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  • 09 June 2021

Heart health

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During the time it takes to read this brief article, ischaemic heart disease, in its various forms, will claim the lives of about 50 people around the world. This interrelated constellation of conditions — including myocardial infarction, atrial fibrillation and cardiac arrest — account for more deaths globally than any other cause.

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Nature 594 , S1 (2021)

doi: https://doi.org/10.1038/d41586-021-01449-2

This article is part of Nature Outlook: Heart health , an editorially independent supplement produced with the financial support of third parties. About this content .

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Stanford Medicine-led study finds heart shape can predict cardiac disease

While cardiac sphericity was the focus of Stanford Medicine-led research, the possibility of data science expanding the reach of biomedical science was its true core, researchers say.

March 29, 2023 - By Mark Conley

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Heart shapes range from elongated to normal to spherical. Med

A machine learning-aided study on heart shape, led by a researcher at Stanford Medicine, found that sphericity — or roundness — seems to occur more commonly in healthy hearts than previously believed but can also act as a genetic indicator of cardiac problems that lie ahead.

Doctors have long known that a rounder heart, like the one made symbolically popular throughout modern civilization and celebrated with the ubiquitous Valentine’s Day heart shape, actually depicts an organ under duress. But that detail has typically been studied only after the onset of a cardiac condition.

“Most people who practice cardiology are well aware that after someone develops heart disease, the heart will look more spherical,” said Shoa Clarke, MD, PhD, preventive cardiologist and an instructor in the Stanford School of Medicine ’s departments of medicine and pediatrics.

Artificial intelligence allowed the researchers to demonstrate at scale that hearts come in all shapes, including more full and round, even before a troubling clinical diagnosis — and those details can offer important health clues, they maintain.

The study , which was published March 29 in Med, revealed new details about the genetic underpinnings of cardiomyopathy, which includes conditions such as heart arrhythmia, known as atrial fibrillation, and congestive heart failure. In atrial fibrillation, the heart beats too quickly, too slowly or in an irregular way; in congestive heart failure, the heart can’t pump enough blood.

Clarke and David Ouyang, MD, of the Smidt Heart Institute of Cedars-Sinai, were senior authors on the study; Milos Vukadinovic, a bioengineering student at UCLA, was the lead author.

Clarke and Ouyang landed upon heart shape after clinical experience showed “variability in the shape and morphology, even when all the standard metrics seem normal,” Clarke said.

They wondered if shape is an important predictive variable of heart health well before a clinical diagnosis. Using images from the UK Biobank, the researchers measured the left-ventricle sphericity of 38,897 otherwise healthy hearts.

They focused on the left ventricle, which is normally cone-shaped, because it is the core part of the muscle, doing the heart’s mechanical heavy lifting, and is especially susceptible to damage. As the pumper of blood throughout the body, it can dilate and become wider or more round over time.

First the researchers used biobank data to show that increased sphericity is a risk factor for developing cardiomyopathy, atrial fibrillation or heart failure, finding that a small increase in roundness was associated with a 47% increase in developing those conditions up to 10 years later.

Then they looked at biobank participants’ health records, studying the genetic markers of both sphericity and those cardiac conditions, and discovered an overlap.

They concluded that intrinsic disease of the heart muscle — meaning damage not suffered during a heart attack — triggered sphericity in the left ventricle, even before heart disease has made itself known.

Shoa Clarke

Shoa Clarke

The presence of increased sphericity, the researchers concluded, may “identify individuals with underlying molecular/cellular abnormalities that place them at heightened risk for developing overt cardiomyopathy or related diseases such as atrial fibrillation.”

If shape were to become more of a baseline detail collected in clinical settings, Clarke explained, “We may start to see changes in the sphericity that are indicative of someone already going down that path of developing a heart problem.”

Medical imaging a rich source of info

The proof-of-concept learnings on cardiac sphericity was only one take-away for Clarke, who said the existing MRI imagery of the cardiovascular system, such as the samples they used, could provide a deep reservoir of previously unexplored scientific clues for all kinds of new studies.

“The main point I’m trying to make with this study is that there is information in current medical imaging that’s not being used,” Clarke said.

Clarke and Ouyang — who met and became friends as Stanford Medicine cardiology fellows — are as pointedly focused on data science as they are on biomedical science. They said artificial intelligence, while a much-talked-about, tech-spawned advancement, has yet to bear firm results in the field.

“There is broad enthusiasm for using artificial intelligence, biobanks and genomics to accelerate biomedical research,” Clarke said. “Yet, the number of practicing clinicians who have the technical skills to lead such research is still relatively small.”

Their report noted a lack of racial diversity within the UK Biobank as one of the study’s limitations. Clarke said diversity will remain an issue, especially in large biobanks, until the systems in place target improvement. “For imaging studies, this was a very large number,” Clarke said. “But one problem with it being the only source of such large-scale data is that it lacks diversity.”

The data was also collected as part of a study, not from a clinic, which avoids a bias toward those who are seeing a physician because of a problem.

It should be noted, Clarke said, that an increase in sphericity doesn’t necessarily portend a serious condition down the line. The majority of people in their study cohort who had a degree of sphericity did not go on to develop any clinical disease, at least in the follow-up period, which in some cases extended up to a decade.

“It’s not a guarantee that having high sphericity means you will have some clinical manifestation,” he said. “It’s just a marker for people who are at higher risk. Other factors could be at play.”

The next frontier could be heart conditions beyond cardiomyopathy, Clarke said, anything “relevant to any of the main categories of heart disease, which include things like rhythm disturbances, valve diseases and vascular diseases like coronary artery disease.”

“I think all of those categories could benefit from learning new ways of looking at images and trying to pull more information out of those images than we currently do,” he said.

“There’s a lot more information available than what physicians are currently using,” Ouyang told Med . “And just as we’ve previously known that a bigger heart isn’t always better, we’re learning that a more-round heart is also not better.”

This study was funded by the National Institutes of Health (grants K99-HL157421 and KL2TR003143).

Mark Conley

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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A Heart-Healthy Diet for Cardiovascular Disease Prevention: Where Are We Now?

1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

2 Department of Medicine, Greater Baltimore Medical Center, Baltimore, MD, USA

L Nedda Dastmalchi

3 Division of Cardiology, Temple University Hospital, Philadelphia, PA, USA

Martha Gulati

4 Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, LA, USA

Erin D Michos

5 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Purpose of Review

The relationship between cardiovascular health and diet is evolving. Lifestyle modifications including diet changes are the primary approach in managing cardiometabolic risk factors. Thus, understanding different diets and their impact on cardiovascular health is important in guiding primary and secondary prevention of cardiovascular disease (CVD). Yet, there are many barriers and limitations to adopting a heart healthy diet.

Recent Findings

Diets rich in fruits, vegetables, legumes, whole grains, and lean protein sources, with minimization/avoidance of processed foods, trans-fats, and sugar sweetened beverages, are recommended by prevention guidelines. The Mediterranean, DASH, and plant-based diets have all proven cardioprotective in varying degrees and are endorsed by professional healthcare societies, while other emerging diets such as the ketogenic diet and intermittent fasting require more long-term study. The effects of diet on the gut microbiome and on cardiovascular health have opened a new path for precision medicine to improve cardiometabolic risk factors. The effects of certain dietary metabolites, such as trimethylamine N-oxide, on cardiometabolic risk factors, along with the changes in the gut microbiome diversity and gene pathways in relation to CVD management, are being explored.

In this review, we provide a comprehensive up-to-date overview on established and emerging diets in cardiovascular health. We discuss the effectiveness of various diets and most importantly the approaches to nutritional counseling where traditional and non-traditional approaches are being practiced, helping patients adopt heart healthy diets. We address the limitations to adopting a heart healthy diet regarding food insecurity, poor access, and socioeconomic burden. Lastly, we discuss the need for a multidisciplinary team-based approach, including the role of a nutrition specialist, in implementing culturally-tailored dietary recommendations. Understanding the limitations and finding ways to overcome the barriers in implementing heart-healthy diets will take us miles in the path to CVD prevention and management.

Plain Language Summary

The Mediterranean, DASH, and plant-based diets remain the leading heart healthy diets that match cardiology professional society recommendations. Emerging diets like the ketogenic diet and intermittent fasting are effective weight loss diets with unknown heart protective benefits, and require further studies on whether the benefits outweigh the risks. Adopting a heart-healthy diet is a foundational component for cardiovascular disease prevention, but barriers and limitations to adopting heart healthy diets exist and need to be assessed as part of cardiovascular risk assessment.

Introduction

Despite the advances in medical management and evidence-supported dietary interventions for improved heart health, cardiovascular disease (CVD) remains the leading cause of death in the United States. 1 Over time, various diets have been studied for their effectiveness in CVD prevention. 2 One of the earliest epidemiological studies investigating the link between diet and CVD was the Seven Countries Study led by Ancel Keys between 1958 and 1964, which demonstrated that the myocardial infarction (MI) rate was lower in countries where fruits, vegetables, grains, beans, and fish formed the major part of the diet. 3 , 4 The INTERHEART Study then showed that 90% of MIs were due to preventable factors, with daily consumption of fruits and vegetables, along with regular physical activity, being associated with a 40% reduction in MI [Odds Ratio (OR)=0.60 (95% CI=0.51–0.71)]. 5 The Prospective Urban Rural Epidemiology (PURE) study conducted in over 130,000 individuals from 18 countries demonstrated that diets rich in fruits, vegetables, and legumes were associated with 19% lower risk of all-cause mortality [Hazard Ratio (HR)=0.81 (95% CI=0.68–0.96)] over 7-years of follow-up. 6

Lifestyle changes, including a heart-healthy diet, are the foundation of all CVD prevention guidelines. 7–10 The main cardiometabolic risk factors are diabetes, hypertension, dyslipidemia, and excess abdominal fat, which are all affected by dietary changes. 11 Unfortunately, there has been a worsening trend in CVD risk factors globally. 12 In the United States, the prevalence of type 2 diabetes (T2D) is 37 million adults, or 11% of the adult population, but an estimated 88 million US adults have prediabetes. 13 Globally, in 2021, 537 million individuals were affected by T2D, corresponding to 10.5% of the world’s population. 14 On a similar trend, the prevalence of controlled blood pressure, which had improved between 1999–2008, did not significantly change from 2007–2014, and then decreased after 2014. 15 Globally, between 1975 and 2016, the prevalence of obesity [defined in this study as a Body Mass Index (BMI) ≥25 kg/m 2 )] has tripled in adults. 16 In the US in 2017–2018, the age-adjusted prevalence of obesity (BMI ≥30 kg/m 2 ) among adults was 42% and severe obesity (BMI ≥40 kg/m 2 ) was 9%. 17 Increased visceral adiposity is a main driver of excess cardiometabolic risk, and increased abdominal waist circumference has become a CVD risk marker by itself. 18

Lifestyle modifications from exercise and dietary interventions have been well studied and proven effective toward CVD prevention and management. A healthy diet is one of the American Heart Association (AHA)’s “Life’s Essential 8” cardiovascular health metrics, which also include favorable levels of physical activity, sleep, nicotine exposure, BMI, blood lipids, blood glucose, and blood pressure. 19 However, <1% of US adults met “ideal” criteria for the AHA’s healthy diet metric in 2013–2014. 20

Diets rich in fruits, vegetables, legumes, whole grains, and lean protein sources, with minimization/avoidance of processed foods, trans-fats, and sugar sweetened beverages, are recommended by prevention guidelines. The Mediterranean, the Dietary Approaches to Stop Hypertension (DASH), and plant-based diets all have proven cardioprotective in varying degrees and are endorsed by professional healthcare societies, while other emerging diets such as the ketogenic diet and intermittent fasting require more long-term study. The effects of diet on the gut microbiome and on cardiovascular health have opened a new path for precision medicine to improve cardiometabolic risk factors. The effects of certain dietary metabolites, such as trimethylamine N-oxide (TMAO), on cardiometabolic risk factors, along with the changes in the gut microbiome diversity and gene pathways in relation to CVD management, are being explored.

In this review, we will provide a comprehensive up-to-date overview on established and emerging diets for cardiovascular health and CVD prevention. We will address the limitations to adopting a heart healthy diet from food insecurity, poor access, and socioeconomic burden. Lastly, we will discuss the need for additional nutritional education in health professional schools, and the importance of a multidisciplinary team to partner with patients to improve their nutritional knowledge and self-efficacy in adopting heart healthy diets.

Established Heart Healthy Diets

Three major dietary patterns (the Mediterranean diet, the DASH diet, and the healthy plant-based diet) ( Figure 1 ) have the most evidence for CVD prevention and are described below.

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The Heart Healthy Dietary Patterns: Mediterranean Diet, DASH Diet, and Healthy Plant-Based Diet.

The Mediterranean Diet

The Mediterranean diet, which was inspired by the eating habits of countries that border the Mediterranean sea (ie, Spain, Italy, and Southern Greece) is one that is rich in whole-grains, leafy green vegetables, fruits, legumes, unsalted nuts, herbs, spices, and extra virgin olive oil (EVOO), with a moderate intake of lean proteins such as fish and poultry, moderate alcohol consumption, and limited intake of red meat and sweets. By its very nature, the Mediterranean diet limits or eliminates many of the culprits in the standard American diet that drive CVD – saturated fat, highly processed refined grains and sugars, and red meat. 2 , 10 , 21 The Mediterranean diet differs from other dietary patterns as there is a greater emphasis on EVOO, nuts, reduced dairy consumption, and eating with family. 22 The Mediterranean diet has been found to be favorable as a food pattern, rather than single nutrient supplementation, as it inherently provides anti-oxidants, reduces inflammation of the vascular wall, modulates pro-atherogenic genes, alters gut microbiome, and improves lipid panels by decreasing low density lipoprotein cholesterol (LDL-C) and raising high density lipoprotein cholesterol (HDL-C). 21 , 23–25

Nutritional genomic studies show that greater adherence to a Mediterranean diet blunt the development of an adverse cardiometabolic phenotype in genetically susceptible individuals, with interactions between the Mediterranean diet and polymorphisms of the cyclooxygenase-2, interleukin-6, apolipoprotein A2, cholesteryl ester transfer protein plasma, and transcription factor 7-like 2 genes. 26 One study found that the Mediterranean diet plus EVOO prevented increases in levels of pro-atherothrombotic genes such as Cox-2, low-density lipoprotein receptor-related protein, and monocyte chemoattractant protein 1 expression compared to a control diet. 27

As mentioned above, the benefits of the Mediterranean diet were first appreciated in the Seven Countries Study (Yugoslavia, Italy, Greece, Finland, the Netherlands, Japan, and the US), led by Ancel Keys in 1958, who found there was a higher rate of mortality from coronary heart disease (CHD) in men from the US and Northern Europe in comparison to regions in Southern Europe. 3 , 28 The countries in southern Europe had higher consumption of olive oil, fruits, vegetables and fish, and lower consumption of meat and animal fats, in comparison to populations in the US and Northern Europe. These populations were also found to be leaner and had active lifestyles, a stark contrast from the US and Northern Europe populations who were mainly sedentary. 28 Prospective observational studies also found similar correlations, where persons living in Greece who reported higher adherence to the Mediterranean dietary pattern (per 2 point increment in Mediterranean diet score) were found to have a significantly lower risk of CHD death with an adjusted HR of 0.67 (95% CI=0.47–0.94) over an average of 44 months. 29 In another cohort of 15,482 patients who had stable CHD, higher adherence to a Mediterranean-style diet (per 1 unit increase in scores above 12) was independently associated with a 5% reduction in cardiovascular events over 3.7 years (HR=0.95; 95% CI=0.91–0.98). 30 Closer adherence to a Mediterranean-style diet has also been shown to be associated with a lower risk of preeclampsia. 31

Randomized controlled trials (RCTs) followed these epidemiological studies and have demonstrated the cardiovascular benefits of the Mediterranean style diet. The Lyon Diet Heart Study was a RCT that assessed whether the Mediterranean diet was beneficial in the secondary prevention of CVD among patients after a first MI. 32 The authors found a greater than 70% reduction in recurrent non-fatal MI and greater than 50% reduction in mortality in the group adhering to the Mediterranean diet, compared to a prudent diet control group, over a 4-year period. 32 , 33

The Prevención con Dieta Mediterránea (PREDIMED) trial was a RCT that aimed to assess the role of the Mediterranean diet for the primary prevention of CVD among 7,447 patients at elevated cardiovascular risk. 34 Participants were randomized to one of three diets: the Mediterranean diet with higher amounts of EVOO, the Mediterranean diet with higher amounts of nuts, or a standard diet that was low in fat, with dietary guidance. 34 After 4.8 years, there was approximately a 30% reduction in MI, stroke, or CVD death among those consuming the Mediterranean diet with EVOO (HR=0.69; 95% CI=0.53–0.91) as well as in the group consuming the Mediterranean diet with nuts (HR=0.72; 95% CI=0.54–0.95), compared to the low-fat diet. 34 Risk factors for CVD were also shown to benefit with Mediterranean diet intervention, with the incidence of diabetes being 52% lower (95% CI=27–86%) in the two pooled Mediterranean diet groups compared to controls. 35 In a biomarkers subgroup analysis, patients following the Mediterranean diet had reduction in N-terminal pro-B-type natriuretic peptide, and those on the Mediterranean diet with EVOO were found to have a reduction in oxidized LDL and lipoprotein(a) plasma concentrations, in comparison to those on the low fat diet. 36 Overall the PREDIMED study was one of the groundbreaking trials to show that a Mediterranean diet rich in unsaturated fats and polyphenols can be useful for primary CVD prevention.

Further research has been done to understand why the Mediterranean diet is so valuable in reducing CVD risk. One meta-analysis of observational epidemiologic studies evaluated whether EVOO itself shows benefit in CVD. 37 Researchers found that a higher consumption of fats from EVOO had a reduced relative risk (RR) of 0.85 (95% CI=0.77–0.93) for CVD and of 0.83 (95% CI=0.77–0.90) for all-cause mortality. The researchers believed that the anti-inflammatory and antioxidant effects play a role through its abundance of phenolic compounds and vitamin E with the addition of substituting saturated fats from the diet with monounsaturated and polyunsaturated fats. 37 Additionally, the anti-inflammatory properties of EVOO play a role in reducing platelet aggregation. 21 The emphasis of high fiber foods, such as whole grains and vegetables, in the Mediterranean-style diet provides benefit in the gut microbiome. 38 With improvement in the biodiversity of the gut microbiome (as discussed further later in this review), beneficial effects of blood pressure control, reduction in metabolic syndrome and diabetes, lower levels of pro-atherogenic compounds, and ultimately lower rates of CVD have been demonstrated. 39 Red meat, which is minimized in the traditional Mediterranean diet, contains the nutrient L-Carnitine, which produces the pro-atherogenic compound γ-butyrobetaine (γBB) as it gets converted to trimethylamine and TMAO by the gut microbes, both of which accelerate atherosclerosis. 40 These favorable elements of the Mediterranean dietary pattern are further enhanced by the emphasis of physical activity, which has shown to improve cardiometabolic health and reduce CVD. 21

The DASH Diet

The DASH diet was created in 1997 by the National Heart Lung and Blood Institute to prevent and treat hypertension, a known risk factor for CVD. 41 The DASH diet is rich in fruits and vegetables, low-fat dairy, whole grain, poultry, fish, nuts, and seeds, while limiting fatty meats, sweets, sugar sweetened beverages, and full-fat dairy products. 42 The standard DASH diet restricts salt consumption to 2,300 mg per day. It meets the Dietary Guidelines for Americans’ recommendation of limiting daily salt consumption to less than 2,300 mg. A reduced-sodium version of DASH limits sodium intake to 1,500 mg per day. Significant reduction in cardiometabolic risk is seen with the DASH diet by lowering blood pressure, total cholesterol, and LDL-C, all of which are significant risk factors which are accounted for in the atherosclerotic CVD (ASCVD) risk score and eventually leads to improvement in cardiac function and decreased incidence of diabetes. 43–46 One of the main key elements of the DASH diet in lowering blood pressure is the sodium restriction in comparison to other diets. 41 , 42 , 46

A DASH diet has been shown to reduce blood pressure in persons with or without hypertension, where in an RCT, the DASH diet reduced blood pressure by 5–6 mmHg systolic and 3 mmHg diastolic, while also lowering LDL-C by 11 mg/dL. 41 In observational data, a DASH-style dietary pattern has also been associated with a lower risk of CVD, heart failure, and diabetes. 47 , 48 In the Dietary Intervention to Stop Coronary Atherosclerosis in Computed Tomography (DISCO) RCT, 92 individuals, 41% women, with non-obstructive coronary atherosclerosis were randomized to either DASH diet with optimal medical therapy or control group of just optimal medical treatment. 49 At a mean of just 67 weeks, a significant reduction in noncalcified plaque in the DASH diet intervention group was found in comparison to the medical treatment alone group. 49

The Healthy Plant-Based Diet

A healthy plant-based diet has been shown to be associated with lower cardiovascular risk. 50–55 Plant-based diets, a diet consistently of predominantly plants, can be diverse in content, patterns, and even have subsets. The subsets branch into vegetarian (which excludes meat, poultry, seafood, and fish) and vegan (in which all animal food and their products are eliminated from the diet). Other plant-based diet subsets include lacto-vegetarians, who consume dairy products, lacto-ovo-vegetarians, who consume dairy and eggs, pesco-vegetarians or pescatarians, who consume fish, dairy, and eggs, and lastly, semi-vegetarians, who exclude red meats, possibly poultry as well.

These diets are assessed based on the vegetable content of the diet, but do not necessarily account for the sugar, fat, and sodium content, which can decrease the cardioprotective nature of a plant-based diet. 51 Indeed, unhealthy plant-based diets (such as those higher in refined grains, potatoes/fries, juices/sweetened beverages, sweets) may have similar CVD risk as animal-based diets. 51 The main foundation of a healthy plant-based diet is the whole grains, fruits, vegetables, nuts, and legumes with the low frequency and content of animal food. It has low energy density, with low saturated fats and high fiber content, which triggers early satiety cues and helps with digestion by delaying gastric emptying, with moderate insulinemic and glycemic responses. 56 , 57 Furthermore, studies have shown improved lipid profiles in individuals who follow a plant-based diet due to increased fiber intake, as fat absorption decreases overall. 58

Many studies examined this type of diet from different aspects using a pro-vegetarian diet score, which assigns higher scores to plant foods and negative scores to animal foods, or a similar plant-based diet index. In the PREDIMED trial in Spain, vegetarian diets were associated with lower cardiovascular mortality (HR=0.47; 95% CI=0.21–1.04 for highest quintile compared to lowest; p -trend=0.039 across quintiles). 59 In two combined observational cohorts of more than 200,000 male and female health professionals in the US, a higher plant-based diet index was inversely associated with incidence of CVD (HR comparing extreme deciles: 0.92; 95% CI=0.83–1.01; p -trend=0.003 across deciles), a relationship which was stronger for a healthy plant-based diet index (HR 0.75; 95% CI=0.68–0.83; p -trend<0.001). 51 In another cohort of young and middle-aged adults from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort followed for nearly 32 years, the highest vs lowest quintile of plant-based diet score (time-averaged) was associated with a 52% reduction in incident CVD (HR=0.48; 95% CI=0.28–0.81). 60

Furthermore, plant-based diets have low processed meat content or none. Preservatives found in processed meats such as nitrates and sodium contribute to blood pressure elevation, impaired insulin response, and endothelial dysfunction. 61 Substantial reductions in cardiometabolic modifiable risk factors, such as blood pressure, LDL-C, blood glucose levels, inflammatory markers, and unhealthy weight patterns, even with similar caloric intake, were seen in plant-based diets in comparison to omnivorous diets. 55 , 61–63 Thus, this type of diet has a great potential in CVD prevention. However, this diet tends to have lower vitamin B12, vitamin D, calcium, zinc, protein, and retinol in comparison to omnivorous diets; for example, those following a vegan diet may require additional supplementation with vitamin B12. 64

Reconciling the Healthy Diet Patterns and the Importance of Minimally Processed Food

The Mediterranean, DASH, and healthy plant-based diets have more similarities than differences. Each of these diets emphasize fruits, vegetables, legumes, nuts, and whole grains. Diets rich in fruits and vegetables have been shown to be associated with lower risk of CVD and mortality. 6 , 65 Increased whole grain consumption is also associated with lower risk of CVD and mortality. 66 Higher consumption of nuts has also been shown to be associated with lower CVD risk. 67

Eating minimally processed whole foods is an important component to all healthy diets, as consuming poor diet quality is one of the leading contributors to cardiometabolic disease globally. 68 , 69 Ultra-processed foods are high in refined carbohydrates, added sugars, saturated and trans fats, sodium, and possibly artificial colors, flavors, and preservatives, and have high energy density and glycemic load, which all contribute to increased cardiometabolic risk factors. They also tend to be highly palatable so that individuals eat more calories in total. 70 Furthermore, eating more ultra-processed foods can result in displacement of cardioprotective foods such as fruits and vegetables. In the Framingham Offspring Study, each additional serving a day of ultra-processed foods was associated with a 7% increased risk of incident CVD (HR=1.07; 95% CI=1.03–1.12). 70 Similarly, in another cohort from Spain, each additional serving/day of ultra-processed food was associated with 18% higher mortality (HR=1.18; 95% CI=1.05–1.33). 71 In controlled feeding trials comparing diets that were matched for total calories, sugar, fat, fiber, and macronutrients, participants allowed ad libitum food intake ate ~500 kcal/day on the ultra-processed diet vs an unprocessed diet, and body weight changes were correlated with dietary differences in energy intake. 72

Emerging or Controversial Diets

Additional emerging diet patterns have been studied for their impact on cardiometabolic risk; these are more controversial due to conflicting data regarding their net cardiovascular health benefits or insufficient data to determine their long-term cardiovascular benefits. Two of the more promising ones, the Keto Diet and Time-Restricted Eating (TRE), are discussed below.

The Keto and Other Very Low Carb Diets

The ketogenic (or “keto”) diet is generally characterized by intake of very-low carbohydrate (VLC), high fat, and moderate protein. The class ketogenic diet divided total daily energy intake to be 90% from fat, 7% from protein, and only 3% from carbohydrates. Since that time, other formulations of the ketogenic diet have been proposed to improve compliance, as well as other low or very low carbohydrate diets that generally follow similar patterns of high fat low carbs, but do not generate ketosis. VLC diets have been promoted for their effects on weight loss, improvement in insulin resistance, and glycemic control; however, the high fat diet can promote increases in LDL-C, particularly in the subset of individuals who are LDL hyper-responders, suggestive of latent genetic dyslipidemias. 73–75 This has limited the enthusiasm of many professional medical societies from endorsing its use. 73 , 75

The ketogenic diet emerged in the early 1920s as an anti-seizure intervention, but with medical innovation and the development of effective anti-seizure medication, the ketogenic diet is no longer used for management of epilepsy. 76 Throughout time the ketogenic diet has been revisited by many nutritionists and scientists to explore the ketosis state of the body. It has been found that antioxidants and anti-inflammatory functions of genes were activated by the beta-hydroxybutyrate (BHB) metabolite product of ketosis. 75 BHB has been found to reduce reactive oxygen species production mainly by activating the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) which is the major inducer of detoxification genes. Furthermore, it is an endogenous inhibitor of class I and class IIa histone deacetylases which upregulates the transcription of detoxifying genes including catalase, mitochondrial superoxide dismutase and metallothionein 2. 77 In an open label non-randomized control study of the nutritional ketosis state of patients with T2D, reductions in diabetes medication use, hemoglobin A1c (HbA1c), and overall weight were seen after 1 year, while patients were being supported in a continuous care model. 78 Individuals with insulin resistance or diabetes cannot properly metabolize glucose in the blood, which makes excess carbohydrates intake unfavorable in terms of glycemic control, and as such, following a VLC diet helps improve glycemic control and HbA1c. 79 , 80 Other studies evaluating VLC diets in the management of obesity found it more effective than low fat diets in improvement in cardiometabolic risk factors. 80–83 Furthermore, increased satiety due to the high fat and protein content and possible effects of the ketones on the appetite was found in individuals following a ketogenic diet. 84

On the other hand, some of the adverse effects that limit adoption of the ketogenic diet are the increase in total cholesterol, LDL-C, non-HDL cholesterol, triglycerides, and total apoB, all of which increase the risk of CVD. 73 , 74 , 82 , 85 , 86 The effect of a ketogenic diet on LDL-C is inconsistent, 86 but some patients can have a very dramatic increase in LDL-C in response. This dramatic increase in LDL-C levels can possibly exacerbate development of hyperlipidemia if an underlying genetic predisposition is present. 87 Furthermore,a recent meta-analysis found the ketogenic diet conferred unfavorable effects on LDL-C, apoB, and total cholesterol in normal weight adults. 88 The potential deleterious effect on lipids needs to be considered carefully before initiating a ketogenic diet, especially for individuals at elevated CVD risk such as those with T2D, and lipid levels should be monitored in patients following a ketogenic diet. Theoretically, a plant-based, ketogenic diet that is low in saturated fats may limit these adverse consequences, but there are no trials examining this. Long-term data of the efficacy and safety of ketogenic diets are still lacking.

Intermittent Fasting/Intermittent Energy Restrictions

Intermittent fasting (IF) (also known as intermittent energy restriction) diets have different forms and patterns with three general goals: prolonged periods of fasting prompting a state of ketosis, decreasing oxidative stress, and feeding and circadian rhythm synchronization. 89 The IF strategy holds promise for cardiovascular health, but the evidence is still limited, and lacking long-term studies. 90–93 A recent systematic review of RCTs studied the cardiovascular health benefits of IF in comparison to continuous calories restriction; although IF was found to be more effective in weight loss, it was not clinically significant in reduction of cardiometabolic risk factors. 93 Benefits on the molecular and cellular level of improved mitochondrial health, DNA repair, autophagy, and promotion of stem cell-based regeneration were found in laboratory mice. 94 Reducing oxidative stress is thought to decrease mitochondrial energy production and in return free radical production leading to reduced overall inflammation. 95 Alternatively, the reduction in weight and, hence, cardiometabolic risk factors with IF type diets may simply be the result of fewer total calories consumed given the reduced/restricted hours of feeding.

There are two main patterns of IF: alternate day fasting (ADF) and time restricted eating (TRE). TRE limits consumption of calories to a certain window of time each day, usually a 6–10 hour period. The ADF pattern is having a fast day followed by a feast day. A systemic review and meta-analysis on whether ADF helps with weight loss found the cumulative evidence suggests that ADF does reduce weight, BMI, and total cholesterol. 96 However, the studies were of short duration (<6 months long). In an RCT studying the effects of ADF in comparison to a calorie restricted diet or control diet on cardiometabolic risk factors, during a 1 year follow-up period of 6 months weight loss and 6 months maintenance, it was found that ADF was not superior to calories restriction in weight loss, weight maintenance, and reduction of cardiometabolic risk factors. 97

Regarding TRE, in a study of 139 individuals with unhealthy weight, no significant weight loss difference was found between individuals who adopted TRE with calorie restriction of 1,500 to 1,900 calories in comparison to calorie restriction alone (net difference=−1.8 kg; 95% CI=−4.0 to 0.4; P =0.11). 98 On the other hand, several studies have shown that TRE from a 6 to 10 hours window was effective in weight loss, cardiometabolic health enhancement, while maintaining muscle mass. 99–101 In one recent study of firefighters who have a shift-work occupation, researchers demonstrated that a 10-hour/day TRE window was feasible with improvement in cardiometabolic risk factors over 12 weeks compared to a standard feeding pattern. 102

Another pattern of TRE is one that is focused on aligning diet with the circadian rhythm with the aim to improve insulin sensitivity and weight loss. 103 Having feeding in sync with the circadian rhythm is hypothesized to optimize energy metabolism with the active and inactive phases of the circadian rhythm. Studies have shown that when the circadian rhythm is set (whether it be nocturnal or diurnal), TRE during the active phase has more health benefits and improved glucose tolerance with lower insulin levels needed. 104 For example, for a nocturnal rhythm, the active phase would be the dark time.

The Gut Microbiome and Heart Health

Lifestyle modifications of diet and exercise have been discussed extensively, but the relationship between cardiometabolic risk factors and the gut microbiome (the heart–gut axis) ( Figure 2 ) is an emerging area of study. 39 , 105 The gut microbiome is affected by dietary intake, antimicrobials, pre-and pro-biotics, and fecal microbial transplant, with potential impact on cardiovascular risk factors. For example, probiotics use has shown benefits in mild reduction in blood pressure, blood glucose, and TMAO levels. 106 Higher fiber intake is associated with increased diversity of the gut microbiota, 38 and a higher fiber diet is associated with lower risk of hypertension and CVD. 107

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The Heart–Gut axis (the role of the Gut Microbiome in Cardiovascular Health).

Individuals with hypertension were found to have altered microbial gut structure, function, and interaction. 108 While the autonomic nervous system plays a key role in regulating blood pressure, derangements in the gut microbiome triggers the release of inflammatory mediators and metabolites leading to neuroinflammation and increased blood pressure in return. 109 Furthermore, in resistant hypertension, researchers have found altered microbial pathways and metabolites that may drive the increase in blood pressure and be potential targets for new therapeutic approaches in hypertension management. 110 Additionally, certain dietary metabolites, such as TMAO, that are found in red meat, poultry, and fish, have been associated with increased risk of CVD. 111 TMAO have been linked to kidney fibrosis and loss of function, heart failure, atherosclerosis, and vascular inflammation, as well as thrombosis through platelet hyper-responsiveness. 39 , 111 , 112 One of the dietary protein metabolites of the gut microbiota is phenylacetic acid, which is metabolized by the liver and converted to phenylacetylglutamine that activates adrenergic receptors and in return increases platelets responsiveness and aggregation. 112 Understanding the pathways and interactions of the gut microbiome with diet and medication will help direct precision medicine in CVD management to have specific dietary recommendations, and possibly microbiome targeted therapies.

Cardiology Professional Society Recommendations

The AHA dietary guidance statement to promote cardiometabolic health was most recently released in 2021. 113 Diet recommendations were also included in the 2019 American College of Cardiology (ACC)/AHA Primary Prevention of CVD Guideline. 7 These guidelines recognize that sedentary lifestyle and increased caloric intake has led to increased excess body weight, which is a modifiable cardiometabolic risk factor. Thus, adjusting energy intake and expenditure to achieve and maintain a healthy body weight was the first recommendation in the dietary guidance. 113 These guidelines recognize the importance of healthy dietary patterns, rather than focusing on individual foods or nutrients, and recommend healthy nutrition to begin early in life. 113

Additionally the AHA statement recommends eating plenty and a variety of colorful fruits and vegetables; 113 “eating the rainbow” is one such approach. 114 Leafy green vegetables, other vegetables, whole fruits rather than juice, and legumes can be consumed in all forms such as fresh, frozen, or dried, although canned fruit which often contains added syrups should be avoided. 115 The guidelines also recommend choosing whole grain foods and products over refined grains. Whole grains, or products made with 51% whole grains, are rich in fiber which help support healthy weight patterns, improve digestion, and decrease absorption of cholesterol and associated with lower CVD risk. 57 , 107

The AHA statement also recommends eating healthy sources of protein, predominantly plant-based such as legumes and nuts. 113 Non-fried fish and seafood intake is recommended given the high omega-3 fatty acid content, especially when it substitutes animal sources of red and processed meat or full-fat dairy products, with ~2 to 3 servings per week of fish being associated with lower CVD incidences. 113 , 116 Other sources of protein include the low-fat or fat-free dairy products which have been shown to have neutral or beneficial effects on CVD risk. 113 , 117 If poultry or meat is desired, the AHA guidelines recommend eating lean and unprocessed forms. Several studies showed increased CVD and mortality incidence with increased intake of red meats. 118–121 Increased saturated fats, heme iron content, and l-carnitine metabolites such as TMAO from red meat contribute to atherosclerosis. 121 , 122

The AHA statement recommends using liquid plant oils instead of tropical oils or partially hydrogenated fats. 113 The benefits of EVOO, which is high in monounsaturated fat, was reviewed in the Mediterranean diet section. Dietary unsaturated fats, that are found in liquid plant oils such as soybean, corn, safflower and sunflower oils, walnuts, and flax seeds have shown cardiovascular health benefits of reducing LDL-C and total cholesterol levels. 123 On the other hand, tropical oils like coconut and palm oils, animal fats like butter and lard, as well as hydrogenated fats raise LDL-C and total cholesterol levels. 124 , 125 Another source of healthy fats is intake of fish that is rich in omega-3 fatty acids, which may have benefits on triglycerides and overall CVD risk, although little effect on LDL-C. 123

There had been some conflicting studies about whether linoleic acid (LA), which is found in vegetable oils such as corn, sunflower, and soybean oils, has a harmful effect on cancer and cardiovascular risk. However the purported pro-inflammatory effects of LA and other omega-6 fatty acids have not been conclusively confirmed, with even some studies showing a reduction in inflammation. 126 Furthermore, a meta-analysis found higher intakes of LA to be associated with lower (not higher) risk of CVD 127 and, along with other evidence, an author of a review concluded that LA intake within the range recommended by AHA has no harms associated with it. 128 Another more recent systematic review confirmed the reduction in CHD, CVD, and all-cause mortality with LA, but a slight increased risk in cancer mortality was noted (RR=1.06; 95% CI=1.02–1.11). 129 Other meta-analyses have not confirmed an excess cancer risk with higher LA intake. 130 Laboratory studies suggest, at higher thresholds, LA does not have tumor-promoting effects and may even be beneficial. 131 , 132 Although a small increase risk in cancer cannot be definitely excluded, there is not sufficient evidence that higher intake of LA substantially increases risk for breast, colorectal, or prostate cancer risk and, thus, should not be specifically avoided. 132

The ACC/AHA prevention guidelines discussed reducing added sugars and minimizing sugar-sweetened beverages, 7 , 113 as added sugars have been associated with increased risk of T2D, obesity, and CVD. 133 , 134 Additionally, the AHA guidance is to choose or prepare foods with little or no added salt, and to choose minimally processed foods instead of ultra-processed foods. 7 , 113 As for alcohol intake, the guidelines do not support initiation of alcohol intake for cardio-protection, and to limit alcohol if one does choose to drink. 113 Although moderate alcohol intake of 1–2 glasses per day has been associated with low risk of CHD and ischemic stroke, 135 the evidence behind this is not strong, 135 and some data suggest any alcohol intake, even one glass, is associated with increased risk of atrial fibrillation. 136

Approaches to Nutrition Counseling in CV Health

With the vast number of dietary behaviors proven to benefit cardiovascular health, implementation of these patterns can be cumbersome. Studies show that, despite ~80% of CVDs being preventable by adopting a healthier lifestyle, healthy eating behaviors are low, and there are numerous barriers to implementing these recommendations. Healthcare professionals have adopted multiple methods, such as nutrition counseling, culinary medicine, food pharmacies, and inpatient nutrition, all of which have been evaluated as effective means to implement dietary changes to patients. 137–139 Nutrition counseling through cognitive or behavioral theory has been shown to be most effective in dietary behaviors, weight, and cardiovascular risk factors as it is a supportive process that helps set priorities, establish goals, and create an individualized plan. 138–140 Motivational interviews modeled through behavioral theory, with self-monitoring, meal replacements, and/or meal plans help create a method of self-care. Client-centered counseling techniques in the long-term have been shown to be beneficial in effective chronic disease prevention where one study showed improvement in blood pressure and salt intake. 138 , 140 As nutrition counseling by a dietitian is shown to be beneficial, group counseling is a modality that takes the elements of individual nutrition counseling into a larger population through group therapy or culinary medicine. 137 , 138

Culinary medicine is an evidence-based approach to healthy eating where there is an emphasis on health promotion and illness management through dietary regimens. 141 Food pharmacies are designed to increase public access to fruits and vegetables and fully integrate the concept of “food is medicine” into health care systems. 142 These centers address financial barriers, knowledge gaps regarding healthy eating, and cooking skills by prescribing fruits and vegetables to patients. Community outreach programs have been successful in dietary changes through education, group counseling, and culinary medicine. 143 One such outreach program, “Shop With Your Doc”, has been shown to help implement positive dietary changes by patients gaining knowledge on how to read nutrition labels, read ingredients, and how to choose fresh produce. 144 Using surveys, one study found that there was an improvement in fresh vegetable consumption and less waste after produce allocation and educational intervention in low income populations. 143 Using the skills from nutrition counseling and applying them to an interactive community model, where patients can gain skills and apply them to their daily routines, may help implement larger scale changes. 141 , 143 , 144

The outpatient and community programs may offer guidance from a physician, dietitian, and a health coach to assist in not only improved diet, but also improve lifestyle with exercise programs with stress management techniques. Similarly, inpatient dietary guidance can be a method to implement the importance of nutrition when patients may be amenable to lifestyle changes. 139 , 145 Studies support that patients are most vulnerable to lifestyle changes after a life altering event, such as an MI. 146 In response to the data supporting the importance of nutrition in treating and preventing CVD, there has been greater pressure from hospital institutions in providing nutritious meals to inpatients. 139 Public policies, such as the Healthy Food in Health Care initiative, have been placed to assist hospitals in obtaining local produce and reducing meat products on the menu to improve patient nutrition and decrease environmental impact. 147 Despite these efforts to improve hospital menus, the effect on dietary behaviors needs to be further studied.

Limitations and Disparities to Implementing Dietary Changes

There are many challenges, but also many opportunities, to implementing healthy heart eating patterns ( Figure 3 ).

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Challenges and Opportunities for Implementing a Heart Healthy Diet.

Some of the main challenges and barriers to behavior or diet change have to do with the compatibility of regimen with patient lifestyles, including social and cultural factors of socioeconomic status, lack of social support, and certain cultural values, all of which have to be taken into consideration when recommending dietary changes. All diet recommendations need to be considered in the context of social determinants of health and societal barriers that drive health inequities. 148–151 Underserved populations, ethnic minorities, gender, and sexual minorities have been found to have a higher incidence of CVD and suffer from greater mortality. 151 , 152 These same groups are also faced with social barriers that make it difficult to adhere to preferable dietary patterns to improve their cardiovascular health. Additionally, individuals of lower income have been shown to be less likely counseled on diet modifications for CVD prevention in a representative US sample. 153

“Food deserts” (or grocery areas that lack fresh produce), “food swamps” (with excess of ultra-processed poor quality foods), and food insecurity all are contributors to obesity and chronic disease. 150 , 154 , 155 Recent studies have shown that food insecurity is a growing problem in the United States. 156 As a result of the COVID-19 pandemic, food insecurity has tripled, with an even higher prevalence among US adults with an income below the poverty level. 156 In comparison to high and middle income families, persons of low socioeconomic class are more likely to under consume fruits, vegetables, and whole grains and instead consume highly processed meats and beverages. 143 The fluctuating nature of eating food insecurity causes has been found to increase insulin resistance, increase blood pressure, and lead to poor weight management, which ultimately increase CVD risk. 152 , 156 These groups of patients may also not be able to access health care or seek treatment, which could lead to undiagnosed cardiovascular risk factors; this trend has been seen in gender and sexual minorities. 152 Food insecurity thus may pose as a strong barrier to adhering to lifestyle interventions, thus social and political support to provide access is needed.

Opportunities remain for improvement. Community engagement, such as through faith-based organizations, has been demonstrated to be successful at promoting fruit and vegetable consumption, along with other preventive strategies. 157 Culturally relevant and language appropriate resources are needed to assist patients from diverse backgrounds in making healthier choices. Family meals eaten together can be an important factor for cardiovascular health promotion, especially with parental modeling of healthy behaviors such as intake of vegetables and fruits; companionship at mealtimes that establishes a positive atmosphere around meals has been associated with improved dietary quality. 158

Physicians and other healthcare professionals can be the greatest advocates for their patients and can help provide counseling and information to access foods. However, medical schools are lacking in nutrition education and on average provide 20 hours of nutrition education to medical students. 159 Additionally, there is little emphasis on counseling and teaching patients about diet and how to make foods on a budget while maintaining cultural appropriateness. In recent years, programs have been placed where students engage in community outreach and culinary medicine practices. 137 These programs help to improve confidence in the knowledge of nutrition and their ability to provide counseling. Improving the nutritional education of physicians and other healthcare professionals, working as part of interdisciplinary teams, can help improve partnerships with their patients in improving nutritional quality and dietary behaviors with the aim to reduce CVD. 159

Conclusions

The AHA highlights diet as one of “Life’s Essential Eight” to help promote cardiovascular health and avoid disease. The Mediterranean diet remains one of the most effective and recommended balanced diets for cardiovascular health promotion, followed by the DASH diet for hypertension prevention and management, and healthy plant-based diet with careful consideration to its sugar and salt content as well as nutrient deficiencies. Other emerging diets that are widely adopted for weight loss like the keto or VLC diets remain controversial on whether the benefits of weight loss outweigh potential adverse changes to the lipid profile for example, and whether IF patterns have additional cardiometabolic benefits beyond simply the reduction of total calorie intake. The effects of diet on the gut microbiome and the importance of the gut–heart axis may be the future of our cardiovascular dietary recommendations where precision nutrition guides precision prevention.

Funding Statement

Dr. Michos is funded by the Amato Fund for Women’s Cardiovascular Health at Johns Hopkins University and by an American Heart Association Award, Number: 946222. Dr. Gulati is funded by the Anita Dann Friedman Chair in Women’s Cardiovascular Medicine and Research, and by the Department of Defense (Award Number: W81XWH-17-2-0030).

Abbreviations

ACC, American College of Cardiology; AHA, American Heart Association; ADP, Alternate Day Fasting; BMI, Body Mass Index; CVD, Cardiovascular Disease; DASH, Dietary Approaches to Stop Hypertension; HDL-C, High Density Lipoprotein Cholesterol; IF, Intermittent Fasting; LDL-C, Low Density Lipoprotein Cholesterol; MI, Myocardial Infarction; RCT, Randomized Controlled Trial; T2D, Type 2 Diabetes; TRE, Time Restricted Eating; TMAO, Trimethylamine-N-oxide; US, United States; VLC, Very Low Carbohydrate.

Unrelated to this work, Dr. Michos has served on advisory boards for Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Esperion, Novartis, Novo Nordisk, and Pfizer. Dr. Gulati has served on advisory boards for Novartis and Bayer. The authors report no other conflicts of interest in this work.

Exam 4 for the Generation 3, Omni 2 and New Offspring Spouse (NOS) cohorts is in full swing!

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June 25, 2024

Xylitol may affect cardiovascular health

At a glance.

  • Higher blood levels of the artificial sweetener xylitol were associated with increased risk of heart attack and stroke in people.
  • Xylitol enhanced blood clotting in mice and isolated human blood.
  • The results highlight the need for further study of long-term cardiovascular health risks from sugar alcohols, artificial sweeteners that were thought to be safe.

Xylitol crystals in a birch bowl beside a birch branch with leaves.

Many people use artificial, low-calorie sweeteners to reduce their sugar intake. Dietary guidelines recommend them for people with cardiometabolic diseases like obesity and diabetes. But their long-term effects on heart health have not been well studied.

A recent NIH-funded study by a team of researchers, led by Dr. Stanley Hazen at the Cleveland Clinic, suggested that an artificial sweetener called erythritol might exacerbate heart disease . Erythritol belongs to a class of compounds called sugar alcohols. Another sugar alcohol, xylitol, is also commonly used as a low-calorie sweetener and sugar substitute. Like erythritol, small amounts of xylitol occur naturally in fruits and vegetables. It is also produced in our bodies as part of normal metabolism. But levels of xylitol in artificially sweetened foods can be more than 1,000-fold greater than those found naturally in foods.

In their earlier study, the team found that blood erythritol levels were associated with future risk of major adverse cardiovascular events, such as heart attack or stroke. They also found that other sugar alcohols in the blood were associated with this risk, one of which they tentatively identified as xylitol. For the new study, the team examined a group of more than 2,000 people using a method to better distinguish xylitol from related compounds. Results appeared in the European Heart Journal on June 6, 2024.

The team found that people with the highest xylitol levels (top third) were about 50% more likely to have cardiovascular events over the next three years as those with the lowest (bottom third).

Blood components called platelets help blood to clot. In the group’s earlier research, erythritol made platelets more sensitive to blood clotting signals. In this study, the researchers exposed human platelets to xylitol to see if it had the same effect. Doing so increased the platelets’ sensitivity to blood clotting signals, much like erythritol did. Increasing blood xylitol levels also sped up blood clot formation and artery blockage in mice.

The team next tested how xylitol consumption affects blood xylitol levels and platelet function in people. To find out, they took blood samples from 10 healthy people before and after drinking a xylitol-sweetened beverage. Blood xylitol levels increased 1,000-fold within 30 minutes of drinking and returned to baseline after 4 to 6 hours. The platelets became more sensitive to blood clotting signals when xylitol blood levels were high.

These results suggest that xylitol, like erythritol, could have long-term cardiovascular health risks. Both xylitol and erythritol were associated with increase blood clot formation. This, in turn, could increase the risk of heart attack or stroke. Given these findings, further safety studies of sugar alcohol as artificial sweeteners are warranted.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Hazen says. “It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

—by Brian Doctrow, Ph.D.

Related Links

  • Erythritol and Cardiovascular Events
  • How Excess Niacin May Promote Cardiovascular Disease
  • Eating Red Meat Daily Triples Heart Disease-Related Chemical
  • Gut Cells Distinguish Between Sugar and Artificial Sweeteners
  • Sweet Stuff: How Sugars and Sweeteners Affect Your Health
  • Healthy Body, Happy Heart: Improve Your Heart Health
  • Coronary Heart Disease

References:  Xylitol is prothrombotic and associated with cardiovascular risk. Witkowski M, Nemet I, Li XS, Wilcox J, Ferrell M, Alamri H, Gupta N, Wang Z, Tang WHW, Hazen SL. Eur Heart J. 2024 Jun 6:ehae244. doi: 10.1093/eurheartj/ehae244. Online ahead of print. PMID: 38842092.

Funding:  NIH’s National Heart, Lung, and Blood Institute (NHLBI); Deutsche Forschungsgemeinschaft; Stifterverband für die Deutsche Wissenschaft.

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June 27, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

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New study shows a relationship between heart disease and spontaneous loss of Y chromosome

by Boston Medical Center

Y chromosome

Researchers at Boston Medical Center (BMC) and Boston University (BU) Chobanian & Avedisian School of Medicine, in collaboration with an international team of scientists, shared findings from a new study published in the American Heart Association journal, Circulation: Heart Failure that explores a common cause of heart disease in older men called transthyretin cardiac amyloidosis (ATTR-CA).

The study examines the relationship between spontaneous loss of the Y chromosome (LOY), a condition in aging men where the Y chromosome is spontaneously deleted in blood cells , and ATTR-CA, a progressive disease that causes heart failure and death. The team found that men with a higher proportion of blood cells missing Y chromosomes have a higher ATTR-CA mortality rate, informing future treatment for patients with ATTR-CA. The study team included investigators from Columbia University, University of Virginia, and Osaka Metropolitan Hospital in Japan.

LOY is the most common acquired genetic mutation in men, with more than half of men in their early 90s having lost the Y chromosome in some of their blood cells according to the National Cancer Institute. While LOY has been associated with heart failure survival rates in large population studies, it has never been examined in relation to ATTR-CA. The current study suggests that men with ATTR-CA who have LOY in greater than 21.6% of their blood cells were 2.6 times more likely to not survive this form of heart disease.

"Our study suggests that spontaneous LOY in circulating white blood cells contributes both to the development of ATTR-CA in men and influences the severity of disease," said Frederick L. Ruberg, MD, Chief of Cardiovascular Medicine at BMC, Professor of Medicine at BU Chobanian & Avedisian School of Medicine, and lead researcher in this study. "Additionally, our study's findings indicate that elevated LOY may be an important reason why some patients do not respond to the ATTR-CA therapy that is typically effective."

Current treatments for ATTR-CA work well for many patients, but roughly 30 percent of patients do not respond to treatment, leading to hospitalization and death. Findings from this study support elevated LOY as a potential barrier to treatment response. The findings could one day inform a clinician's choice in designing a treatment course for a patient with ATTR-CA and high level of LOY in hopes of a more favorable health outcome. Additionally, the findings could lead to the development of new treatments for those with heart disease, including ATTR-CA.

"Our study team represents an international collaboration that sought to explore an association between a common blood disorder and ATTR-CA that has never been previously considered," said Ruberg. "We provide evidence that these two conditions may be related, supporting a new way of understanding how ATTR-CA progresses as well as how to develop new potential targets for treatment."

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Is Fish Oil Helpful or Harmful for the Heart?

Despite decades of research, the evidence for omega-3 supplements is murky.

An illustration of a white cardboard heart-shaped box with a single fish oil pill in it. The background color is orange.

By Alice Callahan

In 1970, two Danish researchers traveled to Greenland to investigate a nutritional paradox: The Inuit people living in the region consumed foods very high in fat, yet reportedly had very low rates of heart attacks.

That observation flew in the face of nutrition dogma at the time, which held that eating fatty foods — like whale and seal meat and oily fish — would clog your arteries and cause heart disease.

The Inuit on Greenland, a Danish territory, had lower levels of blood cholesterol and triglycerides than people back in Denmark, the researchers reported . The reason, they hypothesized, was that the Inuit diet was rich in omega-3 fatty acids — particularly EPA and DHA, which are concentrated in fish and the animals that eat them.

These findings sparked decades of scientific and commercial interest in the role omega-3 fatty acids play in heart health, even after later studies suggested that, in fact, the Inuit had rates of heart disease similar to those found in Europe, the United States and Canada. Today, omega-3 supplements are among the most popular in the United States, surpassed only by multivitamins and vitamin D. Among U.S. adults 60 and older, about 22 percent reported taking omega-3s in a 2017-2018 survey.

Unlike most other supplements , fish oil has been rigorously studied, said Dr. JoAnn Manson, a professor of medicine at Harvard Medical School. But the results of those studies have been mixed, leaving researchers and doctors still debating whether fish oil is beneficial for heart health. They have also revealed that taking fish oil is linked to a slightly greater risk of developing atrial fibrillation , a type of irregular heartbeat.

Here’s where the evidence for both the benefits and risks of fish oil stands today.

A boatload of studies, but unclear benefits

After reading the dispatches from Greenland, researchers began looking at people elsewhere in the world and finding, in study after study , that those who consumed fish at least once per week were less likely to die from coronary heart disease than those who rarely ate fish. In animal experiments , they found that fish oil helped keep electrical signaling in heart cells functioning properly, said Dr. Dariush Mozaffarian, a cardiologist and director of the Food is Medicine Institute at Tufts University.

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Accelerating heart failure research

A 3D image of a heart is shown.

An NIH-supported research partnership aims to transform heart failure research to bring personalized therapies to patients

Every minute of every day the heart pumps about five quarts of blood – nearly 20 glassfuls – throughout the body. But when changes occur, such as the heart becoming weak or not filling adequately with blood, it loses its ability to fully support the body’s needs, causing a condition called heart failure.

Heart failure affects about 6.2 million Americans , including one in five adults older than age 65, and is expected to rise with an aging population. Common symptoms include shortness of breath, fatigue, or swelling in the lower body, such as the legs and feet.

Currently the condition has no cure, so to support earlier detection and treatment, researchers are pooling knowledge across industries and disciplines through a new, potentially game-changing initiative called the Accelerating Medicines Partnership® Heart Failure (AMP® HF) Program.

Supported by the Foundation for the National Institutes of Health, this private-public partnership aims to help researchers identify new, personalized therapies for heart failure – especially for one of the most common types, called heart failure with preserved ejection fraction (HFpEF). HFpEF affects about half of patients with heart failure. However, it can be harder to identify and treat – often because of the complex and different ways it impacts the body.

“The group of patients who have heart failure with preserved ejection fraction is very heterogenous,” said Vandana Sachdev, M.D. , a senior research clinician at NHLBI. “The goal is to understand the different subtypes of disease and identify treatment targets for each type.”

Classifying heart failure subtypes

Current heart failure treatment is often based on a person’s cardiac structure and function. To assess function a doctor typically measures the ejection fraction – the percent of blood in the left ventricle that is pumped out of the heart each time it contracts.

If the left ventricle pumps out less than 40% of blood in one beat, a person may be diagnosed with a type of heart failure called heart failure with reduced ejection fraction (HFrEF). People who have coronary heart disease or who have had a heart attack or other conditions that weaken the heart muscle are more likely to have this type.

Heart failure with preserved ejection fraction is different, occurring despite the fact that the heart’s pumping function is normal. HFpEF results when the walls of the heart become too stiff to fully relax between beats, which makes it difficult for the heart to fill up with enough blood.

High blood pressure, obesity, diabetes, and other conditions that contribute to chronic inflammation can stiffen the walls of the heart leading to HFpEF.

Unlike with HFrEF, however, diagnosing and treating HFpEF is tricky. One reason: an ejection fraction of 55% or more is considered normal and a person with HFpEF can appear to have normal heart-pumping function when given cardiac tests.

“The ejection fraction may be normal, but from the patient’s perspective, symptoms of HFpEF and HFrEF are very similar,” Sachdev said. That’s because as blood from the stiff heart backs up into the lungs, people can get short of breath and develop swelling in the legs – which are classic heart failure symptoms. But they can also experience different symptoms, underscoring the challenges of detecting HFpEF.

Studying multiple systems

To categorize HFpEF, researchers are looking for clues from multiple systems that support the body’s functions, including genes, proteins, and gut bacteria. They are then pairing that information with a patient’s physical symptoms, their medical history, and cardiac imaging exams to understand how it affects them.

For example, using cohorts of the Framingham Heart Study, researchers analyzed 71 proteins from more than 7,000 adults, including nearly 200 who later died from heart failure. Through this analysis , they identified five biomarkers associated with HFpEF, which suggested inflammation, stress to the heart, and a hardening of the heart’s muscles and blood vessels were in play. They also found 14 biomarkers associated with HFrEF that provided insight about inflammation and changes in the heart’s structure. Three were linked to both types.

Some of the biomarkers, such as increased levels of natriuretic peptides – hormones secreted from the heart – are used to screen adults for heart failure. The study is now helping explain the role of other biomarkers and how HFpEF differs from HFrEF.

“We still have a lot to learn,” said Jennifer E. Ho, M.D., a cardiologist at Beth Israel Deaconess Medical Center and an associate professor of medicine at Harvard Medical School. Previous research, she said, has found that 87% of these same 71 circulating proteins associated with cardiovascular disease differ between men and women.

However, Ho and others studying biomarkers for heart failure are already finding patterns in these proteins – unrelated to gender – that may be as significant. And they envision that one day physicians could pair these patterns, or “signatures,” with traditional risk factors, like high blood pressure, to better assess a patient’s risk for heart failure.

“In the future, I see that in addition to using a one-size-fits-all approach for the therapies we have available, we’ll also think about other adjunct therapies that we can tailor to individual patients,” Ho said.

Using big data

Through the AMP HF program, results from many previous trials and studies, like those that Ho and others are working on, will be pooled together through a cloud-based system called BioData Catalyst . The digital portal will enable researchers to store, share, and analyze data with others in the program.

“To use new advanced analytic techniques, you need large numbers of patients,” Sachdev said. This is why the HeartShare program, which is the public portion of AMP HF’s public-private-partnership, will enable researchers to analyze data from the electronic health records of 100,000 adults with and without heart failure. Around 10,000 of these adults – those with heart failure – will help researchers analyze HFpEF subtypes.

Within the group of adults with heart failure, 1,000-1,500 with HFpEF will also enroll in a five-year clinical research study. They will undergo comprehensive medical exams, enabling researchers to collect information about their heart, their cardiopulmonary function, and the health of their other organs and systems. Artificial intelligence and machine learning models will be trained to scan echocardiographs and other heart and chest images. These data, along with data from prior studies, will then be added to BioData Catalyst so that scientists can study HFpEF patterns, which they can use to conduct follow-up studies.

Researchers at Northwestern University, one of six study sites, will guide the collection and translation of the HeartShare data, which will be integrated into BioData Catalyst. Massachusetts General Hospital and Brigham and Women’s Hospital, the Mayo Clinic, the University of Pennsylvania, Wake Forest University, and the University of California-Davis will serve as the other study sites.

Built into the HeartShare program, Sachdev said, is the ability to aggregate data not only from multiple sources like medical exams and images, but directly from the trial participants themselves. For example, participants may be able to share information from physical activity monitors through an app called Eureka.

As a first step to enable researchers to access this information, scientists plan to harmonize data, images, and biospecimens from other studies with universal terms and search tools. This will enable researchers to ask questions about HFpEF using the existing datasets, while eliminating the need to create additional background resources for their studies.

Throughout the five-year program, study participants will also be invited to join other trials, such as those that explore connections between HFpEF and sleep disruptions, gut health, genetic and family links, and cognitive dysfunction.

Sachdev hopes that, by the study’s end, researchers will have identified different subtypes of HFpEF and will have learned about treatment targets for individual subtypes so that patients with HFpEF can receive more personalized treatments compared to general medications and devices used today.

Previous studies have started to cluster HFpEF into categories, but more work is needed with diverse populations and to delve deeper into the molecular mechanisms of each subtype.

Sachdev and others envision that bringing researchers from the public and private sectors together may help achieve the biggest goal of all: to create personalized therapeutic options for people living with HFpEF – not just in the United States, but throughout the world.

“We hope the AMP HF partnership will be the stimulus to help us reach that goal,” Sachdev said.

To learn about heart failure, visit https://www.nhlbi.nih.gov/health/heart-failure .

To learn about the AMP HF program, visit https://amphf.org .

ACCELERATING MEDICINES PARTNERSHIP® and AMP® are registered service marks of the U.S. Department of Health and Human Services.

Related Health Topics

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Texas abortion ban linked to 13% increase in infant and newborn deaths

A Texas law that banned abortions in early pregnancy is associated with a stark increase in infant and newborn deaths, a study published Monday in JAMA Pediatrics found. 

Lawmakers passed Texas Senate Bill 8 , or SB8, in September 2021. The state law banned abortions as soon as a fetal heartbeat is detected, which can be as early as five weeks. This effectively banned abortion in the state, which used to allow abortion up to 22 weeks of pregnancy. 

The law did not include exemptions for congenital anomalies, including conditions that will cause a newborn to die soon after birth. 

The new study compared infant death rates in Texas from 2018 to 2022 to those of 28 other states. The data included newborns 28 days or younger and infants up to 12 months old. Infant deaths in Texas rose by nearly 13% the year after SB8 was passed, from 1,985 in 2021 to 2,240 in 2022. During that same period, infant deaths rose by about 2% nationwide.

Babies born with congenital anomalies also increased in Texas, by nearly 23%, but decreased by about 3% nationwide. 

“This is pointing to a causal effect of the policy; we didn’t see this increase in infant deaths in other states,” said Alison Gemmill, assistant professor of population, family and reproductive Health at the Johns Hopkins Bloomberg School of Public Health, who led the research. 

While some congenital anomalies can be corrected after birth, including cleft palate and some heart defects, others are deemed “incompatible with life.” 

“The specific increase in deaths attributable to congenital anomalies really makes an ironclad link between the change in the law and the terrible outcomes that they’re seeing for infants and families,” said Nan Strauss, senior policy analyst of maternal health at the National Partnership for Women & Families, who was not involved with the research. “The women and families have to suffer through an excruciating later part of pregnancy, knowing that their baby is likely to die in the first weeks of life.”

Gemmill said the new insight is important for other states, since Texas passed SB8 about a year before the Dobbs decision overturned federal abortion protections , leading to total bans on abortion in 14 states, according to the latest data from the Guttmacher Institute, an organization that researches and supports sexual and reproductive rights. 

“This might foreshadow what is happening in other states,” Gemmill said. “Texas is basically a year ahead.”

A Centers for Disease Control and Prevention report already found that infant and newborn mortality rates in the U.S. rose in 2022 for the first time since 2001. 

“This shows what probably was expected before the Dobbs decision, that there would be downstream unintended consequences by banning abortions in early pregnancy,” said Dr. Mary Rosser, director of Integrated Women’s Health at Columbia University Irving Medical Center, who was not involved with the study. 

Rosser added that such bans disproportionately affect marginalized populations including low-income families and people of color, and that further research is needed to better understand these effects. 

The researchers of the new study also highlighted the ripple effect that a newborn or infant’s death can have on a family, including trauma and medical bills. 

“Behind these numbers are people,” said Dr. Erika Werner, chair of obstetrics and gynecology at Tufts Medical Center, who was not involved in the research. “For each of these pregnancies, that’s a pregnant person who had to stay pregnant for an additional 20 weeks, carrying a pregnancy that they knew likely wouldn’t result in a live newborn baby.”

Kaitlin Sullivan is a contributor for NBCNews.com who has worked with NBC News Investigations. She reports on health, science and the environment and is a graduate of the Craig Newmark Graduate School of Journalism at City University of New York.

research study on heart

Jason Kane is a producer in the NBC News Health & Medical Unit. 

COMMENTS

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  4. Framingham Heart Study (FHS)

    The Framingham Heart Study marked its 75th anniversary in 2023. Findings from the study over three generations of participants have changed how Americans and their doctors view heart disease and how to prevent, predict, and treat it. The study has expanded its research activities to other disease domain areas such as stroke, dementia, and ...

  5. A Systematic Review of Major Cardiovascular Risk Factors: A Growing

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  6. Scientific Research

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  8. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019:

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  9. Trial of an Intervention to Improve Acute Heart Failure Outcomes

    The following patients were excluded: patients who did not have a clinical diagnosis of heart failure according to Framingham Heart Study criteria or had a B-type natriuretic peptide level that ...

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  12. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation

    Turakhia MP, Desai M, Hedlin H, et al. Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: the Apple Heart Study. Am Heart J 2019;207:66-75 ...

  13. Coronary Heart Disease Research

    Heart disease, including coronary heart disease, remains the leading cause of death in the United States. However, the rate of heart disease deaths has declined by 70% over the past 50 years, thanks in part to NHLBI-funded research. Many current studies funded by the NHLBI focus on discovering genetic associations and finding new ways to ...

  14. Heart Attack Research

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  17. Cardiovascular Effects and Benefits of Exercise

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  18. A Heart-Healthy Diet for Cardiovascular Disease Prevention: Where Are

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  20. Framingham Heart Study

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  21. What might the next century hold for cardiovascular disease prevention

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  22. Many older adults are still taking daily aspirin, even though some

    The latest research on the prevalence of aspirin use to prevent cardiovascular disease suggests that in 2021, nearly a third of adults 60 or older without cardiovascular disease were still using ...

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  24. Phase 2 Study of JK07 in Chronic Heart Failure

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  25. Xylitol may affect cardiovascular health

    But their long-term effects on heart health have not been well studied. A recent NIH-funded study by a team of researchers, led by Dr. Stanley Hazen at the Cleveland Clinic, suggested that an artificial sweetener called erythritol might exacerbate heart disease. Erythritol belongs to a class of compounds called sugar alcohols.

  26. New study shows a relationship between heart disease and spontaneous

    The current study suggests that men with ATTR-CA who have LOY in greater than 21.6% of their blood cells were 2.6 times more likely to not survive this form of heart disease. "Our study suggests ...

  27. Is Fish Oil Helpful or Harmful for the Heart?

    These findings sparked decades of scientific and commercial interest in the role omega-3 fatty acids play in heart health, even after later studies suggested that, in fact, the Inuit had rates of ...

  28. Accelerating heart failure research

    For example, using cohorts of the Framingham Heart Study, researchers analyzed 71 proteins from more than 7,000 adults, including nearly 200 who later died from heart failure. ... 1,000-1,500 with HFpEF will also enroll in a five-year clinical research study. They will undergo comprehensive medical exams, enabling researchers to collect ...

  29. Report calls out gaps in women's heart disease research, care

    According to AHA statistics, heart disease is the leading cause of death for U.S. men and women, and 44% of women age 20 years and older between 2015 and 2018 had some form of cardiovascular disease, including high blood pressure. But awareness among women, which rose before 2009, is slipping. In 2019, only 44% of women understood that heart ...

  30. Texas abortion ban linked to sharp rise in infant and newborn deaths

    The new study compared infant death rates in Texas from 2018 to 2022 to those of 28 other states. The data included newborns 28 days or younger and infants up to 12 months old.