Circulation. 2008;117:1247
doi: 10.1161/CIRCULATIONAHA.107.189181
doi: 10.1161/CIRCULATIONAHA.107.189181
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(Circulation. 2008;117:1247.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Metabolic Syndrome and Risk of Development of Atrial Fibrillation: The Niigata Preventive Medicine Study |
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Metabolic Syndrome and Risk...
Cost-Effectiveness of Providing...The metabolic syndrome and atrial fibrillation (AF) are common disorders, and the prevalence of both disorders is currently increasing with a growing elderly population and changing lifestyle. Because many of the components of the metabolic syndrome also are risk factors for the development of AF, an association between the metabolic syndrome and AF has been proposed. Furthermore, inflammation and oxidative stress have been implicated in the pathogenesis of both the metabolic syndrome and AF. Therefore, we studied the association between the metabolic syndrome and new-onset AF in the general population. In the present study, subjects meeting the criteria for the metabolic syndrome were at increased risk of development of AF. Among the components of the metabolic syndrome, obesity, elevated blood pressure, impaired glucose tolerance, and reduced high-density lipoprotein cholesterol, but not elevated triglycerides, were associated with AF. The risk of developing AF increased across a number of the fulfilled metabolic syndrome components. Our data suggest that the metabolic syndrome increases not only the risk of atherosclerotic diseases but also the risk of AF. It is likely that an interaction between the metabolic syndrome and deranged biochemical indexes activates signaling pathways important in the pathogenesis of AF. Modulation of the pathways may be of therapeutic value for preventing AF. See p 1255.
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Cost-Effectiveness of Providing Full Drug Coverage to Increase Medication Adherence in Post–Myocardial Infarction Medicare Beneficiaries |
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Effective therapies for the secondary prevention of coronary heart disease–related events are significantly underused, and attempts to improve adherence have often yielded disappointing results. Elimination of patient out-of-pocket costs may be an effective strategy to enhance medication use. We created a Markov cost-effectiveness model to estimate the incremental cost-effectiveness of providing Medicare beneficiaries with full coverage for combination pharmacotherapy compared with current coverage under the Medicare Part D program. We found that compared with current prescription drug coverage, full coverage for post–myocardial infarction secondary preventive therapies would result in greater functional life expectancy (0.35 quality-adjusted life-year) and less resource use ($2500). The elimination of patient cost sharing for medications commonly prescribed to post–myocardial infarction patients would therefore both improve health and save money from the societal perspective. The magnitude of observed changes in health outcomes is large and substantially greater than that observed for other interventions widely used to improve post–myocardial infarction outcomes. From the standpoint of Medicare, full drug coverage was highly cost-effective ($7182/quality-adjusted life-year) but not cost saving. Our results strongly support the hypothesis that post–myocardial infarction Medicare beneficiaries should receive statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and β-blockers without cost sharing and emphasize the urgent need for prospective clinical studies to confirm the effectiveness of this approach. See p 1261.
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Biglycan Is Required for Adaptive Remodeling After Myocardial Infarction |
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Known mechanisms leading to heart failure after myocardial infarction include subsequent cardiac dilatation and infarct thinning, also called infarct expansion, which may lead to the development of aneurysm and left ventricle rupture. Therefore, adaptive changes in cardiac remodeling are essential so that the ventricle forms a stable scar rather than rupturing after myocardial infarction. Collagenous networks elaborated by cardiac fibroblasts provide the mechanical support for the scar tissue. It seems important to consider that the stability and 3-dimensional arrangement of cardiac collagen matrixes are controlled by accessory molecules such as biglycan. Biglycan is a proteoglycan that binds to the d bands of collagen type 1 fibrils and controls fibrillogenesis and proteolysis of collagen by matrix metalloproteinases. The present study reveals that after myocardial infarction, the scar tissue of biglycan-deficient mice was characterized by perturbed collagen fibril arrangement and that ventricular ruptures occur more frequently compared with wild-type mice. Furthermore, the surviving biglycan-deficient mice showed impaired hemodynamic function with subsequent cardiac dilatation, suggesting that in the absence of biglycan, adverse ventricular remodeling is aggravated. Therefore, biglycan appears to play a critical role in the formation of stable infarct scars and the preservation of hemodynamic function after myocardial infarction. Because biglycan accumulates in the scar tissue of human ischemic infarctions, it is possible that the present findings extend to human postinfarct remodeling. In the future, it will be of interest to determine whether differences in cardiac biglycan expression may be modulated by pharmacological treatment and whether this may change clinical outcome. See p 1269.
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Catecholamines Regulate the Activity, Secretion, and Synthesis of Renalase |
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The present work describes the renalase system, a previously unrecognized mechanism for regulating catecholamines, cardiac function, and blood pressure. In this pathway, the kidney secretes prorenalase into the blood and is primarily responsible for maintaining steady levels of the enzyme. Although prorenalase has no detectable amine oxidase active in the basal state, it is rapidly converted to renalase by increased catecholamines and systolic blood pressure. Renalase in turn degrades catecholamines and decreases blood pressure. Excess catecholamines not only regulate the activation of prorenalase but also promote its secretion and synthesis. Not surprisingly, abnormalities in the renalase pathway occur in chronic kidney disease and end-stage renal disease, as evidenced by decreased plasma levels in humans and in rats subjected to subtotal nephrectomy. Unexpectedly, however, renalase deficiency was documented not only in kidney tissue but also in the heart of rats with chronic kidney disease. Assuming that a similar reduction in cardiac renalase occurs in patients with chronic kidney disease and end-stage renal disease, we speculate that it could account for the increased risk of ischemic and arrhythmic events described in this population. It also has been reported that renalase deficiency occurs early in the development of salt-dependent hypertension before significant renal damage has occurred. Collectively, these data suggest that renalase deficiency contributes importantly to the development and maintenance of hypertension and is associated with an increased risk for cardiovascular events. Therefore, renalase replacement therapy may modify cardiovascular risks. See p 1277.
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Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden: Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy |
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Considerable controversy was generated by the main results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, in which no difference in long-term outcome was reported for stable patients with coronary disease randomized to an initial strategy of percutaneous coronary intervention (PCI) plus optimal medical therapy versus optimal medical therapy alone. The COURAGE nuclear substudy published in this issue of Circulation was designed a priori to evaluate the near-term effectiveness of treatment on ischemia as measured quantitatively by myocardial perfusion imaging. The greater relative effectiveness of PCI to reduce ischemia in patients with moderate to severe baseline ischemia is consistent with the observation that patients randomized to early PCI had better initial relief from angina. The findings support the efficacy of PCI to reduce ischemia and improve symptoms and set the stage for a future randomized clinical trial using quantitative measures of ischemia. The message from the COURAGE trial remains that PCI may be safely deferred in stable patients but may be refined such that patients with substantial residual ischemia on optimal medical therapy should be considered for crossover PCI. These conclusions from the COURAGE nuclear substudy should be greeted with cautious enthusiasm because of its nonrandomized nature and small sample size. See p 1283.
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CD137 Is Expressed in Human Atherosclerosis and Promotes Development of Plaque Inflammation in Hypercholesterolemic Mice |
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Recruitment and activation of inflammatory cells in the vascular wall are key events in the development of atherosclerosis. Intensified inflammation is associated with clinical events such as myocardial infarction. We identified CD137, a T-cell costimulatory molecule, in human atherosclerotic lesions and found that its expression correlated with the local levels of several agents associated with plaque destabilization such as adhesion molecules, proinflammatory cytokines, and matrix metalloproteinases. Activation of CD137 reduced proliferation of cultured smooth muscle cells and increased surface levels of adhesion molecules in endothelial cells. In a murine model of atherosclerosis, treatment with agonistic CD137 antibodies caused significantly increased CD8+ T-cell infiltration and increased levels of murine major histocompatibility complex class II proteins in atherosclerotic lesions, as well as increased vascular levels of proinflammatory cytokines and intercellular adhesion molecule-1. Taken together, these observations suggest that CD137 activation in the vasculature may contribute to the progression and increased vulnerability of atherosclerotic lesions via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype. See p 1292.
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Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II–Induced Abdominal Aortic Aneurysm Formation |
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Abdominal aortic aneurysm is an inflammatory disorder characterized by localized connective tissue degradation and smooth muscle cell apoptosis, leading to aortic dilatation and rupture. Abdominal aortic aneurysm represents a major cause of morbidity and mortality in humans. Many cases are undiagnosed until they declare clinically by leakage or rupture. Nonsurgical treatments that retard aneurysm development or induce its regression remain to be identified. Human aortic aneurysm biopsies stain strongly for cyclooxygenase-2 ex vivo, and some earlier studies provided evidence for the potential efficacy of nonsteroidal antiinflammatory drugs, particularly those selective for inhibition of cyclooxygenase-2. However, cyclooxygenase-2–selective inhibitors themselves increase the risk of myocardial infarction, heart failure, and stroke. In the present study, we explored the potential utility of targeting microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1), an antiinflammatory drug target downstream of cyclooxygenase-2 and a major source of PGE2. We have shown previously that mPGES-1 retards atherogenesis; here gene deletion retarded formation of abdominal aortic aneurysm induced by an angiotensin II infusion in mice lacking low-density lipoprotein receptor. This occurred concomitant with suppression of aortic and systemic indices of oxidative stress, previously implicated in the pathogenesis of abdominal aortic aneurysm. Deletion of mPGES-1 inhibited production of PGE2 but also resulted in substrate rediversion to augment production of PGI2 and PGD2, both of which upregulate antioxidant enzymes and restrain oxidant stress. This study raises the possibility that inhibition of mPGES-1 might have therapeutic potential in this potentially fatal disease. See p 1302.
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Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase- Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes
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The role of inflammation in all stages of atherosclerotic cardiovascular disease has become an active area of investigation. Various inflammatory cells and immune mediators participate in processes that begin with fatty streak development and culminate in cardiac infarctions when the plaque is disrupted. The generation of mice that lack phosphoinositide-3 kinase-
(PI3K) showed an involvement of this kinase in a wide variety of signaling pathways triggered by the G-protein–coupled receptor. Interestingly, most PI3K functions are related to reactions to inflammation, because a major role of PI3K is to recruit inflammatory cells by acting downstream of the chemokine receptor. Specific PI3K inhibitors have been developed and have shown immunomodulatory properties, which makes PI3K a good candidate for drug design for use in autoimmune diseases. Using this pharmacological PI3K inhibitor and a hematopoietic PI3K-deficient mouse model of atherosclerosis, we demonstrated that PI3K inhibition could alleviate the development of atherosclerotic lesions by modulating inflammatory process. Our results identify PI3K as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment. Our results, as well as other data concerning the involvement of PI3K in cardiac pathologies, provide convincing arguments to advocate the development of PI3K inhibitor in cardioprotective therapy. See p 1310.
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