Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000026397.78200.C4
J. Cabrera, D. Sánchez-Quintana, J. Farré, F. Navarro, J. Rubio, F. Cabestrero, Robert H. Anderson, S. Ho
Background—Pulmonary vein isolation with radiofrequency catheter ablation techniques is used to prevent recurrences of human atrial fibrillation. Visualization of the architecture at the venoatrial junction could be crucial for these ablative techniques. Our study assesses the potential for intravascular ultrasound to provide this information. Methods and Results—We retrieved 32 pulmonary veins from 8 patients dying from noncardiac causes. We obtained cross-sectional intravascular ultrasound (IVUS) images with a 3.2F, 30-MHz ultrasound catheter at intervals on each vein. Histological cross-sections at the intervals allowed comparisons with ultrasonic images. The pulmonary venous wall at the venoatrial junction revealed a 3-layered ultrasonic pattern. The inner echogenic layer represents both endothelium and connective tissue of the media (mean maximal thickness, 1.4±0.3 mm). The middle hypoechogenic stratum corresponds to the sleeves of left atrial myocardium surrounding the external aspect of the venous media. This layer was thickest at the venoatrial junction (mean maximal thickness, 2.6±0.8 mm) and decreased toward the lung hilum. The outer echodense layer corresponds to fibro-fatty adventitial tissue (mean maximal thickness, 2.15±0.36 mm). We found a close agreement among the IVUS and histological measurements for maximal luminal diameter (mean difference, −0.12±1.3 mm) and maximal muscular thickness (mean difference, 0.17±0.13 mm) using the Bland and Altman method. Conclusions—Our experimental study demonstrates for the first time that IVUS images of the pulmonary veins can provide information on the distal limits and thickness of the myocardial sleeves and can be a valuable tool to help accurate targeting during ablative procedures.
{"title":"Ultrasonic Characterization of the Pulmonary Venous Wall: Echographic and Histological Correlation","authors":"J. Cabrera, D. Sánchez-Quintana, J. Farré, F. Navarro, J. Rubio, F. Cabestrero, Robert H. Anderson, S. Ho","doi":"10.1161/01.CIR.0000026397.78200.C4","DOIUrl":"https://doi.org/10.1161/01.CIR.0000026397.78200.C4","url":null,"abstract":"Background—Pulmonary vein isolation with radiofrequency catheter ablation techniques is used to prevent recurrences of human atrial fibrillation. Visualization of the architecture at the venoatrial junction could be crucial for these ablative techniques. Our study assesses the potential for intravascular ultrasound to provide this information. Methods and Results—We retrieved 32 pulmonary veins from 8 patients dying from noncardiac causes. We obtained cross-sectional intravascular ultrasound (IVUS) images with a 3.2F, 30-MHz ultrasound catheter at intervals on each vein. Histological cross-sections at the intervals allowed comparisons with ultrasonic images. The pulmonary venous wall at the venoatrial junction revealed a 3-layered ultrasonic pattern. The inner echogenic layer represents both endothelium and connective tissue of the media (mean maximal thickness, 1.4±0.3 mm). The middle hypoechogenic stratum corresponds to the sleeves of left atrial myocardium surrounding the external aspect of the venous media. This layer was thickest at the venoatrial junction (mean maximal thickness, 2.6±0.8 mm) and decreased toward the lung hilum. The outer echodense layer corresponds to fibro-fatty adventitial tissue (mean maximal thickness, 2.15±0.36 mm). We found a close agreement among the IVUS and histological measurements for maximal luminal diameter (mean difference, −0.12±1.3 mm) and maximal muscular thickness (mean difference, 0.17±0.13 mm) using the Bland and Altman method. Conclusions—Our experimental study demonstrates for the first time that IVUS images of the pulmonary veins can provide information on the distal limits and thickness of the myocardial sleeves and can be a valuable tool to help accurate targeting during ablative procedures.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"28 1","pages":"968-973"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82285743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000029801.86489.50
M. Packer, R. Califf, M. Konstam, H. Krum, J. McMurray, J. Rouleau, K. Swedberg
Background—Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. Methods and Results—We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point—the combined risk of death or hospitalization for heart failure requiring intravenous treatment—was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P =0.187)—a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P =0.024) and a 6% lower risk of death (P =0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P =0.012). Conclusion—Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.
{"title":"Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE)","authors":"M. Packer, R. Califf, M. Konstam, H. Krum, J. McMurray, J. Rouleau, K. Swedberg","doi":"10.1161/01.CIR.0000029801.86489.50","DOIUrl":"https://doi.org/10.1161/01.CIR.0000029801.86489.50","url":null,"abstract":"Background—Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. Methods and Results—We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point—the combined risk of death or hospitalization for heart failure requiring intravenous treatment—was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P =0.187)—a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P =0.024) and a 6% lower risk of death (P =0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P =0.012). Conclusion—Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"1 1","pages":"920-926"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89578840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000027103.54792.9C
V. Fast, O. Sharifov, Eric R. Cheek, Jonathan C. Newton, R. Ideker
Background—It is believed that defibrillation is due to shock-induced changes of transmembrane potential (&Dgr;Vm) in the bulk of ventricular myocardium (so-called virtual electrodes), but experimental proof of this hypothesis is absent. Here, intramural shock-induced &Dgr;Vm were measured for the first time in isolated preparations of left ventricle (LV) by an optical mapping technique. Methods and Results—LV preparations were excised from porcine hearts (n=9) and perfused through a coronary artery. Rectangular shocks (duration 10 ms, field strength E ≈2 to 50 V/cm) were applied across the wall during the action potential plateau by 2 large electrodes. Shock-induced &Dgr;Vm were measured on the transmural wall surface with a 16×16 photodiode array (resolution 1.2 mm/diode). Whereas weak shocks (E≈2 V/cm) induced negligible &Dgr;Vm in the wall middle, stronger shocks produced intramural &Dgr;Vm of 2 types. (1) Shocks with E>4 V/cm produced both positive and negative intramural &Dgr;Vm that changed their sign on changing shock polarity, possibly reflecting large-scale nonuniformities in the tissue structure; the &Dgr;Vm patterns were asymmetrical, with &Dgr;V−m>&Dgr;V+m. (2) Shocks with E>34 V/cm produced predominantly negative &Dgr;Vm across the whole transmural surface, independent of the shock polarity. These relatively uniform polarizations could be a result of microscopic discontinuities in tissue structure. Conclusions—Strong defibrillation shocks induce &Dgr;Vm in the intramural layers of LV. During action potential plateau, intramural &Dgr;Vm are typically asymmetrical (&Dgr;V−m>&Dgr;V+m) and become globally negative during very strong shocks.
{"title":"Intramural Virtual Electrodes During Defibrillation Shocks in Left Ventricular Wall Assessed by Optical Mapping of Membrane Potential","authors":"V. Fast, O. Sharifov, Eric R. Cheek, Jonathan C. Newton, R. Ideker","doi":"10.1161/01.CIR.0000027103.54792.9C","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027103.54792.9C","url":null,"abstract":"Background—It is believed that defibrillation is due to shock-induced changes of transmembrane potential (&Dgr;Vm) in the bulk of ventricular myocardium (so-called virtual electrodes), but experimental proof of this hypothesis is absent. Here, intramural shock-induced &Dgr;Vm were measured for the first time in isolated preparations of left ventricle (LV) by an optical mapping technique. Methods and Results—LV preparations were excised from porcine hearts (n=9) and perfused through a coronary artery. Rectangular shocks (duration 10 ms, field strength E ≈2 to 50 V/cm) were applied across the wall during the action potential plateau by 2 large electrodes. Shock-induced &Dgr;Vm were measured on the transmural wall surface with a 16×16 photodiode array (resolution 1.2 mm/diode). Whereas weak shocks (E≈2 V/cm) induced negligible &Dgr;Vm in the wall middle, stronger shocks produced intramural &Dgr;Vm of 2 types. (1) Shocks with E>4 V/cm produced both positive and negative intramural &Dgr;Vm that changed their sign on changing shock polarity, possibly reflecting large-scale nonuniformities in the tissue structure; the &Dgr;Vm patterns were asymmetrical, with &Dgr;V−m>&Dgr;V+m. (2) Shocks with E>34 V/cm produced predominantly negative &Dgr;Vm across the whole transmural surface, independent of the shock polarity. These relatively uniform polarizations could be a result of microscopic discontinuities in tissue structure. Conclusions—Strong defibrillation shocks induce &Dgr;Vm in the intramural layers of LV. During action potential plateau, intramural &Dgr;Vm are typically asymmetrical (&Dgr;V−m>&Dgr;V+m) and become globally negative during very strong shocks.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"28 1","pages":"1007-1014"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87175202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000027109.14149.67
Ken Y. Lin, Akira Ito, T. Asagami, P. Tsao, S. Adimoolam, M. Kimoto, H. Tsuji, G. Reaven, J. Cooke
Background—An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM. Methods and Results—Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33±0.31 versus 0.48±0.08 &mgr;mol/L;P <0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P <0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol–conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis. Conclusions—A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.
一种内源性一氧化氮合酶抑制剂不对称二甲基精氨酸(ADMA)在2型糖尿病(DM)患者中升高。方法与结果:雄性Sprague-Dawley大鼠分别饲喂正常饲料和高脂饲料(每组5只)，注射适量链脲佐菌素诱导2型糖尿病。糖尿病大鼠血浆ADMA升高(1.33±0.31 vs 0.48±0.08;P <0.05)。糖尿病大鼠血浆二甲基精氨酸二甲氨基水解酶(DDAH)活性降低，与血浆ADMA水平呈负相关(P <0.05)。暴露于高葡萄糖(25.5 mmol/L)的血管平滑肌细胞和人内皮细胞(HMEC-1)的DDAH活性显著降低。血管细胞中DDAH活性的损害与ADMA的积累和cGMP生成的减少有关。在人内皮细胞中，与抗氧化剂聚乙二醇偶联超氧化物歧化酶(22 U/mL)共孵育可逆转高糖条件对DDAH活性、ADMA积累和cGMP合成的影响。结论:葡萄糖诱导的DDAH损伤可引起ADMA积累，并可能导致糖尿病患者内皮血管扩张剂功能障碍。
{"title":"Impaired Nitric Oxide Synthase Pathway in Diabetes Mellitus: Role of Asymmetric Dimethylarginine and Dimethylarginine Dimethylaminohydrolase","authors":"Ken Y. Lin, Akira Ito, T. Asagami, P. Tsao, S. Adimoolam, M. Kimoto, H. Tsuji, G. Reaven, J. Cooke","doi":"10.1161/01.CIR.0000027109.14149.67","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027109.14149.67","url":null,"abstract":"Background—An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM. Methods and Results—Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33±0.31 versus 0.48±0.08 &mgr;mol/L;P <0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P <0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol–conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis. Conclusions—A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"2 1","pages":"987-992"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74507490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000030181.63741.56
S. Kagiyama, S. Eguchi, G. D. Frank, T. Inagami, Yuan Clare Zhang, M. Ian Phillips
Background—Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via “trans”-activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II–induced cardiovascular hypertrophic effects. Methods and Results—The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II–induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II–infused hypertensive rats. In VSMCs, EGFR-AS (2.5 &mgr;mol/L) reduced EGFR expression and inhibited the Ang II–induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184±6 mm Hg versus 122±3 mm Hg; n=7;P <0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169±8 mm Hg; n=8;P <0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75±0.08 versus 2.33±0.07;P <0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II–infused rats (2.32±0.06;P <0.01) and attenuated Ang II–enhanced EGFR expression and ERK phosphorylation. Conclusion—Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.
血管紧张素II (angii)是一种血管收缩剂，也是一种生长因子。然而，Ang II型1受体不具有介导细胞有丝分裂信号的酪氨酸激酶结构域。我们已经证明Ang II通过“反式”激活表皮生长因子受体(EGFR)来诱导血管平滑肌细胞(VSMCs)中酪氨酸激酶和丝裂原活化蛋白激酶/细胞外信号调节激酶(ERK)的激活。为了研究EGFR是否参与左心室肥厚(LVH)的发展，我们用一种特殊的反义寡核苷酸抑制EGFR，以减轻Ang ii诱导的心血管肥厚效应。方法与结果:设计EGFR反义寡脱氧核苷酸(EGFR- as)，并对Angⅱ诱导的VSMCs中ERK的激活进行检测。我们还研究了EGFR-AS对angii输注高血压大鼠LVH和血压的影响。在VSMCs中，EGFR- as (2.5 mol/L)降低EGFR表达，抑制Ang ii诱导的ERK磷酸化。在大鼠中，与对照组相比，Ang II (150 ng/h，持续14天)使血压升高(184±6 mm Hg vs 122±3 mm Hg);n = 7; P < 0.01)。持续静脉输注EGFR-AS (2 mg/kg)降低血压(169±8 mm Hg);n = 8; P < 0.05)。与对照组相比，Angⅱ输注使大鼠左室/体重(LV/BW)比升高(2.75±0.08∶2.33±0.07;P <0.01)。EGFR- as能使注入angii的大鼠的LV/BW恢复正常(2.32±0.06;P <0.01)，并能减弱angii增强的EGFR表达和ERK磷酸化。结论:angii需要EGFR介导VSMCs和心脏的ERK活化。EGFR在angii诱导的LVH中起关键作用。
{"title":"Angiotensin II–Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense","authors":"S. Kagiyama, S. Eguchi, G. D. Frank, T. Inagami, Yuan Clare Zhang, M. Ian Phillips","doi":"10.1161/01.CIR.0000030181.63741.56","DOIUrl":"https://doi.org/10.1161/01.CIR.0000030181.63741.56","url":null,"abstract":"Background—Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via “trans”-activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II–induced cardiovascular hypertrophic effects. Methods and Results—The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II–induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II–infused hypertensive rats. In VSMCs, EGFR-AS (2.5 &mgr;mol/L) reduced EGFR expression and inhibited the Ang II–induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184±6 mm Hg versus 122±3 mm Hg; n=7;P <0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169±8 mm Hg; n=8;P <0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75±0.08 versus 2.33±0.07;P <0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II–infused rats (2.32±0.06;P <0.01) and attenuated Ang II–enhanced EGFR expression and ERK phosphorylation. Conclusion—Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"39 1 1","pages":"909-912"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77750289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000027107.54614.1A
C. Urbich, Elisabeth Dernbach, A. Aicher, A. Zeiher, S. Dimmeler
Background—The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration. Methods and Results—Stimulation of ECs with recombinant CD40L prevented vascular endothelial growth factor (VEGF)-induced EC migration, as determined by a “scratched wound assay.” In addition, activated T lymphocytes and platelets significantly inhibited VEGF-induced EC migration and tube formation in vitro. Because the activation of endothelial nitric oxide (NO) synthase and the release of NO are required for EC migration and angiogenesis, we analyzed the effect of NO. Coincubation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) did not reverse the inhibitory effect of CD40L on VEGF-induced EC migration and tube formation. In addition, EC migration induced by SNAP was completely inhibited by CD40L. CD40L, however, induced the production of reactive oxygen species and reduced endothelial NO bioavailability. This reactive oxygen species-dependent effect of CD40L stimulation was reversed with vitamin C or N-acetylcysteine. Conclusions—The activation of the CD40 receptor inhibits EC migration by increasing reactive oxygen species. The blockade of EC migration by CD40L may critically affect endothelial regeneration after plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L.
{"title":"CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species","authors":"C. Urbich, Elisabeth Dernbach, A. Aicher, A. Zeiher, S. Dimmeler","doi":"10.1161/01.CIR.0000027107.54614.1A","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027107.54614.1A","url":null,"abstract":"Background—The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration. Methods and Results—Stimulation of ECs with recombinant CD40L prevented vascular endothelial growth factor (VEGF)-induced EC migration, as determined by a “scratched wound assay.” In addition, activated T lymphocytes and platelets significantly inhibited VEGF-induced EC migration and tube formation in vitro. Because the activation of endothelial nitric oxide (NO) synthase and the release of NO are required for EC migration and angiogenesis, we analyzed the effect of NO. Coincubation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) did not reverse the inhibitory effect of CD40L on VEGF-induced EC migration and tube formation. In addition, EC migration induced by SNAP was completely inhibited by CD40L. CD40L, however, induced the production of reactive oxygen species and reduced endothelial NO bioavailability. This reactive oxygen species-dependent effect of CD40L stimulation was reversed with vitamin C or N-acetylcysteine. Conclusions—The activation of the CD40 receptor inhibits EC migration by increasing reactive oxygen species. The blockade of EC migration by CD40L may critically affect endothelial regeneration after plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"48 1","pages":"981-986"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80458823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000027561.41736.3C
J. Pekkanen, A. Peters, G. Hoek, P. Tiittanen, B. Brunekreef, J. D. de Hartog, J. Heinrich, A. Ibald-Mulli, W. Kreyling, T. Lanki, K. Timonen, E. Vanninen
Background—Daily variations in ambient particulate air pollution have been associated with cardiovascular mortality and morbidity. We therefore assessed the associations between levels of the 3 main modes of urban aerosol distribution and the occurrence of ST-segment depressions during repeated exercise tests. Methods and Results—Repeated biweekly submaximal exercise tests were performed during 6 months among adult subjects with stable coronary heart disease in Helsinki, Finland. Seventy-two exercise-induced ST-segment depressions >0.1 mV occurred during 342 exercise tests among 45 subjects. Simultaneously, particle mass <2.5 &mgr;m (PM2.5) and the number concentrations of ultrafine particles (particle diameter 10 to 100 nm [NC0.01–0.1]) and accumulation mode particles (100 to 1000 nm [NC0.1–1]) were monitored at a central site. Levels of particulate air pollution 2 days before the clinic visit were significantly associated with increased risk of ST-segment depression during exercise test. The association was most consistent for measures of particles reflecting accumulation mode particles (odds ratio 3.29; 95% CI, 1.57 to 6.92 for NC0.1–1 and 2.84; 95% CI, 1.42 to 5.66 for PM2.5), but ultrafine particles also had an effect (odds ratio 3.14; 95% CI, 1.56 to 6.32), which was independent of PM2.5. Also, gaseous pollutants NO2 and CO were associated with an increased risk for ST-segment depressions. No consistent association was observed for coarse particles. The associations tended to be stronger among subjects who did not use &bgr;-blockers. Conclusions—The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to myocardial ischemia.
{"title":"Particulate Air Pollution and Risk of ST-Segment Depression During Repeated Submaximal Exercise Tests Among Subjects With Coronary Heart Disease: The Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) Study","authors":"J. Pekkanen, A. Peters, G. Hoek, P. Tiittanen, B. Brunekreef, J. D. de Hartog, J. Heinrich, A. Ibald-Mulli, W. Kreyling, T. Lanki, K. Timonen, E. Vanninen","doi":"10.1161/01.CIR.0000027561.41736.3C","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027561.41736.3C","url":null,"abstract":"Background—Daily variations in ambient particulate air pollution have been associated with cardiovascular mortality and morbidity. We therefore assessed the associations between levels of the 3 main modes of urban aerosol distribution and the occurrence of ST-segment depressions during repeated exercise tests. Methods and Results—Repeated biweekly submaximal exercise tests were performed during 6 months among adult subjects with stable coronary heart disease in Helsinki, Finland. Seventy-two exercise-induced ST-segment depressions >0.1 mV occurred during 342 exercise tests among 45 subjects. Simultaneously, particle mass <2.5 &mgr;m (PM2.5) and the number concentrations of ultrafine particles (particle diameter 10 to 100 nm [NC0.01–0.1]) and accumulation mode particles (100 to 1000 nm [NC0.1–1]) were monitored at a central site. Levels of particulate air pollution 2 days before the clinic visit were significantly associated with increased risk of ST-segment depression during exercise test. The association was most consistent for measures of particles reflecting accumulation mode particles (odds ratio 3.29; 95% CI, 1.57 to 6.92 for NC0.1–1 and 2.84; 95% CI, 1.42 to 5.66 for PM2.5), but ultrafine particles also had an effect (odds ratio 3.14; 95% CI, 1.56 to 6.32), which was independent of PM2.5. Also, gaseous pollutants NO2 and CO were associated with an increased risk for ST-segment depressions. No consistent association was observed for coarse particles. The associations tended to be stronger among subjects who did not use &bgr;-blockers. Conclusions—The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to myocardial ischemia.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"33 1","pages":"933-938"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90696847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000027106.88111.77
P. Boekstegers, P. Raake, R. Al Ghobainy, J. Horstkotte, R. Hinkel, T. Sandner, R. Wichels, F. Meisner, E. Thein, K. March, D. Boehm, H. Reichenspurner
Background—Ventricle-to–coronary artery bypass (VCAB) is an experimental revascularization procedure that provides predominantly systolic instead of diastolic blood flow to a coronary artery. Methods and Results—In a pig model, a stent-based procedure (VSTENT) was developed to create a VCAB. After thoracotomy, a covered VSTENT was implanted between the left ventricle and the left anterior descending coronary artery (LAD). Distal LAD flow, regional myocardial function, and intracoronary pressures were determined at different degrees of LAD stenosis and during complete LAD occlusion. During 3 hours of LAD occlusion, VSTENT preserved net forward flow at 70±6% and regional myocardial function at 71±8% of baseline. Preservation of net flow was influenced by the positioning of the VSTENT, with higher preservation also under conditions of increased oxygen demand if a “valve-like mechanism” was present during diastole. At a hemodynamically relevant level of LAD stenosis (>70%), systolic inflow was predominant after VSTENT implantation. Changes in mean diastolic intracoronary pressure that resulted from different degrees of LAD stenosis were linearly correlated to net flow after VSTENT implantation (r =0.88;P <0.001). Conclusions—VSTENT for ventricle-to–coronary artery bypass was feasible and preserved 70±6% of baseline flow during complete LAD occlusion. The degree of preservation was dependent on the position of the VSTENT creating a valve-like mechanism during diastole. Residual diastolic blood flow through a high-grade LAD stenosis influenced net flow favorably, because diastolic backflow decreased with increasing mean diastolic intracoronary pressure.
{"title":"Stent-Based Approach for Ventricle–to–Coronary Artery Bypass","authors":"P. Boekstegers, P. Raake, R. Al Ghobainy, J. Horstkotte, R. Hinkel, T. Sandner, R. Wichels, F. Meisner, E. Thein, K. March, D. Boehm, H. Reichenspurner","doi":"10.1161/01.CIR.0000027106.88111.77","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027106.88111.77","url":null,"abstract":"Background—Ventricle-to–coronary artery bypass (VCAB) is an experimental revascularization procedure that provides predominantly systolic instead of diastolic blood flow to a coronary artery. Methods and Results—In a pig model, a stent-based procedure (VSTENT) was developed to create a VCAB. After thoracotomy, a covered VSTENT was implanted between the left ventricle and the left anterior descending coronary artery (LAD). Distal LAD flow, regional myocardial function, and intracoronary pressures were determined at different degrees of LAD stenosis and during complete LAD occlusion. During 3 hours of LAD occlusion, VSTENT preserved net forward flow at 70±6% and regional myocardial function at 71±8% of baseline. Preservation of net flow was influenced by the positioning of the VSTENT, with higher preservation also under conditions of increased oxygen demand if a “valve-like mechanism” was present during diastole. At a hemodynamically relevant level of LAD stenosis (>70%), systolic inflow was predominant after VSTENT implantation. Changes in mean diastolic intracoronary pressure that resulted from different degrees of LAD stenosis were linearly correlated to net flow after VSTENT implantation (r =0.88;P <0.001). Conclusions—VSTENT for ventricle-to–coronary artery bypass was feasible and preserved 70±6% of baseline flow during complete LAD occlusion. The degree of preservation was dependent on the position of the VSTENT creating a valve-like mechanism during diastole. Residual diastolic blood flow through a high-grade LAD stenosis influenced net flow favorably, because diastolic backflow decreased with increasing mean diastolic intracoronary pressure.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"193 1","pages":"1000-1006"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75851934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000026394.01888.18
E. Perin, G. Silva, R. Sarmento-Leite, A. Sousa, M. Howell, R. Muthupillai, B. Lambert, W. Vaughn, S. Flamm
Background—This study was designed to define myocardial viability and establish practical cut-off values for differentiating normal myocardial tissue from subendocardial and transmural scar tissue by using electromechanical mapping (EMM). We validated our results by delayed-enhancement cardiac MRI (DE-MRI). Methods and Results—We prospectively studied 15 ambulatory patients with stable coronary disease who were candidates for cardiac catheterization. Within 48 hours of EMM, DE-MRI was performed. Using EMM software, we created a bull’s eye precisely matched to that generated by DE-MRI. Segment by segment, we compared the MRI results to the corresponding unipolar voltage value for that same segment in the EMM bull’s eye. Of 300 total segments, 275 were compared. The segments were divided into normal (n=211), subendocardial scar (n=49), and transmural scar (n=15). We found that subendocardial (6.8±2.9 mV) and transmural (4.6±1.9 mV) scar segments had significantly less unipolar voltage than normal (11.6±4.5 mV) segments (P <0.05 for each comparison). When normal myocardium was compared with myocardium with subendocardial scar, the threshold for differentiating between the two areas was 7.9 mV (sensitivity, 80%; specificity, 80%). Comparison of normal tissue to transmural scar yielded a threshold of 6.9 mV (sensitivity, 93%; specificity, 88%). Conclusions—Our results demonstrate that normal myocardium can be accurately distinguished from myocardium with subendocardial or transmural infarcts on the basis of unipolar voltage values obtained through EMM. This is the first study to validate these results by using cardiac DE-MRI in humans.
{"title":"Assessing Myocardial Viability and Infarct Transmurality With Left Ventricular Electromechanical Mapping in Patients With Stable Coronary Artery Disease: Validation by Delayed-Enhancement Magnetic Resonance Imaging","authors":"E. Perin, G. Silva, R. Sarmento-Leite, A. Sousa, M. Howell, R. Muthupillai, B. Lambert, W. Vaughn, S. Flamm","doi":"10.1161/01.CIR.0000026394.01888.18","DOIUrl":"https://doi.org/10.1161/01.CIR.0000026394.01888.18","url":null,"abstract":"Background—This study was designed to define myocardial viability and establish practical cut-off values for differentiating normal myocardial tissue from subendocardial and transmural scar tissue by using electromechanical mapping (EMM). We validated our results by delayed-enhancement cardiac MRI (DE-MRI). Methods and Results—We prospectively studied 15 ambulatory patients with stable coronary disease who were candidates for cardiac catheterization. Within 48 hours of EMM, DE-MRI was performed. Using EMM software, we created a bull’s eye precisely matched to that generated by DE-MRI. Segment by segment, we compared the MRI results to the corresponding unipolar voltage value for that same segment in the EMM bull’s eye. Of 300 total segments, 275 were compared. The segments were divided into normal (n=211), subendocardial scar (n=49), and transmural scar (n=15). We found that subendocardial (6.8±2.9 mV) and transmural (4.6±1.9 mV) scar segments had significantly less unipolar voltage than normal (11.6±4.5 mV) segments (P <0.05 for each comparison). When normal myocardium was compared with myocardium with subendocardial scar, the threshold for differentiating between the two areas was 7.9 mV (sensitivity, 80%; specificity, 80%). Comparison of normal tissue to transmural scar yielded a threshold of 6.9 mV (sensitivity, 93%; specificity, 88%). Conclusions—Our results demonstrate that normal myocardium can be accurately distinguished from myocardium with subendocardial or transmural infarcts on the basis of unipolar voltage values obtained through EMM. This is the first study to validate these results by using cardiac DE-MRI in humans.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"106 1","pages":"957-961"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87597366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-08-20DOI: 10.1161/01.CIR.0000029802.88087.5E
S. Verma, Chao-Hung Wang, Shu‐hong Li, A. Dumont, P. Fedak, M. Badiwala, B. Dhillon, R. Weisel, Ren-Ke Li, Donald A. G. Mickle, D. Stewart
Background—Given the central importance of nitric oxide (NO) in the development and clinical course of cardiovascular diseases, we sought to determine whether the powerful predictive value of C-reactive protein (CRP) might be explained through an effect on NO production. Methods and Results—Endothelial cells (ECs) were incubated with recombinant CRP (0 to 100 &mgr;g/mL, 24 hours), and NO and cyclic guanosine monophosphate (cGMP) production was assessed. The effects of CRP on endothelial NO synthase (eNOS) protein, mRNA expression, and mRNA stability were also examined. In a separate study, the effects of CRP (25 &mgr;g/mL) on EC cell survival, apoptosis, and in vitro angiogenesis were evaluated. Incubation of ECs with CRP resulted in a significant inhibition of basal and stimulated NO release, with concomitant reductions in cGMP production. CRP caused a marked downregulation of eNOS mRNA and protein expression. Actinomycin D studies suggested that eNOS downregulation was related to decreased mRNA stability. In conjunction with a decrease in NO production, CRP inhibited both basal and vascular endothelial growth factor–stimulated angiogenesis as assessed by EC migration and capillary-like tube formation. CRP did not induce EC survival but did, however, promote apoptosis in a NO-dependent fashion. Conclusions—CRP, at concentrations known to predict adverse vascular events, directly quenches the production of the NO, in part, through posttranscriptional effect on eNOS mRNA stability. Diminished NO bioactivity, in turn, inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. Through decreasing NO synthesis, CRP may facilitate the development of diverse cardiovascular diseases. Risk reduction strategies designed to lower plasma CRP may be effective by improving NO bioavailability.
{"title":"A Self-Fulfilling Prophecy: C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits Angiogenesis","authors":"S. Verma, Chao-Hung Wang, Shu‐hong Li, A. Dumont, P. Fedak, M. Badiwala, B. Dhillon, R. Weisel, Ren-Ke Li, Donald A. G. Mickle, D. Stewart","doi":"10.1161/01.CIR.0000029802.88087.5E","DOIUrl":"https://doi.org/10.1161/01.CIR.0000029802.88087.5E","url":null,"abstract":"Background—Given the central importance of nitric oxide (NO) in the development and clinical course of cardiovascular diseases, we sought to determine whether the powerful predictive value of C-reactive protein (CRP) might be explained through an effect on NO production. Methods and Results—Endothelial cells (ECs) were incubated with recombinant CRP (0 to 100 &mgr;g/mL, 24 hours), and NO and cyclic guanosine monophosphate (cGMP) production was assessed. The effects of CRP on endothelial NO synthase (eNOS) protein, mRNA expression, and mRNA stability were also examined. In a separate study, the effects of CRP (25 &mgr;g/mL) on EC cell survival, apoptosis, and in vitro angiogenesis were evaluated. Incubation of ECs with CRP resulted in a significant inhibition of basal and stimulated NO release, with concomitant reductions in cGMP production. CRP caused a marked downregulation of eNOS mRNA and protein expression. Actinomycin D studies suggested that eNOS downregulation was related to decreased mRNA stability. In conjunction with a decrease in NO production, CRP inhibited both basal and vascular endothelial growth factor–stimulated angiogenesis as assessed by EC migration and capillary-like tube formation. CRP did not induce EC survival but did, however, promote apoptosis in a NO-dependent fashion. Conclusions—CRP, at concentrations known to predict adverse vascular events, directly quenches the production of the NO, in part, through posttranscriptional effect on eNOS mRNA stability. Diminished NO bioactivity, in turn, inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. Through decreasing NO synthesis, CRP may facilitate the development of diverse cardiovascular diseases. Risk reduction strategies designed to lower plasma CRP may be effective by improving NO bioavailability.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"4 1","pages":"913-919"},"PeriodicalIF":0.0,"publicationDate":"2002-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82472215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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