Pub Date : 2002-09-03DOI: 10.1161/01.CIR.0000028422.51668.A2
S. Konstantinides, A. Geibel, M. Olschewski, W. Kasper, N. Hruska, S. Jäckle, L. Binder
Background—Assessment of risk and appropriate management of patients with acute pulmonary embolism (PE) remains a challenge. Cardiac troponins I (cTnI) and T (cTnT) are reliable indicators of myocardial injury and may be associated with right ventricular dysfunction in PE. Methods and Results—The present prospective study included 106 consecutive patients with confirmed acute PE. cTnI was elevated (≥0.07 ng/mL) in 43 patients (41%), and cTnT (≥0.04 ng/mL) was elevated in 39 (37%). Elevation of cTnI or cTnT was significantly associated with echocardiographically detected right ventricular dysfunction (P =0.001 and P <0.05, respectively). Moreover, a significant correlation was found between elevation of cTnI or cTnT and the two major end points overall mortality and complicated in-hospital course. The negative predictive value of cardiac troponins for major clinical events was 92% to 93%. Importantly, there was obvious escalation of in-hospital mortality, the rate of complications, and the incidence of recurrent PE, when patients with high troponin concentrations (cTnI >1.5; cTnT >0.1 ng/mL) were compared with those with only moderately elevated levels (cTnI, 0.07 to 1.5; cTnT, 0.04 to 0.1 ng/mL). Logistic regression analysis confirmed that the mortality risk (OR) was significantly elevated only in patients with high cTnI (P =0.019) or cTnT (P =0.038) levels. Furthermore, the risk of a complicated in-hospital course was almost 5 times higher (15.47 versus 3.16) in the high-cTnI group compared with patients with moderate cTnI elevation. Conclusions—Our results indicate that cTnI and cTnT may be a novel, particularly useful tool for optimizing the management strategy in patients with acute PE.
{"title":"Importance of Cardiac Troponins I and T in Risk Stratification of Patients With Acute Pulmonary Embolism","authors":"S. Konstantinides, A. Geibel, M. Olschewski, W. Kasper, N. Hruska, S. Jäckle, L. Binder","doi":"10.1161/01.CIR.0000028422.51668.A2","DOIUrl":"https://doi.org/10.1161/01.CIR.0000028422.51668.A2","url":null,"abstract":"Background—Assessment of risk and appropriate management of patients with acute pulmonary embolism (PE) remains a challenge. Cardiac troponins I (cTnI) and T (cTnT) are reliable indicators of myocardial injury and may be associated with right ventricular dysfunction in PE. Methods and Results—The present prospective study included 106 consecutive patients with confirmed acute PE. cTnI was elevated (≥0.07 ng/mL) in 43 patients (41%), and cTnT (≥0.04 ng/mL) was elevated in 39 (37%). Elevation of cTnI or cTnT was significantly associated with echocardiographically detected right ventricular dysfunction (P =0.001 and P <0.05, respectively). Moreover, a significant correlation was found between elevation of cTnI or cTnT and the two major end points overall mortality and complicated in-hospital course. The negative predictive value of cardiac troponins for major clinical events was 92% to 93%. Importantly, there was obvious escalation of in-hospital mortality, the rate of complications, and the incidence of recurrent PE, when patients with high troponin concentrations (cTnI >1.5; cTnT >0.1 ng/mL) were compared with those with only moderately elevated levels (cTnI, 0.07 to 1.5; cTnT, 0.04 to 0.1 ng/mL). Logistic regression analysis confirmed that the mortality risk (OR) was significantly elevated only in patients with high cTnI (P =0.019) or cTnT (P =0.038) levels. Furthermore, the risk of a complicated in-hospital course was almost 5 times higher (15.47 versus 3.16) in the high-cTnI group compared with patients with moderate cTnI elevation. Conclusions—Our results indicate that cTnI and cTnT may be a novel, particularly useful tool for optimizing the management strategy in patients with acute PE.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"24 1","pages":"1263-1268"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88306949","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 : 2002-09-03DOI: 10.1161/01.CIR.0000027586.64231.1B
Ya-Fei Chen, Pin-Lan Li, A. Zou
Background—Hyperhomocysteinemia (hHcys) is considered an independent risk factor of cardiovascular diseases. Recent studies in our laboratory have shown that hHcys produced glomerular dysfunction and sclerosis independently of hypertension. However, the mechanism mediating these pathogenic effects of homocysteine (Hcys) is poorly understood. Because Hcys and adenosine (Ado) are simultaneously produced via hydrolysis of S-adenosylhomocysteine (SAH), we hypothesized that hHcys may produce its pathogenic effects by decrease in plasma or tissue Ado concentrations. Methods and Results—l-Hcys (1.5 &mgr;mol/min per kilogram) was infused intravenously for 60 minutes to produce acute hHcys in Sprague-Dawley rats. Plasma Hcys levels increased from 6.7±0.4 to 14.7±0.5 &mgr;mol/L, but Ado decreased from 141.7±15.1 to 52.4±6.8 nmol/L in these rats with acute hHcys. This hHcys-induced reduction of Ado was also observed in the kidney dialysate. In rats with chronic hHcys, plasma Ado levels were also significantly decreased. By kinetic analysis of the enzyme activities, decrease in renal Ado levels in hHcys was shown to be associated with inhibition of SAH hydrolase but not 5′-nucleotidase. Functionally, intravenous infusion of Hcys was found to decrease renal blood flow, glomerular filtration rate, and sodium and water excretion, which could be blocked by the Ado receptor antagonist 8-SPT. Conclusions—These results strongly suggest that hHcys decreases plasma and tissue Ado concentrations associated with inhibition of SAH hydrolase. Decrease in plasma and tissue Ado may be an important mechanism mediating the pathogenic effects of Hcys.
{"title":"Effect of Hyperhomocysteinemia on Plasma or Tissue Adenosine Levels and Renal Function","authors":"Ya-Fei Chen, Pin-Lan Li, A. Zou","doi":"10.1161/01.CIR.0000027586.64231.1B","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027586.64231.1B","url":null,"abstract":"Background—Hyperhomocysteinemia (hHcys) is considered an independent risk factor of cardiovascular diseases. Recent studies in our laboratory have shown that hHcys produced glomerular dysfunction and sclerosis independently of hypertension. However, the mechanism mediating these pathogenic effects of homocysteine (Hcys) is poorly understood. Because Hcys and adenosine (Ado) are simultaneously produced via hydrolysis of S-adenosylhomocysteine (SAH), we hypothesized that hHcys may produce its pathogenic effects by decrease in plasma or tissue Ado concentrations. Methods and Results—l-Hcys (1.5 &mgr;mol/min per kilogram) was infused intravenously for 60 minutes to produce acute hHcys in Sprague-Dawley rats. Plasma Hcys levels increased from 6.7±0.4 to 14.7±0.5 &mgr;mol/L, but Ado decreased from 141.7±15.1 to 52.4±6.8 nmol/L in these rats with acute hHcys. This hHcys-induced reduction of Ado was also observed in the kidney dialysate. In rats with chronic hHcys, plasma Ado levels were also significantly decreased. By kinetic analysis of the enzyme activities, decrease in renal Ado levels in hHcys was shown to be associated with inhibition of SAH hydrolase but not 5′-nucleotidase. Functionally, intravenous infusion of Hcys was found to decrease renal blood flow, glomerular filtration rate, and sodium and water excretion, which could be blocked by the Ado receptor antagonist 8-SPT. Conclusions—These results strongly suggest that hHcys decreases plasma and tissue Ado concentrations associated with inhibition of SAH hydrolase. Decrease in plasma and tissue Ado may be an important mechanism mediating the pathogenic effects of Hcys.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"360 1","pages":"1275-1281"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76466694","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 : 2002-09-03DOI: 10.1161/01.CIR.0000028146.71416.2E
S. Ellis, D. Chew, A. Chan, P. Whitlow, J. Schneider, E. Topol
Background—Creatine kinase (CK)-MB elevation after percutaneous coronary intervention (PCI) has been associated with subsequent cardiac death. The patients at risk, the timing of risk, and potential treatment implications are uncertain. Methods and Results—Eight thousand, four hundred nine consecutive non– acute myocardial infarction patients with successful PCI and no emergency surgery or Q-wave myocardial infarction were followed for 38±25 months; 1446 (17.2%) had post-PCI CK-MB above normal on routine ascertainment. Patients were prospectively stratified into those with CK-MB 1 to 5× or CK-MB >5× normal. No patient with CK-MB 1 to 5× normal died during the first week after PCI, and excess risk of early death for patients with CK-MB elevation occurred primarily in the first 3 to 4 months. The actuarial 4-month risk of death was 8.9%, 1.9%, and 1.2% for patients with CK-MB >5×, CK-MB 1 to 5×, and CK-MB ≤1× normal (P <0.001). Death within 4 months was independently correlated with the degree of CK-MB elevation, creatinine ≥2 mg%, post-PCI C-reactive protein, low ejection fraction, age, and congestive heart failure class (P <0.01 for all). In a matched subset analysis, incomplete revascularization (P <0.001), congestive heart failure class (P =0.005), and no statin treatment at hospital discharge (P =0.009) were associated with death. Conclusions—Patients with CK-MB elevation after PCI are at excess risk of death for 3 to 4 months, although prolonging hospitalization for CK-MB 1 to 5× is unlikely to modify risk. CK-MB >5× normal, incomplete revascularization, elevated C-reactive protein, heart failure, the elderly, and hospital discharge without on statin therapy increases risk. Several of these factors suggest that inflammation may play a part in the excess risk of death.
{"title":"Death Following Creatine Kinase-MB Elevation After Coronary Intervention: Identification of an Early Risk Period: Importance of Creatine Kinase-MB Level, Completeness of Revascularization, Ventricular Function, and Probable Benefit of Statin Therapy","authors":"S. Ellis, D. Chew, A. Chan, P. Whitlow, J. Schneider, E. Topol","doi":"10.1161/01.CIR.0000028146.71416.2E","DOIUrl":"https://doi.org/10.1161/01.CIR.0000028146.71416.2E","url":null,"abstract":"Background—Creatine kinase (CK)-MB elevation after percutaneous coronary intervention (PCI) has been associated with subsequent cardiac death. The patients at risk, the timing of risk, and potential treatment implications are uncertain. Methods and Results—Eight thousand, four hundred nine consecutive non– acute myocardial infarction patients with successful PCI and no emergency surgery or Q-wave myocardial infarction were followed for 38±25 months; 1446 (17.2%) had post-PCI CK-MB above normal on routine ascertainment. Patients were prospectively stratified into those with CK-MB 1 to 5× or CK-MB >5× normal. No patient with CK-MB 1 to 5× normal died during the first week after PCI, and excess risk of early death for patients with CK-MB elevation occurred primarily in the first 3 to 4 months. The actuarial 4-month risk of death was 8.9%, 1.9%, and 1.2% for patients with CK-MB >5×, CK-MB 1 to 5×, and CK-MB ≤1× normal (P <0.001). Death within 4 months was independently correlated with the degree of CK-MB elevation, creatinine ≥2 mg%, post-PCI C-reactive protein, low ejection fraction, age, and congestive heart failure class (P <0.01 for all). In a matched subset analysis, incomplete revascularization (P <0.001), congestive heart failure class (P =0.005), and no statin treatment at hospital discharge (P =0.009) were associated with death. Conclusions—Patients with CK-MB elevation after PCI are at excess risk of death for 3 to 4 months, although prolonging hospitalization for CK-MB 1 to 5× is unlikely to modify risk. CK-MB >5× normal, incomplete revascularization, elevated C-reactive protein, heart failure, the elderly, and hospital discharge without on statin therapy increases risk. Several of these factors suggest that inflammation may play a part in the excess risk of death.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"161 1","pages":"1205-1210"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83529659","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 : 2002-09-03DOI: 10.1161/01.CIR.0000031524.49139.29
S. Jono, Y. Ikari, A. Shioi, K. Mori, T. Miki, K. Hara, Y. Nishizawà
Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD). Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94±0.34, 1.04±0.38, 1.19±0.38, and 1.44±0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0]. Conclusions—Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.
{"title":"Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease","authors":"S. Jono, Y. Ikari, A. Shioi, K. Mori, T. Miki, K. Hara, Y. Nishizawà","doi":"10.1161/01.CIR.0000031524.49139.29","DOIUrl":"https://doi.org/10.1161/01.CIR.0000031524.49139.29","url":null,"abstract":"Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD). Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94±0.34, 1.04±0.38, 1.19±0.38, and 1.44±0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0]. Conclusions—Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"232 1","pages":"1192-1194"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78783505","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 : 2002-09-03DOI: 10.1161/01.CIR.0000027583.73268.E7
Yuejin Wu, Joel D. Temple, Rong-huai Zhang, I. Dzhura, Wei Zhang, R. Trimble, D. Roden, R. Passier, E. Olson, R. Colbran, M. Anderson
Background—Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown. Methods and Results—We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective. Conclusions—These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after &bgr;-adrenergic stimulation is independent of enhanced EAD frequency.
{"title":"Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy","authors":"Yuejin Wu, Joel D. Temple, Rong-huai Zhang, I. Dzhura, Wei Zhang, R. Trimble, D. Roden, R. Passier, E. Olson, R. Colbran, M. Anderson","doi":"10.1161/01.CIR.0000027583.73268.E7","DOIUrl":"https://doi.org/10.1161/01.CIR.0000027583.73268.E7","url":null,"abstract":"Background—Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown. Methods and Results—We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective. Conclusions—These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after &bgr;-adrenergic stimulation is independent of enhanced EAD frequency.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"15 1","pages":"1288-1293"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87493355","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 : 2002-09-03DOI: 10.1161/01.CIR.0000032135.98011.C4
Thomas J. Wang, M. Larson, D. Levy, E. Benjamin, Michelle J. Kupka, W. Manning, M. Clouse, R. D'Agostino, P. Wilson, C. O’Donnell
Background—High C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis. Methods and Results—We studied a stratified random sample of 321 men and women (mean age 60 years) from the Framingham Heart Study who were free of clinically apparent cardiovascular disease. Subjects underwent electron-beam computed tomography to assess the number of coronary calcifications and the coronary artery calcification (CAC) Agatston score. Spearman correlation coefficients between CRP and CAC score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. For both sexes, CRP was significantly correlated with the Agatston score (age-adjusted Spearman correlation: 0.25 for men, 0.26 for women; both P <0.01). After adjustment for age and Framingham risk score, the correlation remained significant (P =0.01) for both sexes. Further adjustment for body mass index attenuated the correlation coefficient for women (0.14, P =0.09) but not for men (0.19, P <0.05). Conclusions—High CRP levels are associated with increased coronary calcification. Among individuals with elevated CRP, subclinical atherosclerosis may contribute to an increased risk for future cardiovascular events.
{"title":"C-Reactive Protein Is Associated With Subclinical Epicardial Coronary Calcification in Men and Women: The Framingham Heart Study","authors":"Thomas J. Wang, M. Larson, D. Levy, E. Benjamin, Michelle J. Kupka, W. Manning, M. Clouse, R. D'Agostino, P. Wilson, C. O’Donnell","doi":"10.1161/01.CIR.0000032135.98011.C4","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032135.98011.C4","url":null,"abstract":"Background—High C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis. Methods and Results—We studied a stratified random sample of 321 men and women (mean age 60 years) from the Framingham Heart Study who were free of clinically apparent cardiovascular disease. Subjects underwent electron-beam computed tomography to assess the number of coronary calcifications and the coronary artery calcification (CAC) Agatston score. Spearman correlation coefficients between CRP and CAC score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. For both sexes, CRP was significantly correlated with the Agatston score (age-adjusted Spearman correlation: 0.25 for men, 0.26 for women; both P <0.01). After adjustment for age and Framingham risk score, the correlation remained significant (P =0.01) for both sexes. Further adjustment for body mass index attenuated the correlation coefficient for women (0.14, P =0.09) but not for men (0.19, P <0.05). Conclusions—High CRP levels are associated with increased coronary calcification. Among individuals with elevated CRP, subclinical atherosclerosis may contribute to an increased risk for future cardiovascular events.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"73 1","pages":"1189-1191"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86875910","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 : 2002-09-03DOI: 10.1161/01.CIR.0000031525.61826.A8
D. Simper, P. Stalboerger, C. Panetta, Shaohua Wang, N. Caplice
Background—Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. Methods and Results—Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB–enriched medium caused rapid outgrowth and expansion of SOC to >40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell–specific &agr; actin (&agr;SMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle–specific markers. Integrin &agr;5&bgr;1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (P <0.001), an effect that could be decreased using an &agr;5&bgr;1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (P <0.001). Conclusions—This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing. (Circulation. 2002;106:1199–1204.)
{"title":"Smooth Muscle Progenitor Cells in Human Blood","authors":"D. Simper, P. Stalboerger, C. Panetta, Shaohua Wang, N. Caplice","doi":"10.1161/01.CIR.0000031525.61826.A8","DOIUrl":"https://doi.org/10.1161/01.CIR.0000031525.61826.A8","url":null,"abstract":"Background—Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. Methods and Results—Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB–enriched medium caused rapid outgrowth and expansion of SOC to >40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell–specific &agr; actin (&agr;SMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle–specific markers. Integrin &agr;5&bgr;1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (P <0.001), an effect that could be decreased using an &agr;5&bgr;1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (P <0.001). Conclusions—This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing. (Circulation. 2002;106:1199–1204.)","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"81 6 1","pages":"1199-1204"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89516037","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 : 2002-09-03DOI: 10.1161/01.CIR.0000032141.31476.15
F. Kolodgie, M. John, C. Khurana, A. Farb, P. S. Wilson, Eduardo Acampado, N. Desai, P. Soon-Shiong, R. Virmani
Background—Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis. Methods and Results—A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (P ≤0.02) by doses of nPXL ≥2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (P ≤0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing. Conclusions—Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.
{"title":"Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel","authors":"F. Kolodgie, M. John, C. Khurana, A. Farb, P. S. Wilson, Eduardo Acampado, N. Desai, P. Soon-Shiong, R. Virmani","doi":"10.1161/01.CIR.0000032141.31476.15","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032141.31476.15","url":null,"abstract":"Background—Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis. Methods and Results—A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (P ≤0.02) by doses of nPXL ≥2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (P ≤0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing. Conclusions—Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"1 1","pages":"1195-1198"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79889453","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 : 2002-09-03DOI: 10.1161/01.CIR.0000028145.58654.41
H. Iso, C. Date, A. Yamamoto, H. Toyoshima, N. Tanabe, S. Kikuchi, T. Kondo, Yoshiyuki Watanabe, Y. Wada, Teruo Ishibashi, Hiroshi Suzuki, A. Koizumi, Y. Inaba, A. Tamakoshi, Y. Ohno
Background—Perceived mental stress has been associated with risk of coronary heart disease (CHD) in white men, but no prospective data are available for other ethnic groups. Methods and Results—From 1988 to 1990, a total of 73 424 Japanese (30 180 men and 43 244 women), aged 40 to 79 years, without a history of stroke, CHD, or cancer completed a lifestyle questionnaire including perception of mental stress under the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study). Systematic surveillance was completed until the end of 1997, with a 580 378 person-year follow-up, and the underlying causes of death were determined according to the International Classification of Diseases, 10th revision. For women, there were 316 with total stroke, 113 with CHD, and 643 with total cardiovascular disease (CVD); for men, there were 341, 168, and 778, respectively. Women who reported high stress had a 2-fold higher age-adjusted risk of mortality from total stroke and CHD and 1.5-fold higher risk of total CVD compared with those who reported low stress. Further adjustment for known cardiovascular risk factors and selected psychological variables did not alter the associations materially. The multivariate relative risk for women who perceived high stress versus low stress was 2.24 (95% CI 1.52 to 3.31, P <0.001) for total stroke, 2.28 (95% CI 1.17 to 4.43, P =0.02) for CHD, and 1.64 (95% CI 1.25 to 2.16, P <0.001) for total CVD. For men, these relations were generally weaker but suggestive of myocardial infarction. Conclusions—Perceived mental stress was associated with increased mortality from stroke for women and with CHD for men and women.
在白人男性中，感知到的精神压力与冠心病(CHD)的风险相关，但没有其他种族的前瞻性数据。方法和结果:1988年至1990年，共有73 424名日本人(30 180名男性和43 244名女性)，年龄在40至79岁之间，无中风、冠心病或癌症病史，完成了一份生活方式问卷，包括心理压力的感知，该问卷由日本文博所赞助的日本癌症风险评估合作队列研究(JACC研究)。系统监测工作于1997年底完成，每年随访580378人，并根据《国际疾病分类》第十次修订确定了潜在的死亡原因。对于女性，有316人患有中风，113人患有冠心病，643人患有心血管疾病;男性则分别为341、168和778。与报告压力低的妇女相比，报告压力大的妇女因中风和冠心病死亡的年龄调整风险高2倍，患心血管疾病的风险高1.5倍。进一步调整已知的心血管危险因素和选定的心理变量并没有实质性地改变相关性。高压力女性与低压力女性的多变量相对危险度，卒中总危险度为2.24 (95% CI 1.52 ~ 3.31, P <0.001)，冠心病总危险度为2.28 (95% CI 1.17 ~ 4.43, P =0.02)，心血管总危险度为1.64 (95% CI 1.25 ~ 2.16, P <0.001)。对于男性来说，这些关系通常较弱，但暗示心肌梗死。结论:感知到的精神压力与女性中风死亡率增加以及男性和女性冠心病死亡率增加有关。
{"title":"Perceived Mental Stress and Mortality From Cardiovascular Disease Among Japanese Men and Women: The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study)","authors":"H. Iso, C. Date, A. Yamamoto, H. Toyoshima, N. Tanabe, S. Kikuchi, T. Kondo, Yoshiyuki Watanabe, Y. Wada, Teruo Ishibashi, Hiroshi Suzuki, A. Koizumi, Y. Inaba, A. Tamakoshi, Y. Ohno","doi":"10.1161/01.CIR.0000028145.58654.41","DOIUrl":"https://doi.org/10.1161/01.CIR.0000028145.58654.41","url":null,"abstract":"Background—Perceived mental stress has been associated with risk of coronary heart disease (CHD) in white men, but no prospective data are available for other ethnic groups. Methods and Results—From 1988 to 1990, a total of 73 424 Japanese (30 180 men and 43 244 women), aged 40 to 79 years, without a history of stroke, CHD, or cancer completed a lifestyle questionnaire including perception of mental stress under the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study). Systematic surveillance was completed until the end of 1997, with a 580 378 person-year follow-up, and the underlying causes of death were determined according to the International Classification of Diseases, 10th revision. For women, there were 316 with total stroke, 113 with CHD, and 643 with total cardiovascular disease (CVD); for men, there were 341, 168, and 778, respectively. Women who reported high stress had a 2-fold higher age-adjusted risk of mortality from total stroke and CHD and 1.5-fold higher risk of total CVD compared with those who reported low stress. Further adjustment for known cardiovascular risk factors and selected psychological variables did not alter the associations materially. The multivariate relative risk for women who perceived high stress versus low stress was 2.24 (95% CI 1.52 to 3.31, P <0.001) for total stroke, 2.28 (95% CI 1.17 to 4.43, P =0.02) for CHD, and 1.64 (95% CI 1.25 to 2.16, P <0.001) for total CVD. For men, these relations were generally weaker but suggestive of myocardial infarction. Conclusions—Perceived mental stress was associated with increased mortality from stroke for women and with CHD for men and women.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"37 1","pages":"1229-1236"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85935277","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 : 2002-09-03DOI: 10.1161/01.CIR.0000028335.31300.DA
David R. Holmes, M. Savage, J. Lablanche, L. Grip, P. Serruys, P. Fitzgerald, D. Fischman, S. Goldberg, Jeffrey A. Brinker, A. Zeiher, Leonard M. Shapiro, J. Willerson, Barry R. Davis, James J. Ferguson, J. Popma, Spencer B. King, A. M. Lincoff, J. Tcheng, R. Chan, J. Granett, M. Poland
Background—Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. Methods and Results—In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P =0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P =0.061 for intent-to-treat population). The primary reason for not completing treatment was ≥1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P <0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76±0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78±0.76 to 80 mm, P =0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm3, respectively;P =0.16 to 0.72). Conclusions—Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.
{"title":"Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial","authors":"David R. Holmes, M. Savage, J. Lablanche, L. Grip, P. Serruys, P. Fitzgerald, D. Fischman, S. Goldberg, Jeffrey A. Brinker, A. Zeiher, Leonard M. Shapiro, J. Willerson, Barry R. Davis, James J. Ferguson, J. Popma, Spencer B. King, A. M. Lincoff, J. Tcheng, R. Chan, J. Granett, M. Poland","doi":"10.1161/01.CIR.0000028335.31300.DA","DOIUrl":"https://doi.org/10.1161/01.CIR.0000028335.31300.DA","url":null,"abstract":"Background—Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. Methods and Results—In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P =0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P =0.061 for intent-to-treat population). The primary reason for not completing treatment was ≥1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P <0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76±0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78±0.76 to 80 mm, P =0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm3, respectively;P =0.16 to 0.72). Conclusions—Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"1 1","pages":"1243-1250"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88483336","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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