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Sacubitril/valsartan leads to greater reduction in plasma NT-proBNP levels compared to valsartan alone after stabilisation for worsening heart failure (HF) in patients with an ejection fraction (EF) above 40%, according to late breaking science presented today at Heart Failure 2023, a scientific congress of the European Society of Cardiology (ESC), and published in the Journal of the American College of Cardiology.

Principal investigator Dr Robert Mentz of Duke University Medical Center, Durham, US said: “These data add to the evidence supporting a potential treatment benefit of sacubitril/valsartan in patients with EF over 40% and particularly in those with EF below normal (< 60%). The findings may influence future guidance for the use of the drug in this population, both in and out of hospital and for those with acute, chronic or de novo heart failure.”

Guidelines recommend consideration of sacubitril/valsartan to reduce hospitalisations in patients with HF with preserved EF (HFpEF; EF >50%) and/or mildly reduced EF (HFmrEF; EF 41–49%). Recommendations differ around the world, with some noting benefits are more evident in those with EF on the lower end of this spectrum (ie below normal).

The PARAGON-HF trial excluded patients with decompensated heart failure, but a post-hoc analysis suggested a larger benefit with sacubitril/valsartan in those recently hospitalised. Whether initiation of sacubitril/valsartan is safe and effective in patients with EF over 40% stabilised after a worsening HF event was unknown. In addition, further data were needed in populations excluded by PARAGON-HF (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m², systolic blood pressure < 110mmHg, and body mass index [BMI] > 40kg/m²).

PARAGLIDE-HF evaluated the effect of sacubitril/valsartan versus valsartan on changes in NT-proBNP, safety and tolerability in HF patients with EF above 40% who had been stabilised after a worsening HF event. The primary endpoint was the time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. It was chosen to mirror the PIONEER-HF trial, which found that among patients with heart failure with reduced EF (< 40%) who were hospitalised for acute decompensated HF, sacubitril/valsartan led to a greater reduction in NT-proBNP concentration than enalapril.

Patients were recruited from 100 sites in the US and Canada. A total of 466 patients with EF above 40% were enrolled within 30 days of a worsening heart failure event (69% were enrolled while in hospital). The average age was 70 years, 52% were women and 22% were Black. Participants were randomly allocated in a 1:1 ratio to sacubitril/valsartan or valsartan. The time-averaged reduction in NT-proBNP was greater with sacubitril/valsartan compared with valsartan (ratio of change 0.85; p=0.049).

The secondary composite hierarchical outcome consisted of a) time to cardiovascular death, b)number and timing of HF hospitalisations, c) number and timing of urgent HF visits and d) time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8. This outcome was evaluated using a win ratio analysis, which considers the clinical hierarchy and timing of each component of the endpoint. More serious events are given a higher priority and are analysed first. The hierarchical outcome favoured sacubitril/valsartan (as did each of the components) but was not significant (unmatched win ratio 1.19; 95% CI 0.93–1.52; p=0.16).

Regarding other secondary endpoints, compared with valsartan, sacubitril/valsartan reduced worsening renal function (odds ratio [OR] 0.61). There was more symptomatic hypotension in the sacubitril/valsartan group (OR 1.73). Importantly, subgroup analyses showed evidence of a larger treatment effect in those with EF ≤60% for the change in NT-proBNP (0.78) and the hierarchical outcome (win ratio 1.46).

Dr Mentz said: “PARAGLIDE-HF complements PARAGON-HF by focusing on patients stabilised after a worsening heart failure event with EF above 40% similar to the manner in which PIONEER-HF complemented PARADIGM-HF in patients with reduced EF. PARAGLIDE-HF had no run-in period, allowed both newly diagnosed heart failure and improved EF, included those with acute heart failure without specific echocardiographic requirements and overall had a diverse study population (52% women, 22% Black individuals). The trial also permitted patients with eGFR down to 20 mL/min/1.73m², systolic blood pressure as low as 100mmHg, and any BMI. The broad and diverse population included in PARAGLIDE-HF supports the generalisability of these data to similar patients seen in routine practice.”

Source: European Society of Cardiology

A new study published in Psychological Reports has shed light on the way present fathers play a positive role in adolescent psychological development. The researchers observed that when adolescents grow up with fathers present, they experience more ‘failure learning’, which supports the development of resilience.

Adolescence is a difficult time, with new social and academic pressures emerging. Resilience, or the capacity to cope with and recover from challenges, has been identified as a critical component to success in adolescence.

They explored the mediating effects of four subfactors of failure learning: failure cognition, reflection and analysis, experience transformation, and prudent attempt.

Failure cognition is the understanding and perception of a failure event. It includes recognising the occurrence of a failure and understanding the causes.

Reflective analysis involves evaluation of the events leading to the failure, and critically analysing one’s own actions and decisions. This helps identification of mistakes and areas for improvement.

Experience transformation involves taking the insights from reflective analysis and transforming the experience of failure into a learning opportunity.

Prudent attempt involves putting the lessons learned into practice, and taking calculated risks to improve subsequent performance. This component emphasises the importance of persistence and not being put off by prior failures.

Using questionnaires, the researchers assessed 626 Chinese middle school students, average age 14. They measured levels of father presence, resilience, and failure learning. The researchers found that: (1) there was a significant association between father presence, failure learning, and resilience; (2) failure learning played a mediating role between father presence and adolescents’ resilience; (3) the mediating effect of experience transformation and prudent attempt between father presence and adolescents’ resilience was significant, but not failure cognition and reflective analysis.

The researchers posited that the presence of a father helped to mediate resilience, especially in the two aspects of failure learning most linked to resilience. By supporting the decisions made around the failure, they help their adolescent children to recognise that a prudent attempt was made and to accept the failure.

Limitations included being the adolescents being exclusively Chinese, with cultural factors that may not be applicable to adolescents of other cultures. Additionally, the effect of mothers was not accounted for, and it was possible that the positive effects were only possible through the co-parenting support of a mother,

Source: PsyPost

It is well known that diets with a high sodium-to-potassium ratio are linked to poor cardiovascular outcomes. To date, most attention has mostly focused on high sodium, but low potassium is also a culprit in cardiovascular disease. Now, research published in Cell Reports has revealed that low dietary potassium also causes direct kidney injury.

Using in vitro and in vivo approaches, Andrew Terker, MD, PhD, and colleagues demonstrated that the injury effects depend on the Kir4.2 potassium channel in kidney proximal tubule cells. First, they reduced dietary potassium levels to determine changes in kidney injury markers, and then lowered blood potassium levels to confirm that it indeed drove kidney injury.

Efflux of potassium from the cells caused intracellular acidosis and activated the enzyme glutaminase. This increased enzyme activity contributed to kidney injury, leading to hypertrophy, inflammation and fibrosis. They found that deleting Kir4.2 or glutaminase protected proximal tubule cells from injury in both cell culture and animal models. 

The findings identify Kir4.2 and glutaminase as mediators of low potassium-related kidney injury and potential therapeutic targets. The findings also suggest that the standard practice of recommending excessive restriction of dietary potassium for patients with chronic kidney disease could unintentionally contribute to disease progression in certain settings

Source: Vanderbilt University

The method by which a baby was delivered is associated with how its immune system will respond to pneumococcal and meningococcal vaccinations, according to a study in Nature Communications. After vaccination, babies born naturally had higher antibody levels than those born via Caesarian section.

Experts say the findings could help to inform conversations about C-sections between expectant mothers and their doctors, and shape the design of more tailored vaccination programmes.

Researchers studied the relationship between gut microbes and antibody levels after vaccination in a cohort of 120 babies, who were vaccinated at 8 and 12 weeks against lung infections and meningitis.

The researchers tracked the development of the gut microbiome in the child’s first year of life and their immune response to the vaccines by testing saliva samples at 12 and 18 months.

Research was carried out by a team from the University of Edinburgh, Spaarne Hospital and University Medical Centre in Utrecht and the National Institute for Public Health and the Environment in The Netherlands.

In the 101 babies tested for antibodies as a result of the vaccine that protects against lung infections, the investigators found double the antibody levels in babies delivered naturally compared with those delivered by C-section.

Breastfeeding was linked with 3.5 times higher antibody levels compared with formula-fed children who had been delivered naturally.

Levels of antibodies as a result of the vaccine that protects against meningitis were tested in 66 babies. Experts found the levels of antibodies were 1.7 times higher for naturally delivered babies, regardless of breastfeeding, compared with those delivered via C-section.

The gut microbiome is seeded at birth, developing rapidly over the first few months of life, and is influenced mostly by delivery mode, breastfeeding, and antibiotic use.

The team found a clear relationship between microbes in the gut of those babies and levels of antibodies.

For example, among a host of bacteria in the gut, high levels of two in particular — Bifidobacterium and E. Coli — were associated with a high antibody response to the vaccine that protects against lung infections.

High levels of E. Coli were also linked with a high antibody response to the vaccine that protects against meningitis.

The baby acquires the Bifidobacterium and E.coli bacteria through natural birth and human milk is needed to provide the sugars for these bacteria to thrive on.

The team concludes that the babies’ microbiome in early life contributes the immune system’s response to the vaccines and sets the level of protection against certain infections in childhood.

Vaccination schedules could also be adjusted based on mode of delivery or an analysis of the baby’s microbiome in the future, experts say.

Dr Emma de Koff, first author and microbiology trainee at the Amsterdam University Medical Center, said: “We expected to find a link between the gut microbiome and the babies’ vaccine responses, however we never thought to find the strongest effects in the first weeks of life.”

Professor Debby Bogaert study lead and Chair of Paediatric Medicine at the University of Edinburgh said “I think it is especially interesting that we identified several beneficial microbes to be the link between mode of delivery and vaccine responses. In the future, we may be able to supplement those bacteria to children born by C-section shortly after birth through, for example, mother-to-baby ‘faecal transplants’ or the use of specifically designed probiotics.”

Many factors dictate whether a vaccine provokes an immune response, including specific biomarkers within a person’s immune system, but until now there has been no evidence showing whether these factors were universal across a wide range of vaccines.

New findings from a meta-analysis published in Nature Immunology examine the biological mechanisms responsible for why some people’s immune systems respond differently to vaccinations, which could have global implications for the development and administration of vaccines.

As part of a series of studies for The Human Immunology Project Consortium (HIPC), a network of national research institutions studying the range of responses to different infections and vaccinations, Emory researchers analysed the molecular characteristics of 820 healthy young adults who were immunised with 13 different vaccines to identify specific biomarkers that generate antibody response to vaccines.

The participants were separated into three endotypes, or groups with a common gene expression, based on the level of inflammatory response prior to vaccination – a high inflammatory group, a low inflammatory group, and a mid-inflammatory group. After studying the immunological changes that occurred in participants following vaccination, researchers found the group that had the highest levels of inflammation prior to vaccine had the strongest antibody response.

“We were surprised because inflammation is usually depicted as something that is bad,” says Slim Fourati, PhD, bioinformatic research associate at Emory University and first author on the paper. “These data indicate that some types of inflammation can actually foster a stronger response from a vaccine.”

Fourati, Dr Rafick-Pierre Sekaly, professor and senior author of the paper, and the HIPC team identified specific biomarkers among this group and cellular features that characterised the pre-vaccination inflammatory signature, information that can be used to predict how well an individual will respond to a vaccine.

“With the knowledge we now have about what characteristics of the immune system enable a more robust response, vaccines can be tailored to induce this response and maximize their effectiveness,” says Fourati. “But we still have more questions to answer.”

More research is needed to determine the cause of this inflammation in otherwise healthy adults. Additionally, Fourati suggests future studies should look at how these biomarkers facilitate vaccine protection in older age groups and among populations who are immunocompromised.

These findings can serve to improve vaccine response across all individuals. Better understanding of how various pre-vaccine immune states impact antibody responses opens the possibility of altering these states in more vulnerable individuals. For example, scientists may give patients predicted to have a weaker immune response an adjuvant with the vaccine to trigger the inflammatory genes associated with greater protection.

This work will help enable improved, more efficient clinical trials for the development of new vaccines.

Source: Emory Health Sciences

In the journal Molecular Therapy, researchers report that it may be possible to heal wounds by using a healing protein that is active in foetuses, but largely inactive in adults and absent in diabetic adults.

“We already know from previous studies at other institutions that if a foetus is wounded, it can regenerate the tissue, or repair it to be like new,” said Chandan K. Sen, PhD, at Indiana University School of Medicine. “But after birth, such regenerative wound healing ability is lost. Healing in adults is relatively inefficient often associated with undesirable scar formation.”

In the study,  the team focused on a protein called nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase, or NPGPx. NPGPx is active in foetal tissue but becomes mostly inactive in the skin after birth.

“Nature essentially hides this foetal regenerative repair pathway in the adult body,” Sen said. “We spotted its absence, and then activated it to improve healing of diabetic wounds.”

Researchers used tissue ‘nanotransfection’ technology to deliver the NPGPx gene to the wound site. Diabetic wounds, which are complicated skin injuries in people with diabetes, are particularly difficult to treat and often lead to amputations or other complications because of how easily they can become infected.

“This is an exciting new approach to harness foetal repair mechanisms to close diabetic wounds in adults,” Sen said. “The study results show that while NPGPx has been known to be abundant in the foetal skin, but not after birth, it can be reactivated in the skin after an injury. We look forward to continued study aiming to achieve a more complete regenerative repair by improving our understanding of how NPGPx functions.”

Source: Indiana University School of Medicine

Reproduction permanently alters the skeletons of females in ways not previously known, a team of anthropologists has concluded from research findings published in PLOS ONE. This discovery, based on an analysis of primates, sheds new light on how giving birth can permanently change the body.

“Our findings provide additional evidence of the profound impact that reproduction has on the female organism, further demonstrating that the skeleton is not a static organ, but a dynamic one that changes with life events,” explains Paola Cerrito, who led the research as a doctoral student in NYU’s Department of Anthropology and College of Dentistry.

Specifically, the researchers found that calcium, magnesium, and phosphorus concentrations are lower in females who have experienced reproduction. These changes are linked to giving birth itself and to lactation.

However, they caution that while other clinical studies show calcium and phosphorus are necessary for optimal bone strength, the new findings do not address overall health implications for either primates or humans. Rather, they say, the work illuminates the dynamic nature of our bones.

“A bone is not a static and dead portion of the skeleton,” notes NYU anthropologist Shara Bailey, one of the study’s authors. “It continuously adjusts and responds to physiological processes.”

It’s been long-established that menopause can have an effect on females’ bones. Less clear is how preceding life-cycle events, such as reproduction, can influence skeletal composition. To address this, the researchers studied the primary lamellar bone, the main type of bone in a mature skeleton. This aspect of the skeleton is an ideal part of the body to examine because it changes over time and leaves biological markers of these changes, allowing scientists to monitor alterations during the life span.

The researchers examined the growth rate of lamellar bone in the femora, or thigh bones, of both female and male primates who had lived at the Sabana Seca Field Station in Puerto Rico and died of natural causes. Veterinarians at the field station had monitored and recorded information on these primates’ health and reproductive history, allowing the researchers to match bone-composition changes to life events with notable precision.

Cerrito and her colleagues used electron microscopy and energy-dispersive X-ray analysis to calculate changes in concentrations of calcium, phosphorus, oxygen, magnesium, and sodium in the primates’ bones.

Their results showed different concentrations of some of these elements in females who gave birth compared males as well as females who did not give birth. Specifically, in females who gave birth, calcium and phosphorus were lower in bone formed during reproductive events. Moreover, there was a significant decline in magnesium concentration during these primates’ breastfeeding of infants.

“Our research shows that even before the cessation of fertility the skeleton responds dynamically to changes in reproductive status,” says Cerrito, now a research fellow at ETH Zurich. “Moreover, these findings reaffirm the significant impact giving birth has on a female organism – quite simply, evidence of reproduction is ‘written in the bones’ for life.”

Source: New York University