Fetal Myocardium Research Articles

Ineffective Therapy, Underpowered Studies, or Merely Too Little, Too Late?

It is estimated that 2% to 3% of pregnant women carry the anti-SSA/Ro antibody, which can be found in various autoimmune disorders, including Sjogren syndrome (SS), systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disorder.1,2 In addition, many women are asymptomatic carriers, with less than one third of anti-SSA/Ro–positive women diagnosed with a rheumatological disorder preceding the discovery of advanced heart block in the fetus.3,4 Prospective studies have demonstrated that, in the absence of a previously affected pregnancy, the fetuses of these women bear up to a 3% risk of developing cardiac manifestations of neonatal lupus (NL), including cardiac conduction abnormalities, structural cardiac defects, and isolated cardiomyopathies.5–7 In women with a previously affected pregnancy, the recurrence rate of congenital heart block can reach as high as 17%.8,9 Articles see p 1919 and p 1927 The cardiac conduction manifestations of NL are thought to result from a pathological response to the transplacental acquisition of anti-SSA/Ro whereby an immune-mediated inflammatory pathway triggers injury and eventually fibrosis of the atrioventricular (AV) node.10 In addition, anti-SSA/Ro antibodies appear to inhibit activation of the cardiac L-type calcium channels, which are essential to normal AV node conduction.11 The role of anti-SSB/La antibodies is less clearly defined. Although anti-SSB/La alone has not been associated with conduction abnormalities, some evidence suggests that it may potentiate the effects of anti-SSA/Ro–mediated injury.12 Antibody-exposed infants without cardiac involvement at birth have little risk of later developing AV block; however, complete AV block can evolve in fetuses with second-degree AV block in utero or neonates born with first- or second-degree AV block.9 Jaeggi and colleagues3 reported that the timing of initial presentation of complete AV block correlated with mortality. Among the 29 cases diagnosed …

Myocardial Response in Preterm Fetal Sheep Exposed to Systemic Endotoxinaemia

Exposure of the fetus to antenatal inflammation can occur from chorioamnionitis, which may progress to a fetal inflammatory response syndrome (FIRS) and to fetal sepsis. We tested whether the fetal myocardium responded to systemic Gram-negative endotoxinaemia. We hypothesized that the myocardium would respond to inflammation by changes in hypoxia-inducible factor-α (HIF-1α), inducible NO-synthase (iNOS), Toll-like receptors 2 and 4 (TLR2 and TLR4), IL-6, and phosphorylated signal transducer and activator of transcription-3 (pSTAT3). To model systemic endotoxinaemia, fetal sheep were exposed to Gram-negative endotoxin or saline i.v. 3 d before preterm delivery at 113 d of gestation (term = 147 d). All endotoxin-exposed animals developed cardiac dysfunction within these 72 h. Cardiac mRNA and protein levels of HIF-1α and TLR2 and TLR4 mRNA increased, whereas STAT3 phosphorylation decreased significantly. IL-6 and iNOS mRNA remained unchanged. Fetal systemic endotoxinaemia induced myocardial inflammation by activating TLR2 and 4. The following cardiac dysfunction seems not to be mediated via cardiac iNOS.

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.

The Myocardium of Fetuses with Endocardial Fibroelastosis Contains Fewer B and T Lymphocytes than Normal Control Myocardium

The observation that endocardial fibroelastosis (EFE) can result from an immune response to maternal autoantibody deposition in the fetal myocardium raises the possibility that the fetal immune system may contribute to the pathogenesis of idiopathic EFE and dilated cardiomyopathy (DCM). This study sought to characterize myocardial immune cell presence in fetuses and neonates with idiopathic EFE + DCM, in those with EFE + structural heart disease, and in normal control subjects. Paraffin tissue sections from fetuses identified from the pathology database were stained for B cell, T cell, macrophage, and general hematopoietic cell surface markers. Of the 14 fetuses included in the study, 5 had EFE + DCM, 4 had EFE + structural heart disease, and 5 were normal control fetuses. The EFE + DCM group had fewer B cells than the control group (0.15 vs. 0.44 cells/mm(2); p = 0.005). The EFE + heart disease group had both fewer B cells (0.18 vs. 0.44 cells/mm(2); p = 0.08) and T cells (0.29 vs. 0.80 cells/mm(2); p = 0.04) than the control group. The CD4/CD8 ratio was similar in the EFE + DCM and EFE + heart disease groups (1.0 vs. 0.9; p = 0.17) but higher in the EFE + DCM group than in the control group (0.9 vs. 0.3; p = 0.03). The myocardium of fetuses with EFE contains fewer B and T lymphocytes than normal control fetuses.

Assessment of Left Ventricular Global and Regional Longitudinal Peak Systolic Strain, Strain Rate and Velocity with Feature Tracking in Healthy Fetuses

The aim of this study was to evaluate the correlation of feature-tracking-derived measurements of the left ventricular myocardium in healthy fetuses with gestational age. The global and segmental longitudinal peak systolic strain, strain rate and velocity values of the left ventricular myocardium for each gestational age were assessed by a novel feature tracking technique in 150 healthy fetuses (gestational age range 13-39 weeks of gestation). The interobserver and intraobserver variability was analyzed. The global longitudinal peak systolic velocity exhibited a segmental base to apex gradient (p<0.001). From 13 to 39 weeks of gestation, the global and segmental longitudinal peak systolic velocities increased significantly throughout gestation (p<0.001), while the global longitudinal peak systolic strain remained constant (p=0.34) and the strain rate exhibited only a tendency to decrease (p=0.045). The interobserver and intraobserver variability of the global LV peak systolic strain, strain rate and velocity was acceptable. The standard deviations of measurement error between the two observers were 2.5%, 0.7s (-1) and 0.5cm/sec, respectively. The global myocardial peak systolic velocities of the left ventricle increase with gestational age, while the global myocardial peak systolic strain and strain rate remained nearly constant throughout gestation. This novel angle-independent, noninvasive technique offers a new objective approach to quantify global and segmental fetal myocardial performance throughout gestation.

Assessment of right ventricular global and regional longitudinal peak systolic strain, strain rate and velocity in healthy fetuses and impact of gestational age using a novel speckle/feature‐tracking based algorithm

To evaluate the correlation between feature tracking-derived measurements of the right ventricular myocardium and gestational age in healthy fetuses. Global and segmental longitudinal peak systolic strain, strain rate and velocity values of the right ventricular myocardium were assessed by a novel feature-tracking technique in 150 healthy fetuses at between 13 and 39 weeks' gestation. Reference ranges were constructed with respect to gestational age, and inter- and intraobserver variability was analyzed. Strain, strain rate and velocity exhibited a segmental base to apex gradient (P < 0.001). Global longitudinal peak systolic velocities increased significantly across the gestational age range considered (P < 0.001), whereas global longitudinal peak systolic strain and strain rate (taken as absolute values) decreased significantly (P < 0.001 and P < 0.001). Inter- and intraobserver variability of global right ventricular peak systolic strain, strain rate and velocity was acceptable. The SDs of measurement error between the two observers were 5.9%, 0.7/s and 0.5 cm/s, respectively. Global myocardial peak systolic velocities of the right ventricle increase with gestational age whereas global myocardial peak absolute systolic strain and strain rate significantly decrease throughout gestation. This novel angle-independent technique offers a new non-invasive approach for quantifying and monitoring fetal myocardial function throughout gestation.

Color Doppler myocardial imaging demonstrates reduced diastolic tissue velocity in growth retarded fetuses with flow redistribution

ObjectivesIn fetuses suffering from intrauterine growth retardation with cerebroplacental redistribution (IUGR CPR), the diastolic heart function may be particularly susceptible to hypoxemia as described in postnatal pathological conditions. Using the newly introduced ultrasound technique, color Doppler myocardial imaging (CDMI), we investigated the correlation between diastolic tissue velocities and diastolic blood flow velocities and compared diastolic myocardial tissue velocities in fetuses with IUGR CPR and normal fetuses. Study designPeak early and active atrial tissue velocities (E’ and A’) were acquired from both ventricular free walls in 18 fetuses with IUGR CPR and 42 normal fetuses. In 35 normal fetuses, blood flow across the atrio-ventricular valves was also recorded. Umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV) flows were obtained in all fetuses. Nonparametric tests were used for statistical analysis. ResultsThere was a tendency towards increased E’ and A’ with fetal age in normal pregnancies. No correlation between tissue velocity and blood flow velocity was established. IUGR CPR fetuses had significantly lower E’ and A’, but when indexing to heart length, only A’ remained significantly lower. E’/A’ ratio was increased in the left ventricle but unchanged in the right. ConclusionCDMI is easily applicable during standard fetal echocardiography and provides new information on the diastolic properties of the fetal myocardium. In fetuses with IUGR CPR, diastolic tissue velocities are abnormal and especially A’ may be a marker of diastolic dysfunction.

Comparison of global and regional right and left ventricular longitudinal peak systolic strain, strain rate and velocity in healthy fetuses using a novel feature tracking technique

To compare the feature tracking derived measurements of the right (RV) and left ventricular (LV) myocardium in healthy fetuses and evaluate the correlation with advancing pregnancy. Global and segmental longitudinal peak systolic strain, strain rate and velocity of the RV and LV myocardium were assessed with feature tracking technique in 150 healthy fetuses (13-39, median 22 weeks). RV global and free wall strain and strain rate values were significantly higher than those in the LV segments (P<0.001 and P<0.001). In all segments on both ventricles longitudinal peak systolic velocity measurements exhibited a significant base to apex gradient (P<0.001) and increased with advancing pregnancy (P<0.001). LV global strain and strain rate values remained constant throughout gestation, whereas RV measurements decreased (P<0.05). With advancing pregnancy the difference between RV and LV global longitudinal velocity increased significantly, whereas the difference of strain and strain rate decreased significantly. RV deformation parameters and velocity values are significantly higher compared to LV values. LV deformation parameters are stable throughout gestation, whereas RV measurements decrease significantly. The difference between global RV and LV myocardial values were significant throughout gestation, velocity values increased, whereas deformation parameters decreased.

Maternal obesity induces fibrosis in fetal myocardium of sheep

Maternal obesity (MO) has harmful effects on both fetal development and subsequent offspring health. The impact of MO on fetal myocardium development has received little attention. Fibrogenesis is regulated by the transforming growth factor-β (TGF-β)/p38 signaling pathway. Using the well-established model of MO in pregnant sheep, we evaluated the effect of MO on TGF-β/p38 and collagen accumulation in fetal myocardium. Nonpregnant ewes were assigned to a control diet [Con, fed 100% of National Research Council (NRC) nutrient recommendations] or obesogenic diet (OB, fed 150% of NRC recommendations) from 60 days before conception. Fetal ventricular muscle was sampled at 75 and 135 days of gestation (dG). At 75 dG, the expression of precursor TGF-β was 39.9 ± 9.9% higher (P < 0.05) in OB than Con fetal myocardium, consistent with the higher content of phosphorylated Smad3 in OB myocardium. The phosphorylation of p38 tended to be higher in OB myocardium (P = 0.08). In addition, enhanced Smad complexes were bound to Smad-binding elements in 75 dG OB fetal myocardium measured by DNA mobility shift assay (130.2 ± 26.0% higher, P < 0.05). Similar elevation of TGF-β signaling was observed in OB fetal myocardium at 135 dG. Total collagen concentration in OB was greater than Con fetal myocardium (2.42 ± 0.16 vs. 1.87 ± 0.04%, P < 0.05). Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 were higher in the Con group compared with OB sheep (43.86 ± 16.01 and 37.23 ± 7.97% respectively, P < 0.05). In summary, MO results in greater fetal heart connective tissue accumulation associated with an upregulated TGF-β/p38 signaling pathway at late gestation; such changes would be expected to negatively impact offspring heart function.

Fetal Right Ventricular Myocardial Function Is Better Preserved by Fibrillatory Arrest During Fetal Cardiac Bypass

Protection and preservation of fetal myocardial function are important for successful fetal intracardiac repair. Our objective was to determine fetal biventricular cardiac performance after two cardiac-arrest techniques. Three groups of midterm ovine fetuses underwent 90-minute bypass. A control group (no arrest shams, n = 3), and two groups that included 20 minutes of arrest, using fibrillatory (n = 3) or blood cardioplegia (n = 3), were compared. Blood cardioplegia consisted of 4:1 cold blood to crystalloid solution induction every 10 minutes, followed by a warm shot terminal dose before clamp removal. Myocardial function variables from biventricular intracardiac pressure catheters, and 3-axes cardiac sonomicrometry, fetal hemodynamics, and arterial blood gases were continuously recorded. Fetal myocardium was collected for troponin-I analysis at 90 minutes. Statistical analysis was by two-way analysis of variance for repeated measures. Compared with sham, right ventricular myocardial contractility was reduced with plegia but not fibrillation at 90 minutes after arrest: dP/dt max (511 ± 347 vs 1208 ± 239, p < 0.01) and preload-recruitable stroke work (7.2 ± 8.5 vs 32.3 ± 14.6, p < 0.01). Right ventricular end diastolic pressure-volume relationship (ventricular stiffness) worsened by 90 minutes for plegia vs fibrillation (0.84 ± 0.18 vs 0.25 ± 0.16, p < 0.05). There were no differences in left ventricle performance between groups. Fetal heart rate increased in shams by 30 minutes after arrest compared with both arrest groups (p < 0.05). Right ventricular troponin-I degradation increased with plegia, but not fibrillation, compared with sham (p < 0.05). In vivo, fetal right ventricular contractile function deteriorates with a common blood-plegia regimen. Fibrillatory arrest better preserves right ventricular function, the dominant ventricle in fetal life, for short arrest periods.

Current Status of Fetal Cardiac Intervention

The potential benefits of fetal cardiac intervention (FCI) have been realized for many years. In 1975, Eibschitz et al1 reported intrapartum treatment of fetal ventricular tachycardia by administering propranolol to the mother, and as early as 1986, in utero pacing was attempted for complete heart block in a human fetus.2 Recently, however, interest in FCI has accelerated.3–18 As with other fetal interventions,19,20 FCI can only become a highly useful clinical tool if it is applied to conditions in which a feasible mode of therapy is available and either the fetus is at risk for demise as a result of the condition or intervention may alter the evolution of the condition such that the severity of the postnatal disease is substantially reduced (Table 1). For conditions in which the fetus is at high risk for prenatal or neonatal death, the rationale for FCI is obvious, to improve survival. If death is not imminent but the disease is likely to have major lifelong morbidity, the rationale is that FCI will modify the course of cardiac growth, function, and/or development in utero sufficiently to alter postnatal outcome and justify the potential risks of the procedure. Prenatal intervention may also allow the fetus to recover in the supportive in utero environment, during a developmental period when there is enhanced wound healing and the capacity for myocyte proliferation.21,22 View this table: Table 1. Congenital Cardiovascular Anomalies Potentially Amenable to FCI This construct rightfully emphasizes death or significant morbidity as therapeutic targets. FCI can entail substantial short-term risk to the fetus, uncertain long-term risk to the fetus and child, and at least some risk to the mother. There are no known medical benefits to the mother. With that risk profile, FCI will not be embraced by the maternal-fetal medicine and cardiology communities unless it …

Left ventricle shortening fraction: a comparison between euploid and trisomy 21 fetuses in the first trimester

Measurement of the shortening fraction of the left ventricle (SFLV) is an objective way to assess systolic performance. The aim of the study was to compare first trimester SFLV values in euploid fetuses to those in fetuses with trisomy 21. We measured SFLV in 56 fetuses from 11 weeks to 13 weeks 6 days. The left ventricular diastolic diameter (LVDD) and left ventricular systolic diameter (LVSD) were measured offline, and SFLV was calculated. The data were analyzed using Mann-Whitney U test. We found a significant difference in the SFLV measurements between the group of 49 euploid fetuses and the 7 fetuses with trisomy 21 [38.00 (95% CI: 33.72-42.27) vs 49.93 (95% CI: 43.72-56.13)] (p < 0.05). There was also a significant difference in the nuchal translucency measurements between the two groups: 1.78 mm (95% CI: 1.08-2.48 mm) in the euploid population versus 5.06 mm (95% CI: 3.61-6.71 mm) in the fetuses with trisomy 21 (p < 0.05). There were no significant differences between the group of euploid fetuses and the group of trisomy 21 fetuses in the following parameters: CRL (chorionic villus sampling), LVDD and LVSD. SFLV is a well-defined, simple measurement of systolic function of the fetal myocardium. SFLV values in fetuses with trisomy 21 appear to be significantly higher than in euploid fetuses.

Restoration of Function Following in Utero Fetal MI Is Associated with Increased Cardiac Progenitor Cell Recruitment

Background: We have previously shown that following myocardial infarction (MI), the fetal heart has the capability to heal by regeneration with restoration of normal tissue architecture and left ventricular (LV) function. Early in the fetal healing response, there are proliferating cells that surround the infarct; however, it is unknown whether cardiac progenitor cells play a significant role in fetal regenerative cardiac healing. We hypothesized that following fetal MI; there would be migration of nkx 2.5+ cardiac progenitor cells to the area of infarction. Methods: Fetal anteroapical MI encompassing approximately 20% of the LV mass was created in early gestation fetal sheep. The fetal heart was harvested at 3 days following MI. Immunohistochemistry utilizing confocal microscopy was used to identify the presence of nkx 2.5+ cells in the infarct, the border zone, and the uninfarcted myocardium. Age matched uninfarcted fetal sheep heart was the control. Results: Three days following fetal MI, the presence of nkx 2.5+ cells was preferentially increased at the endocardial, the epicardial, and perivascular borders within the anteroapical infarct. Nkx 2.5+ cells were also seen in the border zone and the uninfarcted myocardium; however, the numbers decreased significantly away from the infarct. Nkx 2.5+ cells were identified in control hearts; however, there was no evidence of increased numbers in the apex or clustering around blood vessels within the fetal myocardium. Conclusions: Following fetal MI, nkx 2.5+ cells preferentially migrate to the area of infarction, suggesting that active recruitment of cardiac progenitor cells is partially responsible for the regenerative capacity of the fetal heart following MI. In addition, the increased numbers of nkx 2.5+ cells surrounding blood vessels suggests that some of these cardiac progenitor cells are recruited from the peripheral circulation. Understanding the mechanisms driving recruitment of cardiac progenitor cells to the fetal infarct may help us alter the post-natal response to MI.

Late‐gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis

Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Pre-breeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation. Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR. Early apoptotic cells and late apoptotic/necrotic cells were significantly increased in fetal hearts from STZ or STZ+FCA dams. Pre-treatment with FCA reduced late apoptotic/necrotic cells to control level, suggesting some cell death protection was rendered by FCA. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased. Maternal hyperglycemia causes dys-regulated apoptosis of fetal myocardial cells. Such effect may be prevented by maternal immune stimulation.

Orientation andcomposition ofcollagen fibers withinthe scar aftermyocadial lesion in ratfetuses

This study was undertaken to examine orientation and composition of collagen fibers within the myocardial scar after mechanical injury in 16-day-old rat fetuses and in adult male rats. Measurements were performed from 7 to 40 days after lesion. Angles of fiber bundles relative to the longitudinal axis of wound channel were measured and were analyzed with circular statistic techniques. Proportion of collagen types I and III was determined when studying sections stained with picrosirius red under polarized light. In adult myocardium fibers of collagen type I were abundant and longitudinally aligned, the lesion developed into a mature scar. Fetal scar contained thinner fibers, which did not display a homogeneous distribution. This suggests that fetal scar is immature, its mechanical strength is less and that fetal myocardium shows incomplete repair.

ICD Implantation in Noncompaction of the Left Ventricular Myocardium: A Case Report

Isolated noncompaction of the ventricular myocardium (INVM) is an uncommon cardiomyopathy characterized by the persistence of fetal myocardium with prominent trabecular meshwork and deep intertrabecular recesses, often associated with systolic dysfunction and ventricular dilatation. A 23-year-old man from Burkina Faso was referred to our operative unit with a diagnosis of INVM, made with echocardiogram and magnetic resonance imaging and nonsustained ventricular tachycardia. The literature reports the incidence of malignant ventricular arrhythmias in as many as 47% of the patients and sudden cardiac death in almost 50% of them and this supported our decision to perform implantable cardioverter-defibrillators implantation.

Systolic myocardial velocity alterations in the growth‐restricted fetus with cerebroplacental redistribution

Intrauterine growth restriction (IUGR) is associated with cerebroplacental redistribution (CPR), fetal stress and poor outcome, all of which may be related to dysfunction of the fetal myocardium. The aim of this study was to specifically assess myocardial function in IUGR fetuses with CPR in comparison with normal fetuses using color Doppler myocardial imaging (CDMI). CDMI was used to evaluate and compare myocardial velocities in the left and right ventricles in normal fetuses and in IUGR fetuses with CPR. Peak systolic tissue velocities (S') were acquired from both ventricular free walls in 20 IUGR fetuses (gestational age at scan ranged from 26 + 1 to 34 + 6 weeks, with serial measurements obtained in nine) and 42 normal fetuses (35 at week 28, with the remaining seven undergoing serial scans every 4 weeks, ranging from 18 + 6 to 39 + 1 weeks). Umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV) flows were also recorded. Left and right S' increased with gestational age in normal pregnancy. Fetuses with IUGR and CPR had lower left ventricular S' than normal fetuses (mean, 2.41 (95% CI, 1.96-2.86) cm/s vs. 3.30 (95% CI, 3.05-3.55) cm/s; P = 0.0006). This reduction in S' correlated with the grade of UA flow abnormality (P = 0.0002). Fetuses with reversed diastolic UA flow had significantly lower left S' (mean, 2.0 (95% CI, 1.4-2.6) cm/s; P = 0.001) than normal fetuses. There was no correlation between left S' and MCA pulsatility index (P = 0.37) in the IUGR-CPR group, but there was a reduction in S' approaching statistical significance in fetuses with reversed DV flow in comparison to those without it (P = 0.09). Right S' was similar in the two study groups and did not correlate with worsening UA flow class. All fetuses with a left S' below 1.6 cm/s and reversed UA flow died in the perinatal period. CDMI facilitates acquisition of fetal myocardial ventricular S'. The combination of IUGR and CPR is associated with a reduced left ventricular S', especially in those with reversed UA flow. In this subgroup a left S' below 1.6 cm/s seemed to predict mortality in the perinatal period.

Engineered Early Embryonic Cardiac Tissue Increases Cardiomyocyte Proliferation by Cyclic Mechanical Stretch via p38-MAP Kinase Phosphorylation

Cardiomyocyte (CM) transplantation is one therapeutic option for cardiac repair. Studies suggest that fetal CMs display the best cell type for cardiac repair, which can finitely proliferate, integrate with injured host myocardium, and restore cardiac function. We have recently developed an engineered early embryonic cardiac tissue (EEECT) using embryonic cardiac cells and have shown that EEECT contractile properties and cellular proliferative response to cyclic mechanical stretch stimulation mimic developing fetal myocardium. However, it remains unknown whether cyclic mechanical stretch-mediated high cellular proliferation activity within EEECT reflects CM or non-CM population. Studies have shown that p38-mitogen-activated protein kinase (p38MAPK) plays an important role in both cyclic mechanical stretch stimulation and cellular proliferation. Therefore, in the present study, we tested the hypothesis that cyclic mechanical stretch (0.5 Hz, 5% strain for 48 h) specifically increases EEECT CM proliferation mediated by p38MAPK activity. Cyclic mechanical stretch increased CM, but not non-CM, proliferation and increased p38MAPK phosphorylation. Treatment of EEECT with the p38MAPK inhibitor, SB202190, reduced CM proliferation. The negative CM proliferation effects of SB202190 were not reversed by concurrent stretch stimulation. Results suggest that immature CM proliferation within EEECT can be positively regulated by mechanical stretch and negatively regulated by p38MAPK inhibition.

The experimental study of homogenous bone marrow mesenchymal stem cells transplantation in treating acute myocardial infarction

Objective To investigate the allngeneic bone marrow mesenchymal stem cells (mesenchymal stem cells, MSCs) transplantation on cardiac rehabilitation and cardiac function after acute myocardial infarction (AMI). Method Acute myocardial infarction models were made by ligating the left anterior descending coronary artery of rats. A total of 90 rats were randomly divided into the cell transplantation group and control group, 45 rars in each group. Rats in the cell transplantation group were subdivided into 3 groups according to the administration time of the allogeneic bone marrow mesenchymal stem cells (2 weeks, 4 weeks and 12 weeks), and the control group was subdivided the same as in the cell transplantation group. The success criteria included the anterior my-ocardial wall darked and the Sr-segment elevation. The rat femur bone marrow cells were separated using centrifu-gal method, mononuclear cells were isolated by lymphocyte fluid, and the third generation of mesenchymal stem cells were obtained by washing, culture, passage and marked by 4, 6 diacetyl-2-phenyl Indole (DAPI). The ani-mals' chest was opened again a week later, the stem cell suspension was injected into the border zone of infarct area, and the control group was injected with medium. Pre-operative,2 weeks, 4 weeks and 12 weeks after trans-plantation, cardiac function was tested by ultrasonic, myocardial biopsy was observed by HE conventional staining, cardiac stem cells division were observed by immunofluorescence. All data was analyzed by software SPSS 10.0, Independent-Samples T test and Chi-Square test was used, and P≤0.05 was considered as statistically signif-icant. Results The markered hone marrow mesenchymal stem cells were left in the myocardial cells and differen-tiated to eardiomyocyte-like cells. After 12 weeks, the left ventricular internal diameter of rats in cell transplanta-tion group was about (0.58±0.09) mm(P<0.05). Thickness of myocardial infarction zone was (0.25±0.01) mm (P<0.05),ejection fraction was (67.52±0.61) (P<0.05) and left ventricular fractional shortening was (39.86±3.00) (P<0.05). In the transplantation group, the DAPI marked nucleus presented as blue, and the cytoplasm of myocardial cell presented as green. HE staining showed that, in the cell transplantation group, there was less scar tissue and a large proportion of nuclear, similar to the fetal or newhom myocardium cells. Conclu-sions The homogeneus mesenchymal stem cell could repair myocardial infarction and improve cardiac function af-ter infarction. Key words: Homogenous mesenchymal stem cell; Cell transplantation; Acute myocardia infarction; My-ocardia repaire; Cardiac function

Cardiac Stem Cell Research: An Elephant in the Room?

Heart disease is the leading cause of death in the industrialized world, and stem cell therapy seems to be a promising treatment for injured cardiac tissue. To reach this goal, the scientific community needs to find a good source of stem cells that can be used to obtain new myocardium in a very period range of time. Since there are many ethical and technical problems with using embryonic stem cells as a source of cells with cardiogenic potential, many laboratories have attempted to isolate potential cardiac stem cells from several tissues. The best candidates seem to be cardiac "progenitor" and/or "stem" cells, which can be isolated from subendocardial biopsies from the same patient or from embryonic and/or fetal myocardium. Regardless of the technique used to isolate and characterize these cells, it appears that the different cells isolated from adult myocardium to date are all phenotypic variations of a unique cell type that expresses several markers, such as c-Kit, CD34, MDR-1, Sca-1, CD45, nestin, or Isl-1, in various combinations.