Sarah Chua

Short- and long-term results of catheter balloon percutaneous transvenous mitral commissurotomy

Percutaneous transvenous mitral commissurotomy (PTMC) was performed in 219 patients with symptomatic, severe rheumatic mitral stenosis. There were 59 men and 160 women, aged 19 to 76 years (mean 43). Pliable, noncalcified valves were present in 139 (group 1), and calcified valves or severe mitral subvalvular lesions, or both, in 80 patients (group 2). Atrial fibrillation was present in 133 patients (61%) and 1+ or 2+ mitral regurgitation in 59 (27%). Technical failure occurred with 3 patients in our early experience. There was no cardiac tamponade or emergency surgery. The only in-hospital death occurred 3 days after the procedure in a group 2 premoribund patient in whom last-resort PTMC created 3+ mitral regurgitation. Mitral regurgitation appeared or increased in 72 patients (33%); 3+ mitral regurgitation resulted in 12 patients (6%). There were 3 systemic embolisms. Atrial left-to-right shunts measured by oximetry developed in 33 patients (15%). Immediately after PTMC, there were significantly reduced (p = 0.0001) left atrial pressure (24.2 +/- 5.6 to 15.1 +/- 5.1 mm Hg), mean pulmonary artery pressure (39.7 +/- 13.0 to 30.6 +/- 10.9 mm Hg) and mitral valve gradient (13.0 +/- 5.1 to 5.7 +/- 2.6 mm Hg). Mitral valve area increased from 1.0 +/- 0.3 to 2.0 +/- 0.7 cm2 (p = 0.0001) and cardiac output from 4.4 +/- 1.4 to 4.7 +/- 1.2 liters/min (p less than 0.01). The results mirrored clinical improvements in 209 patients (97%). Multivariate analysis showed an echo score greater than 8, and valvular calcification and severe subvalvular lesions as independent predictors for suboptimal hemodynamic results.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose-Derived Mesenchymal Stem Cell Protects Kidneys against Ischemia-Reperfusion Injury through Suppressing Oxidative Stress and Inflammatory Reaction

BackgroundReactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury.MethodsAdult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed.ResultsSerum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02)ConclusionADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.

Direct Measurement of Vena Contracta Area by Real-Time 3-Dimensional Echocardiography for Assessing Severity of Mitral Regurgitation

We tested the hypothesis that the vena contracta (VC) cross-sectional area in patients with mitral regurgitation (MR) can be reproducibly measured by real-time 3-dimensional (3D) echocardiography and correlates well with the volumetric effective regurgitant orifice area (EROA). Earlier MR repair requires accurate noninvasive measures, but practically, the VC area is difficult to image in 2-dimensional views, which are often oblique to it. 3D echocardiography can provide an otherwise unobtainable true cross-sectional view. In 45 patients with mild or greater MR, 44% eccentric, 2-dimensional and 3D VC areas were measured and correlated with the EROA derived from the regurgitant stroke volume. Real-time 3D echocardiography of the VC area correlated and agreed well with the EROA for both central and eccentric jets (r(2) = 0.86, SEE 0.02 cm(2), difference 0.04 +/- 0.06 cm(2), p = NS). For eccentric jets, 2-dimensional echocardiography overestimated the VC width compared with 3D echocardiography (p = 0.024) and correlated more poorly with the EROA (r(2) = 0.61 vs 0.85, p <0.001), causing clinical misclassification in 45% of patients with eccentric MR. The interobserver variability for the 3D VC area was 0.03 cm(2) (7.5% of the mean, r = 0.95); the intraobserver variability was 0.01 cm(2) (2.5% of the mean, r = 0.97). In conclusion, real-time 3D echocardiography accurately and reproducibly quantified the vena contracta cross-sectional area in patients with both central and eccentric MR. Rapid acquisition and intuitive analysis promote practical clinical application of this central, directly visualized, measure and its correlation with outcome.

Autologous Transplantation of Adipose-Derived Mesenchymal Stem Cells Markedly Reduced Acute Ischemia-Reperfusion Lung Injury in a Rodent Model

BackgroundThis study tested the hypothesis that autologous transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can effectively attenuate acute pulmonary ischemia-reperfusion (IR) injury.MethodsAdult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus intravenous transplantation of 1.5 × 106 autologous ADMSCs at 1h, 6h, and 24h following IR injury). The duration of ischemia was 30 minutes, followed by 72 hours of reperfusion prior to sacrificing the animals. Blood samples were collected and lungs were harvested for analysis.ResultsBlood gas analysis showed that oxygen saturation (%) was remarkably lower, whereas right ventricular systolic pressure was notably higher in group 2 than in group 3 (all p < 0.03). Histological scoring of lung parenchymal damage was notably higher in group 2 than in group 3 (all p < 0.001). Real time-PCR demonstrated remarkably higher expressions of oxidative stress, as well as inflammatory and apoptotic biomarkers in group 2 compared with group 3 (all p < 0.005). Western blot showed that vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, oxidative stress, tumor necrosis factor-α and nuclear factor-κB were remarkably higher, whereas NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 activities were lower in group 2 compared to those in group 3 (all p < 0.004). Immunofluorescent staining demonstrated notably higher number of CD68+ cells, but significantly fewer CD31+ and vWF+ cells in group 2 than in group 3.ConclusionADMSC therapy minimized lung damage after IR injury in a rodent model through suppressing oxidative stress and inflammatory reaction.

Bone marrow-derived mononuclear cell therapy alleviates left ventricular remodeling and improves heart function in rat-dilated cardiomyopathy.

Objectives: This study hypothesized that bone marrow–derived mononuclear cell (BMDMNC) therapy may improve cardiac function through preventing cell death, alleviating left ventricular (LV) remodeling, and enhancing angio-/vasculo-genesis, as well as preserving LV contractility in a rat model of dilated cardiomyopathy (DCM). Design: A model of DCM in Sprague-Dawley rats was used to investigate the effects of BMDMNC therapy on inflammatory and oxidative response, energy depression, cellular apoptosis, expressions of protein kinase C-(PKC)-&egr;, and connexin43 protein (Cx43) in LV myocardium and heart function. Setting: An animal model research laboratory at Kaohsiung Chang Gung Memorial Hospital. Measurements: The rats were divided into group 1 (normal control, n = 8), group 2 (saline-treated DCM, n = 10), and group 3 (1.2 × 106 BMDMNC implanted into LV anterior wall on day 35 after DCM induction, n = 10). The DCM and normal control rats were killed on day 90 following DCM induction. Results: The results demonstrated that Cx43 protein expression and messenger RNA expressions of peroxisome proliferator-activated receptor-&ggr; coactivator 1 &agr;, endothelial nitric oxide synthase, and interleukin-10 were higher, whereas messenger RNA expressions of endothelin-1 and matrix metalloproteinase-9 were lower in groups 1 and 3 than in group 2 (all p < 0.05). Additionally, expressions of PKC-&egr; in plasma membrane and mitochondria and LV function were conserved in group 1 and improved in group 3, whereas cardiomyocyte apoptosis, mitochondrial oxidative stress, and fibrosis of LV myocardium were reduced in groups 1 and 3 than in group 2 (all p < 0.005). Conclusion: BMDMNC therapy in DCM significantly improves LV function by limiting cellular apoptosis, inflammatory and oxidative responses, and by up-regulating expressions of Cx43, PKC-&egr;, and energy transcription factors.

Early Combined Treatment with Cilostazol and Bone Marrow- Derived Endothelial Progenitor Cells Markedly Attenuates Pulmonary Arterial Hypertension in Rats

We investigated whether early combined cilostazol and bone marrow-derived endothelial progenitor cell (BMDEPC) treatment offers synergistic benefit in ameliorating monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Male Sprague-Dawley rats (n = 10/group) were randomized to receive saline injection only (group 1), MCT (70 mg/kg) (group 2), and MCT plus cilostazol (20 mg/kg/day) (group 3), MCT plus BMDEPCs (2.0 × 106 cells) (group 4), and MCT plus combined cilostazol/BMDEPCs (group 5). Intravenous BMDEPCs and oral cilostazol were given on day 3 after MCT administration. By day 42, connexin43 protein expression in right ventricle (RV) was reduced in group 2 compared with other groups and also was decreased in groups 3 and 4 compared with groups 1 and 5 (all p < 0.05). In addition, mRNA expressions of matrix metalloproteinase-9, tumor necrosis factor-α, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric-oxide synthase were lower in lung and RV in group 2 compared with the other groups (all p < 0.05). The number of alveolar sacs and lung arterioles was lower in group 2 than in other groups and lower in groups 3 and 4 than in group 5 (all p < 0.05). RV systolic pressure (RVSP) and weight were increased in group 2 compared with the other groups (all p < 0.0001). Moreover, RVSP and RV-to-left ventricle plus septum weight ratio were higher in groups 3 and 4 than in groups 1 and 5 (p < 0.001) but showed no difference between groups 1 and 5. In conclusion, early combined autologous BMDEPC/cilostazol treatment is superior to BMDEPC or cilostazol only for preventing MCT-induced PAH.

Usefulness of intracardiac echocardiography in transseptal puncture during percutaneous transvenous mitral commissurotomy.

P ercutaneous transvenous mitral commissurotomy has become an effective and safe alternative to surgical treatment in well-selected patients.’ Transseptal catheterization is a vital component of the procedure. Because of its technical complexity and difEculty, transseptal catheterization is recommended to be restricted to highvolume catheterization laboratories equipped with biplane fluoroscopy.2 Recently, usefulness of transthoracic 2dimensional echocardiography and transesophageal echocardiography‘t in guiding transseptal puncture has been reported. However, transthoracic 2-dimensional echocardiography may be limited by suboptimal interatria1 septum visualization. In addition, placement of the transducer on the patient’s chest not only interferes with the fluoroscopic images, but also poses a radiation hazard to the echocardiographer. Space limitations in the catheterization laboratory and a need to preserve a sterile field also make this examination cumbersome. Transesophageal echocardiography allows high-quality visualization of the interatrial septum in relation to surrounding cardiac structures, thus facilitating a safe transseptal puncture. However, it adds discomfort and stress to the patients, aside from the possible risk of esophageal injury and lung aspiration. Because of the disadvantages and limitations of transthoracic and transesophageal echocardiography, we investigated the feasibility and usefulness of intracardiac echocardiography using a commercially available 10 MHz over-the-wire intravascular ultrasound catheter to perform transseptal puncture. Seven patients with symptomatic severe mitral stenosis were studied including 2 men and 5 women aged 36 to 55 years (mean 45). Informed consent was obtained from each patient. After diagnostic catheterization, a IOFr 10 MHz ultrasound catheter was inserted into the superior vena cava over a preplaced 0.025inch guidewire through a IlFr sheath in the lef femoral vein. The catheter was interfaced with a real-time ultrasound imaging system (CVIS Inc., Sunnyvale, California). The ultrasound catheter was withdrawn caudally from the superior vena cava to the midright atrium to image the interatrial septum and the atria (Figure IA, lef panel). A 7Fr Mullins transseptal catheter with a Brockenbrough needle was inserted through the right femoral vein and its tip was set at the optimal transseptal puncture site. The latter was determined under f?on-tal fluoroscopic view according to landmark selection guidelines previously described.‘a5 The position of the catheter ultrasound transducer was adjusted so that the

Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice

BackgroundObesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice.Methods and resultsEight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001).ConclusionImpaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity.

Extracorporeal Shock Wave Therapy Reverses Ischemia-Related Left Ventricular Dysfunction and Remodeling: Molecular-Cellular and Functional Assessment

An optimal treatment for patients with diffuse obstructive arterial disease unsuitable for catheter-based or surgical intervention is still pending. This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy may be a therapeutic alternative under such clinical situation. Myocardial ischemia was induced in male mini-pigs through applying an ameroid constrictor over mid-left anterior descending artery (LAD). Twelve mini-pigs were equally randomized into group 1 (Constrictor over LAD only) and group 2 (Constrictor over LAD plus ECSW [800 impulses at 0.09 mJ/mm2] once 3 months after the procedure). Results showed that the parameters measured by echocardiography did not differ between two groups on days 0 and 90. However, echocardiography and left ventricular (LV) angiography showed higher LV ejection fraction and lower LV end-systolic dimension and volume in group 2 on day 180 (p<0.035). Besides, mRNA and protein expressions of CXCR4 and SDF-1α were increased in group 2 (p<0.04). Immunofluorescence staining also showed higher number of vWF-, CD31-, SDF-1α-, and CXCR4-positive cells in group 2 (all p<0.04). Moreover, immunohistochemical staining showed notably higher vessel density but lower mean fibrosis area, number of CD40-positive cells and apoptotic nuclei in group 2 (all p<0.045). Mitochondrial protein expression of oxidative stress was lower, whereas cytochrome-C was higher in group 2 (all p<0.03). Furthermore, mRNA expressions of MMP-9, Bax and caspase-3 were lower, whereas Bcl-2, eNOS, VEGF and PGC-1α were higher in group 2 (all p<0.01). In conclusion, ECSW therapy effectively reversed ischemia-elicited LV dysfunction and remodeling through enhancing angiogenesis and attenuating inflammation and oxidative stress.

Intra-coronary administration of cyclosporine limits infarct size, attenuates remodeling and preserves left ventricular function in porcine acute anterior infarction

BACKGROUND We tested whether intra-coronary administration of cyclosporine effectively preserves left ventricular (LV) function in porcine acute anterior wall infarction (AMI). METHODS AND RESULTS Eighteen male mini-pigs were randomized into groups 1 (control), 2 (AMI alone), and 3 (AMI with cyclosporine treatment). AMI was induced by ligating middle left anterior descending artery (LAD). Fifteen minutes after ligation, saline and cyclosporine (2.5 mg) combination was injected into LAD beyond ligation in groups 2 and 3, respectively. Echocardiography was performed after 14 days, followed by animal sacrifice. Larger infarcted area (IA) was noted in group 2 than in group 3 (p < 0.001). In both IA and peri-IA, mRNA expressions of IL-8, MMP-9, caspase 3 and Bax were higher, whereas PGC-1α, eNOS and Bcl-2 were lower in group 2 than in groups 1 and 3 (p < 0.01). The mRNA expression of IL-10 was upregulated in both IA and peri-IA in group 3 compared with groups 1 and 2. Apoptotic nuclei and CD40-positive cells were higher in both peri-IA and non-IA in group 2 than in groups 1 and 3 (p < 0.001). Oxidative stress and cytosolic cytochrome C in IA were increased in group 2 than in groups 1 and 3 (p < 0.001). Mid-LV end-systolic areas were higher, whereas mid-LV wall fractional area change was lower in group 2 than in groups 1 and 3 (p < 0.001). CONCLUSIONS Intra-coronary administration of cyclosporine effectively limits infarct size, attenuates LV remodeling and preserves LV function.