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Commentary on the 2023 study: "The artificial sweetener erythritol and cardiovascular event risk" by Witkowski M., et al.
Polyphenols may be missing component in regulating inflammatory immune responses
Midwifery care safe for moderate- and high-risk pregnancies
Low estrogen levels paired with higher CGRP levels may jump start migraine
New study to examine link between air quality, climate change, and birth outcomes
Ultrasound device may offer new treatment option for hypertension
Obesity makes it harder to diagnose and treat heart disease
Commentary on the 2023 study: "The artificial sweetener erythritol and cardiovascular event risk" by Witkowski M., et al.
Cristiana Paul, MSa and David M. Brady, ND, DACBN, IFMCP, FACNb
A recent study by Witkowski M., et al., has investigated correlations between various plasma "metabolomics," including sugar alcohols, such as erythritol (ET), and cardiovascular disease (CVD) events.1 Plasma ET may be derived from either endogenous production of ET (glucose or fructose) or exogenous intake of ET, some naturally occurring in fruits and some as a food sweeteners. Data included two cohorts, one in the U.S. (n = 2,149) and one in Europe (n = 833), and both were followed for three years; however, it did not include the intake of dietary ET or other carbohydrates, which is a severe limitation of the cohorts’ analyses.1 Fasting blood ET levels were assessed only once at enrollment in the three-year-long cohort studies. The authors state that the time of enrollment largely preceded the proliferation of erythritol in processed foods, so they believe that the blood ET likely reflected endogenously produced ET. Thus, it is not clear how much of the blood ET was derived from ET intake and there is certainly a possibility most of it came from endogenous production.1
The correlation analyses found that the highest quartile of blood ET levels had significantly more CVD events than the lowest quartile of blood ET levels.1 It is well known that correlations do not always imply causation, as also stated by the authors. Most importantly, their analysis cannot be used to imply that the intake of ET raises CVD risk because ET intake was not assessed.1 Various news outlets picked up the wording from the correlation results and spun this into the headline, "Erythritol sweetener may increase your risk of heart attacks and stroke." Unfortunately, this alarming conclusion is very misleading, typical of media sensationalism and overzealous public relations departments at academic institutions attempting to create "buzz" for studies being published from their university.
It is also surprising that for a study of such magnitude, Witkowski M., et al., did not discuss the relevant issues related to the endogenous production of ET from glucose and fructose. A 2020 study by Ortiz SR, described the conversion pathways where fructose seems to be a more direct precursor to ET.2
The causal effect between glucose and/or fructose and CVD is well established (e.g., its impacts on cholesterol, triglycerides, insulin, blood pressure, and thrombosis). Thus, it is very likely that the correlation between high blood levels of ET and CVD may be due, at least in part, to the vascular and lipid problems caused by an excess intake of glucose, fructose, and/or starch.
A 2023 study from the journal Nutrients addressed the issue in question and noted "observational studies indicate positive association between plasma erythritol and obesity and cardiometabolic disease."3 The authors’ explanation of this phenomena suggests that elevated blood ET is a mere marker of excess intake of caloric sugars and sugar-specific effects as the underlying culprits "It is unlikely that dietary erythritol is mediating these associations, rather they reflect dysregulated pentose phosphate pathway due to impaired glycemia or glucose-rich diet."3
The 2023 study by Witkowski M., et al., also included an in vitro experiment that showed adding ET to platelet cells increased platelet aggregation.1 However, adding ET to a medium with platelets does not necessarily reproduce the effects of ingesting ET and how it is metabolized or incorporated as such in various body and blood cells or plasma. They showed a similar effect in an animal model but also acknowledged that the results of these experiments may not be translated into effects on human risk of thrombosis because that is determined by a complex set of factors.1 The authors’ statement was omitted from media reports. Human studies are needed to explore this further if it were to have merit.
The same study by Witkowski M. et al. included a small (n = 8) intervention with eight subjects that were given 30 g of ET and measured plasma ET for 7 days. They found the resulting ET plasma levels to increase manyfold.1 However, the significance of this finding is unclear, considering that ET ingestion may result in a different distribution of ET in blood cells and serum compared to that from endogenous ET synthesis, which occurs inside all types of cells. No thrombotic markers were measured, and no adverse effects were noted.1
Another 2023 study and a 2018 study reviewed many potential benefits of ET, including its following properties and functions: as an antioxidant, promoting flow-mediated dilation, non-insulinemic, nonglycemic, non-caloric (with the majority being excreted in the urine unmetabolized), no impact on blood lipids, no gastrointestinal distress, and beneficial effects on oral health (demonstrated by reduced plaque and pathogenic oral bacteria). The authors of both studies ultimately recommended the use of ET as a beneficial substitute for glucose or fructose.3,4
According to the Food and Drug Administration (written communication, June 5, 2018), "…erythritol, described in the enclosed notification is exempt from the premarket approval requirement of the Federal Food, Drug, and Cosmetic Act because it has been determined to be generally recognized as safe (GRAS), based on scientific procedures, for addition to food." Erythritol is a naturally occurring compound found in a variety of foods and beverages, including fruits (e.g., melons, pears, and grapes) at levels of 10-20 mg/lb, soy sauce at 0.9 mg/L, wine at 300 mg/L, miso paste at 1.3 mg/L, and sake at 1.5 mg/L.5 Consumption of a few common servings from a variety of such foods may add up to less than 0.5 g/day.
aIndependent Research Consultant
bChief Medical Officer, Designs for Health, Inc.; Director, Nutrition Institute & Professor Emeritus, University of Bridgeport, CT (USA)
1Witkowski M, Nemet I, Alamri H, et al. The artificial sweetener erythritol and cardiovascular event risk [published online ahead of print, 2023 Feb 27]. Nat Med. 2023;10.1038/s41591-023-02223-9. doi:10.1038/s41591-023-02223-9.
2Ortiz SR, Field MS. Mammalian metabolism of erythritol: a predictive biomarker of metabolic dysfunction. Curr Opin Clin Nutr Metab Care. 2020;23(5):296-301. doi:10.1097/MCO.0000000000000665.
3Mazi TA, Stanhope KL. Erythritol: An in-depth discussion of its potential to be a beneficial dietary component. Nutrients. 2023; 15(1):204. https://doi.org/10.3390/nu15010204.
4de Cock P. Erythritol functional roles in oral-systemic health. Adv Dent Res. 2018;29(1):104-109. doi:10.1177/0022034517736499.
5Sreenath K, Venkatesh YP. Analysis of erythritol in foods by polyclonal antibody-based indirect competitive ELISA. Anal Bioanal Chem. 2008;391(2):609-615. doi:10.1007/s00216-008-2016-x.
Polyphenols may be missing component in regulating inflammatory immune responses
PCB2DG, a polyphenol with anti-inflammatory properties, works by targeting and directly interacting with the major glutamine transporter protein, alanine serine cysteine transporter 2 (ASCT2), to inhibit the uptake of glutamine, an important amino acid found in the blood. This reduction of intracellular glutamine accumulation in CD4+ T cells also reduces the production of interferon-gamma, or IFN-γ showing promise in the future of dietary polyphenol treatment for those suffering from autoimmune diseases. Additionally, the identification of ASCT2 as the target protein of PCB2DG is one of the main achievements of the study, giving way to new opportunities to study the effects dietary polyphenols have on immune responses.
Researchers published their results on December 23rd, 2022 in International Immunopharmacology where the target molecule of polyphenols in immune cells was identified, as well as clarification on how PCB2DG works to suppress glutamine influxes within CD4+ T cells. The study used previous research by the same team to build upon their original hypothesis of cytokine inhibition in the presence of PCB2DG and other common food-derived polyphenols.
“Since activated T cells have been suggested to cause autoimmune diseases, it is expected that administration of PCB2DG will improve the pathologies of these diseases” said Katsunori Endo, first author of the paper and researcher at Shinshu University.
Procyanidins are dietary polyphenol compounds found in many commonly consumed plant materials, such as tea leaves, grapes (and therefore wine), and cacao. These procyanidins are combined with the functional group “gallate, "allowing for greater interactions with various protein surfaces. Combine the two and we have our subject: PCB2DG. This subject has been shown to inhibit glutamine uptake in CD4+ T cells thanks to its ability to bind to the glutamine transporter protein discovered in this study, ASCT2.
By “starving” cells of glutamine, an amino acid response (AAR) is generated, then inducing the activity of activating transcription factor 4 (ATF4) which promotes gene expression to synthesize amino acids. Since T cell activation depends on the presence of extracellular amino acids like glutamine for use as a base to build upon, glutamine and other amino-acid deficient cells are unable to supply the requirements for such T cell activation, leading to a reduced inflammatory response.
“We showed previously that the immunomodulatory effects of PCB2, PCB2 3-O-gallate, and PCB2 3′′-O- gallate were obviously lower than those of PCB2DG. Therefore, the specific structure of PCB2DG, i.e. a dimeric polyphenol including two gallate groups, is likely important for its binding to ASCT2 and remarkable immunomodulatory effects,” Endo said.
Configuration and structure of molecules are crucial when it comes to physiological responses, as most interactions are not possible unless a “lock and key” mechanism is present to set off a chain of reactions. Understanding exactly what structure is needed to unlock the immunomodulating capabilities of polyphenols on immune cells was a large part of the question this research has helped to answer.
Midwifery care safe for moderate- and high-risk pregnancies
New UBC research shows that midwives in British Columbia are providing safe primary care for pregnancies of all medical risk levels, contrary to a popular belief that midwives mostly manage low-risk pregnancies.
The study, published in the Canadian Medical Association Journal, examined a decade of births in B.C. between 2008 and 2018. The researchers compared birth outcomes for people who had a midwife as their most responsible provider (MRP), with those who were cared for by a family physician or obstetrician.
The findings reveal that people who had a midwife as their MRP had comparable or improved birth outcomes relative to family physician- or obstetrician-led care across medical risk levels. Midwifery clients were less likely to have preterm births and low-birth-weight babies compared to physician-led care, and the risk of infant death was comparable across MRPs.
"The study provides evidence that midwifery care in B.C. is a safe and effective option for childbearing people, regardless of medical risk," said Dr. Kathrin Stoll (she/her), a research associate in UBC’s department of family practice. “As medical risk increases, midwives and family physicians collaborate with obstetrician specialists to ensure that birthing people are receiving safe and appropriate care that is right for them."
The researchers say the findings are a reflection of how midwives are integrated into B.C.’s health system.
“Midwives operate in two worlds: They are in the community working with people in their homes, but they are also integrated into the hospital system,” said Dr. Stoll. “When complications develop, midwives are a bridge to the specialist and hospital care that a person needs.”
Midwifery clients also had consistently lower caesarean delivery rates compared to people with physician MRPs, although the rate of caesarean delivery increased as medical risk increased. Close to 37 per cent of births in B.C. were caesarean deliveries in 2019-2020, the highest in the country.
The changing face of midwifery care
The new study shows how midwifery care in B.C. has evolved since it became a regulated health profession in 1998.
The proportion of births that had a midwife MRP increased from 9.2 per cent in 2008 to 19.8 per cent in 2018. That proportion has continued to climb in more recent years, with midwives now assisting with nearly a third of all births in B.C. — the highest proportion in Canada.
The profile of midwifery clients is also changing.
“Whereas midwifery care may have started out primarily with low-risk clients, the study provides evidence that the profile of clients is changing and that midwives are increasingly caring for clients safely at all medical risk levels,” said Dr. Stoll.
The researchers say they were not surprised by the findings because medical risk has always been a core part of the profession.
“A large part of midwifery education is teaching students about medical complexities and how to triage clients in terms of their medical risk. It’s always been a part of midwifery training and the care midwives provide,” says Dr. Luba Butska (she/her), an assistant professor of teaching with UBC’s midwifery program in the department of family practice.
Despite increases in midwifery care during the study period, Canada has some of the lowest rates of midwifery access in the world and increasing rates of caesarean delivery.
The study recommends that the growing midwifery profession should be supported by policies and payment structures that enable retention of midwives, and by health system integration and collaboration with physician colleagues.
"As the midwifery profession continues to grow in Canada, it holds potential for meeting national mandates to lower obstetric intervention rates and to increase access to midwifery care to under-served communities," said Dr. Butska. “It's the combination of good outcomes and lower intervention rates that make midwifery a great public health strategy.”
Low estrogen levels paired with higher CGRP levels may jump start migraine
As estrogen levels fluctuate, a new study has found for female participants with migraine, their levels of the protein calcitonin gene-related peptide (CGRP) that plays a key role in starting the migraine process also fluctuate. The study is published in the February 22, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“This elevated level of CGRP following hormonal fluctuations could help to explain why migraine attacks are more likely during menstruation and why migraine attacks gradually decline after menopause,” said study author Bianca Raffaelli, MD, of Charité – Universitätsmedizin Berlin in Germany. “These results need to be confirmed with larger studies, but we’re hopeful that they will help us better understand the migraine process.”
The study involved three groups of female participants with episodic migraine. All had at least three days with migraine in the month before the study. The groups were those with a regular menstrual cycle, those taking oral contraceptives, and those who had gone through menopause. Each group was compared to a group of female participants of similar ages who did not have migraine. Each group had 30 people, for a total of 180.
Researchers collected blood and tear fluid to determine CGRP levels. In those with regular menstrual cycles, the samples were taken during menstruation when estrogen levels are low and around the time of ovulation, when levels are the highest. In those taking oral contraceptives, samples were taken during the hormone-free time and the hormone-intake time. Samples were taken once from postmenopausal participants at a random time.
The study found that female participants with migraine and a regular menstrual cycle had higher CGRP concentrations during menstruation than those without migraine. Those with migraine had blood levels of 5.95 picograms per milliliter (pg/ml) compared to 4.61 pg/ml for those without migraine. For tear fluid, those with migraine had 1.20 nanograms per milliliter (ng/ml) compared to 0.4 ng/ml for those without migraine.
In contrast, female participants taking oral contraceptives and in postmenopause had similar CGRP levels in the migraine and non-migraine groups.
“The study also suggests that measuring CGRP levels through tear fluid is feasible and warrants further investigation, as accurate measurement in the blood is challenging due to its very short half-life,” Raffaelli said. “This method is still exploratory, but it is non-invasive.”
Raffaelli noted that while hormone levels were taken around the time of ovulation, they may not have been taken exactly on the day of ovulation, so the fluctuations in estrogen levels may not be fully reflected.
Learn more about migraine at BrainandLife.org, home of the American Academy of Neurology’s free patient and caregiver magazine focused on the intersection of neurologic disease and brain health. Follow Brain & Life® on Facebook, Twitter and Instagram.
When posting to social media channels about this research, we encourage you to use the hashtags #Neurology and #AANscience.
The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 38,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.
For more information about the American Academy of Neurology, visit AAN.com
New study to examine link between air quality, climate change, and birth outcomes
On Monday February 27, the U.S. Environmental Protection Agency (EPA) announced that nonprofit research institute PSE Healthy Energy has been awarded $1,350,000 to study local disparities in exposure to air pollution, heat, and humidity throughout Contra Costa County. The Contra Costa Climate, Air Pollution, and Pregnancy Study will be conducted in partnership with the University of California, Berkeley and will analyze birth outcomes and develop targeted solutions to protect the region’s most vulnerable populations.
“We know that climate change is already increasing exposure to air pollution, extreme heat, and humidity and that these events increase health risks, particularly for vulnerable populations,” said Elena Krieger, director of research at PSE Healthy Energy and principal investigator for the study. “Our aim is to better understand how these exposures relate to birth outcomes and to work with communities and policy makers to develop targeted, community-led, and effective interventions.”
The study will leverage PSE Healthy Energy’s Richmond Air Monitoring Network (RAMN) in combination with additional low-cost air monitors in place throughout Contra Costa County, enabling the team to study local variations in exposure across the region. Over the course of three years, the study will assess disparities in exposure to air pollution, heat, and humidity and their relationship with birth outcomes. The researchers will also assess areas and populations facing the greatest increase in risk from climate change impacts, such as increased heat, humidity, and wildfire smoke.
“Low-cost air pollution sensors can help us understand microscale variations in exposure to air pollution, temperature, and humidity. This more granular understanding can help us uncover how local climate impacts may compound socioeconomic risk factors, such as poverty, low educational attainment, and linguistic isolation, and lead to greater exposure and health disparities,” said Ajay Pillarisetti, assistant professor of Environmental Health Sciences at UC Berkeley and the study’s co-principal investigator.
In the final phase of the project, researchers will work with the identified populations and communities to co-develop a suite of interventions to mitigate exposures, ranging from house-level retrofits to community planning measures such as tree planting. The team will use a mix of cost-benefit and distributional analyses, incorporating community-identified priorities and strategies, to identify policy solutions.
The research grant is part of the EPA’s Science to Achieve Results (STAR) program and was part of $21M in research grant funding announced to investigate cumulative health impacts of climate change on underserved communities.
Ultrasound device may offer new treatment option for hypertension
A device that uses ultrasound to calm overactive nerves in the kidneys may be able to help some people get their blood pressure under control.
A new study led by researchers at Columbia University and Université de Paris, France, has found that the device consistently reduced daytime ambulatory blood pressure by an average of 8.5 points among middle-aged people with hypertension.
Doctors usually prescribe lifestyle changes, such as reducing salt intake or losing weight, and medications to lower blood pressure in patients with hypertension. Yet about one-third of hypertensive patients are unable to control their blood pressure despite these interventions.
“Many patients in our clinical practice are just like the patients in our study, with uncontrolled blood pressure in the 150s despite some efforts,” says Ajay Kirtane, MD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study.
Leaving blood pressure uncontrolled for too long can lead to heart failure, strokes, heart attacks, and irreversible kidney damage.
“Renal ultrasound could be offered to patients who are unable to get their blood pressure under control after trying lifestyle changes and drug therapy, before these events occur,” says Kirtane, who is also an interventional cardiologist and director of cardiac catheterization laboratories at NewYork-Presbyterian/Columbia University Irving Medical Center.
The results of the study, published in JAMA Cardiology, tested the device, which is used in an outpatient procedure called ultrasound renal denervation. The device is still investigational and has not yet been approved by the FDA for use outside of clinical trials.
Kidney nerves and hypertension
Hypertension in middle age is thought to be caused in part by overactive nerves in the kidneys, which trigger water and sodium retention and release hormones that can raise blood pressure. (In older people, hypertension often occurs as blood vessels stiffen). Antihypertensive drugs work in different ways to lower blood pressure, by dilating blood vessels, removing excess fluid, or blocking hormones that raise blood pressure. But none of these medications target the renal nerves directly.
Ultrasound therapy calms overactive nerves in the renal artery, disrupting signals that lead to hypertension. The therapy is delivered to the nerves via a thin catheter that is inserted into a vein in the leg or wrist and threaded to the kidney.
Study results
The new study pooled data from three randomized trials encompassing more than 500 middle-aged patients with varying degrees of hypertension and medication use.
Twice as many patients who received the ultrasound therapy reached their target daytime blood pressure (less than 135/85 mmHg) compared to patients in the sham groups.
"The result was almost identical across the different study groups, which definitively shows that the device can lower blood pressure in a broad range of patients,” Kirtane says.
The procedure was well-tolerated, and most patients were discharged from the hospital the same day. According to Kirtane, improvements in blood pressure were seen as soon as one month after the procedure.
The treatment will be evaluated by the FDA in the coming months.
Bottom line for patients with resistant hypertension
The investigators expect the treatment could be offered as an adjunct to medication therapy and lifestyle changes for patients with uncontrolled hypertension.
“Once the device is available, we envision recommending it to patients who have tried other therapies first. The hope is that by controlling blood pressure, we might be able to prevent kidney damage and other effects of uncontrolled blood pressure,” Kirtane adds.
More information
The study, titled “Patient-Level Pooled Analysis of Ultrasound Renal Denervation in the Sham-Controlled RADIANCE II, RADIANCE-HTN SOLO and RADIANCE-HTN TRIO Trials," was published on February 28 in JAMA Cardiology. The study includes data from the RADIANCE II trial, which was published simultaneously in JAMA and was also co-led by Kirtane.
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Columbia University Irving Medical Center
Obesity makes it harder to diagnose and treat heart disease
Being overweight impacts your heart health in more ways than you might think. A new JACC review paper from Mayo Clinic outlines how obesity affects the common tests used to diagnose heart disease and impacts treatments. Cardiovascular disease is the leading cause of death in the U.S. and globally, yet it is largely preventable.
"Excess fat acts as a kind of filter and can skew test readings to under-or overdiagnosis," says senior author Francisco Lopez-Jimenez, M.D., director of preventive cardiology at Mayo Clinic. "Obesity affects nearly all the diagnostic tests used in cardiology, such as ECG, CT scan, MRI and echocardiogram.
Procedural interventions such as stent placement via the leg, or heart surgery, can be more difficult to perform in patients with significant obesity and may involve more complications, like increased risk of infection at the wound site.
Common drug therapies to treat cardiovascular disease may need to be adjusted up or down in patients with obesity. Some medications, such as beta-blockers, may affect a patient’s ability to lose weight, and Dr. Lopez-Jimenez stresses the importance of trying alternative approaches to prevent these patients from gaining weight or help them to lose weight.
Recommendations to lose weight can be difficult to follow because heart patients have a harder time moving and will feel symptoms like shortness of breath when they exercise. Those symptoms often discourage patients from doing physical activity, but Dr. Lopez-Jimenez notes that exercise is important, not only to lose weight but for heart health.
"Obesity is an important risk factor to address in patients with heart disease and it requires us to do something," says Dr. Lopez-Jimenez." The patient needs to know that their clinician can help them lose weight. Overall, weight loss solutions come down to finding the right therapy for the patient."
A standard weight loss program will involve a therapist, dietitian and sometimes a psychologist. If that doesn’t do enough, Dr. Lopez-Jimenez says there are other resources like bariatric surgery and medications that can effectively help patients lose weight. Mayo Clinic recently started a multidisciplinary cardiometabolic program to address obesity, reduce related disease conditions and help patients improve their quality of life.
Accurately defining a person's level of obesity is important. Body mass index (BMI) ? a measure of body fat based on height and weight ? has long been used to define the severity of obesity. But people with significant amounts of muscle will have a high BMI. People with little muscle mass and more waistline fat might record a low BMI but have normal-weight obesity. Measurements such as waist-to-hip ratio and waist circumference provide a more accurate assessment of cardiovascular risk.
"In general, patients with heart disease and a particularly advanced degree of obesity will benefit from trying lifestyle modification. And if that doesn’t work, or if they have tried that in the past, it is reasonable to consider bariatric surgery or medications," says Dr. Lopez-Jimenez.
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