Month: September 2021

Radiation Therapy Can Reprogram Faulty Heart Cells

Photo from Olivier Collett on Unsplash
Photo from Olivier Collett on Unsplash

New research published in Nature Communications suggests that radiation therapy can reprogram heart muscle cells to what appears to be a younger state, fixing electrical problems that cause life-threatening arrhythmia without the need for an invasive catheter ablation procedure.

In catheter ablation, a catheter is threaded into the heart, and the tissue that triggers ventricular tachycardia is burned, creating scars that block the errant signals. The new study, however, shows that noninvasive radiation therapy can reprogram the heart muscle cells to a younger and perhaps healthier state, fixing the electrical fault in the cells themselves without needing scar tissue to block the overactive circuits. Previous research showed that radiation therapy typically reserved for cancer treatment could be directed at the heart to treat ventricular tachycardia.

Radiation therapy could in theory reproduce the scar tissue of catheter ablation, in a quicker and totally noninvasive procedure, making the treatment available to more severely ill patients. The doctors found that, surprisingly, patients experienced large improvements in their arrhythmias just days to weeks after radiation therapy, much quicker than the months it can take scar tissue to form after radiation therapy, suggesting that a single radiation dose diminishes the arrhythmia without forming scar tissue. Analysis showed the radiation treatment was at least as effective as catheter ablation for certain patients with ventricular tachycardia, albeit for different, unknown reasons.

“Traditionally, catheter ablation creates scar tissue to block the electrical circuits that are causing ventricular tachycardia,” said senior author and cardiologist Stacey L. Rentschler, MD, PhD, an associate professor of medicine, of developmental biology and of biomedical engineering. “To help us understand whether the same thing was happening with radiation therapy, some of the first patients to have this new treatment gave us permission to study their heart tissue – following heart transplantation or if they had passed away for another reason, for example. We saw that scar tissue alone could not explain the remarkable clinical effects, suggesting that radiation improves the arrhythmia in some other way, so we delved into the details of that.”

Radiation treatment triggered heart muscle cells to begin expressing different genes, the researchers found. Increased activity was seen in a signaling pathway called Notch, which is known for its vital role in early development, including in forming the heart’s electrical conduction system.

A single dose of radiation temporarily activates Notch signalling – normally dormant in adult cells – and leading to a long-term increase in sodium ion channels in the heart muscle, a key physiologic change that can reduce arrhythmias.

“Arrhythmias are associated with slow electrical conduction speeds,” Rentschler said. “Radiation therapy seems to kick up the speed faster by activating early developmental pathways that revert the heart tissue back into a healthier state.”

The researchers studied these effects in mice and in donated human hearts. In human samples, the researchers found that these changes in heart muscle cells were only present in areas of the heart that received the targeted radiation dose.

“Radiation does cause a type of injury, but it’s different from catheter ablation,” said co-author and radiation oncologist Julie K. Schwarz, MD, PhD, a professor of radiation oncology and director of the Cancer Biology Division in the Department of Radiation Oncology. “As part of the body’s response to that injury, cells in the injured portion of the heart appear to turn on some of these early developmental programs to repair themselves. It’s important to understand how this works because, with that knowledge, we can improve the way we’re treating these patients and then apply it to other diseases.”

The researchers also found that the beneficial effects of radiation continued for at least two years in surviving patients. And importantly, they were able to demonstrate in mice that a lower dose of the radiation produced the same effect. A lower radiation dose could reduce long-term side effects and allow such treatment in other types of heart arrhythmias. And while Notch was a big player in these effects, Prof Schwarz said it’s not the only pathway involved. The researchers are continuing to investigate how radiation triggers heart cells to revert to a healthier state.

Source: Washington University School of Medicine

Treating a Mutation Tames The ‘Red Devil’ Chemotherapy Drug

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Harmful side effects from the common chemotherapy drug doxorubicin could be caused by a single mutation, according to a study published in Cell Stem Cell.

The cardiotoxic effects of the chemotherapy drug doxorubicin – an infamous drug nicknamed the ‘Red Devil’ because of its bright red colour and side effects – could be prevented in patients with the mutation by treating them with retinoic acid, according to Paul Burridge, PhD, assistant professor of Pharmacology and senior author of the study.

“In the future patients could be given CD1530, or a similar drug, and this would reduce their chances of experiencing cardiotoxicity,” said Prof Burridge.

Doxorubicin is the most common chemotherapy drug and is mostly used in children and in breast cancer. However, patients receiving doxorubicin experience dose-dependent cardiotoxicity; up to 10% of childhood cancer survivors will develop heart failure in the 30 years after their treatment.

A previous study showed that people who experience cardiotoxicity from chemotherapy were more likely to have a genetic variation called a single nucleotide polymorphism (SNP) in a gene called retinoic acid receptor gamma (RARG).

In this study, Dr Burridge and colleagues created patient-derived heart cells with this SNP and administered doxorubicin, finding that those cells indeed were more sensitive to the treatment. After correcting the mutation using genetic editing tools, the additional toxicity disappeared.

“This confirmed to us that RARG is important in doxorubicin cardiotoxicity sensitivity,” Prof Burridge said.

The researchers tried several drugs that could block the downstream effects of this mutation, finding that one drug, CD1530, made cardiomyocytes less sensitive to the chemotherapy. The drug activates retinoic acid receptors that are usually left inactivated in patients with the SNP, preventing activation of a cardio-protective pathway that is ill-suited for chemotherapy.

The investigators hope to test this drug in human patients, thanks to their use of human cells.

“Because all of our data was generated in human cells, there isn’t a need for a second basic research step,” Prof Burridge said. “We believe we will be able to begin the first stages of a clinical trial, testing the safety of RARG agonists and how effective they are in patients.”

Source: Northwestern University

ECG Readings Can Predict Worsening and Mortality in COVID and Influenza

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Specific and dynamic changes on electrocardiograms (ECGs) of hospitalised COVID patients with COVID or influenza can help predict a timeframe for worsening health and death, according to a new Mount Sinai study.

Published in the American Journal of Cardiology, the study shows that shrinking waveforms on these tests can be used to help better identify high-risk patients and provide them more aggressive monitoring and treatment.  

“Our study shows diminished waveforms on ECGs over the course of COVID illness can be an important tool for health care workers caring for these patients, allowing them to catch rapid clinical changes over their hospital stay and intervene more quickly. […] ECGs may be helpful for hospitals to use when caring for these patients before their condition gets dramatically worse,” said senior author Joshua Lampert, MD, Cardiac Electrophysiology fellow at The Mount Sinai Hospital. “This is particularly useful in overwhelmed systems, as there is no wait for blood work to return and this test can be performed by the majority of health care personnel. Additionally, the ECG can be done at the time of other bedside patient care, eliminating the potential exposure of another health care worker to COVID.”

Researchers did a retrospective analysis of ECGs on 140 hospitalised COVID patients across the Mount Sinai Health System in New York City, and compared them with 281 ECGs from patients with laboratory-confirmed influenza A or B admitted to The Mount Sinai Hospital.  
For each patient, the researchers compared three ECG time points: a baseline scan done within a year prior to COVID or influenza hospitalisation, a scan taken at hospital admission, and follow-up ECGs performed during hospitalisation.

They manually measured QRS waveform height on all electrocardiograms – changes in this electrical activity can indicate failing ventricles. The researchers analysed follow-up ECGs after hospital admission and analysed changes in the waveforms according to a set of criteria they designed  called LoQRS amplitude (LoQRS) to identify a reduced signal. LoQRS was defined by QRS amplitude of less than 5mm measured from the arms and legs or less than 10mm when measured on the chest wall as well as a relative reduction in waveform height in either location by at least 50%.

Fifty-two COVID patients in the study did not survive, and 74% of those had LoQRS. Their ECG QRS waveforms reduced approximately 5.3 days into their hospital admission and they died approximately two days after the first abnormal ECG was observed.

Out of the 281 influenza patients studied, LoQRS was identified in 11 percent of them. Seventeen influenza patients died, and 39% had LoQRS present. Influenza patients met LoQRS criteria a median of 55 days into their hospital admission, and the median time to death was six days from when LoQRS was identified. Overall, these results show influenza patients followed a less virulent course of illness when compared to COVID patients.

“When it comes to caring for COVID patients, our findings suggest it may be beneficial not only for health care providers to check an EKG when the patient first arrives at the hospital, but also follow-up ECGs during their hospital stay to assess for LoQRS, particularly if the patient has not made profound clinical progress. If LoQRS is present, the team may want to consider escalating medical therapy or transferring the patient to a highly monitored setting such as an intensive care unit (ICU) in anticipation of declining health,” added Dr Lampert.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Documents Reveal Funding Attempts for Pre-pandemic Coronavirus Research

COVID heat map. Photo by Giacomo Carra on Unsplash

A recent article by The Telegraph revealed documents on grant applications by US and Wuhan scientists to conduct coronavirus research in 2018. However, it is important to note that these grants were not funded, and are not direct evidence of a ‘lab leak’ or research-related origin for the coronavirus. 

The documents, obtained by a scientist-activist group calling itself DRASTIC and confirmed as authentic by a member of the Trump administration, detail grant requests for antigen-bearing nanoparticles and aerosols to be released into bat caves to immunise bat populations. Note that “coronavirus particles” as The Telegraph describes them would be immunising nanoparticles which could describe coronavirus vaccines. Another proposal involved adding “human-specific cleavage sites” to bat coronaviruses to facilitate entry into human cells. The Defense Advanced Research Projects Agency (DARPA) however, refused to fund the work, saying it would have “put local communities at risk.”

What is perhaps more concerning were details of an effort for gain of function research in MERS-CoV, which has a 30% fatality rate, something which an anonymous World Health Organization COVID researcher suggests could have resulted in a pandemic that was “nearly apocalyptic.”

Scientists, however, urge continued impartiality and examining all possibilities, even controversial ones. In an article published on Friday, 24 September in The Lancet, authors point out that there is neither solid evidence for either a natural origin or a for a research origin. In the nineteen months since the beginning of the pandemic, no natural origin has been found despite extensive searching, and independent international researchers do not have access to the investigation sites in China, raw data or samples. However, it took several years for the natural origins of SARS-CoV-1 to be discovered.

They also point out that a research origin for the virus cannot be excluded. Optimisation of the receptor binding domain for human ACE2 could occur through selection or cell cultures, without requiring knowledge of it in advance. Although certain genetic engineering techniques leave signatures in the genome, so-called ‘seamless’ techniques exist. 

“On the basis of the current scientific literature, complemented by our own analyses of coronavirus genomes and proteins, we hold that there is currently no compelling evidence to choose between a natural origin (ie, a virus that has evolved and been transmitted to humans solely via contact with wild or farmed animals) and a research-related origin (which might have occurred at sampling sites, during transportation or within the laboratory, and might have involved natural, selected, or engineered viruses).”

Sources: The Telegraph (paywall)The Lancet

Most Trials in Clinical Practice Hold Up Over Time

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According to a new paper in Family Practice, medical practice can often be undermined by later research, randomised trials relevant to primary care generally hold up over time.

Medical reversal describes a problem whereby new research causes doctors to stop using a popular medication, procedure or test based on previous evidence. Vinayak Prasad, associate professor at the University of California, San Francisco, had found that up to 46% of original studies on adopted medical practices led to a reversal or shift in evidence of effect.

Evidence-based medicine lets doctors be confident when their decisions are grounded in high quality research. But decisions supported by robust evidence from randomised controlled trials can be reversed. For example, although aspirin is prescribed commonly to prevent cardiovascular disease, new studies indicate this treatment is unlikely to be effective.

Researchers studied the extent to which evidence from randomised control trials relevant to primary care were contradicted in subsequent research. Examining 408 randomised controlled trials from 2002 to 2005 relevant to primary care, the researchers found that over 12-17 years of follow up time, there were just 35 occurrences of evidence reversal, or roughly two a year. About nine in ten of such randomised control trials were not reversed.

“Conclusions from randomised trials relevant to primary care that also meet criteria for validity are stable over time,” said study lead author Christian Ruchon.

Source: EurekAlert!

WHO Tightens Air Quality Guidelines

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New WHO Global Air Quality Guidelines (AQGs) have lowered the acceptable limits of air pollution, providing evidence that even lower concentrations than previously understood have a negative health impact.

Increasing evidence showing how air pollution affects different aspects of health, WHO has adjusted almost all the AQGs levels downwards, warning that exceeding the new air quality guideline levels is associated with significant risks to health.

Air pollution is estimated to cause 7 million premature deaths and the loss of millions more healthy years of life. In children, this could include reduced lung growth and function, respiratory infections and aggravated asthma. In adults, deaths from ischaemic heart disease and stroke are the most common, as well as emerging evidence of diabetes and neurodegenerative conditions. This makes the disease burden from air pollution on par with others such as unhealthy diet and tobacco smoking.

Besides climate change, air pollution is one of the biggest environmental threats to human health. Improving air quality will also help mitigate climate change, thereby reducing the negative health impacts of both.
WHO’s new guidelines recommend air quality levels for 6 pollutants, where evidence has advanced the most on health effects from exposure. When action is taken on these so-called classical pollutants – particulate matter (PM), ozone (O₃), nitrogen dioxide (NO₂) sulfur dioxide (SO₂) and carbon monoxide (CO), it also has an impact on other damaging pollutants.

Particulate matter equal or smaller than 10 and 2.5 microns (µm) in diameter (PM₁₀ and PM₂.₅, respectively) is a particular health concern. Both PM₂.₅ and PM₁₀ can penetrate deep into the lungs but PM₂.₅ can even enter the bloodstream, primarily resulting in cardiovascular and respiratory impacts, and also affecting other organs, and were classified as carcinogenic in 2013.

“Air pollution is a threat to health in all countries, but it hits people in low- and middle-income countries the hardest,” said WHO Director-General, Dr Tedros Adhanom Ghebreyesus. “WHO’s new Air Quality Guidelines are an evidence-based and practical tool for improving the quality of the air on which all life depends. I urge all countries and all those fighting to protect our environment to put them to use to reduce suffering and save lives.”

In 2019, over 90% of the world’s population lived in areas where concentrations exceeded the 2005 WHO air quality guideline for long term exposure to PM₂.₅.

Almost 80% of PM₂.₅-related deaths could be avoided if current air pollution levels were reduced to those proposed in the updated guideline. At the same time, reaching interim targets would reduce the burden of disease, of which the greatest benefit would be observed in countries with high concentrations of fine particulates (PM₂.₅) and large populations.

Source: World Health Organization

Mastectomies Significantly Impact Quality of Life in Young Women

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Many young women with breast cancer choose mastectomies but afterwards experience a persistent decline in their sexual and psychosocial well-being, according to new research reported in JAMA Surgery.

In surveys conducted after patients underwent breast cancer surgery, significant quality of life (QoL) impacts were seen with mastectomies, with a greater extent of surgery worsening the QoL outcomes. The findings are important in light of recent trends towards younger women with breast cancer opting for bilateral mastectomies for unilateral breast cancer when breast conserving surgery was also an option.

“Historically, it was felt that 75 percent of breast cancer patients should be eligible for breast conserving surgery. Over time, however, more women, particularly young women, are electing to have a mastectomy,” said study lead author Laura Dominici, MD, a surgeon at Dana-Farber Brigham Cancer Center. “They frequently offer peace of mind as the reason for their decision – even though research shows that unless a woman has a genetic predisposition to breast cancer, she has a very low risk of developing cancer in the healthy breast.”

In this study, 560 participants, 40 and younger with breast cancer, filled in a patient reported outcomes survey known as BREAST-Q, an average 5.8 years after diagnosis.

Compared to those who had breast-sparing surgery, patients who had a mastectomy scored significantly lower in three QoL measures – satisfaction with the appearance of their breasts, psychosocial well-being, and sexual well-being. The results were consistent regardless of whether one or both breasts were removed, and that most had breast reconstruction surgery.

  • For breast satisfaction, patients who had breast-conserving surgery had an average BREAST-Q score of 65.5, compared with 54.6 in the bilateral mastectomy group.
  • For psychosocial well-being,  patients who had breast-conserving surgery had an average BREAST-Q score of 75.9, compared with 65.1 in the bilateral mastectomy group.
  • For sexual well-being, patients who had breast-conserving surgery had an average BREAST-Q score of 57.4, compared with 53.4 for the unilateral mastectomy group and 46.2 for the bilateral mastectomy group.

A fourth area examined by the survey, physical function, showed no difference between the groups. Women with financial challenges tended to have lower scores in all four categories.

“The decision of whether to have a mastectomy or breast-conserving surgery should be a shared decision between patients and their doctors,” Dr Dominici added. “Particularly when talking to young women, who are likely to have a long period of survivorship, it’s important that we as clinicians discuss the potential impacts of mastectomy on their quality of life. As our study indicates, those impacts are not insignificant and persist years into the future.”

The study’s main limitation is that it was not randomised, and quality of life was only evaluated at a single time point. Dr Dominici added there was no information about women’s quality of life prior to the study, which could have infuenced their decision making and their quality of life after surgery.

Source: Dana-Farber Cancer Institute

Muscles are Timekeepers for the Liver

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Researchers have found that skeletal muscles play a large part in regulating the liver’s biological clock. The findings were published in Science Advances.

The circadian rhythm is coordinated by the brain at a general level, but each organ or tissue is also subjected to specific regulation, adjusting to time to optimise their processes. However it was not known how the liver “knows” whether it is day or night.

The liver’s main role is digestion, mainly of fats and sugars: the brain is the main consumer of sugar while skeletal muscle is the main consumer of fat.

Scientists at IRB Barcelona discovered a surprising relationship: that it is skeletal muscle which regulates liver function and determines fat metabolism. Skeletal muscle accomplishes this by secreting a that is transported to the liver through serum is responsible for modulating around 35% of the metabolic functions of the liver. The remaining basal functions of this organ and others related to carbohydrate metabolism are independent of muscle activity and are regulated by the basal circadian rhythm from the brain.

“It’s a very nice discovery because it is the first demonstration of the need for communication between the circadian clocks of tissues and organs outside the brain, and we can see that this communication between muscle and liver is altered by aging,” said study leader Dr Salvador Aznar-Benitah at IRB Barcelona. “When we get older, cells stop obeying the biological clock and begin to perform functions in a non-optimal manner, leading to errors that cause tissues to age.”

The researcher’s results show that the liver does not independently regulate the metabolism of fats and that it is muscle that sends the message that it is time to switch on fatty acid metabolism and how it should go about this. “We didn’t expect to find this connection between the liver and muscle because it wasn’t known previously, but, on second thought, it makes complete sense that fat management is coordinated by one of its main consumers,” said Dr Aznar-Benitah. Carbohydrate metabolism meanwhile is dependent on the basal coordination exercised by the brain.

Source: Institute for Research in Biomedicine (IRB Barcelona)

Osteoclast Signalling Could Yield Osteoporosis Treatments

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A new discovery about a signalling function in osteoclasts suggests a potential treatment target for osteoporosis and for bone loss from rheumatoid arthritis.

The findings from University of Virginia School of Medicine researchers and their collaborators help us understand why osteoclasts begin to break down more bone than the body replaces.

“Bone degradation and subsequent repair are fine-tuned through complex interactions between the cells that degrade the bone – osteoclasts – and those that produce new bone matrix. Simple elimination of osteoclasts is, therefore, not always the best approach to treat pathologic bone loss. Instead, we found a ‘signalling node’ in osteoclasts that regulates their function in degrading the bone, but doesn’t reduce osteoclast numbers,” said researcher Sanja Arandjelovic of UVA’s Department of Medicine and UVA’s Carter Immunology Center.

With further research, it may be possible for scientists to one day be able to develop drugs that target the signalling node to prevent or treat bone loss. This discovery also helps explain why some previous attempts to develop osteoporosis treatments produced disappointing results.
Researcher Kodi Ravichandran, chair of UVA’s Department of Microbiology, Immunology and Cancer Biology and director of UVA’s Center for Cell Clearance, noted the potential of the findings to inform efforts to develop better treatments for osteoporosis: “In this study,” he said, “we identified previously unappreciated factors that contribute to osteoclast function that are truly exciting and open up new avenues to pursue.”

The researchers have found an important contributor, a cellular protein called ELMO1, which promotes the activity of the bone-removing osteoclasts. Osteoclasts are critical for bone health, as they normally remove just enough to stimulate new bone growth. The problem arises when the osteoclasts become too aggressive and remove more bone than the body makes, resulting in bone mass loss.

This excessive bone degradation is likely influenced by genetic factors, the researchers say. They note that many of the genes and proteins linked to ELMO1 have been previously associated with bone disorders and osteoclast function.

Encouragingly, the researchers were able to prevent bone loss in lab mice by blocking ELMO1, including in two different models of rheumatoid arthritis. That suggests clinicians may be able to target the protein in people as a way to treat or prevent bone loss caused by osteoporosis and rheumatoid arthritis, the researchers say.

They note that prior efforts to treat osteoporosis by targeting osteoclasts have had only mixed success, and they offer a potential explanation for why: Osteoclasts not only remove bone, but play a role in calling in other cells to do bone replacement. As such, targeting ELMO1 may offer a better option than simply waging war on the osteoclasts.

“We used a peptide to target ELMO1 activity and were able to inhibit degradation of the bone matrix in cultured osteoclasts without affecting their numbers,” Ravichandran said. “We hope that these new osteoclast regulators identified in our study can be developed into future treatments for conditions of excessive bone loss such as osteoporosis and arthritis.”

Source: University of Virginia

High Fat Dairy Intake not Tied to CVD Risk

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In a study of countries with high dairy consumption, higher intakes of dairy fat, as measured by bloodstream levels of fatty acids, had a lower risk of cardiovascular disease (CVD) compared to those with low intakes. Higher intakes of dairy fat were not linked to an increased mortality risk.

In a study published in PLoS Medicine, researchers combined results from 4000 Swedish adults with those from 17 similar studies in other countries, creating the most comprehensive evidence to date on the relationship between this more objective measure of dairy fat consumption, risk of  and death.

Dr Matti Marklund from The George Institute for Global Health, Johns Hopkins Bloomberg School of Public Health, and Uppsala University said that with rising dairy consumption around the world, a better understanding of the health impact was needed.

“Many studies have relied on people being able to remember and record the amounts and types of dairy foods they’ve eaten, which is especially difficult given that dairy is commonly used in a variety of foods.

“Instead, we measured blood levels of certain fatty acids, or fat ‘building blocks’ that are found in dairy foods, which gives a more objective measure of dairy fat intake that doesn’t rely on memory or the quality of food databases,” he added.

“We found those with the highest levels actually had the lowest risk of CVD. These relationships are highly interesting, but we need further studies to better understand the full health impact of dairy fats and dairy foods.”

Sweden has one of the world’s highest consumption of dairy. An international team of researchers assessed dairy fat consumption in 4150 Swedish 60-year-olds by measuring blood levels of a particular fatty acid that is mainly found in dairy foods and therefore can be used to reflect intake of dairy fat.

The participants were then followed up for an average of 16 years, recording heart attacks, strokes and other serious circulatory events, and all cause mortality.

After adjustment for other known CVD risk factors including things like age, income, lifestyle, dietary habits, and other diseases, the CVD risk was lowest for those with high levels of the fatty acid (which reflects a high intake of dairy fats). Those with the highest levels had no increased all-cause mortality risk.

These findings highlight the uncertainty of evidence in this area, which is reflected in dietary guidelines, noted  Dr Marklund.

“While some dietary guidelines continue to suggest consumers choose low-fat dairy products, others have moved away from that advice, instead suggesting dairy can be part of a healthy diet with an  emphasis on selecting certain dairy foods — for example, yoghurt rather than butter — or avoiding sweetened dairy products that are loaded with added sugar,” he said.

Combining these results with 17 other studies with a total of almost 43 000 participants from the US, Denmark, and the UK confirmed these findings in other populations.

“While the findings may be partly influenced by factors other than dairy fat, our study does not suggest any harm of dairy fat per se,” Dr. Marklund said.

Lead author Dr Kathy Trieu from The George Institute for Global Health pointed out that consumption of some dairy products, especially fermented products, have been shown to be linked to cardiovascular benefits.

“Increasing evidence suggests that the health impact of dairy foods may be more dependent on the type — such as cheese, yoghurt, milk, and butter — rather than the fat content, which has raised doubts if avoidance of dairy fats overall is beneficial for cardiovascular health,” she said.

“Our study suggests that cutting down on dairy fat or avoiding dairy altogether might not be the best choice for heart health.”

“It is important to remember that although dairy foods can be rich in saturated fat, they are also rich in many other nutrients and can be a part of a healthy diet. However, other fats like those found in seafood, nuts, and non-tropical vegetable oils can have greater health benefits than dairy fats,” Dr Trieu added.

Source: The George Institute for Global Health