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Newswise — As Valentine’s Day approaches, a Cleveland Clinic survey finds that two-thirds of Americans (66%) in a committed relationship are concerned with their partner’s heart health. Moreover, 60% of Americans say they are more motivated to live a heart healthy lifestyle for their partners than for themselves. This is especially true for men – 67% compared to 52% for women.  The survey was conducted as part of Cleveland Clinic Heart, Vascular and Thoracic Institute’s “Love your Heart” consumer education campaign in celebration of American Heart Month. It looked at how relationships affect heart health.  The survey found most Americans in committed relationships are looking to their partners for motivation. An overwhelming majority (83%) agreed that if their partner adopted a heart-healthy diet, they would join in, and 57% said they are more likely to exercise with their partner than by themselves.  “We know that strong emotions can affect the heart, if only temporarily. But, partners can make a long-term impact on each other’s heart health,” said Samir Kapadia, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. “I recommend partners undertake heart healthy habits together. Make it fun but hold each other accountable – find new healthy recipes and cook them together, join an exercise class, or go on daily walks with your partner. Simple lifestyle changes can go a long way in keeping your heart strong and healthy.”  Alternatively, partners can be a negative influence. About two-thirds (64%) of Americans in committed relationships acknowledge that they enable or are enabled by their partner in unhealthy heart habits. For example, far more couples said they were likely to binge watch a TV show with their partner (66%) than exercise together (46%).  Additional survey findings include:  The majority of Americans (86%) believe that emotional heartbreak can result in physical pain, and seven-in-ten (71%) also believe it’s possible to die of a broken heart. Physicians say there is a “broken heart syndrome”, called Takotsubo cardiomyopathy, which is a response to sudden emotional stress, but it is rare. Seven-in-ten (70%) Americans consider sex exercise, especially younger Americans under 55.  Men in a committed relationship especially said that their partners were a positive influence on their heart health- 78% compared to 67% of women.  Heart disease is the leading cause of death in the United States, accounting for 1 in every 4 deaths. Cleveland Clinic has been ranked the No. 1 hospital in the country for cardiology and cardiac surgery for 25 years in a row by US News & World Report.   Methodology Cleveland Clinic’s survey of the general population gathered insights into Americans’ perceptions of heart health and prevention. This was an online survey conducted among a national probability sample consisting of 1,000 adults 18 years of age and older, living in the continental United States. The total sample data is nationally representative based on age, gender, ethnicity and educational attainment census data. The online survey was conducted by Dynata and completed between September 23 and September 26, 2018. The margin of error for the total sample at the 95% confidence level is +/- 3.1 percentage points.   About Cleveland Clinic Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 66,000 employees are more than 4,200 salaried physicians and researchers and 16,600 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic’s health system includes a 165-acre main campus near downtown Cleveland, 11 regional hospitals in northeast Ohio, more than 180 northern Ohio outpatient locations – including 18 full-service family health centers and three health and wellness centers – and locations in southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2018, there were 7.9 million total outpatient visits, 238,000 hospital admissions and observations, and 220,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/CCforMedia and twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
Newswise — (SACRAMENTO, Calif.) -- A Western diet rich in fat and sugar may lead to inflammatory skin diseases such as psoriasis, a study by UC Davis Health researchers has found.  The study, published today in Journal of Investigative Dermatology, suggests that dietary components, rather than obesity itself, may lead to skin inflammation and the development of psoriasis. A common and chronic skin disease, psoriasis causes skin cells to form scales and red patches that are itchy and sometimes painful.    Diet and Skin Inflammation  Previous studies have shown that obesity is a risk factor for the development or worsening of psoriasis. The Western diet, characterized by a high dietary intake of saturated fats and sucrose and low intake of fiber, has been linked to the increased prevalence of obesity in the world. “In our study, we found that short-term exposure to Western diet is able to induce psoriasis before significant body weight gain,” said Sam T. Hwang, professor and chair of dermatology at UC Davis and senior author on the study. For the UC Davis Health study, which used a mouse model, Hwang and his colleagues found that a diet containing both high fat and high sugar (mimicking the Western diet in human) was required to induce observable skin inflammation. In four weeks only, mice on Western diet had significantly increased ear swelling and visible dermatitis compared to mice fed a controlled diet and those on high fat diet alone. “Eating an unhealthy diet does not affect your waistline alone, but your skin immunity too,” said Zhenrui Shi, visiting assistant researcher in UC Davis Department of Dermatology and lead author on the study.   Bile Acids and Skin Inflammation The study detailed the mechanisms by which inflammation happens following a Western diet. It identified bile acids as key signaling molecules in the regulation of skin immunity. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. They play an important role in dietary lipid absorption and cholesterol balance in the blood. The study found that cholestyramine, a drug used to lower cholesterol levels by binding to bile acids in the intestine, helped reduce the risk of skin inflammation. The finding suggests that bile acids mediate the development of psoriasis. The binding of cholestyramine to bile acids in the gut and its subsequent release through the stool allows for lowering of skin inflammation. Further studies are needed to understand the mechanism behind diet-induced skin inflammation and the interaction between metabolism, microbes and immunity. This study was supported by a National Psoriasis Foundation Discovery Grant, an NIH/NIAMS R01 grant (1R01AR063091-01A1) and an NCI/NIH grant (U01-CA179582-03A1). Other collaborators include Xuesong Wu, Mindy Huynh and Mimi Nguyen from Department of Dermatology at UC Davis, Prasant Jena and Yui-Jui Yvonne Wan from Medical Pathology and Laboratory Medicine at UC Davis and Sebastian Yu from Department of Dermatology at Kaohsiung Medical University.
This painting depicts a coronavirus just entering the lungs, surrounded by mucus secreted by respiratory cells, secreted antibodies, and several small immune systems proteins. The virus is enclosed by a membrane that includes the S (spike) protein, which will mediate attachment and entry into cells, M (membrane) protein, which is involved in organization of the nucleoprotein inside, and E (envelope) protein, which is a membrane channel involved in budding of the virus and may be incorporated into the virion during that process. The nucleoprotein inside includes many copies of the N (nucleocapsid) protein bound to the genomic RNA.   Newswise — The Protein Data Bank archive, which contains more than 160,000 3D structures for proteins, DNA, and RNA, this month released a new Coronavirus protease structure following the recent  coronavirus outbreak, an ongoing viral epidemic primarily affecting mainland China that now threatens to spread to populations in other parts of the world. The structure, the topic of the PDB’s current ‘Molecule of the Month’ feature, is a high-resolution crystal structure of 2019-nCoV coronavirus 3CL hydrolase (Mpro) as determined by Zihe Rao and Haitao Yang's research team at ShanghaiTech University. Rapid public release of this structure of the main protease of the virus, known within the archive as PDB 6lu7, will enable research on this newly-recognized human pathogen. More details from the PDB can be found here. The PDB archive is jointly managed by the Worldwide Protein Data Bank partnership, involving data centers in the United States, Europe and Asia. U.S. operations are led by the RCSB Protein Data Bank at Rutgers, the San Diego Supercomputer Center (SDSC) at UC San Diego, and UC San Francisco. PDB data provide a starting point for structure-guided drug discovery. Such viruses have increasingly become a danger to world health, given the increase in global travel, according to the PDB release. Particularly virulent forms have emerged from their natural animal hosts and pose a threat to human communities. In 2003, the Severe Acute Respiratory Syndrome (SARS) virus emerged in China from bat populations, moving to civets and finally to humans. Ten years later, the MERS virus also emerged from bats, transferring in the Middle East to dromedary camels and then to humans. While the latest entry is currently the only public-domain 3D structure from this specific coronavirus, the PDB archive also contains structures of the corresponding enzyme from other coronaviruses. The 2003 outbreak of the closely-related SARS virus led to the first 3D structures, and today there are more than 200 PDB structures of SARS proteins. “Function follows form in biology,” said Stephen K. Burley, physician-scientist and director of the RCSB Protein Data Bank and faculty member at Rutgers University and UC San Diego-SDSC. “Open access to PDB data ensures that rapid access to rigorously validated and expertly curated 3D structure information contributes broadly to research and education in fundamental biology, biomedicine, bioenergy, and biotechnology.” The coronavirus 3CL hydrolase (Mpro) enzyme, also known as the main protease, is essential for proteolytic maturation of the virus. It is thought to be a promising target for discovery of small-molecule drugs that would inhibit cleavage of the viral polyprotein and prevent spread of the infection. Comparison of the protein sequence of the 2019-nCoV coronavirus 3CL hydrolase (Mpro) against the PDB archive identified 95 PDB proteins with at least 90% sequence identity. Furthermore, these related protein structures contain approximately 30 distinct small molecule inhibitors, which could guide discovery of new drugs. Of particular significance for drug discovery is the very high amino acid sequence identity (96%) between the 2019-nCoV coronavirus 3CL hydrolase (Mpro) and the SARS virus main protease (PDB 1q2w). Summary data about these closely-related PDB structures are available (CSV) to help researchers more easily find this information. In addition, the PDB houses 3D structure data for more than 20 unique SARS proteins represented in more than 200 PDB structures, including a second viral protease, the RNA polymerase, the viral spike protein, a viral RNA, and other proteins (CSV). “Coronavirus main proteases represent attractive targets for drug discovery and development. 3D structure information freely available from the PDB includes small chemicals bound tightly to the enzyme active site (the business end of the main protease), confirming that they are druggable targets,” explained Burley. “Some of these structures provide starting points for structure-guided drug discovery of protease inhibitors with drug-like properties suitable for preclinical testing. We hope that this new structure, and those from SARS and MERS, will help researchers and clinicians address the 2019-nCoV coronavirus global public health emergency.” Reproducible and Scalable Structural Bioinformatics Scientists face time-consuming barriers when applying structural bioinformatics analysis, including complex software setups, non-interoperable data formats, and lack of documentation, all which make it difficult to reproduce results and reuse software pipelines. A further challenge is the ever-growing size of datasets that need to be analyzed. To address these challenges, SDSC’s Structural Bioinformatics Laboratory, directed by Peter Rose, is developing a suite of reusable, scalable software components called MMTF-PySpark, using three key technologies: its parallel distributed processing framework provides scalable computing; the MacroMolecular Transmission Format (MMTF), a new binary and compressed representation of Macromolecular structures, which enables high-performance processing of PDB structures. “The use of MMTF-PySpark could easily shave off a year of a graduate student’s or postdoc’s work in Structural Bioinformatics,” said Rose. “We bank on contributions from the community to develop and share an eco-system of interoperable tools.” About SDSC As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s petascale Comet supercomputer is a key resource within the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program.   Image Credit: David S. Goodsell, RCSB Protein Data Bank
Credit: U.S. Centers for Disease Control and Prevention An influenza virus binds to receptors on a respiratory tract cell, allowing the virus to enter and infect the cell.   Newswise — A Rutgers-led team has developed a tool to monitor influenza A virus mutations in real time, which could help virologists learn how to stop viruses from replicating.The gold nanoparticle-based probe measures viral RNA in live influenza A cells, according to a study in The Journal of Physical Chemistry C. It is the first time in virology that experts have used imaging tools with gold nanoparticles to monitor mutations in influenza, with unparalleled sensitivity.“Our probe will provide important insight on the cellular features that lead a cell to produce abnormally high numbers of viral offspring and on possible conditions that favor stopping viral replication,” said senior author Laura Fabris, an associate professor in the Department of Materials Science and Engineering in the School of Engineering at Rutgers University–New Brunswick.Viral infections are a leading cause of illness and deaths. The new coronavirus, for example, has led to more than 24,000 confirmed cases globally, including more than 3,200 severe ones and nearly 500 deaths as of Feb. 5, according to a World Health Organization report.Influenza A, a highly contagious virus that arises every year, is concerning due to the unpredictable effectiveness of its vaccine. Influenza A mutates rapidly, growing resistant to drugs and vaccines as it replicates.The new study highlights a promising new tool for virologists to study the behavior of influenza A, as well as any other RNA viruses, in host cells and to identify the external conditions or cell properties affecting them. Until now, studying mutations in cells has required destroying them to extract their contents. The new tool enables analysis without killing cells, allowing researchers to get snapshots of viral replication as it occurs. Next steps include studying multiple segments of viral RNA and monitoring the influenza A virus in animals.The lead author is Kholud Dardir, who earned a doctorate at Rutgers. Rutgers co-authors include senior postdoctoral associate Hao Wang and Maria Atzampou, a doctoral student. Researchers at the University of Illinois at Urbana Champaign contributed to the study.
Credit: Zhen Gu Lab/UCLA Schematic picture of cold plasma patch for cancer immunotherapy.   Newswise — Los Angeles - An interdisciplinary team of researchers at the UCLA Jonsson Comprehensive Cancer Center has developed a medicated patch that can deliver immune checkpoint inhibitors and cold plasma directly to tumors to help boost the immune response and kill cancer cells. The thumb-sized patch has more than 200 hollow microneedles that can penetrate the skin and enter the tumor tissue. The cold plasma is delivered through the hollow structure, destroying cancer cells, which facilitates the release of tumor-specific antigens and boosts an immune response. The immune checkpoint inhibitors — antibodies that block checkpoint proteins, which interferes with immune system function and prevents the immune system from destroying cancer cells — are also released from the sheath of microneedles to boost the T cell-mediated anti-cancer effects. In the study, which is published in the Proceedings of the National Academy of Sciences, the UCLA researchers found that delivering the two therapies to mice with melanoma using the patch enabled the immune system to better attack the cancer, significantly inhibiting the growth of the tumor and prolonging the survival of the mice. The team also found that the therapy not only inhibit the growth of the targeted tumor, but it also could inhibit the growth of tumors that had spread to other parts of the body. “Immunotherapy is one of the most groundbreaking advances in cancer treatment,” said study senior author Zhen Gu, professor of bioengineering at the UCLA Samueli School of Engineering and member of the Jonsson Cancer Center. “Our lab has been working on engineering new ways to apply or deliver drugs to the diseased site that could help improve the effectiveness of cancer immunotherapy, and we found the patch to be a quite promising delivery system.” The study is also the first to demonstrate that cold plasma can be effective in synergizing cancer immunotherapy. Plasma, which is usually hot, is an ionized gas that comprises more than 99% of the universe. Here, cold plasma is generated by a small device operating at atmospheric pressure and room temperature. Therefore, cold plasma can be applied directly to the body — internally or externally. “This study represents an important milestone for the field of plasma medicine,” said co-senior author Richard Wirz, professor of mechanical and aerospace engineering at UCLA Samueli. “It demonstrates that the microneedle patch can realize the plasma delivery while also working with the drug to improve the effectiveness of cancer therapy.” “Plasma can generate reactive oxygen species and reactive nitrogen species, which are a group of chemical species that can destroy cancer cells,” said Guojun Chen, who is the co-first author of the study and a postdoctoral fellow in Gu’s laboratory. “Those cancers can then release tumor-associated antigens, which can enhance immune response to kill cancers,” said Zhitong Chen, who is the other co-first author and a postdoctoral fellow in Wirz’s lab. The team tested the cold plasma patch on mice with melanoma tumors. The mice that received the treatment showed an increased level of dendritic cells, which are a specific type of white blood cells that alert the immune system of a foreign invader and initiate a T cell-mediated immune response. The group of mice also showed delayed tumor growth compared to the untreated group and 57% were still alive at 60 days, while mice in other control groups had all died. “This treatment strategy can potentially go beyond cancer immunotherapy,” said Gu, who is also a member of the California NanoSystems Institute at UCLA. “Integrated with other treatments, this minimally invasive method can be extended to treat different cancer types and a variety of diseases.” The patch will have to go through further testing and approvals before it could be used in humans. But the team members believe the approach holds great promise. The work was funded by the National Institutes of Health and the Air Force Office of Scientific Research.
Newswise — A plant-based diet may be key to lowering risk for heart disease. Penn State researchers determined that diets with reduced sulfur amino acids — which occur in protein-rich foods, such as meats, dairy, nuts and soy — were associated with a decreased risk for cardiovascular disease. The team also found that the average American consumes almost two and a half times more sulfur amino acids than the estimated average requirement. Amino acids are the building blocks of proteins. A subcategory, called sulfur amino acids, including methionine and cysteine, play various roles in metabolism and health. “For decades it has been understood that diets restricting sulfur amino acids were beneficial for longevity in animals,” said John Richie, a professor of public health sciences at Penn State College of Medicine. “This study provides the first epidemiologic evidence that excessive dietary intake of sulfur amino acids may be related to chronic disease outcomes in humans.” Richie led a team that examined the diets and blood biomarkers of more than 11,000 participants from a national study and found that participants who ate foods containing fewer sulfur amino acids tended to have a decreased risk for cardiometabolic disease based on their bloodwork. The team evaluated data from the Third National Examination and Nutritional Health Survey. They compiled a composite cardiometabolic disease risk score based on the levels of certain biomarkers in participants’ blood after a 10-16 hour fast including cholesterol, triglycerides, glucose and insulin. “These biomarkers are indicative of an individual’s risk for disease, just as high cholesterol levels are a risk factor for cardiovascular disease,” Richie said. “Many of these levels can be impacted by a person’s longer-term dietary habits leading up to the test.” Participants were excluded from the study if they reported having either congestive heart failure, heart attack or a reported change in diet due to a heart disease diagnosis. Individuals were also omitted if they reported a dietary intake of sulfur amino acids below the estimated average requirement of 15 mg/kg/day recommended by the Food and Nutrition Board of the National Academy of Medicine. For a person weighing 132 pounds, food choices for a day that meet the requirement might include a medium slice of bread, a half an avocado, an egg, a half cup of raw cabbage, six cherry tomatoes, two ounces of chicken breast, a cup of brown rice, three quarters of a cup of zucchini, three tablespoons of butter, a cup of spinach, a medium apple, an eight inch diameter pizza and a tablespoon of almonds. Nutritionists collected information about participants’ diets by doing in-person 24-hour recalls. Nutrient intakes were then calculated using the U.S. Department of Agriculture Survey Nutrient Database. After accounting for body weight, the researchers found that average sulfur amino acid intake was almost two and a half times higher than the estimated average requirement. Xiang Gao, associate professor and director of the nutritional epidemiology lab at the Penn State University and co-author of the study, published today (Feb. 3) in Lancet EClinical Medicine, suggested this may be due to trends in the average diet of a person living in the United States. “Many people in the United States consume a diet rich in meat and dairy products and the estimated average requirement is only expected to meet the needs of half of healthy individuals,” Gao said. “Therefore, it is not surprising that many are surpassing the average requirement when considering these foods contain higher amounts of sulfur amino acids.” The researchers found that higher sulfur amino acid intake was associated with a higher composite cardiometabolic risk score after accounting for potential confounders like age, sex and history of diabetes and hypertension. They also found that high sulfur amino acid intake was associated with every type of food except grains, vegetables and fruit. “Meats and other high-protein foods are generally higher in sulfur amino acid content,” said Zhen Dong, lead author on the study and College of Medicine graduate. “People who eat lots of plant-based products like fruits and vegetables will consume lower amounts of sulfur amino acids. These results support some of the beneficial health effects observed in those who eat vegan or other plant-based diets.” Dong said that while this study only evaluated dietary intake and cardiometabolic disease risk factors at one point in time, the association between increased sulfur amino acid intake and risk for cardiometabolic disease was strong. She said the data supports the formation of a prospective, longitudinal study evaluating sulfur amino acid intake and health outcomes over time. “Here we saw an observed association between certain dietary habits and higher levels of blood biomarkers that put a person at risk for cardiometabolic diseases,” Richie said. “A longitudinal study would allow us to analyze whether people who eat a certain way do end up developing the diseases these biomarkers indicate a risk for.” Vernon Chinchilli, Raghu Sinha, Joshua Muscat and Renate Winkels of Penn State College of Medicine also contributed to this research. The authors declare no conflict of interest or specific financial support for this research. About Penn State College of MedicineLocated on the campus of Penn State Health Milton S. Hershey Medical Center in Hershey, Pa., Penn State College of Medicine boasts a portfolio of nearly $100 million in funded research. Projects range from development of artificial organs and advanced diagnostics to groundbreaking cancer treatments and understanding the fundamental causes of disease. Enrolling its first students in 1967, the College of Medicine has more than 1,700 students and trainees in medicine, nursing, the health professions and biomedical research on its two campuses.   Photo Credit: Getty Images | nensuria
Newswise — In response to the youth vaping crisis, experts at The University of Texas Health Science Center at Houston (UTHealth) developed CATCH My Breath, a program to prevent electronic cigarette use among fifth – 12th grade students. Research published in Public Health Reports reveals the program significantly reduces the likelihood of e-cigarette use among students who complete the curriculum. Since a 2018 declaration citing the vaping crisis a public health epidemic, the number of middle school students who use e-cigarettes has more than doubled. According to 2019 data from the Centers for Disease Control and Prevention, about 1 in 10 middle school students reported using e-cigarettes in the last 30 days. This marks a troubling trend with dangerous consequences, as 60 deaths in the U.S. have been linked to lung injury associated with vaping product use. The research collected from the program’s pilot study found that students in schools that received the CATCH My Breath program were half as likely to experiment with e-cigarettes compared with those in schools that did not receive the program. According to the research team, CATCH My Breath is the only evidence-based e-cigarette prevention program that has demonstrated effectiveness for middle school-aged youth. While the program focuses primarily on vaping, it also educates students to resist other forms of tobacco. Research has shown that around 40% of youth tobacco users reported using more than one tobacco product. “This program was created to address the youth vaping crisis and to reverse the growing trend of e-cigarette use among adolescents,” said Steven H. Kelder, PhD, MPH, Beth Toby Grossman Distinguished Professor in Spirituality and Healing at UTHealth School of Public Health in Austin and the study’s lead author. “Most children are using JUUL devices, which has the nicotine equivalent of 20 cigarettes for one pod. Many do not know there is nicotine in these devices, much less such a high level. This is why it is urgent to educate schools, families, and kids.” Experts at UTHealth School of Public Health who developed the program received input from school administrators, health education coordinators, and tobacco prevention educators, as well as teachers, students, and parents. The curriculum emphasizes active, student-centered learning through group discussions, goal setting, refusal skills training, capacity building with analyzing tobacco company advertising, and creating counter-advertising and non-smoking policies. The program is disseminated by the nonprofit CATCH Global Foundation and has been implemented in over 2,000 schools across all 50 states.  “We designed CATCH My Breath to be easy for teachers to implement in their classrooms. All program materials are available online and are age-appropriate for middle and high school students,” said Kelder, who developed the program as part of his ongoing research at the Michael & Susan Dell Center for Healthy Living at UTHealth School of Public Health in Austin. The research team was recently awarded a $3.1 million grant from the National Institutes of Health to conduct a long-term assessment of the program, a first-of-its-kind study on a nationwide nicotine vaping prevention program. Through this large-scale study, the research team will add a parent component to the CATCH My Breath program to further enhance support for e-cigarette prevention.  “CATCH My Breath offers theory- and practice-informed strategies for parents to understand the vaping epidemic and how to talk to their children as well,” said Andrew Springer, DrPH, an associate professor at UTHealth School of Public Health in Austin and co-investigator of the CATCH My Breath study. Other UTHealth authors of the study included Dale Mantey, MPA; Kathleen Case, DrPH; and Alexandra Haas, MPH. Research was funded by a grant from the St. David’s Foundation.
Newswise — The heart’s ability to beat normally over a lifetime is predicated on the synchronized work of proteins embedded in the cells of the heart muscle. Like a fleet of molecular motors that get turned on and off, these proteins cause the heart cells to contract, then force them to relax, beat after life-sustaining beat.  Now a study led by researchers at Harvard Medical School, Brigham and Women’s Hospital and the University of Oxford shows that when too many of the heart’s molecular motor units get switched on and too few remain off, the heart muscle begins to contract excessively and fails to relax normally, leading to its gradual overexertion, thickening and failure. Results of the work, published Jan. 27 in Circulation, reveal that this balancing act is an evolutionary mechanism conserved across species to regulate heart muscle contraction by controlling the activity of a protein called myosin, the main contractile protein of the heart muscle. The findings—based on experiments with human, mouse and squirrel heart cells—also demonstrate that when this mechanism goes awry it sets off a molecular cascade that leads to cardiac muscle over-exertion and culminates in the development of hypertrophic cardiomyopathy (HCM), the most common genetic disease of the heart and a leading cause of sudden cardiac death in young people and athletes. “Our findings offer a unifying explanation for the heart muscle pathology seen in hypertrophic cardiomyopathy that leads to heart muscle dysfunction and, eventually, causes the most common clinical manifestations of the condition,” said senior author Christine Seidman, professor of genetics in the Blavatnik Institute at Harvard Medical School, a cardiologist at Brigham and Women’s Hospital and a Howard Hughes Medical Institute Investigator. Importantly, the experiments showed that treatment with an experimental small-molecule drug restored the balance of myosin arrangements and normalized the contraction and relaxation of both human and mouse cardiac cells that carried the two most common gene mutations responsible for nearly half of all HCM cases worldwide. If confirmed in further experiments, the results can inform the design of therapies that halt disease progression and prevent complications. “Correcting the underlying molecular defect and normalizing the function of heart muscle cells could transform treatment options, which are currently limited to alleviating symptoms and preventing worst-case scenarios such as life-threatening rhythm disturbances and heart failure,” said study first author Christopher Toepfer, who performed the work as a postdoctoral researcher in Seidman’s lab and is now a joint fellow in the Radcliffe Department of Medicine at the University of Oxford. Some of the current therapies used for HCM include medications to relieve symptoms, surgery to shave the enlarged heart muscle or the implantation of cardioverter defibrillators that shock the heart back into rhythm if its electrical activity ceases or goes haywire. None of these therapies address the underlying cause of the disease.  Imbalance in the motor fleet Myosin initiates contraction by cross-linking with other proteins to propel the cell into motion. In the current study, the researchers traced the epicenter of mischief down to an imbalance in the ratio of myosin molecule arrangements inside heart cells. Cells containing HCM mutations had too many molecules ready to spring into action and too few myosin molecules idling standby, resulting in stronger contractions and poor relaxation of the cells.  An earlier study by the same team found that under normal conditions, the ratio between “on” and “off” myosin molecules in mouse heart cells is around 2-to-3. However, the new study shows that this ratio is off balance in heart cells that harbor HCM mutations, with disproportionately more molecules in active versus inactive states. In an initial set of experiments, the investigators analyzed heart cells obtained from a breed of hibernating squirrel as a model to reflect extremes in physiologic demands during normal activity and hibernation. Cells obtained from squirrels in hibernation—when their heart rate slows down to about six beats per minute—contained 10 percent more “off” myosin molecules than the heart cells of active squirrels, whose heart rate averages 340 beats per minute. “We believe this is one example of nature’s elegant way of conserving cardiac muscle energy in mammals during dormancy and periods of deficient resources,” Toepfer said. Next, researchers looked at cardiac muscle cells from mice harboring the two most common gene defects seen in HCM. As expected, these cells had altered ratios of “on” and “off” myosin reserves. The researchers also analyzed myosin ratios in two types of human heart cells: Stem cell-derived human heart cells engineered in the lab to carry HCM mutations and cells obtained from the excised cardiac muscle tissue of patients with HCM. Both had out-of-balance ratios in their active and inactive myosin molecules.  Further experiments showed that this imbalance perturbed the cells’ normal contraction and relaxation cycle. Cells harboring HCM mutations contained too many “on” myosin molecules and contracted more forcefully but relaxed poorly. In the process, the study showed, these cells gobbled up excessive amounts of ATP, the cellular fuel that sustains the work of each cell in our body. And because oxygen is necessary for ATP production, the mutated cells also devoured more oxygen than normal cells, the study showed. To sustain their energy demands, these cells turned to breaking down sugar molecules and fatty acids, which is a sign of altered metabolism, the researchers said. “Taken together, our findings map out the molecular mechanisms that give rise to the cardinal features of the disease,” Seidman said. “They can help explain how chronically overexerted heart cells with high energy consumption in a state of metabolic stress can, over time, lead to a thickened heart muscle that contracts and relaxes abnormally and eventually becomes prone to arrhythmias, dysfunction and failure.”Restoring balance Treating both mouse and human heart cells with an experimental small-molecule drug restored the myosin ratios to levels comparable to those in heart cells free of HCM mutations. The treatment also normalized contraction and relaxation of the cells and lowered oxygen consumption to normal levels. The drug, currently in human trials, restored myosin ratios even in tissue obtained from the hearts of patients with HCM. The compound is being developed by a biotech company; two of the company’s co-founders are authors on the study. The company provided research support for the study.   In a final step, the researchers looked at patient outcomes obtained from a database containing medical information and clinical histories of people diagnosed with HCM caused by various gene mutations. Comparing their molecular findings from the laboratory against patient outcomes, the scientists observed that the presence of genetic variants that distorted myosin ratios in heart cells also predicted the severity of symptoms and likelihood of poor outcomes, such as arrhythmias and heart failure, among the subset of people that carried these very genetic variants. What this means, the researchers said, is that clinicians who identify patients harboring gene variants that disrupt normal myosin arrangements in their heart muscle could better predict these patients’ risk of adverse clinical course. “This information can help physicians stratify risk and tailor follow-ups and treatment accordingly,” Seidman said. Other investigators on the research included Amanda Garfinkel, Gabriela Venturini, Hiroko Wakimoto, Giuliana Repetti, Lorenzo Alamo, Arun Sharma, Radhika Agarwal, Jourdan Ewoldt, Paige Cloonan, Justin Letendre, Mingyue Lun, Iacopo Olivotto, Steven Colan, Euan Ashley, Daniel Jacoby, Michelle Michels, Charles Redwood, Hugh Watkins, Sharlene Day, James Staples, Raúl Padrón, Anant Chopra, Christopher Chen, Carolyn Ho, Alexandre Pereira and Jonathan Seidman. The work was supported by the Wellcome Trust (grant 206466/Z/17/Z), Sarnoff Cardiovascular Research Foundation, National Science Foundation (cooperative agreement EEC-1647837), MyoKardia, Italian Ministry of Health (grant RF-2013-02356787 NET-2011-02347173), American Heart Association, A. Alfred Taubman Medical Research Institute, British Heart Foundation (grant RG/12/16/29939), British Heart Foundation Centre of Research Excellence, Leducq Foundation, National Institutes of Health (grants 1P50HL112349, 1U01HL117006, HL11572784, U01HL098166, 5R01HL080494 and 5R01HL084553), São Paulo Research Foundation (2017/20593-7) and Howard Hughes Medical Institute. Relevant disclosures:  Researchers Christine Seidman and Jonathan Seidman are founders and own shares in MyoKardia, a company developing therapies that target the heart muscle, including the chemical compound used in the experiments.
Newswise — The NYU Langone Transplant Institute on Monday became the first center in the United States to transplant a heart using a novel method in which, after the heart has stopped beating and death has been declared, surgeons place the organ donor on cardiopulmonary bypass and blood is circulated through the body.  This enables transplant surgeons to assess a heart for transplant while mitigating potential injury to all organs. It also holds the promise of significantly increasing the number of heart transplants from donors who have died from cardiac arrest as opposed to the typical donation after brain death.  The procedure was performed by a team of cardiothoracic surgeons, anesthesiologists, intensivists, nurses, perfusionists, and others from the Transplant Institute, in collaboration with LiveOnNY, the organ procurement organization. It is the first in an ongoing research study to evaluate the feasibility and safety of the protocol.  “This groundbreaking transplant procedure is the culmination of nearly two years of hard work to ensure all the ethical, logistical, and regulatory needs and requirements were met,” says Nader Moazami, MD, professor of cardiothoracic surgery and Surgical Director of Heart Transplantation & Mechanical Circulatory Support at NYU Langone. Other transplant centers in the country have recently launched clinical trials to study Donation after Circulatory Death, or DCD, using a device which circulates warm, oxygenated blood through the heart after it has been removed from the body. NYU Langone’s innovative protocol uses the standard cardiopulmonary bypass used in cardiac surgery to reestablish circulation while the heart is still in the body.  “We’re thrilled with the success of this first transplant surgery, which has promise to increase not only heart donation rates, but other lifesaving organs as well,” says Zachary N. Kon, MD, associate professor of cardiothoracic surgery and Surgical Director of Lung Transplantation at NYU Langone. “One of the advantages of this novel method is that it gives all organs the potential benefit of restoring perfusion prior to procurement.”  While transplant centers across the country have made great strides to address organ shortages, the demand still far exceeds the supply. According to the Organ Procurement and Transplantation Network, there were 3,399 heart transplants in 2018, with 3,800 patient remaining on the wait list, resulting in 314 deaths and 330 becoming too sick for transplantation.  Most heart donations in the United States are from patients who are declared brain dead; experts hypothesize that the widespread dissemination of controlled DCD could increase the donor pool by as much as 20 percent.  NYU Langone developed the new protocol in collaboration with LiveOnNY, New York City’s organ procurement organization.  “This quantum leap forward in American transplantation is a game changer for those desperately awaiting heart transplants by expanding the pool of suitable donors,” says Amy L. Friedman, MD, Executive Vice President and Chief Medical Officer at LiveOnNY, which helped NYU Langone identify the organ donor. “It resulted from the generosity and commitment of this one donor and their loved ones who honored the donor’s wish to save the lives of others.”  Drs. Kon and Moazami are co-authors on an article published January 8 in the American Journal of Transplantation, investigating the ethical and logistical concerns for establishing controlled DCD heart transplantation in the United States. They collaborated with colleagues in NYU Langone’s Division of Medical Ethics, Brendan Parent, JD, adjunct instructor in the Department of Population Health, and Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics in the Department of Population Health, among others. “The NYU Langone Transplant Institute is constantly seeking to drive discovery and innovation in the field of transplantation, to help all those waiting for a lifesaving organ,” says Robert Montgomery, MD, DPhil, Professor of Surgery and Director of the NYU Langone Transplant Institute. “This is an exciting advancement that will likely have a major impact on transplantation rates in this country.”
Newswise — What keeps most infectious disease researchers up at night aren’t infamous viruses like Ebola. Instead, influenza, commonly known as the flu, continues to be a clear and present danger to humanity. “Influenza is a huge problem, as the virus sickens or kills millions of people each year,” says David Markovitz, M.D., professor of internal medicine in the division of infectious diseases at Michigan Medicine. “A new pandemic along the lines of the 1918 Spanish flu has the potential to kill millions here and abroad.” To that end, he and an extensive team of collaborators have worked for years on broad-spectrum antiviral drugs developed from, of all things, banana plants. In a new paper published in the Proceedings of the National Academy of Sciences, Markovitz, first author Evelyn Coves-Datson, a M.D., Ph.D. student, Akira Ono, Ph.D., professor of microbiology and immunology and their team have shown that an engineered compound based on a banana lectin, a protein called H84T, has real potential for clinical use against influenza. In their experiments, more than 80% of mice exposed to a form of influenza that is typically fatal were able to survive the disease after receiving an injection of the protein, even up to 72 hours after exposure. The team also provides early evidence that the compound is safe. A downside of naturally occurring banana lectin—which can cause inflammation by inappropriately activating the immune system—wasn’t present in mice given H84T. Furthermore, because H84T is a protein, there was concern that the body would recognize it as foreign and develop antibodies against it, thereby neutralizing it or causing harm. The team found that while mice did develop antibodies against H84T, they didn’t appear to be adversely affected by them. The compound works because it targets a sugar called high mannose, which is present on the outside of certain viruses but not on most healthy cells. “We were able to show that H84T blocks the ability of the influenza virus to fuse with structures termed endosomes in the human cell, a key step in infection,” he explains. Doing so disabled their ability to replicate and wreak havoc. Amazingly, this mechanism of action, binding of high mannose sugars on the surface of viruses, means that H84T is effective not only against influenza, but also against Ebola, HIV, measles, MERS, a new deadly viral illness that was first reported in Saudi Arabia in 2012, SARS and all other coronaviruses tested. Even more promising is that the compound works where Tamiflu (oseltamivir), the current standard therapy for severe flu, has failed. “We’ve also shown that there may be a synergistic effect between H84T and Tamiflu,” says Markovitz. His team hopes to do more research with the compound in humans in the hopes of getting it to market. “We envision the government potentially stockpiling it in the event of a pandemic.” However, he says, “there are many difficulties to commercialization. Pharmaceutical economics do not seem to favor the development of antivirals or antibacterials for one-time usage, which is a huge problem.”  This paper also included the following U-M researchers: Steven King, Maureen Legendre, Auroni Gupta, Susana Chan and Emily Gitlin. Paper cited: “A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo,” Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.191515211