Reducing Left Ventricular Wall Stress through Aortic Valve Enlargement via Transcatheter Aortic Valve Implantation in Severe Aortic Stenosis.

Background: In aortic stenosis, the left ventricle exerts additional force to pump blood through the narrowed aortic valve into the downstream arterial vasculature. Adaptive hypertrophy helps to maintain wall stress homeostasis but at the expense of impaired compliance. Advanced ventricular deformation impacts the extent of functional recovery benefits achieved through transcatheter aortic valve implantation. Methods and Results: Subgroups were stratified based on output, with low-flow severe aortic stenosis defined as stroke volume index <35 mL· m-2. Before intervention, the low-flow subgroup exhibited worse effective orifice area index and arterial and global impedance, along with thinner wall thickness and larger chamber volume marginally. LV performance, including stroke volume index, ventricular elastance, and ventricular-arterial coupling, were notably inferior, consistent with worse adverse remodeling. Although the effective orifice area index was similarly augmented after TAVI, inferior recovery benefits were noted. Persistently higher wall stress and energy consumption were observed, along with poorer ventricular-arterial coupling. These changes in wall stress showed an inverse relationship with alterations in wall thickness and were proportional to changes in dimension and volume. Additionally, they were proportional to changes in left ventricular end-systolic pressure, pressure-volume area, and ventricular-arterial coupling but inversely related to ventricular end-systolic elastance. Conclusions: The study revealed that aortic valve enlargement through transcatheter aortic valve implantation reduces left ventricular wall stress in severe aortic stenosis. The reduced recovery benefits in the low-flow subgroup were evident. Wall stress could serve as a marker of mechanical benefit after the intervention.

Acute Effect in Mechanical Efficiency by Pressure-Volume Loop Analysis after Transcatheter Aortic Valve Implantation.

Background: This study aimed to evaluate the immediate effect of transcatheter aortic valve implantation (TAVI) on mechanical efficiency. Methods: A total of 46 patients (25 females) with an average age of 83 ± 6.4 years underwent TAVI using the CoreValve system. During the same hospitalization, we conducted a comprehensive comparison of the patients before and after TAVI without inotropic support using echocardiography. The parameters encompassed left ventricular (LV) geometry, valvular load, global LV afterload and ventricular hemodynamics. The analysis using pressure-volume loops enabled the determination of load-independent contractility (Ees) and afterload, in addition to assessing potential energy, stroke work, and mechanical efficiency. Results: The immediate effect was an augmented aortic valve area accompanied by a reduction in the transvalvular pressure gradient. We observed reductions in left ventricular end-systolic volume and end-diastolic volume, and also reductions in global afterload and end-systolic meridional wall stress. The Ea index decreased, while the Ees index remained relatively stable. We noted increases in stroke volume and systemic arterial compliance, indicating more efficient blood transfer from the ventricle to aorta. These changes contributed to the normalization of ventricular-arterial coupling. In terms of mechanical work of the chamber, we observed significant decreases in potential energy, stroke work, and pressure-volume area. There was an increase in the mechanical efficiency of the chamber. Conclusions: The TAVI procedure immediately reduced global afterload and improved diastolic compliance of the chamber, resulting in enhanced ventricular function and mechanical efficiency.

Impact of Recurrent Mitral Regurgitation on Left Ventricular Mass Regression and Cardiac Events following Mitral Valve Repair.

BACKGROUND: Mitral valve regurgitation results in volume overload, followed by left ventricular remodeling. Variation of reverse remodeling following mitral repair influences the clinical outcomes. We aimed to evaluate the association between recurrent mitral regurgitation and mass regression following mitral valve repair and the impact on major adverse cardiovascular events. METHODS: A retrospective cohort study was conducted on 164 consecutive patients with severe mitral regurgitation who underwent elective mitral valve repair. Subgroups were classified based on the presence of recurrent mitral regurgitation exceeding moderate severity. The hemodynamic parameters were evaluated according to geometry, mass, and function with Doppler echocardiography before and after surgery. Cox regression analysis was performed to evaluate the association between hemodynamics and mass regression and clinical outcomes. RESULTS: The results for MR indicated 110 cases with non-recurrent MR and 54 with recurrent MR, along with 31 major adverse cardiovascular events. The tracked echocardiographic results revealed less reduction in dimension and volume, along with less mass regression in the recurrent MR subgroup. Significant differences were revealed in the relative change of the LV end-diastolic volume index and relative mass regression between subgroups. The relative change in the LVEDVI was proportionally correlated with relative mass regression. Cox regression analysis identified correlations with major adverse cardiovascular events, including suture annuloplasty, recurrent mitral regurgitation, tracked LV mass, relative LV mass regression, and systolic dysfunction. CONCLUSION: LV mass regression and relative change of the LV end-diastolic volume could be risk predictors of recurrent mitral regurgitation. The extent of LV mass regression is correlated with adverse cardiac events.

Extent of Left Ventricular Mass Regression and Impact of Global Left Ventricular Afterload on Cardiac Events and Mortality after Aortic Valve Replacement.

Patient-prosthesis mismatch (PPM) causes a high transvalvular pressure gradient and residual left ventricular (LV) hypertrophy, consequently influencing long-term results. This study aimed to find the relationships between hemodynamic parameters and LV mass regression and determine the risk predictors of major adverse cardiovascular and cerebral events (MACCE) after aortic valve replacement (AVR) for aortic stenosis. Methods and Results: Preoperative and postoperative Doppler echocardiography data were evaluated for 120 patients after AVR. The patients' mean age was 67.7 years; 55% of the patients were male. Forty-four (37%) patients suffered from MACCE during a mean follow-up period of 3.6 ± 2 years. The following hemodynamic parameters at follow-up were associated with lower relative indexed LV mass (LVMI) regression: lower postoperative indexed effective orifice area, greater mean transvalvular pressure gradient (MPG), greater stroke work loss (SWL), and concentric or eccentric LV remodeling mode. The following hemodynamic parameters at follow-up were associated with a higher risk of MACCE: higher valvuloarterial impedance (ZVA), greater SWL, greater MPG, greater relative wall thickness, greater LVMI, and hypertrophic LV remodeling mode. Lower relative LVMI regression was associated with a higher risk of MACCE (hazard ratio, 1.01: 95% confidence interval, 1.003-1.03). The corresponding cutoff of relative LVMI regression was -14%. Conclusions: Changes in hemodynamic parameters were independently associated with relative LVMI regression. Impaired reverse remodeling and persistent residual LV hypertrophy were independent risk predictors of MACCE. An LVMI regression lower than 14% indicated higher MACCE. A postoperative ZVA greater than 3.5 mmHg/mL/m2 was an independent risk predictor of cardiac events and mortality after AVR. Preventive strategies should be used at the time of the operation to avoid PPM.

Diabetes Upregulates Oxidative Stress and Downregulates Cardiac Protection to Exacerbate Myocardial Ischemia/Reperfusion Injury in Rats.

Diabetes exacerbates myocardial ischemia/reperfusion (IR) injury by incompletely understood mechanisms. We explored whether diabetes diminished BAG3/Bcl-2/Nrf-2/HO-1-mediated cardioprotection and overproduced oxidative stress contributing to exaggerated IR injury. Streptozotocin-induced diabetes enhanced hyperglycemia, cardiac NADPH oxidase p22/p67 expression, malondialdehyde amount and leukocyte infiltration, altered the mesenteric expression of 4-HNE, CaSR, p-eNOS and BAG3 and impaired microvascular reactivity to the vasoconstrictor/vasodilator by a wire myography. In response to myocardial IR, diabetes further depressed BAG3/Bcl-2/Nrf-2/HO-1 expression, increased cleaved-caspase 3/poly(ADP-ribose) polymerase (PARP)/TUNEL-mediated apoptosis and exacerbated IR-induced left ventricular dysfunction characterized by further depressed microcirculation, heart rate, left ventricular systolic pressure and peak rate of pressure increase/decrease (±dp/dt) and elevated left ventricular end-diastolic pressure (LVEDP) and Evans blue-2,3,5-triphenyltetrazolium chloride-stained infarct size in diabetic hearts. Our results implicated diabetes exacerbated IR-induced myocardial dysfunction through downregulated BAG3/Bcl-2/Nrf-2/HO-1 expression, increased p22/p67/caspase 3/PARP/apoptosis-mediated oxidative injury and impaired microvascular reactivity.

Multiple Progressive Thermopreconditioning Improves Cardiac Ischemia/Reperfusion-induced Left Ventricular Contractile Dysfunction and Structural Abnormality in Rat.

BACKGROUND: Triple progressive thermopreconditioning (3PTP) may induce high Hsp-70 expression to maintain cardiac function. We suggest that 3PTP may reduce myocardial ischemia/reperfusion (I/R) injury during organ transplantation through Bag3/Hsp-70 mediated defense mechanisms. METHODS: Male Wistar rats were divided into sham control group and 72 h after 3PTP in a 42°C water bath (3PTP) group. Rats underwent 60 min of ischemia by occlusion of the left anterior descending coronary artery followed by 240 min reperfusion. Hemodynamic parameters, including the electrocardiogram, microcirculation, heart rate, left ventricular end-diastolic pressure, maximal rate of rise (+dp/dt), and fall (-dp/dt) in the left ventricular pressure for index of contraction and relaxation were determined. Myocardial infarct size was evaluated by the Evans blue-2,3,5-triphenyltetrazolium chloride method. 3PTP-induced protective mechanisms were determined by Western blot and immunohistochemistry. RESULTS: Cardiac I/R depressed cardiac microcirculation, induced S-T segment elevation, and R-R and P-R interval elongation increased infarct size associated with erythrocyte extravasation, leukocytes and macrophage/monocyte infiltration, granulocyte colony-stimulating factor, poly(ADP-ribose) polymerase 1 stain, and transferase-mediated dUTP-biotin nick end labeling positive cells. However, 3PTP evoked significant cardioprotection against I/R injury, characterized by the increased +dp/dt value and the decreased elevated left ventricular end-diastolic pressure, erythrocyte extravasation, leukocyte and macrophage/monocyte infiltration, granulocyte colony-stimulating factor expression, poly(ADP-ribose) polymerase 1 expression, transferase-mediated dUTP-biotin nick end labeling positive cells, and fragmentation and infarct area. In addition, 3PTP increased Hsp-70 and Bag3 expression and decreased Bax/Bcl-2 ratio, but did not affect the Beclin-1 and LC3-II/LC3-I ratio in the heart with I/R injury. CONCLUSIONS: 3PTP therapies may through Bag3 upregulation alleviate I/R injury-induced left ventricular structural deterioration and dysfunction.

Tocilizumab, a Humanized Monoclonal Antibody Against the Interleukin-6 Receptor, Inhibits High Glucose-Induced Vascular Smooth Muscle Cell Migration Through Mitogen-Activated Protein Kinase Signaling Pathways.

Rheumatoid arthritis (RA) with diabetes increases the risk of cardiovascular diseases. Interleukin-6 (IL-6) promotes the disease activity of RA and insulin resistance. This study aimed to evaluate the potential effects and molecular mechanisms of IL-6 blocker, tocilizumab, in atherosclerosis with diabetes. Human aortic smooth muscle cells (HASMCs) cultured under hyperglycemic conditions were evaluated for migration, expression of adhesion molecules, and matrix metalloproteinases before and after treatment with tocilizumab. High glucose (HG) significantly increased expression of IL-6, intercellular adhesion molecule (ICAM-1), matrix metalloproteinase-2 & 9, and migration of vascular smooth muscle cells. Tocilizumab suppressed HG-induced expression of ICAM-1, MMP-2, and MMP-9. Pretreatment with tocilizumab also inhibited migration, MAPK signaling, and nuclear translocation of p65-NF-κB in HG-stimulated HASMCs. Our data suggested that tocilizumab may exert an antiatherosclerotic activity in diabetes.

Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury.

OBJECTIVE: Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS-/-, TP-/- and TXAS-/-TP-/- mice. APPROACH AND RESULTS: The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS-/-, TP-/- and TXAS-/-TP-/- mice in response to intravenous saline, endothelin-1, U46619 (a TXA2 agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1ß, cell apoptosis, coronary effluent thromboxane B2 (TXB2) and superoxide anions (O2 -) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl3 stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1ß, apoptosis, coronary endothelin-1, TXB2, O2 - release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS-/-, TP-/- and TXAS-/-TP-/- mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl3 stimulation. CONCLUSION: Inhibiting TXAS/TXA2/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.

Formation of TiO(2) nano-network on titanium surface increases the human cell growth.

OBJECTIVES: This study was to improve human cell growth on titanium (Ti) used for dental implants through formation of a nano-network surface oxide layer created by an electrochemical anodization treatment. METHODS: An electrochemical anodization treatment was used to produce a network oxide layer on Ti surface. Surface characterization of the network layer was carried out using thin film X-ray diffractometer and field emission scanning electron microscopy. Human bone marrow mesenchymal stem cells (hMSCs) were made to express green fluorescent protein (GFP) by retroviral transduction. The GFP signal was measured in situ to assess in vitro and in vivo cell growth on Ti surfaces. In vivo experiments on Ti-supported cell growth were carried out on the back skin of nude mice. Alizarin red staining and immunofluorescent staining were used to observe cell differentiation. RESULTS: A multilayer TiO(2) nano-network was produced rapidly on Ti surface using a simple electrochemical anodization treatment. The TiO(2) nano-network layer on the anodized Ti surfaces significantly improved in vitro and in vivo hMSC growth, as assessed by measurement of GFP fluorescence, relative to hMSC growth on untreated Ti surface. The TiO(2) nano-network layer on the anodized Ti surfaces can also induce the differentiation of hMSCs after 28-day in vivo test. SIGNIFICANCE: The formation of TiO(2) nano-network on the Ti surfaces can increase the hMSC growth in vitro and in vivo.

Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells.

OBJECTIVES: Resveratrol (RV), a natural polyphenol derived from red wine, recently showed the potential of anticancer and radiosensitizing effects. A recent study has suggested that the cancer stem cells (CSCs) may reflect the clinical refractory malignancy of brain tumors, including medulloblastoma (MB). The aim of the present study is to investigate the possible role of RV in radiosensitivity of MB cells and MB-associated CSCs. MATERIALS AND METHODS: MB-associated CSCs were isolated and cultured by serum-free medium with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The parental MB cells and MB-CSCs were treated with RV in different concentrations and assessed for cell viability. The treatment includes RV alone, radiation alone, or radiation combined with RV. RESULTS: MB-CSCs selected by serum-free medium with bFGF and EGF can form 3D spheroid formation and display enhanced self-renewal and highly co-expressed "stem cell" genes (Oct-4, Nanog, Nestin, and Musashi-1) as well as antiapoptotic genes (Bcl-2 and Bcl-xL). These MB-CSCs showed significant resistance to radiotherapy as compared to the parental MB cells. Importantly, 100 muM RV could effectively inhibit the proliferation of MB-CSCs and significantly enhance the radiosensitivity in RV-treated MB-CSCs. CONCLUSIONS: Our data suggest that RV can effectively inhibit the proliferation and tumorigenicity of MB-CSCs and significantly synergistically enhance radiosensitivity in RV-treated MB-CSCs.

Reduction of hexa(sulfobutyl)fullerence on oxidative injury by xanthine and xanthine oxidase in isolated rat lungs.

UNLABELLED: The present study was undertaken to evaluate whether some fullerenols could effectively reduce direct damages of free radicals produced by xanthine/xanthine oxidase (X/XO) in isolated rat lungs. METHODS: Female Wistar rats (205 +/- 4 g) were used in studies in pulmonary vascular response to the challenge of xanthine/xanthine oxidase by an isolated-perfused lung method. Free radicals were determined by chemiluminescence (CL) to confirm the release of free radicals after X/XO treatment. The CL count in the lung perfusate was 737 +/- 213 (CL/10 sec); 5 min and 45 min after X/XO administration, the CL counts were 3,778 +/- 425 (CL/10 sec) and 1,183 +/- 193 (CL/10 sec), respectively. Challenge with X/XO caused a mild but significant increase in pulmonary arterial pressure (P(pa)) and a marked increase of filtration coefficient (K(fc)). The pretreatment of Hexa (sulfobutyl) fullerence antioxidant, K(fc) became insignificantly increased in pretreated lungs. In conclusion, We found that hexa(sulfobutyl) fullerene, but not Co60(glucosamine)6, nor superoxide dismutase could attenuate the oxidative stress, judged from the attenuated increase in pulmonary filtration coefficient after challenge.

HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection: a long-term prospective sibling cohort study in Taiwan.

OBJECTIVE: To conduct a prospective cohort study to clarify the relationship between human leukocyte antigen (HLA) polymorphisms and the seroconversion of hepatitis B e antigen (HBeAg). STUDY DESIGN: In the prospective cohort study, 81 HBeAg-positive children with chronic hepatitis B virus (HBV) infection from 40 unrelated families were recruited and followed-up regularly for a mean period of 17.70 +/- 3.23 years. The association between HLA antigen and the age at HBeAg seroconversion was analyzed using Cox regression model with shared frailties under left truncation and right censorship. RESULTS: HLA-B61 and HLA-DQB1*0503 antigens predicted a higher HBeAg seroconversion rate (relative incidence = 6.17 and 3.22, P = .024 and .017, respectively). Within-family frailty in our sibling cohort study demonstrated a negligible or a low degree of within-family correlation with spontaneous HBeAg seroconversion in each HLA antigen. CONCLUSIONS: HLA class I antigen B61 and class II antigen DQB1*0503 are associated with earlier HBeAg seroconversion in Taiwanese children with chronic HBV infection.