Cardiovascular
Episodes
In this clip, Dr. Rhonda Patrick explains ApoB's role in cardiovascular health, omega-3 mechanisms, diet impacts, and concerns about heavy metals in fish.
In this clip, Drs. Peter Attia and Rhonda Patrick discuss VO2 max testing, peak fat oxidation, and the longevity benefits of elite cardiovascular fitness.
Dr. Levine details his research findings that show how a structured exercise regimen can reverse up to 20 years of heart aging.
-
In this clip, Dr. Rhonda Patrick explains ApoB's role in cardiovascular health, omega-3 mechanisms, diet impacts, and concerns about heavy metals in fish.
-
In this clip, Drs. Peter Attia and Rhonda Patrick discuss VO2 max testing, peak fat oxidation, and the longevity benefits of elite cardiovascular fitness.
-
Dr. Levine details his research findings that show how a structured exercise regimen can reverse up to 20 years of heart aging.
-
Rhonda Diet Omega-3 Pregnancy Mitochondria Vitamin B12 Muscle Sauna Cardiovascular Blood Test Red Light TherapyDr. Rhonda Patrick explores blood tests to track health, statin alternatives, mitochondrial supplements, and vitamin B12 and autism risk in her latest Q&A.
-
In this clip, Dr. Peter Attia examines statins, detailing their benefits, side effects, and the alternatives for cardiovascular health.
-
In this clip, Dr. Peter Attia discusses the importance of reducing ApoB to lower cardiovascular disease risk.
-
Dr. Rhonda Patrick describes strategies you can apply immediately to enhance your health and prevent chronic disease.
-
In this clip, Dr. Martin Gibala emphasizes tailoring HIIT to one's fitness level by briefly exceeding comfort zones.
-
In this clip, Dr. Martin Gibala explores HIIT's effects on VO2 max, highlighting the importance of personalized exercise routines.
-
In this clip, Dr. Martin Gibala discusses the ongoing studies and their objectives in understanding the impact of "exercise snacks".
-
In this clip, Dr. Martin Gibala describes the benefits and public health potentials of Reduced Exertion High-Intensity Training.
-
Rhonda Vitamin D Microbiome Hormones Omega-3 Melatonin Bone Time-Restricted Eating Cardiovascular SupplementsDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
In this clip, Drs. Levine and Patrick discuss genetic and environmental factors that can accelerate or slow epigenetic aging.
-
In this clip, Dr. Ronald Krauss discusses that in clinical practice, cholesterol particle size may be more relevant than the amount of cholesterol.
-
In this clip, Dr. Ronald Krauss discusses the complexities of HDL cholesterol and its relationship to heart disease risk.
-
In this clip, Dr. Ronald Krauss describes why it may be more beneficial to reduce LDL levels than to raise HDL levels.
-
In this clip, Dr. Ronald Krauss debunks common myths of dietary cholesterol and saturated fat.
-
In this clip, Dr. Krauss shares his thoughts on the prescription pattern of statins in the United States.
-
In this clip, Dr. Krauss discusses why women taking statins have higher risk for diabetes.
-
In this clip, Rich Roll and Dr. Rhonda Patrick discuss how IGF-1 levels impact cancer risk.
-
In this clip, Dr. Mark Mattson explains the importance of stressing the cardiovascular system with behaviors such as exercise and fasting to maximize health.
-
In this clip, Dr. Mark Mattson shares his opinions regarding the possible life-extension properties of intermittent fasting.
-
Dr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
Rhonda Vitamin D Exercise Parkinson's Epigenetics Omega-3 Fasting Melatonin Vaccine Resveratrol Sauna Insulin COVID-19 Cardiovascular AutoimmunityDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
In this clip, Dr. Bill Harris describes the recent large clinical trials evaluating whether omega-3 decreases heart disease risk.
-
Broccoli sprouts contain more glucoraphanin, the precursor to sulforaphane, than mature broccoli. Glucoraphanin activates the Nrf2 pathway to protect cells from oxidative stress and damage. In this episode, we describe the basics of sprouting broccoli seeds.
-
Rhonda Vitamin D Brain Microbiome Depression Probiotics Fasting Coffee Anxiety Sauna Iron Blood Sugar COVID-19 Cardiovascular Ketogenic DietDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
In this clip, Dr. Rhonda Patrick describes how the physiological effects observed during sauna use are comparable to those that occur during physical exercise.
-
Rhonda Vitamin D Brain Cancer Epigenetics Aging Hormones Diabetes Vitamin C Antibiotics Vitamin K Sulforaphane Sauna Glutathione Oxidative Stress NAD+ CardiovascularDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
In this clip, Dr. Peter Attia discusses the role of the APOE4 gene variant and the associated risk for Alzheimer’s disease and cardiovascular disease.
-
In this clip, Dr. David Sinclair identifies some of the practical considerations of resveratrol supplementation and discusses his personal use of the compound.
-
In this clip, Dr. David Sinclair identifies some of the practical considerations of resveratrol supplementation and discusses his personal use of the compound.
-
Sauna use boosts lifespan and overall health supported by compelling data from observational, interventional, and mechanistic studies.
-
Dr. Jari Laukkanen discusses the benefits and risks associated with cold water immersion following sauna use.
-
Dr. Rhonda Patrick describes the role that heat shock proteins play in reducing the risk of disease.
-
Dr. Jari Laukkanen discusses the optimal temperature and amount of time for sauna use to obtain the greatest health benefits.
-
Drs. Rhonda Patrick and Jari Laukkanen discuss findings from a study linking sauna use and lower risk of death from cardiovascular disease.
-
Mitophagy: a signal for mitochondrial biogenesis, metabolic adaptation, and cellular differentiationDr. Guido Kroemer describes mitophagy, a cellular signal for mitochondrial biogenesis, and a key player in other physiological processes.
-
Dr. Guido Kroemer describes the cellular process of autophagy and what factors trigger its activation.
-
Rhonda Nutrition Exercise Alzheimer's Aging Fasting Memory Genetics Mortality Sauna Time-Restricted Eating Cardiovascular Supplements Ketogenic DietDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
Rhonda Omega-3 Fasting Circadian Rhythm Mushroom Sugar Sauna Saturated Fat Vegetarian Protein Dairy NAD+ Cardiovascular SupplementsDr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.
-
Heat Stress Alzheimer's Aging Heart Disease Podcast Video Blood Pressure Protein Aerobic CardiovascularDr. Jari Laukkanen discusses the role of heat stress in the prevention of cardiovascular & Alzheimer’s disease.
Topic Pages
-
Alcohol
Alcohol is one of the most widely used and abused drugs and is associated with several health conditions.
-
Cocoa flavonoids (chocolate)
stub
A wide range of beneficial health effects has been attributed to the consumption of cocoa and chocolate, many of which are due to their flavonoid content.
-
Creatine and Cardioprotection
Creatine may have benefits for reducing cardiovascular disease risk based on in-vitro and in-vivo evidence and small studies in adults humans.
-
Exercise Intensity
Vigorous exercise exerts several benefits on cardiovascular health, metabolic health, and longevity.
-
Microplastics
Microplastics are tiny plastic particles, less than 5 millimeters in size, that pose immense environmental and health risks due to their widespread presence.
-
Myocardial infarction (Heart attack)
A heart attack is a critical and often life-altering event that strikes suddenly, but its underlying causes develop over time.
-
Nicotinamide mononucleotide
Nicotinamide mononucleotide is a precursor of NAD+, a coenzyme necessary for cellular energy production and DNA repair. It is available as a supplement.
-
Nicotinamide riboside
Nicotinamide riboside is a precursor of NAD+, a coenzyme necessary for energy production and cellular repair. It is available from food and supplements.
-
Resveratrol
Resveratrol is a polyphenolic compound produced in plants that demonstrates anti-inflammatory and anti-aging properties in humans.
-
Small vessel disease
Small vessel disease is a generic term that describes dysfunction of blood vessels that occurs with aging and contributes to cognitive decline, cardiovascular disease, frailty, and stroke.
-
Sodium (Salt)
Sodium plays a crucial role in human physiology, yet its consumption remains a topic of ongoing debate in health and nutrition science.
News & Publications
-
That morning cup of coffee might do more than boost alertness—it might promote longevity. While many studies link moderate coffee drinking to better health, the timing of those effects is less clear. However, a recent study found that morning-only coffee drinkers were more than 30% less likely to die from cardiovascular disease.
Researchers analyzed data from more than 40,000 adults in the National Health and Nutrition Examination Survey and 1,400 adults in the Women’s and Men’s Lifestyle Validation Study. They searched for patterns in the timing of coffee consumption and tracked participants for an average of nearly 10 years to monitor deaths from all causes, cardiovascular disease, and cancer.
Two coffee-drinking patterns emerged: a morning-only pattern (4 a.m. to noon) and an all-day pattern. Compared with people who didn’t drink coffee at all, those who drank coffee only in the morning had a 16% lower risk of dying from any cause and a 31% lower risk of dying from cardiovascular disease, indicating that the health benefits of drinking more coffee were strongest among morning-only drinkers. Surprisingly, caffeine didn’t explain the difference. When the researchers adjusted for both caffeinated and decaffeinated coffee intake, the timing of coffee drinking still mattered.
These findings suggest that drinking coffee earlier in the day offers more health benefits than drinking it over the course of the day. Coffee induces autophagy–a critical process that helps reduce the risk of cancer and other chronic diseases. Learn more in this clip featuring Dr. Guido Kroemer.
-
Strawberry consumption boosts thinking speed and lowers systolic blood pressure by 3% in older adults. www.sciencedirect.com
Cognitive decline and cardiovascular disease often go hand in hand—and both become more common with age. Nutrition plays a key role in protecting brain and heart health, and certain fruits rich in antioxidants may offer targeted benefits. A recent study found that consuming fresh strawberries daily improved cognitive function and lowered systolic blood pressure by an average of 3% in older adults.
Researchers provided 35 healthy adults, ages 60 to 78, a strawberry powder or a placebo each day for eight weeks. Each person tried both options in random order, with a four-week break in between. The strawberry powder, made from freeze-dried fruit, delivered the same nutrients and antioxidants as two cups of fresh strawberries. The researchers measured the participants' cognitive function using standard tests and tracked markers of heart health, including blood pressure, waist size, blood lipids, and antioxidant levels.
The participants' thinking speed improved during the strawberry phase, while episodic memory improved modestly during the placebo phase. After eight weeks of strawberry consumption, systolic blood pressure dropped by an average of 3%, and waist size decreased slightly. Participants' blood antioxidant capacity increased with strawberries but decreased with the placebo. Triglycerides increased during the placebo period but remained stable with strawberries.
The findings from this small study suggest that regular strawberry intake supports brain and heart health in older adults. Strawberries are rich in polyphenols. Learn more about polyphenols in our overview article.
-
Heart disease is the leading cause of death worldwide, and clogged arteries—caused by a buildup of fatty plaques—are a major culprit. While some plaques remain stable, others can rupture and trigger heart attacks. A recent study found that high-intensity interval training (HIIT) may help shrink fatty arterial plaquesin people with coronary artery disease who have undergone stent placement, reducing plaque size by 1.2% in just six months.
Researchers randomly assigned 60 patients with stable coronary artery disease to a supervised HIIT program or standard preventive care twice a week. After six months, they used intravascular ultrasound to measure changes in plaque size inside the coronary arteries.
They found that patients who did HIIT had a 1.2% reduction in plaque size, while those who followed standard preventive care saw no change. The total plaque volume in the HIIT group also dropped by about 9 cubic millimeters, but it remained the same in the standard care group. Even small reductions in plaque size can be meaningful because they reflect a slowing—or even a reversal—of coronary artery disease progression.
These findings suggest that HIIT may help slow or even reverse the progression of coronary artery disease. It’s important to note that these patients were closely supervised to minimize risk. Learn about some of the contraindications and considerations for HIIT in this episode featuring Dr. Martin Gibala.
-
A daily dose of coenzyme Q10—100 milligrams or less—reduces blood pressure by about 4mmH systolic and 3mmHG diastolic in people with type 2 diabetes, potentially lowering cardiovascular risk. www.clinicaltherapeutics.com
Most people with type 2 diabetes know they need to manage their blood glucose levels, but many may not realize they are at higher risk for heart disease. One potential option for reducing that risk is coenzyme Q10, a naturally occurring antioxidant. A recent study found that supplementing with coenzyme Q10 (CoQ10) helps lower blood pressure in people with type 2 diabetes.
Researchers reviewed data from 16 clinical trials that measured CoQ10 levels in people with type 2 diabetes. They focused on changes in blood pressure and cholesterol levels, comparing those who took the supplement to those who did not.
Their analysis revealed that CoQ10 lowered systolic blood pressure by about 4 mmHg and diastolic blood pressure by about 3 mmHg. While it didn’t improve cholesterol levels overall, some subgroup analyses showed better results with lower doses (100 milligrams daily or less) and shorter study durations (less than 12 weeks). Notably, these findings were more pronounced in studies with larger participant groups (more than 50 people) and participants aged 55 or younger.
A reduction of 4 mmHg in systolic blood pressure may seem modest, but even small reductions can lower the risk of heart disease and stroke. For example, a comprehensive analysis found that a 5-mmHg decrease in systolic blood pressure reduced the risk of major cardiovascular events by approximately 10%00590-0/fulltext).
These findings suggest that CoQ10 could be a useful addition to diabetes treatment for managing blood pressure and reducing cardiovascular risk. A common feature of diabetes and cardiovascular disease is inflammation. Learn how to reduce chronic inflammation in Aliquot #84: Putting the Brakes on Chronic Inflammation
-
Cancer remains one of the leading causes of death globally, with millions of new cases and deaths each year. Despite treatment advancements, cancer patients are at a greater risk of death due to muscle loss, heart complications, and inadequate physical activity. A recent study found that higher muscle strength and cardiorespiratory fitness reduce the risk of death in cancer patients, with a 31% to 46% lower likelihood of premature death.
Researchers conducted a systematic review and meta-analysis of 42 studies involving more than 47,000 cancer patients across various types and stages to examine how muscle strength and cardiorespiratory fitness influence survival rates. They sought to determine whether higher fitness levels were associated with better outcomes in terms of overall and cancer-specific death.
Their analysis revealed that patients with higher muscle strength or cardiorespiratory fitness were 31% to 46% less likely to die prematurely from any cause than those with lower fitness levels. Each increase in muscle strength was associated with an 11% lower risk of all-cause mortality. Furthermore, patients with advanced cancer stages, as well as those with lung and digestive cancers, saw significant reductions in death risks—ranging from 8% to 46% lower for all-cause mortality. Increments in cardiorespiratory fitness were particularly important, with each improvement in cardiorespiratory fitness linked to an 18% reduced risk of dying specifically from cancer.
These findings suggest that boosting muscle strength and cardiorespiratory fitness can improve cancer patients' survival rates. Given the strong connection between physical fitness and mortality risk, health professionals should prioritize fitness assessments for cancer patients as part of their treatment strategies. Learn more about the role of exercise in cancer prevention and recurrence in this episode featuring Dr. Kerry Courneya.
-
GLP-1 receptor agonists may lower risks for major illnesses like dementia and seizures. www.nature.com
Ozempic, Wegovy, and other glucagon-like peptide-1 (GLP-1) drugs have catapulted into the mainstream of diabetes care, with more than 15 million people in the U.S. currently taking one. Evidence suggests GLP-1 drugs have many off-target effects—both good and bad—but healthcare providers don’t currently know the full extent of the drugs' effects. However, a recent analysis found that GLP-1s may reduce the risk of dementia, seizures, respiratory illnesses, cardiometabolic disorders, and certain infections more effectively than other diabetes drugs and typical care.
Using the U.S. Department of Veterans Affairs healthcare databases, researchers identified roughly two million people with diabetes who were using a GLP-1 drug, one of three common anti-diabetes drugs (sulfonylureas, DPP4 inhibitors, or SGLT2 inhibitors), or continuing their usual care without adding new therapies. They tracked the participants' health for about 3.6 years.
They found that GLP-1 use was associated with a reduced risk of dementia (8%), seizures (10%), respiratory illnesses (10% to 25%), cardiometabolic disorders (7% to 22%), and certain infections (12% to 25%). However, the drugs were associated with an increased risk of gastrointestinal issues (5% to 20%), low blood pressure (10%), kidney problems (10% to 15%), arthritic disorders (10% to 16%), and pancreatitis (15% to 20%).
These findings suggest that GLP-1 receptor agonists offer promising benefits for people with diabetes while highlighting potential risks. Further research will illuminate the full range of the drugs' effects. Learn more about GLP-1 drugs in this clip featuring Dr. Rhonda Patrick.
-
Poor cardiorespiratory fitness may double the risk of early death, regardless of body weight. bjsm.bmj.com
How fit you are may matter more than how much you weigh when it comes to your risk of dying early. A recent review and meta-analysis found that poor cardiorespiratory fitness increases the risk of early death from cardiovascular disease and other causes, regardless of body weight.
Researchers analyzed the findings of 20 studies investigating the effects of cardiorespiratory fitness and body weight on the rates of early death from cardiovascular disease and all other causes. The various studies included nearly 400,000 participants and compared the risks among people who were overweight or obese to those who were normal weight.
They found that overweight, fit people were about 50% more likely to die from cardiovascular disease and had roughly the same overall risk of early death as those with normal weight. Obese, fit people were 62% more likely to die from cardiovascular disease and had an 11% higher overall risk of early death, but these differences were not statistically significant.
However, being unfit was linked to a much higher risk of death. Normal-weight people who were unfit were about twice as likely to die from cardiovascular disease and all causes. Overweight, unfit people had roughly 2.5 times the risk of cardiovascular death and 82% higher overall risk of early death. Obese, unfit people had more than triple the risk of cardiovascular death and twice the risk of dying from any cause compared to those with normal weight.
These findings suggest that cardiorespiratory fitness robustly predicts the risk of early death from cardiovascular disease and other causes. Vigorous exercise, such as high-intensity interval training, is a great way to boost cardiorespiratory fitness and prevent early death. Learn more in this episode featuring Dr. Rhonda Patrick.
-
Drinking more than eight sugar-sweetened drinks a week increases the risk of cardiovascular diseases by up to 31%. pubmed.ncbi.nlm.nih.gov
It’s no surprise that sugar-sweetened drinks can contribute to weight gain, dental problems, and metabolic impairments. But emerging evidence suggests they can also harm your heart. A recent study found that consuming more than eight sugar-sweetened drinks weekly increases the risk of various cardiovascular diseases by as much as 31%.
Researchers investigated links between sugar intake and cardiovascular disease among nearly 70,000 people. They asked participants about their sugar intake from various sugar-sweetened foods and drinks. Then, using national disease registers, they ascertained the incidence of various cardiovascular diseases, including ischemic and hemorrhagic stroke, myocardial infarction (heart attack), heart failure, aortic stenosis (narrowing of the aorta), atrial fibrillation (abnormal heart rhythm), and abdominal aortic aneurysm (ballooning of the major blood vessel in the abdomen).
They found that the risk of developing cardiovascular disease varied according to disease type and sugar source. However, drinking more than eight sugar-sweetened beverages weekly carried the greatest risk, increasing a person’s chances of ischemic stroke by 19%, heart failure by 18%, atrial fibrillation by 11%, and abdominal aortic aneurysms by 31%.
The investigators posited that sugar in beverages is readily metabolized, increasing its potential for harm. Learn more about the health effects of sugar-sweetened beverages in our overview article.
-
High-protein breakfasts in teens may mitigate future heart disease risk by increasing gene expression associated with blood vessel growth and staving off inflammation. www.sciencedirect.com
Breakfast is often touted as the most important meal of the day. But for teenagers, the composition of that breakfast may be more critical than previously thought. A recent study found that eating a high-protein breakfast increases gene expression associated with cardiovascular health, potentially protecting teens against heart disease later in life.
The study included 30 teens who routinely skipped breakfast. For six months, 10 of the teens ate a normal-protein breakfast (10 grams of protein) daily, 10 ate a high-protein breakfast (30 grams of protein), and 10 continued skipping breakfast. The normal-protein and high-protein breakfasts both provided 350 calories. Researchers measured the teens' levels of microRNAs (small, non-coding RNA molecules that regulate gene expression) associated with higher cardiovascular disease risk.
They found no difference in miRNA levels among the three groups. However, they observed a significant pattern over time for one microRNA—miR-126-3p—which increased more in those eating high-protein breakfasts than those who skipped breakfast. miR-126-3p regulates angiogenesis (the formation of new blood vessels) and helps maintain blood vessel integrity. It also reduces inflammation—a driver of cardiovascular disease.
This small study suggests that eating a high-protein breakfast can have lasting effects on teens who regularly skip breakfast, potentially reducing their risk of cardiovascular disease later in life. Skipping breakfast coupled with late-night eating can have harmful effects on metabolic health, too. Learn more in this clip featuring Dr. Ruth Patterson.
-
The primary contributor to cardiovascular disease risk is simply age. Our blood vessels become thicker and less flexible as we get older, rendering them less efficient. However, a recent study found that creatine supplementation restores aspects of cardiovascular function, including blood vessel flexibility and efficiency, in older adults.
Researchers conducted a small pilot study involving 12 sedentary but healthy older adults. Half of the participants consumed 20 grams of creatine monohydrate daily for five days, followed by 5 grams daily for 23 days. The other half consumed a placebo for 28 days. The researchers measured aspects of the participants' cardiovascular health, including flow-mediated dilation (how flexible a blood vessel is), microvascular perfusion rates (how quickly and efficiently tiny blood vessels fill), blood glucose levels, and triglycerides.
They found that participants who consumed creatine experienced small but meaningful improvements in their cardiovascular markers, including increased flow-mediated dilation, improved microvascular perfusion rates, and decreased blood glucose and triglycerides. Those who consumed the placebo did not experience these beneficial effects, suggesting that creatine restored their cardiovascular function.
Creatine is a nitrogen-containing compound that plays an essential role in the recycling of ATP. It is widely used as a dietary supplement to build and maintain muscle mass. Although creatine is available in many forms, most of the research on the compound has focused on creatine monohydrate. Learn more about creatine in this clip featuring Dr. Stuart Phillips.
-
A daily cup of coffee could reduce your risk of heart disease and diabetes by half. academic.oup.com
Drinking your daily cup of coffee or tea might do more than give you a boost—it could lower your risk of developing multiple serious cardiometabolic conditions simultaneously, like diabetes, heart disease, or stroke. A recent study found that moderate coffee or caffeine consumption may cut your risk of cardiometabolic multimorbidity by as much as 50%.
Researchers analyzed data from more than 172,000 participants enrolled in the UK Biobank who had no cardiometabolic diseases at the start. Participants reported their coffee, tea, and caffeine consumption; about half provided blood samples for metabolic marker analysis.
They found that people who drank about three cups of coffee daily (or consumed 200 to 300 milligrams of caffeine daily) were 40% to 50% less likely to develop multiple cardiometabolic diseases than those who drank little or no caffeine. They also discovered that specific blood markers, such as certain lipid components, were linked to coffee and caffeine consumption and a lower risk of cardiometabolic conditions.
These findings suggest that moderate coffee or caffeine intake reduces the risk of developing cardiometabolic diseases but also slows their progression if they occur. Other evidence points to the many health benefits associated with coffee and caffeine, but it’s crucial to remember their effects on sleep. Learn more in this Aliquot featuring Drs. Guido Kroemer, Satchin Panda, Elissa Epel, Matthew Walker, and Rhonda Patrick
-
What are the optimal time-restricted eating patterns for cardiovascular wellness? pubmed.ncbi.nlm.nih.gov
Time-restricted eating is a dietary pattern that restricts the time during which a person eats to a specific window, such as a “16:8" pattern, where they fast for 16 hours a day and consume food only during the remaining eight hours. Evidence suggests that time-restricted eating improves cognitive function, supports weight loss, and reduces systemic inflammation. Findings from a recent review and meta-analysis suggest that time-restricted eating also reduces the risk of cardiovascular disease.
Researchers analyzed the findings of 33 studies involving 1,725 participants investigating the effects of time-restricted eating on markers of cardiovascular health. They conducted a sub-group analysis to determine how age, health characteristics, and eating patterns influenced the effects of time-restricted eating.
They found that the effects of time-restricted eating on cardiovascular disease varied according to a person’s risk factors, age, and when they ate. The table below presents their findings for the optimal time-restricted eating for different groups.
This meta-analysis and review identifies the optimal time-restricted eating interventions for blood pressure, obesity, lipids, and glucose. It effectively provides a best-practices guide for people interested in implementing time-restricted eating as a lifestyle modification to improve cardiovascular health. Learn more about time-restricted eating in this episode featuring Dr. Satchin Panda.
-
Poor cardiorespiratory fitness linked to 70 percent higher risk of premature death and 56 percent greater heart and cardiovascular disease risk. jamanetwork.com
Cardiorespiratory fitness is a measure of the body’s aerobic capacity – the ability to deliver oxygen to skeletal muscles – during sustained physical activity. A 2009 meta-analysis found that people with low cardiorespiratory fitness were 70 percent more likely to die prematurely and 56 percent more likely to experience a heart or cardiovascular disease-related event.
Researchers evaluated data from 33 studies examining connections between cardiorespiratory fitness and the risk of premature death from all causes (more than 102,000 participants) and combined heart disease and cardiovascular disease events (more than 84,000 participants). They used maximal aerobic capacity, measured in metabolic equivalent (MET) units, to estimate cardiorespiratory fitness. They grouped participants into three categories based on their cardiorespiratory fitness levels: low (<7.9 METs), intermediate (7.9-10.8 METs), and high (≥10.9 METs).
They found that for each 1-MET increase in maximal aerobic capacity (equivalent to a 1-kilometer per hour increase in running/jogging speed), the risk of death from all causes and heart disease/cardiovascular disease events. Compared to participants with high cardiorespiratory fitness, those with low cardiorespiratory fitness were 70 percent more likely to die prematurely and 56 percent more likely to experience a heart disease/cardiovascular disease event. However, even intermediate cardiorespiratory fitness conferred substantial benefits. Compared to participants with intermediate cardiorespiratory fitness, those with low cardiorespiratory fitness were 40 percent more likely to die prematurely and 47 percent more likely to experience a heart disease/cardiovascular disease event.
These findings demonstrate that having low cardiorespiratory fitness markedly increases one’s risk of dying prematurely or developing heart or cardiovascular disease. The most accurate way to assess cardiorespiratory fitness involves measuring maximal oxygen uptake, often referred to as VO2 max, during a graded exercise test in a laboratory, clinical, or research setting. However, online calculators, such as the World Fitness Level, can predict VO2 max based on various personal factors. Learn more about VO2 max and the World Fitness Level calculator in this episode featuring Dr. Martin Gibala.
-
Breastfeeding benefits mothers by promoting post-partum weight loss and reducing the risk of certain types of cancer later in life. A new study suggests that breastfeeding also supports maternal cardiometabolic health. Women who breastfed for at least six months were leaner and had lower blood pressure than those who didn’t.
Researchers conducted health check-ups on 160 mother-child pairs enrolled in Screening Tests to Predict Poor Outcomes of Pregnancy, a long-term study that assessed women’s risk for pregnancy complications. They assessed the women’s cardiometabolic health via blood pressure, body measurements, and serum metabolic markers (glucose and lipids). They determined breastfeeding duration via the children’s health records.
They found that the cardiometabolic health of women who breastfed for at least six months was considerably better than those who did not breastfeed, as evidenced by lower body mass index (BMI) and blood pressure. These differences persisted even after considering factors like BMI, socioeconomic status during early pregnancy, prenatal smoking, and maternal age during early pregnancy. In women who had experienced pregnancy complications (such as preeclampsia or gestational diabetes), breastfeeding for at least six months reduced blood pressure, insulin, and triglycerides, while increasing HDL cholesterol levels.
These findings suggest that breastfeeding for a minimum of six months benefits the cardiovascular health of mothers, particularly those who experienced pregnancy complications. They also highlight the importance of breastfeeding as a potential means to reduce the risk of cardiovascular issues in women following childbirth. However, the investigators conceded that this was a small study, potentially hindering its translatability to a broad audience. Learn more about the maternal benefits of breastfeeding in our overview article.
-
Pomegranate juice improves blood pressure and reduces arterial plaques in people with atherosclerosis. www.clinicalnutritionjournal.com
Pomegranate juice reduces symptoms associated with the narrowing of arteries that supply the brain, a small study has found. Patients who drank pomegranate juice for one year experienced improvements in blood pressure, antioxidant status, and carotid artery thickness (an indicator of the extent of plaque buildup in the arteries).
The study involved 19 people who had atherosclerosis with carotid artery stenosis, a condition in which the arteries that supply the brain thicken and narrow due to the accumulation of plaque. Ten of the participants drank 50 milliliters (about 1.7 ounces) of pomegranate juice daily for one year, while the remaining nine participants did not consume any pomegranate juice. The researchers assessed various aspects of the participants' cardiovascular health before, during, and after the intervention.
They found that several parameters of cardiovascular health improved after one year of pomegranate juice consumption. For example, the participants' carotid artery thickness decreased by up to 30 percent and their blood pressure decreased by 21 percent. In addition, their total antioxidant status increased by 130 percent. Participants who didn’t drink pomegranate juice did not experience these improvements, and in some cases, their cardiovascular measures worsened.
This small study shows that drinking pomegranate juice may improve symptoms associated with narrowing of the arteries. Pomegranates are rich in various bioactive polyphenols, including tannins, ellagic acid, and anthocyanins, that exert potent antioxidant, anti-inflammatory, or cardioprotective effects in humans.
-
Can chronic use of anti-inflammatory agents paradoxically promote chronic inflammation through compensatory host response? pubmed.ncbi.nlm.nih.gov
NSAIDs may promote a paradoxical pro-inflammatory effect, increasing the risk of blood clots and cardiovascular events.
Non-steroidal anti-inflammatory drugs, or NSAIDs, are among the most widely used drugs worldwide, available in both prescription and over-the-counter forms, such as aspirin, ibuprofen, naproxen, and others. Despite the drugs' anti-inflammatory effects, their chronic use is associated with a higher risk of acute clot-related cardiovascular events, such as heart attack, stroke, or deep-vein thrombosis. Authors of a 2005 article posited that NSAIDs induce a rebound effect that promotes inflammation, driving the formation of blood clots and predisposing a person to acute cardiovascular events.
Inflammation is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes. Inflammation initiates the clotting process and impairs the activity of natural anti-clotting mechanisms.
Most NSAIDs, with the exception of aspirin, dampen inflammation via the inhibition of cyclooxygenases, a family of pro-inflammatory enzymes. However, evidence from animal studies suggests that when these enzymes are inhibited, the body responds by producing more of the enzymes. The authors posited that by turning off the body’s natural inflammatory processes, NSAIDs might drive a compensatory response – ramping up the activity of pro-inflammatory pathways.
Lifestyle behaviors may reduce inflammation and the need for NSAIDs. For example, sauna use reduces levels of pro-inflammatory C-reactive protein and increases levels of anti-inflammatory protein interleukin (IL)-10. Similarly, cold exposure decreased the pro-inflammatory protein IL-2 and the inflammatory E2 series of prostaglandins while increasing the anti-inflammatory protein IL-10. Other lifestyle behaviors that may reduce inflammation include exercise, meditation, and dietary intake of polyphenols.
-
Dysregulated tryptophan metabolism contributes to abdominal aortic aneurysm formation in mice. (2017) www.eurekalert.org
From the article:
“Our data found a previously undescribed causative role for 3-hydroxyanthranilic acid (3-HAA), a product of tryptophan metabolism, in abdominal aortic aneurysm formation,” said Dr. Ming-Hui Zou, director of the Center for Molecular and Translational Medicine at Georgia State and a Georgia Research Alliance Eminent Scholar in Molecular Medicine. “We believe agents that alter tryptophan metabolism may have therapeutic potential for preventing or treating abdominal aortic aneurysm. Our findings suggest that reducing 3-HAA may be a new target for treating cardiovascular diseases.”
The kynurenine pathway is the major route for the metabolism of tryptophan, and other studies have found this pathway plays a key role in the increased prevalence of cardiovascular disease. The researchers sought to identify the role of the kynurenine pathway and its products in angiotensin II (AngII)-induced abdominal aortic aneurysm. AngII is a hormone that increases blood pressure by constricting the blood vessels and is the principal mediator for the development and progression of abdominal aortic aneurysm.
The researchers generated mice with genetic deficiencies by crossbreeding, and then infused the mice with AngII.
The study is the first to show that genetic deletion of indoleamine 2,3-dioxygenase (IDO) or the decrease in the gene expression of kynureninase (KNU) in the body restrained AngII-induced abdominal aortic aneurysm in mice deficient in apolipoprotein e.
In addition, the researchers made the discovery that 3-HAA was responsible for AngII-induced abdominal aortic aneurysm in the body.
-
Doses of omega‐3 fatty acid intake above the recommended 3 grams per day may be associated with additional benefits in lowering blood pressure www.ahajournals.org
Higher omega-3 fatty acid intake may be necessary to reduce blood pressure.
Nearly two-thirds of adults living in the United States have high blood pressure, defined as having a systolic pressure of 130 mmHg or higher or a diastolic pressure of 80 mmHg or higher. High blood pressure increases a person’s risk for heart disease and stroke and contributes to small vessel disease, a major risk factor for cardiovascular disease, dementia, and stroke. Although some evidence suggests that omega-3s reduce blood pressure, researchers have not identified the optimal dose necessary to achieve this effect. Findings of a recent meta-analysis suggests that 3 grams of omega-3 fatty acids daily reduce blood pressure.
Observational data suggest that omega-3 fatty acids, especially fish-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are cardioprotective. For example, a prospective study involving more than 20,000 healthy males found that those who ate one to two servings of fish twice a week had a lower risk of sudden cardiac death than those who ate fish less than once a month, likely due to the omega-3s found in fish. But the findings from the five decades of study have been remarkably inconsistent, with some studies showing benefits, and others not. Some of these inconsistencies have arisen from differences in study designs, which vary markedly in terms of study population, dose, and duration.
The authors of the analysis searched the scientific literature for randomized controlled trials investigating associations between omega-3 fatty acids and blood pressure. Then they filtered their findings based on a set of criteria designed to identify high-quality studies. Finally, they combined data from these high-quality studies and reanalyzed them so they could interpret the results on a large scale.
They identified 71 trials, involving nearly 5,000 participants. On average, those who consumed 2 to 3 grams of combined EPA and DHA daily experienced reductions in blood pressure of approximately 2 mm Hg (and as much as 3.5 mm Hg). Participants who had high blood pressure and consumed more than 3 grams of EPA and DHA daily experienced reductions of 4.5 mm Hg for those with hypertension, compared to about 2 mm Hg for those without. Higher doses (5 grams daily) of omega-3s did not confer any additional benefit, with blood pressure decreasing by approximately 4 mm Hg for those with hypertension and less than 1 mm Hg for those without.
These findings suggest that 3 grams of combined EPA and DHA daily is the optimal dose of omega-3 fatty acids necessary to achieve reductions in blood pressure. Learn more about the heart-health benefits of omega-3s in this episode featuring Dr. Bill Harris.
-
Drinking tea may reduce the risk of cardiovascular disease and premature death. journals.sagepub.com
Cardiovascular disease is the number one killer worldwide, claiming the lives of nearly 18 million people each year. Health experts estimate that more than 75 percent of all cardiovascular diseases are preventable through healthy lifestyle habits. Findings from a 2020 study suggest that drinking tea is a healthy lifestyle habit that reduces the risk of cardiovascular-related disease and death and all causes of premature death.
Teas – black, green, or white – are among the most popular beverages in the world. Their consumption is linked to a wide range of health benefits, including lower blood pressure, improved blood sugar regulation, and greater weight loss in people with obesity.
The researchers drew on data collected during the China-PAR project, an ongoing study of cardiovascular and metabolic disease risk among three cohorts of adults living in China. They used data from more than 100,000 participants to investigate links between tea consumption and cardiovascular-related disease and death, as well as all causes of premature death. Their analysis accounted for a wide range of demographic and lifestyle habits, including age, sex, family history, education, smoking, and dietary patterns, among others.
They found that roughly one-third of the participants were regular tea drinkers, consuming three or more tea drinks per week. Regular tea drinkers were 22 percent less likely to die from cardiovascular disease and 15 percent less likely to die from all causes of premature death. Drinking tea also appeared to extend healthspan – the number of years lived disease-free. Regular tea drinkers lived 1.41 years longer free of cardiovascular disease and had 1.26 years longer life expectancy at the index age of 50 years compared to non-drinkers.
These findings suggest that regular tea consumption reduces the risk of cardiovascular-related disease and death and all causes of premature death. Tea drinking may also extend the number of years a person lives disease-free.
Teas are rich in polyphenols – a broad class of bioactive plant-based compounds that confer beneficial properties to humans. Learn more about polyphenols in our overview article.
-
Omega-3s reduce risk of death from cardiovascular disease. pubmed.ncbi.nlm.nih.gov
The American Heart Association recommends that adults consume at least eight ounces of fish and shellfish each week, especially those that are rich in omega-3 fatty acids. Previous research supports the benefits of omega-3 consumption in preventing coronary heart disease and sudden cardiac death; however, additional research is needed to support the benefits of omega-3s for other cardiovascular disorders. Investigators reviewed the molecular, clinical, and epidemiological evidence for the effects of omega-3s on cardiovascular disease.
Omega-3 fatty acids cannot be produced by the body and must be consumed in the diet. Major food sources of omega-3s include fatty fish, which are rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Plant sources of omega-3s include flax seeds, chia seeds, and walnuts, but the predominant omega-3 fat in these foods is alpha-linolenic acid, which must be converted to EPA before it can be used by the body. Omega-3s and their metabolites improve cardiovascular health through altering the composition of cell membranes and regulating gene expression, among other functions.
The authors searched the literature for randomized controlled trials, in which researchers randomly assign participants to an intervention or a comparable control treatment, and observational studies, which observe a group of participants at a single time point. Randomized controlled trials are suitable for identifying cause-and-effect relationships, but because observational studies measure associations between behavior and health, they are not. Review papers aggregate data from previous research and compare results, a process that can be difficult because dose, sample size, and participant characteristics vary among studies.
The analysis revealed that the dose of omega-3s utilized in the randomized controlled trials ranged from 376 milligrams to 1,800 milligrams. Some of these trials instructed participants to consume the recommended two servings of fish per week. Data from these trials showed that omega-3 consumption decreased cardiovascular disease, with risk reductions ranging from two to 32 percent among trials; however, some trials did not find a benefit of omega-3 consumption for reducing the risk of death from cardiovascular disease. In observational studies, the benefits of omega-3 consumption were strongest for coronary heart disease and sudden cardiac death, confirming previous reports. Evidence from the randomized controlled trials and observational studies was inadequate to support assertions that consumption of omega-3 fatty acids reduce the risk of heart attack, stroke, atrial fibrillation, arrhythmias, and heart failure.
Current data support the consumption of omega-3s for reduced risk of death from cardiovascular disease. The authors concluded that future research should explore the effects of dose, source (i.e., seafood or supplements; plant or animal), and other molecular, physiological, and clinical effects.
-
Omega-3 fats reduce inflammation and cardiovascular disease risk. www.atherosclerosis-journal.com
Treatment strategies for cardiovascular disease that reduce inflammation are an important area of research. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) both reduce inflammation by decreasing pro-inflammatory cytokines and increasing anti-inflammatory compounds, although EPA may be more cardioprotective. In a recent report, investigators tested the effects of EPA and DHA supplementation on vascular inflammation, a mediator of atherosclerosis.
In epidemiological research, higher fish consumption is associated with lower risk of cardiovascular disease and death. In clinical trials, EPA supplementation reduced major cardiovascular events in those with high cholesterol; however, the role of inflammation in this research is unclear.
In the first experiment, participants consumed 4 grams of either EPA only, DHA only, EPA + DHA (2:1 ratio), or a placebo for 30 days. They completed a health assessment and gave a sample of blood before and after treatment. The researchers used the serum collected from participants to culture human vascular cells and measured the response of those cells to an inflammatory stimulus. In a second experiment of acute inflammation, researchers treated mice with EPA (600 milligrams per kilogram of body weight), DHA (600 milligrams per kilogram body weight), olive oil, or no treatment daily for 30 days. They measured several markers of vascular inflammation and blood lipids before and after treatment. Finally, in a third experiment of chronic inflammation, the researchers fed mice a heart disease-promoting diet for 16 weeks. During the final eight weeks of the diet, they treated mice with the same EPA, DHA, olive oil, or no treatment conditions as the second experiment and measured markers of atherosclerosis and blood lipids.
In humans, EPA supplementation reduced markers of vascular inflammation better than DHA only or fish oil. In mice from the second experiment, both EPA and DHA supplementation significantly reduced multiple markers of vascular inflammation without affecting cholesterol and triglyceride levels. EPA was more effective in reducing inflammation than DHA. In mice from the third experiment, DHA and EPA both reduced cholesterol and triglyceride levels, with DHA being more effective. EPA supplementation reduced multiple markers of vascular inflammation; however, neither treatment improved markers of atherosclerosis.
The authors concluded the high-dose omega-3 supplementation can reduce vascular inflammation at early and late stages of cardiovascular disease. They also noted that the small sample size of their study may have limited their results and suggested that EPA supplementation should be tested in larger trials.
Learn more about cholesterol and atherosclerosis in this episode featuring expert Dr. Ronald Krauss.
-
Exercise reverses effects of sleep deprivation on cardiovascular health. link.springer.com
Just one night of sleep deprivation can impair arterial function, and chronically poor sleep increases the risk of developing cardiovascular disease. Conversely, high intensity interval exercise can improve multiple markers of heart health. In this report, researchers tested the effects of exercise on flow mediated dilation, a measure of vascular function, in sleep-deprived participants.
Flow mediated dilation is a measure of how wide an artery expands in response to increased blood flow. Meals high in fat normally cause dysfunction in blood vessels, impairing their ability to dilate. Previous research reports that high intensity exercise improves flow mediated dilation following a meal.
Fifteen healthy active men (average age, 31 years) completed three nights of sleep for this study. The first night, participants slept a full eight hours and ate a high-fat test meal the next morning. The second night, participants slept a full eight hours, then performed high intensity interval training before eating. The third night, participants slept three and one half hours or less, then performed the same exercise and ate the same meal. The researchers measured flow mediated dilation at multiple time points.
After comparing the post-meal flow mediated dilation following a full night of sleep and a full night of sleep plus exercise, the authors found that exercise improved arterial function. Impressively, the benefit of exercise remained following a night of sleep deprivation. Flow mediated dilation rates were similar between exercise conditions regardless of sleep duration the night before.
The authors concluded that high intensity exercise improves artery function and that these benefits remain even after a night of sleep deprivation. However, they recommended that people get a full night of sleep before strenuous exercise to get the most benefit.
-
A woman's cardiovascular health influences her children's cardiovascular health. www.sciencedaily.com
Cardiovascular disease is an umbrella term that includes coronary artery disease, heart attack, and stroke, among others. Together, these diseases are the primary cause of death among people living in the United States. Findings from a recent study indicate that a woman’s cardiovascular health influences her children’s cardiovascular health.
The study drew on data from nearly 6,000 mother-father-child triads of participants enrolled in the Framingham Heart Study, a long-term, ongoing study of cardiovascular disease risk among people living in Framingham, Massachusetts. The authors of the study scored the participants' cardiovascular health according to the American Heart Association scoring system, ranking them as having poor, intermediate, or ideal cardiovascular health.
The study spanned nearly 72,000 person-years, during which 718 cardiovascular events occurred. Children of mothers whose cardiovascular health was ideal lived nine more years free of cardiovascular disease than those whose mothers had poor cardiovascular health. Onset of poor cardiovascular health occurred earlier among children whose mothers had poor cardiovascular health, with nearly twice the risk of early-onset cardiovascular disease compared with children of women with ideal cardiovascular health.
These findings suggest that a woman’s cardiovascular health can predict that of her children’s and underscore the importance of public health and clinical interventions designed to improve cardiovascular fitness.
-
Insulin resistance increases a person’s risk of developing type 2 diabetes and atherosclerosis. Findings from a new study suggest that lean beef as part of a healthy dietary pattern may reduce this risk in people with insulin resistance.
The randomized, crossover, controlled trial, which involved 23 men and women (average age, 44 years) who were overweight or obese and had been diagnosed with prediabetes and/or metabolic syndrome, compared the effects of two dietary patterns on insulin sensitivity and cardiometabolic risk markers. One diet followed the USDA Healthy US-Style Eating Pattern, which is low in saturated fat and provides less than 40 grams of red meat per day. The other diet mirrored the first but provided an additional 150 grams (roughly five ounces) of lean beef per day as a replacement for carbohydrates (of nearly equal caloric content). Each participant consumed the two diets for four weeks, separated by a two-week washout period. At the end of each four-week diet period, the authors of the study assessed the participants' responses to the respective diets via measures of insulin sensitivity, lipid profiles, inflammation (measured by C-reactive protein), and blood pressure.
The participants' responses to the diets did not differ significantly with the exception of a notable increase in larger, more buoyant low-density lipoprotein (LDL) particles when consuming the higher beef content diet. LDLs are formed in the liver and transport lipid molecules to cells. Often referred to as the “bad cholesterol,” LDLs can drive cardiovascular disease if they become oxidized within the walls of arteries. LDL particles exist in different sizes, ranging from large, “fluffy” molecules to small, dense molecules.
Scientific evidence suggests that small LDL particles are more susceptible to oxidative modification. Conversely, more buoyant particles are associated with a reduced risk of atherosclerotic disease. Learn more about LDL particles and disease risk in this podcast featuring Dr. Ronald Krauss.
Note: This study has industry funding sources, see press release for details.
-
Current options for addressing cardiovascular complications of COVID-19. www.frontiersin.org
Current options for addressing cardiovascular complications of COVID-19. Although COVID-19 commonly presents as a respiratory infection, the illness targets multiple organ systems, including the cardiovascular system. In one study, patients with cardiac injury accounted for nearly one-fourth of severe cases of COVID-19. A recent article describes the inflammatory aspects of COVID-19, identifies current therapies used in regard to cardiac injury, and suggests guidelines for clinical practice.
The authors of the article identify three primary drivers of cardiac injury in COVID-19: direct viral infection to cardiac tissues, cytokine storm, and aggravation of preexisting cardiovascular disease. They posited that direct infection of cardiac tissue might be related to increased expression of angiotensin-converting enzymes-2 (ACE2) receptors in the heart. SARS-CoV-2, the virus that causes COVID-19, exploits ACE2 to gain entry into cells. Cytokine storm can occur in COVID-19 when SARS-CoV-2 infection provokes an excessive immune response that, in turn, induces multiple organ dysfunction. COVID-19 infection severely burdens the cardiovascular system, aggravating preexisting cardiovascular morbidities and triggering grave events, such as exacerbation of heart failure or acute coronary syndromes.
The authors also suggest that targeting inflammation – the underlying cause of the aforementioned drivers of cardiac injury – is critical to preserving cardiac health in COVID-19. They identify various drugs currently in use that target the central pathways associated with inflammation; balance the body’s immune responses; and reduce inflammation.
-
FDA approves use of drug to reduce risk of cardiovascular events in certain adult patient groups www.reuters.com
Cardiovascular disease is the number one cause of death of people living in the United States (US). Having elevated (abnormal) triglyceride levels may contribute to atherosclerosis, which increases the risk of cardiovascular disease. The US Food and Drug Administration has approved the use of a drug to reduce the risk of cardiovascular events in adults who have elevated triglyceride levels.
The drug, called Vascepa (icosapent ethyl), reduces blood triglyceride levels by one-third when accompanied by low-fat, low-cholesterol dietary modification. It has been shown to reduce the rate of heart attacks, strokes, and other cardiovascular events by 25 percent compared to a placebo.
Candidates for Vascepa therapy must have triglyceride levels of 150 milligrams per deciliter or higher. They should also have established cardiovascular disease or type 2 diabetes and two or more additional cardiovascular disease risk factors.
The active ingredient in Vascepa is eicosapentaenoic acid, a type of omega-3 fatty acid derived from fish oil. The drug, which is taken orally, has demonstrated a safety profile similar to placebos. Adverse events associated with Vascepa include atrial fibrillation and increased risk of bleeding. People who are allergic to fish or shellfish may be at risk for allergic reactions to Vascepa.