- Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy
- 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
- Associations of Gestational Weight Gain With Offspring Body Mass Index and Blood Pressure at 21 Years of Age: Evidence From a Birth Cohort Study
- 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
- Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion
- 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
- Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation
- Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent: Initial Feasibility Study in a Swine Model
- Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
- Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease
- Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
- Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm
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Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy
In patients with hypertrophic cardiomyopathy, syncope can be neurally mediated or a warning of dangerous arrhythmias or hemodynamic impairment, but its prognostic significance is not clearly established. We assessed the relationship between syncope and sudden death in 1511 consecutive hypertrophic cardiomyopathy patients; 205 (14%) had a history of unexplained or neurally mediated syncope. Over a 5.6-year mean follow-up, 74 patients died suddenly. Unexplained syncope but not neurally mediated syncope was associated with an increased risk of sudden death (hazard ratio 1.78, P=0.08 compared with patients without syncope). Temporal proximity of unexplained syncope to initial patient evaluation was important. Patients with recent unexplained syncope (≤6 months before initial evaluation) showed a 5-fold increase in risk compared with patients without syncope, a relationship that was maintained throughout all age groups. In adolescents, unexplained syncope was associated with a 60% cumulative risk at 5 years. Older patients (≥40 years) with remote syncope (>5 years before initial evaluation) showed no increased sudden death risk. Thus, unexplained syncope is a marker for increased risk in hypertrophic cardiomyopathy, particularly when it occurs in close temporal proximity to patient evaluation. Remote syncopal events are not a marker of increased risk in older patients. See p 1703.
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
Oxidized phospholipids (OxPLs) play a central role in mediating a variety of immune, proinflammatory, and plaque-destabilizing processes that further amplify inflammatory responses. We have found that OxPLs circulate on apolipoprotein B-100 (apoB) particles primarily on lipoprotein(a) [Lp(a)]. OxPL/apoB levels are elevated in patients with coronary, carotid, and femoral artery disease; with acute coronary syndromes; and after percutaneous coronary intervention and independently predict new cardiovascular events. OxPL/apoB levels were measured in 1831 black, 1047 white, and 603 Hispanic subjects in the Dallas Heart Study. OxPL/apoB levels were highest in blacks, followed by whites and Hispanics, and did not correlate with any traditional risk factors except Lp(a). The highest correlation between OxPL/apoB and Lp(a) was present in blacks, followed by whites and Hispanics; was dependent on apolipoprotein(a) [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 regardless of racial/ethnicity group. This study demonstrates that elevated OxPL/apoB levels are associated with both small apo(a) isoforms and high Lp(a), which explains the differences in racial groups, which have genetic differences in both apo(a) and Lp(a) levels. The association of OxPL with small apo(a) isoforms, in which a similar relationship is present among all racial subgroups despite differences in Lp(a) levels, may be a key determinant of cardiovascular risk. See p 1711.
Associations of Gestational Weight Gain With Offspring Body Mass Index and Blood Pressure at 21 Years of Age: Evidence From a Birth Cohort Study
Routine measurement of maternal weight during pregnancy is controversial. The practice was abandoned in many countries in the late 1990s because it was found to be a poor indicator of intrauterine growth retardation. However, this position is now being reconsidered as emerging evidence suggests that greater weight gain in pregnancy might indicate those women who are at increased risk of future cardiovascular and metabolic disease and may be a risk factor for future offspring health. In this study, we examined the association of maternal weight gain in pregnancy with offspring body mass index and blood pressure at 21 years of age. We found that greater weight gain during pregnancy was independently associated with greater risk for offspring body mass index and obesity. We also found some evidence that this association with greater body mass index might result in greater offspring systolic blood pressure. This study supports other evidence suggesting that excessive pregnancy weight gain should be avoided for the health of both mother and offspring. Further large studies are required to confirm these findings and to determine what should be considered healthy weight gain for the short- and long-term health of both mother and offspring. Ultimately, trials are required to explore whether routine monitoring of weight gain in pregnancy and provision of advice about healthy weight gain are effective at reducing obesity-related outcomes in mothers and offspring in the long term. See p 1720.
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
Over the past several decades, a marked decline has occurred in mortality from cardiovascular disease. Despite this decline, diabetes mellitus remains a key risk factor for cardiovascular disease and is associated with a 2- to 4-fold higher risk of cardiovascular disease, as well as an increased risk of mortality by up to 3-fold. Declines in mortality rates over time have been observed in people with and without diabetes mellitus. However, a recent analysis of national trends data from the National Health and Nutrition Examination Survey suggested that declines in all-cause mortality have occurred among men with diabetes mellitus but not women. In this study, we assessed time-period trends in all-cause mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, in which diabetes status has been routinely screened for and all deaths have been adjudicated. The analysis included participants who attended examinations during an “earlier” (1950 to 1975) and a “later” (1976 to 2001) time period. Our results showed a decline in all-cause and cardiovascular disease mortality rates among both men and women with and without diabetes mellitus over the period of 1950 to 2005. Additionally, both men and women with diabetes mellitus continue to remain at a higher risk of all-cause and cardiovascular disease mortality than those without diabetes mellitus. In summary, reductions in all-cause mortality among both women and men with diabetes mellitus have occurred over time. See p 1728.
Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion
Metabolic responses to surgical cardioplegic arrest have been incompletely characterized in humans. We applied targeted mass spectrometry-based “metabolomics” analysis to arterial and venous blood samples taken before and after ischemia/reperfusion in patients undergoing cardiac surgery. We observed significant alterations in myocardial fuel substrate uptake at baseline among patients with coronary artery disease and after ischemia/reperfusion among those with preexisting left ventricular dysfunction relative to subjects presenting with neither left ventricular dysfunction nor coronary artery disease. Additionally, net release of acylcarnitine species and lactate by the myocardium after ischemia/reperfusion is suggestive of severe impairment of oxidative metabolism. The ability to maintain oxidative metabolism in the immediate postischemic phase was diverse in the study cohort and associated with improved periprocedural hemodynamics. We conclude that myocardial metabolism is severely altered after surgically induced global ischemia, with the dysfunctional ventricle being particularly susceptible to this insult. Furthermore, metabolic profiling in the perioperative period has the potential to predict the postoperative hemodynamic course, highlight pathways most severely dysregulated by ischemia/reperfusion, and target future cardioprotective strategies. See p 1736.
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
This is the first prospective multicenter study with Doppler stress echocardiography devoted to screening for exercise- and hypoxia-induced pulmonary hypertension in relatives of idiopathic or familial pulmonary arterial hypertension patients and to investigate the threshold of normal pulmonary artery pressures during exercise in a large collective of healthy control subjects. One main finding of this study is that relatives of patients with idiopathic or familial pulmonary arterial hypertension have a significantly higher frequency of a hypertensive tricuspid regurgitation velocity response to exercise and to prolonged hypoxia than control subjects. The highest proportion of subjects with hypertensive tricuspid regurgitation velocity response was found in relatives who shared a BMPR2 mutation with the index patients. The data in this study suggest that a hypertensive pulmonary artery pressure response to exercise and hypoxia is genetically determined with familial clustering. The clinical significance of hypertensive pulmonary artery pressure response to exercise and hypoxia, however, is currently unsettled. It may reflect a normal variation in pulmonary artery pressures without clinical significance, or it may be related to some limitation in exercise capability that is relevant only under stress conditions. However, it may also reflect a genetic trait associated with increased risk for the development of pulmonary hypertension or high-altitude pulmonary edema. Although great effort was necessary to standardize the echocardiographic examination and to obtain high-quality tricuspid regurgitation velocity profiles, the study showed that this screening approach is applicable in clinical settings. Follow-up assessments in relatives of idiopathic or familial pulmonary arterial hypertension patients may provide a basis to decide whether stress echocardiography is an appropriate tool for early diagnosis of pulmonary arterial hypertension. See p 1747.
Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation
Catheter ablation has become an increasingly popular and acceptable treatment option for the atrial fibrillation patient. Nevertheless, many questions remain about preprocedural predictors of ablation failure. Here, we describe a novel delayed-enhancement magnetic resonance imaging-based method to detect and quantify preexistent left atrial structural remodeling in patients undergoing ablation of atrial fibrillation. We found that patients with extensive preablation left atrial enhancement were more likely to suffer atrial fibrillation recurrence after ablation than those with minimal or moderate degrees of enhancement. This noninvasive modality would allow patients to be selectively screened before ablation to determine whether they are appropriate candidates for the procedure. The ability to properly select ablation patients will reduce the unnecessary risks and costs to those patients who stand to benefit little from the procedure. See p 1758.
Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent: Initial Feasibility Study in a Swine Model
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 needed. 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 small-peptide molecular contrast agent that binds reversibly to myocardial collagen. EP-3600 was investigated for myocardial perfusion imaging in a large-animal (swine) model of nonocclusive coronary stenosis. Molecular MR imaging was performed on a clinically used 1.5-T whole-body scanner with a sequence that can be used in humans during daily routine. It could be shown that remote myocardium demonstrates a significant signal increase over the entire examination time (60 minutes), whereas the perfusion defect was visible as a hypointense area for at least 20 minutes after intravenous contrast administration. Thus, EP-3600 enables prolonged, high-contrast, high-spatial-resolution visualization of myocardial perfusion defects in a human-size animal model and may lead to a paradigm shift in clinical cardiac perfusion MR imaging. This new approach could also enable the use of exercise stress outside the MR room instead of currently used drug-induced hyperemia inside the MR gantry. See p 1768.
Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
Clinical trials of vascular endothelial growth factor (VEGF) gene therapy have proven that VEGF has beneficial effects on ischemic heart disease; however, potential problems associated with the prolonged and excessive production of VEGF cannot be ignored. Clinical studies of VEGF protein revealed evidence of a dose-dependent effect (ie, high-dose VEGF protein resulted in a better therapeutic effect). Given the side effects of high-level VEGF in the circulation, an increase in the local VEGF level may represent a reasonable treatment for ischemic heart disease. In the present study, we investigated the angiogenic effect of a fusion protein composed of VEGF and a collagen-binding domain (CBD-VEGF) and its therapeutic effects in a rat acute myocardial infarction model. The results demonstrated that CBD-VEGF induced much more blood vessel formation than native VEGF in collagen membranes implanted subcutaneously. Compared with native VEGF, CBD-VEGF maintained a higher level in extracellular matrix and a lower level in circulation, and it preserved heart function, reduced scar size, and increased capillary vessels after injection into the border zone of acute myocardial infarction in rats. Although the latent side effects and precise role of CBD-VEGF during healing must be investigated further, our results may suggest a novel therapeutic approach for patients with ischemic heart disease. See p 1776.
Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease
Aging societies face a growing burden of vascular and valvular calcification. Half of all individuals with chronic renal disease succumb to cardiovascular complications. Despite its vast clinical significance, the mechanisms of accelerated cardiovascular calcification, particularly in chronic renal disease, remain obscure, and we currently lack therapies to prevent its progression. Recent clinical trials showed no benefit of statin therapy on progression of calcific aortic valve stenosis, a growing clinical challenge without alternatives to costly invasive treatments. Hence, the need to discover new pathways that contribute to cardiovascular calcification and to develop new therapeutic strategies to prevent or reverse calcification has driven our recent research investigations. The present study provides support for the hypothesis that elastin breakdown products produced by cathepsin S, a proteinase regulated by inflammation and overexpressed in diseased arteries and valves, can trigger osteogenesis. These results indicate that antiinflammatory therapies and preservation of elastin integrity might prevent cardiovascular calcification and its complications when introduced early. Therapeutic interventions in calcification-prone patients with chronic renal disease may target inflammation and phosphate balance. New therapeutic options may also include inhibition of elastolytic cathepsins, particularly cathepsin S. Although calcification in atherosclerosis typically occurs in the intima, chronic renal disease calcification primarily involves the media. Therefore, development of high-resolution imaging of calcification in different arterial layers may distinguish the cause of calcification and provide a powerful tool in personalized medicine. More importantly, identification of high-risk patients requires new imaging modalities to detect calcifying atherosclerotic plaques and aortic valve lesions at stages during which the disease remains silent or reversible. See p 1785.
Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
Acute ischemic syndromes are related primarily to rupture of unstable plaques, leading to thrombus formation and occlusive complications. Unstable plaques are typically constituted of the most prominent cell types in atherosclerosis: macrophages and macrophage-derived foam cells. Most of these macrophages are postapoptotic and form a graveyard of dead collapsed cells that might contribute to constitution of the necrotic core. Genetic manipulations of apoptotic genes have been shown to differentially alter atherosclerotic lesion size in murine models of atherosclerosis; however, the potential beneficial or detrimental role of apoptotic macrophage death in plaque development remains controversial. To address this question, we created transgenic mice in which both the lifespan of macrophages was increased in response to elevated resistance to apoptosis (CD68-hBcl2) and targeted induction of lesional macrophage apoptosis (CD11c-DTR) could be achieved. These data provide the first in vivo evidence that macrophage apoptosis is atheroprotective in fatty streak lesions; in contrast, however, defective clearance of apoptotic debris in advanced lesions favors arterial wall inflammation and enhanced recruitment of monocytes, thereby leading to enhanced atherogenesis. Considered together, these findings suggest that attenuating macrophage apoptosis in advanced plaques represents a promising therapeutic strategy. See p 1795.
Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is a disease characterized by chronic inflammation and remodeling of aortic wall tissue. Studies using “end-stage” human AAA tissues procured at surgery have identified a number of candidate molecules; however, these may or may not contribute to the initiation and progression of AAA. To better understand the mechanisms that promote AAA, we turned to an elastase-induced mouse model that recapitulates many features of human AAA. In this model, neutrophils are identified as critical mediators of AAA development. Neutrophil depletion or impaired neutrophil recruitment protects against AAA development; however, the signal that initiates the influx of neutrophils to the aortic wall remains undefined. We hypothesized that complement participates in the development of elastase-induced AAA, possibly by providing the chemotactic signal that recruits neutrophils to the aortic wall. In the present experiments, we showed that complement depletion abrogated AAA development. We also demonstrated that the alternative pathway of the complement system plays a major role in this process by generating the potent anaphylatoxins C3a and C5a, which recruit neutrophils to the aortic wall. Ruptured AAA is the cause of death in 1% to 3% of men over the age of 65 years. Although elective surgical repair is usually definitive, this operation is reserved for large aneurysms. At present, no therapies are available that alter the progressive growth of small aneurysms. The identification of the involvement of the complement system in the pathophysiology of AAA provides a new target for therapeutic intervention in this common disease. See p 1805.
- Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy
- Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
- Info & Metrics