Tag: 2/9/24

Categories : Cardiovascular DiseaseTags : Leave a comment

Weekend Sleep Catchup may Lower Heart Disease Risk by up to 20%

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Photo by Mert Kahveci on Unsplash

The demands of the working week, often influenced by school or work schedules, can lead to sleep disruption and deprivation. Fortunately, new research presented at ESC Congress 2024 shows that people that ‘catch up’ on their sleep by sleeping in at weekends may see their risk of heart disease fall by one-fifth.  

“Sufficient compensatory sleep is linked to a lower risk of heart disease,” said study co-author Mr Yanjun Song of the State Key Laboratory of Infectious Disease, Fuwai Hospital, National Centre for Cardiovascular Disease, Beijing, China. “The association becomes even more pronounced among individuals who regularly experience inadequate sleep on weekdays.” 

It is well known that people who suffer sleep deprivation ‘sleep in’ on days off to mitigate the effects of sleep deprivation. However, there is a lack of research on whether this compensatory sleep helps heart health.  

The authors used data from 90 903 subjects involved in the UK Biobank project, and to evaluate the relationship between compensated weekend sleep and heart disease, sleep data was recorded using accelerometers and grouped by quartiles (divided into four approximately equal groups from most compensated sleep to least). Q1 (n = 22 475 was the least compensated, having -16.05 hours to -0.26 hours (ie, having even less sleep); Q2 (n = 22 901) had -0.26 to +0.45 hours; Q3 (n=22 692) had +0.45 to +1.28 hours, and Q4 (n=22 695) had the most compensatory sleep (1.28 to 16.06 hours). 

Sleep deprivation was self-reported, with those self-reporting less than 7 hours sleep per night defined as having sleep deprivation.  A total of 19 816 (21.8%) of participants were defined as sleep deprived. The rest of the cohort may have experienced occasional inadequate sleep, but on average, their daily hours of sleep did not meet the criteria for sleep deprivation – the authors recognise this a limitation to their data. 

Hospitalisation records and cause of death registry information were used to diagnose various cardiac diseases including ischaemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), and stroke. 

With a median follow-up of almost 14 years, participants in the group with the most compensatory sleep (quartile 4) were 19% less likely to develop heart disease than those with the least (quartile 1). In the subgroup of patients with daily sleep deprivation those with the most compensatory sleep had a 20% lower risk of developing heart disease than those with the least. The analysis did not show any differences between men and women. 

Co-author Mr Zechen Liu, also of State Key Laboratory of Infectious Disease, Fuwai Hospital, National Centre for Cardiovascular Disease, Beijing, China, added: “Our results show that for the significant proportion of the population in modern society that suffers from sleep deprivation, those who have the most ‘catch-up’ sleep at weekends have significantly lower rates of heart disease than those with the least.”  

Source: European Society of Cardiology

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When is the Best time of Day for Chemotherapy?

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Photo by Malvestida on Unsplash

Researchers from Charité are developing new methods to use the internal clock inside tumour cells to optimise cancer therapies

One of the factors determining the effectiveness of certain medications depends on various factors, including the time of day when they are administered. This is due to circadian rhythms, which vary across individuals and makes it difficult to tailor medication schedules. Researchers at Charité – Universitätsmedizin Berlin have now developed a method for determining the optimum time of cancer treatment based on certain breast cancer cell lines. They describe their approach in the journal Nature Communications.

As well as bodily functions and metabolic processes, such as sleep and digestion, individual cells also follow a circadian rhythm. This is hugely important to chemotherapy. Previous studies have shown that chemotherapy is most effective when the tumour cells are dividing. But this finding has been hardly used at all in clinical treatment to date.

An interdisciplinary team at Charité headed by Dr. Adrián Enrique Granada from the Charité Comprehensive Cancer Center (CCCC) set out to close this gap. The team began looking for the optimum time to administer medication, based on the individual circadian rhythms of the tumors.

Triple-negative breast cancer as an example

“We cultured cells from patients with triple-negative breast cancer to observe how they respond at different times of day to the medications administered,” explains Carolin Ector, a research associate in Granada’s working group. Triple-negative breast cancer is a highly aggressive form of breast cancer, with few effective treatments available. “We used live imaging, a method of continuously monitoring living cells, and complex data analysis techniques to monitor and evaluate the circadian rhythms, growth cycles, and medication responses of these cancer cells in detail.”

In this way, the researchers identified certain times of the day at which cancer cells are most responsive to medication-based treatments. For example, the chemotherapeutic drug 5-fluorouracil (5-FU) turned out to have peak efficacy against a certain cancer cell line between eight and ten a.m. As the study also shows, the crucial aspects here are certain cellular and genetic factors. The scientists were even able to identify which genes are key to the circadian effects of certain medications. “We call them ‘core clock genes’. They have a significant impact on how responsive cancer cells are to treatments administered at different times of day,” Granada explains.

Profiles show how cancer cell types respond to medications

This approach can be used to create detailed profiles showing how different types of cancer cells respond to different medications at various times. “This can help to identify the most effective combinations of drugs,” Granada says. “Overall, our findings indicate that personalized treatment plans based on individual circadian rhythms could substantially improve the efficacy of cancer treatment”, he concludes. Moreover, undesirable side effects could also be reduced.

For these findings to contribute to clinical practice soon, the results should be validated in studies involving larger groups of patients. “We’re also planning to study the molecular mechanisms behind the circadian influences on medication sensitivity to further optimize treatment times and identify new therapeutic targets,” Granada says.

Source: Charité – Universitätsmedizin Berlin

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Hospital Association Tables Proposal for Enhanced Healthcare through a Viable Proven Solution

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Netcare Christiaan Barnard Memorial Hospital

Monday, 2 September – Johannesburg, South Africa

Mandatory health cover of formally employed is tried and tested and if put to use in South Africa could reduce the public health burden, increase public per capita spend on health, and free up resources that could help address the country’s most pressing health crises.

With widespread concern that the National Health Insurance Fund is unaffordable and will take too long to implement while most South Africans already struggle to access quality healthcare services, Netcare Chief Executive Office Dr Richard Friedland has raised the possibility of near-term solutions including an under-explored alternative.

Speaking at the Hospital Association of South Africa Conference in Sandton, he stated that private hospitals wish to work with government to find solutions to our country’s healthcare problems. He pointed to mandatory medical cover for the formally employed as a potential solution that has been well-researched over two decades and is a “workable solution that if implemented will be quick to roll out and in a very short time provide enhanced healthcare to all South Africans.”

Friedland pointed out that the African National Congress’ 1994 Health Plan recommended mandatory cover for the formally employed and the National Department of Health Social Health Insurance Working Group in 1997 recommended that mandatory cover for formal sector employees should be confined to those above the income tax threshold, due to affordability concerns.

What this all offers, explained Friedland, is a middle ground option. If the government mandates those South Africans who are formally employed together with their families to be covered by some form of health insurance or medical aid, “This will enable public health sector resources to be dedicated to the informally employed, unemployed and indigent.”

“With a formally employed population of 11.5 million, together with the estimated number of dependants, based on a 2.4 beneficiary ratio, this could result in up to 27.5 million of our population that could potentially over time become covered, leaving the remaining 35.5 (56% of the population) people dependent on public health resources,” Friedland said.

Government public health per capita spend, he said, could increase over time by 52% without any additional funding of the public sector budget.

“In simple terms, if one considered the entire population in South Africa, government’s responsibility would reduce from the current 85% of the population covered by public health to 56%,” he said.

The latest per capita public expenditure based on a consolidated health budget of R271 billion works out to R5054, when considering the population and excluding medical scheme users. With formal employment coverage, that per capita public expenditure on public health users would increase 52% to R7 659, research shows.

Friedland also told the audience that getting the scheme off the ground could be done in three phases.

Phase one would involve including the formally employed and their dependants who are above the tax threshold. This would grow the medical scheme coverage from 9,2 to 15,4 million. The completion of Phase 1 would also expand public per capita spend by 12,9% at present day levels.

Phase 2 would include those formally employed and dependents who are below the tax threshold. This would push medical scheme coverage to 27,5 million and expand public per capita spend to 52%.

Phase 3, Friedland explained, will allow for the expansion of the economy through recovery and an increase in employment.

This will have further benefits to South Africa’s health care system with research showing that for every one million formal jobs created, the public health system would benefit with a reduction of approximately 2.4 million people, it will no longer have to serve. Additionally, this will add a 7% increase from Phase 2 on per capita public health spend.

“The health system stands to benefit in more immediate and visceral ways. The reduced load on the public sector will result in a reduced burdens on doctors, nurses and other healthcare workers, will reduce overcrowding, shorten queues and free up funding to fix infrastructure, fund unfunded medical posts, and grow our medical skills training capacity – remember, we have a shortage of 27 000 nurses in South Africa, and this is expected to grow to 70 000 by 2030.

Not only is the idea not new, says Friedland, but similar approaches are adopted elsewhere. In Africa 61% of countries have contributory mandatory programmes for civil servants and 50% of them programmes for sector employees.

The private hospital sector, says Friedland, stands ready to explore this idea and others that result in lessening the load on the shoulders of all South Africans who need accessible quality healthcare today.

“We stand ready to collaborate on further system strengthening, to more private public partnerships, to addressing public sector elective surgery waiting lists, to joint efforts on human resource training collaboration,” he says.

Categories : NeurologyTags : Leave a comment

Pulling Back the Curtain on the Brain Circuit for Memory Recall

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Photo by Anna Shvets

Deep within either hemisphere of the brain is the “claustrum complex”, which contributes to consciousness and awareness. Many diseases known to be related to higher cognitive function, such as Alzheimer’s, schizophrenia, and ADD/ADHD, are also closely linked to abnormal function of this particular part of the brain. But how the different parts of the claustrum complex work or how its circuits and communication system are organised is not fully understood.

Researchers at Aarhus University have now uncovered this, and their results identify, down to the cellular level, which part of the claustrum complex controls our ability to discriminate familiar and novel things.

“Our study focuses on an area of the claustrum called the ‘endopiriform,’ which is a relatively unknown brain structure despite its unique brain network and cellular properties,” explains Asami Tanimura, an associate professor and the lead researcher of the study appearing as a preprint in eLife.

“For the first time, we have dissected the circuit of endopiriform to the hippocampus, and demonstrated how this pathway is crucial for recognition memory.”

In mouse models, researchers were able to observe how the mice’s behaviour changed when they respectively ‘turned on’ and ‘turned off’ the activity in this specific cell group.

Asami explains: “We observed that the cells in the endopiriform were active when the mice interacted with new conspecifics or objects, and when we inhibited this cell group, it reduced the mice’s ability to distinguish novel mouse or object from familiar ones.”

Based on this, the researchers concluded that this specific cell group in the claustrum seems to play a key role in sending memory-guided attention signal to the hippocampus.

“This is entirely new knowledge about this small but important part of the brain, and it gives us a unique understanding of the special circuit involved in recognition memory,” explains Asami.

What this knowledge might mean, and whether it could lead to the development of new treatment methods targeted at disorders in this part of the brain, remains to be seen. However, Asami and her colleagues are optimistic:

“To develop effective treatment methods, a very detailed understanding of the cells’ circuits is required. With our study, we have at least opened a door that has previously been closed in terms of specific role of the endopiriform-hippocampal circuit on higher cognitive function.”

Source: Aarhus University

Categories : Cancer NeurologyTags : Leave a comment

Serotonin-producing Neurons Regulate Malignancy in Ependymoma Brain Tumours

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Credit: National Cancer Institute

A study published in Nature reveals the functional relevance of tumour-neuron interactions that regulate the growth of ependymoma brain tumours, one of the most common types in children. The study, conducted by researchers at Baylor College of Medicine and St. Jude Children’s Research Hospital, highlights how neuronal signalling, modifications in DNA-associated proteins and developmental programs are intertwined to drive malignancy in brain cancer.

“Ependymomas are the third most common type of paediatric brain tumours,” said co-corresponding author, Dr Benjamin Deneen professor in the Department of Neurosurgery. “These tumours are aggressive, resistant to chemotherapy and lack tumour-specific therapies, leading to poor survival.”

“We have not made an impact on patient survival in the last three decades. A major factor has been a poor understanding of the disease. The motivation of our collaborative work with the Deneen lab is to dissect the biology of these tumours as a basis for developing new therapies,” said co-corresponding author Dr Stephen Mack, associate member at St. Jude Children’s Research Hospital and member of the Department of Neurobiology, Neurobiology and Brain Tumor Program and Center of Excellence in Neuro-Oncology Sciences.

Previous studies have shown in other types of brain tumours that brain activity surrounding the tumour can influence its growth. “In the current study, we investigated whether brain activity played a role in ependymoma growth, specifically in a very aggressive type driven by a protein called ZFTA-RELA,” said first author Hsiao-Chi Chen, a graduate student in the Deneen lab. “In collaboration with the Mack lab, we developed an animal model to study this rare paediatric brain tumour and validated these findings in human tumour samples.”

The researchers discovered evidence of abnormal neuronal activity in ependymoma’s environment and investigated whether it affected ependymoma growth. They found that while hyperactivity of some neural circuits promoted tumour growth, hyperactivity of other neural circuits surprisingly reduced tumour growth, which had not been described before. Their study revealed a novel chain of events at play that regulates tumour growth, which may hold therapeutic applications.

“First, we found that normal neurons located in the brain region called dorsa raphe nucleus (dRN) project towards the cortex, where ependymoma grows. These neurons secrete serotonin, a brain chemical that carries messages between nerve cells, which surprisingly slows tumour growth,” Chen said.

Interestingly, ependymoma cells carry a serotonin transporter, a molecule that imports serotonin within the cell. “We were surprised to discover that serotonin enters ependymoma cells and binds to histone H3, a protein that is tightly associated with DNA,” Chen said. “Histone serotonylation, the addition of serotonin to histone, regulated tumour growth. Promoting it enhanced tumour growth while preventing it slowed down ependymoma growth in animal models.”

“Discovering histone serotonylation in ependymoma piqued our interest because a previous study from our lab had revealed that adding serotonin to histones affects which genes the cell turns on,” Deneen said.

The team discovered that histone serotonylation in ependymoma increases the expression of transcription factors, genes that regulate the expression of other genes,” Chen said. “We focused on transcription factor ETV5 whose overexpression accelerated tumour growth. But how does it do it?”

The next experiments showed that ETV5 expression triggers changes in the 3D structure of chromatin, the combination of DNA and proteins that forms chromosomes. The 3D changes prevent the activation of genes encoding neurotransmitters, molecules that mediate neural activity. The team focused on a neurotransmitter called neuropeptide Y (NPY) and found that growing tumours have little NPY. Restoring the levels of NPY in tumours slowed down tumour progression and tumour-associated neural hyperactivity through the remodeling of surrounding synapses or neuron-to-neuron communication.

“We knew that brain tumours release factors that remodel synapses towards hyperactivity. Here we found the opposite also can happen, that ependymoma tumours can release factors that suppress excitatory synaptic remodeling and that repressing this mechanism is essential for tumour progression,” Deneen said.

“I am excited that this work has redefined our understanding of how brain tumour cells grow, and how they take advantage of factors in their surrounding environment to initiate tumours,” Mack said. “I am equally excited that this work has revealed many new avenues for research that may in the future lead to new therapies, which is desperately needed for this devastating disease.”

Source: Baylor College of Medicine

Categories : Cardiovascular DiseaseTags : Leave a comment

Is Long-term Beta-blocker Therapy Needed after a Heart Attack?

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Pexels Photo by Freestocksorg

For patients with a history of myocardial infarction (MI), cardiovascular safety of interrupting beta-blocker could not be shown in comparison to continuation and there was no benefit to the patients’ quality of life, according to late-breaking research presented in a Hot Line session today at ESC Congress 2024.1 

“Improvements in MI management and data from observational studies have led physicians to question whether continuing beta-blockers after one year post-MI is needed since unnecessary treatment may result in side effects.2-5 We conducted the ABYSS trial to provide conclusive randomised data on the effects of beta-blocker interruption vs. continuation on cardiovascular events and quality of life, but we were unable to show safety preservation in terms of clinical events nor any benefit on quality of life with beta-blocker interruption,” said Principal Investigator, Professor Johanne Silvain of the Sorbonne University, Paris, France. 

The open-label, non-inferiority, randomised ABYSS trial, conducted by the ACTION Group, included patients with a prior MI taking long-term beta-blockers, with a left ventricular ejection fraction of at least 40% and no cardiovascular events in the previous six months. Participants were randomised (1:1) to interrupting or continuing their β-blocker medication. 

The primary endpoint was a composite of death, non-fatal MI, non-fatal stroke or hospitalisation for cardiovascular reasons at the longest follow-up (minimum, one year), according to an analysis of non-inferiority (defined as a between-group absolute difference of < 3 percentage points for the upper boundary of the two-sided 95% confidence interval [CI]). The main secondary endpoint was the change in quality of life as measured by the European Quality of Life–5 Dimensions questionnaire. 

In total 3698 patients were randomised from 49 sites in France. The mean age was 64 years and 17% were female. The median time between last MI and randomisation was 2.9 years (interquartile range 1.2–6.4 years). 

Over median follow-up of 3 years, interruption of long-term beta-blocker treatment was not shown to be non-inferior to beta-blocker continuation. A primary-outcome event occurred in 23.8% of patients in the interruption group and in 21.1% in the continuation group (risk difference 2.8 percentage points; 95% CI <0.1–5.5), with a hazard ratio of 1.16 (95% CI 1.01–1.33; p = 0.44 for non-inferiority).  

Death occurred in 4.1% in the interruption group and 4.0% in the continuation group, while MI occurred in 2.5% and 2.4%, respectively. Of note, hospitalisation for cardiovascular causes occurred in 18.9% in the interruption group and 16.6% in the continuation group. Beta-blocker interruption was also associated with increases in systolic and diastolic blood pressure and heart rate at 6 months (all p<0.001 vs. beta-blocker continuation) and during the study follow up. Beta-blocker interruption did not improve the patients’ quality of life.  

Summing up the evidence from the ABYSS trial, Professor Silvain concluded: “Differences between the groups with respect to hospitalisation for cardiovascular reasons and the negative effect on blood pressure levels, together with the absence of quality-of-life improvement do not support interruption of a chronic beta-blocker treatment in post-MI patients. These results must be put into context with recent findings from the open-label REDUCE-MI6 trial and ongoing trials to provide additional evidence on the optimal use of beta-blockers after MI.”  

References

  1. ‘Beta blocker interruption in patients with prior myocardial infarction: results of the ABYSS trial and effect on blood pressure and heart rate control’ will be discussed during Hot Line 1 on Friday 30 August in room London. 
  2. Holt A, Blanche P, Zareini B, et al. Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study. Eur Heart J. 2021;42:907–914. 
  3. Park CS, Yang H-M, Ki Y-J, et al. Left ventricular ejection fraction 1 year after acute myocardial infarction identifies the benefits of the long-term use of beta-blockers: analysis of data from the KAMIR-NIH Registry. Circ Cardiovasc Interv. 2021;14:e010159.  
  4. Puymirat E, Riant E, Aissaoui N, et al. β Blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study. BMJ. 2016;354:i4801. 
  5. Kim J, Kang D, Park H, et al. Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study. Eur Heart J. 2020;41:3521–3529. 
  6. Yndigegn T, Lindahl B, Mars K, et al. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med. 2024;390:1372–1381.  

Source: European Society of Cardiology