Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in Men : The Aerobics Center Longitudinal Study
- Prevalence and Significance of Alterations in Cardiac Structure and Function in Patients With Heart Failure and a Preserved Ejection Fraction
- Mild Retinopathy Is a Risk Factor for Cardiovascular Mortality in Japanese With and Without Hypertension : The Ibaraki Prefectural Health Study
- Benefit of Transferring ST-Segment–Elevation Myocardial Infarction Patients for Percutaneous Coronary Intervention Compared With Administration of Onsite Fibrinolytic Declines as Delays Increase
- m-Calpain Induction in Vascular Endothelial Cells on Human and Mouse Atheromas and Its Roles in VE-Cadherin Disorganization and Atherosclerosis
- A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension
- Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy
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Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in Men : The Aerobics Center Longitudinal Study
If overweight or obese persons, who comprise two thirds of the US population, can reduce the risk of premature mortality by improving physical activity or fitness, this carries a large clinical and public health implication. Studies of cardiorespiratory fitness (hereafter fitness) change and mortality are sparse, and long-term effects of body mass index (BMI) change on mortality are inconsistent. Also, the combined associations of changes in fitness and BMI with mortality remain controversial and uncertain. This study found that maintaining or improving fitness was associated with a lower risk of death from both all-causes and cardiovascular disease in 14 345 men during 11.4 years of follow-up, after accounting for possible confounding effects of baseline risk factors, changes in lifestyle factors and medical conditions, and simultaneous BMI change. Men who lost fitness also had a higher mortality risk regardless of BMI change in our combined analyses. Given the great difficulties of losing weight and maintaining a reduced weight over the long term, this study underscores the benefits of maintaining and improving fitness to reduce mortality risk independent of weight change, and is important for the development of health recommendations and policies. To date, extensive attention has been given to weight loss. However, the long-term effect of fitness change, primarily resulting from increasing physical activity, is likely to be at least as important as weight loss for reducing premature mortality. Increased attention needs to be placed on strategies to maintain or improve fitness. See p 2483.
Prevalence and Significance of Alterations in Cardiac Structure and Function in Patients With Heart Failure and a Preserved Ejection Fraction
The purpose of this study was to examine the prevalence and pattern of structural remodeling and alterations in function present in patients with heart failure and a preserved ejection fraction (HFPEF) and to determine whether there was an association among changes in cardiac structure, function, morbidity, and mortality. An echocardiographic substudy of the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-PRESERVE) enrolled 745 patients. Structural remodeling and diastolic dysfunction was present in the majority of patients with HFPEF. Structural remodeling and diastolic dysfunction predicted clinical outcomes. Increased left ventricular mass, mass/volume ratio, and left atrial size were independently associated with an increased risk of morbidity and mortality. These findings may be pivotal to the development of improved diagnostic criteria and prognostic assessment of patients with HFPEF. For example, the inclusion of measurements of left ventricular mass, geometry, and diastolic function could be added to the diagnostic criteria for HFPEF and could be used to predict the risk of morbidity and mortality in patients with HFPEF. With these data, studies could be developed to test the hypothesis that the reversal of the changes in left ventricular structure and function would result in reduced morbidity and mortality in patients with HFPEF. Taken together, these findings serve to enhance our understanding of the pathophysiology underlying clinical heart failure in these patients with HFPEF. See p 2491.
Mild Retinopathy Is a Risk Factor for Cardiovascular Mortality in Japanese With and Without Hypertension : The Ibaraki Prefectural Health Study
Previous studies have suggested that moderate and severe hypertensive retinopathy is associated with an increased risk of cardiovascular disease. The present study extends the evidence of an association between mild retinopathy and cardiovascular risk among populations with and without hypertension. We show an association between grade 1 or 2 retinopathy graded by the Keith-Wagener-Barker classification and increased risk of death resulting from cardiovascular disease in the general population. The present findings suggest that mild retinopathy can be an independent predictor for cardiovascular disease even in a normotensive population. See p 2502.
Benefit of Transferring ST-Segment–Elevation Myocardial Infarction Patients for Percutaneous Coronary Intervention Compared With Administration of Onsite Fibrinolytic Declines as Delays Increase
The 2 major reperfusion strategies for ST-segment–elevation myocardial infarction are primary percutaneous coronary intervention (PCI) and fibrinolytic therapy (FT). Because not all hospitals perform primary on a full-time basis, patients with ST-segment–elevation myocardial infarction presenting to hospitals without primary PCI capability are often transferred for primary PCI (X-PCI) and do not receive onsite fibrinolytic therapy (O-FT). Although randomized trials support X-PCI over O-FT, these trials inform the clinician only about the comparative efficacy of the 2 strategies for the small group of ST-segment–elevation myocardial infarction patients who can be transferred rapidly with short treatment times. In the United States, the majority of patients who are transferred for PCI do not receive it in a timely fashion. This analysis evaluates the time-dependent loss of X-PCI benefit compared with O-FT and finds that the survival benefit of X-PCI over O-FT is lost after ≈120 minutes of PCI-related delay. Almost half of the patients transferred for PCI exceeded this threshold. The clinician should consider a patient's risk for ischemic complications, bleeding, and stroke and PCI-related delay when selecting X-PCI or O-FT for patients with ST-segment–elevation myocardial infarction presenting to hospitals without primary PCI capability. See p 2512.
m-Calpain Induction in Vascular Endothelial Cells on Human and Mouse Atheromas and Its Roles in VE-Cadherin Disorganization and Atherosclerosis
One of the earliest pathological features of atherosclerosis is barrier dysfunction in vascular endothelial cells, which triggers the infiltration of monocytes/macrophages or plasma active constituents into subendothelial space, allowing further increase in the atherosclerosis susceptibility in the large artery. Although VE-cadherin–mediated adherence junctions, a dominant determinant of endothelial cell barrier functions, are known to decay in the early phase of atherosclerosis, the molecular mechanism underlying this disorder remains unknown. Here, we show that m-calpain, an intracellular cysteine protease, is induced in vascular endothelial cells in murine and human atherosclerotic aortas. Furthermore, this study provides direct evidence that m-calpain proteolytically cleaves VE-cadherin at its juxtamembrane regions, leading to endothelial cell barrier dysfunction. Importantly, atherosclerosis in mouse models is ameliorable by calpain inhibition trials. Thus, m-calpain can be regarded as a unique molecular target for controlling atherosclerosis. Subtype-selective m-calpain inhibitor may be highly desirable to achieve a better therapeutic outcome. See p 2522.
A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) remains a devastating disease with an unacceptably high mortality. Although initial therapies focused on the regulators of pulmonary vascular tone, few patients have a clinical response to acute pulmonary vasodilators, and chronic therapy rarely modifies pulmonary vascular resistance due to the structural alterations in the pulmonary vasculature. Pulmonary vascular remodeling results from dysregulated endothelial and smooth muscle cell function and phenotype. Altered rates of proliferation and apoptosis result in increased pulmonary arterial smooth muscle cell (PASMC) proliferation/hypertrophy and contribute to remodeling in animal models and clinical samples. Parallels between these phenotypic alterations and the changes characteristic of a neoplastic process have been increasingly recognized. Identification of novel molecular determinants of pathological remodeling is critical for the development of new pharmacological targets. Here, we provide the first demonstration that the apoptosis repressor with caspase recruitment domain (ARC), an intracellular inhibitor of apoptosis that is upregulated in several human cancers, is also selectively upregulated in the pulmonary arterial circulation in both rodent models of pulmonary arterial hypertension (PAH) and in patients with idiopathic PAH. Loss of function studies, both in vivo and in isolated cells, demonstrate that ARC is a critical determinant of pathological vascular remodeling contributing to altered smooth muscle cell proliferation and apoptosis during disease development. Further, we provide evidence that ARC is obligatory for hypoxia-induced alterations of select potassium channels critical for alterations of pulmonary vascular tone and smooth muscle cell phenotypic changes. Thus, ARC represents a novel determinant of pathological vascular remodeling obligatory for multiple molecular and cell biological derangements critical for pathological remodeling in PAH. See p 2533.
Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy
In pregnancy, disarray of highly coordinated hemostatic processes at the maternal-fetal interface may lead to fetal growth restriction, preeclampsia, placental abruption, and/or fetal death. Although the link between inherited thrombophilia and these adverse pregnancy outcomes remains controversial, heparin, a recognized modulator of angiogenesis, is commonly used as prophylaxis for maternal thrombosis and as therapy for antiphospholipid antibody syndrome to prevent these complications. Herein, we investigated whether heparin altered the maternal circulatory profile of pro- and antiangiogenic factors (VEGF, PlGF, sFlt-1, and soluble endoglin) in women who received anticoagulation during pregnancy. We found that heparin upregulated maternal circulating sFlt-1 levels in the absence of preeclampsia, fetal growth restriction, or abruption. Our in vitro data showed that placental apoptosis, necrosis, increased transcription, or alterations in protein secretion could not explain these results. Western blotting discerned that heparin induced shedding of the N-terminus of Flt-1 receptor. Using an angiogenesis assay, it was noted that serum of heparin-treated patients inhibited VEGF-induced capillary-like tube formation. These findings imply that, in the setting of heparin treatment, increased sFlt-1 immunoreactivity concurs with enhanced antiangiogenic potential. This study provides new insights into the mechanism responsible for the rise in circulating sFlt-1 associated with heparin treatment that may lead to improved therapeutic strategies aimed to prevent adverse pregnancy outcomes. See p 2543.
- © 2011 American Heart Association, Inc.
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