Tag Archives: #heart

Fast heart, Slow heart: Changes in the Molecular Motor Myosin Explain the Difference (Biology)

A molecular explanation for an old physiologic observation

The human heart contracts about 70 times per minute, while that of a rat contracts over 300 times; what accounts for this difference? In a new study publishing 10th June in the open-access journal PLOS Biology, led by Michael Geeves and Mark Wass of the University of Kent and Leslie Leinwand from the University of Colorado Boulder, reveal the molecular differences in the heart muscle protein beta myosin that underly the large difference in contraction velocity between the two species.

Myosin is a “molecular motor” – an intricate nanomachine that forms the dynamic core of a muscle’s contractile machinery, burning cellular chemical energy in the form of ATP to rapidly and reversibly exert force against cables of actin. In so doing, it pulls the ends of the muscle cell closer together, causing muscle contraction. It has long been known that the maximal rate of contraction, called V0, varies predictably among mammals: In small mammals with their high metabolic rate, V0 is higher than in larger mammals, which have lower metabolic rates.

There are multiple kinds of myosin, which serve diverse roles not only in muscle but in every other cell of the body. It is the muscle-specific forms, called sarcomeric myosins, that shows the pronounced difference in V0 between species (the V0 values of non-muscle isoforms show little in the way of between-species differences). Not surprisingly, the amino acid sequence of these sarcomeric myosins varies between species, but which of these variations is responsible for the small mammal/big mammal difference in V0?

The authors compared beta myosin (the sarcomeric myosin present in slow muscle and in heart) sequences from 67 different mammals, and found that differences in the motor domain, the region of the molecule that binds and burns ATP, were most closely correlated with differences in V0. Further analysis of two different evolutionary lineages of mammals, each containing both large and small species, led them to identify 16 sites on the molecule that were associated specifically with size difference, independent of lineage. Humans and rats differed at nine of these sites. When the authors then changed the human protein to include the rat amino acids at these sites, the rat-human chimeric protein functioned more like the rat protein, with a doubling of motility and a faster release of the waste product ADP (the velocity-limiting step in contraction).

An increase in size is a common trend in mammalian evolution, seen in multiple lineages, including our own. “The change in V0 that we observed in the chimeric protein demonstrates that changes in these residues likely enabled the slower heart rate required in larger animals as they have evolved from small to large,” Chloe Johnson one of the authors said. “The fact that the two lineages tested in this study both hit upon the same solution to slowing contraction suggests there may be few molecular options for altering beta myosin’s rate of contraction.”

Research Article: Peer reviewed; Experimental Study; Cells

In your coverage please use these URLs to provide access to the freely available articles in PLOS Biologyhttp://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001248

Funding: MNW was supported by a Royal Society research grant. JEM was supported by an EPSRC PhD studentship. MAG & JW were supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 777204 SILICO FCM. LAL was supported by NIH GM29090 and NIH HL117138. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Reference: Johnson CA, McGreig JE, Jeanfavre ST, Walklate J, Vera CD, Farré M, et al. (2021) Identification of sequence changes in myosin II that adjust muscle contraction velocity. PLoS Biol 19(6): e3001248. https://doi.org/10.1371/journal.pbio.3001248


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Researchers Uncover The Embryonic Origin of the Heart (Biology)

Researchers from the Francis Crick Institute have studied the earliest point at which the heart forms during embryonic development and revealed, for the first time, that each part of the heart has a unique origin. Their study in mice, published in PLoS Biology today (Thursday), has implications for understanding congenital heart diseases.

As an embryo develops, cells become increasingly specialised to form different tissues and organs. A key period is known as gastrulation, which leads to the formation of the main tissues of body, including the heart. 

The team, a collaboration between two leading Crick developmental biology labs, identified the cells that form the heart during gastrulation and traced each individual cell’s destiny from this earliest stage until the heart had fully formed.

They found that the four chambers of the heart all have distinct spatial and temporal origins. The very first set of cells create the left ventricle, followed by cells forming the right ventricle and finally the two atria.

We can now envisage generating cells pre-determined to become specific parts of the heart and could use these to model disease or develop and test new regenerative therapies. Kenzo Ivanovitch

Jim Smith, head of the Crick’s Developmental Biology Laboratory, said: “Investigating how different types of cell in an embryo form at the right time and in the right place is crucial for understanding why this can sometimes go wrong. Congenital heart diseases affect around one in 180 babies worldwide and work like ours may help explain why just a single chamber of the heart is affected in heart defects such as left ventricle hypoplasia.”

In their study, the team first measured gene activity in individual cells, and concluded that distinct genes are active in the predecessors of the heart at very early stages of embryonic development. This means they would be allocated to distinct anatomical structures of the heart.

They then used an advanced imaging technique called multiphoton live-imaging to microscopically film mouse embryos developing outside the womb. They were able to follow the fate of individual cells as they migrated through the embryo to establish different parts of the heart.

Kenzo Ivanovitch, lead author and postdoctoral training fellow at the Crick, said: “Our finding that different parts of the heart arise in different locations may help researchers build better models using stem cells. Current methods produce a mix of atrial and ventricular cells which can make studying diseases that affect particular chambers of the heart more difficult. 

“We can now envisage generating cells pre-determined to become specific parts of the heart and could use these to model disease or develop and test new regenerative therapies.”

James Briscoe, head of the Crick’s Developmental Dynamics Laboratory, said: “Different heart cell populations having distinct origins may mean that each group is uniquely predisposed or sensitive to genetic or environmental changes.
 
“New technologies are giving us unprecedented insight into the make-up and behaviour of individual cells in developing tissues. This is offering a new understanding into the causes of congenital diseases and identifying targets for new treatments.”

Featured image: Picture of mouse embryo at gestational day 8. The heart is labelled in white. © Francis Crick Institute


Reference: Ivanovitch K, Soro-Barrio P, Chakravarty P, Jones RA, Bell DM, Mousavy Gharavy SN, et al. (2021) Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak. PLoS Biol 19(5): e3001200. doi:10.1371/journal.pbio.3001200


Provided by Francis Crick Institute

Taking More Steps Daily May Lead To A Longer Life (Physiology)

American Heart Association Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Conference – Presentation 69

Research Highlights:

  • Taking more steps per day, either all at once or in shorter spurts, may help you live longer.
  • The benefits of more daily steps occurred with both uninterrupted bouts  of steps (10 minutes or longer) and short spurts such as climbing stairs.

Taking more steps per day, either all at once or in shorter spurts, may help you live longer, according to preliminary research to be presented at the American Heart Association’s Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Conference 2021. The meeting is virtual, May 20-21, and offers the latest science on population-based health and wellness and implications for lifestyle.

Walking is one of the safest and easiest ways to improve fitness and health including heart health. The American Heart Association’s fitness guidelines for adults recommend at least 150 minutes per week of moderate or 75 minutes of vigorous physical activity, or a combination of both. Popular fitness apps and step counters make it easy to count steps, so researchers used a wearable step counting device to compare the effects of uninterrupted bouts of steps (10 minutes or longer) to occasional short spurts, such as climbing the stairs and general daily activities throughout the day.

“Technological advances made in recent decades have allowed researchers to measure short spurts of activity. Whereas, in the past we were limited to only measuring activities people could recall on a questionnaire,” said lead study author Christopher C. Moore, M.S., a Ph.D. student in epidemiology at the University of North Carolina at Chapel Hill. “With the help of wearable devices, more research is indicating that any type of movement is better than remaining sedentary.”

From 2011-2015, 16,732 women wore a waist step counter that measured their daily steps and walking patterns for four to seven days. The women were all over age 60 (average age of 72; mostly non-Hispanic white women) and were participants in the Women’s Health Study, a large, national study of heart disease, cancer and other long-term disease prevention.

The researchers divided the total number of steps for each study participant into two groups: 1) 10 minutes or longer bouts of walking with few interruptions; and 2) short spurts of walking during regular daily activities such as housework, taking the stairs, or walking to or from a car. In follow-up, they tracked deaths from any cause for an average of six years, through December 31, 2019.

Researchers found:

  • Overall, 804 deaths occurred during the entire study period of 2011-2019.
  • Study participants who took more steps in short spurts lived longer, regardless of how many steps they had in longer, uninterrupted bouts. The benefits leveled off at about 4,500 steps per day in short spurts.
  • Compared to no daily steps, each initial increase of 1,000 steps per day was associated with a 28% decrease in death during the follow-up period.
  • A 32% decrease in death was noted in participants who took more than 2,000 steps daily in uninterrupted bouts.

A prior analysis of the same women reported that those who took 4,500 steps per day had a significantly lower risk of death compared to the least active women. “Our current results indicate that this finding holds even for women who did not engage in any uninterrupted bouts of walking. Taking 2,000 or more additional steps during bouts was associated with further benefits for longevity,” Moore said.

“Older adults face many barriers to participating in structured exercise programs, so some may find it more convenient and enjoyable to increase everyday walking behaviors, like parking slightly further from their destination or doing some extra housework or yardwork,” Moore said.

Since all study participants were older and mostly non-Hispanic white women, more research is needed to determine if the results apply to men, younger women and people from diverse racial and ethnic groups.

Co-authors are Kelly R. Evenson, Ph.D.; Eric J. Shiroma Jr., Ph.D.; Annie G. Howard, Ph.D.; Carmen C. Cuthbertson, Ph.D.; Julie E. Buring, Sc.D.; and I-Min Lee, Sc.D. The authors’ disclosures are listed in the abstract.

The Women’s Health Study is funded by Brigham and Women’s Hospital, and the National Heart, Lung, and Blood Institute and the National Cancer Institute of the National Institutes of Health. The lead author is funded by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

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How The Coronavirus Attacks the Heart? (Medicine)

A RUB research team has found out which mechanisms the coronavirus uses to attack the heart – and how it can be stopped.

The Sars-Cov-2 coronavirus can cause severe organ damage in humans. Heart complications are also one of the consequences of a Covid 19 infection. The severe acute respiratory syndrome triggered by corona is usually associated with additional stress on the heart, especially in people with weak hearts or other pre-existing cardiac diseases. The virus also attacks the heart directly, causing myocarditis and heart failure. But how does the virus get into the heart? And how can it be stopped?

Nazha Hamdani is head of the research area for molecular and experimental cardiology at the University Hospital Bochum.© Roberto Schirdewahn

Doctor Dr. Nazha Hamdani, who heads the research area for molecular and experimental cardiology at the University Hospital Bochum. The researcher closely followed the virus’ journey into the heart and discovered a new mechanism of entry and damage: the virus docks onto the heart cells using so-called extracellular vesicles and exosomes, i.e. particles outside the cell, and infects them.

Our study shows for the first time that there is another mechanism that the virus uses to get through the bloodstream into the human heart.- Nazha Hamdani

In order to track down the new entry mechanism, the research team at the University Hospital analyzed the blood sera and heart tissue structures of patients suffering from Covid-19 and those who died from the disease using histochemical methods and microscopy.

Virus detected in heart cells

In a first step, Hamdani’s team provided evidence that the virus can actually and directly be detected in the cells of the heart muscle. “Our observations show that the virus exerts pressure on the heart muscle, attacks and weakens the force of contraction, ie the pumping function of the heart,” says Hamdani.

Hamdani and her team analyze the blood serum of patients suffering from Covid-19 using light and electron microscopy.© Roberto Schirdewahn

But how does the virus penetrate the heart in the first place? In previous studies on Sars-Cov-2, it was already possible to demonstrate that the novel virus attaches itself to a certain surface molecule of the human cell, the angiotensin-converting protein, via an enzyme, the so-called spike protein, which sits on the outside of the virus envelope. Enzyme 2 (ACE-2), binds. “The virus penetrates the cell interior via the ACE-2 receptor and then multiplies. This process has already been observed in the lungs, intestines, kidneys and liver ”, Hamdani summarizes the results of international research groups so far. Since ACE-2 can also be found on the cell surface of the heart, the Bochum doctor assumed that the virus would also attack the heart in this way.

To their astonishment, Hamdani and her team found the infected ACE-2 receptor only in the endothelium, the cell layer on the inner surface of the blood cells, and in extracellular particles, but not in the heart muscle cells. For the doctor it was clear: “The virus infection of human cells succeeds via ACE-2, but the virus seeks its way into the heart independently of it”. So there had to be other factors that enable the virus to enter the heart’s vascular cells. Hamdani and her team found what they were looking for in just four months.

Discovered a new mechanism

The key are what are known as extracellular vesicles. These lie outside the cells and are responsible for cell-to-cell communication. They are able to transport molecules, and thus also the messenger RNA of the virus, from infected cells to healthy cells. “Like a taxi that drives through the bloodstream and distributes the genetic information of the virus,” explains Hamdani.

The research team made the vesicles visible using a fluorescent dye, so-called double gold marking, and then observed them through a special light microscope, a confocal microscope, and an electron microscope. They were able to clearly identify the vesicles including the virus and components such as double-stranded RNA and spike protein in the blood and heart cells of severely infected patients. Follow-up experiments should show whether other organ cells are also attacked via this additional mechanism.

Alternative entry gate

In addition, the Bochum researchers were able to support the existing findings that the virus also uses the protein Neuropilin-1 (NRP-1) as a gateway into the cells. “Neuropilin lies on the outer wall of the epithelium, the top layer of cells in human skin, and thus makes it easier for the virus to penetrate. We measured an increased NPR-1 activity in the heart cells. This indicates that neuropilin-1 is an alternative receptor for Sars-Cov-2 entry alongside the ACE-2 receptor, ”Hamdani explains the important find. Neuropilin produces the messenger substance interleukin-6, which in turn regulates the inflammatory reaction of the organism and is essential for immune defense processes. If the production of interleukin-6 increases, this can lead to cell damage and cell death.

By using fluorescent dyes, the particles in the cells can be made visible and the path of the virus can be precisely followed.© Roberto Schirdewahn

Why the novel Sars-Cov-2 is so virulent?

Hamdani’s research shows that this means that several mechanisms are available for the coronavirus to spread in human organs. “The fact that the new virus is able to distribute itself independently of receptors via infected endothelial vesicles sets it apart from its predecessor Sars-Cov-1 and makes it a lot more virulent,” explains Hamdani. “The susceptibility to infection is also favored by an inflamed and oxidized cell environment, as often occurs in the elderly, people with high blood pressure, diabetics or those affected by obesity,” the doctor continues. Hamdani has been researching the pathophysiological causes of heart disease for years. What they all have in common: inflamed and oxidized vascular cells. Such a cell environment also increases the risk of Covid 19 patients

Breakthrough in Covid-19 therapy

Since the beginning of the corona pandemic, therapies have been sought that can contain the virus infection and prevent severe disease. The new mechanism that the Bochum research team has uncovered holds a promising therapeutic approach in store. It could be possible to load the extracellular vesicles with a medicinal cocktail of antibodies, anti-oxidants and anti-inflammatory agents that stop the virus from spreading, reduce inflammation levels and boost the immune system. “Our future cocktail drug would help people who have not yet been vaccinated but are already infected,” says Hamdani, explaining the therapeutic potential. It would also work against all virus variants. “The drug should prevent entry into the heart and other organs, regardless of the type of mutant,” says the researcher.

Featured image: A RUB doctor has discovered how the coronavirus penetrates the heart muscle cells. © Roberto Schirdewahn


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Provided by Ruhr Universitat Bochum

Slow Synchronization Keeps Heart Cells Beating in Time (Biology)

For a beating heart cell, noise is a problem. Researchers showed that single cells can regulate their inner noise

If you dance cheek-to-cheek with a partner, your rhythms soon synchronize, so you move smoothly across the floor. Heart cells that beat – cardiomyocytes – are the same. In fact, if you grow embryonic heart cells on a flexible material, you can not only observe this synchronization, you can get these cells to change the rhythm of their beats from “rhumba” to “waltz” or vice versa, just by jiggling them so they “feel” a new pace. But you’ll have to keep the jiggling up for tens of minutes to get them to make the transition, and once you stop, it will take the cells a similar amount of time to return to their normal pulse.

Video: Beating cardiomyocytes in the lab of Prof. Shelly Tzlil, the Technion

That finding arose from experiments done in the lab of Prof. Shelly Tzlil, of the Technion – Israel Institute of Technology. “This was puzzling,” says Prof. Sam Safran, a theoretical physicist at the Weizmann Institute of Science’s Chemical and Biological Physics Department. Together with his PhD student Ohad Cohen, Safran had previously shown that the spontaneous beating of cardiomyocytes – which occurs at a frequency of about once per second – could be described using an analogy to a mechanical system akin to a vibrating spring.

The puzzle was this: If, for the spring-like oscillations, a beating cycle takes place about every second, why is the time needed to get it to change its pace so much longer? Over an hour, the cell would contract 3,600 times – that is, if it were at a dance, a cell would keep waltzing while its partner jitterbugged until it was nearly time to leave. If the only characteristic of the spontaneously beating cardiomyocyte were that spring-like mechanism, the physics of such a system would dictate that it would react within the short timescale of the vibration, and new rhythms would be adopted within several seconds, not many minutes. “When such a mismatch in timing happens, you first examine the intrinsic properties of the system, itself – even in the absence of forces that change its pace – and ask if a different characteristic timescale is involved,” says Safran.

Prof. Sam Safran (sitting) and Ohad Cohen © Weizmann Institute of Science

Safran and Cohen suspected that a possible longer timescale might have to do with the intrinsic response of a spontaneously beating cell to the noise – the “fuzziness” often seen in data from living systems – that was noted in the previous experiments. That is, cardiomyocytes beat about once a second – sometimes in nine-tenths of a second, sometimes waiting an extra tenth of a second to contract. Could an additional, slower mechanism be functioning in the cells to keep that noise close to the “ideal” one second mark?

To test this idea, Tzlil grew cardiomyocytes in her lab and, working in collaboration with Cohen and Safran, timed the natural, unperturbed beating of individual cells for several hours. The researchers thus obtained “cardiograms” of these single cells. Viewing the data over the course of a minute or so, they plotted the difference between the actual timing of each contraction and its “ideal” average timing, plus or minus, from the one-second mark. More challenging was the plotting of beats over hours, rather than minutes, but these revealed a new pattern: The pulses that were slower or faster than average appeared in bunches – many slower beats, followed by many faster beats. The timescale associated with these bunches was tens of minutes, a far cry from the natural one-second timing of an “average” beat.

It was as if a somewhat clumsy, invisible hand were continually adjusting the knob on a staticky radio station, turning the frequency up and down in an attempt to hit the exact right interval. This pattern of regulation occurred over a span of ten to thirty minutes. When the team then compared the regulation from different lab-grown cardiomyocytes, after first mathematically accounting for the differences in their ranges (so that a regulation cycle taking, say, fifteen minutes could be compared with one taking twenty-five), they found that the graphs looked very similar, implying that such a slow, noise-regulating mechanism is intrinsic to the functioning of all of these heart cells, no matter how fast or slow they beat.

(I) Measured over a few minutes, cardiomyocyte beats regularly deviate up and down from the one second mark. (r) But seen over several hours, a longer oscillation around the one-second goal can be seen ©Weizmann Institute of Science

How did the heart cell “know” that it was beating too quickly or slowly, and why did it take it so long to compensate for faster or slower beating by introducing the opposite pace? “Though we still don’t know the detailed biochemistry that accounts for this long regulation time,” says Safran, “its scale of tens of minutes suggests that gene transcription and protein translation are involved, possibly to modify the channels and pumps that area involved in the transport of calcium within the cell.” Further experiments may reveal whether the duration of the regulation time is an indicator of cellular “good health”; too long a regulation time might mean that the cell is not oscillating properly over longer intervals. Extending the research to heart tissue may reveal the functional importance of overly long regulation times to the integrity of the beating tissue and perhaps in the future, to the heart itself.

“We showed, once again, that even as heart cells are noisy – in the manner of all biological systems – the noise is interesting; using physics to analyze its patterns reveals how the cell attempts to deal with its imperfect behavior,” he adds.Prof. Samuel Safran’s research is supported by the Benoziyo Endowment Fund for the Advancement of Science; the Henry Krenter Institute for Biomedical Imaging and Genomics; and the Harold Perlman Family. Prof. Safran is the incumbent of the Fern and Manfred Steinfeld Professorial Chair. 


Provided by Weizmann Institute of Science

Long-term Space Travelers Will Need High-intensity Exercise to Protect Heart Health (Medicine)

Research Highlights:

  • Sustained low-intensity exercise does not completely counteract the effects of weightlessness on the heart muscle, which will atrophy over time in a gravity-free environment.
  • Short bursts of repeated high-intensity activity during shorter space missions may be more successful in keeping the heart healthy.

As NASA seeks to build a lunar outpost, visit Mars and commercialize spaceflight, the long-term effects of weightlessness on the human heart are of critical importance, according to researchers. By analyzing data from astronaut Scott Kelly’s year in space and comparing it to information from extreme long-distance swimming, which simulates weightlessness, of Benoît Lecomte, researchers found that low-intensity exercise was not enough to counteract the effects of prolonged weightlessness on the heart, according to new research published today in the American Heart Association’s flagship journal Circulation.

Each time a person sits or stands, gravity draws blood into the legs. The work the heart does to keep blood flowing as it counters Earth’s gravity helps it maintain its size and function. Removing gravitational effects causes the heart to shrink.

Researchers examined data from retired astronaut Scott Kelly’s stint aboard the International Space Station from 2015 to 2016 and elite endurance swimmer Benoît Lecomte’s swim across the Pacific Ocean in 2018.

In this new study, researchers evaluated the effects of long-term weightlessness on the structure of the heart and to help understand whether extensive periods of low-intensity exercise can prevent the effects of weightlessness.

“The heart is remarkably plastic and especially responsive to gravity or its absence. Both the impact of gravity as well as the adaptive response to exercise play a role, and we were surprised that even extremely long periods of low-intensity exercise did not keep the heart muscle from shrinking,” said Benjamin D. Levine, M.D., the study’s senior author and a professor of internal medicine at UT Southwestern Medical Center and director of Texas Health Presbyterian’s Institute for Exercise and Environmental Medicine, both in Dallas.

The research team examined the health data of Kelly’s year in space aboard the International Space Station and Lecomte’s swim across the Pacific Ocean to investigate the impact of long-term weightlessness on the heart. Water immersion is an excellent model for weightlessness since water offsets gravity’s effects, especially in a prone swimmer, a specific swimming technique used by long-distance endurance swimmers.

Kelly exercised six days a week, one to two hours per day during his 340 days in space, March 27, 2015 to March 1, 2016, using a stationary bike, a treadmill and resistance activities. Researchers hoped Lecomte’s 159-day swim from June 5 to Nov. 11, 2018 of 1,753 miles from Choshi, Japan, during which he averaged nearly six hours a day swimming, would keep his heart from shrinking and weakening. Doctors performed various tests to measure the health and effectiveness of both Kelly’s and Lecomte’s hearts before, during and after each man embarked on his respective expeditions.

The analysis found:

  • Both Kelly and Lecomte lost mass from their left ventricles over the course of the experiences (Kelly 0.74 grams/week; Lecomte 0.72 grams/week).
  • Both men suffered an initial drop in the diastolic diameter of their heart’s left ventricle (Kelly’s dropped from 5.3 to 4.6 cm; Lecomte’s reduced from 5 to 4.7 cm.).
  • Even the most sustained periods of low-intensity exercise were not enough to counteract the effects of prolonged weightlessness.
  • Left ventricle ejection fraction (LVEF) and markers of diastolic function did not consistently change in either individual throughout their campaign.

This case study examined two extraordinary feats by two unique individuals. While it is important to understand how the body responds to extreme circumstances, more study is required to understand how these results can be applied to the general population. Analysis of Lecomte’s cardiac MRIs from before and after his swim are forthcoming and will also be helpful for the researchers to further understand whether long-term effects of weightlessness can be reversed. Kelly did not receive cardiac MRIs, and currently, there are no further follow up plans with him.

Co-authors are James P. MacNamara, M.D., M.S.C.S.; Katrin A. Dias, Ph.D.; Satyam Sarma, M.D.; Stuart M.C. Lee, Ph.D., David Martin, M.S., R.D.C.S.; Maks Romeijn, M.D.; and Vlad G. Zaha, M.D., Ph.D.

Featured image: Benjamin D. Levine M.D. FACC FAHA FACSM, Professor of internal medicine, UT Southwestern Medical Center; director of Texas Health Presbyterian’s Institute for Exercise and Environmental Medicine, Dallas, Texas © copyright UT Southwestern


Reference: James P. MacNamara, Katrin A. Dias, Satyam Sarma, Stuart M. C. Lee, David Martin, Maks Romeijn, Vlad G. Zaha, and Benjamin D. Levine, “Cardiac Effects of Repeated Weightlessness During Extreme Duration Swimming Compared With Spaceflight”, Circulation, 29 Mar 2021. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050418 https://doi.org/10.1161/CIRCULATIONAHA.120.050418


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A Healthy Heart May Help Delay or Prevent Dementia (Neuroscience)

New study shows targeting arterial stiffening earlier in a person’s lifespan could provide cognitive benefits in older age and may help to delay the onset of dementia.

Researchers at the University of Oxford and University College London investigated 542 older adults who received two measurements of aortic stiffness, at 64 years old and 68 years old. Subsequent cognitive tests and brain magnetic resonance imaging (MRI) scans assessed the size, connections and blood supply of different brain regions.

The body’s largest artery (the aorta) gets stiffer with age, and the study found that faster aortic stiffening in mid-life to older age was linked to markers of poorer brain health, for example:

  • Lower brain blood supply
  • Reduced structural connectivity between different brain regions
  • Worse memory

Medical interventions and changes of lifestyle made earlier in the lifespan could help to slow down arterial stiffening. In an ageing society where we expect a near tripling in the number of people living with dementia by 2050, identifying ways to prevent or delay its onset could have significant societal and economic impact.

Dr Sana Suri, Alzheimer’s Society Research Fellow at the Department of Psychiatry, University of Oxford, said, ‘Our study links heart health with brain health, and gives us insights into the potential of reducing aortic stiffening to help maintain brain health in older ages. Reduced connectivity between different brain regions is an early marker of neurodegenerative diseases such as Alzheimer’s disease, and preventing these changes by reducing or slowing down the stiffening of our body’s large blood vessels may be one way to maintain brain health and memory as we grow older.’

This study shows the importance of interdisciplinary work in this field and stresses the benefits of studying the brain in conjunction with other organ systems. Arteries stiffen faster if someone has pre-existing heart diseases, high blood pressure, diabetes and other vascular diseases. Arterial stiffening is also progressively faster with long-term exposure to poor health behaviours and lifestyle risk factors, such as smoking or poor diets. It is possible to reduce arterial stiffening by medical treatments or lifestyle interventions, such as modifying the diet and exercising.

Dr Scott Chiesa, Research Associate at the UCL Institute of Cardiovascular Science, said, ‘With no cure for dementia, there is an increased focus on understanding how to prevent or delay its onset. Importantly, our study helps us understand when in the lifespan it will be best to target and improve cardiovascular health to benefit the brain.’

Dr Richard Oakley, Head of Research at Alzheimer’s Society, which funded the study, said, ‘Dementia devastates lives, and with the number of people with dementia set to rise to 1 million by 2025 and more families affected than ever before, reducing our risk has never been more important. This Alzheimer’s Society funded study didn’t look for a link between heart health and dementia directly, but it has shed important light on a connection between the health of our blood vessels and changes in the brain that indicate brain health.

‘We know that what’s good for your heart is good for your head, and it’s exciting to see research that explores this link in more detail. But we need even more research to understand the impact of heart health on brain health as we age, and how that affects our own dementia risk. Alzheimer’s Society is committed to funding research into dementia prevention as well as research into a cure. But coronavirus has hit us hard, so it’s vital the Government honours its commitment to double dementia research spending to continue research like this.’

Participants in this study were part of the Imaging subset of the Whitehall II Study, a cohort of British civil service members who have received clinical follow-ups for over 30 years. Participants were predominantly white males and were selected if they had no clinical diagnosis of dementia. Further research in diverse samples and people with more advanced cognitive deficits will be needed to confirm these findings in a wider population.

The Whitehall II Study and the Whitehall II Imaging Sub-study are funded by grants from the UK Medical Research Council, British Heart Foundation, and US National Institute on Aging.

Provided by University of Oxford

Protein That Can be Toxic in the Heart and Nerves May Help Prevent Alzheimer’s (Medicine)

A protein that wreaks havoc in the nerves and heart when it clumps together can prevent the formation of toxic protein clumps associated with Alzheimer’s disease, a new study led by a UT Southwestern researcher shows. The findings, published recently in the Journal of Biological Chemistry, could lead to new treatments for this brain-ravaging condition, which currently has no truly effective therapies and no cure.

Abnormal deposits of the protein amyloid beta in the brain have been linked to Alzheimer’s disease. The above illustration reveals a potential way discovered by UTSW researchers to stop this process, leveraging the protective nature of the protein transthyretin (TTR) to identify a segment of this protein, TTR-S, that halts plaque formation and facilitates its degradation in a test tube. © UT Southwestern Medical Center

Researchers have long known that sticky plaques of a protein known as amyloid beta are a hallmark of Alzheimer’s and are toxic to brain cells. As early as the mid-1990s, other proteins were discovered in these plaques as well.

One of these, a protein known as transthyretin (TTR), seemed to play a protective role, explains Lorena Saelices, Ph.D., assistant professor of biophysics and in the Center for Alzheimer’s and Neurodegenerative Diseases at UTSW, a center that is part of the Peter O’Donnell Jr. Brain Institute. When mice modeled to have Alzheimer’s disease were genetically altered to make more TTR, they were slower to develop an Alzheimer’s-like condition; similarly, when they made less TTR, they developed the condition faster.

In healthy people and animals, Saelices adds, TTR helps transport thyroid hormone and the vitamin A derivative retinol to where they’re needed in the body. For this job, TTR forms a tetramer – a shape akin to a clover with four identical leaflets. However, when it separates into molecules called monomers, these individual pieces can act like amyloid beta, forming sticky fibrils that join together into toxic clumps in the heart and nerves to cause the rare disease amyloidosis. In this condition, amyloid protein builds up in organs and interferes with their function.

Saelices wondered whether there might be a connection between TTR’s separate roles in both preventing and causing amyloid-related diseases. “It seemed like such a coincidence that TTR had such opposing functions,” she says. “How could it be both protective and damaging?”

Lorena Saelices Gomez, Ph.D. © UT Southwestern Medical Center

To explore this question, she and her colleagues developed nine different TTR variants with differing propensities to separate into monomers that aggregate, forming sticky fibrils. Some did this quickly, over the course of hours, while others were slow. Still others were extremely stable and didn’t dissociate into monomers at all.

When the researchers mixed these TTR variants with amyloid beta and placed them on neuronal cells, they found stark differences in how toxic the amyloid beta remained. The variants that separated into monomers and aggregated quickly into fibrils provided some protection from amyloid beta, but it was short-lived. Those that separated into monomers but took longer to aggregate provided significantly longer protection. And those that never separated provided no protection from amyloid beta at all.

Saelices and her colleagues suspected that part of TTR was binding to amyloid beta, preventing amyloid beta from forming its own aggregations. However, that important piece of TTR seemed to be hidden when this protein was in its tetramer form. Sure enough, computational studies showed a piece of this protein that was concealed when the leaflets were conjoined could stick to amyloid beta. However, this piece tended to stick to itself to quickly form clumps. After modifying this piece with chemical tags to halt self-association, the researchers created peptides that could prevent the formation of toxic amyloid beta clumps in solution and even break apart preformed amyloid beta plaques. The interaction of modified TTR peptides with amyloid beta resulted in the conversion to forms called amorphous aggregates that were easily broken up by enzymes. In addition, the modified peptides prevented amyloid “seeding,” a process in which fibrils of amyloid beta extracted from Alzheimer’s disease patients can template the formation of new fibrils.

Saelices and her colleagues are currently testing whether this modified TTR peptide can prevent or slow progression of Alzheimer’s in mouse models. If they’re successful, she says, this protein snippet could form the basis of a new treatment for this recalcitrant condition.

“By solving the mystery of TTR’s dual roles,” she says, “we may be able to offer hope to patients with Alzheimer’s.”

Other researchers who contributed to this study include Qin Cao, Daniel H. Anderson, Wilson Y. Liang, and Joshua Chou, all of the University of California, Los Angeles.

This work was supported by Amyloidosis Foundation grants 20160759 and 20170827 and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under Research Executive Agency (REA) Grant Agreement 298559.

Provided by UT Southwestern Medical Center

Tracking the Formation of the Early Heart, Cell by Cell (Biology)

Richard Tyser and colleagues have mapped the origins of the embryonic mouse heart at single-cell resolution, helping to define the cell types that make up the heart in the earliest days of development.

© Gettyimages

Their techniques allowed them to identify for a first time a pool of progenitor cells that contributes to the formation of heart muscle cells as well as the early epicardium, the outermost layer of the heart. This layer provides cells and other proteins that guide the development and repair of heart tissue, so a better understanding of its origins could better inform regenerative heart therapies as well as improve our understanding of congenital heart defects.

Tyser et al. performed a micro-dissection of a portion of the embryonic mouse heart to observe a very early stage streak of cells called the cardiac crescent transform into the linear heart tube. Combining single-cell RNA sequencing to identify cell types with high-resolution imaging and time-lapse microscopy, the researchers were able to follow the development of distinct populations of progenitor heart cells over about 12 hours of development.

Reference: Richard C. V. Tyser, Ximena Ibarra-Soria, Katie McDole, Satish A. Jayaram, Jonathan Godwin, Teun A. H. van den Brand, Antonio M. A. Miranda, Antonio Scialdone, Philipp J. Keller, John C. Marioni, Shankar Srinivas, “Characterization of a common progenitor pool of the epicardium and myocardium”, Science 07 Jan 2021:
eabb2986 DOI: 10.1126/science.abb2986 https://science.sciencemag.org/content/early/2021/01/07/science.abb2986

Provided by AAAS