Predictors of dying suddenly versus surviving heart attack identified

ScienceDaily (July 25, 2011) — Is it possible to predict whether someone is likely to survive or die suddenly from a heart attack? A new study by researchers at Wake Forest Baptist Medical Center has answered just that.See Also:Health & MedicineHeart DiseaseCholesterolStroke PreventionMind & BrainStrokeMultiple SclerosisSchizophreniaReferenceIschaemic heart diseaseCoronary heart diseaseCardiac arrestEchocardiography

"For some people, the first heart attack is more likely to be their last," said Elsayed Z. Soliman, M.D., M.Sc., M.S., director of the Epidemiological Cardiology Research Center (EPICARE) at Wake Forest Baptist and lead author of the study. "For these people especially, it is important that we find ways to prevent that first heart attack from ever happening because their chances of living through it are not as good."

While there are many traits that are common among heart attack patients -- both those who survive the event and those who die suddenly -- researchers found that some traits, such as hypertension, race/ethnicity, body mass index (BMI), heart rate, and additional markers that can be identified by an electrocardiogram (ECG) can differentiate between dying suddenly versus living through a heart attack, Soliman said.

The study, published by the journal Heart, is now available online.

Somewhere between 230,000 and 325,000 people in the U.S. succumb to sudden cardiac death every year, Soliman said. Most of these sudden deaths are caused by coronary heart disease.

"Since sudden cardiac death usually occurs before patients ever make it to the hospital, there is very little that can be done to save them," Soliman said. "Identifying specific predictors that separate the risk of sudden cardiac death from that of non-fatal or not immediately fatal heart attacks would be the first step to address this problem, which was the basis for our study."

Researchers analyzed data from two of the largest U.S. cardiovascular studies -- the ARIC (Atherosclerosis Risk in Communities) and the CHS (Cardiovascular Health Study) -- containing records for more than 18,000 participants. After taking into account common risk factors for coronary heart disease and the competing risk of sudden cardiac death with coronary heart disease, they found that:

Black race/ethnicity (compared to non-black) was predictive of high sudden cardiac death risk, but less risk of coronary heart disease. Hypertension and increased heart rate were stronger predictors of high risk of sudden cardiac death compared to coronary heart disease. Extreme high or low body mass index was predictive of increased risk of sudden cardiac death but not of coronary heart disease. Additional, more technical traits that a doctor evaluating an ECG report could use to evaluate risk of sudden cardiac death in their patients. (Prolongation of QTc and abnormally inverted T wave were stronger predictors of high risk of sudden cardiac death. On the other hand, elevated electrocardiographic ST height in V2 was not predictive of sudden cardiac death but predictive of coronary heart disease.)

If the results are validated and confirmed in other studies, Soliman predicts that doctors will have a way to identify patients who are at greater risk of dying suddenly if they experience a heart attack and, therefore, a group of patients for whom early intervention, including risk factor modification, may be a life-saving option.

"Our next step in this path of research is to see if we can come up with a risk stratification score that can be applied to the general population, as well as to look at interventions that reverse the effect that these traits are having on susceptibility to sudden cardiac death," Soliman said. "We need to know if lowering hypertension, BMI or resting heart rate would reduce the risk of dying suddenly."

The study was funded by the Donald W. Reynolds Cardiovascular Clinical Research Center at the Johns Hopkins University School of Medicine. The ARIC and CHS studies are supported by the National Heart, Lung, and Blood Institute.

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Gray Platelet Syndrome: Elusive gene that makes platelets gray identified

ScienceDaily (July 25, 2011) — Researchers have identified an elusive gene responsible for Grey Platelet Syndrome, an extremely rare blood disorder in which only about 50 known cases have been reported. As a result, it is hoped that future cases will be easier to diagnose with a DNA test.See Also:Health & MedicineGenesBirth DefectsDiseases and ConditionsHuman BiologyBlood ClotsGene TherapyReferenceHaemophiliaLeukemiaAlleleStroke

The findings were made following a collaborative study by Professor Willem Ouwehand and Dr Cornelis Albers, who are both based at the Wellcome Trust Sanger Institute and the University of Cambridge, and Dr Paquita Nurden, from the Rare Platelet Disorders laboratory, based in Bordeaux, who have described their study.

Platelets are the second most abundant cell in the blood. Their main task is to survey the blood vessel wall for damage and to orchestrate its repair where required. On the flip side, platelets also play a "darker" role after vessel wall damage and cause blood clots that may lead to heart attacks or stroke.

Some people are born with platelets that do not function well and these rare conditions are thought to be inherited. Grey Platelet Syndrome poses a risk of bleeds, some of which can be severe and life threatening, e.g. if they occur in the brain. Grey Platelet Syndrome was first identified in the 1970s and is named for the greyish appearance of these platelets when viewed with a microscope.

Identifying the cause of increased bleeding in young patients has been a painstaking process. An important step in translating research findings in human genetics in improvements of patient care has focused around the need to develop simpler and rapid DNA-based diagnostic test. To achieve this, researchers needed to discover the gene responsible for the rare platelet bleeding disorders.

In the past it was a major challenge to discover which genes caused rare disorders because DNA samples from numerous large families affected by the same disorder had to be identified and genetically analysed to pinpoint the region harbouring the causative gene.

To achieve their latest findings, researchers used a simpler approach and deciphered about 40 million letters of genetic code covering the entire coding fraction of the genome of four non-related French patients.

They identified the gene NBEAL2 as not functioning well in Grey Platelet Syndrome, a member of a family of genes that all contain a unique domain, called the BEACH domain. The team showed that protein encoded by this gene is altered at a different position in the four non-related cases and the patients affected by the disorder have inherited two non-functioning copies of the gene, one from father and mother each.

"It is really great to see how the use of modern genomics technologies is going to be of direct benefit for patient care. It is exciting that we have shown that the genetic basis of a rare bleeding disorder can be discovered with relative ease," said Professor Willem Ouwehand, who heads a NHS Blood and Transplant research team on platelet biology at both the Wellcome Trust Sanger Institute and the University of Cambridge. "This study is one such example and it gives us confidence to achieve the same for a large number of other rare inherited platelet bleeding disorders. It is now important that we use this discovery to improve patient care in the NHS and beyond."

The team's identification of the NBEAL2 gene was confirmed by functional studies in zebrafish. Fish also have platelets named thrombocytes, and switching off the NBEAL2 gene in fish caused a complete absence of these cells which resulted in nearly half of the fish suffering spontaneous bleeds similar to patients with the disorder.

It is hoped that this gene identification will make it simpler to diagnose future cases of Grey Platelet Syndrome with a simple DNA test. This new test is now being developed with researchers at the NHS Blood and Transplant Centre at the Addenbrooke's Biomedical campus in Cambridge as part of the international ThromboGenomics initiative.

The scientists also observed that other members from the same family of BEACH proteins are implicated in other rare inherited disorders. Their findings showed that LYST protein did not function well in Chediak-Higashi syndrome, another rare but severe disorder paralysing the immune system but also causing a mild platelet bleeding disorder. As a result, a picture is emerging that BEACH proteins are essential in the way granules in blood cells and brain cells are formed or retained showing that in platelets the BEACH proteins are essential for both alpha and dense granules.

"Our discovery that another member of the family of BEACH proteins is underlying a rare but severe granule disorder in platelets firmly nails down the important role of this class of proteins in granule biology," said Cornelis Albers, a British Heart Foundation research fellow at the Sanger Institute and the University of Cambridge. "The reasons why the platelets of patients with Grey Platelet Syndrome are grey is because they lack alpha granules. The alpha granules carry the cargo of proteins that induce vessel wall repair and also form the platelet plug.

"A better understanding of how these granules are formed and how their timely release by the platelet is coordinated at the molecular level may one day underpin the development of a new class of safer anti-platelet drugs for use in patients with heart attacks and stroke. It has been a fascinating journey to identify a new and important pathway by combining the rapid advances in sequencing technology with computational analysis."

The French collaboration leader, Dr Paquita Nurden, set up the Network for Rare Platelet Disorders at the Laboratoire d'Hématologie, Hopital Xavier Arnozan close to Bordeaux. Their team made the Heruclian effort to find the French families affected by this rare disorder.

"We have worked for years to identify the families across France that suffer from rare platelet disorders and my group of scientists have used powerful microscopes to determine what was wrong with the platelets from patients with Grey Platelet Syndrome. Researchers across the world discovered in the 1980s that something was wrong with the alpha granules because they were lacking in most of the cases," said Dr Nurden, an international expert in platelet biology. "The gene, however, remained elusive for another 30 years, and it is great how our joint working has discovered the causative gene very quickly."

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Signaling molecule identified as essential for maintaining a balanced immune response

ScienceDaily (July 22, 2011) — St. Jude Children's Research Hospital investigators have identified a signaling molecule that functions like a factory supervisor to ensure that the right mix of specialized T cells is available to fight infections and guard against autoimmune disease.See Also:Health & MedicineImmune SystemStem CellsLymphomaNervous SystemBrain TumorCancerReferenceNatural killer cellT cellImmune systemInflammation

The research also showed the molecule, phosphatase MKP-1, is an important regulator of immune balance. Working in laboratory cell lines and mice with specially engineered immune systems, scientists demonstrated that MKP-1 serves as a bridge between the innate immune response that is the body's first line of defense against infection and the more specialized adaptive immune response that follows. The results are published in the July 22 print edition of the scientific journal Immunity.

The results raise hopes that the MKP-1 pathway will lead to new tools for shaping the immune response, said Hongbo Chi, Ph.D., assistant member of the St. Jude Department of Immunology and the study's senior author. The co-first authors are Gonghua Huang, Ph.D., and Yanyan Wang, Ph.D., both postdoctoral fellows in Chi's laboratory.

The findings provide new details about how dendritic cells regulate the fate of naïve or undifferentiated T cells. Dendritic cells are the sentinels of the innate immune response, patrolling the body and ready to respond at the first sign of infection.

Investigators were surprised that a single molecule regulated production of three out of the four major subsets of T cells, which each play different roles. MKP-1 is a negative regulator of the enzyme p38, which is part of the MAP kinase family of enzymes that control pathways involved in cell proliferation, differentiation and death.

Chi and his colleagues demonstrated that MKP-1 works in dendritic cells by altering production of protein messengers known as cytokines. Those cytokines determine which subset of specialized T cells the undifferentiated T cells are fated to become. In this study, scientists showed that MKP1 controls production of the cytokines that yield T helper 1 (Th1), T helper 17 (Th17) and regulatory T (Treg) cells. Th1 cells combat intracellular bacterial and viral infections. Th17 cells fight extracellular bacterial infections and fungi. Treg cells help with immune suppression, protecting against autoimmune diseases.

The study showed that suppression of p38 by MKP-1 promotes production of interleukin 12 (IL-12), which leads to an increase in Th1 cells. Rising IL-12 coincides with a drop in interleukin 6 (IL-6) and a corresponding dip in production of Th17. MKP-1 also inhibited the generation of Treg cells by down-regulating production of a third cytokine, TGF-beta.

Knocking out MKP-1 in mice disrupted production of IL-12 and IL-6 in dendritic cells as well as the anti-bacterial and anti-fungal immune response, researchers reported. MKP-1 deficiency also promoted T-cell driven inflammation in a mouse model of colitis, an inflammatory disease.

"MKP-1 is the first signaling molecule found in dendritic cells to program differentiation of these diverse T- cell subsets," Chi said.

Previous work by other scientists focused on T cell differentiation in response to stimulation by cytokines. "This research fills a gap in our understanding of dendritic cell-mediated control of T-cell lineage choices," Chi said. "T cells do not recognize pathogens directly, but dendritic cells do. T cells need dendritic cells to tell them what to do. In this study, we show that MKP-1 signaling in dendritic cells bridges the innate and adaptive immune responses by regulating cytokine production."

Other authors are Lewis Shi and Thirumala-Devi Kanneganti, both of St. Jude.

The research was supported in part by the National Institutes of Health, the National Multiple Sclerosis Society, the Cancer Research Institute, The Hartwell Foundation and ALSAC.

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