Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis
- Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function
- Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries: The RE-LY Atrial Fibrillation Registry
- Antiplatelet Therapy for Stable Coronary Artery Disease in Atrial Fibrillation Patients Taking an Oral Anticoagulant: A Nationwide Cohort Study
- Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension
- Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets
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Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis
Cholesterol that accumulates in arterial plaque foam cells has previously been assumed to be mainly in macrophages derived from monocytes that migrate into the plaque following endothelial injury. Smooth muscle cells (SMCs) also migrate into arterial intima in the preatherosclerotic stage and during plaque development, and also become foam cells, but the contribution of SMCs to foam cell formation in comparison with monocytes has never been quantified. Using human hearts explanted at the time of transplantation, we found that >50% of the foam cells in human coronary arteries are derived from SMCs rather than monocyte/macrophages and that these SMCs have a selective loss of the cholesterol exporter ATP-binding cassette transporter A1 as lesions advance that is not seen in the monocyte-type cells. This provides a possible explanation for the overaccumulation of cholesterol in these SMC foam cells and in the plaque. We also found that the SMCs in the intima start to express a commonly used marker of macrophage cells, meaning they may be confused for monocyte-derived macrophages in the plaque. Overall, this research shifts our thinking about which cells accumulate cholesterol in the plaque more toward SMCs, and opens up a new direction for research to understand why this occurs in SMCs, and how to prevent it to reduce ischemic vascular events. See p 1551.
Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function
A robust body of evidence indicates that markers of cardiovascular health are critical modifiable risk factors for cognitive impairment and dementia. The association between midlife cardiovascular risk factors (CVRFs) and late-life cognitive function is well characterized, but the role of young adult CVRFs in cognitive aging is unclear. Furthermore, few studies have considered the cumulative nature of CVRF exposures. In this large, prospective cohort of >3000 black and white young adults, cumulative exposure to CVRFs over 25 years, including systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol, were associated with worse midlife executive function, processing speed, and verbal memory. These associations were notably significant for cumulative exposure to elevated but subclinical levels of CVRFs. To the best of our knowledge, this is the first study to demonstrate a relationship between cumulative CVRF exposure in early adulthood and cognitive impairment in middle age. Although changes in treatment guidelines for CVRFs may not be warranted at this stage, the findings suggest that young adults with elevated CVRFs may be a promising target group for early intervention. This study provides a novel perspective on the relationship between cardiovascular health and cognitive aging, with implications for future research and policies related to the role of primary prevention across the life course. See p 1560.
Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries: The RE-LY Atrial Fibrillation Registry
Atrial fibrillation (AF) is the most common cardiac arrhythmia; it is a leading cause of stroke and is associated with increased mortality. AF is associated with advancing age and underlying cardiovascular disease; however, our current understanding of AF is largely based on data from North America and Europe. The purpose of this prospective registry was to evaluate regional differences in the risk factors and management of patients with AF. We enrolled 15 400 patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America. The most common AF risk factor was hypertension, ranging from 41.6% in India to 80.7% in Eastern Europe. Rheumatic heart disease was present in only 2.2% of North American patients, but it was present in 21.5% in Africa and in 31.5% in India. The use of oral anticoagulation among patients with a CHADS2 score of ≥2 was greatest in North America (65.7%), but oral anticoagulation was used in only 11.2% patients in China. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but <40% in India, China, Southeast Asia, and Africa. In conclusion, there is a large global variation in age, risk factors, concomitant diseases, and treatment of AF. We believe that the improvement of outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings. See p 1568.
Antiplatelet Therapy for Stable Coronary Artery Disease in Atrial Fibrillation Patients Taking an Oral Anticoagulant: A Nationwide Cohort Study
In an era of increased complexity concerning the management of patients with multiple indications for antithrombotic therapy, knowledge of the effectiveness and safety of combinational therapies is crucial for providing optimal care. Current recommendations for atrial fibrillation patients with stable coronary disease are supported by weak evidence; thus, the present study explored the effectiveness of and safety related to frequently used combinations of vitamin K antagonist and antiplatelet therapy in a real-life setting. We found no additional benefit of adding an antiplatelet agent (either aspirin, clopidogrel, or both) to a vitamin K antagonist in atrial fibrillation patients 12 months after myocardial infarction/coronary intervention with regard to cardiovascular ischemic events, whereas the risk of bleeding was increased. Together with former trials that showed coronary protection with a vitamin K antagonist and limited evidence of additional protection with prolonged aspirin use after the acute event of a myocardial infarction, the present data suggest that monotherapy with a vitamin K antagonist is a valid consideration for atrial fibrillation patients with stable coronary artery disease. With limited data from randomized trials, our findings provide novel insights regarding safety concerns in particular but also the effectiveness of antithrombotic therapy strategies in real-world patients that, it is hoped, will aid physicians in clinical decision making. See p 1577.
Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension
Pulmonary vascular remodeling, occurring mostly in the small to midsized pulmonary arterioles (<500 μm), is a hallmark of most forms of pulmonary hypertension and frequently leads to progressive functional decline in patients despite treatment with currently available therapies. In the present study, to the best of our knowledge, we report for the first time increased pericyte coverage of distal pulmonary arteries in experimental (in chronic hypoxia and monocrotaline-induced pulmonary hypertension) and human (patients carrying or not a bone morphogenetic protein receptor 2 mutation) pulmonary arterial hypertension (PAH), an abnormality that is a potential source of smooth muscle–like cells involved in the PAH pulmonary vascular remodeling. We obtained evidence that dysfunctional endothelial cells from patients with idiopathic PAH, through an aberrant release of key growth factors and chemoattractants (ie, fibroblast growth factor-2 and interleukin-6), contribute to this vascular abnormality. In vitro, we found that exogenous or endothelial-derived fibroblast growth factor-2 and interleukin-6 enhance pulmonary pericyte migration and that fibroblast growth factor-2 is also a pericyte mitogen. In addition, we demonstrated, in human lungs from patients with PAH and in a murine model of pulmonary hypertension, that these pericytes can differentiate into smooth muscle–like cells, expressing contractile proteins. We also found that transforming growth factor-β1 is overactivated in pulmonary pericytes from patients with idiopathic PAH and promotes human pulmonary pericyte differentiation into contractile smooth muscle–like cells. We thus suspect that neutralization of fibroblast growth factor-2, interleukin-6, and transforming growth factor-β1 may prevent pericyte recruitment and differentiation in idiopathic and heritable PAH and thus may be beneficial against the disease progression. Additional investigations are required to determine whether pulmonary pericytes contribute to other forms of pulmonary hypertension. See p 1586.
Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets
Currently, more than 19.7 million adults (8.3%) in the United States have diagnosed diabetes mellitus, and 38.2% of the US adult population has prediabetes. Most diabetic patients will die of thrombotic cardiovascular events. Of great concern is that many diabetic patients are biochemically resistant to aspirin, the drug most commonly used to prevent and treat such thrombotic events. There is a need to provide new, effective antiplatelet drug targets. We report a novel pathway that gives rise to mitochondrial damage and increased thrombosis in diabetes mellitus. Using both human and mouse platelets from diabetic and normal subjects, we report a unique hyperglycemia-mediated platelet aldose reductase, reactive oxygen species, p53-mediated pathway that leads to mitochondrial dysfunction and damage. This is particularly intriguing because platelets do not have a nucleus, which normally mediates many of the well-recognized functions of p53. Moreover, we demonstrate that this mitochondrial damage can lead to 2 distinct pathways, apoptosis and platelet hyperactivity, both of which can promote thrombus formation. A mouse carotid ligation model was used to produce moderate blood stasis, which demonstrated that hyperglycemia-induced aldose reductase activation and mitochondrial dysfunction enhanced arterial thrombosis in vivo. This explains in part the enhanced risk for thrombosis observed in human patients with diabetes. These pathway components may provide novel targets for pathway-specific therapy to combat increased thrombosis in patients with diabetes. See p 1598.
- © 2014 American Heart Association, Inc.
- Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function
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