Pub Date : 2002-08-27DOI: 10.1161/01.CIR.0000027567.49283.FF
S. Achenbach, D. Ropers, K. Pohle, A. Leber, C. Thilo, A. Knez, T. Menéndez, R. Maeffert, M. Kusus, M. Regenfus, A. Bickel, R. Haberl, G. Steinbeck, W. Moshage, W. Daniel
Background—Coronary calcification measured by fast computed tomography techniques is a surrogate marker of coronary atherosclerotic plaque burden. In a cohort study, we prospectively investigated whether lipid-lowering therapy with a cholesterol synthesis enzyme inhibitor reduces the progression of coronary calcification. Methods and Results—In 66 patients with coronary calcifications in electron beam tomography (EBT), LDL cholesterol >130 mg/dL, and no lipid-lowering treatment, the EBT scan was repeated after a mean interval of 14 months and treatment with cerivastatin was initiated (0.3 mg/d). After 12 months of treatment, a third EBT scan was performed. Coronary calcifications were quantified using a volumetric score. Cerivastatin therapy lowered the mean LDL cholesterol level from 164±30 to 107±21 mg/dL. The median calcified volume was 155 mm3 (range, 15 to 1849) at baseline, 201 mm3 (19 to 2486) after 14 months without treatment, and 203 mm3 (15 to 2569) after 12 months of cerivastatin treatment. The median annualized absolute increase in coronary calcium was 25 mm3 during the untreated versus 11 mm3 during the treatment period (P =0.01). The median annual relative increase in coronary calcium was 25% during the untreated versus 8.8% during the treatment period (P <0.0001). In 32 patients with an LDL cholesterol level <100 mg/dL under treatment, the median relative change was 27% during the untreated versus −3.4% during the treatment period (P =0.0001). Conclusions—Treatment with the cholesterol synthesis enzyme inhibitor cerivastatin significantly reduces coronary calcium progression in patients with LDL cholesterol >130 mg/dL.
{"title":"Influence of Lipid-Lowering Therapy on the Progression of Coronary Artery Calcification: A Prospective Evaluation","authors":"S. Achenbach, D. Ropers, K. Pohle, A. Leber, C. Thilo, A. Knez, T. Menéndez, R. Maeffert, M. Kusus, M. Regenfus, A. Bickel, R. Haberl, G. Steinbeck, W. Moshage, W. Daniel","doi":"10.1161/01.CIR.0000027567.49283.FF","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027567.49283.FF","url":null,"abstract":"Background—Coronary calcification measured by fast computed tomography techniques is a surrogate marker of coronary atherosclerotic plaque burden. In a cohort study, we prospectively investigated whether lipid-lowering therapy with a cholesterol synthesis enzyme inhibitor reduces the progression of coronary calcification. Methods and Results—In 66 patients with coronary calcifications in electron beam tomography (EBT), LDL cholesterol >130 mg/dL, and no lipid-lowering treatment, the EBT scan was repeated after a mean interval of 14 months and treatment with cerivastatin was initiated (0.3 mg/d). After 12 months of treatment, a third EBT scan was performed. Coronary calcifications were quantified using a volumetric score. Cerivastatin therapy lowered the mean LDL cholesterol level from 164±30 to 107±21 mg/dL. The median calcified volume was 155 mm3 (range, 15 to 1849) at baseline, 201 mm3 (19 to 2486) after 14 months without treatment, and 203 mm3 (15 to 2569) after 12 months of cerivastatin treatment. The median annualized absolute increase in coronary calcium was 25 mm3 during the untreated versus 11 mm3 during the treatment period (P =0.01). The median annual relative increase in coronary calcium was 25% during the untreated versus 8.8% during the treatment period (P <0.0001). In 32 patients with an LDL cholesterol level <100 mg/dL under treatment, the median relative change was 27% during the untreated versus −3.4% during the treatment period (P =0.0001). Conclusions—Treatment with the cholesterol synthesis enzyme inhibitor cerivastatin significantly reduces coronary calcium progression in patients with LDL cholesterol >130 mg/dL.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"66 5","pages":"1077-1082"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91512042","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 : 2002-08-27DOI: 10.1161/01.CIR.0000026820.87824.6A
M. Forgione, André Cap, R. Liao, N. Moldovan, R. Eberhardt, C. Lim, J. Jones, P. Goldschmidt-Clermont, J. Loscalzo
Background—Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress. Methods and Results—A murine model of heterozygous deficiency of GPx-1 (GPx+/−) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1+/− mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, −13.0±2.8% versus 13.2±2.8%, P <0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF2&agr;-III, a marker of oxidant stress, in GPx-1+/− mice compared with wild-type mice (170.4±23 pg/mL plasma versus 98.7±7.1 pg/mL plasma, P <0.03; 11.7±0.87 pg/mg aortic tissue versus 8.2±0.55 pg/mg aortic tissue, P <0.01). Histological sections from the coronary vasculature of GPx-1+/− mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion. Conclusions—These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.
{"title":"Heterozygous Cellular Glutathione Peroxidase Deficiency in the Mouse: Abnormalities in Vascular and Cardiac Function and Structure","authors":"M. Forgione, André Cap, R. Liao, N. Moldovan, R. Eberhardt, C. Lim, J. Jones, P. Goldschmidt-Clermont, J. Loscalzo","doi":"10.1161/01.CIR.0000026820.87824.6A","DOIUrl":"https://doi.org/10.1161/01.CIR.0000026820.87824.6A","url":null,"abstract":"Background—Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress. Methods and Results—A murine model of heterozygous deficiency of GPx-1 (GPx+/−) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1+/− mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, −13.0±2.8% versus 13.2±2.8%, P <0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF2&agr;-III, a marker of oxidant stress, in GPx-1+/− mice compared with wild-type mice (170.4±23 pg/mL plasma versus 98.7±7.1 pg/mL plasma, P <0.03; 11.7±0.87 pg/mg aortic tissue versus 8.2±0.55 pg/mg aortic tissue, P <0.01). Histological sections from the coronary vasculature of GPx-1+/− mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion. Conclusions—These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"29 1","pages":"1154-1158"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75840888","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 : 2002-08-27DOI: 10.1161/01.CIR.0000026802.79202.96
Gertrud U. Schuster, P. Parini, Ling Wang, S. Alberti, K. Steffensen, G. Hansson, B. Angelin, J. Gustafsson
Background—The nature of some of the target genes for liver X receptors (LXRs)-&agr; and -&bgr;, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux. Methods and Results—Mice depleted for LXR&agr;, LXR&bgr;, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXR&agr; and LXR&bgr; was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall. Conclusions—Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.
{"title":"Accumulation of Foam Cells in Liver X Receptor-Deficient Mice","authors":"Gertrud U. Schuster, P. Parini, Ling Wang, S. Alberti, K. Steffensen, G. Hansson, B. Angelin, J. Gustafsson","doi":"10.1161/01.CIR.0000026802.79202.96","DOIUrl":"https://doi.org/10.1161/01.CIR.0000026802.79202.96","url":null,"abstract":"Background—The nature of some of the target genes for liver X receptors (LXRs)-&agr; and -&bgr;, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux. Methods and Results—Mice depleted for LXR&agr;, LXR&bgr;, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXR&agr; and LXR&bgr; was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall. Conclusions—Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"78 1","pages":"1147-1153"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84756523","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 : 2002-08-27DOI: 10.1161/01.CIR.0000028147.92190.A7
R. Myerburg, J. Fenster, M. Velez, D. Rosenberg, S. Lai, P. Kurlansky, Starbuck Newton, Melenda Knox, A. Castellanos
Background—Disappointing survival rates from out-of-hospital cardiac arrests encourage strategies for faster defibrillation, such as use of automated external defibrillators (AEDs) by nonconventional responders. Methods and Results—AEDs were provided to all Miami-Dade County, Florida, police. AED-equipped police (P-AED) and conventional emergency medical rescue (EMS) responders are simultaneously deployed to possible cardiac arrests. Times from 9-1-1 contact to the scene were compared for P-AED and concurrently deployed EMS, and both were compared with historical EMS experience. Survival with P-AED was compared with outcomes when EMS was the sole responder. Among 420 paired dispatches of P-AED and EMS, the mean±SD P-AED time from 9-1-1 call to arrival at the scene was 6.16±4.27 minutes, compared with 7.56±3.60 minutes for EMS (P <0.001). Police arrived first to 56% of the calls. The time to first responder arrival among P-AED and EMS was 4.88±2.88 minutes (P <0.001), compared with a historical response time of 7.64±3.66 minutes when EMS was the sole responder. A 17.2% survival rate was observed for victims with ventricular fibrillation or pulseless ventricular tachycardia (VT/VF), compared with 9.0% for standard EMS before P-AED implementation (P =0.047). However, VT/VF benefit was diluted by the observation that 61% of the initial rhythms were nonshockable, reducing the absolute survival benefit among the total study population to 1.6% (P-AED, 7.6%; EMS, 6.0%). Conclusions—P-AED establishes a layer of responders that generate improved response times and survival from VT/VF. There was no benefit for victims with nonshockable rhythms.
{"title":"Impact of Community-Wide Police Car Deployment of Automated External Defibrillators on Survival From Out-of-Hospital Cardiac Arrest","authors":"R. Myerburg, J. Fenster, M. Velez, D. Rosenberg, S. Lai, P. Kurlansky, Starbuck Newton, Melenda Knox, A. Castellanos","doi":"10.1161/01.CIR.0000028147.92190.A7","DOIUrl":"https://doi.org/10.1161/01.CIR.0000028147.92190.A7","url":null,"abstract":"Background—Disappointing survival rates from out-of-hospital cardiac arrests encourage strategies for faster defibrillation, such as use of automated external defibrillators (AEDs) by nonconventional responders. Methods and Results—AEDs were provided to all Miami-Dade County, Florida, police. AED-equipped police (P-AED) and conventional emergency medical rescue (EMS) responders are simultaneously deployed to possible cardiac arrests. Times from 9-1-1 contact to the scene were compared for P-AED and concurrently deployed EMS, and both were compared with historical EMS experience. Survival with P-AED was compared with outcomes when EMS was the sole responder. Among 420 paired dispatches of P-AED and EMS, the mean±SD P-AED time from 9-1-1 call to arrival at the scene was 6.16±4.27 minutes, compared with 7.56±3.60 minutes for EMS (P <0.001). Police arrived first to 56% of the calls. The time to first responder arrival among P-AED and EMS was 4.88±2.88 minutes (P <0.001), compared with a historical response time of 7.64±3.66 minutes when EMS was the sole responder. A 17.2% survival rate was observed for victims with ventricular fibrillation or pulseless ventricular tachycardia (VT/VF), compared with 9.0% for standard EMS before P-AED implementation (P =0.047). However, VT/VF benefit was diluted by the observation that 61% of the initial rhythms were nonshockable, reducing the absolute survival benefit among the total study population to 1.6% (P-AED, 7.6%; EMS, 6.0%). Conclusions—P-AED establishes a layer of responders that generate improved response times and survival from VT/VF. There was no benefit for victims with nonshockable rhythms.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"21 1","pages":"1058-1064"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83206023","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 : 2002-08-27DOI: 10.1161/01.CIR.0000027149.83473.B6
E. Bocchi, G. Guimãraes, A. Mocelin, F. Bacal, G. Bellotti, J. Ramires
Background—Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF). ED reduces quality of life, and it may affect compliance, thereby impairing the success of CHF treatment. Methods and Results—In the first phase (fixed-dose double-blind, randomized, placebo-controlled, two-way crossover study), we studied in 23 men with CHF the effects of 50 mg sildenafil on exercise and neurohormonal activation. Patients underwent a treadmill 6-minute cardiopulmonary walking (6′WT) test followed by a maximal cardiopulmonary exercise test (ET). In the second phase, patients received sildenafil, taken as required for ED. Sildenafil reduced the heart rate (HR) (bpm) before the 6′WT (from 75±15 to 71±14, P =0.02) and ET (from 75±15 to 71±15, P =0.02); the systolic blood pressure (mm Hg) before the 6′WT (from 116±18 to 108±18, P =0.004) and ET (from 116±15 to 108±17, P =0.001); the diastolic blood pressure before the 6′WT (from 69±9 to 63±11, P =0.01) and ET (from 70±8 to 65±10, P =0.004); and the Ve/Vco2 slope during the 6′WT (from 32±7 to 31±6, P =0.04) and ET (from 33±8 to 31±5, P =0.03). Sildenafil attenuated the HR increment during the 6′WT (P =0.003) and ET (P =0.000). Sildenafil increased the peak ˙ o2 from 16.6±3.4 to 17.7±3.4 mL/kg per min (P =0.025) and the exercise time from 12.3±3.4 to 13.7±3.2 minutes (P =0.003). Sildenafil improved most scores of International Index of Erectile Function. Conclusions—Sildenafil was tolerated and effective for ED treatment in CHF, and improved the exercise capacity. The reduction of HR during exercise with sildenafil could theoretically decrease the myocardial oxygen consumption during sexual activity.
{"title":"Sildenafil Effects on Exercise, Neurohormonal Activation, and Erectile Dysfunction in Congestive Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Study Followed by a Prospective Treatment for Erectile Dysfunction","authors":"E. Bocchi, G. Guimãraes, A. Mocelin, F. Bacal, G. Bellotti, J. Ramires","doi":"10.1161/01.CIR.0000027149.83473.B6","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027149.83473.B6","url":null,"abstract":"Background—Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF). ED reduces quality of life, and it may affect compliance, thereby impairing the success of CHF treatment. Methods and Results—In the first phase (fixed-dose double-blind, randomized, placebo-controlled, two-way crossover study), we studied in 23 men with CHF the effects of 50 mg sildenafil on exercise and neurohormonal activation. Patients underwent a treadmill 6-minute cardiopulmonary walking (6′WT) test followed by a maximal cardiopulmonary exercise test (ET). In the second phase, patients received sildenafil, taken as required for ED. Sildenafil reduced the heart rate (HR) (bpm) before the 6′WT (from 75±15 to 71±14, P =0.02) and ET (from 75±15 to 71±15, P =0.02); the systolic blood pressure (mm Hg) before the 6′WT (from 116±18 to 108±18, P =0.004) and ET (from 116±15 to 108±17, P =0.001); the diastolic blood pressure before the 6′WT (from 69±9 to 63±11, P =0.01) and ET (from 70±8 to 65±10, P =0.004); and the Ve/Vco2 slope during the 6′WT (from 32±7 to 31±6, P =0.04) and ET (from 33±8 to 31±5, P =0.03). Sildenafil attenuated the HR increment during the 6′WT (P =0.003) and ET (P =0.000). Sildenafil increased the peak ˙ o2 from 16.6±3.4 to 17.7±3.4 mL/kg per min (P =0.025) and the exercise time from 12.3±3.4 to 13.7±3.2 minutes (P =0.003). Sildenafil improved most scores of International Index of Erectile Function. Conclusions—Sildenafil was tolerated and effective for ED treatment in CHF, and improved the exercise capacity. The reduction of HR during exercise with sildenafil could theoretically decrease the myocardial oxygen consumption during sexual activity.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"46 1","pages":"1097-1103"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73053863","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 : 2002-08-27DOI: 10.1161/01.CIR.0000031063.20871.B5
C. Lenfant
Since the 1940s, when major breakthroughs occurred in the surgical treatment of congenital malformations, great strides have been made in the treatment of cardiovascular disease in infants and children. Nonetheless, significant difficulties remain that hinder our ability to treat the very youngest and smallest patients with cardiovascular disease, including those still in utero. Heart disease in infants, children, and adolescents is still a large problem, with substantial burden and cost for both families and society. Although surgical and technological innovations have greatly advanced treatment of cardiovascular disease in adult patients, treatment of infants, children, and adolescents has not kept pace. The most obvious reason for this situation is that children are not simply smaller adults. If they were, the appropriate miniaturization of instruments and equipment, scaling down from adults to children, would be sufficient. However, when considering interventions for neonates, or even fetuses, one must remember that they exhibit marked physiological characteristics that distinguish them from adults, such as increased heart rate and immature tissue development. To stimulate clinical research and thereby enhance our ability to treat infants, children, and adolescents, the National Heart, Lung, and Blood Institute (NHLBI) has launched 2 major initiatives. First, in May of 2000, we issued a solicitation for the establishment of a Pediatric Heart Disease Clinical Research Network of interactive pediatric clinical research centers (http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-00-013.html). Its purpose is to promote efficient evaluation of innovative treatment methods and management strategies for children with structural congenital heart disease, inflammatory heart disease, heart muscle disease, and arrhythmias. We anticipate that one outcome of the Network will be to promote rapid dissemination of the findings from these clinical studies to the medical community. Seven clinical centers and a data-coordinating center were funded in September 2001, and it is expected that 2 protocols will be under way by the …
{"title":"Report of the Task Force on Research in Pediatric Cardiovascular Disease","authors":"C. Lenfant","doi":"10.1161/01.CIR.0000031063.20871.B5","DOIUrl":"https://doi.org/10.1161/01.CIR.0000031063.20871.B5","url":null,"abstract":"Since the 1940s, when major breakthroughs occurred in the surgical treatment of congenital malformations, great strides have been made in the treatment of cardiovascular disease in infants and children. Nonetheless, significant difficulties remain that hinder our ability to treat the very youngest and smallest patients with cardiovascular disease, including those still in utero. Heart disease in infants, children, and adolescents is still a large problem, with substantial burden and cost for both families and society.\u0000\u0000Although surgical and technological innovations have greatly advanced treatment of cardiovascular disease in adult patients, treatment of infants, children, and adolescents has not kept pace. The most obvious reason for this situation is that children are not simply smaller adults. If they were, the appropriate miniaturization of instruments and equipment, scaling down from adults to children, would be sufficient. However, when considering interventions for neonates, or even fetuses, one must remember that they exhibit marked physiological characteristics that distinguish them from adults, such as increased heart rate and immature tissue development.\u0000\u0000To stimulate clinical research and thereby enhance our ability to treat infants, children, and adolescents, the National Heart, Lung, and Blood Institute (NHLBI) has launched 2 major initiatives. First, in May of 2000, we issued a solicitation for the establishment of a Pediatric Heart Disease Clinical Research Network of interactive pediatric clinical research centers (http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-00-013.html). Its purpose is to promote efficient evaluation of innovative treatment methods and management strategies for children with structural congenital heart disease, inflammatory heart disease, heart muscle disease, and arrhythmias. We anticipate that one outcome of the Network will be to promote rapid dissemination of the findings from these clinical studies to the medical community. Seven clinical centers and a data-coordinating center were funded in September 2001, and it is expected that 2 protocols will be under way by the …","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"23 1","pages":"1037-1042"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77862041","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 : 2002-08-27DOI: 10.1161/01.CIR.0000030182.35880.3E
B. V. Van Lenten, A. Wagner, G. Anantharamaiah, D. Garber, M. Fishbein, Lopa Adhikary, D. Nayak, S. Hama, M. Navab, A. Fogelman
Background—We reported that HDL loses its antiinflammatory properties during acute influenza A infection in mice, and we hypothesized that these changes might be associated with increased trafficking of macrophages into the artery wall. The present study tested this hypothesis. Methods and Results—D-4F, an apolipoprotein A-I mimetic peptide, or vehicle in which it was dissolved (PBS) was administered daily to LDL receptor–null mice after a Western diet and after influenza infection. D-4F treatment increased plasma HDL cholesterol and paraoxonase activity compared with PBS and inhibited increases in LDL cholesterol and peak levels of interleukin-6 after infection. Lung viral titers were reduced by 50% in mice receiving D-4F. Injection of female mice with male macrophages, which were detected with real-time polymerase chain reaction to measure the male Sry gene, revealed a marked increase in macrophage traffic into the aortic arch and innominate arteries after infection that was prevented by administration of D-4F. Conclusions—We conclude that loss of antiinflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.
{"title":"Influenza Infection Promotes Macrophage Traffic Into Arteries of Mice That Is Prevented by D-4F, an Apolipoprotein A-I Mimetic Peptide","authors":"B. V. Van Lenten, A. Wagner, G. Anantharamaiah, D. Garber, M. Fishbein, Lopa Adhikary, D. Nayak, S. Hama, M. Navab, A. Fogelman","doi":"10.1161/01.CIR.0000030182.35880.3E","DOIUrl":"https://doi.org/10.1161/01.CIR.0000030182.35880.3E","url":null,"abstract":"Background—We reported that HDL loses its antiinflammatory properties during acute influenza A infection in mice, and we hypothesized that these changes might be associated with increased trafficking of macrophages into the artery wall. The present study tested this hypothesis. Methods and Results—D-4F, an apolipoprotein A-I mimetic peptide, or vehicle in which it was dissolved (PBS) was administered daily to LDL receptor–null mice after a Western diet and after influenza infection. D-4F treatment increased plasma HDL cholesterol and paraoxonase activity compared with PBS and inhibited increases in LDL cholesterol and peak levels of interleukin-6 after infection. Lung viral titers were reduced by 50% in mice receiving D-4F. Injection of female mice with male macrophages, which were detected with real-time polymerase chain reaction to measure the male Sry gene, revealed a marked increase in macrophage traffic into the aortic arch and innominate arteries after infection that was prevented by administration of D-4F. Conclusions—We conclude that loss of antiinflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"3 1","pages":"1127-1132"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75467858","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 : 2002-08-27DOI: 10.1161/01.CIR.0000023218.39412.32
R. Califf, D. DeMets
This last installment of a 4-part series discusses the final 5 of 11 principles derived from clinical trials during the last 2 decades of cardiovascular clinical research and the need to apply them to the care of individual patients with heart diseases. As therapies have become more biologically potent, it has become increasingly clear that every treatment can be harmful in some patients while being beneficial in others, and often both good and bad effects occur in the same patient. With many therapies, clinical characteristics can identify patients with greater expected benefit or risk, and pharmacogenetics may offer further insight into predicting which patients will achieve the greatest benefit and which will have the greatest risk of harm. For example, we know that women are at higher risk for torsades de pointes when they are treated with QT-interval-prolonging drugs, and it is likely that a genetic predisposition may be important.1 Unfortunately, however, the relative power of these findings is limited, and we are left with broad treatment guidelines that will leave patients at risk of harm that cannot be predicted in absolute terms. The recognition that therapeutics are not commonly either “good” or “bad,” but carry a mixture of good and bad effects, has spawned the concept of risk-management in therapeutics. Each clinician has the responsibility of helping the patient place these risks and benefits in perspective when making decisions about therapeutics. Inevitably, this approach will require an improved grasp of probabilities and quantitative outcome estimates by clinicians and patients. Furthermore, there is an implied responsibility, both to participate in the generation of knowledge about risks and benefits through clinical trials and to report adverse events observed in the post-marketing period. Such adverse event reporting played the critical role in identifying cisapride as a cause of sudden death2 …
{"title":"Principles From Clinical Trials Relevant to Clinical Practice: Part II","authors":"R. Califf, D. DeMets","doi":"10.1161/01.CIR.0000023218.39412.32","DOIUrl":"https://doi.org/10.1161/01.CIR.0000023218.39412.32","url":null,"abstract":"This last installment of a 4-part series discusses the final 5 of 11 principles derived from clinical trials during the last 2 decades of cardiovascular clinical research and the need to apply them to the care of individual patients with heart diseases.\u0000\u0000As therapies have become more biologically potent, it has become increasingly clear that every treatment can be harmful in some patients while being beneficial in others, and often both good and bad effects occur in the same patient. With many therapies, clinical characteristics can identify patients with greater expected benefit or risk, and pharmacogenetics may offer further insight into predicting which patients will achieve the greatest benefit and which will have the greatest risk of harm. For example, we know that women are at higher risk for torsades de pointes when they are treated with QT-interval-prolonging drugs, and it is likely that a genetic predisposition may be important.1 Unfortunately, however, the relative power of these findings is limited, and we are left with broad treatment guidelines that will leave patients at risk of harm that cannot be predicted in absolute terms.\u0000\u0000The recognition that therapeutics are not commonly either “good” or “bad,” but carry a mixture of good and bad effects, has spawned the concept of risk-management in therapeutics. Each clinician has the responsibility of helping the patient place these risks and benefits in perspective when making decisions about therapeutics. Inevitably, this approach will require an improved grasp of probabilities and quantitative outcome estimates by clinicians and patients. Furthermore, there is an implied responsibility, both to participate in the generation of knowledge about risks and benefits through clinical trials and to report adverse events observed in the post-marketing period. Such adverse event reporting played the critical role in identifying cisapride as a cause of sudden death2 …","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"40 1","pages":"1172-1175"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88978456","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 : 2002-08-27DOI: 10.1161/01.CIR.0000027584.85865.B4
S. Murasawa, J. Llevadot, Marcy Silver, J. Isner, Douglas Losordo, T. Asahara
Background—The regulatory molecule for cell life span, telomerase, was modified by human telomerase reverse transcriptase (hTERT) gene transfer to investigate its effect on regenerative properties of endothelial progenitor cells (EPCs) in neovascularization. Methods and Results—Telomerase activity was enhanced in hTERT-transduced EPCs (Td-TERTs) (1.2-fold versus no transduced EPCs [no-Td] and 1.2-fold versus GFP-transduced EPCs [Td/GFPs] at day 8; 5.2-fold versus no-Td and 4.8-fold versus Td/GFP at day 21, respectively) Mitogenic capacity in Td/TERTs exceeded that in Td/GFPs at day 8 (0.62±0.02 versus 0.53±0.01, respectively;P <0.01). Vascular endothelial growth factor-induced cell migration in EPCs was markedly enhanced by hTERT overexpression (Td/TERTs versus Td/GFPs, 292±12 versus 174±6 cells, respectively;P <0.01). hTERT overexpression has rescued EPCs from starvation-induced cell apoptosis, an outcome that was further enhanced in response to vascular endothelial growth factor. The colony appearance of totally differentiated endothelial cells (tdECs) was detected before day 30 only in Td/TERT, whereas no tdEC colonies could be detected in both Td/GFPs and no-Tds. Finally, we investigated in vivo transplantation of heterologous EPCs. Td/TERTs dramatically improved postnatal neovascularization in terms of limb salvage by 4-fold in comparison with that of Td/GFPs; limb perfusion was measured by laser Doppler (0.77±0.10 versus 0.47±0.06;P =0.02), and capillary density (224±78 versus 90±40 capillaries/mm2;P <0.01). Conclusions—These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.
研究背景:利用人端粒酶逆转录酶(hTERT)基因转移对细胞寿命调控分子端粒酶进行修饰，探讨其对新生血管内皮祖细胞(EPCs)再生特性的影响。方法和结果:第8天，htert转导的EPCs (Td- terts)的端粒酶活性增强(与未转导的EPCs [no-Td]相比增强1.2倍，与gfp转导的EPCs [Td/GFPs]相比增强1.2倍);第8天，Td/TERTs组的有丝分裂能力分别高于Td/GFP组(0.62±0.02比0.53±0.01,P <0.01)。hTERT过表达可显著增强内皮生长因子诱导的EPCs细胞迁移(Td/TERTs vs Td/GFPs，分别为292±12 vs 174±6,P <0.01)。hTERT过表达使内皮祖细胞免于饥饿诱导的细胞凋亡，这一结果在血管内皮生长因子的作用下进一步增强。完全分化内皮细胞(tdECs)在30天前仅在Td/TERT中检测到，而在Td/ gfp和no- tds中均未检测到tdECs集落。最后，我们研究了异种EPCs的体内移植。与Td/GFPs相比，Td/TERTs在肢体保留方面显著改善了出生后新生血管的形成，提高了4倍;激光多普勒测量肢体灌注(0.77±0.10比0.47±0.06,P =0.02)和毛细血管密度(224±78比90±40支/mm2, P <0.01)。结论:这些发现提供了端粒酶活性参与EPC血管生成特性的新证据;有丝分裂活性，迁移活性和细胞存活。通过hTERT移植增强EPCs的再生活性将为严重缺血性疾病患者的出生后新生血管提供新的治疗策略。
{"title":"Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells","authors":"S. Murasawa, J. Llevadot, Marcy Silver, J. Isner, Douglas Losordo, T. Asahara","doi":"10.1161/01.CIR.0000027584.85865.B4","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027584.85865.B4","url":null,"abstract":"Background—The regulatory molecule for cell life span, telomerase, was modified by human telomerase reverse transcriptase (hTERT) gene transfer to investigate its effect on regenerative properties of endothelial progenitor cells (EPCs) in neovascularization. Methods and Results—Telomerase activity was enhanced in hTERT-transduced EPCs (Td-TERTs) (1.2-fold versus no transduced EPCs [no-Td] and 1.2-fold versus GFP-transduced EPCs [Td/GFPs] at day 8; 5.2-fold versus no-Td and 4.8-fold versus Td/GFP at day 21, respectively) Mitogenic capacity in Td/TERTs exceeded that in Td/GFPs at day 8 (0.62±0.02 versus 0.53±0.01, respectively;P <0.01). Vascular endothelial growth factor-induced cell migration in EPCs was markedly enhanced by hTERT overexpression (Td/TERTs versus Td/GFPs, 292±12 versus 174±6 cells, respectively;P <0.01). hTERT overexpression has rescued EPCs from starvation-induced cell apoptosis, an outcome that was further enhanced in response to vascular endothelial growth factor. The colony appearance of totally differentiated endothelial cells (tdECs) was detected before day 30 only in Td/TERT, whereas no tdEC colonies could be detected in both Td/GFPs and no-Tds. Finally, we investigated in vivo transplantation of heterologous EPCs. Td/TERTs dramatically improved postnatal neovascularization in terms of limb salvage by 4-fold in comparison with that of Td/GFPs; limb perfusion was measured by laser Doppler (0.77±0.10 versus 0.47±0.06;P =0.02), and capillary density (224±78 versus 90±40 capillaries/mm2;P <0.01). Conclusions—These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"604 1","pages":"1133-1139"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85332873","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 : 2002-08-27DOI: 10.1161/01.CIR.0000027819.19722.EE
F. Martín, P. Sánchez, E. Doherty, P. Colon-Hernandez, G. Delgado, I. Inglessis, N. Scott, J. Hung, M. E. King, F. Buonanno, Z. Demirjian, M. D. de Moor, I. Palacios
Background—Percutaneous transcatheter closure of patent foramen ovale (PFO) is used as an alternative to surgery or long-term anticoagulation for the treatment of patients with paradoxical embolism and PFO. Methods and Results—We report the immediate and long-term clinical and echocardiographic outcome of 110 consecutive patients (58 males, mean age 47±14 years) who underwent transcatheter closure of PFO because of paradoxical embolism between 1995 and 2001. Procedural success, defined as successful deployment of the device and effective occlusion (no, or trivial, shunt after device placement), was achieved in all (100%) patients. There was no in-hospital mortality, 1 device migration requiring surgical intervention (0.9%), and 1 episode of cardiac tamponade (0.9%) requiring pericardiocentesis. A progressive increment in full occlusion was observed (44%, 51%, 66%, and 71% at 1 day, 6 months, and 1 and 2 years, respectively, after device placement). At a mean follow-up of 2.3 years, 2 patients experienced recurrent neurological events (1 fatal stroke and 1 transient ischemic attack), representing an annual risk of recurrence of 0.9%. In addition, 4 (3.6%) of the patients required reintervention for device malalignment or significant shunt. Kaplan-Meier analysis showed a freedom from recurrent embolic events and reintervention of 96% and 90% at 1 and 5 years, respectively. Conclusions—Transcatheter closure of PFO is a safe and effective therapy for patients with paradoxical embolism and PFO. It is associated with a high success rate, low incidence of hospital complications, and low frequency of recurrent systemic embolic events.
{"title":"Percutaneous Transcatheter Closure of Patent Foramen Ovale in Patients With Paradoxical Embolism","authors":"F. Martín, P. Sánchez, E. Doherty, P. Colon-Hernandez, G. Delgado, I. Inglessis, N. Scott, J. Hung, M. E. King, F. Buonanno, Z. Demirjian, M. D. de Moor, I. Palacios","doi":"10.1161/01.CIR.0000027819.19722.EE","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027819.19722.EE","url":null,"abstract":"Background—Percutaneous transcatheter closure of patent foramen ovale (PFO) is used as an alternative to surgery or long-term anticoagulation for the treatment of patients with paradoxical embolism and PFO. Methods and Results—We report the immediate and long-term clinical and echocardiographic outcome of 110 consecutive patients (58 males, mean age 47±14 years) who underwent transcatheter closure of PFO because of paradoxical embolism between 1995 and 2001. Procedural success, defined as successful deployment of the device and effective occlusion (no, or trivial, shunt after device placement), was achieved in all (100%) patients. There was no in-hospital mortality, 1 device migration requiring surgical intervention (0.9%), and 1 episode of cardiac tamponade (0.9%) requiring pericardiocentesis. A progressive increment in full occlusion was observed (44%, 51%, 66%, and 71% at 1 day, 6 months, and 1 and 2 years, respectively, after device placement). At a mean follow-up of 2.3 years, 2 patients experienced recurrent neurological events (1 fatal stroke and 1 transient ischemic attack), representing an annual risk of recurrence of 0.9%. In addition, 4 (3.6%) of the patients required reintervention for device malalignment or significant shunt. Kaplan-Meier analysis showed a freedom from recurrent embolic events and reintervention of 96% and 90% at 1 and 5 years, respectively. Conclusions—Transcatheter closure of PFO is a safe and effective therapy for patients with paradoxical embolism and PFO. It is associated with a high success rate, low incidence of hospital complications, and low frequency of recurrent systemic embolic events.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"199 1","pages":"1121-1126"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79892978","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：