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Find video protocols related to scientific articles indexed in Pubmed.
Electron transfer kinetics on mono- and multilayer graphene.
ACS Nano
PUBLISHED: 10-13-2014
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Understanding of the electrochemical properties of graphene, especially the electron transfer kinetics of a redox reaction between the graphene surface and a molecule, in comparison to graphite or other carbon-based materials, is essential for its potential in energy conversion and storage to be realized. Here we use voltammetric determination of the electron transfer rate for three redox mediators, ferricyanide, hexaammineruthenium, and hexachloroiridate (Fe(CN)6(3-), Ru(NH3)6(3+), and IrCl6(2-), respectively), to measure the reactivity of graphene samples prepared by mechanical exfoliation of natural graphite. Electron transfer rates are measured for varied number of graphene layers (1 to ca. 1000 layers) using microscopic droplets. The basal planes of mono- and multilayer graphene, supported on an insulating Si/SiO2 substrate, exhibit significant electron transfer activity and changes in kinetics are observed for all three mediators. No significant trend in kinetics with flake thickness is discernible for each mediator; however, a large variation in kinetics is observed across the basal plane of the same flakes, indicating that local surface conditions affect the electrochemical performance. This is confirmed by in situ graphite exfoliation, which reveals significant deterioration of initially, near-reversible kinetics for Ru(NH3)6(3+) when comparing the atmosphere-aged and freshly exfoliated graphite surfaces.
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Calcium and phosphorus concentrations in native and decellularized semilunar valve tissues.
J. Heart Valve Dis.
PUBLISHED: 10-10-2014
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Native, allograft, xenograft and bioprosthetic semilunar valves are all susceptible to calcific degeneration. However, intrinsic differences in baseline calcium and phosphorus tissue concentrations within mammalian normal valve structural components (e.g., cusps, sinus, vessel wall) additionally subdivided by tripartite regions (e.g., right-, left- and non-coronary leaflets) have never been systematically measured and reported. It was originally hypothesized that variations in normative tissue concentrations of calcium and phosphorus may correspond to subsequent clinical patterns of acquired dystrophic calcification; decellularization was also expected to reduce the tissue concentrations of these elements.
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Age-Related Decline of Autocrine Pituitary Adenylate Cyclase-Activating Polypeptide Impairs Angiogenic Capacity of Rat Cerebromicrovascular Endothelial Cells.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 08-18-2014
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Aging impairs angiogenic capacity of cerebromicrovascular endothelial cells (CMVECs) promoting microvascular rarefaction, but the underlying mechanisms remain elusive. PACAP is an evolutionarily conserved neuropeptide secreted by endothelial cells and neurons, which confers important antiaging effects. To test the hypothesis that age-related changes in autocrine PACAP signaling contributes to dysregulation of endothelial angiogenic capacity, primary CMVECs were isolated from 3-month-old (young) and 24-month-old (aged) Fischer 344 x Brown Norway rats. In aged CMVECs, expression of PACAP was decreased, which was associated with impaired capacity to form capillary-like structures, impaired adhesiveness to collagen (assessed using electric cell-substrate impedance sensing [ECIS] technology), and increased apoptosis (caspase3 activity) when compared with young cells. Overexpression of PACAP in aged CMVECs resulted in increased formation of capillary-like structures, whereas it did not affect cell adhesion. Treatment with recombinant PACAP also significantly increased endothelial tube formation and inhibited apoptosis in aged CMVECs. In young CMVECs shRNA knockdown of autocrine PACAP expression significantly impaired tube formation capacity, mimicking the aging phenotype. Cellular and mitochondrial reactive oxygen species production (dihydroethidium and MitoSox fluorescence, respectively) were increased in aged CMVECs and were unaffected by PACAP. Collectively, PACAP exerts proangiogenic effects and age-related dysregulation of autocrine PACAP signaling may contribute to impaired angiogenic capacity of CMVECs in aging.
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IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.
J. Cereb. Blood Flow Metab.
PUBLISHED: 08-06-2014
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Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.Journal of Cerebral Blood Flow & Metabolism advance online publication, 24 September 2014; doi:10.1038/jcbfm.2014.156.
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Endothelin-1-Induced Focal Cerebral Ischemia in the Growth Hormone/IGF-1 Deficient Lewis Dwarf Rat.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 08-06-2014
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Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia.
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Association of high-density lipoprotein subclasses and incident coronary heart disease: The Jackson Heart and Framingham Offspring Cohort Studies.
Eur J Prev Cardiol
PUBLISHED: 07-27-2014
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We aimed to clarify the associations of high-density lipoprotein cholesterol (HDL-C) subclasses with incident coronary heart disease (CHD) in two large primary prevention cohorts.
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Calcific embolization with infective endocarditis involving the posterior mitral leaflet in a patient with underlying hypertrophic obstructive cardiomyopathy.
J. Thromb. Thrombolysis
PUBLISHED: 07-18-2014
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We report a case of infective endocarditis (IE) involving the posterior mitral leaflet (PML) with calcific embolization in a patient with hypertrophic obstructive cardiomyopathy (HOCM). Amongst HOCM patients with IE, the anterior mitral leaflet and basal septal myocardium are almost always involved due to the endocardial damage caused by recurrent outflow obstruction and valvular regurgitation. The management of our patient was complicated by moderate mitral stenosis, repeated calcific embolic strokes, dynamic left ventricular outflow track obstruction, and respiratory failure due to flash pulmonary edema. To our knowledge, this is the first reported case of PML involvement in HOCM presenting in this manner.
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HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the lipoprotein investigators collaborative.
Eur. Heart J.
PUBLISHED: 07-02-2014
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High-density lipoprotein (HDL) is highly heterogeneous and the link of its subclasses to prognosis remains controversial. We aimed to rigorously examine the associations of HDL subclasses with prognosis in secondary prevention.
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Combination therapy in dyslipidemia: Where are we now?
Atherosclerosis
PUBLISHED: 06-23-2014
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Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27-55%. Several lipid goal-driven guidelines recommend reducing LDL-C to <2.59 mmol/L (100 mg/dL) or <1.81 mmol/L (70 mg/dL) in very high-risk patients. Many patients treated with statins do not reach these goals, and remain at risk of future cardiovascular events. The 2013 American College of Cardiology/American Heart Association guidelines move away from advocating LDL-C treatment targets with focus placed on identifying patients most likely to benefit from high-intensity or moderate-intensity statin therapy. While increasing the statin dose can prove efficacious in some patients, this approach typically offers limited additional LDL-C lowering, and is associated with increased incidence of adverse side effects. Indeed, this has led to the investigation of statins in combination with other lipid-modifying agents for the treatment of dyslipidemia. This review of the evidence for statin use in combination with fibrates, niacin, bile acid sequestrants, and the cholesterol absorption inhibitor, ezetimibe, in dyslipidemic patients at increased risk of cardiovascular disease, explores the impact of such combination therapies on lipids, attainment of lipid targets, inflammatory markers, and on cardiovascular outcomes and pathology. Additionally, new and emerging dyslipidemia treatments are summarized.
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JCL roundtable: HDL in the primary care setting.
J Clin Lipidol
PUBLISHED: 06-18-2014
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One of the most difficult and confusing issues for clinical lipidologists and physicians in general has been the management of low concentrations of high-density lipoprotein cholesterol. We know this to be a very powerful predictor of risk in scores of community-based and clinical trial cohorts. Raising this number in many patients would seem to provide a great therapeutic opportunity, but so far this concept has been very difficult to prove. I have been joined for this discussion by a cardiovascular epidemiologist, Dr. Rachel Mackey, from the University of Pittsburgh and two clinical lipidologists who have studied and written in depth about this problem. These are Dr. Benjamin Ansell from the University of California in Los Angeles and Dr. Peter Toth from Johns Hopkins University School of Medicine. Our objective in this discussion is to give primary care clinicians our thoughts about the recent research findings and the implications of these data on the best clinical practice.
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Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 06-06-2014
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In rodents, moderate caloric restriction (CR) without malnutrition exerts significant cerebrovascular protective effects, improving cortical microvascular density and endothelium-dependent vasodilation, but the underlying cellular mechanisms remain elusive. To elucidate the persisting effects of CR on cerebromicrovascular endothelial cells (CMVECs), primary CMVECs were isolated from young (3 mo old) and aged (24 mo old) ad libitum-fed and aged CR F344xBN rats. We found an age-related increase in cellular and mitochondrial oxidative stress, which is prevented by CR. Expression and transcriptional activity of Nrf2 are both significantly reduced in aged CMVECs, whereas CR prevents age-related Nrf2 dysfunction. Expression of miR-144 was upregulated in aged CMVECs, and overexpression of miR-144 significantly decreased expression of Nrf2 in cells derived from both young animals and aged CR rats. Overexpression of a miR-144 antagomir in aged CMVECs significantly decreases expression of miR-144 and upregulates Nrf2. We found that CR prevents age-related impairment of angiogenic processes, including cell proliferation, adhesion to collagen, and formation of capillary-like structures and inhibits apoptosis in CMVECs. CR also exerts significant anti-inflammatory effects, preventing age-related increases in the transcriptional activity of NF-?B and age-associated pro-inflammatory shift in the endothelial secretome. Characterization of CR-induced changes in miRNA expression suggests that they likely affect several critical functions in endothelial cell homeostasis. The predicted regulatory effects of CR-related differentially expressed miRNAs in aged CMVECs are consistent with the anti-aging endothelial effects of CR observed in vivo. Collectively, we find that CR confers persisting anti-oxidative, pro-angiogenic, and anti-inflammatory cellular effects, preserving a youthful phenotype in rat cerebromicrovascular endothelial cells, suggesting that through these effects CR may improve cerebrovascular function and prevent vascular cognitive impairment.
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Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 06-03-2014
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Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.
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Direct oral anticoagulants as alternative treatment options for the effective long-term treatment of patients with pulmonary embolism in primary care: a review.
Ann. Med.
PUBLISHED: 06-03-2014
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Pulmonary embolism (PE) represents a potentially life-threatening venous thromboembolic disorder, and prompt treatment is vital to prevent early mortality. However, diagnosis of PE is complicated by the range of signs and symptoms with which it presents. Clinical risk scores, imaging techniques, and laboratory tests are recommended in clinical guidelines to aid diagnosis, and risk stratification strategies can be used to inform treatment decisions. Long-term anticoagulation is key to avoid the risk of later complications of acute PE, such as recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension. Rivaroxaban is a direct oral anticoagulant that has been approved for the treatment of PE (and deep vein thrombosis) and prevention of recurrent venous thromboembolism; other direct oral anticoagulants have undergone phase III trials for these indications. These agents may provide advantages over traditional anticoagulants, such as vitamin K antagonists, because they are administered at fixed doses and do not require routine coagulation monitoring. These advantages may improve patient adherence and aid general practitioners by simplifying long-term management of PE in daily primary care.
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The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice.
Atheroscler Suppl
PUBLISHED: 05-21-2014
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Reducing low-density lipoprotein cholesterol (LDL-C) levels using statins is associated with significant reductions in cardiovascular (CV) events in a wide range of patient populations. Although statins are generally considered to be safe, recent studies suggest they are associated with an increased risk of developing Type 2 diabetes (T2D). This led the US Food and Drug Administration (FDA) to change their labelling requirements for statins to include a warning about the possibility of increased blood sugar and HbA1c levels and the European Medicines Agency (EMA) to issue guidance on a small increased risk of T2D with the statin class. This review examines the evidence leading to these claims and provides practical guidance for primary care physicians on the use of statins in people with or at risk of developing T2D. Overall, evidence suggests that the benefits of statins for the reduction of CV risk far outweigh the risk of developing T2D, especially in individuals with higher CV risk. To reduce the risk of developing T2D, physicians should assess all patients for T2D risk prior to starting statin therapy, educate patients about their risks, and encourage risk-reduction through lifestyle changes. Whether some statins are more diabetogenic than others requires further study. Statin-treated patients at high risk of developing T2D should regularly be monitored for changes in blood glucose or HbA1c levels, and the risk of conversion from pre-diabetes to T2D should be reduced by intensifying lifestyle changes. Should a patient develop T2D during statin treatment, physicians should continue with statin therapy and manage T2D in accordance with relevant national guidelines.
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Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality.
Best Pract. Res. Clin. Endocrinol. Metab.
PUBLISHED: 05-21-2014
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High-density lipoprotein (HDL) particles are highly complex polymolecular aggregates capable of performing a remarkable range of atheroprotective functions. Considerable research is being performed throughout the world to develop novel pharmacologic approaches to: (1) promote apoprotein A-I and HDL particle biosynthesis; (2) augment capacity for reverse cholesterol transport so as to reduce risk for the development and progression of atherosclerotic disease; and (3) modulate the functionality of HDL particles in order to increase their capacity to antagonize oxidation, inflammation, thrombosis, endothelial dysfunction, insulin resistance, and other processes that participate in arterial wall injury. HDL metabolism and the molecular constitution of HDL particles are highly complex and can change in response to both acute and chronic alterations in the metabolic milieu. To date, some of these interventions have been shown to positively impact rates of coronary artery disease progression. However, none of them have as yet been shown to significantly reduce risk for cardiovascular events. In the next 3-5 years a variety of pharmacologic interventions for modulating HDL metabolism and functionality will be tested in large, randomized, prospective outcomes trials. It is hoped that one or more of these therapeutic approaches will result in the ability to further reduce risk for cardiovascular events once low-density lipoprotein cholesterol and non-HDL-cholesterol targets have been attained.
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Should low high-density lipoprotein cholesterol (HDL-C) be treated?
Best Pract. Res. Clin. Endocrinol. Metab.
PUBLISHED: 05-21-2014
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The first observations linking a low serum level of HDL-C to increased risk for cardiovascular disease were made over 50 years ago. High serum levels of HDL-C appear to protect against the development of atherosclerotic disease, while low serum levels of this lipoprotein are among the most important predictors of atherosclerotic disease in both men and women and people of all racial and ethnic groups throughout the world. It has long been assumed that therapeutic interventions targeted at raising HDL-C levels would lower risk for such cardiovascular events as myocardial infarction, ischemic stroke, and death. Even after five decades of intensive investigation, evidence to support this assumption has been fleeting. A number of post hoc analyses of randomized controlled trials and meta-analyses suggest that HDL-C raising, particularly when coupled with aggressive LDL-C reduction, impacts risk for cardiovascular events and rates of progression of atherosclerotic disease. Unfortunately, four recent prospective trials performed with the intent of testing the "HDL hypothesis" (ILLUMINATE, dal-OUTCOMES, AIM-HIGH, and HPS2-THRIVE) failed to meet their primary composite endpoints. These results have lead many clinicians and investigators to question the validity of the assumption that HDL-C raising reduces risk for cardiovascular events. Additional trials with other drugs are underway. In the meantime, HDL-C cannot be considered a target of therapy. Given the complexity of the HDL proteome and lipidome, there is biological plausibility for how HDL particles might exert atheroprotection. We explore the evidence supporting the inverse relationship between HDL-C and cardiovascular disease risk, documented mechanisms by which HDL particles may exert atheroprotection, and the findings either supporting or negating specific therapeutic interventions in patients afflicted with low HDL-C.
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Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.
Eur J Prev Cardiol
PUBLISHED: 04-30-2014
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Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.
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Use of microsomal triglyceride transfer protein inhibitors in patients with homozygous familial hypercholesterolemia: translating clinical trial experience into clinical practice.
Rev Cardiovasc Med
PUBLISHED: 04-26-2014
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Homozygous familial hypercholesterolemia (HoFH) is associated with severe hypercholesterolemia and premature cardiovascular morbidity and mortality. The most frequent cause of HoFH is loss of function mutations in the gene for the low-density lipoprotein receptor, resulting in reduced clearance of low-density lipoprotein (LDL) cholesterol from the circulation. Patients with HoFH have attenuated responsiveness to lipidlowering therapies such as statins, cholesterol absorption inhibition, and bile acid binding resins because of impaired LDL receptor expression. Lomitapide is a novel microsomal triglyceride transfer protein inhibitor that does not depend on the ability to upregulate LDL receptors on the surface of hepatocytes. Lomitapide reduces production of apolipoprotein B-containing lipoproteins, significantly reduces serum levels of LDL cholesterol, and is approved for use in patients with HoFH in the United States and the European Union.
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Narrowing sex differences in lipoprotein cholesterol subclasses following mid-life: the very large database of lipids (VLDL-10B).
J Am Heart Assoc
PUBLISHED: 04-24-2014
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Women have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife.
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An update on the benefits and risks of rosuvastatin therapy.
Postgrad Med
PUBLISHED: 04-02-2014
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Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) that reduces low-density lipoprotein cholesterol levels to the greatest extent of all currently marketed statins. Prospective, randomized studies demonstrate the ability of rosuvastatin to reduce the risk of cardiovascular events and stabilize atherosclerosis. However, the efficacy of rosuvastatin in patient subpopulations (eg, patients with chronic kidney disease, women, ethnic subgroups) is not well described in the literature. To provide an updated, comprehensive review of the efficacy and safety of rosuvastatin, a literature search of PubMed was conducted using statins as a major topic, MESH topic, or a word in the title (including rosuvastatin, fluvastatin, atorvastatin, pitavastatin, lovastatin, pravastatin, and simvastatin). Publications selected for inclusion in this review were published from January 1, 2010 to December 31, 2013, and provide new information pertaining to the efficacy and safety of rosuvastatin.
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Resveratrol Encapsulated in Novel Fusogenic Liposomes Activates Nrf2 and Attenuates Oxidative Stress in Cerebromicrovascular Endothelial Cells From Aged Rats.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 03-20-2014
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Resveratrol (3,4',5-trihydroxystilbene) is a plant-derived polyphenolic trans-stilbenoid, which exerts multifaceted antiaging effects. Here, we propose a novel delivery system for resveratrol, which significantly increases its cellular uptake into aged cells. Combination of resveratrol with a positively charged lipid component to "conventional" liposomes converts these lipid vesicles to a robust fusogenic system. To study their cellular uptake and cellular effects, we treated primary cerebromicrovascular endothelial cells isolated from aged F344xBN rats with resveratrol encapsulated in fusogenic liposomes (FL-RSV). To demonstrate effective cellular uptake of FL-RSV, accumulation of the lipophilic tracer dye, DiR, and resveratrol in cerebromicrovascular endothelial cells was confirmed using flow cytometry and confocal microscopy and high-performance liquid chromatography electrochemical detection. Treatment of aged cerebromicrovascular endothelial cells with FL-RSV activated Nrf2 (assessed with a reporter gene assay), significantly decreased cellular production of reactive oxygen species (assessed by a flow cytometry-based H2DCFDA fluorescence method), and inhibited apoptosis. Taken together, encapsulation of resveratrol into novel fusogenic liposomes significantly enhances the delivery of resveratrol into aged cells, which subsequently results in rapid activation of cellular Nrf2-driven antioxidant defense mechanisms. Our studies provide proof-of-concept for the development of a novel, translationally relevant interventional strategy for prevention and/or control of oxidative stress-related pathophysiological conditions in aging.
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HDL hypothesis: where do we stand now?
Curr Atheroscler Rep
PUBLISHED: 03-13-2014
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There is robust epidemiological evidence dating back to the original Framingham Heart Study from 1977 that indicates an important inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk of incident coronary artery disease (CAD). Despite this body of scientific information demonstrating that low levels of HDL-C are an independent predictor of subsequent CAD events, multiple therapeutic attempts to raise HDL-C levels have failed to demonstrate a consistent reduction in prognostically important endpoints such as death, myocardial infarction (MI), and stroke. Recently, several major randomized trials using different therapeutic interventions have raised appropriate concerns about our basic understanding of HDL-C and whether the "HDL hypothesis" of lowering cardiovascular events through therapeutic interventions directed at raising HDL-C is a scientifically viable one. While two recent randomized controlled trials (AIM-HIGH and HPS2-THRIVE) failed to show a reduction in cardiovascular events in patients treated to optimally low levels of low-density lipoprotein cholesterol (LDL-C) at baseline with extended-release niacin on a background of simvastatin, these clinical trials studied specific populations of stable ischemic heart disease patients. The data from these two contemporary trials cannot be extrapolated to all patient populations, such as those with acute coronary syndromes or myocardial infarction or those with significant residual mixed dyslipidemia not treated with optimal doses of intensive statin therapy, as these patients were excluded by trial design in both studies. Therefore, at the present time, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction in CAD patients. However, we will review the relevant data from recent major trials (AIM-HIGH, HPS2-THRIVE, ILLUMINATE, and dal-OUTCOMES) and highlight the potential clinical implications of these trials in modern pharmacotherapy as it relates to HDL-C raising and potential cardiovascular event reduction.
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High-density lipoprotein subfractions: current views and clinical practice applications.
Trends Endocrinol. Metab.
PUBLISHED: 03-06-2014
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High-density lipoprotein (HDL) is astonishingly complex, but the de facto standard for its measurement has been remarkably simple: total cholesterol content. It is time to prioritize higher-resolution HDL measurement techniques that capture better the biologically and clinically important characteristics of HDL. Scientific advances have ushered in a new era in which we view HDL in terms of its subfractions, particle structure, metabolism, and functional integration of its proteome and lipidome. HDL subfractions appear to be associated with function. In general, smaller, denser HDL3 is more tightly linked to favorable atheroprotective functions and clinical outcomes. Techniques to measure the cholesterol content or particle concentrations of HDL subfractions are available clinically. In the future, we anticipate subfractionating HDL based on its functional properties.
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A clinician's guide to statin drug-drug interactions.
J Clin Lipidol
PUBLISHED: 02-27-2014
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The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.
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Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets.
Atherosclerosis
PUBLISHED: 02-18-2014
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Previous research suggests that LDL particle number (LDL-P) may be a better tool than LDL cholesterol (LDL-C) to guide LDL-lowering therapy. Using real-world data, this study has two objectives: [1] to determine the incidence of CHD across LDL-P thresholds; and [2] to compare CHD/stroke events among patients achieving comparably low LDL-P or LDL-C levels.
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Therapeutic practice patterns related to statin potency and ezetimibe/simvastatin combination therapies in lowering LDL-C in patients with high-risk cardiovascular disease.
J Clin Lipidol
PUBLISHED: 02-18-2014
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Statin combination therapy and statin uptitration have been shown to be efficacious in low-density lipoprotein cholesterol (LDL-C) lowering and are recommended for patients with high-risk coronary heart disease (CHD) who do not reach guideline-endorsed LDL-C goals on statin monotherapy.
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Residual macrovascular risk in 2013: what have we learned?
Cardiovasc Diabetol
PUBLISHED: 01-24-2014
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Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptor? agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.
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Prevalence of dyslipidemia and associated risk factors in Turkish adults.
J Clin Lipidol
PUBLISHED: 01-19-2014
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Dyslipidemia is a modifiable major risk factor for coronary heart disease. The objective of this study was to determine the prevalence of dyslipidemia among Turkish adults and its associations with other cardiovascular risk factors.
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Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.
Int. J. Cardiol.
PUBLISHED: 01-15-2014
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Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.
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Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.
J Clin Lipidol
PUBLISHED: 01-04-2014
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Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.
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Dyslipidemia in women: etiology and management.
Int J Womens Health
PUBLISHED: 01-01-2014
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Dyslipidemia is highly prevalent among women. The management of dyslipidemia is a cornerstone in the prevention of both primary and secondary cardiovascular events, such as myocardial infarction, ischemic stroke, and coronary death. All major international guidelines on the treatment of dyslipidemia recommend similar approaches to the management of dyslipidemia in both men and women. Estrogen replacement therapy should not be considered as a therapeutic option for managing dyslipidemia in women. The reduction of atherogenic lipoprotein burden (reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol based on risk-stratified thresholds and treatment targets) provided the framework for managing dyslipidemia in the US, Europe, Canada, and elsewhere in the world. Very recently, new guidelines in the US have changed this paradigm, whereby rather than focusing on treatment targets, risk now defines the intensity of treatment with statin therapy, with no specific goals for what level of low-density lipoprotein cholesterol should be attained. It is not clear if this will lead to changes in lipid guidelines in other parts of the world. In the meantime, region-specific guidelines should be followed. Lipid lowering with statin therapy does correlate with reductions in cardiovascular event rates in women. The clinical impact of treating dyslipidemias in women with nonstatin drugs (eg, fibrates, nicotinic acid, bile acid-binding resins, omega-3 fish oils) is as yet not determined.
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The Therapeutic Role of Niacin in Dyslipidemia Management.
J. Cardiovasc. Pharmacol. Ther.
PUBLISHED: 12-20-2013
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There is abundant epidemiologic evidence to support the independent, inverse relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and incident cardiovascular (CV) risk, the clinical importance of which is underscored by the high prevalence of low HDL-C in populations with coronary heart disease (CHD), with or without elevated levels of low-density lipoprotein cholesterol (LDL-C). The National Cholesterol Education Program recommended that optimal treatment for high-risk patients includes both lowering LDL-C and non-HDL-C to risk stratified levels and raising HDL-C when it is <40 mg/dL, although no target level for the latter lipoprotein was suggested. Niacin is the most powerful agent currently available for raising low levels of HDL-C. It also induces significant reductions in triglycerides, lipoprotein(a), and LDL-C levels while also favorably altering LDL particle size and number. In the Coronary Drug Project, niacin treatment was associated with significant reductions in CV events and long-term mortality, similar to the reductions seen in the statin monotherapy trials. In combination trials, niacin plus a statin or bile acid sequestrant produces additive reductions in CHD morbidity and mortality and promotes regression of coronary atherosclerosis. Recently, 2 clinical outcome trials (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study [HPS-2 THRIVE]) failed to show a reduction in CV events in patients treated to optimally low levels of LDL-C. Despite favorable effects on HDL-C and triglycerides, these studies did not demonstrate incremental clinical benefit with niacin when added to simvastatin, although notable limitations were identified in each of these trials. Thus, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction at the present time. However, niacin should continue to be used as an adjuvant therapy for reducing atherogenic lipoprotein burden in patients who have not reached their risk stratified LDL-C and non-HDL-C targets.
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Resveratrol treatment rescues neurovascular coupling in aged mice:role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidas.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 12-06-2013
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Moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher brain function, increasing the risk for vascular cognitive impairment (VCI). Resveratrol is a polyphenolic compound that exerts significant anti-aging protective effects in large vessels but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24 months old) C57BL/6 mice L-NAME sensitive, NO-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired as compared to those in young (3 months old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with down-regulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in ROS production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via down-regulation of NADPH-oxidase derived ROS production. Beneficial cerebromicrovascular effects of resveratrol likely contribute to its protective effects on higher brain function in aging.
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Obesity in Aging Exacerbates Blood-Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimers Disease.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 11-22-2013
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There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.
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Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile.
JAMA
PUBLISHED: 11-19-2013
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In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels.
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Saving genetic resources of native pigs in occidental and Oriental countries - practical examples of the characterization and utilization of native pigs in Hungary and Laos.
J. Reprod. Dev.
PUBLISHED: 10-29-2013
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Worldwide, only a few "fatty" pig breeds exist with different and/or regional utilization. Using the Hungarian Mangalica, which almost went extinct in Europe and the Lao Moo Lat pig, which still has a large population in South-East Asia as exemples, we wanted to demonstrate that indigenous (fatty) pig breeds may represent both national value and tremendous economic potential. Since these less prolific and less productive breeds cannot contribute to mass production, new market roles and methods should be established for them in the premium segment of pork trading. Thus their preservation and propagation needs the comprehensive collaboration of commercial, governmental actors and researchers. Briefly summarizing the history, we report the current results of reproductive physiology research. The commercial renaissance of Mangalica pigs is indebted to the enthusiastic efforts of basic scientists, pig breeding experts and dedicated Mangalica producers. Scientific achievements were applied to practical breeding and production of delicious pork and processed products, which ultimately made the economic success in the Mangalica sector possible. Both, research on and utilization of endangered (pig) breeds maintain not only breed diversities, but also may improve the livelihood of farmers worldwide.
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Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 10-04-2013
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Hypertension in the elderly substantially increases the risk of stroke and vascular cognitive impairment in part due to an impaired functional adaptation of aged cerebral arteries to high blood pressure. To elucidate the mechanisms underlying impaired autoregulatory protection in aging, hypertension was induced in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic infusion of angiotensin II and pressure-induced changes in smooth muscle cell (SMC) intracellular Ca(2+) concentration ([Ca(2+)]i) and myogenic constriction of middle cerebral arteries (MCA) were assessed. In MCAs from young hypertensive mice, pressure-induced increases in vascular SMC [Ca(2+)]i and myogenic tone were increased, and these adaptive responses were inhibited by the cytochrome P-450 ?-hydroxylase inhibitor HET0016 and the transient receptor potential (TRP) channel blocker SKF96365. Administration of 20- hydroxyeicosatetraenoic acid (HETE) increased SMC [Ca(2+)]i and constricted MCAs, and these responses were inhibited by SKF96365. MCAs from aged hypertensive mice did not show adaptive increases in pressure-induced calcium signal and myogenic tone and responses to HET0016 and SKF96365 were blunted. Inhibition of large-conductance Ca(2+)-activated K(+) (BK) channels by iberiotoxin enhanced SMC [Ca(2+)]i and myogenic constriction in MCAs of young normotensive animals, whereas it was without effect in MCAs of young hypertensive mice. Iberiotoxin did not restore myogenic adaptation in MCAs of aged hypertensive mice. Thus functional maladaptation of aged cerebral arteries to hypertension is due to the dysregulation of pressure-induced 20-HETE and TRP channel-mediated SMC calcium signaling, whereas overactivation of BK channels is unlikely to play a role in this phenomenon.
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Treatment with the cytochrome P450 ?-hydroxylase inhibitor HET0016 attenuates cerebrovascular inflammation, oxidative stress and improves vasomotor function in spontaneously hypertensive rats.
Br. J. Pharmacol.
PUBLISHED: 08-24-2013
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Hypertension increases cerebrovascular oxidative stress and inflammation and impairs vasomotor function. These pathological alterations lead to dysregulation of cerebral blood flow and exacerbate atherogenesis, increasing the morbidity of ischaemic cerebrovascular diseases and promoting vascular cognitive impairment. We aimed to test the hypothesis that increased production of the arachidonic acid metabolite 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) contributes to hypertension-induced cerebrovascular alterations.
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Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in ?-amyloid generation and Alzheimers disease.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 08-16-2013
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Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimers disease (AD), but the underlying mechanisms remain elusive. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in ?-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein (APP)-dependent signaling, APP cleavage, A? processing and A?-degradation, synaptic function, dysregulation of microtubule-associated ? protein, and apolipoprotein-E signaling. Aged hypertensive mice exhibited spatial memory impairments in the Y-maze and impaired performance in the novel object recognition assay. Surprisingly, hypertension in aging did not increase the expression of APP, ?- and ?-secretases, or genes involved in tauopathy. These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of APP binding proteins, e.g., [Mint3/amyloid ? A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid ? A4 precursor protein-binding family B member 1 (APBB1)], amyloid ? (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD.
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High-density lipoproteins: a consensus statement from the National Lipid Association.
J Clin Lipidol
PUBLISHED: 07-29-2013
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For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the "HDL hypothesis" have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panels conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.
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A meta-analysis of the role of statins on renal outcomes in patients with chronic kidney disease. Is the duration of therapy important?
Int. J. Cardiol.
PUBLISHED: 07-10-2013
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The efficacy of statin treatment in chronic kidney disease (CKD) patients remains controversial. Therefore, we performed a meta-analysis to investigate whether statins modulate renal function in patients with CKD.
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Very Large Database of Lipids: Rationale and Design.
Clin Cardiol
PUBLISHED: 07-09-2013
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Blood lipids have major cardiovascular and public health implications. Lipid-lowering drugs are prescribed based in part on categorization of patients into normal or abnormal lipid metabolism, yet relatively little emphasis has been placed on: (1) the accuracy of current lipid measures used in clinical practice, (2) the reliability of current categorizations of dyslipidemia states, and (3) the relationship of advanced lipid characterization to other cardiovascular disease biomarkers. To these ends, we developed the Very Large Database of Lipids (NCT01698489), an ongoing database protocol that harnesses deidentified data from the daily operations of a commercial lipid laboratory. The database includes individuals who were referred for clinical purposes for a Vertical Auto Profile (Atherotech Inc., Birmingham, AL), which directly measures cholesterol concentrations of low-density lipoprotein, very low-density lipoprotein, intermediate-density lipoprotein, high-density lipoprotein, their subclasses, and lipoprotein(a). Individual Very Large Database of Lipids studies, ranging from studies of measurement accuracy, to dyslipidemia categorization, to biomarker associations, to characterization of rare lipid disorders, are investigator-initiated and utilize peer-reviewed statistical analysis plans to address a priori hypotheses/aims. In the first database harvest (Very Large Database of Lipids 1.0) from 2009 to 2011, there were 1?340?614 adult and 10?294 pediatric patients; the adult sample had a median age of 59 years (interquartile range, 49-70 years) with even representation by sex. Lipid distributions closely matched those from the population-representative National Health and Nutrition Examination Survey. The second harvest of the database (Very Large Database of Lipids 2.0) is underway. Overall, the Very Large Database of Lipids database provides an opportunity for collaboration and new knowledge generation through careful examination of granular lipid data on a large scale.
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[Role of continuous subcutaneous glucose monitoring in intensive care].
Orv Hetil
PUBLISHED: 07-03-2013
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Critical care associated with stress hyperglycaemia has gained a new view in the last decade since the demonstration of the beneficial effects of strong glycaemic control on the mortality in intensive care units. Strong glycaemic control may, however, induce hypoglycaemia, resulting in increased mortality, too. Pediatric population has an increased risk of hypoglycaemia because of the developing central nervous system. In this view there is a strong need for close monitoring of glucose levels in intensive care units. The subcutaneous continuous glucose monitoring developed for diabetes care is an alternative for this purpose instead of regular blood glucose measurements. It is important to know the limitations of subcutaneous continuous glucose monitoring in intensive care. Decreased tissue perfusion may disturb the results of subcutaneous continuous glucose monitoring, because the measurement occurs in interstitial fluid. The routine use of subcutaneous continuous glucose monitoring in intensive care units is not recommended yet until sufficient data on the reliability of the system are available. The Medtronic subcutaneous continuous glucose monitoring system is evaluated in the review partly based on the authors own results.
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Stroke prevention in patients with atrial fibrillation: focus on new oral anticoagulants.
Postgrad Med
PUBLISHED: 06-11-2013
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Patients with atrial fibrillation are at an increased risk for stroke. Anticoagulation therapy has been shown to significantly reduce the risk for stroke in these patients. Warfarin therapy is effective at reducing the risk for thromboembolic events, but requires frequent monitoring of its anticoagulation effect using the international normalized ratio and significantly increases the risk for hemorrhagic events, including intracranial hemorrhage. Novel oral anticoagulants provide simpler, effective stroke prophylaxis in patients with atrial fibrillation. These drugs include dabigatran (a direct thrombin inhibitor) as well as rivaroxaban and apixaban (factor Xa inhibitors). The new anticoagulants have rapid onset of effect; their anticoagulatory effect is stable, predictable, and dose related; and they do not require monitoring of anticoagulation effect using the international normalized ratio. The pharmacology, clinical efficacy, and potential adverse effects of these drugs in patients with atrial fibrillation are reviewed herein.
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Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosens
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 05-20-2013
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Cerebromicrovascular rarefaction is believed to play a central role in cognitive impairment in patients receiving whole-brain irradiation therapy. To elucidate the mechanism underlying the deleterious effects of ?-irradiation on the cerebral microcirculation, rat primary cerebromicrovascular endothelial cells (CMVECs) were irradiated in vitro. We found that in CMVECs, ?-irradiation (2-8 Gy) elicited increased DNA damage, which was repaired less efficiently in CMVECs compared with neurons, microglia, and astrocytes. Increased genomic injury in CMVECs associated with increased apoptotic cell death. In the surviving cells, ?-irradiation promotes premature senescence (indicated by SA-?-galactosidase positivity and upregulation of p16 (INK4a) ), which was associated with impaired angiogenic capacity (decreased proliferation and tube-forming capacity). ?-Irradiated CMVECs acquired a senescence-associated secretory phenotype, characterized by upregulation of proinflammatory cytokines and chemokines (including IL-6, IL-1?, and MCP-1). Collectively, increased vulnerability of ?-irradiated CMVECs and their impaired angiogenic capacity likely contribute to cerebromicrovascular rarefaction and prevent regeneration of the microvasculature postirradiation. The acquisition of a senescence-associated secretory phenotype in irradiated CMVECs is biologically highly significant as changes in the cytokine microenvironment in the hippocampus may affect diverse biological processes relevant for normal neuronal function (including regulation of neurogenesis and the maintenance of the blood brain barrier).
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New Obesity Indices and Adipokines in Normotensive Patients and Patients With Hypertension: Comparative Pilot Analysis.
Angiology
PUBLISHED: 05-01-2013
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We compared the obesity parameters and selected adipokines-leptin, adiponectin, and resistin-in obese patients with hypertension and normotensive patients. A total of 67 nondiabetic obese outpatients were divided into 2 groups: A-hypertensive and B-normotensive. Serum levels of leptin, adiponectin, resistin, and insulin were measured. Weight, height, waist circumference, and hip circumference were measured to calculate waist-to-hip ratio (WHR), weight-to-height ratio, visceral adiposity index, and body adiposity index (BAI). Among patients with hypertension, significant positive correlations were observed between leptin and body mass index and BAI (r = .31 and r = .63, respectively). In normotensive patients, leptin positively correlated with BAI (r = .73, P < .01) and negatively with WHR (r = -.55, P < .0001); adiponectin negatively correlated with WHR (r = .38, P < .01) and BAI (r = .52; P < .0001), and resistin negatively correlated with WHR (r = -.36, P < .05). In conclusion, visceral obesity and leptin are associated with hypertension in obese patients.
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Non-High-Density Lipoprotein Cholesterol, Guideline Targets, and Population Percentiles for Secondary Prevention in 1.3 Million Adults: The VLDL-2 Study (Very Large Database of Lipids).
J. Am. Coll. Cardiol.
PUBLISHED: 04-24-2013
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This study sought to examine patient-level discordance between population percentiles of non-high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
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Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.
J. Mol. Med.
PUBLISHED: 03-24-2013
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The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart. We hypothesized that glutaminolysis occurs in RVH and assessed the precipitating factors, transcriptional mechanisms, and physiological consequences of this metabolic pathway. RVH was induced in two models, one with PAH (Monocrotaline-RVH) and the other without PAH (pulmonary artery banding, PAB-RVH). Despite similar RVH, ischemia as determined by reductions in RV VEGF?, coronary blood flow, and microvascular density was greater in Monocrotaline-RVH versus PAB-RVH. A sixfold increase in (14)C-glutamine metabolism occurred in Monocrotaline-RVH but not in PAB-RVH. In the RV working heart model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) decreased glutaminolysis, caused a reciprocal increase in glucose oxidation, and elevated cardiac output. Consistent with the increased glutaminolysis in RVH, RV expressions of glutamine transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated (Monocrotaline-RVH > PAB-RVH > control). Capillary rarefaction and glutamine transporter upregulation also occurred in RVH in patients with PAH. cMyc and Max, known to mediate transcriptional upregulation of glutaminolysis, were increased in Monocrotaline-RVH. In vivo, DON (0.5 mg/kg/day?×?3 weeks) restored pyruvate dehydrogenase activity, reduced RVH, and increased cardiac output (89?±?8, vs. 55?±?13 ml/min, p?
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SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo.
J. Mol. Cell. Cardiol.
PUBLISHED: 03-19-2013
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Successful implantation and long-term survival of engineered tissue grafts hinges on adequate vascularization of the implant. Endothelial cells are essential for patterning vascular structures, but they require supportive mural cells such as pericytes/mesenchymal stem cells (MSCs) to generate stable, functional blood vessels. While there is evidence that the angiogenic effect of MSCs is mediated via the secretion of paracrine signals, the identity of these signals is unknown. By utilizing two functionally distinct human MSC clones, we found that so-called "pericytic" MSCs secrete the pro-angiogenic vascular guidance molecule SLIT3, which guides vascular development by directing ROBO4-positive endothelial cells to form networks in engineered tissue. In contrast, "non-pericytic" MSCs exhibit reduced activation of the SLIT3/ROBO4 pathway and do not support vascular networks. Using live cell imaging of organizing 3D vascular networks, we show that siRNA knockdown of SLIT3 in MSCs leads to disorganized clustering of ECs. Knockdown of its receptor ROBO4 in ECs abolishes the generation of functional human blood vessels in an in vivo xenogenic implant. These data suggest that the SLIT3/ROBO4 pathway is required for MSC-guided vascularization in engineered tissues. Heterogeneity of SLIT3 expression may underlie the variable clinical success of MSCs for tissue repair applications.
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Patient-ventilator asynchrony in a traumatically injured population.
Respir Care
PUBLISHED: 03-19-2013
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Prolonged mechanical ventilation, longer hospital stay, and a lower rate of home discharge have been reported with patient-ventilator asynchrony in medical patients. Though commonly encountered, asynchrony is poorly defined within the traumatically injured population.
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Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association.
J Clin Lipidol
PUBLISHED: 03-18-2013
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The term "fat" may refer to lipids as well as the cells and tissue that store lipid (ie, adipocytes and adipose tissue). "Lipid" is derived from "lipos," which refers to animal fat or vegetable oil. Adiposity refers to body fat and is derived from "adipo," referring to fat. Adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol. Adipocytes and adipose tissue are active from an endocrine and immune standpoint. Adipocyte hypertrophy and excessive adipose tissue accumulation can promote pathogenic adipocyte and adipose tissue effects (adiposopathy), resulting in abnormal levels of circulating lipids, with dyslipidemia being a major atherosclerotic coronary heart disease risk factor. It is therefore incumbent upon lipidologists to be among the most knowledgeable in the understanding of the relationship between excessive body fat and dyslipidemia. On September 16, 2012, the National Lipid Association held a Consensus Conference with the goal of better defining the effect of adiposity on lipoproteins, how the pathos of excessive body fat (adiposopathy) contributes to dyslipidemia, and how therapies such as appropriate nutrition, increased physical activity, weight-management drugs, and bariatric surgery might be expected to impact dyslipidemia. It is hoped that the information derived from these proceedings will promote a greater appreciation among clinicians of the impact of excess adiposity and its treatment on dyslipidemia and prompt more research on the effects of interventions for improving dyslipidemia and reducing cardiovascular disease risk in overweight and obese patients.
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Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension.
J. Cereb. Blood Flow Metab.
PUBLISHED: 03-15-2013
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Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.
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Effects of statins on lipid profile in chronic kidney disease patients: a meta-analysis of randomized controlled trials.
Curr Med Res Opin
PUBLISHED: 03-11-2013
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The available data on statin effects in chronic kidney disease (CKD) patients are still conflicting. We investigated the impact of short- and long-term statin therapy on lipid profiles in CKD patients requiring or not requiring dialysis.
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Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy--a meta-analysis of 11 randomized controlled trials involving 21,295 participants.
Pharmacol. Res.
PUBLISHED: 03-07-2013
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The available studies have reported the benefits of statins on all-cause and cardiovascular mortality in chronic kidney disease (CKD) patients. However studies in end-stage renal disease patients on dialysis yielded conflicting results. Therefore, we performed a meta-analysis and provide the most reliable trial data to date on the impact of statin therapy on cardiovascular events and death from all causes in CKD patients. Data from PubMed, Web of Science, Cochrane Library, and Scopus for the years 1966 to October 2012 were searched. The final meta-analysis included 11 randomized controlled trials involving 21,295 participants with CKD. Among them 6857 were on dialysis. The use of statins in subjects with non-dialysis-dependent CKD resulted in a marked reduction in death from all causes (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.55-0.79; p<0.0001), cardiac causes (RR: 0.69; 95%CI: 0.55-0.68; p=0.0012), cardiovascular events (RR: 0.55; 95%CI: 0.4-0.75; p=0.0001) and stroke (RR: 0.66; 95%CI: 0.5-0.88; p=0.0022). The use of statins in dialysis-dependent CKD patients resulted in a non-significant effect on death from all causes (RR: 0.99; 95%CI: 0.88-1.11; p=0.85) and stroke (RR: 1.31; 95%CI: 0.9-1.89; p>0.05), but had the effect of reducing death from cardiac causes (RR: 0.79; 95%CI: 0.64-0.98; p<0.05) and cardiovascular events (RR: 0.81; 95%CI: 0.7-0.94; p<0.05). In conclusion, the use of statins should be indicated in cardiovascular disease prevention especially in patients with non-dialysis-dependent CKD. According to the very limited data the obtained results suggest caution in expecting a reduction in cardiovascular events in patients on dialysis.
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PGC1?-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 03-02-2013
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Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown.
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Emerging LDL therapies: Mipomersen-antisense oligonucleotide therapy in the management of hypercholesterolemia.
J Clin Lipidol
PUBLISHED: 02-11-2013
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Familial hypercholesterolemia (FH) is characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) and poses considerable treatment challenges. Substantive LDL-C reductions are difficult to achieve with standard therapies, and many patients with FH do not tolerate currently available lipid-lowering medications. Mipomersen is an antisense oligonucleotide injectable drug that was recently approved by the Food and Drug Administration for the treatment of homozygous FH. It is complementary in sequence to a segment of the human apolipoprotein (Apo) B-100 messenger RNA and specifically binds to it, blocking translation of the gene product. Reducing the production of Apo B-100 reduces hepatic production of very low-density lipoprotein, consequently decreasing circulating levels of atherogenic very low-density lipoprotein remnants, intermediate-density lipoproteins, LDL, and lipoprotein(a) particles. Results from a pivotal trial conducted in patients with homozygous FH, and supporting trials in patients with heterozygous FH with coronary artery disease (CAD) (LDL-C ? 100 mg/dL, triglycerides < 200 mg/dL), severe hypercholesterolemia (LDL-C ? 300 mg/dL or ? 200 mg/dL with CAD), and individuals at high risk for CAD (LDL-C ? 100 mg/dL, triglycerides ? 200 mg/dL), have indicated that mipomersen reduces all Apo B-containing atherogenic lipoproteins. The average LDL-C reduction was >100 mg/dL in homozygous FH and severe hypercholesterolemia populations. The main on-treatment adverse events were mild-to-moderate injection site reactions and flu-like symptoms. Available data regarding the efficacy, safety and tolerability of mipomersen, including results at up to 104 weeks of therapy, support the use of mipomersen for the treatment of FH.
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Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.
Circ. Res.
PUBLISHED: 01-18-2013
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Rationale: Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. Objective: The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. Methods and Results: Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. Conclusions: Mitochondrial fission is an obligatory, early step in mammalian O2 sensing and offers a promising target for modulating DA patency.
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Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.
J. Am. Coll. Cardiol.
PUBLISHED: 01-14-2013
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The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.
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Is the future of statins aligned with new novel lipid modulation therapies?
Curr Atheroscler Rep
PUBLISHED: 01-12-2013
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Dyslipidemia is an established risk factor for the development of atherosclerotic cardiovascular disease. Statin therapy has been proven in a number of clinical trials to lower the risk of acute cardiovascular events and is the mainstay of cholesterol treatment. Despite current optimal treatment for dyslipidemia, many patients fail to reach adequate cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. Given this residual risk, there is a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins and, in some cases, raise levels of high-density lipoproteins. A number of novel lipid-altering therapies have been developed and are currently in clinical trials. In this review, we discuss these promising therapies, which include PCSK9 inhibitors, apolipoprotein B antisense oligonucleotides, microsomal transfer protein inhibitors, thyroid mimetics, and cholesteryl ester transfer protein inhibitors. Although statin therapy is the current recommended primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic heart disease.
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Flk1+ and VE-Cadherin+ Endothelial Cells Derived from iPSCs Recapitulates Vascular Development during Differentiation and Display Similar Angiogenic Potential as ESC-Derived Cells.
PLoS ONE
PUBLISHED: 01-01-2013
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Induced pluripotent stem (iPS) cells have emerged as a source of potentially unlimited supply of autologous endothelial cells (ECs) for vascularization. However, the regenerative function of these cells relative to adult ECs and ECs derived from embryonic stem (ES) cells is unknown. The objective was to define the differentiation characteristics and vascularization potential of Fetal liver kinase (Flk)1(+) and Vascular Endothelial (VE)-cadherin(+) ECs derived identically from mouse (m)ES and miPS cells.
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Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy.
Vasc Health Risk Manag
PUBLISHED: 01-01-2013
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Many high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US.
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Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells.
PLoS ONE
PUBLISHED: 01-01-2013
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Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.
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Insulin-like growth factor-1 in CNS and cerebrovascular aging.
Front Aging Neurosci
PUBLISHED: 01-01-2013
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Insulin-like growth factor-1 (IGF-1) is an important anabolic hormone that decreases with age. In the past two decades, extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age.
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Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 11-10-2011
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Previous studies suggest that the age-related decline in circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels significantly contribute to vascular dysfunction in aging by impairing cellular oxidative stress resistance pathways. Obesity in elderly individuals is increasing at alarming rates, and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging, GH/IGF-1 deficiency, and obesity interact to promote the development of cardiovascular disease remain unclear. To test the hypothesis that low circulating GH/IGF-1 levels exacerbate the pro-oxidant and proinflammatory vascular effects of obesity, GH/IGF-1-deficient Lewis dwarf rats and heterozygous control rats were fed either a standard diet or a high-fat diet (HFD) for 7 months. Feeding an HFD resulted in similar relative weight gains and increases in body fat content in Lewis dwarf rats and control rats. HFD-fed Lewis dwarf rats exhibited a relative increase in blood glucose levels, lower insulin, and impaired glucose tolerance as compared with HFD-fed control rats. Analysis of serum cytokine expression signatures indicated that chronic GH/IGF-1 deficiency exacerbates HFD-induced inflammation. GH/IGF-1 deficiency also exacerbated HFD-induced endothelial dysfunction, oxidative stress, and expression of inflammatory markers (tumor necrosis factor-?, ICAM-1) in aortas of Lewis dwarf rats. Overall, our results are consistent with the available clinical and experimental evidence suggesting that GH/IGF-1 deficiency renders the cardiovascular system more vulnerable to the deleterious effects of obesity.
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Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 10-21-2011
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Recent studies demonstrate that age-related dysfunction of NF-E2-related factor-2 (Nrf2)-driven pathways impairs cellular redox homeostasis, exacerbating age-related cellular oxidative stress and increasing sensitivity of aged vessels to oxidative stress-induced cellular damage. Circulating levels of insulin-like growth factor (IGF)-1 decline during aging, which significantly increases the risk for cardiovascular diseases in humans. To test the hypothesis that adult-onset IGF-1 deficiency impairs Nrf2-driven pathways in the vasculature, we utilized a novel mouse model with a liver-specific adeno-associated viral knockdown of the Igf1 gene using Cre-lox technology (Igf1(f/f) + MUP-iCre-AAV8), which exhibits a significant decrease in circulating IGF-1 levels (~50%). In the aortas of IGF-1-deficient mice, there was a trend for decreased expression of Nrf2 and the Nrf2 target genes GCLC, NQO1 and HMOX1. In cultured aorta segments of IGF-1-deficient mice treated with oxidative stressors (high glucose, oxidized low-density lipoprotein, and H(2)O(2)), induction of Nrf2-driven genes was significantly attenuated as compared with control vessels, which was associated with an exacerbation of endothelial dysfunction, increased oxidative stress, and apoptosis, mimicking the aging phenotype. In conclusion, endocrine IGF-1 deficiency is associated with dysregulation of Nrf2-dependent antioxidant responses in the vasculature, which likely promotes an adverse vascular phenotype under pathophysiological conditions associated with oxidative stress (eg, diabetes mellitus, hypertension) and results in accelerated vascular impairments in aging.
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Drug safety evaluation of rosuvastatin.
Expert Opin Drug Saf
PUBLISHED: 10-18-2011
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Rosuvastatin is a highly efficacious statin approved for use throughout the world. Rosuvastatin has been exhaustively evaluated in the setting of a broad variety of dyslipidemias and cardiovascular disease states in clinical trials encompassed within the GALAXY program.
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Protamine reversal of low molecular weight heparin: clinically effective?
Blood Coagul. Fibrinolysis
PUBLISHED: 10-01-2011
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Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1-4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness. We retrospectively studied the effect of emergency reversal of LMWH with protamine in actively bleeding patients and patients requiring emergency surgery in our institution. Eighteen patients were identified through haematology referral/pharmacy records of protamine prescriptions between 1998 and 2009. Case notes were checked for the reversal indication, type/dose of LMWH, dose and clinical response to protamine, timing in relation to the last dose of LMWH and anti-Xa levels before and after protamine. All but one patient received enoxaparin. Fourteen were actively bleeding, three required emergency surgery without active bleeding and one had an accidental overdose without bleeding. The three patients requiring surgery had an uneventful procedure. In 12 of 14 patients with active bleeding, protamine could be evaluated. Bleeding stopped in eight. In the four with continuing bleeding, one had an additional coagulopathy. Protamine only partially affected anti-Xa levels. Protamine may be of use in reversing bleeding associated with LMWH but not in all patients. Anti-Xa levels were useful to assess the amount of anticoagulation before protamine administration but unhelpful in assessing its effect. Better reversal agents and methods to monitor LMWH therapy are required.
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CETP Inhibition: does the future look promising?
Curr Cardiol Rep
PUBLISHED: 09-13-2011
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Based on epidemiologic studies conducted throughout the world, it is established that there is an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk for coronary artery disease (CAD). The incidence of low HDL-C is high and increasing throughout the world. A variety of pharmacologic approaches are being developed to therapeutically modulate serum levels of HDL-C. One controversial approach to this is the use of molecules that inhibit the activity of cholesteryl ester transfer protein (CETP), an enzyme involved in neutral lipid transfer between lipoproteins. The inhibition of CETP can lead to substantial elevations in HDL-C. Based on a number of considerations, including the complex relationship between loss of function mutations in CETP and risk for CAD and the clinical experience with torcetrapib, it is difficult to predict if CETP inhibition will be associated with reductions in rates of atherosclerosis disease progression and risk for cardiovascular events.
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[Myocardial infarction associated with oral contraceptive use, smoking and elevated cholesterol level in a young patient].
Orv Hetil
PUBLISHED: 08-26-2011
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Oral hormonal contraceptives are the safest methods for young patients to avoid unwanted pregnancy. They are well accepted and have certain beneficial effects; however, physicians should pay attention to risk factors even when applied in young age. Obesity, dyslipidemia, smoking and oral contraceptive pills alone or in combination may lead to serious adverse events. Authors present a young woman who developed acute myocardial infarction in association with several unconsidered risk factors including the use of contraceptive pills.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.