Gender differences stand out in measuring impact of Viagra as therapy for heart failure

New animal studies by Johns Hopkins cardiovascular researchers strongly suggest that sildenafil, the erectile dysfunction drug sold as Viagra and now under consideration as a treatment for heart failure, affects males and females very differently.

The results of their investigations in varied male and female mouse models of heart failure are so clear-cut, says lead scientist Eiki Takimoto, M.D., Ph.D., that physicians may need to take gender into consideration when prescribing certain medications and that drug developers would be wise to take them into careful account when setting protocols for clinical trials of the medication in people. An online description of the new research appears May 16 in The Journal of Clinical Investigation.
Specifically, in female mice modeling human heart failure, the benefits of sildenafil ranged from robust to practically nonexistent, depending on the animals' levels of the hormone estrogen, says Takimoto, an assistant professor of medicine and a researcher with the Heart and Vascular Institute at Johns Hopkins. In male mice, sildenafil generally appears to work well, but only because it targets a different biological process independent of estrogen, he says. Estrogen is present in both male and female mammals, although in different amounts.
"The research is especially significant," he adds, "because it offers a mechanism to explain how estrogen affects sildenafil's efficacy. That's the first time the actual pathway of a hormone's cause and effect on a drug has been mapped out."
Sildenafil, the generic compound used to initiate and strengthen male erections, works by encouraging blood vessels to dilate and increase blood flow to the penis. The effects are similar to some drugs, such as nitrates, already used to increase blood flow to failing hearts. Besides these effects, beneficial direct effects on heart muscles have been suggested by recent experimental studies, which is why researchers believe it could help patients with heart failure.
Heart failure is the most common reason for hospital admissions in the Medicare population, according to heart experts, and is the leading cause of death in Americans. Useful drugs such as beta-blockers and ACE inhibitors help to increase the blood-pumping efficiency of the heart, "yet they don't fully address the ongoing pathology," says Takimoto.
Whether due to a heart attack, hypertension, arteriosclerosis or other reasons, even moderate injury to heart muscle cells can initiate a downhill remodeling of broad areas of heart tissue, including enlargement of the heart and stiffening of heart chambers as fibrous proteins replace more flexible ones in muscle cells. The weakened and altered heart muscle compromises circulation, a hallmark of heart failure.
"Because cardiac remodeling is an underlying mechanism," Takimoto says, "we've put more than a decade of research into understanding it enough to stop or reverse it."
Key to the Johns Hopkins team's research, Takimoto says, is the molecule cyclic guanosine monophosphate (cGMP), which trips a helpful biochemical cascade that can counter effects of hypertension and other stressors. Heart cells typically maintain a strategic pool of cGMP, but heart-damaging events deplete this pool via the disabling action of an enzyme called PDE5. That's where sildenafil comes in.
As a potent inhibitor of PDE5, sildenafil increases cell levels of cGMP, which helps erectile dysfunction. More recently, research has explored the drug's ability to raise cGMP levels for cardiac disease.
In 2005, Takimoto's group studied sildenafil in mice engineered to have so-called transverse aortic constriction (TAC). A surgically-fitted band around the aorta in mice with TAC raised their internal heart pressure. The result was cardiac remodeling, and then signs of classic human heart failure. "By increasing cGMP with sildenafil, we both blocked and reversed remodeling in the animals, ameliorating heart failure," Takimoto says.
Subsequent work by other research groups with various animal models showed similar effects, laying groundwork for human heart disease studies.
The new gender-based findings are especially interesting, Takimoto says, because of contradictory results of early clinical trials with sildenafil for heart failure. Notably, he says, a small, single-center clinical study showed sildenafil's long-term positive effects against cardiac remodeling and classic human heart failure. But last year, results of the RELAX study -- a National Institutes of Health-sponsored, 26-center U.S. and Canadian study testing sildenafil against placebo for diastolic heart failure, a difficult-to-treat type of heart failure -- found essentially no benefit.
To better understand the protective effects of cGMP activity, Takimoto's team focused on the tie-in with estrogen, also known to be naturally cardioprotective. Women, for example, develop heart disease much later on average than men, usually after menopause and estrogen depletion; estrogen feeds into the cGMP pathway. But this new study by Takimoto's group used sildenafil to shed more light on the process.
The team used both the TAC model and an established, powerful, gene-based model of heart failure that together better reflected human heart failure, according to Takimoto. Half of the female mice his team tested had their ovaries removed, which meant these mice had minimal levels of estrogen. Both groups of female mice received sildenafil. As expected, all the mice developed cardiac remodeling, but those low in estrogen fared far worse. Treating the estrogen-low mice with supplements of the hormone, however, raised cGMP and reversed heart damage. "This tells us that estrogen critically impacts the response to sildenafil in heart failure treatment," Takimoto says.
Male mice, which have naturally low amounts of estrogen, fared differently. Like the females, they had cardiac remodeling. But sildenafil alone was able to stop it.
Takimoto explains the gender effect as a difference in male-female physiology: "In female mice, their normally high estrogen levels insure presence of an ongoing pool of cGMP with its protective effects. In males, however, there's no such pool of cGMP. It's synthesized only in response to stress on the heart."
"Our findings may have important clinical implications," he and study first author Hideyuki Sasaki, M.D., Ph.D., say. They cite the RELAX trial, where half of the participants were 69 or older. That's long after menopause started for women in the trials. "Knowing that sildenafil's benefits to female mice come only with higher estrogen levels offers a possible reason for RELAX's negative results," says Takimoto.
That and the ability of added estrogen to turn around a poor sildenafil response in the mice, he adds, "suggest we need to look more into female-specific strategies with these therapies."
 

Journal Reference:

1. Hideyuki Sasaki, Takahiro Nagayama, Robert M. Blanton, Kinya Seo, Manling Zhang, Guangshuo Zhu, Dong I. Lee, Djahida Bedja, Steven Hsu, Osamu Tsukamoto, Seiji Takashima, Masafumi Kitakaze, Michael E. Mendelsohn, Richard H. Karas, David A. Kass, Eiki Takimoto. PDE5 inhibitor efficacy is estrogen dependent in female heart disease. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI70731

Courtesy: ScienceDaily
 

Frequent arguments with family, friends linked to doubling in death risk in middle age

Frequent arguments with partners, relatives, or neighbors may boost the risk of death from any cause in middle age, suggests research published online in the Journal of Epidemiology & Community Health.

Men and those not in work seemed to be the most vulnerable, the findings indicate.
The evidence suggests that supportive social networks and strong relationships are good for general health and wellbeing, but the authors wanted to find out if the stressors inherent in family relationships and friendships had any impact on the risk of death from any cause.
They therefore quizzed almost 10,000 men and women aged 36 to 52 about their everyday social relationships. All the participants were already taking part in the Danish Longitudinal Study on Work, Unemployment and Health.
The researchers focused particularly on who, among partners, children, other relatives, friends and neighbors, made excess demands, prompted worries, or was a source of conflict, and how often these arose. They also considered whether having a job made any difference.
The health of the study participants was tracked from 2000 to the end of 2011, using data from the Danish Cause of Death Registry.
Between 2000 and 2011, 196 women (4%) and 226 men (6%) died. Almost half the deaths were from cancer, while heart disease/stroke, liver disease, and accidents and suicide made up the rest.
Around one in 10 study participants said that their partner or children were a frequent or constant source of excess demands and worries; around one in 20 (6%) and a further 2% claimed this for relatives and friends, respectively.
Similarly, 6% had frequent arguments with their partner or children, 2% with other relatives, and 1% with friends or neighbors.
After taking account of a range of influential factors, including gender, marital status, long term conditions, depressive symptoms, available emotional support, and social class, as defined by job title, the analysis indicated that frequent worries or demands generated by partners and/or children were linked to a 50%-100% increased risk of death from all causes.
But constant arguing seemed to be the most harmful for health.
Frequent arguments/conflicts with anyone in the social circle -- ranging from partners and relatives to friends and neighbors -- were associated with a doubling to tripling in the risk of death from any cause compared with participants who said these incidents were rare.
Being out of work seemed to amplify the negative impact of social relationship stressors. Those who were unemployed were at significantly greater risk of death from any cause than those who were exposed to similar stressors but had a job.
And men seemed to be particularly vulnerable to the worries and demands generated by their female partners, with a higher risk of death than that normally associated with being a man or with this particular relationship stressor.
The authors accept that personality may have a role in how people perceive, generate, and respond to stress, and so may influence an individual's risk of an early death.
But they conclude that skills in conflict management may help to curb premature deaths associated with social relationship stressors.

Journal Reference:

1. R. Lund, U. Christensen, C. J. Nilsson, M. Kriegbaum, N. Hulvej Rod. Stressful social relations and mortality: a prospective cohort study. Journal of Epidemiology & Community Health, 2014; DOI: 10.1136/jech-2013-203675 

Courtesy: ScienceDaily

New species of metal-eating plant discovered in the Philippines

Scientists from the University of the Philippines, Los Baños have discovered a new plant species with an unusual lifestyle -- it eats nickel for a living -- accumulating up to 18,000 ppm of the metal in its leaves without itself being poisoned, says Professor Edwino Fernando, lead author of the report. Such an amount is a hundred to a thousand times higher than in most other plants. The study was published in the open access journal PhytoKeys.

This photo shows the newly described metal-eating plant, Rinorea niccolifera.

The new species is called Rinorea niccolifera, reflecting its ability to absorb nickel in very high amounts. Nickel hyperaccumulation is such a rare phenomenon with only about 0.5-1% of plant species native to nickel-rich soils having been recorded to exhibit the ability. Throughout the world, only about 450 species are known with this unusual trait, which is still a small proportion of the estimated 300,000 species of vascular plants.
The new species, according to Dr Marilyn Quimado, one of the lead scientists of the research team, was discovered on the western part of Luzon Island in the Philippines, an area known for soils rich in heavy metals.
"Hyperacccumulator plants have great potentials for the development of green technologies, for example, 'phytoremediation' and 'phytomining'," explains Dr Augustine Doronila of the School of Chemistry, University of Melbourne, who is also co-author of the report.
Phytoremediation refers to the use of hyperacccumulator plants to remove heavy metals in contaminated soils. Phytomining, on the other hand, is the use of hyperacccumulator plants to grow and harvest in order to recover commercially valuable metals in plant shoots from metal-rich sites.
The field surveys and laboratory work of the scientists are part of the research project funded by the Department of Science and Technology -- Philippine Council for Industry, Energy, and Emerging Technology Research and Development (DOST-PCIEERD).
 

Journal Reference:

1. Edwino Fernando, Marilyn Quimado, Augustine Doronila. Rinorea niccolifera (Violaceae), a new, nickel-hyperaccumulating species from Luzon Island, Philippines. PhytoKeys, 2014; 37: 1 DOI: 10.3897/phytokeys.37.7136

Courtesy: ScienceDaily

Breastfeeding promotes growth of beneficial bacteria in gut

The nutritional factor that has the greatest impact on the development of a child's gut flora is whether the child is breastfed, according to a new study by the National Food Institute, Technical University of Denmark, and the University of Copenhagen. The study shows that breastfeeding promotes the growth of beneficial lactic acid bacteria in the baby's gut flora, which are beneficial to the development of the child's immune system.

A baby being breastfed (stock image). Children who are breastfed also have a slightly lower incidence of obesity, allergies, diabetes and inflammatory bowel disease later in life. According to a new study, this may be due to the fact that breastfeeding promotes the development of beneficial bacteria in the baby's gut.

A number of studies have shown that breastfed babies grow slightly slower and are slightly slimmer than children who are fed with infant formula. Children who are breastfed also have a slightly lower incidence of obesity, allergies, diabetes and inflammatory bowel disease later in life. According to a new study by the National Food Institute and the University of Copenhagen this may be due to the fact that breastfeeding promotes the development of beneficial bacteria in the baby's gut.
"We have become increasingly aware of how crucially important a healthy gut microbial population is for a well-functioning immune system. Babies are born without bacteria in the gut, and so it is interesting to identify the influence dietary factors have on gut microbiota development in children's first three years of life," research manager at the National Food Institute Tine Rask Licht says.
Gut microbes change in the first years of life
The study shows that there are significant changes in the intestinal bacterial composition from nine to 18 months following cessation of breastfeeding and other types of food being introduced. However, a child's gut microbiota continues to evolve right up to the age of three, as it becomes increasingly complex and also more stable.
"The results help to support the assumption that the gut microbiota is not -- as previously thought -- stable from the moment a child is a year old. According to our study important changes continue to occur right up to the age of three. This probably means that there is a 'window' during those early years, in which intestinal bacteria are more susceptible to external factors than what is seen in adults," Tine Rask Licht explains.
Strategies for the development of healthy gut flora
"The results from the study can be used to support initiatives that can be used to help children develop a type of gut microbiota, which is beneficial for the immune system and for the digestive system. This could for example be advice to mothers about breastfeeding or the development of new types of infant formula to promote the establishment of beneficial bacteria in the gut," Tine Rask Licht says.

Journal Reference:

1. A. Bergstrom, T. H. Skov, M. I. Bahl, H. M. Roager, L. B. Christensen, K. T. Ejlerskov, C. Molgaard, K. F. Michaelsen, T. R. Licht. Establishment of Intestinal Microbiota during Early Life: a Longitudinal, Explorative Study of a Large Cohort of Danish Infants. Applied and Environmental Microbiology, 2014; 80 (9): 2889 DOI: 10.1128/AEM.00342-14 

Courtesy: ScienceDaily

Exploring genetics behind Alzheimer's resiliency

Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer's disease without ever showing clinical symptoms in their lifetime.

Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer's.
"Most Alzheimer's research is searching for genes that predict the disease, but we're taking a different approach. We're looking for genes that predict who among those with Alzheimer's pathology will actually show clinical symptoms of the disease," said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer's Center.
The article, "Genetic modification of the relationship between phosphorylated tau and neurodegeneration," was published online recently in the journal Alzheimer's and Dementia.
The researchers used a marker of Alzheimer's disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer's disease tau forms "tangles" that disrupt cellular messages.
Analyzing a sample of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation -- a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.
"This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau," Hohman said.
"It appears that certain individuals with a genetic predisposition toward a 'bad' neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration."
Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer's disease.
"The work highlights the possible mechanism behind asymptomatic Alzheimer's disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer's symptoms," Hohman said.
 

Journal Reference:

1. Timothy J. Hohman, Mary Ellen I. Koran, Tricia A. Thornton-Wells. Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimer's & Dementia, 2014; DOI: 10.1016/j.jalz.2013.12.022 

Courtesy: ScienceDaily
 

Mother's diet affects the 'silencing' of her child's genes

A mother's diet before conception can permanently affect how her child's genes function, according to a study published in Nature Communications.

An infant from the Gambia.

The first such evidence of the effect in humans opens up the possibility that a mother's diet before pregnancy could permanently affect many aspects of her children's lifelong health.
Researchers from the MRC International Nutrition Group, based at the London School of Hygiene & Tropical Medicine and MRC Unit, The Gambia, utilized a unique 'experiment of nature' in rural Gambia, where the population's dependence on own grown foods and a markedly seasonal climate impose a large difference in people's dietary patterns between rainy and dry seasons.
Through a selection process involving over 2,000 women, the researchers enrolled pregnant women who conceived at the peak of the rainy season (84 women) and the peak of the dry season (83 women). By measuring the concentrations of nutrients in their blood, and later analysing blood and hair follicle samples from their 2-8 month old infants, they found that a mother's diet before conception had a significant effect on the properties of her child's DNA.
While a child's genes are inherited directly from their parents, how these genes are expressed is controlled through 'epigenetic' modifications to the DNA. One such modification involves tagging gene regions with chemical compounds called methyl groups and results in silencing the genes. The addition of these compounds requires key nutrients including folate, vitamins B2, B6 and B12, choline and methionine.
Experiments in animals have already shown that environmental influences before conception can lead to epigenetic changes that affect the offspring. A 2003 study found that a female mouse's diet can change her offspring's coat colour by permanently modifying DNA methylation.1 But until this latest research, funded by the Wellcome Trust and the MRC, it was unknown whether such effects also occur in humans.
Senior author Dr Branwen Hennig, Senior Investigator Scientist at the MRC Gambia Unit and the London School of Hygiene & Tropical Medicine, said: "Our results represent the first demonstration in humans that a mother's nutritional well-being at the time of conception can change how her child's genes will be interpreted, with a life-long impact."
The researchers found that infants from rainy season conceptions had consistently higher rates of methyl groups present in all six genes they studied, and that these were linked to various nutrient levels in the mother's blood. Strong associations were found with two compounds in particular (homocysteine and cysteine), and the mothers' body mass index (BMI) had an additional influence. However, although these epigenetic effects were observed, their functional consequences remain unknown.
Professor Andrew Prentice, Professor of International Nutrition at the London School of Hygiene & Tropical Medicine, and head of the Nutrition Theme at the MRC Unit, The Gambia, said: "Our on-going research is yielding strong indications that the methylation machinery can be disrupted by nutrient deficiencies and that this can lead to disease. Our ultimate goal is to define an optimal diet for mothers-to-be that would prevent defects in the methylation process. Pre-conceptional folic acid is already used to prevent defects in embryos. Now our research is pointing towards the need for a cocktail of nutrients, which could come from the diet or from supplements."
Dr Rob Waterland of Baylor College of Medicine in Houston, who conducted the epigenetic analyses said: "We selected these gene regions because our earlier studies in mice had shown that establishment of DNA methylation at metastable epialleles is particularly sensitive to maternal nutrition in early pregnancy."
The authors note that their study was limited by including only one blood sampling point during early pregnancy, but estimates of pre-conception nutrient concentrations were calculated using results from non-pregnant women sampled throughout a whole calendar year. The authors also plan to increase the sample size in further studies.

Journal Reference:

1. Paula Dominguez-Salas, Sophie E. Moore, Maria S. Baker, Andrew W. Bergen, Sharon E. Cox, Roger A. Dyer, Anthony J. Fulford, Yongtao Guan, Eleonora Laritsky, Matt J. Silver, Gary E. Swan, Steven H. Zeisel, Sheila M. Innis, Robert A. Waterland, Andrew M. Prentice, Branwen J. Hennig. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nature Communications, 2014; 5 DOI: 10.1038/ncomms4746 

Courtesy: ScienceDaily

Regenerative medicine approach improves muscle strength, function in leg injuries; Derived from pig bladder

Damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with extracellular matrix (ECM) derived from pig bladder, according to a new study conducted by researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine. Early findings from a human trial of the process and from animal studies were published today in Science Translational Medicine.

Pigs (stock image). Damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with extracellular matrix (ECM) derived from pig bladder, according to a new study.

When a large volume of muscle is lost, typically due to trauma, the body cannot sufficiently respond to replace it, explained senior investigator Stephen F. Badylak, D.V.M., Ph.D., M.D., professor of surgery at Pitt and deputy director of the McGowan Institute, a joint effort of Pitt and UPMC. Instead, scar tissue can form that significantly impairs strength and function.
Pig bladder ECM has been used for many years as the basis for medical products for hernia repair and treatment of skin ulcers. It is the biologic scaffold that remains left behind after cells have been removed. Previous research conducted by Dr. Badylak's team suggested that ECM also could be used to regenerate lost muscle by placing the material in the injury site where it signals the body to recruit stem and other progenitor cells to rebuild healthy tissue.
"This new study is the first to show replacement of new functional muscle tissue in humans, and we're very excited by its potential," Dr. Badylak said. "These are patients who can't walk anymore, can't get out of a car, can't get up and down from a chair, can't take steps without falling. Now we might have a way of helping them get better."
For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, which is sponsored by the U.S. Department of Defense and is continuing to enroll new participants, five men who had at least six months earlier lost at least 25 percent of leg muscle volume and function compared to the uninjured limb underwent a customized regimen of physical therapy for 12 to 26 weeks until their function and strength plateaued for a minimum of two weeks.
Then, study lead surgeon J. Peter Rubin, M.D., UPMC Professor and chair of plastic surgery, Pitt School of Medicine, surgically implanted a "quilt" of compressed ECM sheets designed to fill into their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 26 additional weeks.
The researchers found that three of the participants, two of whom had thigh injuries and one a calf injury, were stronger by 20 percent or more six months after the surgery. One thigh-injured patient improved on the "single hop test" by 1,820 percent, and the other had a 352 percent improvement in a chair lift test and a 417 percent improvement in the single-leg squat test. Biopsies and scans all indicated that muscle growth had occurred. Two other participants with calf injuries did not have such dramatic results, but both improved on at least one functional measure and said they felt better.
"This work represents an important step forward in our ability to repair tissues and improve function with materials derived from natural proteins. There will be more options to help our patients," Dr. Rubin said.
The study also showed six months after an injury, mice treated with ECM showed signs of new muscle growth while untreated mice appeared to form typical scars.
 

Journal Reference:

1. B. M. Sicari, J. P. Rubin, C. L. Dearth, M. T. Wolf, F. Ambrosio, M. Boninger, N. J. Turner, D. J. Weber, T. W. Simpson, A. Wyse, E. H. P. Brown, J. L. Dziki, L. E. Fisher, S. Brown, S. F. Badylak. An Acellular Biologic Scaffold Promotes Skeletal Muscle Formation in Mice and Humans with Volumetric Muscle Loss. Science Translational Medicine, 2014; 6 (234): 234ra58 DOI: 10.1126/scitranslmed.3008085 

Courtesy: ScienceDaily