Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance
- Ideal Cardiovascular Health in Adolescence: Effect of Lifestyle Intervention and Association With Vascular Intima-Media Thickness and Elasticity (The Special Turku Coronary Risk Factor Intervention Project for Children [STRIP] Study)
- MiR-378 Controls Cardiac Hypertrophy by Combined Repression of Mitogen-Activated Protein Kinase Pathway Factors
- Association Between Postresuscitation Partial Pressure of Arterial Carbon Dioxide and Neurological Outcome in Patients With Post–Cardiac Arrest Syndrome
- Efficacy of the CCR5 Antagonist Maraviroc in Reducing Early, Ritonavir-Induced Atherogenesis and Advanced Plaque Progression in Mice
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Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance
Obesity is associated with low-grade chronic inflammation, dysregulated adipocytokine production, and increased oxidative stress in visceral adipose tissue, which is believed to result in insulin resistance, high blood pressure, and acceleration of atherosclerosis. Although hypoxia has long been known to reduce body weight in both humans and animals, the role of the hypoxia response system, including hypoxia-inducible factor and an oxygen sensor, prolyl hydroxylase domain protein (PHD), in the regulation of fat mass and glucose metabolism remains controversial. Therefore, in the present study, we sought to determine whether deletion of PHD2, a main isoform of PHD, in adipose tissue affects high-fat diet–induced obesity and glucose intolerance. We showed that PHD2 deficiency in adipocyte resulted in upregulation of hypoxia-inducible factor and attenuated high-fat diet–induced body weight gain and glucose intolerance compared with control mice. These effects seemed to be mediated by upregulation of glycolytic enzymes in white adipose tissue and uncoupling protein-1 in brown adipose tissue in the PHD2-deficient mice. The PHD2-deficient mice also showed modest improvement in insulin sensitivity. The improvement in glucose metabolism is associated with a decrease in adipocyte size, macrophage infiltration, and abnormal angiogenesis of white adipose tissue in the PHD2-deficient mice. Because of the worldwide pandemic of obesity and diabetes mellitus, a novel strategy that is effective for the treatment of both conditions has been sought. The present study suggests that PHD2 inhibition in adipocyte may be a new therapeutic approach to reduce body weight and to improve glucose tolerance simultaneously. See p 2078.
Ideal Cardiovascular Health in Adolescence: Effect of Lifestyle Intervention and Association With Vascular Intima-Media Thickness and Elasticity (The Special Turku Coronary Risk Factor Intervention Project for Children [STRIP] Study)
The American Heart Association recently released a set of 7 cardiovascular health metrics for children and adults to describe ideal cardiovascular health. The behavioral criteria include nonsmoking, being physically active, having normal body mass index, and eating a healthy diet. Normal blood pressure, total cholesterol, and plasma glucose levels indicate ideal health factors. The prevalence of ideal cardiovascular health is very low. It is associated with cardiovascular disease incidence and with cardiovascular disease and all-cause mortality. Longitudinal data on the ideal cardiovascular health in adolescence are lacking, and the association of the number of ideal cardiovascular health metrics with vascular intima-media thickness and elasticity–surrogate markers of atherosclerosis–is also unknown in adolescents. In the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), repeated dietary counseling introduced in infancy and maintained until 20 years of age has led to lower intakes of saturated fat and lower serum low-density lipoprotein cholesterol levels. In this study, we examined prospectively the intervention effects on the ideal cardiovascular health concept and the association of the concept with vascular intima-media thickness and elasticity in adolescence between 15 and 19 years of age. This study shows that ideal cardiovascular health can be promoted in adolescents. Importantly, the ideal cardiovascular health score is associated with vascular health already at this young age, and although having all 7 metrics is the ideal target, vascular health benefits are gained by the avoidance of a low ideal cardiovascular health score. Clinicians should target these health behaviors and factors as part of the primordial prevention of cardiovascular diseases. See p 2088.
MiR-378 Controls Cardiac Hypertrophy by Combined Repression of Mitogen-Activated Protein Kinase Pathway Factors
MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, miRs have been shown to regulate many processes in health and disease, including cardiovascular disease. Using a method to screen libraries of multiple synthetic miRs for the induction of cardiomyocyte hypertrophy, a hallmark of the myocardial stress response, we found the first evidence for an antihypertrophic activity of miR-378 in the myocardium. Subsequent analyses showed that miR-378 represses prohypertrophic signaling at 4 levels within the mitogen-activated protein kinase signaling pathway. MiR-378 was found to be downregulated both in animal models of myocardial disease and in human failing myocardium. Compensation for miR-378 downregulation in a cardiac disease model using viral gene transfer in vivo protected the heart against hypertrophy and dysfunction. Together, these data indicate effective interference of miR-378 with a key prohypertrophic signaling pathway. We imagine that targeted delivery of miR-378 to the heart may prove to be an effective therapeutic strategy in myocardial disease. See p 2097.
Association Between Postresuscitation Partial Pressure of Arterial Carbon Dioxide and Neurological Outcome in Patients With Post–Cardiac Arrest Syndrome
Partial pressure of arterial CO2 is a major regulator of cerebral blood flow after brain injury. The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend that ventilation should be titrated to achieve a partial pressure of arterial CO2 of 40 to 45 mm Hg after return of spontaneous circulation from cardiac arrest. However, at the present time, we are unaware of any previous clinical research studies on the subject of hypocapnia and hypercapnia during the post–return of spontaneous circulation period in adult patients. Specifically, it has been unclear if exposure to hypocapnia and hypercapnia during the initial post–return of spontaneous circulation period is common and independently associated with neurological outcome. In this observational study, both hypocapnia and hypercapnia exposure were common and were independently associated with poor neurological function at hospital discharge. Future research is needed to determine the optimal partial pressure of arterial CO2 range after the return of spontaneous circulation. See p 2107.
Efficacy of the CCR5 Antagonist Maraviroc in Reducing Early, Ritonavir-Induced Atherogenesis and Advanced Plaque Progression in Mice
Maraviroc is a small-molecule CCR5 antagonist, the only one available in clinical practice for treating R5 tropic HIV infection, and it is known to be associated with mild side effects. Our studies found that, in a murine model, maraviroc reduced atherosclerotic progression by modulating not only inflammatory cell plaque recruitment but also systemic inflammation. Reports from clinical studies in HIV-infected patients indicate that maraviroc possesses anti-inflammatory properties, and in a recent in vitro study on human adipocytes, it caused a significant decrease in the gene expression and release of interleukin-6, the proinflammatory cytokine that is known to be associated with the severity of coronary artery disease. The efficacy of maraviroc has been reported in other non-HIV clinical settings: graft versus host disease and concomitant inflammatory pathologies. Persistent low-grade chronic inflammation is associated with early aging and the development of cancer and ischemic cardiovascular diseases. Therefore, the antiatherosclerotic efficacy of maraviroc should be evaluated in the HIV clinical setting in patients with a high inflammatory profile and elevated risk of coronary artery disease, as well as in other chronic inflammatory diseases associated with a high risk of coronary artery disease. See p 2114.
- © 2013 American Heart Association, Inc.
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