Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Physical and Sexual Abuse in Childhood as Predictors of Early-Onset Cardiovascular Events in Women
- Physical Activity and Inflammatory Markers Over 10 Years : Follow-Up in Men and Women From the Whitehall II Cohort Study
- Impact of Sex on Cardiovascular Outcome in Patients at High Cardiovascular Risk : Analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET)
- Pathological Cardiac Hypertrophy Alters Intracellular Targeting of Phosphodiesterase Type 5 From Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling
- Toll-Like Receptor 7 Protects From Atherosclerosis by Constraining “Inflammatory” Macrophage Activation
- Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension
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Physical and Sexual Abuse in Childhood as Predictors of Early-Onset Cardiovascular Events in Women
Women with a history of severe sexual abuse in childhood are at increased risk for cardiovascular disease as adults. Severe physical abuse may also increase risk of future cardiovascular disease. More than 10% of women have a history of severe physical or sexual abuse as girls. A large proportion of the cardiovascular disease risk associated with child abuse is explained by adverse lifestyle and medical risk factors for cardiovascular disease in adulthood among women abused as children. This suggests that targeted prevention and treatment of risk factors would reduce the incidence of cardiovascular disease in this high-risk population. Future research should examine whether specialized therapies can be developed to help girls and women with a history of child abuse reduce their cardiovascular risk. See p 920.
Physical Activity and Inflammatory Markers Over 10 Years : Follow-Up in Men and Women From the Whitehall II Cohort Study
The anti-inflammatory effects of exercise are thought to be mechanisms that explain the well-documented cardioprotective effects of physical activity. Although there are abundant cross-sectional data relating C-reactive protein and interleukin-6 levels to physical activity, longitudinal data are sparse, and this is a crucial issue for understanding the complex relationships between exercise, weight loss, and inflammation. The present study, which tracked physical activity and inflammatory markers over 10 years of follow-up in an aging cohort of 4289 men and women, showed that habitually active participants have persistently lower levels of inflammatory markers. In addition, an increase in 2.5 h/wk of moderate to vigorous physical activity through follow-up was associated with lower levels of interleukin-6. The associations observed between physical activity and inflammatory markers were independent of adiposity and changes in body composition. Given that inflammatory markers gradually rise with increasing age and that this proinflammatory status underlies biological mechanisms responsible for cardiovascular disease, physical activity may be regarded as an important factor for the prevention of age-related disease risk. See p 928.
Impact of Sex on Cardiovascular Outcome in Patients at High Cardiovascular Risk : Analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET)
Although uncontrolled epidemiological analyses suggest that sex independently contributes to cardiovascular risk, there are limited controlled large-scale clinical studies on sex-specific cardiovascular outcome. Moreover, clinical trials are often hampered by the enrollment of few female patients. In our analyses based on the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) with patients ≥55 years of age, we included a large proportion of female patients (29.7%). In these large interventional trials, we observed that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus. This ≈20% lower risk for combined cardiovascular events in female patients, who were under optimal, guideline-recommended pharmacological treatment, is driven mainly by a significantly lower incidence of acute myocardial infarction. However, it should be pointed out that diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women. Sex- and age-dependent analyses demonstrate that female patients develop cardiovascular end points ≈5 to 10 years later despite appropriately individualized cardioprotective therapy in both female and male patients. In these controlled cardiovascular end-point trials, we clearly point out significant sex-related differences, with women being at lower net cardiovascular risk than men except when diabetic. These differences should be acknowledged in daily clinical routine when female and male patients at high cardiovascular risk are treated. See p 934.
Pathological Cardiac Hypertrophy Alters Intracellular Targeting of Phosphodiesterase Type 5 From Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling
Phosphodiesterase type 5 (PDE5) hydrolyzes cGMP, and its inhibition is widely used to treat erectile dysfunction and pulmonary hypertension. Recent studies have expanded its role to the cardiomyocyte because PDE5 inhibitors also suppress remodeling and improve function in heart diseases such as hypertrophy, infarction, and dilated heart failure. These preclinical data have spawned clinical trials in heart failure. In the normal myocyte, PDE5 degrades cGMP generated by nitric oxide–stimulated soluble guanylate cyclase but has virtually no impact on natriuretic peptide (NP)–derived cGMP. Yet in heart failure, cGMP from nitric oxide signaling declines whereas NP-generated cGMP rises. This poses a paradox for the inhibitor studies because, if normal PDE5 cGMP-targeting persisted in heart failure, its impact and efficacy of inhibitors should both decline. Here, we reveal an explanation, showing in the hypertrophied/dilated heart that PDE5 is retargeted to degrade NP-cGMP. Even in mice in which nitric oxide synthase 3 is genetically deleted to remove the normal source of PDE5-targeted cGMP, upregulated myocyte PDE5 still worsened hypertrophy and left ventricular dilation/dysfunction to pressure-overload coupled to increased NP-cGMP hydrolysis. This was associated with physical displacement of PDE5 from its normal sarcomere localization to a diffuse cytosolic distribution. Enhanced myocyte PDE5 expression also stimulated reactive oxygen species. However, this was not required for its pathological effects because reactive oxygen species was greatly reduced in mice with codeletion of nitric oxide synthase 3 despite similar adverse remodeling to pressure overload. PDE5 retargeting likely contributes to cardiac NP desensitization and suggests a combined benefit from PDE5 inhibition and NP stimulation in cardiac disease. See p 942.
Toll-Like Receptor 7 Protects From Atherosclerosis by Constraining “Inflammatory” Macrophage Activation
Atherosclerosis underlying cardiovascular mortality is the leading cause of death in developed countries. Efforts are therefore concentrating on unwinding the pathophysiological mechanisms controlling its development and clinical complications. Among them, Toll-like receptors (TLRs) have taken center stage in atherosclerosis research by virtue of their ability to sense danger in response to hypercholesterolemia, tissue stress, or necrosis, and drive macrophage activation and inflammation in the vessel wall. TLR2 and TLR4, in particular, have been shown to play a critical role in promoting plaque development and vulnerability leading to the view that all TLRs are pathogenic for this disease. This article now reports the surprising finding that TLR7, an endosomal TLR that recognizes viral single-stranded RNA and self-RNA released from necrotic cells, is protective. In experimental atherosclerosis in mice, TLR7 prevented lesion development, stenosis, and plaque vulnerability by constraining monocyte chemoattractant protein-1 production, Ly6Chi “inflammatory” monocyte expansion and M1 inflammatory macrophage accumulation to developing atherosclerotic lesions. In human carotid endarterectomy specimens, TLR7 was positively associated with an M2 anti-inflammatory macrophage signature and collagen genes and inversely related/unrelated to proinflammatory mediators and platelet markers, whereas TLR7 activation in human atheroma cultures selectively suppressed the production of monocyte chemoattractant protein-1. Altogether, these findings reveal that TLR7 is part of a protective response that limits atherosclerotic plaque development and vulnerability and challenge the prevailing concept that all TLRs are pathogenic. They also provide new insight about the complex interplay of innate immunity in atherosclerosis and support the exploitation of the TLR7 pathway for therapy. See p 952.
Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension
Despite recent advances in diagnosis and treatment, pulmonary arterial hypertension (PAH) remains a devastating disease that is associated with a 10% mortality rate within the first year of diagnosis. Currently available pharmacotherapies based on known biological mediators of the disease are limited and, in certain cases, have waning long-term efficacy. In this study, we identify aldosterone as a novel contributor to the pathobiology of PAH and demonstrate that mineralocorticoid receptor antagonism is efficacious in the prevention and reversal of experimental PAH. We describe a novel mechanism for the increase in pulmonary aldosterone levels whereby elevated levels of endothelin-1, which have been observed in PAH, function as a potent stimulator of adrenal and extra-adrenal aldosterone synthesis to modulate pulmonary vascular dysfunction. Our findings demonstrate that aldosterone-induced oxidant stress impairs endothelin-B receptor signal transduction to diminish endothelin-B–dependent nitric oxide synthesis in pulmonary artery endothelial cells in vitro and promote negative remodeling of pulmonary arterioles and pulmonary vascular dysfunction in 2 experimental rat models of PAH in vivo. Importantly, mineralocorticoid receptor antagonism with spironolactone or eplerenone prevented or reversed the adverse effects of hyperaldosteronism on pulmonary vascular remodeling and improved pulmonary vascular resistance, pulmonary artery pressure, and remodeling of the right ventricle. Moreover, our findings relating to the potential benefit of spironolactone or eplerenone in attenuating pulmonary vascular dysfunction in PAH may support future clinical trials and/or repurposing of mineralocorticoid receptor antagonists, which are already an accepted medical therapy in patients with certain cardiovascular diseases, to those patients with PAH and other pulmonary vascular diseases with similar pathobiology. See p 963.
- © 2012 American Heart Association, Inc.
- Physical and Sexual Abuse in Childhood as Predictors of Early-Onset Cardiovascular Events in Women
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