Salvatore Carbone, PhD, MS, discusses dietary interventions to reduce cardio metabolic risk.
um it's with great pleasure to welcome to our grand rounds for sent era. Uh dr Salvatori Carboni. Um Dr Carboni is an assistant professor at the department of kinesiology and Health Sciences. With an affiliate appointment at holly heart center at Virginia Commonwealth University. Uh He obtained his bachelor of Science and nutrition and diabetics at Sapienza University in Rome. Then he had completed his master's in cellular and molecular nutrition, also in italy and had a PhD in molecular medicine and metabolism at Sapienza University of Rome. His research investigates the role of different dietary interventions and patients with obesity and heart failure. Reserve ejection fraction is currently funded by his Career Development Award from the American Heart Association. He is also investigating the effect of um as the LT two inhibitors in patients with Type two diabetes and heart failure with reduced ejection fraction, for which He has received a mentor clinical and population research award, also from the American Heart Association. He has published more than 120 manuscripts in peer reviewed journals and wrote more than us to book chapters. He is a member of the research committee of the American Society for parental and entered nutrition aspen. And he's a chair elect of the Energy and MAC near nutrient metabolism research at the American Society for nutrition. He was recently awarded as highly cited author by the Mayo Clinic Proceedings and served as a peer reviewer for more than 50 journals including Lancet circulation Jack Jack Heart failure. An american journalist, complete nutrition is also associate editor of the cardiovascular section of the journal diabetes metabolism research and reviewers. Um Dr Carboni will talk to us today about dietary interventions to reduce argument. Diabolic risk making the case for precision nutrition. Um thank you for joining us Dr Carbone and everybody. And we look forward to your talk today. Good morning everyone. Thank you very much that dr Yehia for this uh kind introduction. Uh and for inviting. Thank you also to amy for coordinating this presentation today. It's really a pleasure to be here. And I hope that by the end of this presentation our commitment to you, that nutrition is really a powerful tool that we have to potentially prevent and treat many cardio metabolic diseases. But I will say that there's also a lot of things that we still don't know exactly about nutrition. And so that's why I think it's an important time to work in this field, particularly research because there's a lot of questions and they need an answer. I don't have any financial disclosure literally to industry. But this I just wanted to mention that I will discuss some data that I've been collecting a BCU. And this was funded by uh an H. A. Award. I really don't think I need to spend much time on this line. This was pre covid 19 clearly. But you can see that heart disease remains the leading cause of death in the United States. And so despite uh you know, several improvements from ecological approaches that have, you know, improved that. We've mid normal discoveries how hard this is remain the leading cause of death. Now, when you actually look at cardiovascular cardiovascular disease related mortality, stroke as well as track to that, it is related mortality. In the last few years, there's been a number of studies showing that party specific dietary factors as the one listed here in this pan. In this figure are associated with approximately 45% of all cardio metabolic death in the United States. Uh So this is really a dramatic number, suggesting that if we're able to improve this dietary components in the night of americans, we could potentially prevent, you know, 45% of cardio, metabolic uh metabolic um importantly, these are all adjusted by caloric intake, suggesting that, for instance, uh higher consumption of sodium independent, whether you have a low calorie diet or a high calorie dive, it's still associated with more detrimental effects on cardiovascular health. On the other hand, having a high nuts and high seats consumption section has to stay with the more feral cardiovascular health independent of the amount of calories that we eat. And I think this is an important point and something that will discuss um in detail today. One thing that I've noticed when I moved to the United States is now it's been a little over seven years is that when I'm not here and I noticed uh some what I would say an obsession with calories. Um, and in fact when you actually look even a demonstration facts, uh, there is a, there's a very large number here that suggests the amount of calories that one serving has or the what is the number of calories that the whole container has? But there is this, you know, counting calories. It's important. But is it really that important? Like this? The only thing that we should look at or maybe quality of diet also plays a major role and perhaps even a more important role than just counting calories. And so this is I think an important question to answer. And I will tell you that I don't think we have definitely answer, but we do have some trials that try to answer this question and perhaps can give you some uh, some additional insights in the next few slides. So one of the very few very uh well controlled, very well conducted randomized controlled trial that investigated the effect of quality, different quality of different diets was the direct study that was published in 2000 and eight in the new England Journal of Medicine where patients with overweight and obesity were randomized to three different diets. A lot of a diet with the goal of achieving less than 30 of total fat in the diet. Uh Mediterranean diet, which was sort of like a uh made high fat diet, reaching a healthy fat and saturated fatty acid. And then it was a little car, a little card doctor And by the end of the 24 months, which was the direction of the study, as you can see here, despite having similar caloric intake, so similar calories, there is a significant different effect on weight loss. Uh the low fat diet was the one with uh you know, the less education, the one with the lower effect on a body weight. While both the Haifa diet, the high UFA diet, the mediterranean diet and the low carb high fat diet. Actually, we're the most powerful in terms of achieving weight loss, suggesting again that despite consuming similar caloric intake, the quality of the food that we actually eating makes a really big difference, but not only with loss, we know that we lost is important, but it's not just the most important thing. We need to look at the effect of nutrition and generally speaking to all therapies on cardiovascular risk factors. And when you look at also, here are the lipid profile and the glycemic control. You can see that the mediterranean diet tends to be a little more favorable in terms of reduction LDL cholesterol, uh not change, not different, significant difference really on regularly arrived between the mediterranean diet and the low card diet, but definitely better than the low fat diet. And then something that I think is really remarkable in fact. And you can see here in Orange with for the military and eyes in patients with diabetes. In the direct study, there was a major significant improvements in uh fasting glucose fasting insulin as well as improvement in oh my I. R. Which is an index of insulin resistance. Um And I think it's important also to point out that the reduction in 3233 million mg produce a later in fasting glucose. It's not just a statistical significant difference, but it's also a very clinically relevant uh effect. Again, suggesting equality is important. Equality matters. What about weight loss alone? And what about specifically low fat dieting used weight loss on what is the role of this on uh cardiovascular outcomes. Until 2013, we really didn't have any cardiovascular outcome study that really could answer the question of whether weight loss was efficacious in reducing cardiovascular events. We knew from prior studies, including the one that I just showed you the direct study that weight loss can improve several cardiovascular risk factor, but is that reduction improvement in risk factors able to eventually improve cardiovascular events, which is what we really want in our patients. And so they look at it was and then engage funded study That looked at the effect of life styling intensive lifestyle intervention, which included weight loss, caloric restriction with a low fat diet and physical activity in patients with type two diabetes. As you can see here by the end of the study, the intervention in Blue was associated with more favorable, you know, with a significant reduction in body weight improvements in cardiorespiratory fitness, uh improvements in Western Conference as well as um small but significant statistically significant improvement in uh hemoglobin A one C. Um And so from a cardio metabolic risk factor, you could say that there are some improvements. They're not, I would say dramatic improvements, but still I would say that there are some changes that will be considered to be favorable. However, When they looked at cardiovascular events, as you can see here, there's a very neutral odds ratio .95 suggestion it really way lost alone in this case did not improve cardiovascular events. And this was quite disappointing because we always thought that we lost would be the answer to all our problems formal cardiovascular standpoint. But that was not the case. Now, the look ahead investigators conducted a post talk analysis of the study. So this needs to be considered exploratory because it was not a pre specified analysis. But what they show here in this publication is that if independent on whether patients were assigned to the intensive lifestyle intervention or to the control group, If they were able to lose 10 or more of their body of their initial body weight within the first year of intervention, There was about 20-24 relative risk reduction uh for the primary and the secondary cardiovascular endpoints, suggesting that maybe in the whole world group, there was not a benefit. But if you take the ones that only lost 10 or more than their body weight within the first year, from the randomization, you were able to achieve a significant reduction in in outcomes. And so this suggests that really we should aim with our patients uh Reducing body weight and really working really hard. Trying to achieve that weight loss of 10 at least 10 of body within the first year. But what about dr intervention that do not necessarily cut calories? So they're not necessarily including calorie restriction. But they modulate quality of their diet, particularly. We know that over the last few decades in the world, while they're always been a debate or whether we should eat a low fat diet compared to the haifa diet and if it's a haifa diet, what kind of fat you eat. And so one of the initial evidence uh to support uh to at least two shows some important data related to the quality of diet. The effect of the quality of diet on cardiovascular lands was the wh I Women's Health Initiative study. As you know, it is a very large studies and I expanded which included a number of trials. Within the same study. Uh One of the three controlled trials of the w child was a dietary modification trial. They look at the events of the effect of low fat diet on cancer, but also in coronary heart disease. And today we will focus for the purpose of this stock on the coronary heart disease component. Um So there's a lot of a diet which with The Loofa died in wh I was a guide which was aimed at reducing calories from fat to less than 20 and the less than 7% from saturated fact, the goal was also to increase percent vegetables to five servings per day, at least grains to six servings per day. And this was uh proposed to achieve this using 18 recession for the first year. So very frequent educational session and then quarterly thereafter. Um And again, initial evidence suggested that low fat diet could improve uh LDL cholesterol, We know the LDL cholesterol is a major contributor to coronary heart disease. So, by reducing LDL perhaps we were able to reduce coronary heart disease. Well, there was not necessarily the case. In fact, a lot of a diet in the wh i this is particularly in post menopausal, women did not have any effect on coronary heart disease. As you can see the, you know, the it couldn't be, you know, couldn't find more neutral, has a ratio really, and uh the interventions dark in black and then in comparison in gray really, there is no significant difference between the low fat diet and the higher fat diet. Um Now, to be fair, within the study, they were not able to patients were not able to achieve that 20 of less than 20 calories from fat, but in fact the amount of fat they were eating was approximately 25 26%. which I think is still an important finding. Um, well, we need to do a nutrition is to propose document conventions that are affected, but there are also sustainable in the long term. And so if one intervention is really not sustainable for the rest of the life for the individuals, it's really, I'm not sure if it's really um appropriate. What about diabetes? There's been a lot of uh, you know, research trying to understand whether low fat diet could prevent incidents diabetes. Uh, but again, when you actually look at the wh I data, low fat diet with neutral, also on incident diabetes, which was defined here as initiation of diabetes therapies About in the same year, is actually the first publication of the Leon died. Heart study came in the Lancet Believers 1990 for uh where there were patients with acute in my time of discharge were being randomized to a Mediterranean diet or a control group would actually control group was essentially just being followed up. But they're typical, you know, by the clinical provided. And with the mediterranean diet, which is a diet rich in unsaturated fats, healthy fat, reduce the whole grains, very little consumption of animal products was associated with a remarkable reduction in uh cardiovascular events uh to the extent that the G. S. M. G. The data safety monitoring board interrupted the study early to just because there was an overwhelming benefit of the military in and dying in these patients. Now, the data were just so good as you can see here and also the cursor. But very early throughout the study that many people did not believe the data, they thought that this was just too good to be true. Uh And so now I'll show you some more recent randomized trials with a similar intervention. Not exactly the same by the similar intervention. And so now we are already showed you that the W. H. I. A. A low fat diet was not effective in the the online in leon died. Heart study high high fat diet. I would say the mediterranean diet was effective in reducing events. But now this was an old study. Can we actually showed up in a more recent trial in the same years. So late nineties early two thousands uh came coming from Greece particularly showing that individuals who were more adherent to mediterranean diet using mediterranean diet score. So they were just asked to you know, answer philosophy questionnaires. Uh those who were more adherent humanitarian brides were the ones with the lower risk for cardiovascular disease and cardiovascular related deaths. And so this suggests that perhaps this military and dietary pattern could potentially reduce cardiovascular events. But as we know, this is just an observational study which was done on using questionnaire. So we definitely need a randomized controlled trial to test uh, what to test this hypothesis. And so initially, uh, in 2013, the Freedom It study was published. The president is a multi center study done in spain is randomized control trial where patients with cardiovascular risk factor, but without an established cardiovascular disease. So this was a primary prevention study were randomized to three diets. One was a mediterranean diet where there was supplemented with extra virgin olive oil. The study team uh provided a leader of extra virgin olive oil uh per week to the study participants with the goal of consuming at least 4 50 g. So at least four tablespoons of extra virgin olive oil per day without providing any after limit so they could eat more if they wanted to. The second group was assigned humanitarian died plus free provision of three nuts, which included walnuts, almonds and hazelnuts. And then the third group was group randomized the lava die, which at the time that the parliament started was designed. There was was being recommended by the american heart association. So here when they compared the control diet, which was a little fat diet with the two diet, the extra virgin olive oil diet. And then that's diet on the primary composite endpoint of academy stroke or death from cardiovascular disease. The mediterranean diet, both with that's an extra virgin olive oil, presents a significant reduction in the primary endpoint. But by approximately 30% relative risk reduction, which was really impressive. And it was again similar to the one die hard study. The study was interrupted early by the D. S. M. B. Because of the overwhelming benefit. But what about diabetes? Similarly, the diabetes uh incident diabetes was also reduced by approximately 36 in the Mediterranean Diet supplemented with extra virgin olive oil. And what is extremely important of this study is that there were no there was no difference in color in caloric intake from baseline to the end of the trial. So this was a study that did not recommend weight loss or at least that was not the primary goal of the study. And so the goal of this study was to improve the quality of the diet by particularly increasing the consumption of food reaching healthy fat. So a high healthy fat diet. Um and something also an important point I would like to make. As you can see here, there was no reduction, dietary cholesterol. And for several years we've been thought also when I was in school that dietary cholesterol, it's a major driver for plasma cholesterol. In reality now we know that dietary cholesterol does not necessarily reflect plasma cholesterol. In fact, dietary guidelines don't recommend the reduction of the dietary cholesterol anymore. But perhaps what we should focus more is the consumption of fat in the diet and the distribution of the status. And as you can see here, this was a very high fat diet. We're talking about 41, you know, some patients up to 46 of calories from fact, so definitely I think this is uh this was a very important study that really changed the way we approach to nutrition research and not just thinking about calorie restriction. Now, to be fair, the president study was initially published in 2013 in 2018. It was retracted and republished on the same day because there were funds an issue in some centers in which the randomization was not performed uh Well. And so the data that are presented today where they re analyzed data and republished data in 2018, which essentially didn't really change the results. But I think that that's a limitation to mention. And of course, the President study was done in Spain. We would I think it's very important to do a President like study in the United States. Considering the baseline diets in the United States, it's very different from a typical diet in Spain and whether these effects could be replicated. The United States, I think needs to be from the state. So we look at to unsaturated fatty acid. When I first joined this year, I was very lucky to have really great mentors and collaborators like doctor about recruiting me here. Dr Van Cast and doctor told we're both clinicians and basic scientists of translational scientist really that allow me to work with their patients and in the lab with them to start collecting data about dietary Um habits in patients they have a disease called heart failure, preserved ejection fraction or half bath, which accounts for about 50 of patients with heart failure. And it's very has very very limited therapeutic strategies. And so what we what I did essentially looked at some patients that were enrolled in some trials from doctors doctors about in Vantaa. So, and look at the battery habits using a doctor to recall what we found I think was very interesting was that that patients were eating the higher amount of unsaturated fats. So food reaching, unsaturated fat are typically olive oil, canola oil, avocado nuts, fatty fish like salmon, mackerel. We're the ones we had a higher exercise capacity measure with the peak oxygen consumption. With a maximum cardiopulmonary exercise testing. They had a better body composition, so more muscle mass and a better cardiac diastolic function. And we know that in patients with half bath, diastolic dysfunction is one of the major cause of their uh you know, they're exercise intolerance. In the meantime, we did a randomized trial and nice um where we basically randomized mice to either eating a Western diet, which is a very high in fat and particularly bad fat, saturated fat and low in good fat. And that high unsaturated fatty acid. Guy. These two diets at the exact same amount of calories, the exact same amount of total fat. But the major difference was the composition of fat. This one was rich in healthy fat and this one, the western diet was reaching unhealthy fat and very low in healthy fat. We followed this my score eight weeks, which is equal to several years in humans. What we found is that actually the Western diet that might became obese and developed severe cardiac dysfunction, particular. Their relaxation of the heart was impaired while the woman spent with the high end security fatty acid diet. Despite consuming the same amount of calories which I was measuring almost every day. There had a preserved cardio function and they did not gain way to not develop obesity. So again suggesting that eating the same calories, it's not necessarily the same if the quality of the guide is different. But this preliminary data led us to develop what we call the UFA preserve pilot study where Rufus does for unsaturated fatty acid in which the population in Richmond Virginia, we want you to see whether we were even able to change their diet and perhaps introduce food in their diet and we're not typical of the typical american diet. And so one of those boys for reasons extra virgin olive oil. So we designed the pilot studies with a single arm open label study where we were really asking patients to change their diet. And uh we give them similar to the pediment recommendation on the minimum amount of food that they were supposed to eat without any upper limit. So we said you have to eat at least four tablespoons of the of extra virgin olive oil to be in the study. But if you want to eat five or six or seven, please go ahead and do that. There is really no upper limit similar for canola oil, unsalted nuts. If we have patients who could not eat any of this, then we will recommend some substitutes such as seeds of locality and fatty fish. But we're encouraging patients to stick with. Our first choices. What we found is that in patients um here in Richmond Virginia, we were able to change their diet and to this the left panel here um this year data obtained from a doctor recall and you can see that there was a significant increase in unsaturated fatty acid consumption. This was particularly driven by an increase in mono unsaturated fatty acids to move to which is the typical movie in our diet was Oleic acid, which you can find in these foods. And so in that sense that this was the one was increased the most. But in addition to just reported that you re engage, we also measure plasma fatty acid. So we're also able to show that even the plasma of unsaturated fatty acid, particularly folic acid, was significantly increase. So we didn't just have a subjective memory based tool like a doctor recall. But we also had an objective operator independent marker to show that actually patients were eating more health effects. We also did some exploratory analysis and we actually saw there was a favorable changes trends toward improvements in exercise capacity, exercise, functional capacity measures exercise, stand and oxygen pulse which is a sort of a surrogate for cardiac output. So um this was clearly exploratory is more simple size. But this suggests that perhaps there are some benefits of these nutrients on in patients with will have passed. Very lucky to have a V. C. U. Uh Dr kelly who is now the chair of endocrinology. But it comes from the NIH has done extensive work looking at the metabolic flexibility or basically investigating the effect of data interventions of pharmacologic interventions on the ability to switch from glucose to a liquid liquid substrate during an overnight fasting. So in healthy individuals, when you give them a meal before going to bed, this is how their our cue the respiratory portion, which is the ratio between the carbon dioxide production oxygen consumption looks like. And then overnight, because there is a fasting, the RQ goes down suggesting a greater utilization of fat. And then in the morning it goes it goes back up because there is production of glucose from the liver. Now, this is what happens in patients who are healthy and in this case in the red line, those who have insulin resistance. So if you are able to show a reduction of the overall RQ, it suggested a better utilization of fat uh in a population. And so what we were able to show in our study is that within 12 weeks from the intervention with a high healthy fat diet, patients were actually able to use fat better. Uh and so this was a significant statistically significant improvement, suggesting a greater utilization of fatty acid in an over uh during an overnight fasting. How do we measure this? We have what is called the metabolic chamber Or a whole room indirect calorie meter, which is essentially like a hospital room. That is however, uh, lot and measures all the oxygen consumption and all the carbon dioxide production in the room throughout the duration of the study. So patients were in the room for over 14 hours And that were basically able to measure every 60 seconds. What is the oxygen consumption and the carbon dioxide production of the individual. And then based on that we can calculate respiratory question also known as respiratory exchange ratio um as well as energy expenditure such as a resting metabolic rate. So this potential beneficial effect of bacteria and saturated fatty acid lead us to develop a randomized trial that is currently ongoing at VCU. This was funded by the H. A. And this is the study I was mentioning earlier during my presentation which were randomizing now patients with obesity and have path to either um uh Rufus supplementation diet. So we're using a similar intervention from our very first pilot data or to what is the standard of care cardio nutrition clinic at this you which focuses on a really for following the directive guidelines for americans with a particular focus on sodium control. After 12 weeks we have a washout period of six weeks and then there is a cross over to the to the other together group. And one of the idea is that by increasing the consumption of this healthy fat, we could potentially improve body composition, cardiac function and possibly cardio respiratory fitness as a measure of exercise capacity For those who are particularly interested in the topic of nutrition in heart failure. We recently were brought a few review articles or editorials that really discussed the evidence of probably the last 50 years related to nutrition of heart failure. So for those who are interested, um, these are all these are all open access uh study articles that you can read now. I cannot do, I could not do a talk on nutrition intervention if I don't talk about without talking about a dash diet. The dash diet, which is placed for dietary approaches to stop hypertension, was one of the first evidence to show that died alone has a remarkable effect on controlling blood pressure. And what they basically found is that in the dash diet patients were eating a higher amount of a lower amount of sodium and a higher amount of food reaching potassium, such as fruits and vegetables could present a dramatic reduction in systolic as well as the diastolic blood pressure. Um and this was an absence of changes in physical activity. So supporting the concept of nutrition quality in this case, because we're talking about sodium and potassium that really do not provide calories can have a remarkable effect on cardiovascular health in this case blood pressure. But I think what's also very important is that the higher the sodium intake was a baseline. The higher was the potential improvements in the diet. And so I think it's important when we recommend a specific sodium restriction of sodium control diet is to investigate whether what is their baseline data intake and perhaps even just by reducing by one grand, by 1000 mg of sodium could be already a great girl and avoid going from seven g of sodium to two g of sodium in a patient because that really changes the flavor. And you know how the food tastes and it could potentially result in reduced adherence. So I think we need to do a better job in analyzing diet of our patients to begin with. To potentially then do a specific intervention. Now, there's been also a lot of interest over the last few years about a low carb, high protein diet. And uh although we don't have a very strong, we don't we don't have a very well conducted randomized control trial. Epidemiologic data actually suggests that low carb here in um it's a blue here in the fourth quartile, the patients were eating the lower carbon, a higher protein intake within the same diet, were the ones represented a highly risk for mortality. And so this this epidemiologic study really suggested that low carb high protein doesn't really seem really to be beneficial. And in fact there is a potential for harm by increasing all cause mortality as a result of that epidemiologic studies and many others. To be fair to be honest, uh the L. A. The National lipid association released a scientific statement where they really suggests that low intake of carbohydrates as well as very high intakes of carbohydrates have been associated with all cause mortality, cardiovascular mortality, as well as cancer mortality in the general population, with the potential harm in the in the position statements. So today we really don't have evidence to support the use of uh low carb high protein diet more recently. Actually, there's been a growing interest in understanding the role of the circadian clock within um and how it interconnects with the nutrition. And the idea is that, you know, within our 24 hour day, there are tons of the day in which our bodies more predisposed to specific activities including food and nutrition. And this in which perhaps we should not feed our body because that's not the purpose of our circadian clock, but it's not necessarily the case. And this is there a lot of research is currently on going to understand whether that's really true. And uh and so with that regard, there's been a major interest in the role of intermittent fasting in improving cardio metabolic disease, kind of metabolic health. But when you hear the word intermittent fasting, remember that it really doesn't mean much unless you specify with form of intermittent fasting you're exactly referring to. And so there are several different forms of intermittent fasting. One is a time restricted feeding one is a 52 diet and one is the after net day fasting. It is important to differentiate, differentiate within this three because clinical trials have used different strategies that could potentially have different results. So the time restricted feeling is uh the one in which individuals are recommended to eat only during a specific time and fasting for the remaining hours. There is really typically no counting calories required. Uh and individuals are allowed to drink non caloric beverages, including coffee. The fact to diet is a not very common, but still, there are some data on that one as well that involves too fast days and which is very limited caloric intake from 0 to $800 per week. And then the rest of the days are limited intake. They also called Feast days. And then there's the alternate day fasting in that involves a fast day that goes from 0 to 100 calories. Typically an aluminum intake day, Feast day, which you say, okay, you can eat as much as you want, as far as tomorrow, you eat from 0 to 800 calories. And each intervention, each study has used a different amount of calories for their fast day. The idea behind intermittent fasting is that for clinical data really show remarkable effects on several cardio metabolic risk factors are including cholesterol improvement in black improvement, also in cardio function. But whether that's the case in patients in clinical trial, that's a that's a whole different story. And today I think there are there's a few randomized control trial by here, I decided to show just the two, probably the one with the largest sample size and the one with the most rigorous study design. So the first one here to your left compared general daily calorie restriction. DCR in the blue squares here to the alternative fastening which individuals were instructed to eat one day uh libit um and one day with severe calorie restriction. And you can see here by the end of the 12 months in terms of weight changes, there were no differences in weight changes. Weight loss comparing the two. The two groups suggesting an alternative fasting as a measure of as a way too do intermittent fasting was associated with weight loss, but this was certainly not superiors to the daily calorie restriction. And more recently, this was just published a few months ago, I think in november or in Jama Internal Medicine. The treat randomized trial was published there really randomized patients with overweight and obesity to a time restricted eating, in which patients were only instructed to eat between 12 pm and eight PM And fast for their at for the following 16 hours until 12 pm. Or the next day. And to look at what their timely strictly eating was efficacious in reducing caloric introducing body weight. And what they found is that in the treats that this is the p values should be looking at. There was no significant reduction. Uh I should say not significant difference between the weight loss achieved in the control group and the time restricted eating groups suggested that the time recirculating was not superior to control and in the control group, the CMT consistently of timing group patients, individuals were recommended to eat at least three meals per day and then if they wanted to also to snacks, possibly always at the same time. Now the trick study also really did a very good uh characterization of this population. They measure body composition using that side of one of the gold standard to measure body composition, the measure physical activity. They measure uh sleep sleep quality and sleeping time. And as you can see her here, that's something that really was very important to highlight is that in the time is strictly eating. Not only there were no significant difference on weight loss, but it was actually a significant reduction in lean mass. So let masses typically a surrogate for skeletal muscle mass. And so these patients, they actually had a lower muscle mass. They also had a lower level of physical activity for some reason. So they accept they moved less throughout the day and he also had a greater awake time. So they spend more time basically awake. So again, not only didn't work, there is potential for harm. Remember that in some population, especially in older adults are induced with some chronic diseases losing muscle mass is a major risk factor for the development of Sacco pina and frailty. So we need to be very careful about intervention using this intervention in this population until we have appropriate data. Now. Another controversy, controversial topic in the world of nutrition is a consumption of red meat. Should we eat red meat? And if yes, how much can we eat in our diet Until a few years ago we were really no, you should not eat red meat because red meat increases your risk of cancer, increase your risk of cardiovascular disease. Uh and this is mostly resulting from observational data. And when this statement came out on the annals of entire medicine a couple of years ago, uh didn't really make everybody happy. But eventually, if you really carefully, you can see that the evidence associated with the role of red meat, both unprocessed and processed meat On the cardiovascular events. So the risk for type two diabetes and over all kinds of mortality is quite low. So does that mean that we can eat all the red meat that we want? Uh definitely that's not what I'm going to. But what I'm trying to say is that perhaps you need to design better studies to answer this scientific question in a rigorous, in a rigorous way without relying necessarily an observational studies. But if direct me potentially, let's say that potentially is a bad for health. What are the mechanisms? And so one of the mechanisms that has been criticized to drive the detrimental effect of red meat as well as typical animal products is through the production of T. M. A. Uh Team T. M. A. Uh now, almost 10 years ago by Wilson tank from the Cleveland clinic was found to be associated the plasma level of T. M. A. Or they could be measured in the blood essentially were found to be associated with a greater risk to develop cardiovascular disease, such as my cardinal in function, stroke or death. Now remember this is an observational study and this is really showing that GMO could be considered a marker for cardiovascular disease but doesn't really mediate cardiovascular events. And so that is something today we still don't know. But another study that the group from Taliban claim did, which I think was very important is to show the T. M. O. Can be more modulated with diet and particularly in a controlled feeding trial where the study team was providing the meals to the participants. This isn't healthy volunteers. They were able to show that if you switch from red meat to non red meat or white meat, you have a significant change of TML plasma levels of which is of course higher during the red meat consumption and lower doing the non meat And and uh and white meat that takes up approximately four weeks to change. So we have TML, which is a marker for cardiovascular disease, but also it can be modulated by diet. So definitely there is potential for um a future randomized control trial, looking not only at about our changes in cardiac cardio, metabolic risk factor, but actually also cardiovascular events. More recently, the diet feet randomized clinical trial was published. This comes from dr Christopher Gardner from stanford, where they looked at 12 months change in body weight in patients that were randomized to a healthy low fat diet and a healthy low carb diet. It's important to emphasize the healthy component because this was a really uh these were really natural patterns that we're emphasizing the consumption of uh Plant based food other days was these were not completely vegetarian or vegan, but at the end of the 12 months, what they were showing is essentially that weight loss was not different between these two groups. Both groups lost some weight, which is always uh you know, you to see that you lose somebody fat, but there were no significant differences between the two groups. But the reason I wanted to show you this study is that when you actually look at individual patients, each bar here is a patient, there is a very large heterogeneous response in terms of weight loss to the very same interventions which cannot just be justified by different appearance. Why does someone lose 30 killers and why does someone gain 10 killers within the same intervention? And so that's something that we don't know. Uh and ideally we're we would love to design studies in which we can potentially identify individuals that benefit the most from that intervention rather than another in a way. Uh Dr Gardner and his team really tried to answer the question. Um and particularly they look at genotype, there were some general types, they were potentially uh favorable favoring a low carb diet and some that were favoring the low fat diet. And so they randomized their participants based on each participants genotype really, they didn't see a significant difference. But this is I think the way to go in nutrition research should try to understand what are those characteristic that could potentially maximize the beneficial effect of an intervention. And not only in terms of being effective on weight loss, but also providing that support and that ability to our to our participant to the participants to actually adhere to the data intervention for the rest of their life. Because lifestyle intervention is not something you can do for three months or six months or even 12 months is it? Uh most likely for the rest of the life of our lives. And I think we're moving toward this. You will hear more uh you know the next year is about precision nutrition to really identify those contributors to the effect of diet and why some individual responding away and uh and others respond different despite following the same diet. So this is a large study from sarah berry from the U. K. Where they were looking at trying to identify what are the potential the contributor to a postprandial glucose and postprandial triglyceride in patients um that are really following a specific specific diet. And they look at a very comprehensive assessment using genetic testing environmental component which were like diet and physical activity as well as individual environmental component. They look at also twins. So really a very well conducted study and what they found is that the postprandial glucose, which is a metabolic risk factor, was could be explained partially by genetic component and partially by individual environmental component. But when you actually look at postprandial lipids, postprandial triglyceride, the genetic component was very, you know, pretty much contributed zero to the response. That individual had to be specific meal rich in fat and sugars while the major component where the environmental factors. So in this environmental factor for the most part where physical activity and microbiome, In fact, diet alone only accounted for about two of these postprandial translation rights, suggesting that really physical activity and microbiome are able to modulate the response of individuals to die. And then the last slide before the conclusion, we talk today and we always talk about treating cardiovascular disease, metabolic diseases or or treating cardiovascular risk factors. Like I showed you in a pediment in the primary prevention. But we should not forget about what is called primordial prevention. So primordial prevention is really the prevention of risk factors in uh Children and and healthy adults. And so we need to prevent risk factors in the first place. So try to prevent blood pressure to increase. Instead of just focusing on treating blood pressure. And one of the major risk factor that we should treat for. Primordial prevention is poor diet quality. We know that for diet quality will increase. There is to develop risk factors and the potential dis risk factor would lead to cardiovascular disease. So, I think we should start very very early in lives uh lives of our patients and family members to change their diet to prevent cardiovascular risk, cardio metabolic risk factor in the first place. Okay, so here we go through the conclusion. I hope I convinced you that diet and specific document factors are associated with cardio metabolic outcomes. The low fat diet are neutral on cardiovascular disease risk and really the mortality as well as the incidence of diabetes. On the other hand, the high healthy healthy fat diet, such as mediterranean diet can reduce cardiovascular disease and type two diabetes incidents in primary prevention. And the leon diehard studies suggest beneficial effects also in secondary prevention. Uh, you know, from our groups potentially suggest benefit also have path, but this is still early. Um, early her did you say? We're currently uh we're currently doing a randomized controlled trial to uh actually answer the question. And to date there is really no not enough evidence to reduce cardiovascular disease um, by recommending low carb, high protein diets. In fact, some observational studies and potential short term benefits of weight loss. But long term harm reduction in meat consumption studies in healthy individuals suggest a potentially detrimental effect through Tiananmen. Oh, what these effects could be prevented with red meat with white meat or non meat. However, these recommendations remain of a low level of evidence. Intermediate fasting is not superior to daily calorie restriction. And in the treat study, I assure you that there were some negative effects on body composition, physical activity and sleep time. Individual individuals, identifying individuals who benefit the most from specific dietary intervention remains an important need we hope to be able to answer within the next few years. And finally, let's not forget, the prevention of cardiovascular risk factors represents a great opportunity to reduce cardiovascular disease later in life and primordial prevention. Children and young adults free of cardiovascular disease. And then finally, I'd like to thank all the collaborators, my mentors at VCU, outside of VCU in cardiology, kinesiology and then my collaborators outside other institutions around the country. Thank you for having me.