Clinical profiles and outcomes of acute type A aortic dissection and intramural hematoma in the current era: lessons from the first registry of aortic dissection in China.

BACKGROUND: Acute type A aortic dissection (ATAAD) and acute type A intramural hematoma (ATAIMH) are life-threatening diseases with high mortality. To better understand their clinical features in the Chinese population, we analyzed the data from the first Registry of Aortic Dissection in China (Sino-RAD) to promote the understanding and management of the diseases. METHODS: All patients with ATAAD and ATAIMH enrolled in Sino-RAD from January 1, 2012 to December 31, 2016 were involved. The data of patients' selection, history, symptoms, management, outcomes, and postoperation complications were analyzed in the study. The continuous variables were compared using the Student's t test for normal distributions and the Mann-Whitney U test for non-normal distributions. Categorical variables were compared using the Chi-square test or Fisher exact test. RESULTS: A total of 1582 patients with ATAAD and 130 patients with ATAIMH were included. The mean age of all patients was 48.4 years. Patients with ATAAD were significantly younger than patients with ATAIMH (48.9 years vs. 55.6 years, P < 0.001). For the total cohort, males were dominant, but the male ratio of patients with ATAAD was significantly higher compared to those with ATAIMH (P = 0.01). The time range from the onset of symptom to hospitalization was 2.0 days. More patients of ATAIMH had hypertension than that of ATAAD (82.3% vs. 67.6%, P < 0.05). Chest and back pain were the most common clinical symptoms. Computerized tomography (CT) was the most common initial diagnostic imaging modality. 84.7% received surgical treatment and in-hospital mortality was 5.3%. Patients with ATAAD mainly received surgical treatment (89.6%), while most patients with ATAIMH received medical treatment (39.2%) or endovascular repair (35.4%). CONCLUSIONS: Our study suggests that doctors should comprehensively use clinical examination and genetic background screening for patients with ATAAD and ATAIMH and further shorten the time range from symptoms onset to intervention, achieving early diagnosis and treatment, thereby reducing the mortality rate of patients with aortic dissection in China. We should standardize the procedures of aortic dissection treatment and improve people's understanding. Meanwhile, the curing and transferring efficiency should also be improved.

Lipopolysaccharide impairs permeability of pulmonary microvascular endothelial cells via Connexin40.

The endotoxin lipopolysaccharide (LPS)-induced pulmonary endothelial barrier disruption is a key pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the molecular mechanisms underlying LPS-impaired permeability of pulmonary microvascular endothelial cells (PMVECs) are not fully understood. Gap junctions, particularly Connexin40 (Cx40), are necessary for the maintenance of normal vascular function. In this study, we for the first time investigated the role of Cx40 in LPS-impaired permeability of PMVECs and provided potential therapeutic approaches based on mechanistic findings of Cx40 regulation by LPS stimuli. Rat PMVECs were isolated, cultured and identified with cell morphology, specific markers, ultrastructural characteristics and functional tests. Western blot analysis demonstrated that Cx40 is the major connexin highly expressed in PMVECs. Furthermore, by inhibiting Cx40 in a time-dependent manner, LPS impaired gap junction function and induced permeability injury of PMVECs. The key role of Cx40 decline in mediating detrimental effects of LPS was further confirmed in rescue experiments through Cx40 overexpression. Mechanistically, LPS stress on PMVECs inhibited the protein kinase C (PKC) pathway, which may synergize with the inflammatory nuclear factor kappaB (NFκB) signaling activation in suppressing Cx40 expression level and phosphorylation. Moreover, through pharmacological PKC activation or NFκB inhibition, Cx40 activity in PMVECs could be restored, leading to maintained barrier function under LPS stress. Our findings uncover a previously unrecognized role of Cx40 and its regulatory mechanisms in impaired endothelial integrity under endotoxin and inflammation, shedding light on intervention approaches to improve pulmonary endothelial barrier function in ALI and ARDS.

Lacidipine attenuates TNF-α-induced cardiomyocyte apoptosis.

This study was designed to investigate whether lacidipine elicited a protective role on cardiomyocyte against apoptosis induced by TNF-α. Neonatal rat cardiomyocytes were randomly assigned into different groups. TUNEL staining was utilized to detect apoptosis, and caspase-3 and caspse-12 were determined. To explore the underlying mechanism, Z-ATAD-FMK (a selective caspase-12 inhibitor) was used to identify the key molecule involved. TNF-α increased caspase-3 expression, which was mediated by increased caspase-12 expression. In the meantime, apoptosis was significantly induced by TNF-α. Lacidipine lowered caspase-12 and caspase-3 expression, and cardiomyocyte apoptosis induced by TNF-α. The results suggest that lacidipine attenuates TNF-α -induced apoptosis via inhibition of caspase-12 and caspase-3 successively.

Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2.

AIMS: Cardiovascular diseases cause significant morbidity and mortality worldwide. Recently, our research team demonstrated that a multifunctional cytokine, pigment epithelium-derived factor (PEDF), plays a critical role in regulating myocardial infarction. However, few researchers have studied the molecular mechanisms by which PEDF and its receptors influence the pathophysiology of cardiovascular disease. We tested the hypothesis that PEDF affects cardiomyocyte apoptosis under hypoxic conditions and determined the role that its receptors phospholipase A2 (PLA2) and laminin receptor play in this process. MAIN METHODS: Cardiomyocytes were isolated from neonatal mice and treated with PEDF under normoxic and hypoxic conditions; then, apoptosis was assessed using Annexin V/PI staining and flow cytometry. Western blotting and immunofluorescence staining were used to detect PEDF receptor expression, and siRNA knockdown of PEDF receptors was performed to determine which receptor was involved in mediating cardiomyocyte apoptosis. KEY FINDINGS: Our results demonstrated that PEDF increased cardiomyocyte apoptosis during hypoxia via Fas and that PEDF receptors were expressed on cardiomyocyte cell membranes. Furthermore, siRNA experiments indicated that the PEDF receptor PLA2 was responsible for inducing cardiomyocyte apoptosis via the Fas pathway. SIGNIFICANCE: PEDF promoted Fas-induced cardiomyocyte apoptosis via its receptor PLA2.

Κ-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension.

The present study was designed to investigate the effect of κ-opioid receptor stimulation with U50,488H on endothelial function and underlying mechanism in rats with hypoxic pulmonary hypertension (HPH). Chronic hypoxia-induced HPH was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. Relaxation of pulmonary artery in response to acetylcholine (ACh) was determined. Expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO production, total antioxidant capacity (T-AOC), gp91(phox) expression and nitrotyrosine content were measured. The effect of U50,488H administration during chronic hypoxia was investigated. Administration of U50,488H significantly decreased mPAP and right ventricular hypertrophy as evidenced by reduction in RVP and RVHI. These effects were mediated by κ-opioid receptor. In the meantime, treatment with U50,488H significantly improved endothelial function as evidenced by enhanced relaxation in response to ACh. Moreover, U50,488H resulted in a significant increase in eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary artery of HPH rats. In addition, the activity of eNOS was enhanced, but the activity of iNOS was attenuated in the pulmonary artery of chronic hypoxic rats treated with U50,488H. On the other hand, U50,488H markedly blunted HPH-induced elevation of gp91(phox) expression and nitrotyrosine content in pulmonary artery, and these effects were blocked by nor-BNI, a selective κ-opioid receptor antagonist. These data suggest that κ-opioid receptor stimulation with U50,488H improves endothelial function in rats with HPH. The mechanism of action might be attributed to the preservation of eNOS activity, enhancement of eNOS phosphorylation, downregulation of iNOS activity and its antioxidative/nitrative effect.

Anxiolytic actions of motilin in the basolateral amygdala.

Motilin is a 22-amino-acid gastrointestinal polypeptide that was first isolated from the porcine intestine. We identified that motilin receptor is highly expressed in GABAergic interneurons in the basolateral nucleus (BLA) of the amygdala, the structure of which is closely involved in assigning stress disorder and anxiety. However, little is known about the role of motilin in BLA neuronal circuits and the molecular mechanisms of stress-related anxiety. Whole-cell recordings from amygdala slices showed that motilin depolarized the interneurons and facilitated GABAergic transmission in the BLA, which is mimicked by the motilin receptor agonist, erythromycin. BLA local injection of erythromycin or motilin can reduce the anxiety-like behavior in mice after acute stress. Therefore, motilin is essential in regulating interneuron excitability and GABAergic transmission in BLA. Moreover, the anxiolytic actions of motilin can partly be explained by modulating the BLA neuronal circuits. The present data demonstrate the importance of motilin in anxiety and the development of motilin receptor non-peptide agonist as a clear target for the potential treatment of anxiety disorders.

The effect of hyperoside on the functional recovery of the ischemic/reperfused isolated rat heart: potential involvement of the extracellular signal-regulated kinase 1/2 signaling pathway.

One of the leading causes of death in the world is ischemia/reperfusion (I/R)-mediated acute myocardial infarction. There are a lot of Chinese traditional patent medicines, such as Xin'an capsules, Xin Xuening tablets, and so on, which have protective effects against myocardial I/R injury and have been routinely used in treating cardiac diseases for a long time in China. Hyperoside (Hyp) is the chief component of these medicines. This study investigated the action of Hyp in isolated myocardial I/R injury, as well as its possible mechanisms. Using the Langendorff model, isolated Sprague-Dawley rat hearts were subjected to 30 min of global ischemia and 50 min of reperfusion. Cardiac function was measured, and infarct size was evaluated by triphenyltetrazolium chloride staining at the end of the reperfusion. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK). Myocardium was also measured for total superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Phosphorylation of extracellular signal-regulated protein kinase (ERK) was analyzed by Western blotting. We report for the first time that administration of Hyp before/after I/R significantly improved heart contraction and limited the infarct size and CK and LDH leakage from the damaged myocardium after I/R. The activity of SOD and the MDA content remarkably changed in the presence of Hyp as well. Phosphorylation of ERK was significantly increased in Hyp-treated hearts compared to controls (p<0.01). Hyp-induced ERK phosphorylation was inhibited by PD98059. We therefore conclude that Hyp can protect cardiomyocytes from I/R-induced oxidative stress through the activation of ERK-dependent signaling.

κ-opioid receptor activation prevents against arrhythmias by preserving Cx43 protein via alleviation of intracellular calcium.

κ-opioid receptor (κ-OR) activation with U50,488H, a selective κ-OR agonist, has been previously demonstrated to prevent against cardiac arrhythmias via stabilizing the synthesis and degradation of an integral membrane protein, Cx43, in gap junctions. However, the exact prevention mechanism remains unclear. The present study tested the hypothesis that the kappa OR agonist U50,488H mediates the prevention of arrhythmia through the regulation of intracellular calcium leading to the preservation of Cx43 protein. By performing electrocardiogram monitoring and immunoblotting in isolated Langendorff-perfused rat hearts, high concentrations of calcium-perfused rat hearts exhibited increased cardiac arrhythmias. Diminished expression of Cx43 protein was observed. The utilization of a whole-cell patch clamp technique revealed that U50,488H inhibited L-type calcium current in single ventricular myocytes in a dose-dependent manner. These effects were blocked by nor-binaltorphimine, potent and selective κ-OR antagonists. Administration of U50,488H before myocardial ischemia resulted in an attenuated of total arrhythmia scores. The attenuation effect was blocked by nor-binaltorphimine. The attenuation effect was antagonized both by Bay K8644, a L-type calcium channel agonist, and also by the Cx43 uncoupler heptanol. Finally, immunoblotting data demonstrated that the preservation of Cx43 protein conferred by U50,488H was reversed in the presence of Bay K8644. In summary, the present study demonstrates κ-OR activation with U50,488H may confer antiarrhythmic effects via modulation of the calcium-Cx43 pathway.

Vasculoprotective effect of U50,488H in rats exposed to chronic hypoxia: role of Akt-stimulated NO production.

Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (l-NAME) on the relaxation of U50,488H, and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9 ± 1.8%, n = 6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by l-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or l-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.

Development of a rat respiratory mask and its application in experimental chronic myocardial ischaemia.

In addressing the challenge of the low survival rates of rats with myocardial ischaemia, we developed a novel respiratory mask. We tested this mask on the rat model. We gave attention to several features of the mask: (1) shape, (2) size, (3) inlet, (4) outlet, (5) compatibility between rat head and the mask, (6) connection between mask and ventilator. We found certain features, especially to influence mask efficacy. These features include: mask shape, mask inlet and outlet, mask connection to the respiratory machine, mask mount on the rat head. We examined the rat mask in a model of chronic myocardial ischaemia; our model was the ligation of the coronary artery. The rats with the masks experienced an increase in survival by a factor of 50-90% compared with rats deprived of the masks. Towards the examination of myocardial ischaemia, our new mask may offer a platform replete with both efficiency and stability.

Improvement of vascular function by acute and chronic treatment with the GPR30 agonist G1 in experimental diabetes mellitus.

The G-protein coupled estrogen receptor 30 (GPR30) is a seven-transmembrane domain receptor that mediates rapid estrogen responses in a wide variety of cell types. This receptor is highly expressed in the cardiovascular system, and exerts vasodilatory effects. The objective of the present study was to investigate the effects of GPR30 on vascular responsiveness in diabetic ovariectomized (OVX) rats and elucidate the possible mechanism involved. The roles of GPR30 were evaluated in the thoracic aorta and cultured endothelial cells. The GPR30 agonist G1 induced a dose-dependent vasodilation in the thoracic aorta of the diabetic OVX rats, which was partially attenuated by the nitric oxide synthase (NOS) inhibitor, nitro-L-arginine methylester (L-NAME) and the GPR30-selective antagonist G15. Dose-dependent vasoconstrictive responses to phenylephrine were attenuated significantly in the rings of the thoracic aorta following the acute G1 administration in the diabetic OVX rats. This effect of G1 was abolished partially by L-NAME and G15. The acute administration of G1 increased significantly the eNOS activity and the concentration of NO in the endothelial cells exposed to high glucose. G1 treatment induced an enhanced endothelium-dependent relaxation to acetylcholine (Ach) in the diabetic OVX rats. Further examination revealed that G1 induced vasodilation in the diabetic OVX rats by increasing the phosphorylation of eNOS. These findings provide preliminary evidence that GPR30 activation leads to eNOS activation, as well as vasodilation, to a certain degree and has beneficial effects on vascular function in diabetic OVX rats.

The association between OGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis of 27 studies.

BACKGROUND: Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 27 publications encompass 9663 cases and 11348 controls to comprehensively evaluate such associations. METHODS: We searched publications from MEDLINE and EMBASE which were assessing the associations between OGG1 Ser326Cys polymorphism and lung cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We used genotype based mRNA expression data from HapMap for SNP rs1052133 in normal cell lines among 270 subjects with four different ethnicities. RESULTS: The results showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk for lung cancer (OR = 1.15, 95% CI = 0.98-1.36) when compared with the Ser/Ser genotype; similarly, no significant association was found in recessive, dominant or heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). However, markedly increased risks were found in relatively large sample size (Ser/Ser vs. Cys/Cys: OR = 1.29, 95% CI = 1.13-1.48, and recessive model: OR = 1.19, 95% CI = 1.07-1.32). As to histological types, we found the Cys/Cys was associated with adenocarcinoma risk (Ser/Ser vs. Cys/Cys: OR = 1.32, 95% CI = 1.12-1.56; Ser/Cys vs. Cys/Cys: OR = 1.19, 95% CI = 1.04-1.37, and recessive model OR = 1.23, 95% CI = 1.08-1.40). No significant difference of OGG1 mRNA expression was found among genotypes between different ethnicities. CONCLUSIONS: Despite some limitations, this meta-analysis established solid statistical evidence for an association between the OGG1 Cys/Cys genotype and lung cancer risk, particularly for studies with large sample size and adenocarcinoma, but this association warrants additional validation in larger and well designed studies.

Calpain inhibitor MDL 28170 protects against the Ca2+ paradox in rat hearts.

The calcium paradox represents an important model in which to study myocardial injuries due to intracellular Ca(2+) overload. In a previous study, calpain was transiently activated in Ca(2+) -paradoxic hearts. The aim of the present study was to determine the role of calpain in myocardial dysfunction in hearts subjected to the Ca(2+) paradox and to elucidate the underlying mechanisms. Rat hearts were isolated, Langendorff perfused and subjected to the Ca(2+) paradox, which was induced by 3 min Ca(2+) depletion followed by 30 min Ca(2+) repletion, in the presence or absence of the calpain inhibitor 10 umol/L MDL 28170. Cardiac function was evaluated. Furthermore, cell death and the degradation of troponin I (TnI) were assessed and calpain activity was determined by measurement of the α-fodrin fragment and confocal image analysis. Upon Ca(2+) repletion, the hearts immediately deteriorated, exhibiting a marked depression in cardiac function and an enlarged myocardial injury area. This was accompanied by significant increases in lactate dehydrogenase, mitochondrial release of cytochrome c, the apoptotic index and degraded TnI. These changes were significantly inhibited by MDL 28170, with the exception of TnI degradation. Compared with the control group, Ca(2+) -paradoxic hearts showed a marked increase in cleaved 150 kDa fragments resulting from specific calpain-mediated proteolysis of α-fodrin. This effect was attenuated by MDL 28170. Confocal image analysis revealed the translocation of both µ- and m-calpain to the sarcolemmal membrane in Ca(2+) -paradoxic hearts, indicating increased activity of both isoforms. The results suggest that the Ca(2+) paradox promotes calpain activity, leading to necrosis, apoptosis and myocardial dysfunction.

Deletion of RBP-J in adult mice leads to the onset of aortic valve degenerative diseases.

Transcription factor RBP-J-mediated Notch signaling has been implicated in several inherited cardiovascular diseases including aortic valve diseases (AVD). But whether Notch signal plays a role in AVD in adults has been unclear. This study aims to test whether the deletion of RBP-J in adult mice would lead to AVD and to investigate the underlying mechanisms. Cre-LoxP-mediated gene deletion was employed to disrupt Notch signal in adult mice. Immunofluorescence and electron microscope observations showed that deletion of RBP-J in adult mice led to early morphological changes of AVD. The size of aortic valve was enlarged. The endothelial homeostasis was perturbed, probably due to the up-regulation of VEGFR2. The endothelial cells exhibited increased proliferation and loose endothelial junctions. The valvular mesenchyme displayed significant fibrosis, consistent with the up-regulation of TGF-ß1 and activation of endothelial-mesenchymal transition. We observed melanin-producing cells in aortic valves. The number of melanin-producing cells increased significantly, and their location changed from the mesenchyme to subendothelial layer of valve cusps in RBP-J deficient mice. These results suggest that RBP-J-mediated Notch signaling in aortic valves may be critically involved in valve homeostasis and valve diseases as well. These findings will be helpful for the understanding of the molecular mechanisms of AVD in adults.

Protective effects of hyperoside against human umbilical vein endothelial cell damage induced by hydrogen peroxide.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperoside (Hyp) is a flavonoid compound isolated from Rhododendron ponticum L. leaves that elicits vascular protective effects in vitro. Treatment with Hyp has been found to attenuate endothelial cell damage induced by oxidative stress, but its mechanisms of action remain unclear. This study investigated the action of Hyp in an endothelial injury model induced by hydrogen peroxide (H(2)O(2)), as well as its possible mechanisms. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with H(2)O(2) alone or in combination with Hyp. The protective effects of Hyp against H(2)O(2) were evaluated, and the activation of extracellular signal-regulated protein kinase (ERK) in Hyp was assayed in HUVECs. RESULTS: Loss of cell viability as well as excessive cell apoptosis and death were observed in HUVECs after 18 h of challenge with H(2)O(2) (400µM); however, both cell apoptosis and death were attenuated in the Hyp-pretreated cells. Western blot analysis revealed that Hyp increased the expression of Bcl-2 but decreased that of Bax. In addition, Hyp induced the phosphorylation of ERK1/2 in HUVECs. CONCLUSION: These observations provide preliminary evidence that Hyp protects HUVECs against H(2)O(2) damage, at least partially, by activating the ERK signaling pathway.

[Clinical follow-up of staged hybrid approach for patients with ventricular septal defects combined with patent ductus arteriosus and pulmonary hypertension].

OBJECTIVE: To evaluate the safety and efficacy of staged hybrid approach in treating ventricular septal defect (VSD) patients combined with patent ductus arteriosus (PDA) and pulmonary artery hypertension (PAH). METHODS: From July 2004 to July 2009, 22 VSD patients with PDA and PAH were enrolled and received staged hybrid approach treatment (transcatheter PDA occlusion and elective open surgery for VSD several days after PDA occlusion). All patients were followed up to examine rhythm change, residual shunt, shape of occlude, possible valve regurgitation, and aortic stenosis by echocardiography. RESULTS: After transcatheter PDA occlusion, pulmonary arterial systolic pressure decreased from (76.2 ± 25.8) mm Hg (1 mm Hg = 0.133 kPa) to (55.4 ± 20.6) mm Hg (P = 0.005), mean pulmonary artery pressure decreased from (53.5 ± 23.5) mm Hg to (36.2 ± 17.8) mm Hg (P = 0.049), total pulmonary resistance decreased from (8.2 ± 4.9) wood units to (6.9 ± 4.3) wood units (P = 0.037), and pulmonary-to-systemic flow ratio (Qp/Qs) increased from 2.8 ± 2.3 to 3.4 ± 1.7 (P = 0.045) post transcatheter interventional PDA occlusion. After VSD repair, pulmonary arterial systolic pressure decreased from (64.5 ± 22.3) mm Hg to (43.1 ± 18.9) mm Hg (P = 0.001) and mean pulmonary artery pressure decreased from (40.2 ± 18.7) mm Hg to (29.5 ± 15.8) mm Hg (P = 0.040). There was no death or right heart failure during the follow-up. CONCLUSION: Staged hybrid approach is an effective and safe strategy for treating VSD patients with PDA and PAH.

[Initial experience of transcatheter implantation with a new aortic valve in sheep].

OBJECTIVE: To evaluate the feasibility and short-term results of transcatheter aortic valve implantation (TAVI) using a new transcatheter valve. METHODS: Twenty healthy adult sheep received general anesthesia. Under the guidance of X-ray and transthoracic echocardiography (TTE), the new anti-calcification transcatheter valve was released from delivery system and implanted at the level of native aortic annulus via left common carotid artery. Position and function of the new anti-calcification transcatheter valve were evaluated by angiography and TTE immediately after intervention. Thirty day survival rate of animals was obtained. RESULTS: New transcatheter valves were implanted in all sheep. Fifteen sheep (75%) survived up to 30 days and post-operative examination showed that the transcatheter valve was in optimal position without migration and mitral valve impingement. The native coronary artery was patent in these animals. There was a slight paravalvular leak in 5 sheep. Postoperative echocardiography showed reflux percentage was significantly increased (P < 0.05) compared pre-intervention. Effective orifice area, aortic systolic pressure, diastolic aortic pressure, mean aortic pressure, left ventricular systolic pressure, left ventricular end diastolic pressure and heart rate were similar between post and pre-intervention (all P < 0.05). Five sheep died after TAVI within 30 days, including one fatal ventricular fibrillation occurred immediately after releasing the transcatheter valve and another sheep died of acute myocardial infarction due to left main coronary artery occlusion evidenced by angiography. Two sheep died of severe mitral regurgitation at 8 and 12 hours post-operation and one died of infective endocarditis at 26 days after intervention. CONCLUSION: Our favorable preliminary results showed that it was feasible to perform TAVI using the new transcatheter valve.

Role of 5-HT 2B receptors in cardiomyocyte apoptosis in noradrenaline-induced cardiomyopathy in rats.

1. Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the development of cardiac hypertrophy via activation of 5-HT receptors. The aim of the present study was to investigate the role of 5-HT(2B) receptors in the development of cardiomyocyte apoptosis and hypertrophy associated with noradrenaline (NA) overload. 2. Cardiac hypertrophy was induced in rats by intraperitoneal injection of 1.5 mg/kg NA for 4 weeks. Starting from Day 15, 5-HT2B receptor antagonist SB 204741 (i.p., 0.5 or 2 mg/kg) or SDZ SER 082 (i.p., 1 mg/kg) was injected twice daily for another 14 days. Whole-cell patch-clamp techniques were used to record ionic currents in freshly isolated ventricular cardiomyocytes. Western blot and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assays were used to assess myocardial apoptosis. 3. Expression of 5-HT(2B) receptors was enhanced in the hypertrophic left ventricle induced by NE overload in vivo. The 5-HT(2B) receptor antagonist SB 204741 partially reversed cardiac hypertrophy induced by NE overload (P < 0.05) and decreased L-type calcium currents in ventricular cardiomyocytes (P < 0.05). In addition, SB 204741 notably attenuated myocardial apoptosis, as evidenced by downregulation of Bax and caspase 3 (P < 0.05) and upregulation of the anti-apoptotic Bcl-2 protein (P < 0.05). 4. In conclusion, the data suggest an involvement of 5-HT(2B) receptors in the generation of apoptotic events associated with cardiac remodelling during increased adrenergic stimulation.

Modulation of intracellular calcium transient in response to beta-adrenoceptor stimulation in the hearts of 4-wk-old rats during simulated weightlessness.

Modulation of intracellular calcium ([Ca(2+)](i)) transient in response to beta-adrenoceptor stimulation in the hearts of hindlimb unweighted (HLU) rats during simulated weightlessness has not been reported. In the present study, we adopted the rat tail suspension for 4 wk to simulate weightlessness. Effects of simulated microgravity on beta-adrenoceptor responsiveness were then studied. Mean arterial blood pressure, left ventricular pressure (LVP), systolic function [maximum positive change in pressure over time (+dP/dt(max))], and diastolic function [maximum negative change in pressure over time (-dP/dt(max))] were monitored during the in vivo experiment. beta-Adrenoceptor density was quantitated by radioactive ligand binding. Single rat ventricular myocyte was obtained by enzymatic dissociation method. +/-dP/dt(max), myocyte contraction, intracellular [Ca(2+)](i) transient, and L-type calcium current in response to beta-adrenoceptor stimulation with isoproterenol were measured. Compared with the control group, no significant changes were found in heart weight, body weight, and mean arterial blood pressure, whereas LVP and +/-dP/dt(max) were significantly reduced. LVP and +/-dP/dt(max) were significantly attenuated in the HLU group in response to isoproterenol administration. In the in vitro study, the beta-adrenoceptor density was unchanged. Effects of isoproterenol on electrically induced single-cell contraction and [Ca(2+)](i) transient in myocytes of ventricles in HLU rats were significantly attenuated. The enhanced L-type Ca(2+) current elicited by isoproterenol in cardiomyocytes was significantly decreased in the HLU group. The above results indicate that impaired function of L-type Ca(2+) current and decreased [Ca(2+)](i) transient cause the depressed responsiveness of the beta-adrenoceptor stimulation, which may be partially responsible for the depression of cardiac function.

[Surface modification of RGD peptides onto acellularized porcine aortic valve to promote cell adhesion].

OBJECTIVE: To investigate the impact of RGD peptides on cell adhesion to acellularized procine aortic valve. METHODS: The acellular porcine aorta valve (APAV) was prepared by removing the cells and cellular components from porcine aortic valve using trypsin and hyposmosis TritonX-100. With the help of epoxy chloropropane (EC), the decelluarized valve scaffolds were immobilized with YGRGDSP peptide. MFBs were seeded onto four groups [acellularized value (AV) group, EC group, glutaraldehyde+EC (GE) group and EC+ RGD group or GE+RGD group] of coupled, coated and untreated decelluarized valve scaffolds. Ninhydrin reaction, cell count and fluorescent imaging test were employed to examine the efficiency of cell adhesion. RESULTS: More cells were attached to the decellularized valve scaffolds when the cells were coupled with RGD peptides compared with the others. The adhesive effect was correlated with the concentration of the RGD peptide and the attaching time. CONCLUSION: With the help of EC, YGRGDSP peptides can be immobilized by covalent bonding. RGD peptides improve cell adhesion to decellularized valve scaffolds.