Researchers Identify New Pathway Linking the Brain to High Blood Pressure

New research by scientists at the University of Maryland School of Medicine (UM SOM) and the Ottawa Heart Institute has uncovered a new pathway by which the brain uses an unusual steroid to control blood pressure. The study, which also suggests new approaches for treating high blood pressure and heart failure, appears today in the journal Public Library of Science (PLOS) One.

“This research gives us an entirely new way of understanding how the brain and the cardiovascular system work together,” said Dr. John Hamlyn, professor of physiology at the University of Maryland School of Medicine, one of the principal authors. “It opens a new and exciting way for us to work on innovative treatment approaches that could one day help patients.”

For decades, researchers have known that the brain controls the diameter of the peripheral arteries via the nervous system. Electrical impulses from the brain travel to the arteries via a network of nerves known as the sympathetic nervous system. This system is essential for daily life, but is often chronically overactive in high blood pressure and heart failure. In fact, many drugs that help with hypertension and heart failure work by decreasing both acute and chronic activity in the sympathetic nervous system. However, these drugs often have serious side effects, such as fatigue, dizziness and erectile dysfunction. “These drawbacks have led to the search for novel ways to inhibit the sympathetic nervous system while causing fewer problems for hypertension and heart failure patients,” says Dr. Frans Leenen, director of hypertension at the Ottawa Heart Institute, and a principal author of the study.

Working with an animal model of hypertension, Dr. Hamlyn and Dr. Mordecai Blaustein, professor of physiology and medicine at the UM SOM, and their research partner, Dr. Leenen, found a new link between the brain and increased blood pressure, namely, a little-known steroid called ouabain (pronounced WAH-bane). Ouabain was discovered in human blood more than 20 years ago by Dr. Hamlyn and Dr. Blaustein, along with scientists at the Upjohn Company. The new study is the first to identify the particular pathway that connects the brain to ouabain’s effects on proteins that regulate arterial calcium and contraction. Through this mechanism, ouabain makes arteries more sensitive to sympathetic stimulation, and as a result the enhanced artery constriction promotes chronic hypertension.

“Now that we understand the role of ouabain, we can begin working on how to modify this new pathway to help people with cardiovascular problems,” said Dr. Blaustein. “The potential for this is big.” Dr. Blaustein, who has been doing research on the substance since 1977, said medications that block ouabain’s effects might improve the lives of people with hypertension and heart failure.

The researchers, who include Vera Golovina, Ph.D., an adjunct associate professor of physiology at UM SOM, and Bing Huang, M.D, Ph.D., a research associate at the Ottawa Heart Institute, also found significant new evidence that ouabain is manufactured by mammals, a question that had not been previously answered.

“This discovery underscores the crucial importance of basic research here at the School of Medicine,” said Dean E. Albert Reece, MD, PhD, MBA, as well as vice president of medical affairs, the University of Maryland and the John Z. and Akiko Bowers Distinguished Professor. “These scientists have spent years unraveling the many potential roles of ouabain and how it works, and now we are beginning to see the fruits of their labor.”

World Alzheimer Report 2014: Evidence for dementia risk reduction

The World Alzheimer Report 2014 ‘Dementia and Risk Reduction: An analysis of protective and modifiable factors’, released today, calls for dementia to be integrated into both global and national public health programmes alongside other major non communicable diseases (NCDs). 

Alzheimer’s Disease International (ADI) commissioned a team of researchers, led by Professor Martin Prince from King’s College London, to produce the report. ADI is publishing this report, in conjunction with World Alzheimer’s Day (21 September) and as a part of World Alzheimer’s Month, an international campaign to raise awareness and challenge stigma.

The report reveals that control of diabetes and high blood pressure as well as measures to encourage smoking cessation and to reduce cardiovascular risk, have the potential to reduce the risk of dementia even in late-life. The report found that diabetes can increase the risk of dementia by 50%. Obesity and lack of physical activity are important risk factors for diabetes and hypertension, and should, therefore, also be targeted.

While cardiovascular health is improving in many high income countries, many low and middle income countries show a recent pattern of increasing exposure to cardiovascular risk factors, with rising rates of diabetes, heart disease and stroke. 

Smoking cessation is strongly linked in the report with a reduction in dementia risk. For example, studies of dementia incidence among people aged 65 years and over show that ex-smokers have a similar risk to those who have never smoked, while those who continue to smoke are at much higher risk. 

Furthermore, the study revealed that those who have had better educational opportunities have a lower risk of dementia in late-life. Evidence suggests that education has no impact on the brain changes that lead to dementia, but reduces their impact on intellectual functioning.

The evidence in the report suggest that if we enter old age with better developed, healthier brains we are likely to live longer, happier and more independent lives, with a much reduced chance of developing dementia. Brain health promotion is important across the life span, but particularly in mid-life, as changes in the brain can begin decades before symptoms appear. 

The report also urges NCD programs to be more inclusive of older people, with the message that it’s never too late to make a change, as the future course of the global dementia epidemic is likely to depend crucially upon the success or failure of efforts to improve global public health, across the population. Combining efforts to tackle the increasing global burden of NCDs will be strategically important, efficient and cost effective. Leading a healthier lifestyle is a positive step towards preventing a range of long-term diseases, including cancer, heart disease, stroke and diabetes. 

However, survey data released by Bupa* has shown that many people are unclear about the causes and actions they can take to potentially reduce their risk of dementia. Just over a sixth (17%) of people realised that social interaction with friends and family could impact on the risk. Only a quarter (25%) identified being overweight as a possible factor, and only one in five (23%) said physical activity could affect the risk of developing dementia and losing their memories. The survey also revealed that over two thirds (68%) of people surveyed around the world are concerned about getting dementia in later life.  

Professor Martin Prince, from King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and author of the report, commented: “There is already evidence from several studies that the incidence of dementia may be falling in high income countries, linked to improvements in education and cardiovascular health. We need to do all we can to accentuate these trends. With a global cost of over US$ 600 billion, the stakes could hardly be higher.”

Marc Wortmann, Executive Director, Alzheimer’s Disease International said: “From a public health perspective, it is important to note that most of the risk factors for dementia overlap with those for the other major non communicable diseases (NCDs). In high income countries, there is an increased focus on healthier lifestyles, but this is not always the case with lower and middle income countries. By 2050, we estimate that 71% of people living with dementia will live in these regions, so implementing effective public health campaigns may help to reduce the global risk.”

Professor Graham Stokes, Global Director of Dementia Care, Bupa, said: “While age and genetics are part of the disease’s risk factors, not smoking, eating more healthily, getting some exercise, and having a good education, coupled with challenging your brain to ensure it is kept active, can all play a part in minimising your chances of developing dementia. People who already have dementia, or signs of it, can also do these things, which may help to slow the progression of the disease.”

* These figures, unless otherwise stated, are from YouGov Plc. Total sample size was 8,513, from the UK (2,401), Australia (1,000), Chile (1,000), China (1,031), Poland (1,002), and Spain (1,077). Fieldwork was undertaken online, between 17–25 July 2014. The figures have been weighted and are representative of all adults (aged 18+) in each country. An even weighting was applied to each country to find a ‘Global Average’.

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Hypertension Could Bring Increased Risk for Alzheimer’s disease

A study in the Journal of the American Medical Association Neurology suggests that controlling or preventing risk factors, such as hypertension, earlier in life may limit or delay the brain changes associated with Alzheimer’s disease and other age-related neurological deterioration.

Dr. Karen Rodrigue, assistant professor in the UT Dallas Center for Vital Longevity (CVL), was lead author of a study that looked at whether people with both hypertension and a common gene had more buildup of a brain plaque called amyloid protein, which is associated with Alzheimer’s disease. Scientists believe amyloid is the first symptom of Alzheimer’s disease and shows up a decade or more before symptoms of memory impairment and other cognitive difficulties begin. The gene, known as APOE 4, is carried by 20 percent of the population.

Until recently, amyloid plaque could be seen only at autopsy, but new brain scanning techniques allow scientists to see plaque in living brains of healthy adults. Findings from both autopsy and amyloid brain scans show that at least 20 percent of typical older adults carry elevated levels of amyloid, a substance made up mostly of protein that is deposited in organs and tissues.

“I became interested in whether hypertension was related to increased risk of amyloid plaques in the brains of otherwise healthy people,” Rodrigue said. “Identifying the most significant risk factors for amyloid deposition in seemingly healthy adults will be critical in advancing medical efforts aimed at prevention and early detection.”

Based on evidence that hypertension was associated with Alzheimer’s disease, Rodrigue suspected that the combination of hypertension and the presence of the APOE-e4 gene might lead to particularly high levels of amyloid plaque in healthy adults.

Hypertension traced to source in brain

When the heart works too hard, the brain may be to blame, says new Cornell research that is changing how scientists look at high blood pressure (hypertension). The study, published in the Journal of Clinical Investigation in November, traces hypertension to a newfound cellular source in the brain and shows that treatments targeting this area can reverse the disease.

In what peer reviewers are calling “a new paradigm” for tackling the worldwide hypertension epidemic, this insight into its roots could give hope to the billion people it currently afflicts. Hypertension occurs when the force of blood against vessel walls grows strong enough to potentially cause such problems as heart attack, stroke and heart or kidney disease. The heart pumps harder, and often the hormone angiotensin-II (AngII) gets the pressure cooking by triggering nerve cells that constrict blood vessels.

"We knew the central nervous system orchestrates this process, and now we’ve found the conductor," said Robin Davisson, the Andrew Dickson White Professor of Molecular Physiology with a joint appointment at Cornell’s College of Veterinary Medicine and Weill Cornell Medical College.

Two-thirds of Americans have hypertension, which is the leading cause of North America’s No. 1 killer: heart disease, according to the Centers for Disease Control and Prevention.

Davisson’s lab traced neurochemical signals back to endoplasmic reticulum (ER), the protein factory and stress-management control center in every cell. If something goes wrong in a cell, the ER activates processes to adapt to the stress. Long-term ER stress can cause chronic disease, and several stressors that ER responds to have been connected to hypertension. Davisson’s lab found that high levels of AngII put stress on the ER, which responds by triggering the cascade of neural and hormonal signals that start hypertension.

But not just any cell’s ER can conduct this complex orchestra. Those that can trigger the signal cascade are clustered near the bottom of the brain in a gatelike structure called the subfornical organ (SFO). Unlike most of the brain, the SFO hangs outside a protective barrier that keeps most circulating particles from entering the brain. The SFO can interact with particles like AngII that are too big to cross through and can also communicate with the brain’s inner chambers.

This is good news for developing therapies—because the SFO sits outside the barrier, it can be reached through such normal treatment routes as pills or injections rather than riskier brain procedures. Davisson’s lab showed that treatments that inhibit ER stress in the SFO can completely stop AngII-based hypertension and lower blood pressure to normal levels.

"Our work provides the first evidence that higher levels of AngII cause ER stress in the SFO, that this causes hypertension, and that we can do something about it," said Davisson. "This finding may also suggest a role for ER stress in hypertension types that don’t involve AngII, like some spontaneous or genetic forms."

Inspired by the paradigm shift that this study has sparked, the editors of the Journal of Clinical Investigation published a commentary concluding that this discovery “opens new avenues for investigation and may lead to new therapeutic approaches for this disease.”