Arrhythmia/Electrophysiology
1、Targeted Mutation Reveals Essential Functions of the Homeodomain Transcription Factor Shox2 in Sinoatrial and Pacemaking Development
Rüdiger J. Blaschke, PhD; Nathan D. Hahurij, MSc; Sanne Kuijper, PhD*; Steffen Just, MD*; Lambertus J. Wisse, BSc; Kirsten Deissler, PhD; Tina Maxelon, BSc; Konstantinos Anastassiadis, PhD; Jessica Spitzer, MD; Stefan E. Hardt, MD; Hans Schöler, PhD; Harma Feitsma, BSc; Wolfgang Rottbauer, MD; Martin Blum, PhD; Frits Meijlink, PhD; Gudrun Rappold, PhD; Adriana C. Gittenberger-de Groot, PhD Abstract
Background— Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves.
Methods and Results— To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2–/– embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos.
Conclusions— From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.
Key Words: arrhythmia • genes • heart defects, congenital • heart rate • immunohistochemistry
2、Mechanistic Role of If Revealed by Induction of Ventricular Automaticity by Somatic Gene Transfer of Gating-Engineered Pacemaker (HCN) Channels
Tian Xue, PhD*; Chung-Wah Siu, MBBS*; Deborah K. Lieu, PhD; Chu-Pak Lau, MD; Hung-Fat Tse, MD; Ronald A. Li, PhD
Background— Although If, encoded by the hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel gene family, is known to be functionally important in pacing, its mechanistic action is largely inferential and indeed somewhat controversial. To dissect in detail the role of If, we investigated the functional consequences of overexpressing in adult guinea pig left ventricular cardiomyocytes (LVCMs) various HCN1 constructs that have been engineered to exhibit different gating properties.
Methods and Results— We created the recombinant adenoviruses Ad-CMV-GFP-IRES (CGI), Ad-CGI-HCN1, Ad-CGI-HCN1-, and Ad-CGI-HCN1-Ins, which mediate ectopic expression of GFP alone, WT, EVY235-7, and Ins HCN1 channels, respectively; EVY235-7 and Ins encode channels in which the S3–S4 linkers have been shortened and lengthened to favor and inhibit opening, respectively. Ad-CGI-HCN1, Ad-CGI-HCN1-, and Ad-CGI-HCN1-Ins, but not control Ad-CGI, transduction of LVCMs led to robust expression of If with comparable densities when fully open (–22 pA/pF at –140 mV; P>0.05) but distinctive activation profiles (V1/2=–70.8±0.6, –60.4±0.7, and –87.7±0.7 mV; P<0.01, respectively). Whereas control (nontransduced or Ad-CGI–transduced) LVCMs were electrically quiescent, automaticity (206±16 bpm) was observed exclusively in 61% of Ad-HCN1-–transduced cells that displayed depolarized maximum diastolic potential (–60.6±0.5 versus –70.6±0.6 mV of resting membrane potential of control cells; P<0.01) and gradual phase 4 depolarization (306±32 mV/s) that were typical of genuine nodal cells. Furthermore, spontaneously firing Ad-HCN1-–transduced LVCMs responded positively to adrenergic stimulation (P<0.05) but exhibited neither overdrive excitation nor suppression. In contrast, the remaining 39% of Ad-HCN1-–transduced cells exhibited no spontaneous action potentials; however, a single ventricular action potential associated with a depolarized resting membrane potential and a unique, incomplete "phase 4–like" depolarization that did not lead to subsequent firing could be elicited on simulation. Such an intermediate phenotype, similarly observed in 100% of Ad-CGI-HCN– and Ad-CGI-HCN1-Ins–transduced LVCMs, could be readily reversed by ZD7288, hinting at a direct role of If. Correlation analysis revealed the specific biophysical parameters required for If to function as an active membrane potential oscillator.
Conclusions— Our results not only contribute to a better understanding of cardiac pacing but also may advance current efforts that focus primarily on automaticity induction to the next level by enabling bioengineering of central and peripheral cells that make up the native sinoatrial node.
Key Words: genes • ion channels • pacemakers • sinoatrial node • tissue engineering
Coronary Heart Disease:
3、Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression
Colin Berry, MD, PhD*; Philippe L. L’Allier, MD*; Jean Grégoire, MD; Jacques Lespérance, MD; Sylvie Levesque, MSc; Reda Ibrahim, MD; Jean-Claude Tardif, MD
Background— The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population.
Methods and Results— We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensions on QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volume on IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028).
Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.
Key Words: angiography • atherosclerosis • coronary disease • ultrasonics
4、A Prospective Study of Trans Fatty Acids in Erythrocytes and Risk of Coronary Heart Disease
Qi Sun, MD; Jing Ma, MD, PhD; Hannia Campos, PhD; Susan E. Hankinson, ScD; JoAnn E. Manson, MD, DrPH; Meir J. Stampfer, MD, DrPH; Kathryn M. Rexrode, MD, MPH; Walter C. Willett, MD, DrPH; Frank B. Hu, MD, PhD
Background— High consumption of trans fat has been linked to the risk of coronary heart disease (CHD). We assessed the hypothesis that higher trans fatty acid contents in erythrocytes were associated with an elevated risk of CHD in a nested case-control study among US women.
Methods and Results— Blood samples were collected from 32 826 participants of the Nurses’ Health Study from 1989 to 1990. During 6 years of follow-up, 166 incident cases of CHD were ascertained and matched with 327 controls. Total trans fatty acid content in erythrocytes was significantly correlated with dietary intake of trans fat (correlation coefficient=0.44, P<0.01) and was associated with increased plasma low-density lipoprotein cholesterol (P for trend =0.06), decreased plasma high-density lipoprotein cholesterol concentrations (P for trend <0.01), and increased plasma low-density lipoprotein to high-density lipoprotein ratio (P for trend <0.01). After adjustment for age, smoking status, and other dietary and lifestyle cardiovascular risk factors, higher total trans fatty acid content in erythrocytes was associated with an elevated risk of CHD. The multivariable relative risks (95% confidence intervals) of CHD from the lowest to highest quartiles of total trans fatty acid content in erythrocytes were 1.0 (reference), 1.6 (0.7 to 3.6), 1.6 (0.7 to 3.4), and 3.3 (1.5 to 7.2) (P for trend <0.01). The corresponding relative risks were 1.0, 1.1, 1.3, and 3.1 (P for trend <0.01) for a total of 18:1 trans isomers and 1.0, 1.5, 2.5, and 2.8 (P for trend <0.01) for a total of 18:2 trans isomers.
Conclusions— These biomarker data provide further evidence that high trans fat consumption remains a significant risk factor for CHD after adjustment for covariates.
Key Words: blood cells • coronary disease • fatty acids • women
Heart Failure:
5、Bioenergetic and Functional Consequences of Bone Marrow–Derived Multipotent Progenitor Cell Transplantation in Hearts With Postinfarction Left Ventricular Remodeling
Lepeng Zeng, PhD*; Qingsong Hu, MD, MS*; Xiaohong Wang, MD, PhD*; Abdul Mansoor, MD, PhD; Joseph Lee, PhD; Julia Feygin, BS; Ge Zhang, MD, PhD; Piradeep Suntharalingam, BS;
Background— The present study examined whether transplantation of adherent bone marrow–derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion.
Methods and Results— Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55±5.6% to 30±5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP (31P magnetic resonance spectroscopy; 1.06±0.30 in infarcted hearts [n=9] versus 1.90±0.15 in normal hearts [n=8; P<0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34±0.29; n=7; P<0.05). The BZ protein expression of creatine kinase–mt and creatine kinase–m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7±9.8%, P<0.01), whereas the left ventricular ejection fraction improved to 42.0±6.5% (P<0.05 versus myocardial infarction). Only 0.35±0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and 2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (P<0.05).
Conclusions— Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.
Key Words: cells • heart failure • hypertrophy • magnetic resonance imaging • metabolism • myocardial contraction • myocardial infarction
Molecular Cardiology:
6、Targeted Cardiac Overexpression of A20 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction
Hong-Liang Li, Ming-Lei Zhuo, Dong Wang, Ai-Bing Wang, Hua Cai, Li-Hong Sun, Qinglin Yang, Yue Huang, Yu-Sheng Wei, Peter P. Liu, De-Pei Liu, and Chih-Chuan Liang
Background— A20 was originally characterized as a tumor necrosis factor–inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-B signaling, A20 protects against apoptosis, inflammation, and cardiac hypertrophy. In the present study, we tested the hypothesis that cardiac-specific overexpression of A20 could protect the heart from myocardial infarction.
Methods and Results— We investigated the role of constitutive human A20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the human A20 gene under the control of the -myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20 transgenic mice and control animals. The extent of infarction was then quantified by 2-dimensional and M-mode echocardiography and by molecular and pathological analyses of heart samples in infarct and remote heart regions 7 days after myocardial infarction. Constitutive overexpression of A20 in the murine heart resulted in attenuated infarct size and improved cardiac function 7 days after myocardial infarction. Significantly, we found a decrease in nuclear factor-B signaling and apoptosis, as well as proinflammatory response, cardiac remodeling, and interstitial fibrosis, in noninfarct regions in the hearts of constitutive A20-expressing animals compared with control animals.
Conclusions— Cardiac-specific overexpression of A20 improves cardiac function and inhibits cardiac remodeling, apoptosis, inflammation, and fibrosis after acute myocardial infarction.
Key Words: apoptosis • cardiovascular diseases • fibrosis • gene therapy • hypertrophy • inflammation • remodeling
7、The pH Hypothesis of Postconditioning
Staccato Reperfusion Reintroduces Oxygen and Perpetuates Myocardial Acidosis
Michael V. Cohen, MD; Xi-Ming Yang, MD, PhD; James M. Downey, PhD
Background— It is unclear how reperfusion of infarcting hearts with alternating cycles of coronary reperfusion/occlusion attenuates infarction, but prevention of mitochondrial permeability transition pore (MPTP) formation is crucial. Acidosis also suppresses MPTP formation. We tested whether postconditioning protects by maintaining acidosis during early reoxygenation.
Methods and Results— After 30-minute regional ischemia in isolated rabbit hearts, reperfusion with buffer (pH 7.4) caused 34.4±2.2% of the risk zone to infarct, whereas 2 minutes of postconditioning (6 cycles of 10-second reperfusion/10-second occlusion) at reperfusion resulted in 10.7±2.9% infarction. One minute (3 cycles) of postconditioning was not protective. Hypercapnic buffer (pH 6.9) for the first 2 minutes of reperfusion in lieu of postconditioning caused equivalent cardioprotection (15.0±2.6% infarction), whereas 1 minute of acidosis did not protect. Delaying postconditioning (6 cycles) or 2 minutes of acidosis for 1 minute aborted protection. Reperfusion with buffer (pH 7.7) blocked postconditioning protection, but addition of the MPTP closer cyclosporin A restored protection. Reactive oxygen species scavenger N-2-mercaptopropionyl glycine, protein kinase C antagonist chelerythrine, and mitochondrial KATP channel closer 5-hydroxydecanoate each blocked protection from 2 minutes of acidosis as they did for postconditioning.
Conclusion— Thus, postconditioning prevents MPTP formation by maintaining acidosis during the first minutes of reperfusion as reoxygenated myocardium produces reactive oxygen species that activate protective signaling to inhibit MPTP formation after pH normalization.
Key Words: acidosis • free radicals • mitochondrial permeability transition pore • myocardial infarction • reperfusion
8、Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction
Kenichi Tsujita, MD; Koichi Kaikita, MD; Takanori Hayasaki, MD; Tsuyoshi Honda, MD; Hironori Kobayashi, MD; Naomi Saka***a, MD; Hiroshi Suzuki, PhD; Tatsuhiko Kodama, MD; Hisao Ogawa, MD; Motohiro Takeya, MD
Background— Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A–/–) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.
Methods and Results— Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A–/– and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A–/– mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A–/– mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A–/– mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A–/– mice compared with WT mice. Furthermore, SR-A–/– mice showed augmented expression of tumor necrosis factor- and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor- and decreased interleukin-10 expression in activated SR-A–/– macrophages.
Conclusions— The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor- and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
Key Words: cytokines • macrophages • myocardial infarction • receptors • remodeling
9、Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction
Kenichi Tsujita, MD; Koichi Kaikita, MD; Takanori Hayasaki, MD; Tsuyoshi Honda, MD; Hironori Kobayashi, MD; Naomi Saka***a, MD; Hiroshi Suzuki, PhD; Tatsuhiko Kodama, MD; Hisao Ogawa, MD; Motohiro Takeya, MD
Background— Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A–/–) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.
Methods and Results— Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A–/– and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A–/– mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A–/– mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A–/– mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A–/– mice compared with WT mice. Furthermore, SR-A–/– mice showed augmented expression of tumor necrosis factor- and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor- and decreased interleukin-10 expression in activated SR-A–/– macrophages.
Conclusions— The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor- and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
Key Words: cytokines • macrophages • myocardial infarction • receptors • remodeling
Valvular Heart Disease:
10、Mutations in FOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb
Russell H. Mellor, PhD; Glen Brice, BSc; Anthony W.B. Stanton, PhD; Jane French, MSc; Alberto Smith, PhD; Steve Jeffery, PhD; J. Rodney Levick, DSc, MRCP; Kevin G. Burnand, MS, FRCS; Peter S. Mortimer, MD, FRCP
Background— Mutations in the FOXC2 gene cause lymphedema distichiasis, an inherited primary lymphedema in which a significant number of patients have varicose veins. Because lymphedema distichiasis is believed to be caused by lymphatic valve failure (reflux), and FOXC2 is highly expressed on venous valves in mouse embryos, we tested the hypothesis that FOXC2 mutations may be linked to venous valve failure and reflux.
Methods and Results— The venous system of the leg was investigated with Duplex ultrasound. Pathological reflux was recorded by color Duplex ultrasound in all 18 participants with a FOXC2 mutation, including 3 without lymphedema. Every participant with a mutation in FOXC2 showed reflux in the great saphenous vein (n=18), compared with only 1 of 12 referents (including 10 family members; P<0.0001, Fisher exact test). Deep vein reflux was recorded in 14 of 18 participants.
Conclusions— FOXC2 is the first gene in which mutations have been strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb. This gene appears to be important for the normal development and maintenance of venous and lymphatic valves.
Key Words: valves • genes • patients • ultrasonics • veinslymphedema
第３篇
Coronary Heart Disease:
3、Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression
Background— The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population.
Methods and Results— We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensionson QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volumeon IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028).
Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.
Key Words: angiography • atherosclerosis • coronary disease • ultrasonics
标题：血管内超声与冠状动脉造影定量分析法对冠状动脉疾病进展的评价比较
背景：冠状动脉造影定量分析法(QCA)和血管内超声(IVUS)对冠状动脉疾病进展评价的优劣势尚不确定。为此，我们对同一时期行冠状动脉造影和IVUS的人群数据进行了分析。
方法与结果：我们通过观察单一时间点（n=525）和随访（n=432）病例来分析QCA和IVUS之间的关系。QCA和IVUS数据经过中心实验室分析。基线相匹配部位的QCA冠状动脉评分和IVUS测得的管腔体积(r=0.65, P<0.0001)及管腔总体积呈显著性相关(r=0.55, P<0.0001)，QCA累积冠状动脉狭窄评分和IVUS测得的动脉粥样斑块体积百分比也显著相关(r=0.32, P<0.0001)。整体QCA和单一血管IVUS测得的数据也表现出类似的相关性。随访过程中，发现QCA和IVUS测得的管腔直径呈有统计学意义的弱相关(P=0.005)，QCA测得的冠状动脉狭窄评分和IVUS测得的动脉粥样斑块体积百分比也呈有统计学意义的弱相关(r=0.14, P=0.01)。但是，接受和未接受造影的病人IVUS测得的斑块体积变化分别为9.13和0.20 mm3（P=0.028)。
结论：基线和随访过程中QCA和IVUS方法测得的管腔直径相关。尽管作为连续性变量分析，动脉粥样斑块体积百分比仅与QCA改变呈弱相关，与未接受造影检查的患者相比，接受QCA的患者IVUS测得的斑块体积显著增大。
关键词：造影，冠状动脉粥样硬化，冠状动脉疾病，超声
领第一及第十篇
1.转录因子Shox2同源结构域的定向变异揭示其在窦房结和起搏点发育中的本质作用
研究背景：识别出调节心脏起搏点发育和协调的心脏起搏之间分子途径是深入理解心率失常相关疾病的关键。由于尚不能确定参与到这一调节过程中的 发育结构和无法利用动物模型中的特异靶器官的相关组织，目前阐明这些分子途径是困难的。这里，我们报道一种在包括窦房结和静脉瓣区域窦静脉心肌中严格限制表达的转录因子Shox2同源结构域的动物模型。
方法和 结果 ：为研究这种基因在活体中的功能，我们培育出携带有定向变异的Shox2基因片段的小鼠模型。尽管杂合动物不能表现出明显的胚胎缺陷，但是纯合的定向等位基因却能导致11.5-13.5 dpc的胚胎致死。Shox2标记的胚胎表现出严重的发育不良。这些发育不良区域主要位于心脏的后面包括窦房结和静脉瓣的窦静脉心肌区域。我们进一步研究证实窦房结区域连接蛋白40和43以及转录因子Nkx2.5呈无序表达，表明Shox2不足以干扰杂合胚胎中起搏点的发育。
结论：根据研究结果，我们推断Shox2基因在包括窦房结的窦静脉心肌区域
的发育中起着关键性作用。
关键词：心率失常，基因，心脏缺陷，先天性，心脏搏动，免疫组织化学
第一次翻译，不是太好，请各位老师改正，
最爱执着 wrote:
1.转录因子Shox2同源结构域的定向变异揭示其在窦房结和起搏点发育中的本质作用
研究背景：识别出调节心脏起搏点发育和协调的心脏起搏之间分子途径是深入理解心率失常相关疾病的关键。由于尚不能确定参与到这一调节过程中的 发育结构和无法利用动物模型中的特异靶器官的相关组织，目前阐明这些分子途径是困难的。这里，我们报道一种在包括窦房结和静脉瓣区域窦静脉心肌中严格限制表达的转录因子Shox2同源结构域的动物模型。
方法和 结果 ：为研究这种基因在活体中的功能，我们培育出携带有定向变异的Shox2基因片段的小鼠模型。尽管杂合动物不能表现出明显的胚胎缺陷，但是纯合的定向等位基因却能导致11.5-13.5 dpc的胚胎致死。Shox2标记的胚胎表现出严重的发育不良。这些发育不良区域主要位于心脏的后面包括窦房结和静脉瓣的窦静脉心肌区域。我们进一步研究证实窦房结区域连接蛋白40和43以及转录因子Nkx2.5呈无序表达，表明Shox2不足以干扰杂合胚胎中起搏点的发育。
结论：根据研究结果，我们推断Shox2基因在包括窦房结的窦静脉心肌区域
的发育中起着关键性作用。
关键词：心率失常，基因，心脏缺陷，先天性，心脏搏动，免疫组织化学
第一次翻译，不是太好，请各位老师改正，
1、我觉得题目这样翻译可能更好:
定向突变揭示了在窦房结和起搏点发育中同源盒转录因子（也可以说同源结构域转录因子）Shox2的重要功能
楼上似乎理解错了,不应该是"结构域"的突变,而应该是Shox2的突变
2、Shox2–/– embryos不是“Shox2标记的胚胎”，而是“Shox2基因缺失的胚胎”。这属于概念错误
3、研究背景这段的最后一句：楼上翻译为：“我们进一步研究证实窦房结区域连接蛋白40和43以及转录因子Nkx2.5呈无序表达，”。
其实从文章来看，不光是窦房结区域存在连接蛋白40和43以及转录因子Nkx2.5呈无序表达，其他区域应该一样存在，只是窦房结区域更为明显和突出而已
以上仅代表个人理解，有误还望见谅
第十篇
10.FOXC2基因的变异与原发性下肢静脉瓣缺陷呈强相关关系
背景：FOXC2基因的变异可导致双下肢淋巴水肿，即一种在相当多数量伴有下肢静脉曲张患者中出现的原发性淋巴水肿。因为双下肢淋巴水肿被认为是 由于淋巴瓣膜缺陷（返流）引起，并且在小鼠胚胎中FOXC2呈强表达，所以我们来验证FOXC2基因变异与静脉瓣膜缺陷返流可能存在关联的 假设。
方法和结果:应用超声多普勒来研究下肢静脉系统.在包括3例没有淋巴水肿的18例存在着FOXC2基因变异的参与者中,病理性的静脉瓣膜返流被用多普勒记录下来。对比12个对照组患者只有一个存在大隐静脉返流的（包括10个家庭成员，P<0.01,Fisher 检验),每一位存在着FOXC2基因变异的参与者中都发现在其大隐静脉中存在着返流。在18例参与者中，14例被多普勒记录到下肢深静脉返流。
结论；FOXC2基因第一个被发现其变异与下肢深浅静脉瓣膜功能缺陷有关的基因。这种基因似乎与静脉和淋巴瓣膜的正常发育和功能维持中起者重要作用。
关键词：瓣膜，基因，患者，超声，静脉淋巴水肿
请各位老师指正，
多谢fixedsoldier
又学到不少
认领第8篇！
8.定向敲除A类巨噬细胞清道夫受体增加实验性心肌梗塞后心脏破裂的风险
Tsujita K, Kaikita K, Hayasaki T, Honda T, Kobayashi H, Saka***a N, Suzuki H, Kodama T, Ogawa H, Takeya M.
背景：A类巨噬细胞清道夫受体 (SR-A)是巨噬细胞特异的多功能分子，可以通过修饰炎症细胞因子的活性调节炎症反应。该研究使用SR-A缺失(SR-A(-/-))小鼠评价SR-A和心肌梗塞后心脏重塑的关系。方法和结果：我们通过结扎SR-A(-/-)小鼠和野生型(WT)小鼠的左冠状动脉产生实验性心肌梗塞。SR-A(-/-)小鼠心梗后四周内的死亡数目显著高于野生型小鼠(P=0.03)。重要地，由心脏破裂导致的心梗后一周内死亡的SR-A(-/-)小鼠死亡比例为31% (54个小鼠中的17个)，而野生型小鼠有心脏破裂导致的死亡比例为12%（51个小鼠中的6个）（P=0.01）。原位酶谱分析显示SR-A(-/-)小鼠与野生型小鼠相比，梗塞的心肌具有较高的裂解明胶的活性。心梗后第三天进行的实时逆转录PCR显示，SR-A(-/-)小鼠与野生型小鼠相比，梗塞心肌表达的基质金属蛋白酶9(MMP-9)的mRNA显著增高。体外实验也显示肿瘤坏死因子α的表达在活化的SR-A(-/-)巨噬细胞中增高，而白介素10的表达水平下降。结论：本研究提示SR-A缺失导致白介素10的表达不足及肿瘤坏死因子α表达水平增高，损伤心梗后心脏重塑最终导致心脏破裂。提示SR-A可能起到预防心梗后心脏破裂的作用。
关键词：细胞因子 巨噬细胞 心肌梗塞 受体 重塑
第４篇
4、A Prospective Study of Trans Fatty Acids in Erythrocytes and Risk of Coronary Heart Disease
Background— High consumption of trans fat has been linked to the risk of coronary heart disease (CHD). We assessed the hypothesis that higher trans fatty acid contents in erythrocytes were associated with an elevated risk of CHD in a nested case-control study among US women.
Methods and Results— Blood samples were collected from 32 826 participants of the Nurses’ Health Study from 1989 to 1990. During 6 years of follow-up, 166 incident cases of CHD were ascertained and matched with 327 controls. Total trans fatty acid content in erythrocytes was significantly correlated with dietary intake of trans fat (correlation coefficient=0.44, P<0.01) and was associated with increased plasma low-density lipoprotein cholesterol (P for trend =0.06), decreased plasma high-density lipoprotein cholesterol concentrations (P for trend <0.01), and increased plasma low-density lipoprotein to high-density lipoprotein ratio (P for trend <0.01). After adjustment for age, smoking status, and other dietary and lifestyle cardiovascular risk factors, higher total trans fatty acid content in erythrocytes was associated with an elevated risk of CHD. The multivariable relative risks (95% confidence intervals) of CHD from the lowest to highest quartiles of total trans fatty acid content in erythrocytes were 1.0 (reference), 1.6 (0.7 to 3.6), 1.6 (0.7 to 3.4), and 3.3 (1.5 to 7.2) (P for trend <0.01). The corresponding relative risks were 1.0, 1.1, 1.3, and 3.1 (P for trend <0.01) for a total of 18:1 trans isomers and 1.0, 1.5, 2.5, and 2.8 (P for trend <0.01) for a total of 18:2 trans isomers.
Conclusions— These biomarker data provide further evidence that high trans fat consumption remains a significant risk factor for CHD after adjustment for covariates.
Key Words: blood cells • coronary disease • fatty acids • women
标题：红细胞内反式脂肪酸和冠心病危险的前瞻性研究
背景：已有研究证明摄入过多反式脂肪酸与冠心病（CHD）相关。本研究假设红细胞内高反式脂肪酸含量与增加CHD危险相关。本研究采用巢式病例对照研究的方法，在美国女性人群中进行。
方法与结果：32826例血样采集于1989至1990年的护士健康研究的受试者。随访6年，共有166例CHD患者和匹配的327例对照组入选。红细胞内的反式脂肪酸含量与饮食中的反式脂肪酸显著相关（相关系数=0.44, P<0.01），并且与升高的血浆LDL-C（P =0.06），降低的HDL-C浓度（P <0.01），增加的LDL/HDL相关（P <0.01）。调整年龄，吸烟，其他与饮食和生活方式有关的心血管疾病危险因子后，细胞内高反式脂肪酸含量与升高CHD危险相关。红细胞内反式脂肪酸含量从最低至最高四分之一位数的受试者发生CHD的相对危险（95%CI）分别为1.0 (对照组), 1.6 (0.7 to 3.6), 1.6 (0.7 to 3.4), and 3.3 (1.5 to 7.2) (P <0.01). 十八碳一烯酸反异构体与之相对应的相对危险度分别为1.0, 1.1, 1.3, and 3.1 (P <0.01)；十八碳二烯酸反异构体与之相对应的相对危险度分别为1.0, 1.5, 2.5, and 2.8 (P <0.01)
结论：调整其他协变量后，上述生物标记物显示高反式脂肪酸摄入量为显著增加CHD风险的危险因子。
关键词：血细胞，冠状动脉疾病，脂肪酸，女性
第9篇.
9、Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction
Background— Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A–/–) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.
Methods and Results— Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A–/– and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A–/– mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A–/– mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A–/– mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A–/– mice compared with WT mice. Furthermore, SR-A–/– mice showed augmented expression of tumor necrosis factor- and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor- and decreased interleukin-10 expression in activated SR-A–/– macrophages.
Conclusions— The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor- and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
Key Words: cytokines • macrophages • myocardial infarction • receptors • remodeling
标题：A型巨噬细胞清道夫受体缺失增加实验性心肌梗死后心脏破裂的危险
背景：A型巨噬细胞清道夫受体(SR-A)是一种巨噬细胞细胞限制性的多功能分子，它通过调节炎症细胞因子的活动来调理炎症反应。本研究通过SR-A缺失(SR-A–/–)老鼠来评估SR-A与心肌梗死后心脏重构的关系。方法与结果：实验性心肌梗死模型通过接扎SR-A–/–型和野生型(WT) 雄老鼠的左冠状动脉获得。心肌梗死后4周内SR-A–/–型死亡的数量显著高于野生型(P=0.03)。重要的是，一周内由于心脏破裂引起的死亡在SR-A–/–型和野生型老鼠分别为：31% (17 / 54)和12% (6/51)，P=0.01。原位酶谱分析显示SR-A–/–型老鼠梗死心肌的明胶溶解活性较野生型老鼠强。梗死后3天行适时定量RT-PCR结果显示：SR-A–/–型老鼠梗死心肌基质金属蛋白酶-9 mRNA表达较野生型显著增强。而且SR-A–/–型老鼠心肌梗死后3天梗死心肌的TNF- 表达增加，IL-10表达减少。体外实验也显示激活的SR-A–/–型巨噬细胞TNF- 表达增加，IL-10表达减少。
结论：本研究提示SR-A缺失可能会通过IL-10表达不足，TNF- 和基质金属蛋白酶-9表达增加引起梗死心肌重构障碍而导致心脏破裂。SR-A可能对梗死后心脏破裂有预防作用。
关键词：细胞因子，巨噬细胞，心肌梗死，受体，重构
认领5和6，谢谢
yjmforever wrote:
第３篇
Coronary Heart Disease:
3、Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression
Background— The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population.
Methods and Results— We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensionson QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volumeon IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028).
Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.
Key Words: angiography • atherosclerosis • coronary disease • ultrasonics
标题：血管内超声与冠状动脉造影定量分析法对冠状动脉疾病进展的评价比较
背景：冠状动脉造影定量分析法(QCA)和血管内超声(IVUS)对冠状动脉疾病进展评价的优劣势尚不确定。为此，我们对同一时期行冠状动脉造影和IVUS的人群数据进行了分析。
方法与结果：我们通过观察单一时间点（n=525）和随访（n=432）病例来分析QCA和IVUS之间的关系。QCA和IVUS数据经过中心实验室分析。基线相匹配部位的QCA冠状动脉评分和IVUS测得的管腔体积(r=0.65, P<0.0001)及管腔总体积呈显著性相关(r=0.55, P<0.0001)，QCA累积冠状动脉狭窄评分和IVUS测得的动脉粥样斑块体积百分比也显著相关(r=0.32, P<0.0001)。整体QCA和单一血管IVUS测得的数据也表现出类似的相关性。随访过程中，发现QCA和IVUS测得的管腔直径呈有统计学意义的弱相关(P=0.005)，QCA测得的冠状动脉狭窄评分和IVUS测得的动脉粥样斑块体积百分比也呈有统计学意义的弱相关(r=0.14, P=0.01)。但是，接受和未接受造影的病人IVUS测得的斑块体积变化分别为9.13和0.20 mm3（P=0.028)。
结论：基线和随访过程中QCA和IVUS方法测得的管腔直径相关。尽管作为连续性变量分析，动脉粥样斑块体积百分比仅与QCA改变呈弱相关，与未接受造影检查的患者相比，接受QCA的患者IVUS测得的斑块体积显著增大。
关键词：造影，冠状动脉粥样硬化，冠状动脉疾病，超声
Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028).
Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.
但是，接受和未接受造影的病人IVUS测得的斑块体积变化分别为9.13和0.20 mm3（P=0.028)。
结论：基线和随访过程中QCA和IVUS方法测得的管腔直径相关。尽管作为连续性变量分析，动脉粥样斑块体积百分比仅与QCA改变呈弱相关，与未接受造影检查的患者相比，接受QCA的患者IVUS测得的斑块体积显著增大。
个人觉得angiographic progression应该是接受造影检查证实的进展。原意不是接受和未接受造影，而是疾病有无进展的意思。
5、Bioenergetic and Functional Consequences of Bone Marrow–Derived Multipotent Progenitor Cell Transplantation in Hearts With Postinfarction Left Ventricular Remodeling
梗死后骨髓多能前体细胞移植后的左室重建以及生物能量学和功能学后果
Background— The present study examined whether transplantation of adherent bone marrow–derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion.
背景：本研究验讫了移植黏着的骨髓来源的干细胞，定义为pMultistem，是否能够诱导新生血管形成和心肌细胞再生，从而稳定冠脉闭塞后梗死区和边缘区的生物能量和收缩功能。
Methods and Results— Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55±5.6% to 30±5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP (31P magnetic resonance spectroscopy; 1.06±0.30 in infarcted hearts [n=9] versus 1.90±0.15 in normal hearts [n=8; P<0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34±0.29; n=7; P<0.05). The BZ protein expression of creatine kinase–mt and creatine kinase–m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7±9.8%, P<0.01), whereas the left ventricular ejection fraction improved to 42.0±6.5% (P<0.05 versus myocardial infarction). Only 0.35±0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and 2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (P<0.05).
方法和结果：永久性冠脉左前降支闭塞导致猪的左心室重建，同时伴有55±5.6%到30±5.4%的射血分数减少（磁共振显像）。左前降支闭塞后四周，边缘区心肌表现出明显的生物能量学异常情况，伴有内膜下磷酸肌酸/ATP的明显减少（磁共振波谱成像；梗死心肌的1.06±0.30 [n=9] VS 正常心肌的1.90±0.15 [n=8; P<0.01]）。移植同种异体的pMultistem细胞后这种异常有明显的改善（内膜下磷酸肌酸/ATP增加至1.34±0.29; n=7; P<0.05）。边缘区本来肌酸激酶mt和甲酸激酶m的表达明显增加，但经过细胞移植后得到明显的改善。MRI显示增厚的梗死区的收缩分数与梗死后未经处理的膨出的梗死区的射血分数相比，有明显的改善(19.7±9.8%, P<0.01)，然而左室射血分数的改善达到42.0±6.5% (P<0.05 与梗死心肌相比)。仅仅0.35±0.05%供体细胞在左前降支结扎四周后可以检测得到，移植后使用环胞素A进行免疫抑制或不使用的独立结果分别为(使用组, n=6; 不使用组, n=7).获得内皮细胞或心肌细胞表型的抑制细胞的分数分别为3% and 2%。梗死区斑片样获救的细胞仅在pMultistem细胞移植后的心脏内被检测到。细胞治疗组的梗死区和边缘区的血管密度明显高于未治疗的梗死心脏。
Conclusions— Thus , allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.
结论：因此，同种异体pMultistem移植可以改善边缘区能量，局部收缩表现以及总的左室射血分数。这些改善，包括边缘区血管密度的增加以及保存梗死区的心肌细胞，来自于旁分泌效应。
Key Words: cells • heart failure • hypertrophy • magnetic resonance imaging • metabolism • myocardial contraction • myocardial infarction
Molecular Cardiology:
6、Targeted Cardiac Overexpression of A20 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction
靶向心脏过表达A20改善左室工作效应和减少梗死后的代偿性心肌肥大
background— A20 was originally characterized as a tumor necrosis factor–inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-B signaling, A20 protects against apoptosis, inflammation, and cardiac hypertrophy. In the present study, we tested the hypothesis that cardiac-specific overexpression of A20 could protect the heart from myocardial infarction.
背景：A20原来被认为具有肿瘤坏死因子的特征――人脐静脉内皮细胞内的可诱导基因。作为核因子B信号传导的抑制子，A20具有对凋亡、炎症和心肌肥大的保护作用。在本研究中，我们检验了心脏特异型过表达A20可以保护心脏免于发生心肌梗死。
Methods and Results— We investigated the role of constitutive human A20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the human A20 gene under the control of the -myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20 transgenic mice and control animals. The extent of infarction was then quantified by 2-dimensional and M-mode echocardiography and by molecular and pathological analyses of heart samples in infarct and remote heart regions 7 days after myocardial infarction. Constitutive overexpression of A20 in the murine heart resulted in attenuated infarct size and improved cardiac function 7 days after myocardial infarction. Significantly, we found a decrease in nuclear factor-B signaling and apoptosis, as well as proinflammatory response, cardiac remodeling, and interstitial fibrosis, in noninfarct regions in the hearts of constitutive A20-expressing animals compared with control animals.
方法和结果：我们利用转基因模型研究了心肌梗死中组成性人类A20基因的表达。在肌球蛋白重链启动子的控制下，构建了含有人类A20基因的转基因小鼠。利用冠脉结扎使A20基因小鼠和对照组小鼠产生心肌梗死。随后利用二维超声和M超声对梗死范围进行量化，同时利用分子和病理学手段对梗死7胎天后梗死区和远隔区的心脏样本进行分析。梗死7天后，组成性过表达A20的小鼠心脏梗死范围减少、心功能有所改善。明显的，与对照组相比，在组成性表达A20的动物中我们发现核因子B信号转导、凋亡、促炎反应、心脏重建以及间质纤维化都有所下降。
Conclusions— Cardiac-specific overexpression of A20 improves cardiac function and inhibits cardiac remodeling, apoptosis, inflammation, and fibrosis after acute myocardial infarction.
结论：心脏特异型过表达A20改善心脏功能，抑制急型心肌梗死后的心脏重建、凋亡、炎症和间质纤维化。
Key Words: apoptosis • cardiovascular diseases • fibrosis • gene therapy • hypertrophy • inflammation • remodeling
7、The pH Hypothesis of Postconditioning
Staccato Reperfusion Reintroduces Oxygen and Perpetuates Myocardial Acidosis
Michael V. Cohen, MD; Xi-Ming Yang, MD, PhD; James M. Downey, PhD
后条件的PH假说――断续性再灌注输入氧和长期保持心肌的酸中毒状态
Background— It is unclear how reperfusion of infarcting hearts with alternating cycles of coronary reperfusion/occlusion attenuates infarction, but prevention of
mitochondrial permeability transition pore (MPTP) formation is crucial. Acidosis also suppresses MPTP formation. We tested whether postconditioning protects by maintaining acidosis during early reoxygenation.
背景：梗死心脏再灌注以及伴随的冠脉再灌注/闭塞环的改变如何减轻梗死尚不清楚，但是预防线粒体通透性转换孔(MPTP)的是极为重要的。酸中毒也可以抑制MPTP的形成。我们检验了是否在早期再氧合的过程中，后条件是否具有通过维持酸中苏而对心梗具有保护作用。
Methods and Results— After 30-minute regional ischemia in isolated rabbit hearts, reperfusion with buffer (pH 7.4) caused 34.4±2.2% of the risk zone to infarct, whereas 2 minutes of postconditioning (6 cycles of 10-second reperfusion/10-second occlusion) at reperfusion resulted in 10.7±2.9% infarction. One minute (3 cycles) of postconditioning was not protective. Hypercapnic buffer (pH 6.9) for the first 2 minutes of reperfusion in lieu of postconditioning caused equivalent cardioprotection (15.0±2.6% infarction), whereas 1 minute of acidosis did not protect. Delaying postconditioning (6 cycles) or 2 minutes of acidosis for 1 minute aborted protection. Reperfusion with buffer (pH 7.7) blocked postconditioning protection, but addition of the MPTP closer cyclosporin A restored protection. Reactive oxygen species scavenger N-2-mercaptopropionyl glycine, protein kinase C antagonist chelerythrine, and mitochondrial KATP channel closer 5-hydroxydecanoate each blocked protection from 2 minutes of acidosis as they did for postconditioning.
方法和背景：离体家兔心脏30分钟局部缺血后，用缓冲液(pH 7.4)进行在灌注导致34.4±2.2%的危险区梗死，然而再灌注中两分钟的后条件（6轮10秒钟的灌注/10秒钟的闭塞）仅导致10.7±2.9%的梗死。一分钟（3轮）的后条件并没有保护作用。头两分钟利用高碳酸缓冲液进行再灌注，代替后条件，具有同样的心肌保护作用(15.0±2.6%梗死)，然而1分钟的酸中毒却没有保护作用。延迟后条件或两分钟的酸中毒1分钟使保护作用流产。用缓冲液(pH 7.7)能阻断后条件的保护作用，而增加MPTP关闭剂环胞素A则可以重新恢复保护作用。活性氧簇清道夫N-2硫丙酰甘氨酸、蛋白激酶C拮抗剂白屈菜红碱、线粒体KATP通道关闭剂5-hydroxydecanoate都可以阻断两分钟的酸中毒和后条件的保护作用。
Conclusion— Thus, postconditioning prevents MPTP formation by maintaining acidosis during the first minutes of reperfusion as reoxygenated myocardium produces reactive oxygen species that activate protective signaling to inhibit MPTP formation after pH normalization.
结论：因此，在第一分钟内，后条件通过维持酸中毒来保护MPTP形成；在PH正常后，再氧合心肌产生活性氧簇激活保护性信号通路抑制MTPT形成。
Key Words: acidosis • free radicals • mitochondrial permeability transition pore • myocardial infarction • reperfusion