Shuping Ge

Left ventricular three-dimensional global systolic strain by real-time three-dimensional speckle-tracking in children: feasibility, reproducibility, maturational changes, and normal ranges.

BACKGROUNDnThree-dimensional (3D) strain analysis may help overcome the limitations of Doppler and two-dimensional strain analysis for the left ventricle and become the method of choice for left ventricular (LV) systolic function. The aims of this study were to evaluate the feasibility and reproducibility of LV global 3D systolic strain by real-time 3D speckle-tracking echocardiography (STE) in children and to establish their maturational growth patterns and normal values.nnnMETHODSnA prospective study was conducted in 256 consecutive healthy subjects using real-time 3D echocardiography. Full-volume 3D data were acquired using a 3D matrix-array transducer. Three-dimensional LV peak systolic global strain (GS), global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) values were determined using real-time 3D STE.nnnRESULTSnA total of 228 patients (89%) met the criteria for analysis; 28 (11%) were excluded. The correlations between age and strain variables by real-time 3D STE were poor (R(2)xa0= 0.01-0.05, P < .05). The differences in GLS and GCS among the five age groups were statistically significant but clinically irrelevant. There were no statistical differences in GRS and GS values among the age groups, nor were there statistical differences between the genders for all 3D strain parameters. Intraobserver and interobserver variability ranged from 5.0 ± 4.3% to 10.1 ± 8.5% versus 6.9 ± 6.1% to 17.0 ± 16.2% for coefficients of variation, respectively. Interclass correlation coefficients ranged from 0.78 to 0.87 and from 0.75 to 0.79 for intraobserver and interobserver measurements for GS, GLS, GCS, and GRS, respectively.nnnCONCLUSIONSnLV global 3D systolic strain analysis using the new 3D STE is feasible and reproducible in the pediatric population. There are small maturational changes in GLS and GCS, but not in GRS and GS, that are statistically significant but probably clinically irrelevant. Further investigation is warranted for potential clinical application of this new technology in a pediatric population.

Inflammation and cardiac dysfunction during sepsis, muscular dystrophy, and myocarditis

Inflammation plays an important role in cardiac dysfunction under different situations. Acute systemic inflammation occurring in patients with severe burns, trauma, and inflammatory diseases causes cardiac dysfunction, which is one of the leading causes of mortality in these patients. Acute sepsis decreases cardiac contractility and impairs myocardial compliance. Chronic inflammation such as that occurring in Duchenne muscular dystropshy and myocarditis may cause adverse cardiac remodeling including myocyte hypertrophy and death, fibrosis, and altered myocyte function. However, the underlying cellular and molecular mechanisms for inflammatory cardiomyopathy are still controversial probably due to multiple factors involved. Potential mechanisms include the change in circulating blood volume; a direct inhibition of myocyte contractility by cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β); abnormal nitric oxide and reactive oxygen species (ROS) signaling; mitochondrial dysfunction; abnormal excitation-contraction coupling; and reduced calcium sensitivity at the myofibrillar level and blunted β-adrenergic signaling. This review will summarize recent advances in diagnostic technology, mechanisms, and potential therapeutic strategies for inflammation-induced cardiac dysfunction.

Enhanced basal contractility but reduced excitation-contraction coupling efficiency and β-adrenergic reserve of hearts with increased Cav1.2 activity

Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca(2+) channel (Cav1.2). However, the effects of enhanced Cav1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the beta-adrenergic system are not clear. To recapitulate the increased Cav1.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavbeta2a subunit in a cardiac-specific and inducible manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon beta-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca(2+) current (I(Ca,L)) density, myocyte fractional shortening (FS), peak Ca(2+) transients, and sarcoplasmic reticulum (SR) Ca(2+) content (caffeine-induced Ca(2+) transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dP/dt and -dP/dt) measurements were significantly greater in DTG mice than in control mice. However, 1) the cardiac contractility (EF, FS, dP/dt, and -dP/dt)-enhancing effect of the beta-adrenergic agonist isoproterenol (2 microg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of beta-adrenergic stimulation on contraction, Ca(2+) transients, I(Ca,L), and SR Ca(2+) content in DTG myocytes; and 2) E-C couplng efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cav1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart.

Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy

AIMSnTo determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.nnnMETHODS AND RESULTSnReplacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca(2+)]i, and sarcoplasmic reticulum (SR) Ca(2+) content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and the Na(+)/Ca(2+) exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.nnnCONCLUSIONnIn young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.

Three-Dimensional Rotation, Twist and Torsion Analyses Using Real-Time 3D Speckle Tracking Imaging: Feasibility, Reproducibility, and Normal Ranges in Pediatric Population.

Background and Objective The specific aim of this study was to evaluate the feasibility, reproducibility and maturational changes of LV rotation, twist and torsion variables by real-time 3D speckle-tracking echocardiography (RT3DSTE) in children. Methods A prospective study was conducted in 347 consecutive healthy subjects (181 males/156 females, mean age 7.12 ± 5.3 years, and range from birth to 18-years) using RT 3D echocardiography (3DE). The LV rotation, twist and torsion measurements were made off-line using TomTec software. Manual landmark selection and endocardial border editing were performed in 3 planes (apical “2”-, “4”-, and “3”- chamber views) and semi-automated tracking yielded LV rotation, twist and torsion measurements. LV rotation, twist and torsion analysis by RT 3DSTE were feasible in 307 out of 347 subjects (88.5%). Results There was no correlation between rotation or twist and age, height, weight, BSA or heart rate, respectively. However, there was statistically significant, but very modest correlation between LV torsion and age (R2 = 0.036, P< 0.001). The normal ranges were defined for rotation and twist in this cohort, and for torsion for each age group. The intra-observer and inter-observer variabilities for apical and basal rotation, twist and torsion ranged from 7.3% ± 3.8% to 12.3% ± 8.8% and from 8.8% ± 4.6% to 15.7% ± 10.1%, respectively. Conclusions We conclude that analysis of LV rotation, twist and torsion by this new RT3D STE is feasible and reproducible in pediatric population. There is no maturational change in rotation and twist, but torsion decreases with age in this cohort. Further refinement is warranted to validate the utility of this new methodology in more sensitive and quantitative evaluation of congenital and acquired heart diseases in children.

Ultrasound-Targeted Microbubble Destruction (UTMD) Assisted Delivery of shRNA against PHD2 into H9C2 Cells.

Gene therapy has great potential for human diseases. Development of efficient delivery systems is critical to its clinical translation. Recent studies have shown that microbubbles in combination with ultrasound (US) can be used to facilitate gene delivery. An aim of this study is to investigate whether the combination of US-targeted microbubble destruction (UTMD) and polyethylenimine (PEI) (UTMD/PEI) can mediate even greater gene transfection efficiency than UTMD alone and to optimize ultrasonic irradiation parameters. Another aim of this study is to investigate the biological effects of PHD2-shRNA after its transfection into H9C2 cells. pEGFP-N1 or eukaryotic shPHD2-EGFP plasmid was mixed with albumin-coated microbubbles and PEI to form complexes for transfection. After these were added into H9C2 cells, the cells were exposed to US with various sets of parameters. The cells were then harvested and analyzed for gene expression. UTMD/PEI was shown to be highly efficient in gene transfection. An US intensity of 1.5 W/cm2, a microbubble concentration of 300μl/ml, an exposure time of 45s, and a plasmid concentration of 15μg/ml were found to be optimal for transfection. UTMD/PEI-mediated PHD2-shRNA transfection in H9C2 cells significantly down regulated the expression of PHD2 and increased expression of HIF-1α and downstream angiogenesis factors VEGF, TGF-β and bFGF. UTMD/PEI, combined with albumin-coated microbubbles, warrants further investigation for therapeutic gene delivery.

Echocardiographic diagnosis of rare pathological patterns of sinus of Valsalva aneurysm

Objective To evaluate the value and improve the diagnostic accuracy of echocardiography in the diagnosis of a sinus of Valsalva aneurysm (SVA) with rare pathological patterns. Methods Echocardiographic features and surgical findings from 270 Chinese patients with SVA treated in the last 18 years (1995–2013) at the Union Hospital were compared retrospectively; 22 of 270 cases had rare patterns. Results The patients with SVA, a rare origin, a rare extending position, or a rare course accounted for 3.4%, 7.4%, and 0.4% of the 270 cases, respectively. The three most common aneurysmal complications of the patients with rare patterns were severe aortic regurgitation (16), obstruction of the ventricular outflow tract or valvular orifice (3), and conduction disturbance (3). The origin, course, extending position and rupture status of the SVAs determined by echocardiography were entirely consistent with surgical findings in 81.8% of the 22 cases. With the exception of one failed diagnosis of an aneurysmal wall dissection and one misdiagnosis of a descending aortic dissection, the echocardiographic results of SVA complications and associated cardiovascular lesions were also confirmed. Conclusion We could accurately diagnose SVAs with rare pathological patterns by echocardiographic identification of distinguishing features. However, for several conditions, we could not accurately identify the origin or course of the aneurysm or define its relationship to adjacent structures using conventional echocardiography alone. Therefore, we recommend combining conventional echocardiography with different imaging techniques, such as transesophageal echocardiography, three-dimensional echocardiography, computed tomography angiography, and aortic angiography.

Reduced Myocardial Reserve in Young X-Linked Muscular Dystrophy Mice Diagnosed by Two-Dimensional Strain Analysis Combined with Stress Echocardiography

Background: Early, sensitive, and reproducible evaluation of left ventricular function is imperative for the diagnosis of cardiac dysfunction in patients with Duchene muscular dystrophy. The aim of this study was to test the hypothesis that combining two‐dimensional strain analysis with catecholamine stress could be a sensitive method for detecting early cardiac dysfunction. Methods: Mdx (C57BL/10ScSn‐Dmdmdx/J, a mouse model of DMD) and control (C57BL/10ScSn) mice were studied with conventional M‐mode and high‐frequency ultrasound‐based two‐dimensional speckle‐tracking echocardiography using long‐ and short‐axis images of the left ventricle at baseline and after intraperitoneal isoprenaline (ISO) administration (2 &mgr;g/g body weight). Results: Conventional M‐mode analysis showed no differences in left ventricular fractional shortening, wall thickness, or internal diameter at diastole between mdx and control mice before the age of 6 months. ISO increased left ventricular ejection fraction and fractional shortening to the same extent in mdx and control mice at young ages (3, 4, and 5 months). No differences in basal peak systolic strain (PSS) but increased SDs of times to PSS between young mdx and control mice were found. After ISO, PSS and percentile changes of PSS were significantly diminished in mdx mice compared with control mice at young ages. ISO increased the normalized maximum difference of times to PSS in young mdx mice but not in young control mice, suggesting that ISO reduces cardiac contractile synchrony in young mdx mice. Conclusions: This study suggests that catecholamine stress coupled with two‐dimensional strain analysis is a feasible and sensitive approach for detecting early onset of cardiac dysfunction, which is instrumental for early diagnosis of cardiac dysfunction and early treatment. HighlightsCardiac dysfunction becomes an important contributing factor to mortality and morbidity in patients with muscular dystrophy.There is still a lack of reliable approaches to diagnose early cardiac dysfunction in patients with DMD.The combination of 2D strain analysis with ISO stress showed reduced &bgr;‐adrenergic reserve and increased contractile dyssynchrony in mdx mice at a very early stage.Two‐dimensional strain analysis with stress testing is a feasible and sensitive approach to diagnose early cardiac dysfunction and to evaluate treatments in patients with DMD.The treatment of cardiac dysfunction should be started at a young age in patients with DMD.

Correction: Echocardiographic diagnosis of rare pathological patterns of sinus of Valsalva aneurysm

[This corrects the article DOI: 10.1371/journal.pone.0173122.].

Preclinical cardiovascular changes in children with obesity: A real-time 3-dimensional speckle tracking imaging study

The aims of this study were (1) to quantify changes in 3-dimensional (3D) strain in obese children using real-time 3D echocardiography (RT3DE) and 3D speckle tracking echocardiography (3DSTE), and (2) to investigate the utility of left ventricular (LV) strain variables in measuring early cardiovascular changes in children with obesity. A total of 181 obese children (study group) aged 4–18 years old were prospectively enrolled and compared with 229 healthy subjects (control group). We acquired demographic, clinical, biochemical, and 2D echocardiography/Doppler data. Also, RT3DE and 3DSTE were performed to measure LV volume, left ventricular ejection fraction (LVEF), LV mass (LVM), LV peak systolic global longitudinal strain (GLS), radial strain (GRS), circumferential strain (GCS), and global strain (GS). There were significant differences in anthropometric measurements, blood pressures, Cholesterol, C-reactive protein (CRP), Intima-media thickness (IMT), left atrium end-systolic dimension (LASD), interventricular septal end-diastolic dimension (IVSD), LV posterior wall end-diastolic dimension (LVPWD), LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), LV end-diastolic volumes (LVEDV), and LV end-systolic volumes (LVESV), E and A velocities, E/A,e’, e’/a’, E/e’, LVM, LV mass index (LVMI), GLS, GRS, GCS, and GS between the study and control groups. The receiver operating characteristic curves (ROC) for the statistically significant echocardiographic variables showed that the range of areas of ROC curves varied from 0.76 (GLS), 0.74 (GRS), 0.72 (LASD), to 0.58 (LVESD), respectively. In conclusion, LV 3D strain variables by RT3DE and 3DSTE decrease in obese children. LV 3D strain is more sensitive than other echocardiographic and vascular ultrasound variables in detecting cardiovascular changes in children with obesity.