (OR): 3.113, P = 0.013] and RVA pacing (OR: 7.873, P < 0.001) independently predicted the deterioration of LV systolic function with pacing period of 4.8 years. CONCLUSION: Early pacing-induced DYS is a significant predictor of reduction of LV systolic function for long-term pacing, which could be prevented by BiV pacing at relatively long-period follow-up. CLINICAL TRIAL REGISTRATION: Centre for Clinical Trials number, CUHK_CCT00037 (URL: http://www.cct.cuhk.edu.hk/Registry/publictrialrecord.aspx?trialid=CUHK_CCT00037).

Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by new bone formation. Recent evidence suggests that new bone formation in AS may be due to upregulation of Wnt signaling in the osteoblastic pathway secondary to low serum Dickkopf homolog 1 (Dkk-1) levels. And miR-29a orchestrates osteoblast differentiation through direct targeting and negative regulation of Dkk-1. METHODS: We initially validated the expression levels of miR-29a in the peripheral blood mononuclear cells (PBMCs) of AS patients (n = 30), rheumatoid arthritis (RA) patients (n = 30) and healthy controls (n = 30) using real-time quantitative reverse transcription PCR (qRT-PCR). Correlation analysis was assessed between miR-29a level in PBMCs of AS patients and disease activity indexes, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis function index (BASFI) and modified Stoke ankylosing spondylitis spinal score (mSASSS). RESULTS: Significantly higher expression of miR-29a was observed in PBMCs of AS patients (Ct 9.18 ± 1.96) compared with that in RA patients (10.97 ± 0.70, p < 0.001) and healthy controls (Ct 11.45 ± 1.23, p < 0.001). There was no significant difference between RA patients and healthy controls in miR-29a expression (p > 0.05). Elevated miR-29a expression is not correlated with disease activity index (p > 0.05). A weak correlation was found between elevated miR-29a expression and mSASSS (r = -0.393, p = 0.032). CONCLUSIONS: We report for the first time elevated miR-29a expression in PBMCs of patients with ankylosing spondylitis, and miR-29a might be used as a useful diagnostic marker in new bone formation but cannot reflect disease activity.

Serum level of eight cytokines in Han Chinese patients with systemic lupus erythematosus using multiplex fluorescent microsphere method.

AIM OF THE STUDY: To investigate the role of 8 cytokines and their correlation with clinical characteristics in systemic lupus erythematosus (SLE) in Han Chinese population by detecting their serum levels using the multiplex fluorescent microsphere method. MATERIAL AND METHODS: Serum was separated from 79 patients with SLE and 40 healthy controls. The serum cytokine detection was conducted according to the instruction of MILLIPLEX MAP human cytokine detection kit on the Luminex liquid phase array platform with 0.01 pg/ml detectable level. The 8 cytokines were interferon α2 (IFN-α2), IFN-γ, interleukin 6 (IL-6), IL-8, IL-10, IFN-γ-inducible protein 10 (IP-10), tumor necrosis factor α (TNF-α) and IL-17. Variable data were in skewed distribution and were expressed with median (P25, P75). Mann-Whitney analysis was used in statistical analysis. RESULTS: At the baseline level without any stimulus, the level of IP-10 expression was the highest among the 8 cytokines and the second highest was IL-8. The level of IL-17 was too low to be detected. The level of 7 cytokines was higher in SLE patients than in healthy controls (p < 0.01). The level of dsDNA antibody, C3, CRP, ESR and anti-nucleosome antibody was correlated with IL-10. Proteinuria was not correlated with any cytokine. CONCLUSIONS: Eight cytokines were measured in our study, while not all of them were detected. The most important finding was the usefulness of IL-10 as a disease activity biomarker for Han Chinese patient with SLE. None of cytokines reflected kidney injury.

Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by new bone formation. Recent evidence suggests that new bone formation in AS may be due to upregulation of Wnt signaling in the osteoblastic pathway secondary to low serum Dickkopf homolog 1 (Dkk-1) levels. And miR-29a orchestrates osteoblast differentiation through direct targeting and negative regulation of Dkk-1. METHODS: We initially validated the expression levels of miR-29a in the peripheral blood mononuclear cells (PBMCs) of AS patients (n = 30), rheumatoid arthritis (RA) patients (n = 30) and healthy controls (n = 30) using real-time quantitative reverse transcription PCR (qRT-PCR). Correlation analysis was assessed between miR-29a level in PBMCs of AS patients and disease activity indexes, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis function index (BASFI) and modified Stoke ankylosing spondylitis spinal score (mSASSS). RESULTS: Significantly higher expression of miR-29a was observed in PBMCs of AS patients (Ct 9.18 ± 1.96) compared with that in RA patients (10.97 ± 0.70, p < 0.001) and healthy controls (Ct 11.45 ± 1.23, p < 0.001). There was no significant difference between RA patients and healthy controls in miR-29a expression (p > 0.05). Elevated miR-29a expression is not correlated with disease activity index (p > 0.05). A weak correlation was found between elevated miR-29a expression and mSASSS (r = -0.393, p = 0.032). CONCLUSIONS: We report for the first time elevated miR-29a expression in PBMCs of patients with ankylosing spondylitis, and miR-29a might be used as a useful diagnostic marker in new bone formation but cannot reflect disease activity.

Normal ranges of non-invasive left ventricular myocardial work indices in healthy young people.

Objectives: Echocardiographic global myocardial work (GMW) indices recently emerged to non-invasively evaluate left ventricular (LV) myocardial performance with less load-dependence than LV ejection fraction (LVEF) or global longitudinal strain (GLS). Yet, few data exist on the descriptions of LV GMW indices in young people. We therefore aimed to provide normal reference values of LV GMW in a healthy young cohort, and simultaneously to investigate factors associated with non-invasive GMW indices. Materials and methods: A total of 155 healthy young people (age 10-24 years, 59% male) underwent transthoracic echocardiography were recruited and further stratified for age groups and divided by gender. Two-dimensional speckle-tracking echocardiography (2D-STE) were performed to determine LV GLS, peak strain dispersion (PSD) and GMW indices, which include global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). LV peak systolic pressure was assumed to be equal to the systolic brachial artery cuff blood pressure. Results: Age and gender specific normal ranges for LV GMW indices were presented. On multivariable analysis, GWI and GCW correlated more closely with systolic blood pressure (SBP) than LV GLS, while both GWW and GWE independently correlated with PSD (P < 0.05 for all). There were no associations between any of the GMW indices with age, sex, body mass index, heart rate, left ventricular mass index as well as LV sizes or LVEF. Of noted, LV GMW indices had good intra-observer and inter-observer reproducibility. Conclusion: We reported echocardiographic reference ranges for non-invasive LV GMW indices in a large group of healthy young subjects, which are reproducible and reliable, and thus can be further used when assessing subclinical dysfunction in young people with myocardial diseases.

Does Masked Hypertension Cause Early Left Ventricular Impairment in Youth?

Objectives: Masked hypertension (MH) is not uncommon in the youth and may increase risks of long-term cardiovascular impairment. However, little is known about the subclinical heart damage in this group of patients. Currently, 3-layer speckle tracking imaging based on two-dimensional echocardiography is feasible to detect the early signs of myocardial damage. We therefore aimed to investigate whether subtle changes of cardiac function occurred in the young MH patients by using advanced quantification with layer-specific speckle tracking. Methods: A total of 40 adolescents with MH (age 18 ± 3 years, 73% males) and 40 age-, gender-, race-, and height-matched normotensive volunteers were enrolled in our study. MH was defined as one or more of the ambulatory blood pressure (BP) parameters (24-h, daytime and night-time average BPs) higher than ≥ 95th percentile for gender and height according to the local reference. Both comprehensive two-dimensional echocardiography with layer-specific strain analysis and 24-h ambulatory BP monitoring were performed. Longitudinal strain and circumferential strain in endocardial, mid-myocardial, and epicardial layers were determined accordingly with the dedicated software (EchoPAC software version 201, GE Healthcare, Horten, Norway). Results: Compared with normotensive controls, youths with MH had higher ambulatory pulse rate and left ventricular mass index, and were more obese. Interestingly, similar ventricular volumes and ejection fraction were observed in the study groups, but further analysis with layer-specific strains revealed that endocardial and mid-myocardial longitudinal and circumferential mechanical function were decreased in the young MH subjects when compared to normotensive individuals (all p < 0.05). However, there were no difference regarding radial strain and apical rotation derived from traditional speckle tracking analysis. Conclusion: Subclinical change of LV mechanic function assessed by layer-specific speckle tracking is present in youth with MH despite considered as normal with conventional ways.Thus, MH in youth should be monitored closely instead of labeling as an entirely benign entity.

Automated left heart chamber volumetric assessment using three-dimensional echocardiography in Chinese adolescents.

BACKGROUND: Several studies have reported the accuracy and reproducibility of HeartModel for automated determination of three-dimensional echocardiography (3DE)-derived left heart volumes and left ventricular (LV) ejection fraction (LVEF) in adult patients. However, it remains unclear whether this automated adaptive analytics algorithm, derived from a 'training' population, can encompass adequate echo images in Chinese adolescents. OBJECTIVES: The aim of our study was to explore the accuracy of HeartModel in adolescents compared with expert manual three-dimensional (3D) echocardiography. METHODS: Fifty-three Chinese adolescent subjects with or without heart disease underwent 3D echocardiographic imaging with an EPIQ system (Philips). 3D cardiac volumes and LVEF obtained with the automated HeartModel program were compared with manual 3D echocardiographic measurements by an experienced echocardiographer. RESULTS: There was strong correlation between HeartModel and expert manual 3DE measurements (r = 0.875-0.965, all P < 0.001). Automated LV and left atrial (LA) volumes were slightly overestimated when compared to expert manual measurements, while LVEF showed no significant differences from the manual method. Importantly, the intra- and inter-observer variability of automated 3D echocardiographic model was relatively low (<1%), surpassing the manual approach (3.5-17.4%), yet requiring significantly less analyzing time (20 ± 7 vs 177 ± 30 s, P < 0.001). CONCLUSION: Simultaneous quantification of left heart volumes and LVEF with the automated HeartModel program is rapid, accurate and reproducible in Chinese adolescent cohort. Therefore, it has a potential to bring 3D echocardiographic assessment of left heart chamber volumes and function into busy pediatric practice.

Importance of chronotropic response and left ventricular long-axis function for exercise performance in patients with heart failure and preserved ejection fraction.

BACKGROUND: We evaluated the relationship between the degree of chronotropic incompetence and left ventricular (LV) impairment during exercise with severity of exercise intolerance in patients with heart failure and preserved ejection fraction (HFPEF). METHODS: All patients underwent exercise echocardiography during bicycle Ergometer exercise with the acquisition of long-axis tissue Doppler imaging (TDI). Peak heart rates during exercise were also recorded and the percentages of maximal age-predicted heart rate (%MPHR) and heart rate reserve (%HRR) were calculated thereby. Besides, cardiopulmonary exercise testing was performed with peak oxygen consumption (VO2) measuring averaged at the highest 30-second during exercise. RESULTS: Forty HFPEF patients (aged 65±9 years; 75% male) were divided into two groups according to the median of peak VO2: patients with peak VO2<16.5 and ≥16.5 ml/kg/min, respectively. Patients with lower peak VO2 had decreased peak heart rates, %MPHR, %HRR, stroke volume and cardiac indices (LVSI and LVCI) than those with higher peak VO2 (all p<0.05). The LV long-axis functions (TDI Sm, Em, s' and e') were reduced in patients with lower peak VO2 (all p<0.05). Moreover, peak VO2 correlated with the following parameters: peak heart rates, %MPHR, %HRR, LVSI, LVCI, TDI Sm, Em, s' and e'(all p<0.05). CONCLUSIONS: The degree of blunted chronotropic response and impaired LV long-axis function were more profound in HFPEF patients with poor exercise performance.

Left ventricular long-axis performance during exercise is an important prognosticator in patients with heart failure and preserved ejection fraction.

BACKGROUND: Although many prognostic variables have been reported, the risk stratification of patients with heart failure and preserved ejection fraction (HFPEF) has long been controversial due to considerable discordance. Ergometry stress echocardiography may provide a more clinical relevant evaluation in HFPEF. We aimed at evaluating the prognostic value of echocardiographic parameters during exercise in HFPEF patients. METHODS: Comprehensive echocardiographic examination with symptom-limited exercise testing on a semi-recumbent and tilting bicycle Ergometer (Lode BV, Groningen, the Netherlands) was performed on 80 consecutive HFPEF patients (aged 66±8years; 64% male). The exercise images for two-dimensional (2D) speckle tracking analysis were acquired with heart rate of 90-100bpm, while exercise images for tissue Doppler imaging (TDI) and M-mode echocardiography were stored with attainment of >85% of maximal age-predicted heart rate. All patients were followed up for 3years after stress echocardiography for all-cause mortality and/or heart failure (HF) hospitalization. RESULTS: During the follow-up, 43 (54%) patients reached the combined end point: 5 (6%) patients died, and another 38 (48%) patients experienced HF hospitalizations. Univariate predictors were: decreased resting left atrial ejection fraction (LAEF), lower peak heart rate, elevated E/e' ratio, reduced TDI myocardial velocities, and impaired 2D global longitudinal strain (GLS) during exercise. Only impaired GLS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67 to 0.91) remained independent after multivariate analysis (p=0.008). CONCLUSIONS: More than half of the HFPEF patients died or were hospitalized for HF at 3-year follow-up and this was significantly related to impaired left ventricular long-axis function during exercise.

Long-term follow-up results of the pacing to avoid cardiac enlargement (PACE) trial.

AIMS: We report the results of long-term follow-up of the Pacing to Avoid Cardiac Enlargement (PACE) trial, a prospective, double-blinded, randomized, multicentre study that confirmed the superiority of biventricular (BiV) pacing compared with right ventricular apical (RVA) pacing in prevention of LV adverse remodelling and deterioration of systolic function at 1 and 2 years. METHODS AND RESULTS: Patients with bradycardia and preserved LVEF were randomized to receive RVA (n = 88) or BiV pacing (n = 89). Co-primary endpoints were LV end-systolic volume (LVESV) and LVEF measured by echocardiography. There were 149 patients who had extended follow-up, with a mean duration of 4.8 ± 1.5 years (2.5-7.8 years). The primary endpoint analyses were performed in 146 patients (74 in the RVA group and 72 in the BiV group). In the RVA pacing group, the LVEF decreased while the LVESV increased progressively at follow-up, but remained unchanged in the BiV pacing group. The differences in LVEF between the RVA and BiV groups were -6.3, -9.2, and -10.7% at 1-year, 2-year, and long-term follow-up, respectively (all P < 0.001). The corresponding differences in LVESV were +7.4, +9.9, and +13.1 mL, respectively (all P < 0.001). The deleterious effects of RVA pacing consistently occurred in all the pre-defined subgroups. Furthermore, patients with RVA pacing had a significantly higher prevalence of heart failure hospitalization than the BiV group (23.9% vs. 14.6%, log-rank χ² = 7.55, P = 0.006). CONCLUSION: Left ventricular adverse remodelling and deterioration of systolic function continued at long-term follow-up in patients with RVA pacing; this deterioration was prevented by the use of BiV pacing. Also, heart failure hospitalization was more prevalent in the RVA pacing group.

Changes of ventricular and peripheral performance in patients with heart failure and normal ejection fraction: insights from ergometry stress echocardiography.

AIMS: We assessed the left ventricular (LV) and peripheral performance at rest and during exercise in healthy and heart failure subjects with normal ejection fraction (HFNEF) or with reduced ejection fraction (HFREF). METHODS: All subjects received echocardiography at rest and with bicycle Ergometer exercise. The exercise images for two-dimensional speckle tracking were acquired with submaximal heart rate of 90-100 beats/min, while images for M-mode and tissue Doppler imaging were stored with attainment of >85% of predicted heart rate. RESULTS: A total of 80 HFNEF, 50 HFREF and 50 controls were studied. There was progressive decrease of two-dimensional global circumferential, radial and longitudinal strains (GCS, GRS and GLS), M-mode and tissue Doppler imaging long-axis parameters from controls, HFNEF to HFREF patients (all P < 0.05) at rest and on exercise. The degree of exercise-induced, long-axis augmentation (GLS and M-mode long axis excursion) decreased progressively from controls, HFNEF to HFREF subjects (all P < 0.05), while the increase in GCS and GRS was similar in all groups. The ventricular-arterial coupling ratio did not change in HFREF but reduced in HFNEF and controls during exercise (P < 0.01). All subjects had a similar resting heart rate, but patients exhibited chronotropic non-competence during exercise (P < 0.001). CONCLUSIONS: Ventricular and peripheral dysfunction was evident in HFNEF at rest and deteriorated during exercise. The HFNEF patients had significantly impaired long-axis augmentation at stress that was intermediate between HFREF patients and controls. These findings have relevance to generation of symptoms on exercise in both HFNEF and HFREF.

Three-dimensional speckle strain echocardiography is more accurate and efficient than 2D strain in the evaluation of left ventricular function.

BACKGROUND: Two-dimensional speckle tracking echocardiography (2DSTE) has been used widely in research, but rarely in clinical practice because data acquisition and analysis are time-consuming. By reducing the acquisition and analysis time, 3-dimensional STE may improve clinical impact. We investigated the feasibility of 3DSTE myocardial deformation, with comparison to 2DSTE. METHODS: Transthoracic 3DSTE and 2DSTE were performed in 230 adults (138 men, 51 ± 14 years, and 142 hypertension, 10 heart failure and 78 normotensive subjects). The variables of LV deformation were analyzed using EchoPAC software. RESULTS: The 3D LV longitudinal (LS) analysis was feasible in 84.9% of the study subjects, which was lower than the 2D analysis (97.2%). The success rates for circumferential strain (CS) and radial strain (RS) were similar between the 2D and 3D techniques. All magnitude of strains measured by 2DSTE and 3DSTE were significantly correlated. The magnitude of 3D LS and CS was lower, but the 3D RS is higher than that of 2DSTE (-18.5 ± 2.8 vs. -21.2 ± 3.5; 20.8 ± 4.1 vs. 21.7; and 50.0 ± 11.2 vs. 37.7 ± 12.6, respectively). Strains measured by 3DSTE exhibited stronger correlation with LV ejection fraction (EF) than that by 2DSTE. In inter- and intra-observer reproducibility for 3D LS, CS, RS and AS were acceptable. The mean time of analysis for LV volume, EF and strains was 116s by 3DSTE, which was significantly shorter than that by 2DSTE (5 min, P<0.0001). CONCLUSIONS: Three-dimensional STE is feasible and reproducible in the estimation of LV function, requires substantially less time than 2DSTE and is a more feasible technique for LV function assessment in clinical practice.

Left anterior descending coronary artery flow impaired by right ventricular apical pacing: the role of systolic dyssynchrony.

INTRODUCTION: Right ventricular (RV) pacing may affect myocardial perfusion and coronary blood flow; however, it remains unknown whether this is related to systolic dyssynchrony induced by RV pacing. This prospective study was aimed to assess the relationship between dyssynchrony and the changes of coronary blood flow. METHODS: Seventy patients with sinus node dysfunction were prospectively enrolled. Coronary flow was evaluated by measuring diastolic velocity time integral (VTI) and duration at the distal-portion of left anterior descending coronary artery (LAD) with transthoracic echocardiography at baseline and follow-up. Systolic dyssynchrony was assessed with tissue Doppler imaging by time standard deviation to peak systolic velocity of 12 left ventricular segments (Ts-SD, cutoff value ≥ 33 ms). RESULTS: Adequate data for analysis was available from 65 patients. At follow-up (mean follow up time: 127 ± 45 days), LAD velocity-time integral (LAD-VTI: 12.1 ± 4.2 vs. 10.7 ± 4.6 cm, p<0.001) was decreased and there was deterioration of left ventricular systolic function (left ventricular ejection fraction: 65 ± 7% vs. 62 ± 7%). However, these changes were only detected in those with RV pacing induced systolic dyssynchrony. Significant reduction of LAD-VTI (defined as ≥ 5%) occurred in 34 (52%) patients which was more prevalent in those with pacing-induced systolic dyssynchrony than those without (85.3% versus 16.1%, χ(2)=31.1, p<0.001). Though similar at baseline, LAD-VTI was significantly lower in the dyssynchrony group at follow up (p<0.001). Cox-regression analysis showed that pacing-inducing systolic dyssynchrony [hazard ratio (HR): 3.62, p=0.009] and higher accumulative pacing percentage (HR: 1.02, p=0.002) were independently associated with reduction of LAD-VTI. ROC curve demonstrated that accumulative pacing percentage ≥ 35% was 97% sensitive and 84% specific in revealing significant reduction (area under the curve: 0.961, p<0.001). CONCLUSIONS: RV pacing induced dyssynchrony is associated with reduced coronary flow and this may account for, in part, the deleterious effect of RV pacing on ventricular function over time.

What can three-dimensional speckle-tracking echocardiography contribute to evaluate global left ventricular systolic performance in patients with heart failure?

PURPOSE: Three-dimensional speckle-tracking echocardiography (3D-STE) is a newly developed technique to evaluate left ventricular (LV) deformation by measuring the area strain (AS) of endocardial surface that combines information from both longitudinal (LS) and circumferential strain (CS). We performed a study to examine myocardial deformation in patients with heart failure (HF) using 3D-STE. METHOD: A total of 149 subjects including 58 patients with HF and preserved ejection fraction (HFPEF), 45 patients with HF and reduced ejection fraction (HFREF), and 46 normal subjects were prospectively studied by 3D-STE. RESULT: After adjusting for age, gender and BSA, global CS, LS, radial strain (RS) and AS derived from 3D-STE in patients with HFPEF were significantly higher than their counterparts in patients with HFREF (all p<0.001), but lower than that in normal subjects (all p<0.05). In addition, among all the strain parameters, global AS exhibited the highest correlation with LV ejection fraction (y=1.243x+6.332, r=0.982, p<0.001) and the best intra- (ICCs: 0.986, p<0.001) and inter-observer variability (ICCs: 0.978, p<0.001) than other parameters of 3D strain (CS: 0.981 and 0.974; LS: 0.908 and 0.841; RS: 0.946 and 0.915; all p<0.001). CONCLUSIONS: Measurement of endocardial surface AS based on 3D-STE technique is reproducible and proves to be accurate and comprehensive in assessing the global LV performance and multidirectional deformation of the LV myocardium in HF patients.

Characterization of mid-term atrial geometrical and electrical remodeling following device closure of atrial septal defects in adults.

PURPOSE: Late-onset atrial arrhythmia after successful closure of atrial septal defect (ASD) is not uncommon. Right atrial (RA) enlargement and increased electrocardiographic P-wave dispersion (Pd) independently predict the development of atrial arrhythmia. Data on the degree of right atrial (RA) geometrical and electrical remodeling following device closure of ASD are limited. METHODS: Echocardiography and electrocardiography (ECG) were performed in 58 consecutive patients (47 ± 17 years) before and at 3 months after ASD closure. Persistent RA enlargement was defined as RA volume index (RAVI) ≥ 21 ml/m(2) at 3 months. Pd was calculated as the difference between maximal and minimal P-wave durations in 12-lead ECG. RESULTS: RA size reduced (RAVI: 50 ± 28 vs. 26 ± 16 ml/m(2), p<0.001) and Pd on ECG decreased (53 ± 17 vs. 49 ± 20 ms, p<0.05) significantly at 3 months when compared to baseline. However, persistent RA enlargement remained evident in 31 patients (53%). As a group, they were older with higher pulmonary arterial systolic pressure, larger Qp/Qs, longer maximal P-wave duration and Pd than those with normalized RA. Pd reduction only occurred in patients with normalized RA size. The 3-month Pd (hazard ratio: 1.033, p<0.001) predicted the presence of incomplete RA geometrical remodeling. ROC curve revealed that Pd ≥ 45 ms at 3 months was 77% sensitive and 86% specific in revealing residual RA enlargement. CONCLUSION: Both atrial geometrical and electrical reverse remodeling were evident at 3 months following ASD closure. However, only half of the included patients had normalization of RA size which could be revealed by a simple ECG surrogate of intra-atrial conduction disturbance.

Quantification of left ventricular performance in different heart failure phenotypes by comprehensive ergometry stress echocardiography.

BACKGROUND: We evaluated the left ventricular (LV) performance in patients with heart failure and preserved ejection fraction (HFPEF) during exercise as compared to those with heart failure and reduced ejection fraction (HFREF) and healthy subjects. METHODS: All subjects received echocardiographic (Vivid7, GE Healthcare) examination with symptom-limited exercise testing on a semi-recumbent and tilting bicycle ergometer (Lode BV, Netherlands). The exercise images for 2-dimensional (2D) speckle tracking were acquired with heart rate of 90-100 bpm, while exercise images for tissue Doppler imaging (TDI) and M-mode echocardiography were stored with attainment of >85% of maximal age-predicted heart rate. RESULTS: Stress echocardiographic examinations were performed in 40 HFPEF (aged 65 ± 9 years; 53% male), 40 HFREF (aged 62 ± 9 years; 90% male) and 30 normal controls (aged 56 ± 5 years; 33% male). Trends of progressive decline in 2D global longitudinal, circumferential and radial strains (GLS, GCS and GRS); TDI septal s' and Sm; and M-mode mitral annular plane systolic excursion (MAPSE) were observed from control, HFPEF to HFREF groups (p<0.05 for all). LV twist was preserved in HFPEF but reduced in HFREF patients as compared to normal controls (p<0.05). Diastolic function measured by TDI septal e', Em and septal E/e' progressively decreased from controls, HFPEF to HFREF patients (all p<0.05). Stroke volumes and cardiac indices (LVSI & LVCI) were preserved in HFPEF but deteriorated in HFREF than controls. CONCLUSIONS: This study provides the reference values of LV performance during exercise in HFPEF and knowledge about these changes provide important insights for future clinical studies.

Improved coronary artery blood flow following the correction of systolic dyssynchrony with cardiac resynchronization therapy.

BACKGROUND: Coronary blood flow (CBF) is improved by cardiac resynchronization therapy (CRT) and impaired by right ventricular apical (RVA) pacing in patients with heart failure. However, the underlying mechanism remains unclear. METHODS: Twenty-nine non-ischemic heart failure patients who responded to CRT underwent transthoracic echocardiography examination including both left anterior descending (LAD) CBF and tissue Doppler imaging in 3 pacing modes: intrinsic conduction, RVA pacing and biventricular (BiV) pacing. LAD velocity-temporal integral (LAD-VTI) and duration were measured. Systolic dyssynchrony was assessed with the standard deviation of a 12-left ventricular segmental model (Ts-SD). RESULTS: BiV pacing improved while RVA pacing reduced CBF compared to intrinsic conduction (all p<0.05). Both Ts-SD and ventricular septal velocity deteriorated during RVA pacing but improved during BiV pacing (all p<0.05). When systolic dyssynchrony was induced, lower LAD-VTI (9.5 ± 3.4 versus 12.7 ± 5.1cm, p=0.001) and shorter LAD diastolic duration (483 ± 92 versus 542 ± 106 ms, p=0.010) were detected than synchronous status. Systolic dyssynchrony was inversely related to septal velocity (r=-0.41), p<0.001 and LAD-VTI (r=-0.30, p=0.007), with the latter found to be moderately correlated to septal velocity (r=0.30, p=0.007). CONCLUSION: Regional LAD flow was improved in patients subjected to BiV but worsened in those treated with RVA pacing in non-ischemic heart failure CRT responders. Systolic dyssynchrony was more commonly observed in patients subjected to RVA pacing. Reduction of septal velocity with dyssynchrony may directly lead to reduced LAD flow. Improvement of septal velocity by CRT and hence LAD flow may be an important mechanism in determining the response to CRT.

Prevalence and determinants of incomplete right atrial reverse remodeling after device closure of atrial septal defects.

Whether the relief of chronic right atrial (RA) volume load by device closure of an atrial septal defect (ASD) normalizes RA size is unknown. The present study evaluated the prevalence and determinants of incomplete RA reverse remodeling (RAR) after ASD closure in adults. Transthoracic echocardiography was performed in 44 consecutive patients with secundum ASD (age 43 ± 17 years, 10 men) without a history of atrial arrhythmia shortly before and at 3 months after device closure of ASD. The pulmonary/systemic flow ratio was derived using invasive oximetry. The RA size had significantly decreased at 3 months of follow-up (RA volume index [RAVI] 52 ± 29 to 27 ± 17 ml/m(2), p <0.001). Incomplete RAR (defined as a RAVI of ≥21 ml/m(2)) was detected in 25 patients (57%) after closure. They were older, had a larger pulmonary/systemic flow ratio, a higher pulmonary arterial systolic pressure, more tricuspid regurgitation, and larger RA, left atrial, and right ventricular sizes before closure than those with a normalized right atrium. Before closure, RAVI was the only independent determinant for incomplete RAR (odds ratio 1.115, 95% confidence interval 1.019 to 1.220; p = 0.018). A cutoff value of RAVI of ≥40 ml/m(2) has a sensitivity of 84% and specificity of 72% in the receiver operating characteristic curve. The preclosure RAVI correlated moderately with the shunt-duration index, calculated by multiplying the age to pulmonary/systemic flow ratio (r = 0.64, p <0.01). In conclusion, incomplete RAR occurred in >1/2 of the adult patients at 3 months after ASD device closure and was related to excessive preclosure RA dilation.