- Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure: Analysis From the Sudden Cardiac Death in Heart Failure Trial
- B-Type Natriuretic Peptides and Cardiovascular Risk: Systematic Review and Meta-Analysis of 40 Prospective Studies
- Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): A Retrospective Analysis
- Prognostic Implications of Myocardial Perfusion Single-Photon Emission Computed Tomography in the Elderly
- Validation of Magnetic Resonance Myocardial Perfusion Imaging With Fractional Flow Reserve for the Detection of Significant Coronary Heart Disease
- High Residual Platelet Reactivity After Clopidogrel Loading and Long-Term Clinical Outcome After Drug-Eluting Stenting for Unprotected Left Main Coronary Disease
- Vascular Endothelial-Specific Dimethylarginine Dimethylaminohydrolase-1–Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine
- Endothelial Progenitor Cells Bind and Inhibit Platelet Function and Thrombus Formation
- Priming With Angiopoietin-1 Augments the Vasculogenic Potential of the Peripheral Blood Stem Cells Mobilized With Granulocyte Colony-Stimulating Factor Through a Novel Tie2/Ets-1 Pathway
- Effect of Increased Exercise in School Children on Physical Fitness and Endothelial Progenitor Cells: A Prospective Randomized Trial
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Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure: Analysis From the Sudden Cardiac Death in Heart Failure Trial
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. This report examined the mode of death in SCD-HeFT. A total of 2521 subjects were randomized to placebo, amiodarone, or shock-only, single-lead implantable cardioverter-defibrillator therapy. Over a median follow-up of 45.5 months, 666 deaths were reviewed by an Events Committee and categorized as sudden death presumed to be ventricular tachyarrhythmic, heart failure related, bradyarrhythmic, nonarrhythmic non–heart failure related, or noncardiac. Implantable cardioverter-defibrillator therapy reduced cardiac and ventricular tachyarrhythmic mortality and had no impact on mortality resulting from heart failure or noncardiac causes compared with placebo. The cardiac and ventricular tachyarrhythmic mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in ventricular tachyarrhythmic mortality with implantable cardioverter-defibrillator therapy was similar in subjects with ischemic and nonischemic disease. Amiodarone compared with placebo had no significant effect on any mode of death, although there was an increase in noncardiac mortality in those with New York Heart Association class III heart failure who were receiving amiodarone. Implantable cardioverter-defibrillator therapy has a beneficial effect on reducing sudden death presumed to be due to ventricular tachyarrhythmias without an effect on heart failure mortality. See p 2170.
B-Type Natriuretic Peptides and Cardiovascular Risk: Systematic Review and Meta-Analysis of 40 Prospective Studies
Measurement of circulating levels of B-type natriuretic peptide (BNP) or its precursor (N-terminal fragment [NT-proBNP]) has been recommended in the diagnosis and prognosis of patients with symptoms of left ventricular dysfunction and for stratification of risk in patients with acute coronary syndromes. However, the relevance of these peptides to subsequent risk of cardiovascular diseases (CVD) other than heart failure remains uncertain. The primary goal of this analysis was to better characterize the association of natriuretic peptides in relation to subsequent risk of CVD using findings from 40 long-term prospective studies involving a total of 87 474 individuals and 10 625 incident CVD outcomes. Overall, there was an almost 3-fold increase in risk of CVD in people in the top third of baseline natriuretic peptide values compared with those in the bottom third, even after adjustment for several conventional risk factors. In studies that were less prone to publication bias, the relative risk for CVD was ≈2-fold. The association was similarly strong in essentially general populations and in people with prevalent CVD, as well as in studies that measured either BNP or NT-proBNP. But, despite the strong associations with CVD risk observed in the present review, assessment of BNP or NT-proBNP in addition to measurement of conventional CVD risk factors yielded modest improvements in risk discrimination for subsequent CVD. Further investigation is warranted to clarify whether measurement of these markers can usefully enhance CVD stratification in general population settings. See p 2177.
Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): A Retrospective Analysis
There is evidence from retrospective analyses and a prospective trial that a high-sensitivity C reactive protein concentration ≥2.0 mg/L identifies patients who benefit from statin treatment independently of low-density lipoprotein cholesterol reduction. To determine whether similar observations are present in patients with ischemic systolic heart failure, we carried out a retrospective analysis of a large statin trial. Although this trial showed no benefit overall of rosuvastatin on the primary end point or all-cause mortality, the present analysis showed that statin treatment was associated with better outcomes than placebo treatment in patients with a high-sensitivity C reactive protein ≥2.0 mg/L than in those with a high-sensitivity C reactive protein <2.0 mg/L, eg, a hazard ratio for death in the former of 0.89 (95% confidence interval, 0.79 to 1.00) and in the latter of 1.17 (95% confidence interval, 0.95 to 1.43; P for interaction=0.026). The possibility that statins might be beneficial in heart failure patients with a high-sensitivity C reactive protein ≥2.0 mg/L needs to be tested prospectively. See p 2188.
Prognostic Implications of Myocardial Perfusion Single-Photon Emission Computed Tomography in the Elderly
We assessed the clinical value of stress myocardial perfusion scintigraphy (MPS) in 5200 elderly patients (≥75 years of age) followed up for 2.8±1.7 years (362 cardiac deaths, 7.0%, 2.6%/y) and in a subset of 684 patients with extended follow-up (6.2±2.9 years; 320 all-cause deaths). The unadjusted cardiac death rate was 1.3%/y after normal MPS but was <1% in patients with normal rest ECG, exercise stress, or age of 75 to 84 years and was 2.3% to 3.7% in patients ≥85 years of age or undergoing pharmacological stress. Importantly, compared with age-matched US population CD rates (75 to 84 years of age, 1.5%; ≥85 years of age, 4.8%), normal MPS cardiac death rates were approximately one-third lower than the baseline risk of US individuals (P<0.05 for both). Survival modeling of cardiac death revealed that MPS data yielded incremental value over pre-MPS data. The addition of gated MPS in a subset of 2472 patients showed that perfusion and ejection fraction data added incrementally to each other and enhanced risk stratification. Modeling of all-cause death in 684 patients with extended follow-up revealed that after risk adjustment, an interaction between early treatment and ischemia was present so that increasing ischemia was associated with increasing survival with early revascularization, whereas in the setting of little or no ischemia, medical therapy had improved outcomes. In an elderly population, stress MPS stratifies cardiac death risk in elderly patients and may identify optimal post-MPS therapy. Postnormal MPS cardiac death rates are low in all subsets in relative terms compared with the age-matched US population. See p 2197.
Validation of Magnetic Resonance Myocardial Perfusion Imaging With Fractional Flow Reserve for the Detection of Significant Coronary Heart Disease
The diagnosis of myocardial ischemia with magnetic resonance myocardial perfusion imaging (MRMPI) has a number of potential advantages over other available noninvasive tests. The majority of previous studies have assessed the clinical utility of MRMPI by comparing it with quantitative coronary angiography, which at intermediate degrees of stenosis has been shown to be a poor indicator of the functional severity of coronary heart disease. The present study in 101 patients with suspected angina is the largest study to assess the accuracy of MRMPI compared with an invasive physiological measurement of the significance of coronary artery disease, namely fractional flow reserve. Fractional flow reserve values of <0.75 have been shown to indicate functionally significant coronary heart disease. Visual analysis of MRMPI scans was compared with fractional flow reserve and quantitative coronary angiography. We have shown that with fractional flow reserve as the gold standard, MRMPI can detect functionally significant coronary heart disease with a sensitivity and specificity of 91% and 94% and positive and negative predictive values of 91% and 94%, respectively. Comparing MRMPI with quantitative coronary angiography led to a reduction in specificity and positive predictive value. We have shown that MRMPI is an excellent test for the diagnosis of significant coronary heart disease compared with the invasive gold standard of fractional flow reserve. It is hoped that our study will promote the use of MRMPI as a radiation-free alternative test for the noninvasive detection of reversible myocardial ischemia. See p 2207.
High Residual Platelet Reactivity After Clopidogrel Loading and Long-Term Clinical Outcome After Drug-Eluting Stenting for Unprotected Left Main Coronary Disease
There is growing evidence that in vitro high residual platelet reactivity after a loading dose of clopidogrel is a strong marker of the risk of stent thrombosis. This study assessed the impact of high residual platelet reactivity after a clopidogrel loading on clinical outcome in 215 patients undergoing drug-eluting stent implantation for unprotected left main disease. The study shows that high residual platelet reactivity is the only independent predictor of stent thrombosis and cardiac death at long-term follow-up, whereas other variables such as left main bifurcation, number of stents, completeness of revascularization, and surgical risk are not related to stent thrombosis and cardiac death. Patients with high residual platelet reactivity had a nearly 4-fold increase in the risk of stent thrombosis and cardiac death compared with patients with low residual platelet reactivity. The cardiac mortality rate in patients with high residual platelet reactivity continues to increase during long-term follow-up, and this finding suggests a persistent increased risk of thrombotic events despite most of these patients receiving a long-term double dose of clopidogrel or shifting to ticlopidine. It is unknown whether high residual platelet reactivity after clopidogrel loading will remain a marker of increased risk of drug-eluting stent thrombosis and more generally of thrombotic events also using new potent antiplatelet agents. Meanwhile, routine assessment of in vitro residual platelet reactivity to a 600-mg loading dose of clopidogrel in patients with unprotected left main disease potentially suitable for drug-eluting stenting should be considered to guide patient care decisions. See p 2214.
Vascular Endothelial-Specific Dimethylarginine Dimethylaminohydrolase-1–Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine
Asymmetrical methylarginines asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine are endogenous NO synthase inhibitors. Recent clinical studies demonstrated that the elevation of ADMA levels is associated with many pathological conditions. Thus, ADMA becomes an independent risk indicator for cardiovascular diseases. Asymmetrical methylarginines are eliminated from the body mainly through degradation by dimethylarginine dimethylaminohydrolase (DDAH). Thus, impaired DDAH activity due to either loss-of-function polymorphisms of the DDAH gene or posttranslational modification of DDAH protein may cause accumulation of asymmetrical methylarginines. In this study, we found that endothelial-specific depletion of DDAH1 in endo-DDAH1−/− mice leads to increases of plasma and tissue ADMA concentration and systemic blood pressure, as well as decrease of acetylcholine-induced NO generation and vasodilation in the isolated vessel rings. These results demonstrated that endothelial DDAH1 plays an important role in metabolizing ADMA and regulating blood pressure and vessel tone. In addition, the endo-DDAH1−/− and the DDAH1flox/flox mouse strains will become useful tools for studies of the NO signaling pathway in various tissues under physiological or pathological conditions. See p 2222.
Endothelial Progenitor Cells Bind and Inhibit Platelet Function and Thrombus Formation
Endothelial progenitor cells (EPCs) represent a promising therapeutic approach for the treatment of cardiovascular diseases. However, comprehensive delineation of the biology of these cells and the manner in which they interact with other blood and vascular cells is critical to fully understand their potential therapeutic properties. Herein, we addressed the interactions between EPCs and platelets and their impact on platelet function and thrombus formation, which may be relevant to the management of atherothrombosis during acute coronary syndromes and after percutaneous coronary interventions. We found that human peripheral blood monocyte–derived EPCs in culture bound platelets via CD62P and inhibited platelet activation, aggregation, and adhesion to collagen in vitro, mainly via upregulation of cyclooxygenase-2 and secretion of prostacyclin. Moreover, in a murine arterial thrombosis model, injection of EPCs led to their incorporation into sites of injury and impaired thrombus formation, leading to an incomplete occlusion. In addition to the well-documented roles of EPCs in angiogenesis and vascular repair, our findings highlight a new biological role for EPCs in regulating platelet function, which may, in turn, limit thrombogenesis while maintaining hemostasis at sites of vascular injury. These antiplatelet properties may ultimately lead to the development of novel EPC-derived antithrombotic therapies. See p 2230.
Priming With Angiopoietin-1 Augments the Vasculogenic Potential of the Peripheral Blood Stem Cells Mobilized With Granulocyte Colony-Stimulating Factor Through a Novel Tie2/Ets-1 Pathway
Although intracoronary cell infusion is the most popular method of cell delivery for cardiovascular disease because of its convenience, its efficacy is limited by the poor engraftment rate to ischemic myocardium after intracoronary delivery. We found that peripheral blood stem cells mobilized with granulocyte colony-stimulating factor (mobPBSCs) expressed high levels of the Tie2 receptor compared with naïve peripheral blood mononuclear cells, suggesting that angiopoietin-1 could be a very specific priming agent for mobPBSCs. Primed cells with angiopoietin-1 increased the expression of adhesion molecules and commitment to endothelial lineage, leading to improved engraftment and vasculogenesis. These results imply that priming with angiopoietin-1 can significantly improve the therapeutic efficacy of stem cells. The approach outlined here in which angiopoietin-1 is used for priming cells ex vivo before infusion requires further clinical studies to demonstrate efficacy. See p 2240.
Effect of Increased Exercise in School Children on Physical Fitness and Endothelial Progenitor Cells: A Prospective Randomized Trial
Childhood obesity is the result of a long-lasting imbalance between energy intake and energy expenditure. The decline of physical activity over the last decades is thought to be one of the main risk factors for the development of overweight and obesity and its comorbidities. Therefore, intervention strategies to treat and prevent childhood obesity are necessary. Physical exercise is one of the cornerstones of obesity prevention, and its preventive value has been proven over the last decades. An attractive setting to start and implement such an exercise program is in school, which is independent of environmental and parental influences. The aim of this prospective randomized trial was to compare sixth-grade students with daily school exercise lessons with a control group with 2 exercise lessons per week with respect to physical fitness, motor skills, body composition, and circulating endothelial progenitor cells as a surrogate parameter for cardiovascular risk/function and tissue repair capabilities. The central message emerging from this study is that some of the harmful trends associated with childhood obesity and sedentary behavior may be reversed by increasing the level of physical activity. In addition, daily exercise leads to an increase of circulating endothelial progenitor cells without improvement of their migratory function. Furthermore, the results demonstrate that implementation of daily exercise lessons into the school curriculum is feasible, well tolerated, and accepted. See p 2251.
- Endothelial Progenitor Cells Bind and Inhibit Platelet Function and Thrombus Formation
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