Guangming Cheng

First Finite Element Model of the Left Ventricle With Mitral Valve: Insights Into Ischemic Mitral Regurgitation

BACKGROUND Left ventricular remodeling after posterobasal myocardial infarction can lead to ischemic mitral regurgitation. This occurs as a consequence of leaflet tethering due to posterior papillary muscle displacement. METHODS A finite element model of the left ventricle, mitral apparatus, and chordae tendineae was created from magnetic resonance images from a sheep that developed moderate mitral regurgitation after posterobasal myocardial infarction. Each region of the model was characterized by a specific constitutive law that captured the material response when subjected to physiologic pressure loading. RESULTS The model simulation produced a gap between the posterior and anterior leaflets, just above the infarcted posterior papillary muscle, which is indicative of mitral regurgitation. When the stiffness of the infarct region was reduced, this caused the wall to distend and the gap area between the leaflets to increase by 33%. Additionally, the stress in the leaflets increased around the chordal connection points near the gap. CONCLUSIONS The methodology outlined in this work will allow a finite element model of both the left ventricle and mitral valve to be generated using noninvasive techniques.

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival.

Androgen receptor (AR) is a critical factor in the development and progression of prostate cancer. We and others recently demonstrated that eliminating AR expression leads to apoptotic cell death in AR-positive prostate cancer cells. To understand the mechanisms of AR-dependent survival, we performed a genome-wide search for AR-regulated survival genes. We found that serum/glucocorticoid-induced protein kinase-1 (SGK-1) mRNA levels were significantly upregulated after androgen stimulation, which was confirmed to be AR dependent. Promoter analysis revealed that the AR interacted with the proximal and distal regions of the sgk1 promoter, leading to sgk-1 promoter activation after androgen stimulation. Functional assays demonstrated that SGK-1 was indispensable for the protective effect of androgens on cell death induced by serum starvation. SGK-1 overexpression not only rescued cells from AR small-interfering RNA (siRNA)-induced apoptosis, but also enhanced AR transactivation, even in the absence of androgen. Additionally, SGK-1 siRNA reduced AR transactivation, indicating a positive feedback effect of SGK-1 expression on AR-mediated gene expression and cellular survival. Taken together, our data suggest that SGK-1 is an androgen-regulated gene that plays a pivotal role in AR-dependent survival and gene expression.

The effect of mitral annuloplasty shape in ischemic mitral regurgitation: a finite element simulation.

BACKGROUND Undersized mitral annuloplasty (MA) is the preferred surgical treatment for chronic ischemic mitral regurgitation. However, the preferred shape of undersized MA is unclear. METHODS A previously described finite element model of the left ventricle with mitral valve based on magnetic resonance images of a sheep with chronic ischemic mitral regurgitation after posterolateral myocardial infarction was used. Saddle-shape (Edwards Physio II) and asymmetric (IMR ETlogix) MA rings were digitized and meshed. Virtual annuloplasty was performed using virtual sutures to attach the MA ring. Left ventricular diastole and systole were performed before and after virtual MA of each type. RESULTS Both types of MA reduced the septolateral dimension of the mitral annulus and abolished mitral regurgitation. The asymmetric MA was associated with lower virtual suture force in the P2 region but higher force in P1 and P3 regions. Although both types of MA reduced fiber stress at the left ventricular base, fiber stress reduction after asymmetric MA was slightly greater. Neither type of MA affected fiber stress at the left ventricular equator or apex. Although both types of MA increased leaflet curvature and reduced leaflet stress, stress reduction with saddle-shape MA was slightly greater. Both MA types reduced stress on the mitral chordae. CONCLUSIONS The effects of saddle-shape and asymmetric MA rings are similar. Finite element simulations are a powerful tool that may reduce the need for animal and clinical trials.

Early in vivo experience with the pediatric Jarvik 2000 heart.

The need for smaller, more efficient ventricular assist devices that can be used in a more chronic setting have led to exploration of mechanical circulatory support in the pediatric population. The pediatric Jarvik 2000 heart (child size), under development, was implanted in six juvenile sheep and studied for both acute fit and chronic performance evaluation. Daily hemodynamic measurements of cardiac output and pump output at varying pump speeds were taken. In addition, plasma free hemoglobin, lactic acid dehydrogenase, and platelet activation from blood samples were determined at baseline, after implantation, and twice a week thereafter. The measured flow through the outflow graft at increasing speeds from 10,000 rpm to 14,000 rpm with an increment of 1,000 rpm were 1.47 ± 0.43, 1.89 ± 0.52, 2.36 ± 0.61, 2.80 ± 0.73, and 3.11 ± 0.86 (L/min). The baseline plasma free hemoglobin was 11.95 ± 4.76 (mg/dL), with subsequent mean values being <30 mg/dL at postimplantation and weekly postimplantation measurements. Both lactic acid dehydrogenase and platelet activation showed an acute increase within the first week after implantation with subsequent return to baseline by 2 weeks after surgery. Our initial animal in vivo experience with the pediatric Jarvik 2000 heart shows that a small axial flow pump can provide partial to nearly complete circulatory support with minimal adverse effects on blood components.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

RATIONALE The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

Functional and Biocompatibility Performances of an Integrated Maglev Pump-Oxygenator

To provide respiratory support for patients with lung failure, a novel compact integrated pump-oxygenator is being developed. The functional and biocompatibility performances of this device are presented. The pump-oxygenator is designed by combining a magnetically levitated pump/rotor with a uniquely configured hollow fiber membrane bundle to create an assembly free, ultracompact, all-in-one system. The hemodynamics, gas transfer and biocompatibility performances of this novel device were investigated both in vitro in a circulatory flow loop and in vivo in an ovine animal model. The in vitro results showed that the device was able to pump blood flow from 2 to 8 L/min against a wide range of pressures and to deliver an oxygen transfer rate more than 300 mL/min at a blood flow of 6 L/min. Blood damage tests demonstrated low hemolysis (normalized index of hemolysis [NIH] approximately 0.04) at a flow rate of 5 L/min against a 100-mm Hg afterload. The data from five animal experiments (4 h to 7 days) demonstrated that the device could bring the venous blood to near fully oxygen-saturated condition (98.6% +/- 1.3%). The highest oxygen transfer rate reached 386 mL/min. The gas transfer performance was stable over the study duration for three 7-day animals. There was no indication of blood damage. The plasma free hemoglobin and platelet count were within the normal ranges. No gross thrombus is found on the explanted pump components and fiber surfaces. Both in vitro and in vivo results demonstrated that the newly developed pump-oxygenator can achieve sufficient blood flow and oxygen transfer with excellent biocompatibility.

Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair than iPSCs

Rationale: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. Objective: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. Methods and Results: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV–treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. Conclusions: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

Moderate Mitral Regurgitation Accelerates Left Ventricular Remodeling After Posterolateral Myocardial Infarction

BACKGROUND Chronic ischemic mitral regurgitation (MR) is associated with poor outcome. However, the effect of chronic ischemic MR on left ventricular (LV) remodeling after posterolateral myocardial infarction (MI) remains controversial. We tested the hypothesis that moderate MR accelerates LV remodeling after posterolateral MI. METHODS Posterolateral MI was created in 10 sheep. Cardiac magnetic resonance imaging was performed 2 weeks before and 2, 8, and 16 weeks after MI. Left ventricular and right ventricular volumes were measured, and regurgitant volume was calculated as the difference between LV and right ventricle stroke volumes. RESULTS Multivariate mixed effects regression showed that LV volumes at end diastole and end systole and LV sphericity were strongly correlated with both regurgitant volume (p < 0.0001, p = 0.0086, and p = 0.0007, respectively) and percent infarct area (p = 0.0156, p = 0.0307, and p < 0.0001, respectively). Conversely, whereas LV hypertrophy (LV wall volume) increased from 2 weeks to 16 weeks after MI, there was no effect of either regurgitant volume or percent infarct. CONCLUSIONS Moderate MR accelerates LV remodeling after posterolateral MI. Further studies are needed to determine whether mitral valve repair is able to slow or reverse MI remodeling after posterolateral MI.

PRESSURE-OVERLOAD INDUCED LV HYPERTROPHY AND DYSFUNCTION: CRITICAL ROLES OF CAMKII AND P38 MAP KINASE IN ER STRESS SIGNALING PATHWAY

The role of endoplasmic reticulum (ER) stress in pressure overload-induced LV hypertrophy and dysfunction is poorly understood. The specific roles of CaMKII and p38 signaling remain unclear. Transverse aortic constriction (TAC) was performed in age-matched CHOP knockout (KO) mice and controls.

NF-KB INHIBITION PROTECTS AGAINST MYOCARDIAL ISCHEMIA/REPERFUSION INJURY VIA ACTIVATION OF ANTIAPOPTOTIC SIGNALING

The molecular details of nuclear factor-kappaB (NF-kB) signaling during myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We hypothesized that inhibition of NF-kB would prevent cell death. We used transgenic mice overexpressing a mutant IkBα with consequent cardiac-specific