The Heart

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World Thrombosis Day sees new focus on risk of blood clots in cancer that 20% of patients may unknowingly face

AntiCoagulation Europe and LEO Pharma today announced the launch of a wide-reaching Cancer-Associated Thrombosis (CAT) awareness, education and support campaign. CAT is a major cause of death in patients with cancer and up to 1 in 5 people with cancer will develop a clot.1

Teresa, who was diagnosed with breast cancer and suffered a clot, following the death of her husband from CAT, welcomed the launch of the materials. "When you are diagnosed with cancer, blood clots are the last thing you are thinking about. The word 'cancer' conjures all sorts of emotions and you are very much focused on the cancer and the treatment you are being offered. I urge people who have been diagnosed with cancer to ask their doctor or nurse about their risk of blood clots."

The campaign is launching with an alert card to be provided to cancer patients following diagnosis to ensure they are aware of the risk of CAT and an educational video 'Cancer, blood clots and you' to educate people on how to avoid clots or what to do if they do suffer one. Cancer charities all over the UK and Ireland are being encouraged to show support for World Thrombosis Day by hosting educational content on CAT on their websites and social media feeds. The materials have also been made available via the AntiCoagulation Europe website at: http://www.anticoagulationeurope.org/cancer-blood-clots

Professor Annie Young, Professor of Nursing at Warwick Medical School, University of Warwick and Honorary Nurse Consultant, University Hospitals Coventry and Warwickshire [UHCW] said: "Obviously there is a great deal to take in when someone is first diagnosed with cancer and a huge amount of information is given at the time. As such, the risk of overwhelming anyone in this situation is all too real - particularly when adding an additional complication to the mix. Nevertheless, it is vitally important that patients are informed of the risk of clots early after diagnosis as more than 50% of cases of CAT occur in the first 3 months after diagnosis."

The launch coincides with the launch of The Three Cs Report (Cancer Chemotherapy and Clots), a report commissioned by the All Party Parliamentary Thrombosis Group to establish the links between cancer, cancer treatment and the increased risks of VTE in England and Wales. The findings of this report paint a worrying picture across the whole of England and Wales for cancer patients as results show that only 41% of Trusts have a dedicated policy or pathway for the management of suspected VTE in patients receiving chemotherapy.

Thromboembolism or blood clots are one of the leading causes of death in patients with cancer, yet the risk of CAT is not commonly discussed with patients.2-4 Preventing and treating CAT is an important focus and is aligned to the current UK forward-looking strategy for cancer put forward in 2014. Currently, low-molecular weight heparin for a course of 6-months is the NICE-recommended treatment for CAT.5

Eve Knight, Chief Executive and Co-founder of Anticoagulation Europe (UK), a charity whose aim is the prevention of thrombosis and the provision of information, education and support said, "Although it is not widely known, cancer patients are at an increased risk of blood clots and getting the right treatment to avoid recurrence is vital. There are approximately 50,000 cancer patients living with Cancer Associated Thrombosis in the UK and greater awareness of this issue is important to reduce deaths which could potentially be avoided."

About Cancer Associated Thrombosis (CAT)

For the general population, the standard treatment for acute venous thromboembolism (VTE) consists of initial therapy with a low-molecular-weight heparin (LMWH) followed by longer-term treatment (3-6 months) with an oral vitamin K antagonist (VKA). Although this approach can be effective for many patients, cancer patients have a substantial risk of recurrent VTE. Several studies have reported incidences of recurrent VTE as high as 20% in patients with cancer.6,7 However, studies on how to treat and identify those at risk of recurrent VTE are limited.8,9 Moreover, the frequent monitoring and dose adjustments required for VKA treatment have a negative impact on Quality of Life.10

Guidelines in Europe and North America recommend extended (at least 6 months) treatment of symptomatic VTE with LMWH in all cancer patients.5,11-14 The major treatment objective is to reduce recurrent thrombosis, including fatal and non-fatal pulmonary emboli (PE).

For more information, visit www.CAThrombosis.com

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Treating aortic aneurysms through virtual reality

Approach addresses problematic visualization of the area needing treatment

Virtual models can be created in the angiography room thanks to an approach developed by researchers at the University of Montreal Hospital Research Centre (CRCHUM) and the university's departments of radiology, radiation oncology, and nuclear medicine. The latest advances were presented by Dr. Gilles Soulez at the Cardiovascular and Interventional Radiology Society of Europe (CIRSE) conference on September 27, 2015.

For 25 years, Dr. Soulez has been involved in developing medical imaging technologies to prevent complication for, operate on, and monitor patients with abdominal aortic aneurysms. The main problem has been the ability to properly visualize the area to be treated. "Remarkable advances in imagery have improved surgery and helped to develop less invasive interventions. But the images are still far from being perfect. We want to develop new software to maximize the use of images generated with current ultrasound, scanning, and magnetic resonance imaging (MRI) technologies to ultimately provide more personalized treatments," he explained.

On the screen is a coloured image of an abdominal aorta, a large blood vessel that begins at the heart and travels down to the abdomen distributing blood throughout the body. But there's something wrong with the photo: an enlarged area that looks like a small balloon. It's an abdominal aortic aneurysm, a disease caused by weakening of the vessel wall. Linked to atherosclerosis risk factors such as hypertension and smoking, the disease is the 13th cause of death in North America. It especially affects men. "If you have a ruptured aneurism, you have a one in two chance of dying," Dr. Soulez said.

To operate, or not to operate?

Currently, a simple abdominal ultrasound or measurement of the aorta with a scanner can detect patients at risk of aneurysm rupture. Beyond 5 cm for women and 5.5 cm for men, surgery is usually recommended. But operations have their own risks, so researchers want to refine screening to provide the most appropriate treatments for patients who really need surgery.

To avoid rupturing the small balloon formed by the abdominal aortic aneurysm, two treatment options exist: open surgery to replace the diseased section or endovascular grafting, in which a catheter is inserted in the groin to deliver a stent-graft through the blood vessels to the aneurysm. This option is less invasive, but in some patients, the morphology of the aneurysm is not suited to this kind of treatment. Using scanner images, Soulez's research provides three-dimensional images of all components of the aneurysm, i.e., the light, the thrombus or clot, the wall, and the calcification. "The grid is used to establish growth profiles of the aneurysm. We are now working to create simulations to better predict the risk of rupture, adding biomechanical properties such as tissue elasticity and connectivity at each pixel of the grid," he explained.

Virtual reality

Simulations will also help in the operating room. Currently, the operation is performed using static images taken by a scanner before the procedure. The procedure itself is done under fluoroscopy by injecting dye into the vessels to be treated. "The image produced by X-ray shows the dye in the vessels and the stent being inserted, but not the wall. This approach requires a lot of dye, which can be toxic for the patient if used in excessive amounts," said the radiologist.

It's thanks to a grant from the Canadian Institutes of Health Research (CIHR), in partnership with Siemens, that Dr. Soulez's laboratory has been able to develop this approach that combines all available data. "We superimpose the images, and this helps to visualize the area to be treated. But in reality, the tools we introduce into the body during the procedure deform the organs. We are testing at the CHUM and in Halifax right now a new approach that uses a computer to automatically recognize the tools introduced into the body and correct the deformities they cause," he said. "We hope this simulation-operation model will improve the accuracy of the procedure."

Dr. Soulez's research in interventional radiology also aims to ensure that the "plumbing" installed in patients fits in place. Sometimes the pipes leak, which can cause an aneurysm rupture, which is what was trying to be avoided in the first place. Following the stent-graft operation, patients have an annual scan. A new ultrasound technology called elastography that was developed in collaboration with Guy Cloutier, also of the University of Montreal Hospital Research Centre, holds the promise of not only effectively identifying leaks, but also evaluating how the aneurysm is healing. And finally, the last word in endovascular repair is the bioactive stent and injection of a gel around the implant to prevent or stop leaks. These new biomaterials are being developed in collaboration with Soulez and Cloutier's colleague Sophie Lerouge.

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Treatment for heparin-induced blood disorder revealed in structure of antibody complex

A potential treatment for a serious clotting condition that can strike patients who receive heparin to treat or prevent blood clots may lie within reach by elucidating the structure of the protein complex at its root, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The team's work, published in Nature Communications, established that an antibody that disrupts the complex may have therapeutic potential. Almost 12 million patients are given heparin annually either as treatment for clots or to prevent clot formation, for example, during cardiopulmonary bypass surgery.

Form and Function
This is the structure of the components of the antigen-antibody complex at the root of HIT.
Credit: Perelman School of Medicine, University of Pennsylvania; Nature Communications

A team from the lab of Mark Greene, MD, PhD, the John W. Eckman Professor of Medical Science, including Zheng Cai, PhD, senior research investigator, as well as the lab of Douglas Cines, MD, director of the Coagulation Laboratory and a professor of Pathology and Laboratory Medicine, solved the crystal structure of the pathogenic immune complex and elucidated the structural basis by which another, potentially therapeutic, antibody disrupts this structure.

HIT (heparin-induced thrombocytopenia) is an autoimmune blood disorder caused by complexes that form among these components: platelet factor 4 (PF4), which is released when platelets are activated; heparin; and antibodies to PF4.

As many as one percent of patients who receive a certain type of heparin for at least five days develop HIT. These patients make antibodies that bind to the heparin-PF4 complex. These antibodies in turn trigger platelets to form clumps. These aggregates, along with other cells, cause blood clots to form, leading to an overall decrease in platelets.

About half of all patients with HIT also develop arterial or venous clotting, which is often recurrent and can be deadly or require amputation. Current therapy with intense and irreversible anticoagulation lowers the risk of recurrence, but the risk of limb loss and death remain high and the risk of bleeding as a result of therapy is considerable. HIT can be difficult to diagnosis definitely, leading to many patients receiving this high-risk therapy unnecessarily. This treatment conundrum has prompted the search for new ways to treat HIT.

Deconstructing to Construct

The team started their hunt by detailing the structure of the components of the antigen-antibody complex at the root of HIT. First, they solved the crystal structure of PF4 in the presence of a critical part of the heparin molecule. In the blood, PF4 molecules can exist singly as monomers, doubly as dimers, and as a four-part complex called a tetramer, which have an "open" end and a "closed" end.

Their new crystal structure showed that heparin bound to the "closed" end of the PF4 tetramer, which stabilized the tetramer. They next solved the crystal structure of PF4 in complex with a pathogenic antibody called KKO. Developed by coauthor Gowthami Arepally at Duke University, with coauthors Mortimer Poncz and Lubica Raouva, from The Children's Hospital of Philadelphia, KKO causes a HIT-like disease in a mouse model.

This crystal structure revealed that KKO bound to the "open" end of the stabilized tetramers, making contact with three out of four monomers in the tetramer. This helped to explain the requirement for heparin as a backbone for the complex. This finding provides new insight into how a normal host protein, in this case PF4, can be converted into a target of the host immune system, leading to the development of an autoimmune disorder.

They studied a second antibody developed by Arepally, called RTO, which also binds to PF4, but does not cause a HIT-like disease. They found that in the crystal structure of PF4 in complex with RTO, this antibody bound to PF4 monomers rather than tetramers.

More importantly, RTO binds to PF4 monomers in a way that the team predicted would prevent PF4 monomers from combining into tetramers. They then confirmed that RTO prevented formation of antigenic complexes, activation of platelets by KKO and by human HIT antibodies in cell experiments. The researchers also prevented clot formation caused by KKO in a mouse model of HIT.

The upshot of this sequence of experiments is that binding of RTO to PF4 monomers prevents formation, and indeed disrupts, pathogenic complexes that are central to the pathology of HIT. The investigators believe that the antibody RTO will provide the basis for new diagnostics and may pave the way for a therapy to stop the disorder early in its progression.

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A walk around the office can reverse vascular dysfunction caused by hours at a computer

Across the country, many employees are seated at desks for the majority of an eight-hour workday. As technology creates an increase in sedentary lifestyles, the impact of sitting on vascular health is a rising concern. Now, researchers from the University of Missouri School of Medicine have found that when a person sits for six straight hours, vascular function is impaired -- but by walking for just 10 minutes after a prolonged period of sitting, vascular health can be restored.

"It's easy for all of us to be consumed by work and lose track of time, subjecting ourselves to prolonged periods of inactivity," said Jaume Padilla, Ph.D., an assistant professor of nutrition and exercise physiology at the MU School of Medicine and lead author of the study. "However, our study found that when you sit for six straight hours, or the majority of an eight-hour work day, blood flow to your legs is greatly reduced. We also found that just 10 minutes of walking after sitting for an extended time reversed the detrimental consequences."

During the study, the researchers compared the vascular function of 11 healthy young men before and after a period of prolonged sitting. The findings indicated that blood flow in the popliteal -- an artery in the lower leg -- was greatly reduced after sitting at a desk for six hours. Researchers then had the participants take a short walk, and found that 10 minutes of self-paced walking could restore the impaired vascular function and improve blood flow.

"When you have decreased blood flow, the friction of the flowing blood on the artery wall, called shear stress, is also reduced," Padilla said. "Moderate levels of shear stress are good for arterial health, whereas low levels of shear stress appear to be detrimental and reduce the ability of the artery to dilate. Dilation is a sign of vascular health. The more the artery can dilate and respond to stimuli, the healthier it is."

Many workplaces are sedentary environments, and the researchers said it's important that people understand the effects of sitting on their vascular health. By breaking up desk time with a short walk, workers can offset the harm caused to vascular blood vessels.

"Studies have shown that sitting less can lead to better metabolic and cardiovascular health," Padilla said. "However, more research is needed to determine if repeated periods of reduced vascular function with prolonged sitting lead to long-term vascular complications."

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Self-assembling material that grows and changes shape could lead to artificial arteries

Researchers at Queen Mary University of London (QMUL) have developed a way of assembling organic molecules into complex tubular tissue-like structures without the use of moulds or techniques like 3D printing.

The study, which appeared on Monday 28 September in the journal Nature Chemistry, describes how peptides and proteins can be used to create materials that exhibit dynamic behaviors found in biological tissues like growth, morphogenesis, and healing.

The method uses solutions of peptide and protein molecules that, upon touching each other, self-assemble to form a dynamic tissue at the point at which they meet. As the material assembles itself it can be easily guided to grow into complex shapes.

This discovery could lead to the engineering of tissues like veins, arteries, or even the blood-brain barrier, which would allow scientists to study diseases such as Alzheimer's with a high level of similarity to the real tissue, which is currently impossible. The technique could also contribute to the creation of better implants, complex tissues, or more effective drug screening methods.

Alvaro Mata, Director of the Institute of Bioengineering at QMUL and lead author of the paper, said: "What is most exciting about this discovery is the possibility for us to use peptides and proteins as building-blocks of materials with the capacity to controllably grow or change shape, solely by self-assembly.

Growing Tubes
The protein/peptide system can grow on demand by simply displacing the interface.
Credit: QMUL
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ACP: Doctors should stratify patients with suspected PE to determine diagnostic strategy

Overuse of computed tomography and D-dimer testing may not improve care and lead to patient harm and unnecessary expense

When evaluating patients with suspected acute pulmonary embolism (PE), physicians should stratify patients into groups for whom different diagnostic strategies are appropriate, the American College of Physicians (ACP) advises in a new paper published in Annals of Internal Medicine.

"The use of computed tomography (CT) for the evaluation of patients with suspected pulmonary embolism is increasing despite no evidence that this increased use has led to improved patient outcomes, while exposing patients to unnecessary risks and expense," said ACP President Dr. Wayne J. Riley. "ACP's advice is designed to help physicians identify patients for whom a PE is so unlikely that they need no further testing, for whom plasma D-dimer testing can provide additional risk stratification, and for whom imaging is indicated because of their high risk and clinical presentation."

A serum d-dimer test is a blood test to check for the presence of blood clots.

The first step for physicians when evaluating patients with suspected acute PE is to use a validated clinical prediction rule to estimate their pre-test probability of PE. The benefit of such a decision tool is that it helps standardize the evaluation for physicians who infrequently encounter and/or evaluate patients for PE, ACP advises. The Wells and Geneva rules have been validated and are considered equally accurate in predicting the probability of PE.

In patients who have a low pre-test probability of PE, physicians should apply the PERC (Pulmonary Embolism Rule-Out Criteria) rule. Physicians should not obtain D-dimer tests or imaging studies in patients with a low pre-test probability of PE and who meet all eight PERC.

Patients who have an intermediate pre-test probability of PE or patients with low pre-test probability of PE who do not meet all PERC should have a high sensitivity D-dimer test as the initial step in diagnosis. Physicians should not use imaging studies as the initial test in patients who have a low or intermediate pre-test probability of PE.

Since normal D-dimer levels increase with age, physicians should use age-adjusted D-dimer thresholds (age times 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine whether imaging is warranted. Physicians should not obtain any imaging studies in low or intermediate risk patients with a D-dimer below the age-adjusted cutoff.

"While highly sensitive, plasma D-dimer testing is nonspecific and false-positives can lead to unnecessary imaging," said Dr. Ali S. Raja, Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital, who co-authored the paper for ACP's Clinical Guidelines Committee. "The use of an age-adjusted threshold resulted in maintenance of sensitivities with improved specificities in all age groups."

Patients with high pre-test probability of PE should obtain imaging with CT pulmonary angiography. Physicians should reserve V/Q scans for patients who have a contraindication for CT pulmonary angiography or if CT pulmonary angiography is not available. Physicians should avoid obtaining a D-dimer measurement in patients with a high pre-test probability of PE.

A pulmonary embolism is a sudden blockage in a lung artery. The cause is usually a blood clot in the leg called a deep vein thrombosis that breaks loose and travels through the bloodstream to the lung.

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Smoking increases hospitalizations, costs of peripheral artery disease

Researchers say clinicians should focus on smoking cessation

An analysis of medical costs associated with atherosclerotic lower extremity peripheral artery disease, a dangerous condition in which a buildup of plaque in the arteries restricts blood flow to the legs and feet, found that health care costs in one year were $18,000 higher in smokers with the condition than non-smokers with the condition.

Within one year, 49 percent of the tobacco users with PAD in the study were hospitalized, a hospitalization rate 35 percent higher than nonusers.

The study published online today in the Journal of the American College of Cardiology, found smokers are more likely to be hospitalized for leg events, heart attack and coronary heart disease related to atherosclerotic peripheral artery disease, known as PAD, than non-smokers with PAD.

Researchers from the University of Minnesota Medical School, led by Sue Duval, PhD, analyzed claims data for 22,203 individuals with PAD from 2011 from the largest health plan in Minnesota.

An accompanying editorial by Elizabeth Jackson, M.D., MPH, of the University of Michigan Health System, said the study highlights the urgent need for smoking cessation among PAD patients and getting patients to quit can improve care and save significant health dollars over the long term.

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New guideline aims to help physicians manage deep vein blood clots in patients

A new Canadian guideline aims to help physicians identify and manage blood clots, specifically iliofemoral deep vein thrombosis (DVT), in the groin and thigh.

Iliofemoral DVT, and associated pulmonary embolism, is a potentially fatal condition that affects over 35 000 Canadians a year, with an estimated 60 000 admissions to hospital per year. The guideline, based on the latest evidence and published in CMAJ (Canadian Medical Association Journal), was developed by a team of hematologists, interventional radiologists, vascular surgeons, emergency department physicians and primary care physicians..

"We think this clinical practice guideline fills an important gap in knowledge for care providers by providing a practical approach to a common problem that can have serious implications for patients. The guideline takes into consideration the Canadian socialized health care model and is based on early recognition by primary care providers," states Dr. David Liu, an interventional radiologist at Vancouver General Hospital and lead author of the INTERdisciplinary Expert Panel on Iliofemoral DVT (InterEPID). "Complications associated with DVT can occur years after the presentation of DVT if it is not managed at onset. DVT is a life-threatening condition in the short term, with long- term implications to the patient and (significant downstream cost to) society if not managed properly."

"The InterEPID guideline assists in determining which patients may benefit from early triage and transfer to tertiary care institutions for clot removal and reduction, a critical aspect in both the short-term and long-term management of this condition," states coauthor Dr. Mark Baerlocher.

The guideline team has created a summary of recommendations and a decision tool to help physicians. Highlights include the following:

All hospital staff must have the diagnostic tools to diagnose and determine the severity of iliofemoral DVT. Anticoagulants are recommended for all patients with iliofemoral DVT, but the type and length of treatment will vary according to presentation.

For patients not able to take anticoagulants, use of inferior vena cava filters is recommended with regular follow-up; they should be removed as soon as possible.

Immediate intervention with clot removal is recommended in patients with phlegmasia cerulea dolens to reduce the associated risks of amputation and death.

Clot removal intervention can also be considered for patients who are at low risk of bleeding to minimize possible long-term complications from iliofemoral DVT that may decrease quality of life (postthrombotic syndrome). To manage postthrombotic syndrome, the use of compression stockings is recommended, although the evidence is weak for effectiveness.

Patient follow-up by the primary care physician is important.

"Anticoagulant therapy remains the cornerstone of management, mainly to prevent recurrent venothromboembolism. However, selected patients with iliofemoral DVT may benefit from alternative clot-management strategies, such as inferior vena cava filters, compression therapy, and clot removal or reduction strategies."

"There is often a somewhat disorganized and varied approach to treating iliofemoral thrombosis. This guideline is meant to help standardize the care of Canadian patients with this common condition," the authors conclude.

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Scientists publish first complete record of genetic mutations behind rare vascular disease

The genetic architecture of a debilitating and potentially fatal vascular disease has for the first time been detailed in its entirety, providing clinicians with the comprehensive data needed to improve diagnosis and deliver more personalised patient care.

Scientists investigating Pulmonary Arterial Hypertension (PAH) have compiled the most up to date and complete record of all the defective variations found in the genes that cause the disease.

The new study, led by Dr Rajiv Machado from the University of Lincoln, UK, draws together the complete genetic information of hundreds of individuals affected by PAH. This advance will not only offer new opportunities to identify the mutation which causes PAH in individual patients but will also provide an important tool to correlate genetic data, allowing for more tailored approaches to the clinical management of the disease. It has been published in the online academic journal Human Mutation.

PAH is an often fatal disorder resulting from several causes, including an assortment of genetic defects. It is a progressive disease characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Symptoms are shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Heritable PAH leads to a chronic elevation of pulmonary arterial pressure, which can result in heart failure.

While mutations in a gene called BMPR2 are the single most common cause for hereditary cases, mutations capable of causing disease have been observed in approximately 25 per cent of patients without a prior family history of disease.

The new study, which brings together data from specialist PAH centres based in Germany, France, North America and the UK, describes molecular genetic analyses of the 10 functionally characterised genes that cause PAH and provides a compilation of all mutations identified to date.

It also describes an additional 370 independent mutations of BMPR2 in patients, either previously excluded from or identified since the last comprehensive mutation update by Dr Machado and colleagues in 2009. Of these, 81 are new variations.

Dr Machado, from the University of Lincoln's School of Life Sciences, said: "This is the most comprehensive and complete compilation of all defective variations in the genetic risk factors for PAH. This will allow the clinical geneticists, with a greater degree of certainty, to conclude that the gene variations present in a patient are either disease causing or of unknown significance. This could inform a patient's decisions about starting a family or undertaking pre-natal testing. Prior to this a clinician would have to try and understand genetic data received for a single patient by trawling through historic manuscripts to make a diagnosis. This report has the potential to be of great importance to the diagnostic centres around the world.

"The continuing identification of genetic factors, as explored in this paper, provides unique insight to the genetic mechanisms driving disorders of pulmonary vascular function. These data provide a key resource in data interpretation and how these genetic insights may lead to the potential discovery and delivery of novel targeted therapeutic options in PAH."

This important resource of clinical and scientific data has now been posted on a freely available public repository, namely ClinVar, and will be accessible through Dr Machado's Lincoln profile page.

The emergence of next-generation sequencing (NGS) allows scientists to sequence much more quickly and cheaply, and as such has revolutionised the study of genomics and molecular biology. NGS has allowed researchers to identify novel, rare genetic variations in the PAH disease spectrum, detailed in this study. It is likely that future avenues will include the use of more NGS technologies, the pinnacle of which is whole-genome sequencing - a process that determines the complete DNA sequence of an organism's genome at a single time.

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UCLA researchers discover new method to measure artery stiffness in the human brain

UCLA researchers have discovered a non-invasive method to measure vascular compliance, or how stiff an artery is, in the human brain, a finding that may have ramifications for preventing stroke and the early diagnoses of Alzheimer's disease.

Using a new MRI technique, the UCLA team measured the volume of cerebral arteries twice using a technique called Arterial Spin Labeling, which can magnetically "label" the blood in arteries without the use of an external agent. The team measured once at the systolic phase of the cardiac cycle, when the heart was pumping the blood into the brain, and again at the diastolic phase, when the heart was relaxing.

That team found that the stiffer the arteries were, the smaller the change in the arterial blood volume between the two cardiac phases, because stiff arteries are not as able to change shape or comply with the blood pressure changes as elastic arteries are, said study senior author Danny J.J. Wang, an associate professor of neurology and a researcher in the Ahmanson-Lovelace Brain Mapping Center at UCLA.

"Vascular compliance is a useful marker for a number of cardiovascular diseases, such as hypertension and diabetes," Wang said. "Growing evidence suggests intracranial vascular pathology also may be associated with the origin and progression of cerebrovascular disorders and neurodegenerative diseases, such as Alzheimer's disease, which is the sixth leading cause of death in the United States. However, to date, few methods are available to assess it."

The study appears this week in the peer-reviewed journal NeuroImage.

The UCLA team compared stiffness measurements in young and elderly patients, and found that arterial stiffness is significantly increased in elderly patients. This finding is consistent with the theory that aging is associated with stiffening of the arteries. They also found that increased arterial stiffness is associated with reduced cerebral blood flow, suggesting stiff arteries impair the blood supply to the brain. Additionally, they found artery stiffness is correlated with the stiffness of the largest artery of the human body, the aorta.

"We hope our technique can provide an early marker for a number of socioeconomically important diseases like Alzheimer's," said study first author Lirong Yan, an assistant researcher in the UCLA Department of Neurology. "A number of studies suggest that vascular dysfunctions, including arterial stiffening, are associated with the development of Alzheimer's. The development of early bio- or imaging markers for Alzheimer's is of great importance for slowing disease progression. Hardened arteries due to the accumulation of plaques on the vessel walls also is linked to cerebrovascular disorders such as stroke. We hope our technique may provide an early marker for the prevention of stroke."

The need for a new approach to treatment of Alzheimer's disease is urgent. Alzheimer's is the most common age-related dementia and the number of cases in the United States is expected to increase from the current number of about five to six million to 15 million by 2050. The costs to family life and on the health care system are enormous. Alzheimer's and other dementias are projected to cost the United States $226 billion in 2015 alone, with that number rising to as high as $1.1 trillion in 2050.

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Childhood kidney stones associated with atherosclerosis, study shows

A recent study published in the Journal of Pediatrics is the first to examine and identify a link between kidney stones in children and thickened or hardened arteries -- precursors to a wide variety of cardiovascular diseases. Understanding the connection between kidney stones and cardiovascular risk factors in children may help physicians and parents implement prevention measures to reduce future risk of stroke, heart attack or other forms of vascular disease for affected children.

Kidney stones in kids are increasingly common, and until recently they were believed to be an isolated medical problem. Research has established a connection between kidney stones and atherosclerosis in adults, but this study, conducted by clinician-scientists at Nationwide Children's Hospital, is the first to identify a significant association between the two health concerns in children.

"If the processes of kidney stone formation and hardening of the arteries are somehow linked in adults, it makes sense that a similar link may exist in children, despite the fact that people don't associate heart and vascular diseases with kids," said Kirsten Kusumi, MD, a nephrology fellow at Nationwide Children's and lead author on the paper. "We wanted to learn whether and why children who have kidney stones may already be showing damage to their arteries."

The study used ultrasound exams to evaluate and compare the thickness of key arteries for 15 children with kidney stones and 15 children without them. None of the participants were diagnosed with conditions known to cause atherosclerosis, so that any damage to the arteries could reasonably be associated with children's kidney stones.

Dr. Kusumi and her collaborators detected a significant increase in the thickness of the right carotid artery and average artery thickness -- potential risk factors for cardiovascular complications or disease -- in children with a recent kidney stone.

"Our findings suggest that there is something going on in the body related to kidney stone formation that also impacts the health of children's arteries," said Dr. Kusumi, who also is a researcher in the Center for Clinical and Translational Medicine at The Research Institute at Nationwide Children's.

The study shows the first evidence of early vascular disease in children with kidney stones who are free of accompanying risk factors in adults, and it points to these children having increased cardiovascular risk that has not been previously recognized.

"Now that we have a clear indication that the association between kidney stones and arterial thickening or hardening begins in childhood, we can take steps as clinicians to treat these vascular symptoms or implement preventive measures, such as exercise and diet programs," Dr. Kusumi says.

The researchers have not yet defined the exact mechanism that connects kidney stones to vascular hardening, but they hypothesize that inflammation may play an important role. The team screened the urine of participants for different biomarkers. In the urine of children with arterial abnormalities, key inflammatory markers appeared at higher levels.

"It could be that different types of kidney stones have different causes and even different risk factors," said Andrew Schwaderer, MD, research director of Nephrology at Nationwide Children's, principal investigator in the Center for Clinical and Translational Medicine and senior author on the publication. "If we can determine what is going on in the body to cause both kidney stones and atherosclerosis, we may be able to simultaneously target or treat both conditions."

Dr. Kusumi and Dr. Schwaderer are already studying the potential shared mechanisms for kidney stones and vascular health problems in animals. They are also expanding their studies of urine biomarkers to obtain new clues about the subtypes of kidney stones and potential molecular processes at play in both conditions.

"Our ultimate goal is to help practitioners identify and treat childhood kidney stones with improved accuracy and attention to a child's overall health. Long term, we hope to improve these children's cardiac morbidity and mortality as is done for other diseases such as diabetes and hypertension," Dr. Kusumi says. "If kidney stones are putting children at risk for serious cardiovascular problems as adults, we need to know sooner rather than later so that we can intervene and make a difference in their future health."

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Risk of stroke at time of carotid occlusion

Preventing carotid artery occlusion (blockage) may not be a valid indication for stenting because the risk of progression to occlusion appears to be below the risk of carotid stenting or endarterectomy (surgical removal of plaque from an artery), according to an article published online by JAMA Neurology.

Increasing evidence indicates that with intensive medical therapy most patients with asymptomatic carotid stenosis (ACS) are more likely to be harmed than to benefit from carotid endarterectomy or carotid stenting. Many of these procedures are performed with the objective to prevent carotid occlusion because the underlying assumption is that carotid occlusion would carry a high risk of stroke.

J. David Spence, M.D., of Western University, Ontario, Canada, and coauthors looked at the risk resulting from progression to occlusion among patients with ACS. They assessed the role of severity of carotid stenosis or the presence of contralateral (on the opposite side of the body) occlusion as factors that may predict the risk of stroke or death after occlusion of a previously asymptomatic carotid stenosis.

The authors analyzed data collected from patients at stroke prevention clinics from 1990 through 1995 or from 1995 through 2012. The authors measured ipsilateral stroke (on the same side of the body as the carotid artery blockage), transient ischemic attack, death from ipsilateral stroke or death from unknown cause.

The study reports that among 3,681 patients, 316 patients were asymptomatic before the initial occlusion. The average age of patients was 66, most patients were men and most had high blood pressure and hyperlipidemia. Most new occlusions (254 of 316) occurred before 2002, when medical therapy was less intensive.

Only one patient (0.3 percent) had a stroke at the time of the occlusion and only three patients (0.9 percent) had an ipsilateral stroke during follow-up. Analyses suggest that neither severity of stenosis nor contralateral occlusion predicted the risk of ipsilateral stroke or transient ischemic attack, death from stroke or death from unknown cause.

"Patients with carotid stenosis are at high risk of death, but as indicated in Table 2, most of the deaths are not from stroke. Carotid stenting or endarterectomy can therefore not be expected to improve those outcomes," the study notes.

Study limitations include that authors did not perform brain imaging unless patients had a stroke and they did not study patients who became symptomatic and had interventions for that reason.

"The risk of ipsilateral stroke at the time of carotid occlusion was well below the risk of carotid stenting or carotid endarterectomy, and the percent stenosis or contralateral occlusion did not identify patients who would benefit from intervention. Preventing carotid occlusion may not be a valid indication for intervention," the study concludes.

In a related editorial, Seemant Chaturvedi, M.D., and Ralph L. Sacco, M.D., M.S., of the University of Miami Miller School of Medicine, write: "In this issue of JAMA Neurology, Yang et al add some 'fuel to the fire' regarding the debate concerning the best treatment for asymptomatic carotid stenosis. ... As a single-center study, the analysis by Yang et al has limitations. ... All these limitations could have led to underestimations in the risk of stroke. ... Ultimately, whether the improvements in aggressive medical therapy are sufficient to reduce the rationale for CEA (carotid endarterectomy) or CAS (carotid artery stenting) in asymptomatic patients will need to be determined by contemporary randomized clinical trials."

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One size doesn't fit all - Patients with metastatic cancer may need stronger anti-coagulation therapy following bone lesion surgery

Jefferson researchers identified a high risk for venous thromboembolism (VTE), or blood clots, following surgery for long-bone reconstruction in patients with metastatic cancer. They published the results in the Journal of Bone and Joint Surgery.

"Our study shows not only that a stronger anti-coagulation therapy may be warranted for these patients, but also that each case needs individualized attention," said senior author John A. Abraham, M.D., Associate Professor of Orthopedic Surgery and Radiation Oncology in the Sidney Kimmel Medical College at Thomas Jefferson University, Director of the Jefferson Sarcoma and Bone Tumor Center, and orthopedic surgeon specializing in orthopedic oncology at Rothman Institute at Jefferson.

The team retrospectively reviewed 336 cases where patients required intramedullary nailing for metastatic bone lesions, during which a surgeon places a metal rod into the bone to provide support. The study revealed that 24 patients (7.1 percent) developed thromboembolism in the 90 days after surgery and found a low incidence of post-operative wound complications (3.1 percent), suggesting a different anti-coagulation protocol may be tolerated.

"Venous thromboembolism, including pulmonary embolism and symptomatic deep vein thrombosis, can have devastating consequences for patients," said co-author Geno J. Merli, M.D., Professor of Medicine and Surgery in the Sidney Kimmel Medical College at Thomas Jefferson University; Co-Director of Jefferson Vascular Center; and expert in anticoagulation therapy. "Our findings underscore the importance of evaluating each patient for risk factors to select the most appropriate and effective anticoagulation therapy. In addition, patients with metastatic cancer may require extended prophylaxis to prevent deep vein thrombosis and pulmonary embolism."

"We also found that 66 percent of the patients who developed blood clots 90 days after surgery also had a primary cancer of the lung," Dr. Abraham said. "This suggests the risk for venous thromboembolism is different depending on the primary cancer. This will require a change in our way of thinking as orthopedic surgeons."

Dr. Abraham's research revealed that patients who did not receive radiation therapy after surgery had a slightly decreased risk of developing a blood clot, which approached statistical significance.

"The implications of this study are quite broad. It demonstrates that skeletal metastatic disease is not just one simple entity, but rather a complex process that has specific effects associated with each individual primary disease," said Atrayee Basu-Mallick, M.D., Clinical Assistant Professor in the Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, who was not involved in the study. "It also highlights the importance of having a team approach to skeletal metastases, which includes the oncologic, medical, radiation, and surgical teams. It should change the way most cancer centers approach skeletal metastases."

Dr. Basu-Mallick, who is also the Medical Program Director of the Center for Sarcoma and Bone Tumor Oncology at Jefferson, pointed out that more studies are needed to prove that a longer duration of anticoagulation is needed for patients with skeletal metastases after surgery to help reduce rates of thromboembolic events in this vulnerable population.

In light of these findings, Dr. Abraham and his team recommend physicians consider a patient's primary cancer while selecting the anti-coagulation therapy following surgery for intramedullary nailing and close coordination with the patient's medical oncology team.

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Whole-body PET scan with new imaging agent can locate hidden blood clots

A novel radiopharmaceutical probe developed at Massachusetts General Hospital (MGH) has the potential of providing physicians with information that could save the lives of patients with ischemic stroke or pulmonary embolism - conditions caused when important blood vessels are blocked by a clot that has traveled from another part of the body. In a report that will appear in the October issue of the journal Arteriosclerosis, Thrombosis and Vascular Biology and has been published online, the MGH team describes using this new probe to conduct full-body scans in an animal model. Preliminary results also were reported earlier this year at the national meeting of the American Chemical Society.

"We found that, with a single intravenous injection of our clot-finding probe 64Cu-FBP8, we were able to detect blood clots anywhere in the body using a positron emission tomography (PET) scan," says lead author Francesco Blasi, PharmD, PhD, formerly a research fellow at the Martinos Center for Biomedical Imaging at MGH and now at the University of Torino in Italy. "We also found that the probe may be able to distinguish recently formed clots from older ones - which can indicate the likelihood that a particular clot is the source the clot causing a stroke or pulmonary embolism - and reveal the composition of a clot, which can determine whether it will respond to clot-dissolving treatments."

The authors note that, although blood clots are a leading cause of illness and death, current imaging techniques for identifying the presence and location of clots only work for particular areas of the body; none is useful for all of the regions from which a clot can originate. Standard practice for identifying the source of a clot that causes a stroke may involve multiple imaging studies - ultrasound, echocardiography, MR or CT angiography - that can be both expensive and time consuming, possibly delaying the use of therapies to prevent a second stroke. Study leader Peter Caravan, PhD, of the Martinos Center and his colleagues have developed several PET imaging agents that target the protein fibrin, which is generated as part of the process of clot formation; and 64Cu-FBP8 appeared to be the most promising.

To test the probe's ability to find clots anywhere in the body, the investigators induced the formation of clots in the carotid arteries and the femoral veins of a group of rats. Whole-body imaging studies combining 64Cu-FBP8 PET and CT scanning were conducted either one, three or seven days after clot formation. The team members reading the images, who had not been informed of the precise locations where clots had been induced, accurately detected the locations 97 percent of the time. The intensity of the signal generated by 64Cu-FBP8 decreased with the age of the clot and with the amount of fibrin it contained, as confirmed by pathologic analysis. Caravan notes that, because older clots are more stable, they are less likely to be the source of a clot that caused a stroke. Since clot-dissolving drugs act by targeting fibrin, younger fibrin-rich clots are better candidates for treatment with those agents, the use of which needs to be balanced against the risk of bleeding.

"A clot causing a stroke can arise in the arteries of the neck, from the aorta in the chest, from within the heart or from veins deep within the legs; and knowing if any clot remains at those locations is important because it indicates a higher risk of a second stroke. The patient may be treated differently if that parent clot is still present than if no clot remains," says Caravan, who is an associate professor of Radiology at Harvard Medical School and co-director of the Institute for Innovation in Imaging at MGH. "A whole-body technique could also determine whether a patient's shortness of breath is caused by a pulmonary embolism and identify both the source and the extent of the parent clot in the deep veins."

Caravan and his colleagues will soon be testing 64Cu-FBP8 in human volunteers to better understand how the probe is distributed through the body and how long it remains after injection, information essential to designing studies of its diagnostic effectiveness in patients. Patent rights for the fibrin-binding peptide used in 64Cu-FBP8 have been licensed to Factor 1A, a company co-founded by Caravan. The current study was supported by National Heart, Lung and Blood Institute grant HL109448.

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Take your PICC: New guide aims to decrease dangers from long-term IV devices

More than a billion times a year, doctors and nurses insert tiny tubes into the veins of American hospital patients, so they can deliver lifesaving medicines, give fluids and nutrition, monitor key vital signs, and help patients with conditions ranging from cancer and pain to kidney failure and serious infections.

But these same devices carry risks as well as benefits - especially those designed to stay in the body for days or weeks, called PICCs, ports and central lines. They tunnel deep into the bloodstream, providing a gateway for microbes and a place for dangerous clots to form.

Yet despite their widespread and rapidly growing use, no clear guide has existed for which kind of device to use, in which patient, for the best and safest result -- and which to avoid at all costs.

Until now.

In the new issue of Annals of Internal Medicine, a team led by University of Michigan Medical School and VA Ann Arbor Healthcare System experts presents the first comprehensive guide to using intravenous, or vascular access, devices of all kinds1.

They call it MAGIC, or Michigan Appropriateness Guide for Intravenous Catheters. Based on an exhaustive review of evidence, and the expertise of top international experts in a wide range of fields, it gives clinicians an easy-to-use framework to pick the right device for each adult patient.

"PICCs, or peripherally inserted central catheters, have become especially convenient to place, and their use has gone up dramatically - as have the complications from them. The easiest way to prevent these complications is not to place a PICC in the first place. So we set out to determine when the use of a PICC is appropriate, and when other choices are the best," says lead author Vineet Chopra, M.D., M.Sc., who has studied risks from PICCS for years.

He and several of his co-authors are members of the Patient Safety Enhancement Program, a joint U-M/VA effort, and of the U-M Institute for Healthcare Policy and Innovation.

The MAGIC criteria are based on experts' review of more than 600 scenarios of different kinds of patient and treatments, and provide color-coded charts or algorithms to indicate which devices are appropriate or inappropriate in each case.

Taking the MAGIC show on the road

MAGIC is already getting its first test in 47 Michigan hospitals taking part in a patient safety project, the Michigan Hospital Medicine Safety Consortium.

Data from that same consortium recently revealed huge variation between hospitals in the use of IV devices for the same conditions. And evidence from this collaborative effort shows that patients with PICCs frequently face a risk of dangerous blood clots called deep vein thrombosis, or DVT.

The U-M/VA team will also test ways to deploy MAGIC across the Veterans Affairs health system, working with the VA National Center for Patient Safety and the No Preventable Harms Campaign. The Infusion Nursing Society is also modifying its standards to incorporate changes based on MAGIC's recommendations.

Even as they evaluate MAGIC's ability to reduce variation, improve appropriate use of different device types, and reduce complications, the team behind the new guide hopes other clinicians will begin using it.

They're preparing to launch a comprehensive website, improvepicc.com, that will offer one-stop access to the MAGIC recommendations, which include information about how clinicians should care for patients who have a vascular access device in the hospital, nursing home or at home. The site will also provide updates on issues and research related to PICCs, central lines and other vascular access issues.

"IV devices of all kinds are being put into patients without much thought about risks, benefits or alternatives. At the end of the day, we hope MAGIC will give providers the information they need to make a good decision for their patient, one that will render these devices appropriate and safe," says Chopra, an assistant professor of general internal medicine and a hospitalist, as well as a research scientist at PSEP.

How the MAGIC happened

The panel of 15 experts included doctors and nurses from a wide range of fields where PICCs and other such devices are commonly used, from vascular nursing, anesthesiology and radiology, to critical care, hospital medicine, infectious disease and oncology. Also participating: a patient who had suffered complications from various IV devices, and still lives with the consequences.

The panel evaluated the scenarios and supporting medical literature, and made its recommendations, using the RAND/UCLA Appropriateness Method.

While in most of the scenarios the experts came to a consensus on which type of device was most appropriate and which were inappropriate, MAGIC also shows where the evidence was neutral, or where experts disagreed to highlight that more research is needed.

The panel also did not consider pediatric use of PICCs and other vascular access devices, but hope their work could provide a framework for a similar effort in pediatrics.

The work that led to the MAGIC gathering and writing of the criteria was sponsored by the Society of Hospital Medicine, by a grant from the Agency for Healthcare Research and Quality (1-K08-HS022835), and by Blue Cross Blue Shield of Michigan, which funds the Michigan Hospital Medicine Safety Consortium.

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Three hours of uninterrupted sitting may damage blood vessels

Three hours of uninterrupted sitting may cause substantial disruption to vascular function in the legs in young girls, suggests a study published in Experimental Physiology.

The researchers used an experiment which involved 7-10 year old girls completing two 3-hour periods of sitting. One of these was uninterrupted and the girls sat for the entire three hours. The other was interrupted once an hour with a 10 minute moderate intensity exercise break. They assessed the health of the main artery in the leg before and after each of the 3-hour periods of sitting. Healthy artery function requires a balance in the dilation (enlargement) and constriction (narrowing) of the artery diameter, which helps to regulate blood flow. Uninterrupted sitting for 3 hours caused a 33% reduction in the ability of the artery to dilate (enlarge). A 10-minute exercise break, however, was able to prevent this adverse impact of uninterrupted sitting.

Prolonged periods of sitting can have a detrimental impact on blood vessels and has previously been shown to even change the anatomy of limb arteries in adults and leads to increased cardiovascular disease risk. Dr Ali McManus, Centre for Heart, Lung and Vascular Health at the University of British Columbia and lead author of the study commented,

'A sedentary lifestyle (excessive sitting) poses a huge health concern for adults and - as our study has shown - also for children. Only 7% of Canadian children now attain the recommended one-hour per day of moderate to vigorous physical activity and are spending up to 5 hours per day sitting.

'Inactive children later become inactive adults. Inactivity is the fourth major risk factor for global mortality, contributing to 3.2 million deaths annually. Every parent should be asking 'is the amount of time my child spends sitting harmful?'

She adds, 'Our study has shown that three hours of uninterrupted sitting is harmful. We have also shown that interrupting sitting with regular exercise breaks prevents the negative health impact from too much sitting. A modest 10% reduction in sedentary behaviour has the potential to reduce direct health care costs by $150 million a year in Canada.'

'Limiting the amount of time we spend sitting will not only result in lower health care costs and a larger and more productive workforce, but also in a reduced death and disability rate. This in turn will boost productivity and increase GDP and builds a strong case for action.

'We only studied girls in this experiment. Future work will include boys and children who are at higher risk for excessive sitting. We will also explore whether the sitting induced reductions in leg blood flow are accompanied by altered brain blood flow and cognitive function. In the longer-term we will develop 'inactivity' surveillance and intervention tools for identifying children 'at sedentary health risk' and preventing excessive sitting.'

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Inadequate sleep linked to early signs of heart disease

Not getting the right amount of sleep can compromise brain functioning and emotional wellbeing. In addition to this, a new study indicates that for young and middle-aged adults, inadequate sleep may increase the risk of early signs of heart disease developing.
A woman is lying in bed unable to sleep.
The researchers found that extreme sleep durations and poor quality of sleep were linked with elevated coronary artery calcium levels and arterial stiffness.

The study, published in the journal Arteriosclerosis, Thrombosis and Vascular Biology, found getting too much sleep, too little sleep or poor quality sleep was associated with raised levels of calcium in the coronary arteries and arterial stiffness.

"Inadequate sleep is a common problem and a likely source of poor health, including visible signs of disease, such as heart attack," reports co-lead author Dr. Chan-Won Kim, a clinical associate professor at Kangbuk Samsun Hospital, Sungkyunkwan University School of Medicine in Seoul, South Korea.

Several previous studies have demonstrated that sleeping for too long or not long enough is linked to an increased risk of cardiovascular disease (CVD) events. However, the association between sleep and the risk of CVD is not fully understood.

To investigate, a team of researchers set out to evaluate the cardiovascular health of individuals alongside the quality of how they slept.

A total of 47,309 young and middle-aged adults had their sleep duration and sleep quality assessed with a sleep questionnaire. Each participant also underwent a health examination to measure coronary artery calcium and arterial stiffness, two subclinical measures of CVD.

The presence of calcium in the coronary arteries indicated the presence of early coronary lesions. The researchers measured arterial stiffness by observing the speed of the pulse between the arteries of the upper arm and the ankle.

Inadequate sleep was linked to raised levels of coronary artery calcium. Participants who slept 5 or fewer hours a day had 50% more coronary artery calcium than those who reported sleeping 7 hours a day.

Likewise, participants who reported sleeping 9 or more hours a day had more than 70% more coronary artery calcium compared with those who slept 7 hours a day. Participants reporting poor quality of sleep had over 20% more coronary artery calcium than those who reported good sleep quality.

The researchers uncovered similar findings when assessing arterial stiffness.

"Adults with poor sleep quality have stiffer arteries than those who sleep 7 hours a day or had good sleep quality," states co-lead author Dr. Yoosoo Chang, an associate professor at Kangbuk Samsun Hospital. "Overall, we saw the lowest levels of vascular disease in adults sleeping 7 hours a day and reporting good sleep quality."

The researchers write that several mechanisms could be behind their findings. Inadequate sleep is associated with several cardiovascular health problems such as elevated blood pressure and impaired glucose metabolism.

Previous research from the team also demonstrated that not sleeping long enough and poor sleep quality are associated with an increased risk of nonalcoholic fatty liver disease - a condition that indicates a form of fat deposition linked with CVD.

They acknowledge that the study is limited by relying on self-reporting to measure sleep duration, and that inadequate sleep could also simply reflect other underlying health issues. Despite these limitations, the researchers believe their findings highlight how important sleep is for maintaining cardiovascular health.

"For doctors, it might be necessary to assess patients' sleep quality when they evaluate the cardiovascular risk and the health status of men and women," Dr. Kim concludes.

Recently, Medical News Today reported on a study demonstrating that a lack of sleep could increase the risk of catching the common cold.

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Researchers identify mechanism that impairs blood flow with aging

With the world's elderly population expected to double by 2050, understanding how aging affects the body is an important focus for researchers globally. Cardiovascular disease, the No. 1 cause of death worldwide, often is associated with aging arteries that restrict blood flow. Now, University of Missouri researchers have identified an age-related cause of arterial dysfunction, a finding that could lead to future treatments for some forms of vascular disease.

"Aging affects everyone and causes changes throughout our bodies," said Erika Boerman, a postdoctoral fellow in the Department of Medical Pharmacology and Physiology at the MU School of Medicine and lead author of the study. "The purpose of our study was to understand how blood vessels are affected by this process. We found that older arteries had a significantly lower number of sensory nerves in the tissues surrounding them and they were less sensitive to an important neurotransmitter responsible for dilation."

Boerman's study focused on mesenteric arteries - a type of artery that supplies blood to the small intestines - of mice that were 4 months and 24 months old. These ages correspond to humans in their early 20s and mid-60s, respectively. Without stimulation, the diameter of the blood vessels of both younger and older mice was approximately the same. However, when stimulated to induce dilation, differences between the age groups became apparent.

"The younger arteries dilated as expected," Boerman said. "However, when we performed the same stimulation to the arteries of older mice, the vessels did not dilate. When we examined the presence of sensory nerves, we noted a 30 percent decrease in the amount surrounding the older arteries compared to the younger arteries."

Additionally, the researchers found that even when purposefully exposing older mesenteric arteries to defined amounts of the neurotransmitter calcitonin gene-related peptide, or CGRP, the arteries' ability to dilate was greatly reduced.

"Poor neurotransmitter function and a reduced presence of sensory nerves surrounding older vessels lead to age-related dysfunction of mesenteric arteries," Boerman said. "The importance of this discovery is that if we can identify why this happens to mesenteric arteries, it may be possible to prevent the same thing from happening to other blood vessels throughout the body."

More research is needed to understand why aging affects sensory nerve distribution and neurotransmitter performance. However, identifying this new mechanism of vascular dysfunction opens the door for future studies that could eventually lead to the treatment of health issues such as stroke and cardiovascular disease.

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Low bleeding and stroke rates in AF patients given rivaroxaban for stroke prevention

Atrial fibrillation (AF) patients treated with rivaroxaban for stroke prevention have low rates of bleeding and stroke, reveals real-world data from the XANTUS study presented at ESC Congress today.1 The findings confirm clinical trial data and demonstrate that oral anticoagulation with rivaroxaban, a direct Factor Xa inhibitor, is safe and effective for stroke prevention in patients with AF at both high- and low-risk of thromboembolic events.

"With 10 million people in Europe alone affected by AF, a number that is only expected to increase, real-world insights on routine anticoagulation management in everyday clinical practice is increasingly important for physicians and patients with AF," said XANTUS principal investigator Professor A. John Camm, professor of clinical cardiology in the Cardiovascular and Cell Sciences Research Institute at St George's University of London, UK.

XANTUS is the first international, prospective real-world non-vitamin K antagonist oral anticoagulant (NOAC) study in patients with AF. These patients are five times more likely than the general population to have a stroke. However, oral anticoagulation therapy can prevent many cases of AF-related stroke.

This single-arm, observational study evaluated the safety and effectiveness of rivaroxaban for stroke prevention in 6 784 patients with non-valvular AF from 311 centres across Europe and Canada in routine clinical practice. All treatment and dosing decisions were at the discretion of the treating physicians and patients were followed up for one year or until 30 days after premature discontinuation. Bleeding events and major thromboembolic events were centrally adjudicated by an independent committee.

By the end of the observation period the majority (96.1%) of patients had not experienced treatment-emergent major bleeding, all-cause death or stroke / systemic embolism. The rate of on-treatment all-cause mortality was 1.9% per year. Overall, 2.1% of patients per year experienced treatment-emergent major bleeding and most of these cases were treated using standard clinical measures. The rate of fatal bleeding was 0.2% per year, while stroke occurred in 0.7% patients per year, and critical organ bleeding occurred at a rate of 0.7% per year with 0.4% per year of patients experiencing an intracranial haemorrhage.

"These results demonstrate low rates of both major bleeding and stroke in patients taking rivaroxaban in routine clinical practice," said Professor Camm. "The findings reaffirm the positive benefit-risk profile of rivaroxaban established in the phase III clinical trial ROCKET AF, in which rivaroxaban was shown to provide effective stroke prevention with a similar overall bleeding profile and significantly lower rates of the most feared intracranial and fatal bleeds compared with vitamin K antagonists (VKAs)."2

He continued: "The patients included in ROCKET AF were at moderate to high risk of stroke with a mean CHADS2 score of 3.5, and the incidence of major bleeding in those taking rivaroxaban was 3.6 per 100 person-years. In XANTUS, patients seen in daily clinical practice had a lower risk of stroke with a mean CHADS2 score of 2.0 and the incidence rate of major bleeding was lower at 2.1 per 100 person-years."

Furthermore, XANTUS showed that the majority of patients (80%) persisted on their treatment with rivaroxaban throughout the one year study period, whereas other recent data on VKAs has shown a persistence rate of 62% after one year. "Treatment persistence is especially important as discontinuation of anticoagulation leaves patients with AF unprotected from the risk of stroke," said Professor Camm.

He concluded: "These real-world insights from XANTUS complement and expand on what we already know from clinical trials, and provide physicians with reassurance to prescribe rivaroxaban as an effective and well-tolerated treatment option for the broad range of patients with AF seen in their everyday clinical practice."

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Recruitment of leukocytes is a hallmark of stent thrombosis

Recruitment of leukocytes is a hallmark of stent thrombosis, according to results from the PRESTIGE study presented at ESC Congress1 and published in European Heart Journal.2 The findings suggest that immune cell mediated thrombotic processes may be a realistic target for novel therapies to prevent stent thrombosis.

"Stent thrombosis (ST) is a life-threatening complication of percutaneous coronary intervention and recent large scale clinical registries reported an incidence of up to 0.4-0.6% per year," said principal investigator Professor Steffen Massberg, director of the Department of Cardiology at the Ludwig-Maximilians University (LMU) Munich, Germany. "The majority of ST patients present with acute myocardial infarction and rates of mortality following presentation are as high as 20-40%."

He continued: "The incidence of ST is highest within the first 30 days after stenting, however, patients treated with drug-eluting stents (DES) - the dominant devices used in contemporary practice - have been shown to be at higher risk of late ST. Clinical practice guidelines therefore recommend a more prolonged duration of dual antiplatelet therapy after stenting with DES as compared to after bare metal stents."

The PREvention of late Stent Thrombosis by an Interdisciplinary Global European effort (PRESTIGE) consortium was established to investigate the mechanisms triggering stent thrombosis across Europe. As part of this study, thrombus specimens retrieved from catheter thrombectomy were systematically collected and analysed in a central core laboratory at the German Heart Centre in Munich, Germany. The main findings from the histopathological evaluation of thrombus specimens from these patients are presented today by Dr Julia Riegger, a cardiologist at the Department of Cardiology at the LMU in Munich.

Dr Riegger said: "Although some pathological processes associated with ST have been identified, the triggering mechanisms remain incompletely understood, and the influence of factors such as timing of ST after the procedure, stent type or polymer coating is poorly characterised. In particular, the potential role of immune cells and related extracellular components has not been elucidated in detail."

The PRESTIGE substudy presented during ESC Congress included patients with ST and undergoing thrombus aspiration at nine centres in Europe between 2010 and 2014. Thrombus specimens were analysed histologically at a core laboratory. Overall 253 thrombus specimens were analysed. Of these, 79 (31.2%) were from patients presenting with early ST and 174 (68.8%) from late ST, while 79 (31.2%) were from bare metal stents, 166 (65.6%) from DES and 8 (3.2%) from stents of unknown type.

The investigators found that the thrombus specimens had heterogeneous morphology with platelet-rich thrombus and fibrin/fibrinogen fragments being most abundant. Leukocyte infiltrations were hallmarks of both early and late ST with neutrophils representing the most prominent subset. Neutrophils were found in similar amounts in early and late ST. "It is important to note that leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction," said Professor Massberg.

Neutrophil extracellular traps (NETs), which are prothrombotic extracellular DNA released by neutrophils, were observed in 23% of samples. Eosinophils were present in all stent types, with higher numbers in patients with late ST in sirolimus-eluting and everolimus-eluting stents. "The presence of NETs supports their pathophysiological relevance in ST, while eosinophil recruitment suggests an allergic component to the process of ST," said Professor Massberg.

He concluded: "Our results suggest that immune cell mediated thrombotic processes may be a realistic target for novel therapies to prevent ST. Inhibition of triggers, such as extracellular nucleic acids activating the contact phase, may not only result in efficient anticoagulation in the setting of ST but might also yield less therapy-associated bleeding. Future studies should evaluate whether inhibition of immune cell-driven thrombotic pathways are effective and safe in clinical practice."

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