Dr. Amit Badiye from Sentara's Advanced Heart Failure Clinic describes guideline-directed medical therapy (GDMT) for heart failure and how we are making progress with medical therapy for heart failure patients.
So I would like to start with this question, which of the following are considered endocrine organs, uh epicardial fat, pericardial fat lima surgeons in the room, um left and right atrium, left ventricle, you know, so we'll try to see uh what the answer is and, and I'm so glad to see that. Now, apart from just the heart failure team, um everyone and every cardiologist and non cardiologist, uh they are talking about this theme of GDMT and how GDMT works, guideline, directed medical therapy. And uh as you may remember, you know, several grand loans given by Doctor Hurry and uh doctor Ya about uh GDMT and all these agents. And we really talk about the four pillars of the GDMT for heart failure and those are the A Arbrr needs, right? The beta blockers, HGLT two inhibitors and mineral or cortical receptor blockers. So, a receptor antigua and you know, the amazing thing is the number needed to treat, to save one life is only four. OK. That's the power of uh you know, GDMT and that's how we have made progress with this medication. So, um talking about HGLT two inhibitors, you know, as I said, you know, diabetic drug causes glycosuria and then um leads to uh natural sis, right? And as you can see that there is um sensing of increased tubular sodium uh and it then leads to inhibition of rain and release, then leads to vasodilation, increased GFR and exodus of sodium. And you can see in the tubular cell, the SGLT two inhibitors and leads to increased concentration of tubular fluid and reduction in extracellular fluid volume. Right. So is that the only mechanism that the SGLT two inhibitors have that they cause uh natural sis with glyco glucosuria. No, they do have direct myocardial and indirect systemic effects, right. Um they reduce inflammation, they reduce autophagy and microphage. They reduce the inflammatory markers like chemo attracting uh macrocyte, they improve renal function, right. We have a lot of data on renal protection with these molecules. They increase Provas progenitor cells. This increase in uh erythropoietin. There's a reduction in uh neurohormonal activation. So there's a reduction in sympathetic nervous system stimulation and it also improves myocardial energetics. And what do we mean by all that? So how does it increase erythropoietin? Right. So as there is reduced glucose and sodium reabsorption, there's a reduced metabolic demand on the kidneys. There is increased sodium excreted in the distal tubule and it leads to a vaso uh a arterial vasoconstriction. What it does is it reduces renal blood flow, this reduce oxidative stress and then with the beta hydroxy mediated erythropoietin synthesis, right. And what does erythropoietin? Does we know that it increases erythrogenic, improves iron utilization and oxygen delivery and increases circulating progenitor cell in case leading to healing. And definitely it improves the oxygen delivery of the heart and reduces the cardiac mass. Right. And also leads to brain neuroprotection and reduce inflammation. Right. So imagine SGLT two causing all these secondary effects. How does it increase uh cardiac energy production? As you can see in an energy deprived heart? That is a heart failure, heart there are all these enzymes which are under express glucose, oxidation, ketone oxidation and glycolysis and 40 fatty acid oxidation is more. So when you give a GLT two inhibitors, there is improved cardiac function because there is more a TP delivery uh given to the to the heart as compared to the patients uh who are not on HGLT two inhibitor. So these are the pleo tropic effects of HGLT two inhibitors. I mean, how does it decrease the severity of heart failure is effect on the heart effect on the kidney vasculature and entire body. What does it does to the body as you know, and you must have witnessed weight loss reduction in symbiotic nervous system increase erythropoid. And we just saw that right. There's also a reduction in blood pressure, pro uh genital cells are increased. This improved vascular function. Kidney we already saw there's a reduced hyperuricemia, there's reduced sodium and hydrogen exchange. There's improved energy metabolism and same thing on the heart. You can see the benefits of improved cardiac remodeling, improved energy metabolism, reduce ischemia perfusion injury, improved autophagy and lysosomal degradation. So all these pleiotropic effect ultimately lead to the benefits. We see clinically in HGLD two inhibitors. So it just not natural Rees um from causing glycosuria. That's what I wanted to emphasize. And just, you know, as we saw the clinical results in both the DAPA HF and Emperor HF trials that they said significant reduction in heart failure, mortality and hospitalization by these two agents. And now the solar is trial. As you just saw the results which is combined GLT two and HGLT one inhibition where HGLT two causes glucosuria and HGLT one inhibition causes inhibition of gastric or intestinal gut uptake of glucose, right. So it delays uptake of glucose in the gut. So, in diabetic patients who were hospitalized with heart failure, who were stable when they were uh given. So ugly flows in, they saw a 33% risk reduction and the number needed to treat was only four and there were 50% risk reduction of heart failure, readmission uh and cardiovascular death within 30 days. So incredible data and that's how I uh FDA has now approved this uh agent as well. And what about Gliptin, the DIPT peptidase for in meters? Right? So we know certain agents like SITagliptin, saxagliptin and linaGLIPtin and these uh the potential G LP one. And what is A glucagon like peptide. One is second incretin mimic, right? What it does is it increases glucose dependent insulin secretion and known to cause you glycemia and diabetic patients. But it also reduces gastric empty and that's why it inhibits food intake, right? But now FDA has issued warning about the increased risk of serious heart failure events in these two agents. Why? So because they increase myocardial cyclic A P, they modulate the neuropeptide Y and they degrade substance B. So there are so many endocrine like effect of all these agents which are acting on the heart. So there has to be some endocrine function of the heart. And what's interesting about these drugs is when they saw patients, when they evaluated and studied patients who on beta blockers, those patients actually got protected from this heart failure, side effect from these Gliptin. So what does it mean? So there is a mechanism where there is an increase in adrenergic drive caused by these agents. So if you are on beta blockers and generally some of the again, uh physicians don't like to put their diabetic patients on beta blockers because they are afraid that it will reduce uh hypoglycemia awareness, right? But look what happens if you don't give beta blockers to these uh patients who are on Gliptin, they increase your risk of heart failure. And then what incr increase adeno drive does is causes increased fibrosis in the heart. So how about semaglutide? Right? The G LP receptor ago is right. So the step HF uh uh FP trial and I have blurred, blurred the graph because you don't even have to see the clear graphs to see the results, right? See the early and persistent graft separation in these two in these agents where when he f patients with diabetics were given um semaglutide, they saw significant weight loss, right? And they saw larger reduction in symptoms, improvement in exercise function and less physical limitations. Um And then comes the news in New York Times, we go be shown to reduce the risk of heart attacks and strokes in some patients. And this is the select trial where semaglutide was studied in patients without diabetes. Right. Again, we are talking about multitudes of anti diabetic drugs now being studied in non diabetic population and showing extensive cardiovascular benefits, right? Um And and this reduced the risk of major adverse events by 20%. And guess what? Um you can see the data that mean follow was almost 40 months in these patients. And you can see clear separation of the curves early on with a very significant p value. And lo and behold, we get an epic in basket from my patient like Dr Beer. I read this New York Times article about possible cardiac benefits of taking Vigo and they addressed it also on today's show just now. So patients so, so patients are upbeat with this information and look what she says or he says because the patients in the trial showed cardiac benefits before they actually lost weight. Please advise to me, shall I be on this medication? So this is the intersection of endocrinology and cardiology we are seeing today and, and our patients want to get that benefit. So as an A HF cardiologist, I'm like, ok, who am I today? Am I a transplant cardiologist? I'm also an L VA cardiologist, cardiogenic shock, and M CS cardiologist, cardio oncologist, cardiac critic, critical care, cardiologist and preventive cardiologist, right? Because all our transplant patients, once the heart is transplanted, we are in a super duper preventive mode. We do everything to prevent from graft failure. And now I'm thinking that I'm becoming an cardio endocrinologist and that's where um the concept of what are the hard derived endocrine hormones, right? Um There is um grow differentiating factor 15. We all know about atrial and brain natriuretic peptides. And then there are several other cardiac hormones which influence other tissues. In turn to reduce the heart burden and coordinate heart and target tissue functions. And you know, in reality, the heart of the matter is the heart is the center of the circulatory system, right? So heart has to use this endocrine mechanism to communicate with the rest of the body, how it's gonna give blood to the rest of the body if it cannot talk to the other organs. And that's where the cardiac endocrine system comes in place. Now this, let's look at these uh hormones, right? So hard drive hormones like GD F-15 myostatin, which, you know, we rarely hear about, but A NP and BNP, we always hear about, they share some common features, right? Um The, the way they are synthesized, the way they are regulated, the way they function and they are degraded on cardiac target organs and additional heart secreted factors. They play an important autocrine and Perrine roles in the local cardiac remodeling. See how heart protects itself while it has to give for the body. Right? And another schematic where you can see that what is the endocrine function of the heart? These na peptides and other cardiac hormones. They just don't cause vasodilation and natural sis, right? They are um associated with free fatty acid oxidation growth hormone secretion regulation of body growth. Do we know that? Yes, we do. What do you see in end stage heart failure, sarcopenia? Where does it come from? Comes from myostatin? Right. G LP one and insulin secretion, right? Oxygen consumption in the muscle free fatty acid oxidation and regulation of muscle mass, right? Same thing myostatin causing sarcopenia, lipolysis, post brandal energy expenditure. Why do we see uh obesity associated cardiovascular problems, obesity associated agenesis. Same reason there is significant involvement of cardiac endocrine system um uh in fat metabolism right there and studies where they uh got micro RN A from epicardial fats of non obese racks and they put them into um epicardial uh adipose tissue in obese rs. And guess what happens? These obese rats, they lost significant amount of um uh weight loss, they had significant amount of weight loss and this is the cardiac endocrine system. Uh We are exploring today, it also has effects on sym nervous system innovation and uh reduce urging in vs of pretties secretion. As we know, which affects directly natural uterus is by acting on the kidneys and a VP secreted by the pituitary. It also leads to vasorelaxation, blood pressure reduction and increased capillary permeability. They also cause of course natural races and diuresis and rass inhibition and blood volume reduction. And this is the only thing we know, not the other factors, right? So that's a tremendous impact of all these hormones which are secreted, none other than our heart, right? So uh what do these heart derived hormones do? Right. So, as we all said that, you know, they are synthesized and secreted by the uh the heart. They are our special uh cells. This could be myocyte, this could be the endothelial cells. This could be the fibroblast, they secrete these hormones and then they enter the circulatory system, right? Um and then they act on their target organs, right? They all act through specific receptors and they're signaling. And now all of you must be thinking like what's doctor B you talking about? Well, this has a big impact on all the agents which we saw they are so beneficial in improving survival in heart failure is because of the endocrine system of the heart. The predominant uh hormones we are going to discuss are the A TL and brain tic peptide growth derived factor 15 myostatin. As you can see that they all have similar structure, they are all pre pro hormones and then they are broken down and uh once they are broken down, their final product is the one which is an active hormone and it works, right? Just like uh pro BNP, right. Pro BNP is converted into BNP, which is the active molecule and anti pro BNP, which is inactive, right? And this is an electron microscope of a um mice atrium where you can see that there are the myofibril, then there's a gauge apparatus in the center and those small circles, these are the surface vesicles and the Granules, they contain the natriuretic peptides, right. Uh And we all know that atrial stretch receptors, they are a strong signal for natriuretic peptide. Actually in 19 fifties, when they were studying the circulatory system, they had the circulatory models of dogs. And they saw that when, whenever they would pound the atria of dog and they stretch the atria, these dogs would start Dior like crazy and they would drop their blood pressure. And that's when they thought that there is something in the atria where the stretching of the atria causes diuresis and drop in systolic blood pressure And now we know that that's um you know, the BNP and this is just a cartoon showing all these hormones, how they act on their receptors and then cause intracellular changes. Like for example, myostatin leads to muscle mass reduction. That's what we see in the sarcopenia. The GD F-15 leads to appetite inhibition and weight loss that's predominantly seen in uh childhood where, you know, you see kids with congenital heart disease, uh having weight loss. This is from GD F-15 secreted from the heart and we already know about the A NP and BNP. So, uh where do the family of A TLN uh brain A peptide stand? Right. So uh these are the hydros sodium, they maintain the hydros sodium hemostasis and systolic blood pressure, right. So, de bolt demonstrated atrial nitrite peptide in 19 eighties, right. And the BNP was discovered in pig brain in 1988. And then the C type natio peptide is predominantly resides in the CNS and CVS and cardiovascular system at low levels and then gets elevated in the states of heart failure, right? Euro din is the fourth member. It's predominantly residing in the in the kidneys, but they all interact to cause homeostasis in the cardiovascular system. And the A NP and the BNP are coded by the genes on chromosome one and the degree of excretion, as I said, they depend on the wall stretch. And as you can see, the half life of BNP is 20 minutes and anti BNP is 1 20 minutes. That's the reason, one of the reasons why your Sbu Valsartan is a twice a day medicine. So look at all the hormonal effect these agents have um uh on physiology, right? Um Whenever there is um biologically inactive BNP, it gets converted to A NP. And BNP, you see that there is increase in cyclic GNP levels, right? The down regulation of the receptors uh leads to reduce intracellular signaling, lack of phosphor dias and that's how those agents are reduced. On the other hand, they causes reduced reduction in aldosterone secretion, right. On the kidneys, increased natural sis, more diuresis and rain in release on heart. It causes positive lucid tropic effect, right? You are stretching the ventricle and you have to have, right. What what do we see in heart hy diastolic dysfunction? And how do you treat diastolic dysfunction by the lucid tropic effect? Is there a negative inotropic effect on these uh agents because they are reducing the cardiac remodeling and fibrosis still needs to be evaluated. We know that they do cause vasodilation. We already talked about the cyto protective effect of these agents by reducing fibrosis. So again, you know these in turn, tell your body give your signal to your body to reduce fluid intake and to reduce salt salt intake. So, can you imagine heart acting through all these hormones to tell your brain what to do to change you and modify your behavior. Well, welcome. That's the neuro system, endocrine system of the heart. So what happens to these um uh receptors and these peptides, you know, if you continue to get exposed to these peptides, you will get dehydrated, right. So they need to be broken down. And the there are two mechanisms. One is a cellular mechanism where the membrane internalizes these receptors. They are no longer available to be served by the specter. The other enzymatic mechanism is the proteolysis, right? And where does nepro come? Where heart failure is a natriuretic peptide deficiency? Right? You don't have enough natriuretic peptides. You have cardiac overload, you have reduced ejection fraction, you have vasoconstriction and remodeling, right? We all know that uh rain in angiotensin system over activation leads to all this right? And heart failure is a state of natural tic peptide deficiency. Now, if you go back to Sacyr Vartan action, right? You can see here, Nerys is inhibited by Sacyr and what does it do it now raises your BNP. What does BNP does NAIS VSO dilation and a proliferative action and reduce sympathetic tone all leading to benefit in cardiovascular health, morbidity and mortality. And on the other hand, by reduction of angiotensin into action, you see that that there is reduced sodium and water retention, um reduce vasoconstriction from the other pathway, right. So that's why you know what I talked about the enzymatic action, how Nepal Lizin works and now why it's important to block that Nepal. And now we see clinical reduction of survival, right, improved survival, improved heart failure, hospitalization and look at the ant pro BNP, they sustained reduction of ant pro BNP by Psych Valsartan from this pathway, right. So another evidence of why heart is an endocrine organ. And then we talked about cyclic GMP, right. So another subcellular level. So heart failure also is a state of cyclic GMP deficiency, right. So when there is endothelial dysfunction, you have oxidative stress and now your lack of nitric oxide which is needed for the endothelium, right. So what happens is the cyclic GMP deficiency leading to vascular dysfunction and myocardial dysfunction. And guess what, what is there as class two A indication is very sear, right? It directly stimulates the soluble uh guan in cycle and guess what it does it improves avail availability of cycling GMP to the cells. And that's why you see the benefit of very secure in heart failure. Now, changing gears a little bit about what about epicardial adipose tissue? We cannot see it uh on ct scans MRI even when we are looking at echoes, right, we look at the precordial fat. But you know there is a strong correlation with that with intraabdominal visceral obesity, insulin resistance metabolic syndrome, coronary artery disease, LV mass and hypertrophy. And it's an independent cardiovascular risk factor and how it is affected is affected by the vaso and Perrine secretion of pro inflammatory cytokine. Again, another evidence by heart is an endocardial is an endocrine system. What is the difference between epicardial and pericardial fat? Is that the same? Right? We talk about the white fat and the brown fat. So that's where the origin of the epicardial fat is completely different. It comes from the splan Peric mesoderm as opposed to pericardial fat, which is just part of the thoracic mesen kind, right? Um The epicardial fat really sits continuation with the visceral uh pericardium in between the myocardium and the visceral pericardium as opposed to the pericardial fat, which is just outside the surface of the parietal pericardium. And as you can see, the blood supply of this epicardial fat comes from coronary arteries as opposed to pericardial fat, which has no relationship with the coronary arteries and the adipocyte also in the epicardial fat are smaller. Why this is important to know because there are so many bio active factors which are coming from this epicardial adipose tissue. And you can see adiponectin adeno meline, these are like, you know, um more benefactor agents than leptin resistant TNF alpha interleukin one interleukin six, all these agents when there is an imbalance leads to more coronary atherosclerosis. And hence, you know, epicardial adipose tissue serves as an endocrine organs, right? Because adipokines, they influence atherosclerotic pathways, adon nectar and resistant, they modulate insulin sensitivity. And that's why I was telling you that why we are becoming endocrinologists because we don't know that heart has all these things TNF alpha. So I'm a transplant cardiologist, right. So uh how do patients with transplant develop Allegra vascularity? Right. So there is a diffuse inflammatory response in the body, right? That's why we give them all these uh agents to suppress their immunity, right? Mycophenolate calcium, urine inhibitors, steroids and all that. And what happens when these agents are withdrawn long term, these patients develop vascularity and if you check the TNF alpha level in heart transplant pain, they are always elevated. Where is this coming from? It's coming from the heart. Heart is an endocrine organ. So in this epicardial tissue, it's just not there. You know, it has several important functions, right? It's a mechanical buffer, it protects the heart, it acts as a myocardial energy source. It keeps the heart warm. Uh it secretes iops and it also attains lipotox and these are the physiological and pathophysiology function. Um I would not read the table but it just, you know, kind again, emphasizing the fact that the heart is just not a pump. It has several other chemo modulators and endocrine system, right? And that's what is reflected in your epicardial adiposity tissue because he p more epicardial fat, obesity type two diabetes. AFI patients have more epicardial fat, coronary artery disease, more epicardial fat and so many other inflammatory conditions. Even uh women who have reduced coronary uh fractional reserve, they have increased epicardial fat. Um and that's why obesity is a state of leptin resistance, right? Whenever the protective adiponectin are reduced and leptin go up, there's increased oxidative stress, endothelial dysfunction, increased inflammation, smooth muscle proliferation, there's more monocyte uh recruitment and foam cells. And what you see is atherosclerosis. And that's why they say that obesity is a systemic inflammatory state. And this epicardial adipose tissue acts as a transducer. So just by sitting between the myocardium, um uh and the epicardial tissue, it acts as it transmits what is happening systemically into the local myocardium even infiltrates the coronary arteries by this mechanism which you see here. And that's why you see that obese patients have more atherosclerosis. And these are several studies which have been studying all these uh you know, endocrine uh chemicals or hormones secreted by the heart. Why this is important because you know, going back to the prior prior sites of all the agents which we are using now, right, semaglutide, hgld two inhibitors, even sac sart and how they have a close interaction with the heart is shown by this because you know these agents under the uh can reduce the thickness of epicardial adipose tissue, thus reducing the barrage of all these endocrine organs, especially in type two diabetes. And this is another same concept where you can see why there is cardiac dysfunction in diabetic cardiomyopathy because all these inflammatory mechanisms are at the end of the day, are acting via the epicardial adipose tissue, right? There's increased insulin resistance more epicardial uh adipose tissue and now with abnormal glucose and lipid metabolism, you're having all this translocation of uh these agents causing inflammatory state in the myocardium. And this is another schematic which shows how obesity and systemic inflammatory disorders via the epicardial adipose tissue affect the local pro inflammatory state. Um who is gonna deny that heart is not an endocrine organ, right? And look what happens with the intramural and perivascular inflammation, epicardial fat. And there is enhanced inflammation of the vessel walls and leads to acceleration of atherosclerotic disease, right. Epicardial fat leads to more inflammation leads to atrial dysfunction and arrhythmias also heart failure with preserved ejection fraction. There are actually studies where in he pa patient, there is a pericardial restrain because of the improved or increased pericardial fat. Uh If they have done hemodynamics on these patients and their MRI studies, I actually had one patient where he was sent to me for FF FF evaluation. And I got MRI to rule out infiltrative disease because on an exam, he had coal sign, he has abnormal septal motion on the echo. And guess what the MRI showed the whole epicardium was full of fat, fatty tissue causing unrestrained. And I was surprised to see when I was trying to prepare this topic that there is there are case reports of pericardial constraints from epicardial fat. And um there have been some case reports of um you know, surgical intervention where they transected the epicardial fat and the hef pep result, you know. So again, uh there are all these autor and Perine effect and really uh metabolic syndrome causes this oxidative stress to the heart where heart has to protect itself. And then it takes over the function as more of an endocrine organ than just something which is pumping blood out of the body, you know, um going back to the G LP receptor expression, right? Um And that's why the semaglutide and all these agents. Now, we know why they are beneficial because the visceral fat ratios were associated with G LP and G LP two receptors, right? And these studies, what they did was they got these patients uh during sternotomy when they're undergoing cabbage, they retrieved the epicardial fat and then they studied which one of the patients they were expressing more of the receptors and those who were obese who had extensive coronary artery disease that over expression of these receptors. No wonder that these patients have uh combination with the rain in angiotensin aldosterone system, they all get expressed. Um and then you have the beneficial effect uh on the heart. So that's why we know by the select trial, the semaglutide was so beneficial, right? Because there are many potential effects on the vascular endothelium, right, directly improving cardiovascular health and reducing the oxidative stress. They also said that the genes promoting beta oxidation conversion of white to brown adipocyte differentiation was associated with the benefit of these medicines, role of statins. How do statins really work? Is it really just an effect on the, you know, uh fat or cholesterol in the blood supply? Or they do have some effect on epicardial adipose tissue, right? So they do reduce the proinflammatory characteristics. And that's another mechanism has been postulated that statins reduce um the epicardial adipose tissue and in turn, help with ventricle filling, uh myocardial micro circulatory derangements and also cardiac fibrosis, right? Uh who would have thought that statins would benefit like this with a cardiac endocrine mechanism. How about mineral cortic antagonist and obesity? Right? There is an hyper aldosterone state in obesity. That's why patients who are obese. They they benefited more with Eplerenone. There was reduced heart failure and cardiac death in patients who were predominantly obese and who had abdominal obesity, right? Um Same thing we already know that why these patients have now benefit apart from this natural sis and raining system. Now going back to Lima, right? Can anyone believe that left internal mammary artery is an endocrine organ? So that's a concept now, you know, so initially, they did this Weinberg procedure where they implanted Lima directly into the myocardium didn't work, right? And then um it became mainstay in 19 fifties as part of coronary artery bypass grafting. Why Lima has this vascular biology for superiority? Does it have an endocrine function? We never looked at Lima like that. We just always thought that, oh well, it's an artery and it's a good conduit and you know, it's there's some data but why the data is superior for Lima. Well, people also try to use RMA. Why Rima is not that superior? Also try to use radial graphs, right, gastroepiploic artery grafts. Why they are not superior? Well, they lack the endocrine function which Lima has because endothelium of the Lima is more um uh f uh more penetrated. And you know, there are like this is a busy slide, but this tells you at the molecular level why Lima is so beneficial. Look all the chemicals which are described for heart failure, cyclic GMP, um nitric oxide levels, everything is high in Lima, right? Lima is the endothelin receptors are more highly expressed, right? And Lima is protected, right. There are higher prostacyclin levels. Uh in uh Lima and Lima also has more superoxide dismutase activity. So less of the oxidation, actually, there is some uh postulate that it also protects worsening atherosclerosis in the native arteries past the you know insertion of Lima. Generally, we see that the native atherosclerosis gets worse after bypass, right. That's why you want the bypass graft to mature. But look, Lima has several exosome, which are much better. On the other hand, with a cephus venous graph and which leads to a reduction in DNA damage, less lipid oxidation and less mitochondrial dysfunction. That's why you have 92 to 95%. Uh patency of lima almost still 10 years, right, as compared to the sinus venous graft and these are the endocrine effects, antioxidant vasodilator, anti plaque and anti laif effect. And I was just surprised to see this uh data how this local um endocrine organs works. And just to, you know, go back, you know, I can go on and on, on these agents, but overall, they all cause less fibrosis, less myocardial hypertrophy and more vasodilation. Uh and there, I mean several agents which are, you know, implicated as uh hormone and paracrine factors coming from the heart. And why this is important is probably in future, just like you see with HGLT two inhibitors or GLP one agonist, these agents may find some way there might be a therapeutic target uh protecting the heart, which is the heart is trying to do being an endocrine organ. So in summary, heart really occupies a best real estate in the circulatory system. And the endocrine hormones secreted from the heart, they have an effective way of communicating with other organs. So that heart does its part, it functions the way it's supposed to function and also protects itself, right. And the recent therapeutic targets including ARNI HGLT two inhibitors G LP receptors, uh blockers, they all reinforce the endocrine function of the heart. And you know, uh to that's what heart does is to maintain homeostasis by reducing its burden by, you know, causing vasodilation or reducing the body size. Uh by, by these hormones, you know, I'm sure there are so many other hormones which are undiscovered and they will be, uh, sure more novel targets for cardiac therapy. And I think we all are soon gonna be cardio endocrinologist. And I would like to stop here.