Hot off the presses! Apr 07 Circulation

The Apr 07 issue of the Circulation is now up on Pubget (About Circulation): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Clinical Summaries
  - Circulation 119(13):1691-1693 (2009)
  
• Pilot Trials in Clinical Research: Of What Value Are They?
  - Circulation 119(13):1694-1696 (2009)
  
• The Science of Uncertainty and the Art of Probability: Syncope and Its Consequences in Hypertrophic Cardiomyopathy
  - Circulation 119(13):1697-1699 (2009)
  
• Metabolomic Profiling of Cardiac Substrate Utilization: Fanning the Flames of Systems Biology?
  - Circulation 119(13):1700-1702 (2009)
  
• Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy
  - Circulation 119(13):1703-1710 (2009)
  Background-- The prognostic significance of syncope has not been investigated systematically in hypertrophic cardiomyopathy, and treatment strategies have been based largely on intuition and experience. Methods and Results-- We assessed the relationship between syncope and sudden death in 1511 consecutive patients with hypertrophic cardiomyopathy. Unexplained (n=153) or neurally mediated (n=52) syncope occurred in 205 patients (14%). Over a 5.6{+/-}5.2-year follow-up, 74 patients died suddenly. Relative risk of sudden death was 1.78 (95% confidence interval 0.88 to 3.51, P=0.08) in patients with unexplained syncope and 0.91 (95% confidence interval 0.00 to 3.83, P=1.0) in those with neurally mediated syncope compared with patients without syncope. In multivariable analysis, the temporal proximity of unexplained syncope to initial patient evaluation was independently associated with risk of sudden death (P=0.006). Patients with unexplained syncope within 6 months befor! e the initial evaluation showed a 5-fold increase in risk compared with patients without syncope (adjusted hazard ratio 4.89, 95% confidence interval 2.19 to 10.94), a relationship that was maintained throughout all age groups (<18, 18 to 39, and [≥]40 years). Older patients ([≥]40 years of age) with remote episodes of syncope (>5 years before initial evaluation) did not show an increased risk of sudden death (adjusted hazard ratio 0.38, 95% confidence interval 0.05 to 2.74). Conclusions-- In the present large cohort of patients with hypertrophic cardiomyopathy, unexplained syncope was a risk factor for sudden death. Patients with syncopal events that occurred in close temporal proximity to the initial evaluation showed a substantially higher risk of sudden death than patients without syncope. Older patients with remote syncopal events did not show an increased risk.
• Relationship of Oxidized Phospholipids on Apolipoprotein B-100 Particles to Race/Ethnicity, Apolipoprotein(a) Isoform Size, and Cardiovascular Risk Factors: Results From the Dallas Heart Study
  - Circulation 119(13):1711-1719 (2009)
  Background-- Elevated levels of oxidized phospholipids (OxPLs) on apolipoprotein B-100 particles (OxPL/apoB) are associated with cardiovascular disease and predict new cardiovascular events. Elevated lipoprotein (a) [Lp(a)] levels are a risk factor for cardiovascular disease in whites and also in blacks if they carry small apolipoprotein(a) [apo(a)] isoforms. The relationship of OxPL/apoB levels to race/ethnicity, cardiovascular risk factors, and apo(a) isoforms is not established. Methods and Results-- OxPL/apoB levels were measured in 3481 subjects (1831 black, 1047 white, and 603 Hispanic subjects) in the Dallas Heart Study and correlated with age, sex, cardiovascular risk factors, and Lp(a) and apo(a) isoforms. Significant differences in OxPL/apoB levels were noted among racial/ethnic subgroups, with blacks having the highest levels compared with whites and Hispanics (P<0.001 for each comparison). OxPL/apoB levels generally did not correlate with age, sex, or risk! factors. In the overall cohort, OxPL/apoB levels strongly correlated with Lp(a) (r=0.85, P<0.001), with the shape of the relationship demonstrating a "reverse L" shape for log-transformed values. The highest correlation was present in blacks, followed by whites and Hispanics; was dependent on apo(a) isoform size; and became progressively weaker with larger isoforms. The size of the major apo(a) isoform (number of kringle type IV repeats) was negatively associated with OxPL/apoB (r=-0.49, P<0.001) and Lp(a) (r=-0.61, P<0.001) regardless of racial/ethnic group. After adjustment for apo(a) isoform size, the relationship between OxPL/apoB and Lp(a) remained significant (r=0.67, P<0.001). Conclusions-- OxPL/apoB levels vary according to race/ethnicity, are largely independent of cardiovascular risk factors, and are inversely associated with apo(a) isoform size. The association of OxPL with small apo(a) isoforms, in which a similar relationship is present among all racial/ethni! c subgroups despite differences in Lp(a) levels, may be a key ! determinant of cardiovascular risk.
• Associations of Gestational Weight Gain With Offspring Body Mass Index and Blood Pressure at 21 Years of Age: Evidence From a Birth Cohort Study
  - Circulation 119(13):1720-1727 (2009)
  Background-- Maternal weight gain in pregnancy is positively associated with offspring body mass index (BMI) and obesity risk in childhood, but whether this increased risk extends into adulthood or results in increases in other cardiovascular risk factors such as elevated blood pressure (BP) is unclear. Methods and Results-- We used a population-based birth cohort of 2432 individuals (50% male) born in Brisbane, Australia, between 1981 and 1983 to prospectively examine the association between maternal gestational weight gain (GWG) and offspring BMI and BP at 21 years. On average, each mother gained 14.8 kg (SD, 5.1 kg) during her pregnancy. At 21 years of age, offspring mean BMI, systolic BP, and diastolic BP were 24.2 kg/m2 (SD, 4.9 kg/m2), 116.4 mm Hg (SD, 14.5 mm Hg), and 67.7 mm Hg (SD, 8.5 mm Hg), respectively. Offspring BMI was on average 0.3 kg/m2 (95% confidence interval, 0.1 to 0.4 kg/m2) higher for each 0.1-kg/wk greater GWG after adjustment for potential co! nfounding factors. Systolic BP also was greater (0.2 mm Hg per 0.1 kg; 95% confidence interval, -0.2 to 0.6) in offspring whose mothers had higher GWG. Although this association was not statistically significant, it was consistent in magnitude with the association of maternal GWG with offspring BMI and of offspring BMI with BP. Conclusions-- Our findings show that greater GWG is associated with greater offspring BMI into early adulthood and that this may translate into higher systolic BP in offspring. Further large studies are required to confirm an effect of GWG on a range of offspring cardiovascular risk factors.
• Trends in All-Cause and Cardiovascular Disease Mortality Among Women and Men With and Without Diabetes Mellitus in the Framingham Heart Study, 1950 to 2005
  - Circulation 119(13):1728-1735 (2009)
  Background-- Despite population declines in all-cause mortality, women with diabetes mellitus may have experienced an increase in mortality rates compared with men. Methods and Results-- We examined change in all-cause, cardiovascular, and non-cardiovascular disease mortality rates among Framingham Heart Study participants who attended examinations during an "earlier" (1950 to 1975; n=930 deaths) and a "later" (1976 to 2001; n=773 deaths) time period. Diabetes mellitus was defined as casual glucose [≥]200 mg/dL, fasting plasma glucose [≥]126 mg/dL, or treatment. Among women, the hazard ratios (HRs) for all-cause mortality in the later versus the earlier time period were 0.59 (95% confidence interval, 0.50 to 0.70; P<0.0001) for those without diabetes mellitus and 0.48 (95% confidence interval, 0.32 to 0.71; P=0.002) for those with diabetes mellitus. Similar results were observed in men. Among women and men, the HR of cardiovascular disease mortality declined amo! ng those with and without diabetes mellitus. Non-cardiovascular disease mortality declined among women without diabetes mellitus (HR, 0.76; P=0.01), whereas no change was observed among women with diabetes mellitus or among men with or without diabetes mellitus. Individuals with versus those without diabetes mellitus were at increased risk of all-cause mortality in the earlier (HR, 2.44; P<0.0001) and later (HR, 1.95; P<0.0001) time periods. Conclusions-- Reductions in all-cause mortality among women and men with diabetes mellitus have occurred over time. However, mortality rates among individuals with diabetes mellitus remain {approx}2-fold higher compared with individuals without diabetes mellitus.
• Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion
  - Circulation 119(13):1736-1746 (2009)
  Background-- Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not been established. Methods and Results-- We applied a mass spectrometry-based platform to profile 63 intermediary metabolites in serial paired peripheral arterial and coronary sinus blood effluents obtained from 37 patients undergoing cardiac surgery, stratified by presence of coronary artery disease and left ventricular dysfunction. The myocardium was a net user of a number of fuel substrates before ischemia, with significant differences between patients with and without coronary artery disease. After reperfusion, significantly lower extraction ratios of most substrates were found, as well as significant release of 2 specific acylcarnitine species, acetylcarnitine and 3-hydroxybutyryl-carnitine. These changes were ! especially evident in patients with impaired ventricular function, who exhibited profound limitations in extraction of all forms of metabolic fuels. Principal component analysis highlighted several metabolic groupings as potentially important in the postoperative clinical course. Conclusions-- The preexisting ventricular state is associated with significant differences in myocardial fuel uptake at baseline and after ischemia/reperfusion. The dysfunctional ventricle is characterized by global suppression of metabolic fuel uptake and limited myocardial metabolic reserve and flexibility after global ischemia/reperfusion stress in the setting of cardiac surgery. Altered metabolic profiles after ischemia/reperfusion are associated with postoperative hemodynamic course and suggest a role for perioperative metabolic monitoring and targeted optimization in cardiac surgical patients.
• Stress Doppler Echocardiography in Relatives of Patients With Idiopathic and Familial Pulmonary Arterial Hypertension: Results of a Multicenter European Analysis of Pulmonary Artery Pressure Response to Exercise and Hypoxia
  - Circulation 119(13):1747-1757 (2009)
  Background-- This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene. Methods and Results-- TRV was estimated by Doppler echocardiography during supine bicycle exercise in normoxia and during 120 minutes of normobaric hypoxia (FIO2=12%; {approx}4500 m) in 291 relatives of 109 PAH patients and in 191 age-matched control subjects. Mean maximal TRVs were significantly higher in PAH relatives during both exercise and hypoxia. During exercise, 10% of control subjects but 31.6% of relatives (P<0! .0001) exceeded the 90% quantile of mean maximal TRV seen in control subjects. Hypoxia revealed hypertensive TRV in 26% of relatives (P=0.0029). Among control subjects, TRV at rest was not related to age, sex, body mass index, systemic blood pressure, smoking status, or heart rate. Within kindreds identified as harboring deleterious mutations of the BMPR2 gene, a hypertensive TRV response occurred significantly more often compared with those without detected mutations. Conclusions-- Pulmonary hypertensive response to exercise and hypoxia in idiopathic/familial PAH relatives appears as a genetic trait with familial clustering, being correlated to but not caused by a BMPR2 mutation. The suitability of this trait to predict manifest PAH development should be addressed in long-term follow-up studies.
• Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation
  - Circulation 119(13):1758-1767 (2009)
  Background-- Atrial fibrillation (AF) is associated with diffuse left atrial fibrosis and a reduction in endocardial voltage. These changes are indicators of AF severity and appear to be predictors of treatment outcome. In this study, we report the utility of delayed-enhancement magnetic resonance imaging (DE-MRI) in detecting abnormal atrial tissue before radiofrequency ablation and in predicting procedural outcome. Methods and Results-- Eighty-one patients presenting for pulmonary vein antrum isolation for treatment of AF underwent 3-dimensional DE-MRI of the left atrium before the ablation. Six healthy volunteers also were scanned. DE-MRI images were manually segmented to isolate the left atrium, and custom software was implemented to quantify the spatial extent of delayed enhancement, which was then compared with the regions of low voltage from electroanatomic maps from the pulmonary vein antrum isolation procedure. Patients were assessed for AF recurrence at leas! t 6 months after pulmonary vein antrum isolation, with an average follow-up of 9.6{+/-}3.7 months (range, 6 to 19 months). On the basis of the extent of preablation enhancement, 43 patients were classified as having minimal enhancement (average enhancement, 8.0{+/-}4.2%), 30 as having moderate enhancement (21.3{+/-}5.8%), and 8 as having extensive enhancement (50.1{+/-}15.4%). The rate of AF recurrence was 6 patients (14.0%) with minimal enhancement, 13 (43.3%) with moderate enhancement, and 6 (75%) with extensive enhancement (P<0.001). Conclusions-- DE-MRI provides a noninvasive means of assessing left atrial myocardial tissue in patients suffering from AF and might provide insight into the progress of the disease. Preablation DE-MRI holds promise for predicting responders to AF ablation and may provide a metric of overall disease progression.
• Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent: Initial Feasibility Study in a Swine Model
  - Circulation 119(13):1768-1775 (2009)
  Background-- Cardiac magnetic resonance (MR) perfusion imaging during the first pass after intravenous administration of extracellular contrast agents is hampered by the spatial and temporal resolution achievable and by the artifacts seen in ultrafast MR imaging. Furthermore, time-consuming quantitative data analysis is often added. The use of molecular MR imaging with a target-specific contrast agent with perfusion-dependent binding to myocardium may enable prolonged visualization of perfusion defects and thus may help to overcome limitations of currently used first-pass extracellular MR imaging. EP-3600 is a new gadolinium-containing molecular contrast agent that binds reversibly to myocardial collagen. Methods and Results-- A significant but nonocclusive coronary artery stenosis was modeled in 7 domestic swine with an undersized MR-compatible balloon positioned in the left anterior descending artery as verified by x-ray angiography. Two animals died before contrast! injection as a result of arrhythmias. In 5 swine, high-spatial-resolution gradient echo imaging ({approx}1x1 mm2 in-plane resolution) was performed before and 5, 20, 40, and 60 minutes after intravenous administration of 12.3 {micro}mol/kg EP-3600. Contrast was administered during stress induced by an infusion of 250 {micro}mol {middle dot} kg-1 {middle dot} min-1 adenosine. Yb-DTPA was administered simultaneously for comparison of myocardium-to-plasma ratios. Images were assessed subjectively by 2 investigators, and signal-to-noise and contrast-to-noise ratios over time were calculated. Normal myocardium showed a significant signal-to-noise ratio increase during the entire examination time. In all animals (n=5), the perfusion defect in the left anterior descending artery territory could be visualized with a high contrast-to-noise ratio for at least 20 minutes after contrast injection. A significantly higher myocardium-to-plasma ratio was found for EP-3600 compared with th! e control agent Yb-DTPA (0.85{+/-}0.26 versus 0.22{+/-}0.08, r! espectively; P<0.01). Conclusion-- EP-3600 is a new molecular MR imaging contrast agent that binds to the myocardium and enables prolonged, high-contrast, high-spatial-resolution visualization of myocardial perfusion defects.
• Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
  - Circulation 119(13):1776-1784 (2009)
  Background-- Vascular endothelial growth factor (VEGF) is an important active protein for the induction of angiogenesis and improvement in cardiac function after myocardial ischemia; however, the lack of a delivery system targeted to the injured myocardium reduces the local therapeutic efficacy of VEGF and increases its possible adverse effects. Methods and Results-- We produced a fusion protein (CBD-VEGF) consisting of VEGF and a collagen-binding domain (CBD). The fusion protein specifically bound to type I collagen in vitro. In addition, CBD-VEGF promoted human umbilical vein endothelial cell proliferation after binding to collagen, which indicates that it retained both growth factor activity and collagen-binding ability. When implanted subcutaneously in rats, collagen membranes loaded with CBD-VEGF were significantly vascularized. After it was injected into rats with acute myocardial infarction, CBD-VEGF was largely retained in the cardiac extracellular matrix, in ! which collagen I was rich. Four weeks after VEGF or CBD-VEGF was injected into the infarct border zone, cardiac function detected by echocardiography and hemodynamics was preserved in the CBD-VEGF group. Administration of CBD-VEGF also induced reduction of scar size, whereas native VEGF did not have these effects. In addition, a significant increase in the number of capillary vessels in infarcted hearts was found in the CBD-VEGF group. Conclusions-- The injection of CBD-VEGF improved cardiac function in rats with induced acute myocardial infarction. This could potentially provide a new treatment option for myocardial infarction.
• Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease
  - Circulation 119(13):1785-1794 (2009)
  Background-- Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy. Methods and Results-- Apolipoprotein-deficient (apoE-/-)/catS+/+ (n=24) and apoE-/-/catS-/- (n=24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those ! without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE-/-/catS+/+ cohort, whereas CRD apoE-/-/catS-/- mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE-/-/catS+/+ than CRD apoE-/-/catS-/- aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium. Conclusions-- The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providi! ng new insight into the pathophysiology of cardiovascular calc! ification.
• Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
  - Circulation 119(13):1795-1804 (2009)
  Background-- Because apoptotic cell clearance appears to be defective in advanced compared with early atherosclerotic plaques, macrophage apoptosis may differentially affect plaque progression as a function of lesion stage. Methods and Results-- We first evaluated the impact of targeted protection of macrophages against apoptosis at both early and advanced stages of atherosclerosis. Increased resistance of macrophages to apoptosis in early atherosclerotic lesions was associated with increased plaque burden; in contrast, it afforded protection against progression to advanced lesions. Conversely, sustained induction of apoptosis in lesional macrophages of advanced lesions resulted in a significant increase in lesion size. Such enhanced lesion size occurred as a result not only of apoptotic cell accumulation but also of elevated chemokine expression and subsequent intimal recruitment of circulating monocytes. Conclusions-- Considered together, our data suggest that macr! ophage apoptosis is atheroprotective in fatty streak lesions, but in contrast, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, leading to enhanced atherogenesis.
• Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm
  - Circulation 119(13):1805-1813 (2009)
  Background-- We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall. Methods and Results-- Using an elastase-induced model of AAA, we showed that pretreatment of C57BL/6 mice with cobra venom factor, which depleted serum of complement activity, protected mice from AAA development. Whereas control mice exhibited a mean aortic diameter of 156{+/-}2% on day 14 after elastase perfusion, mice treated with cobra venom factor exhibited a mean aortic diameter of 90{+/-}4% (P<0.001). Examination of mice deficient in factor B further indicated that the alternative pathway of complement played a major role in this process (m! ean aortic diameter of 105{+/-}4% in factor B-deficient mice, P<0.001 compared with controls). Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, which recruited neutrophils to the aortic wall. Moreover, antagonism of both C3a and C5a activity was required to block AAA, which suggests that each can independently promote the aneurysmal phenotype. In addition, we demonstrated that complement alternative-pathway involvement was not restricted to this experimental model but was also evident in human AAAs. Conclusions-- The identification of involvement of the complement system in the pathophysiology of AAA provides a new target for therapeutic intervention in this common disease.
• Choosing a Research Project and a Research Mentor
  - Circulation 119(13):1832-1835 (2009)
  
• Stem Cell Therapy Is Proarrhythmic
  - Circulation 119(13):1814-1823 (2009)
  
• Stem Cells Are Not Proarrhythmic: Letting the Genie out of the Bottle
  - Circulation 119(13):1824-1831 (2009)
  
• Building a Healthier World, Free of Cardiovascular Diseases and Stroke: Presidential Address at the American Heart Association 2008 Scientific Sessions
  - Circulation 119(13):1838-1841 (2009)
  
• Cannon A Wave
  - Circulation 119(13):e381-383 (2009)
  
• Yew Causes Brugada ECG
  - Circulation 119(13):1836-1837 (2009)
  
• Letter by Lund et al Regarding Article, "Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events"
  - Circulation 119(13):e384 (2009)
  
• Response to Letter Regarding Article, "Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events"
  - Circulation 119(13):e385 (2009)