医药家园

抱歉各位，由于圣诞等原因，Circulation一般会停刊2-3期。本期发的是12月9日的内容，不影响各位翻译爱好者的翻译内容。去年好像是圣诞节和元旦停了两期，不知道今年为什么这么早？
Abstract 1 of 11 (Circulation. 2008;118:2498-2505.)
Arrhythmia/Electrophysiology
Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation
The A4 Study
Background— The mainstay of treatment for atrial fibrillation (AF) remains pharmacological; however, catheter ablation has increasingly been used over the last decade. The relative merits of each strategy have not been extensively studied.
Methods and Results— We conducted a randomized multicenter comparison of these 2 treatment strategies in patients with paroxysmal AF resistant to at least 1 antiarrhythmic drug. The primary end point was absence of recurrent AF between months 3 and 12, absence of recurrent AF after up to 3 ablation procedures, or changes in antiarrhythmic drugs during the first 3 months. Ablation consisted of pulmonary vein isolation in all cases, whereas additional extrapulmonary vein lesions were at the discretion of the physician. Crossover was permitted at 3 months in case of failure. Echocardiographic data, symptom score, exercise capacity, quality of life, and AF burden were evaluated at 3, 6, and 12 months by the supervising committee. Of 149 eligible patients, 112 (18 women [16%]; age, 51.1±11.1 years) were enrolled and randomized to ablation (n=53) or “new” antiarrhythmic drugs alone or in combination (n=59). Crossover from the antiarrhythmic drugs and ablation groups occurred in 37 (63%) and 5 patients (9%), respectively (P=0.0001). At the 1-year follow-up, 13 of 55 patients (23%) and 46 of 52 patients (89%) had no recurrence of AF in the antiarrhythmic drug and ablation groups, respectively (P<0.0001). Symptom score, exercise capacity, and quality of life were significantly higher in the ablation group.
Conclusion— This randomized multicenter study demonstrates the superiority of catheter ablation over antiarrhythmic drugs in patients with AF with regard to maintenance of sinus rhythm and improvement in symptoms, exercise capacity, and quality of life.
Abstract 2 of 11 (Circulation. 2008;118:2506-2514.)
Coronary Heart Disease
Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis
Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)
Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis.
Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P=0.02), and lowered serum potassium (0.11±0.02 mmol/L, P<0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume (r=–0.17, P<0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P=0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (–0.31±0.27 versus 0.88±0.27%, P=0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (–0.69±0.27%, P=0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression (P=0.001).
Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.
Abstract 3 of 11 (Circulation. 2008;118:2515-2522.)
Coronary Heart Disease
Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity
A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials
Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome.
Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change.
Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.
Abstract 4 of 11 (Circulation. 2008;118:2523-2532.)
Coronary Heart Disease
Angiotensin II Type 2 Receptor Stimulation
A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
Background— This study is the first to examine the effect of direct angiotensin II type 2 (AT2) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT2 receptor agonist compound 21 (C21).
Methods and Results— Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1β, and interleukin-2 expression, suggesting an antiinflammatory effect.
Conclusions— Direct AT2 receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.
Abstract 5 of 11 (Circulation. 2008;118:2533-2539.)
Epidemiology
Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease
The Framingham Offspring Study
Background— Von Willebrand factor (vWF) is inconsistently associated with cardiovascular disease (CVD). This might be explained by associations of vWF with type 2 diabetes mellitus and insulin resistance.
Methods and Results— We tested whether vWF predicted incident CVD in 3799 Framingham Offspring Study participants, and in particular, among those with type 2 diabetes mellitus or insulin resistance. During 11 years of follow-up, 351 participants developed CVD. In proportional hazards models (with adjustment for age, sex, blood pressure, smoking, body mass index, total and high-density lipoprotein cholesterol, and treatment with aspirin, insulin, antihypertensives, and lipid-lowering medications) with the lowest quartile of the vWF distribution as the referent, the hazard ratio (HR) for CVD was 0.94 in the second quartile, 0.98 in the third, and 1.32 in the highest (P=0.04 for trend). Additional adjustment for type 2 diabetes mellitus or insulin resistance (homeostasis model) partially attenuated the association (multivariable HRs for top quartile 1.28 and 1.21, respectively). We then stratified the models by diabetes status or the homeostasis model of insulin resistance distribution (top quartile versus lower 3 quartiles). vWF was associated with CVD among participants with diabetes mellitus (HR for top quartile relative to bottom 1.47, P=0.04 for trend) but not among nondiabetic participants (HR 1.15, P=0.5) and similarly among insulin-resistant (HR 1.50, P=0.01) but not insulin-sensitive (HR 1.02, P=0.9) participants.
Conclusions— Higher levels of vWF were associated with risk of CVD in people with type 2 diabetes mellitus or insulin resistance, which suggests that vWF may be a risk factor unique to these populations.
Abstract 6 of 11 (Circulation. 2008;118:2540-2549.)
Imaging
Predictive Value of Myocardial Perfusion Single-Photon Emission Computed Tomography and the Impact of Renal Function on Cardiac Death
Background— Patients with chronic kidney disease (CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT (MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated.
Methods and Results— We followed up 1652 consecutive patients who underwent stress MPS (32% exercise, 95% gated) for cardiac death for a mean of 2.15±0.8 years. MPS defects were defined with a summed stress score (normal summed stress score <4, abnormal summed stress score4). Ischemia was defined as a summed stress score 4 plus a summed difference score 2, and scar was defined as a summed difference score <2 plus a summed stress score 4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD (estimated glomerular filtration rate <60 mL · min–1 · 1.73 m–2) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS (2.7% versus 0.8%, P=0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects (hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD (hazard ratio 1.96, 95% CI 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction (global 2 207.5 versus 169.3, P<0.0001).
Conclusions— MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan.
Abstract 7 of 11 (Circulation. 2008;118:2550-2554.)
Resuscitation Science
Gasping During Cardiac Arrest in Humans Is Frequent and Associated With Improved Survival
Background— The incidence and significance of gasping after cardiac arrest in humans are controversial.
Methods and Results— Two approaches were used. The first was a retrospective analysis of consecutive confirmed out-of-hospital cardiac arrests from the Phoenix Fire Department Regional Dispatch Center text files to determine the presence of gasping soon after collapse. The second was a retrospective analysis of 1218 patients with out-of-hospital cardiac arrests in Arizona documented by emergency medical system (EMS) first-care reports to determine the incidence of gasping after arrest in relation to the various EMS arrival times. The primary outcome measure was survival to hospital discharge. An analysis of the Phoenix Fire Department Regional Dispatch Center records of witnessed and unwitnessed out-of-hospital cardiac arrests with attempted resuscitation found that 44 of 113 (39%) of all arrested patients had gasping. An analysis of 1218 EMS-attended, witnessed, out-of-hospital cardiac arrests demonstrated that the presence or absence of gasping correlated with EMS arrival time. Gasping was present in 39 of 119 patients (33%) who arrested after EMS arrival, in 73 of 363 (20%) when EMS arrival was <7 minutes, in 50 of 360 (14%) when EMS arrival time was 7 to 9 minutes, and in 25 of 338 (7%) when EMS arrival time was >9 minutes. Survival to hospital discharge occurred in 54 of 191 patients (28%) who gasped and in 80 of 1027 (8%) who did not (adjusted odds ratio, 3.4; 95% confidence interval, 2.2 to 5.2). Among the 481 patients who received bystander cardiopulmonary resuscitation, survival to hospital discharge occurred among 30 of 77 patients who gasped (39%) versus only 38 of 404 among those who did not gasp (9%) (adjusted odds ratio, 5.1; 95% confidence interval, 2.7 to 9.4).
Conclusions— Gasping or abnormal breathing is common after cardiac arrest but decreases rapidly with time. Gasping is associated with increased survival. These results suggest that the recognition and importance of gasping should be taught to bystanders and emergency medical dispatchers so as not to dissuade them from initiating prompt resuscitation efforts when appropriate.
Abstract 8 of 11 (Circulation. 2008;118:2555-2562.)
Stroke
Plasma Fetuin-A Levels and the Risk of Myocardial Infarction and Ischemic Stroke
Background— Fetuin-A, a protein almost exclusively secreted by the liver, induces insulin resistance and subclinical inflammation in rodents. Circulating fetuin-A levels are elevated in humans with metabolic syndrome and insulin resistance, conditions that are associated with increased risk of cardiovascular disease.
Methods and Results— We investigated the association between fetuin-A levels and the risk of future myocardial infarction (MI) and ischemic stroke (IS) in a case-cohort study based on the European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam Study comprising 27 548 middle-aged subjects of the general population. Fetuin-A levels were measured in plasma of 227 individuals who developed MI, in 168 who developed IS, and in 2198 individuals who remained free of cardiovascular events during a mean follow-up of 8.2±2.2 years. Individuals in the highest compared with the lowest quintile of plasma fetuin-A had significantly increased risks of MI (relative risk, 3.80; 95% confidence interval, 2.37 to 6.10; P for trend <0.0001) and IS (relative risk, 3.93; 95% confidence interval, 2.17 to 7.12; P for trend <0.0001) after adjustment for sex and age. Additional adjustment for smoking status, body mass index, waist circumference, alcohol consumption, educational attainment, physical activity, hypertension, diabetes mellitus, total and high-density lipoprotein cholesterol, and C-reactive protein only moderately attenuated these risks (MI: relative risk, 3.25; 95% confidence interval, 2.01 to 5.28; P for trend <0.0001; IS: relative risk, 3.78; 95% confidence interval, 2.06 to 6.94; P for trend <0.0001).
Conclusions— Our data provide evidence for a link between high plasma fetuin-A levels and an increased risk of MI and IS. Therefore, more research is warranted to determine the role of fetuin-A in the pathophysiology of cardiovascular disease.
Abstract 9 of 11 (Circulation. 2008;118:2563-2570.)
Vascular Medicine
Degradation and Healing Characteristics of Small-Diameter Poly(-Caprolactone) Vascular Grafts in the Rat Systemic Arterial Circulation
Background— Long-term patency of conventional synthetic grafts is unsatisfactory below a 6-mm internal diameter. Poly(-caprolactone) (PCL) is a promising biodegradable polymer with a longer degradation time. We aimed to evaluate in vivo healing and degradation characteristics of small-diameter vascular grafts made of PCL nanofibers compared with expanded polytetrafluoroethylene (ePTFE) grafts.
Methods and Results— We prepared 2-mm–internal diameter grafts by electrospinning using PCL (Mn=80 000 g/mol). Either PCL (n=15) or ePTFE (n=15) grafts were implanted into 30 rats. Rats were followed up for 24 weeks. At the conclusion of the follow-up period, patency and structural integrity were evaluated by digital subtraction angiography. The abdominal aorta, including the graft, was harvested and investigated under light microscopy. Endothelial coverage, neointima formation, and transmural cellular ingrowth were measured by computed histomorphometry. All animals survived until the end of follow-up, and all grafts were patent in both groups. Digital subtraction angiography revealed no stenosis in the PCL group but stenotic lesions in 1 graft at 18 weeks (40%) and in another graft at 24 weeks (50%) in the ePTFE group. None of the grafts showed aneurysmal dilatation. Endothelial coverage was significantly better in the PCL group. Neointimal formation was comparable between the 2 groups. Macrophage and fibroblast ingrowth with extracellular matrix formation and neoangiogenesis were better in the PCL group. After 12 weeks, foci of chondroid metaplasia located in the neointima of PCL grafts were observed in all samples.
Conclusions— Small-diameter PCL grafts represent a promising alternative for the future because of their better healing characteristics compared with ePTFE grafts. Faster endothelialization and extracellular matrix formation, accompanied by degradation of graft fibers, seem to be the major advantages. Further evaluation of degradation and graft healing characteristics may potentially lead to the clinical use of such grafts for revascularization procedures.
Abstract 10 of 11 (Circulation. 2008;118:2571-2587.)
Contemporary Reviews in Cardiovascular Medicine
Cardiac Mechanics Revisited
The Relationship of Cardiac Architecture to Ventricular Function
The keynote to understanding cardiac function is recognizing the underlying architecture responsible for the contractile mechanisms that produce the narrowing, shortening, lengthening, widening, and twisting disclosed by echocardiographic and magnetic resonance technology. Despite background knowledge of a spiral clockwise and counterclockwise arrangement of muscle fibers, issues about the exact architecture, interrelationships, and function of the different sets of muscle fibers remain to be resolved. This report (1) details observed patterns of cardiac dynamic directional and twisting motions via multiple imaging sources; (2) summarizes the deficiencies of correlations between ventricular function and known ventricular muscle architecture; (3) correlates known cardiac motions with the functional anatomy within the helical ventricular myocardial band; and (4) defines an innovative muscular systolic mechanism that challenges the previously described concept of “isovolumic relaxation.” This new knowledge may open new doors to treating heart failure due to diastolic dysfunction.
Key Words: diastole • heart failure • muscles • ventricles
Abstract 11 of 11 (Circulation. 2008;118:2662-2666.)
ACC/AHA Performance Measures
ACC/AHA Classification of Care Metrics: Performance Measures and Quality Metrics
A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures
The American College of Cardiology (ACC) and the American Heart Association (AHA) have provided leadership in enhancing the quality of cardiovascular care, including the development of clinical performance measures and clinical registries that permit the evaluation of quality of care and stimulate quality improvement. Compliance with ACC/AHA performance measures and metrics encourages the provision of the strongest evidence-based quality of care, including therapies that are life-extending or life-enhancing. Among quality metrics, only a subset should be considered performance measures—that is, those measures specifically suitable for public reporting, external comparisons, and possibly pay-for-performance programs, in addition to quality improvement. These performance measures have been developed using ACC/AHA methodology, often in collaboration with other organizations, and include the process of public comment and peer review. Quality metrics are those measures that have been developed to support self assessment and quality improvement at the provider, hospital, and/or health care system level. These metrics represent valuable tools to aid clinicians and hospitals in improving quality of care and enhancing patient outcomes, but may not meet all specifications of formal performance measures. These quality metrics may also be considered “candidate” measures that with further research or field testing would meet the criteria for formal performance measures in the future. This measure classification is intended to aid providers, hospitals, health systems, and payers in identifying those measures that the ACC and AHA formally endorse as performance measures, while at the same time promoting the broader range of clinical metrics that are useful for quality improvement efforts.
Key Words: ACC/AHA Performance Measures • performance measurement • quality metrics

Arrhythmia/Electrophysiology:
1.Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation: The A4 Study
Background
— The mainstay of treatment for atrial fibrillation (AF) remains pharmacological; however, catheter ablation has increasingly been used over the last decade. The relative merits of each strategy have not been extensively studied.
Methods and Results
— We conducted a randomized multicenter comparison of these 2 treatment strategies in patients with paroxysmal AF resistant to at least 1 antiarrhythmic drug. The primary end point was absence of recurrent AF between months 3 and 12, absence of recurrent AF after up to 3 ablation procedures, or changes in antiarrhythmic drugs during the first 3 months. Ablation consisted of pulmonary vein isolation in all cases, whereas additional extrapulmonary vein lesions were at the discretion of the physician. Crossover was permitted at 3 months in case of failure. Echocardiographic data, symptom score, exercise capacity, quality of life, and AF burden were evaluated at 3, 6, and 12 months by the supervising committee. Of 149 eligible patients, 112 (18 women [16%]; age, 51.1±11.1 years) were enrolled and randomized to ablation (n=53) or “new” antiarrhythmic drugs alone or in combination (n=59). Crossover from the antiarrhythmic drugs and ablation groups occurred in 37 (63%) and 5 patients (9%), respectively (P=0.0001). At the 1-year follow-up, 13 of 55 patients (23%) and 46 of 52 patients (89%) had no recurrence of AF in the antiarrhythmic drug and ablation groups, respectively (P<0.0001). Symptom score, exercise capacity, and quality of life were significantly higher in the ablation group.
Conclusion
— This randomized multicenter study demonstrates the superiority of catheter ablation over antiarrhythmic drugs in patients with AF with regard to maintenance of sinus rhythm and improvement in symptoms, exercise capacity, and quality of life.
Coronary Heart Disease:
2.Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis: Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)
Background
— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis.
Methods and Results
— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P=0.02), and lowered serum potassium (0.11±0.02 mmol/L, P<0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume (r=–0.17, P<0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P=0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (–0.31±0.27 versus 0.88±0.27%, P=0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (–0.69±0.27%, P=0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression (P=0.001).
Conclusions
— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.
3.Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity: A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials
Background
— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome.
Methods and Results
— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change.
Conclusions
— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.
4.Angiotensin II Type 2 Receptor Stimulation: A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
Background
— This study is the first to examine the effect of direct angiotensin II type 2 (AT2) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT2 receptor agonist compound 21 (C21).
Methods and Results
— Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1β, and interleukin-2 expression, suggesting an antiinflammatory effect.
Conclusions
— Direct AT2 receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.
Epidemiology:
5.Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease: The Framingham Offspring Study
Background
— Von Willebrand factor (vWF) is inconsistently associated with cardiovascular disease (CVD). This might be explained by associations of vWF with type 2 diabetes mellitus and insulin resistance.
Methods and Results
— We tested whether vWF predicted incident CVD in 3799 Framingham Offspring Study participants, and in particular, among those with type 2 diabetes mellitus or insulin resistance. During 11 years of follow-up, 351 participants developed CVD. In proportional hazards models (with adjustment for age, sex, blood pressure, smoking, body mass index, total and high-density lipoprotein cholesterol, and treatment with aspirin, insulin, antihypertensives, and lipid-lowering medications) with the lowest quartile of the vWF distribution as the referent, the hazard ratio (HR) for CVD was 0.94 in the second quartile, 0.98 in the third, and 1.32 in the highest (P=0.04 for trend). Additional adjustment for type 2 diabetes mellitus or insulin resistance (homeostasis model) partially attenuated the association (multivariable HRs for top quartile 1.28 and 1.21, respectively). We then stratified the models by diabetes status or the homeostasis model of insulin resistance distribution (top quartile versus lower 3 quartiles). vWF was associated with CVD among participants with diabetes mellitus (HR for top quartile relative to bottom 1.47, P=0.04 for trend) but not among nondiabetic participants (HR 1.15, P=0.5) and similarly among insulin-resistant (HR 1.50, P=0.01) but not insulin-sensitive (HR 1.02, P=0.9) participants.
Conclusions
— Higher levels of vWF were associated with risk of CVD in people with type 2 diabetes mellitus or insulin resistance, which suggests that vWF may be a risk factor unique to these populations.
Imaging:
6.Predictive Value of Myocardial Perfusion Single-Photon Emission Computed Tomography and the Impact of Renal Function on Cardiac Death
Background
— Patients with chronic kidney disease (CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT (MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated.
Methods and Results
— We followed up 1652 consecutive patients who underwent stress MPS (32% exercise, 95% gated) for cardiac death for a mean of 2.15±0.8 years. MPS defects were defined with a summed stress score (normal summed stress score <4, abnormal summed stress score4). Ischemia was defined as a summed stress score 4 plus a summed difference score 2, and scar was defined as a summed difference score <2 plus a summed stress score 4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD (estimated glomerular filtration rate <60 mL · min–1 · 1.73 m–2) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS (2.7% versus 0.8%, P=0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects (hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD (hazard ratio 1.96, 95% CI 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction (global 2 207.5 versus 169.3, P<0.0001).
Conclusions
— MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan.
Resuscitation Science:
7.Gasping During Cardiac Arrest in Humans Is Frequent and Associated With Improved Survival
Background
— The incidence and significance of gasping after cardiac arrest in humans are controversial.
Methods and Results
— Two approaches were used. The first was a retrospective analysis of consecutive confirmed out-of-hospital cardiac arrests from the Phoenix Fire Department Regional Dispatch Center text files to determine the presence of gasping soon after collapse. The second was a retrospective analysis of 1218 patients with out-of-hospital cardiac arrests in Arizona documented by emergency medical system (EMS) first-care reports to determine the incidence of gasping after arrest in relation to the various EMS arrival times. The primary outcome measure was survival to hospital discharge. An analysis of the Phoenix Fire Department Regional Dispatch Center records of witnessed and unwitnessed out-of-hospital cardiac arrests with attempted resuscitation found that 44 of 113 (39%) of all arrested patients had gasping. An analysis of 1218 EMS-attended, witnessed, out-of-hospital cardiac arrests demonstrated that the presence or absence of gasping correlated with EMS arrival time. Gasping was present in 39 of 119 patients (33%) who arrested after EMS arrival, in 73 of 363 (20%) when EMS arrival was <7 minutes, in 50 of 360 (14%) when EMS arrival time was 7 to 9 minutes, and in 25 of 338 (7%) when EMS arrival time was >9 minutes. Survival to hospital discharge occurred in 54 of 191 patients (28%) who gasped and in 80 of 1027 (8%) who did not (adjusted odds ratio, 3.4; 95% confidence interval, 2.2 to 5.2). Among the 481 patients who received bystander cardiopulmonary resuscitation, survival to hospital discharge occurred among 30 of 77 patients who gasped (39%) versus only 38 of 404 among those who did not gasp (9%) (adjusted odds ratio, 5.1; 95% confidence interval, 2.7 to 9.4).
Conclusions
— Gasping or abnormal breathing is common after cardiac arrest but decreases rapidly with time. Gasping is associated with increased survival. These results suggest that the recognition and importance of gasping should be taught to bystanders and emergency medical dispatchers so as not to dissuade them from initiating prompt resuscitation efforts when appropriate.
Stroke:
8.Plasma Fetuin-A Levels and the Risk of Myocardial Infarction and Ischemic Stroke
Background
— Fetuin-A, a protein almost exclusively secreted by the liver, induces insulin resistance and subclinical inflammation in rodents. Circulating fetuin-A levels are elevated in humans with metabolic syndrome and insulin resistance, conditions that are associated with increased risk of cardiovascular disease.
Methods and Results
— We investigated the association between fetuin-A levels and the risk of future myocardial infarction (MI) and ischemic stroke (IS) in a case-cohort study based on the European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam Study comprising 27 548 middle-aged subjects of the general population. Fetuin-A levels were measured in plasma of 227 individuals who developed MI, in 168 who developed IS, and in 2198 individuals who remained free of cardiovascular events during a mean follow-up of 8.2±2.2 years. Individuals in the highest compared with the lowest quintile of plasma fetuin-A had significantly increased risks of MI (relative risk, 3.80; 95% confidence interval, 2.37 to 6.10; P for trend <0.0001) and IS (relative risk, 3.93; 95% confidence interval, 2.17 to 7.12; P for trend <0.0001) after adjustment for sex and age. Additional adjustment for smoking status, body mass index, waist circumference, alcohol consumption, educational attainment, physical activity, hypertension, diabetes mellitus, total and high-density lipoprotein cholesterol, and C-reactive protein only moderately attenuated these risks (MI: relative risk, 3.25; 95% confidence interval, 2.01 to 5.28; P for trend <0.0001; IS: relative risk, 3.78; 95% confidence interval, 2.06 to 6.94; P for trend <0.0001).
Conclusions
— Our data provide evidence for a link between high plasma fetuin-A levels and an increased risk of MI and IS. Therefore, more research is warranted to determine the role of fetuin-A in the pathophysiology of cardiovascular disease.
Vascular Medicine:
9.Degradation and Healing Characteristics of Small-Diameter Poly(ε-Caprolactone) Vascular Grafts in the Rat Systemic Arterial Circulation
Background
— Long-term patency of conventional synthetic grafts is unsatisfactory below a 6-mm internal diameter. Poly(ε-caprolactone) (PCL) is a promising biodegradable polymer with a longer degradation time. We aimed to evaluate in vivo healing and degradation characteristics of small-diameter vascular grafts made of PCL nanofibers compared with expanded polytetrafluoroethylene (ePTFE) grafts.
Methods and Results
— We prepared 2-mm–internal diameter grafts by electrospinning using PCL (Mn=80 000 g/mol). Either PCL (n=15) or ePTFE (n=15) grafts were implanted into 30 rats. Rats were followed up for 24 weeks. At the conclusion of the follow-up period, patency and structural integrity were evaluated by digital subtraction angiography. The abdominal aorta, including the graft, was harvested and investigated under light microscopy. Endothelial coverage, neointima formation, and transmural cellular ingrowth were measured by computed histomorphometry. All animals survived until the end of follow-up, and all grafts were patent in both groups. Digital subtraction angiography revealed no stenosis in the PCL group but stenotic lesions in 1 graft at 18 weeks (40%) and in another graft at 24 weeks (50%) in the ePTFE group. None of the grafts showed aneurysmal dilatation. Endothelial coverage was significantly better in the PCL group. Neointimal formation was comparable between the 2 groups. Macrophage and fibroblast ingrowth with extracellular matrix formation and neoangiogenesis were better in the PCL group. After 12 weeks, foci of chondroid metaplasia located in the neointima of PCL grafts were observed in all samples.
Conclusions
— Small-diameter PCL grafts represent a promising alternative for the future because of their better healing characteristics compared with ePTFE grafts. Faster endothelialization and extracellular matrix formation, accompanied by degradation of graft fibers, seem to be the major advantages. Further evaluation of degradation and graft healing characteristics may potentially lead to the clinical use of such grafts for revascularization procedures.

1. Arrhythmia/Electrophysiology
Electrophysiological Consequences of Acute Regional Ischemia/Reperfusion in Neonatal Rat Ventricular Myocyte Monolayers
Background— Electrophysiological changes promoting arrhythmias during acute regional ischemia/reperfusion are challenging to study in intact cardiac tissue because of complex 3-dimensional myocardial and vascular geometry. We characterized electrophysiological alterations and arrhythmias during regional ischemia/reperfusion in a simpler 2-dimensional geometry of cultured neonatal rat ventricular myocyte monolayers.
Methods and Results— Optical mapping of intracellular Ca (Cai) and voltage was performed with the use of Rhod 2-AM and Rh-237, respectively. Regional ischemia was mimicked by covering the central portion of monolayer with a glass coverslip, and reperfusion was mimicked by removing the coverslip. Monolayers were stained with fluorescent antibodies to detect total and dephosphorylated connexin-43 at various time points. During coverslip ischemia, action potential duration shortened, Cai transient duration was prolonged, and local conduction velocity (CV) slowed progressively, with loss of excitability after 10.6±3.6 minutes. CV slowing was accompanied by connexin-43 dephosphorylation. During ischemia, spontaneous reentry occurred in 5 of 11 monolayers, initiated by extrasystoles arising from the border zone or unidirectional conduction block of paced beats. On reperfusion, excitability recovered within 1.0±0.8 minutes, but CV remained depressed for 9.0±3.0 minutes, promoting reentry in the reperfused zone. As connexin-43 phosphorylation recovered in the reperfused zone, CV normalized, and arrhythmias resolved.
Conclusions— Acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers recapitulates electrophysiological alterations and arrhythmias similar to those observed during acute coronary occlusion/reperfusion in intact hearts. During early reperfusion, slow recovery from connexin-43 dephosphorylation leads to persistent CV slowing, creating a highly arrhythmogenic substrate.
2. Cardiovascular Surgery
Direction of Preoperative Ventricular Shunting Affects Ventricular Mechanics After Tetralogy of Fallot Repair
Background— Tetralogy of Fallot (TOF) typically results in clinical cyanosis or volume overload of the left ventricle (LV), depending on the direction and magnitude of shunting across the ventricular septal defect (VSD). The present study examines the effects of surgical TOF repair on LV mechanics and compares these changes between patients with VSD shunts that are predominantly right-to-left (R-L; “blue TOF”) and those with VSD shunts that are predominantly left-to-right (L-R; “pink TOF”).
Methods and Results— Eleven patients (6 R-L and 5 L-R) 4.3 to 18.4 months old (median 7.1 months old) were studied. LV end-diastolic area (EDA) was calculated from transesophageal echocardiograms obtained during initiation and weaning of cardiopulmonary bypass. LV end-diastolic pressure was measured by micromanometer. Compliance was assessed by end-diastolic pressure-area curves. Contractility was assessed from preload recruitable stroke work by the stroke work–versus–LV EDA relation. VSD shunt direction was determined by preoperative Doppler echocardiography. Changes in LV function at the conclusion of cardiopulmonary bypass included decreased stroke area (from 6.6±0.9 to 4.1±0.4 cm2/m2, P=0.012) and ejection fraction (from 55±2% to 41±3%, P<0.001). LV EDA at a common pressure in 8 patients decreased (from 10.4±1.4 to 7.6±1.2 cm2/m2, P=0.003), which suggests a decrease in ventricular compliance. Additionally, the end-diastolic pressure-area curves shifted to the left in all patients. Preload recruitable stroke work decreased (from 34.8±2.4 to 21.8±2.6 mm Hg, P=0.007), which demonstrates a decrease in ventricular contractility. When separated by preoperative shunt direction, LV EDA increased in R-L patients by 0.9±0.5 cm2/m2 postoperatively but decreased in L-R patients by 4.3±0.8 cm2/m2 (P<0.001). Area ejection fraction decreased in all patients independent of shunting or change in LV EDA.
Conclusions— LV diastolic and systolic function are depressed after TOF repair. Mechanical effects of the VSD patch and myocardial depressant effects of ischemia and reperfusion during surgery probably contribute to the observed changes in LV mechanics. Different effects of surgical repair on LV preload in pink and blue TOF also contribute to the spectrum of clinical results observed after surgery.
3. Congenital Heart Disease
National Practice Patterns for Management of Adult Congenital Heart Disease
Background— Surgery for grown-up (age 18 years) patients with congenital heart disease (GUCH) is frequently performed by surgeons without specialization in pediatric heart surgery. We sought to define national practice patterns and to determine whether outcomes for GUCH patients are improved if they are treated by specialized pediatric heart surgeons (PHSs) compared with non-PHSs.
Methods and Results— We identified index cardiac procedures in patients with 12 congenital heart disease diagnostic groups using the Nationwide Inpatient Sample 1988 to 2003. PHSs were defined as surgeons whose annual practice volumes were made of >75% annual pediatric heart cases. GUCH operations were defined as operations within these 12 diagnoses occurring in patients 18 years of age. We identified 30 250 operations, yielding a national estimate of 152 277±7875 operations. Of these, 111 816±7456 (73%) were pediatric operations, and 40 461±1365 (27%) were GUCH operations. PHSs performed 68% of pediatric operations in all diagnostic groups, whereas non-PHSs performed 95% of GUCH operations within the same diagnostic groups (P<0.0001). In-hospital death rates for GUCH patients operated on by PHSs were lower than death rates for GUCH patients operated on by non-PHSs (1.87% [95% CI, 0.62 to 3.13] versus 4.84% [95% CI, 4.30 to 5.38%]; P<0.0001). Survival advantage increased with increasing surgeon annual pediatric volume (P=0.0031).
Conclusions— Pediatric patients within specific diagnostic groups are more likely to undergo operation by PHSs, whereas GUCH patients within the same diagnostic groups are more likely to undergo operation by non-PHSs. In-hospital death rates are lower for GUCH patients operated on by PHSs. GUCH patients should be encouraged to obtain surgical operation by PHS.
4. Exercise Physiology
Vascular Endothelial Function and Leisure-Time Physical Activity in Adolescents
Background— Exercise training improves endothelial function in high-risk adolescents, but the influence of habitual leisure-time physical activity on endothelial function in healthy adolescents is unknown.
Methods and Results— Brachial artery flow-mediated endothelial function and physical activity habits were assessed in 483 adolescents (13 years of age) participating in an atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project for Children [STRIP]). Endothelial function was examined with ultrasound; physical activity was assessed with self-administered questionnaires. A leisure-time physical activity index was calculated by multiplying mean weekly leisure-time exercise intensity, duration, and frequency [boys, 31.2±23.0 MET h/wk (mean±SD); girls, 24.0±20.9 MET h/wk; P for gender difference=0.0003]. Maximum flow-mediated dilatation (FMD) and total FMD response (the area under the dilatation curve 40 to 180 seconds after hyperemia) were calculated. In boys, maximum FMD and area under the dilatation curve 40 to 180 seconds after hyperemia were directly associated with leisure-time physical activity index in regression analyses adjusted for brachial artery diameter (maximum FMD, P=0.020; area under the dilatation curve 40 to 180 seconds after hyperemia, P=0.0055). These associations remained significant after further adjustments for body mass index, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and systolic blood pressure. A difference of 50 MET h/wk corresponding to 10 hours of moderate intensity activity weekly between sedentary and active boys was associated with an 1% unit difference in maximum FMD.
Conclusions— Leisure-time physical activity is directly associated with brachial artery FMD responses in 13-year-old boys, providing evidence that physical activity beneficially influences endothelial function in healthy male adolescents. Lack of association in girls may reflect their overall lower physical activity level.
5. Interventional Cardiology
Nonrandomized Comparison of Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention for the Treatment of Unprotected Left Main Coronary Artery Disease in Octogenarians
Background— The objective of the present study was to compare the midterm follow-up results of percutaneous coronary intervention (PCI) and coronary bypass graft surgery (CABG) for the treatment of unprotected left main coronary artery disease in octogenarians.
Methods and Results— A total of 249 consecutive patients 80 years of age diagnosed with left main coronary artery disease underwent coronary revascularization in our center between January 2002 and January 2008; 145 patients underwent CABG, and 104 patients had PCI. Major adverse cardiac and cerebrovascular events (MACCE [cardiac death, myocardial infarction, cerebrovascular event, revascularization]) were evaluated at a mean follow-up of 23±16 months. Patients who underwent PCI were older; had higher creatinine levels, lower ejection fraction, and higher EuroSCORE; and presented more frequently with an acute coronary syndrome. Drug-eluting stents were used in 48% of PCI patients. A propensity score analysis was performed to adjust for baseline differences between the 2 groups. Survival free of cardiac death or myocardial infarction (PCI, 65.4%; CABG, 69.7%) and MACCE-free survival (PCI, 56.7%; CABG, 64.8%) at follow-up were similar between the groups (adjusted hazard ratio for survival free of cardiac death or myocardial infarction, 1.28; 95% CI, 0.64 to 2.56; P=0.47; adjusted hazard ratio for MACCE-free survival, 1.11; 95% CI, 0.59 to 2.0; P=0.73). The EuroSCORE value was an independent predictor of MACCE regardless of the type of revascularization (hazard ratio, 1.17 for each EuroSCORE increase of 1 point; 95% CI, 1.09 to 1.25; P<0.0001).
Conclusions— In this single-center, nonrandomized study, there were no significant differences in cardiac death or myocardial infarction and MACCE between CABG and PCI for the treatment of left main coronary artery disease in octogenarians after a mean follow-up of 2 years. Baseline EuroSCORE was the most important predictor of MACCE regardless of the type of revascularization. Randomized studies comparing both revascularization strategies in this high-risk coronary population are warranted.

Abstract 1 of 8
Cardiovascular Surgery
Routine Use of Bilateral Skeletonized Internal Thoracic Artery Grafting
Long-Term Results
Background— Skeletonized harvesting of the internal thoracic artery (ITA) decreases the severity of sternal devascularization, thus reducing the risk of postoperative sternal complications in patients undergoing bilateral ITA grafting.
Methods and Results— Between 1996 and 2001, 1515 consecutive patients underwent skeletonized bilateral ITA grafting. Of the 1179 male and 336 female patients, 641 (42.3%) were >70 years of age, and 519 (34.2%) had diabetes mellitus. Operative mortality was 2.8%. Early postoperative morbidity included sternal infection (1.6%), cerebrovascular accident (3%), and perioperative myocardial infarction (1%). Multiple regression analysis showed chronic obstructive pulmonary disease (odds ratio, 11.3; 95% confidence interval [CI], 4.45 to 28.55), repeat operation (odds ratio, 12.7; 95% CI, 3.25 to 49.56), and diabetes mellitus (non–insulin dependent: odds ratio, 4.64; 95% CI, 1.85 to 11.59; insulin dependent: odds ratio, 6.9; 95% CI, 1.35 to 35.27) to be associated with increased risk of sternal infection. Follow-up (between 5 and 12 years) revealed 305 late deaths. Kaplan-Meier 10-year survival rates for patients <65, 65 to 74, and >75 years of age were 87%, 75%, and 52%, respectively. Cox regression analysis revealed increased overall mortality (early and late) in patients with peripheral vascular disease (hazard ratio [HR], 1.8; 95% CI, 1.39 to 2.33), patients >75 years of age (HR, 7.23; 95% CI, 4.16 to 12.55), those undergoing repeat operations (HR, 2.22; 95% CI, 1.27 to 3.89), patients with preoperative congestive heart failure (HR, 1.64; 95% CI, 1.29 to 3.75), and those with chronic renal failure (HR, 1.52; 95% CI, 1.11 to 2.01). Operations performed without cardiopulmonary bypass were associated with better postoperative survival (HR, 0.66; 95% CI, 0.49 to 0.87).
Conclusions— Bilateral ITA grafting is associated with low morbidity and good long-term results. Use of skeletonized bilateral ITA is appropriate for the elderly and most patients with diabetes; however, it is not recommended for repeat operations or for patients with chronic obstructive pulmonary disease.
Abstract 2 of 8
Heart Failure
Heterogeneity of Left Ventricular Wall Thickening Mechanisms
Background— Myocardial fibers are grouped into lamina (or sheets) 3 to 4 cells thick. Fiber shortening produces systolic left ventricular (LV) wall thickening primarily by laminar extension, thickening, and shear, but the regional variability and transmural distribution of these 3 mechanisms are incompletely understood.
Methods and Results— Nine sheep had transmural radiopaque markers inserted into the anterior basal and lateral equatorial LV. Four-dimensional marker dynamics were studied with biplane videofluoroscopy to measure circumferential, longitudinal, and radial systolic strains in the epicardium, midwall, and endocardium. Fiber and sheet angles from quantitative histology allowed transformation of these strains into transmural contributions of sheet extension, thickening, and shear to systolic wall thickening. At all depths, systolic wall thickening in the anterior basal region was 1.6 to 1.9 times that in the lateral equatorial region. Interestingly, however, systolic fiber shortening was identical at each transmural depth in these regions. Endocardial anterior basal sheet thickening was >2 times greater than in the lateral equatorial region (epicardium, 0.16±0.15 versus 0.03±0.06; endocardium, 0.45±0.40 versus 0.17±0.09). Midwall sheet extension was >2 times that in the lateral wall (0.22±0.12 versus 0.09±0.06). Epicardial and midwall sheet shears in the anterior wall were 2 times higher than in the lateral wall (epicardium, 0.14±0.07 versus 0.05±0.03; midwall, 0.21±0.12 versus 0.12±0.06).
Conclusions— These data demonstrate fundamentally different regional contributions of laminar mechanisms for amplifying fiber shortening to systolic wall thickening. Systolic fiber shortening was identical at each transmural depth in both the anterior and lateral LV sites. However, systolic wall thickening of the anterior site was much greater than that of the lateral site. Fiber shortening drives systolic wall thickening, but sheet dynamics and orientations are of great importance to systolic wall thickening. LV wall thickening and its clinical implications pivot on different wall thickening mechanisms in various LV regions. Attempts to implant healthy contractile cells into diseased hearts or to surgically manipulate LV geometry need to take into account not only cardiomyocyte contraction but also transmural LV intercellular architecture and geometry.
Abstract 3 of 8
Molecular Cardiology
Genetic Ablation of the Bmpr2 Gene in Pulmonary Endothelium Is Sufficient to Predispose to Pulmonary Arterial Hypertension
Background— Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. PAH is now further subclassified as idiopathic PAH, familial PAH, and associated PAH varieties. Heterozygous mutations in BMPR2 can be detected in 50% to 70% of patients with familial PAH and 10% to 40% of patients with idiopathic PAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH.
Methods and Results— The Bmpr2 gene was deleted in pulmonary endothelial cells using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure were observed in mice with heterozygous (21.7 to 44.1 mm Hg; median, 23.7 mm Hg) and homozygous (20.7 to 56.3 mm Hg; median, 27 mm Hg) conditional deletion of Bmpr2 in pulmonary endothelial cells compared with control mice (19.9 to 26.7 mm Hg; median, 23 mm Hg) at 2 to 7 months of age. A subset of mice with right ventricular systolic pressure >30 mm Hg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these mice with high right ventricular systolic pressure, the expression of proteins involved in the pathogenesis of PAH such as serotonin transporter and tenascin-C was elevated in distal arteries and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis.
Conclusions— Conditional heterozygous or homozygous Bmpr2 deletion in pulmonary endothelial cells predisposes mice to develop PAH.
Abstract 4 of 8
Vascular Medicine
Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction
Background— Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-β (PKCβ). Because PKCβ impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo.
Methods and Results— ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKCβ in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCβ. The impaired insulin signaling was restored by PKCβ inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKCβ inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKCβ, which inhibits the IRS-1/PI3K/Akt/eNOS pathway.
Conclusion— Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.
Abstract 5 of 8
Vascular Medicine
Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein Transgenic Mice
Background— Lipoprotein [Lp] is a genetic cardiovascular risk factor that preferentially binds oxidized phospholipids (OxPL) in plasma. There is a lack of therapeutic agents that reduce plasma Lp levels.
Methods and Results— Transgenic mice overexpressing human apolipoprotein B-100 (h-apoB-100 [h-apoB mice]) or h-apoB-100 plus human apo to generate genuine Lp particles [Lp mice] were treated with the antisense oligonucleotide mipomersen directed to h-apoB-100 mRNA or control antisense oligonucleotide for 11 weeks by intraperitoneal injection. Mice were then followed up for an additional 10 weeks off therapy. Lp levels [apo bound to apoB-100] and apo levels ["free" apo plus apo bound to apoB-100] were measured by chemiluminescent enzyme-linked immunoassay and commercial assays, respectively. The content of OxPL on h-apoB-100 particles (OxPL/h-apo was measured by capturing h-apoB-100 in microtiter wells and detecting OxPL by antibody E06. As expected, mipomersen significantly reduced plasma h-apoB-100 levels in both groups of mice. In Lp mice, mipomersen significantly reduced Lp levels by 75% compared with baseline (P<0.0001) but had no effect on apo levels or hepatic apo mRNA expression. OxPL/h-apoB levels were much higher at baseline in Lp mice compared with h-ApoB mice (P<0.0001) but decreased in a time-dependent fashion with mipomersen. There was no effect of the control antisense oligonucleotide on lipoprotein levels or oxidative parameters.
Conclusions— Mipomersen significantly reduced Lp and OxPL/apoB levels in Lp mice. The present study demonstrates that h-apoB-100 is a limiting factor in Lp particle synthesis in this Lp transgenic model. If applicable to humans, mipomersen may represent a novel therapeutic approach to reducing Lp levels and their associated OxPL.
Abstract 6 of 8
Vascular Medicine
Reduced Atherosclerotic Lesions in P2Y1/Apolipoprotein E Double-Knockout Mice
The Contribution of Non–Hematopoietic-Derived P2Y1 Receptors
Background— The P2Y1 receptor plays a key role in arterial thrombosis and is widely expressed in many cell types involved in atherosclerosis. The aim of this study was to evaluate its potential involvement in the development of atherosclerotic lesions.
Methods and Results— Apolipoprotein E–deficient (ApoE–/–) and P2Y1–/–/ApoE–/– mice were maintained on regular chow for 17 or 30 weeks before analysis of atherosclerotic lesions. At 17 weeks, lesions in the aortic sinus and entire aorta were smaller in P2Y1–/–/ApoE–/– compared with those in ApoE–/– animals. At 30 weeks, the aortic sinus lesions in P2Y1–/–/ApoE–/– mice were still diminished in size and displayed reduced inflammation, reflected by decreased macrophage infiltration and diminished VCAM-1 immunostaining, compared with those in ApoE–/– mice. They also had a lower smooth muscle cell content. Unexpectedly, bone marrow transplantation showed that the absence of the P2Y1 receptor in blood cells only led to no significant modification of the lesion compared with control ApoE–/– reconstituted animals. Conversely, the absence of the P2Y1 receptor except in blood cells resulted in a reduction in lesion size similar to that in control P2Y1–/–/ApoE–/– reconstituted mice, pointing to a role of non–hematopoietic-derived P2Y1 receptors, most likely the endothelial or smooth muscle cell P2Y1 receptors. In addition, although this was not statistically significant, plasma cholesterol levels were consistently decreased in P2Y1–/– animals, suggesting that a modification of lipid metabolism could be responsible for the observed phenotype.
Conclusion— The P2Y1 receptor contributes to atherosclerosis, primarily through its role in non–hematopoietic-derived cells.
Abstract 7 of 8
Vascular Medicine
Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries
Background— c-Cbl, a ubiquitously expressed protooncogene, is tyrosine phosphorylated in response to a variety of stimuli, including growth factors such as platelet-derived growth factor (PDGF), and consequently activates signaling proteins such as phosphatidylinositol-3 kinase (PI3K) and Akt. In the present study, we examined the role of c-Cbl tyrosine phosphorylation in vascular injury.
Methods and Results— Western blotting showed that the tyrosine phosphorylation of c-Cbl was increased in balloon-injured rat carotid arteries and in cultured smooth muscle cells on stimulation by PDGF-BB, followed by the activations of Akt and the mammalian target of rapamycin. Adenovirus-mediated overexpression of a c-Cbl mutant that ablates the major tyrosine phosphorylation sites attenuated the Akt and the mammalian target of rapamycin activation and decreased the proliferation and migration of smooth muscle cells in response to PDGF-BB or fibroblast growth factor. These effects could be reversed by constitutively active PI3K or Akt, suggesting that c-Cbl phosphorylation promotes the PDGF-BB–induced proliferation and migration of smooth muscle cells through the PI3K/Akt pathways. In addition, overexpression of c-Cbl-m increased the ubiquitination of the PDGF and fibroblast growth factor receptors. Importantly, in balloon-injured rat carotid arteries, local delivery of c-Cbl-m reduced the phosphorylation of Akt and the mammalian target of rapamycin, inhibited the migration and proliferation of smooth muscle cells, and prevented neointimal hyperplasia.
Conclusions— Our results demonstrate a novel role of c-Cbl in vascular remodeling after injury and suggest that modulation of c-Cbl tyrosine phosphorylation may be a therapeutic approach to treat vascular neointimal hyperplasia such as restenosis after angioplasty.
Abstract 8 of 8
New Drugs and Technologies
Aliskiren
Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg, there are dose-related falls in blood pressure comparable to those seen with other major classes of antihypertensive drugs and that these falls are associated with a placebo level of side effects. Aliskiren was found to be effective either as monotherapy or in combination with drugs from the other major classes. As expected, there was a greater benefit from adding aliskiren to natriuretic drugs than to other blockers of the renin system. However, there was also some consistent benefit from dual renin blockade. Aliskiren is likely to be of most value in patients uncontrolled by, or intolerant of, other classes. Rational understanding of the renin system will maximize its value, for instance, by encouraging greater use of natriuretic agents in patients with resistant hypertension to render their hypertension renin dependent. Whether there are cardiovascular benefits other than blood pressure control in blocking the renin system remains to be demonstrated. It is hoped that long-term outcome studies with aliskiren will finally allow this question to be answered.
Key Words: aliskiren • renin • renin inhibitor