Presented as part of the Department of Cardiovascular Surgery Grand Rounds on November 4, 2020, by Farzan Filsoufi, MD, at the end of this video, viewers will be able to: • Understand the evolution of diagnostic and guideline-directed therapy strategies of infective endocarditis • Summarize the available operative approaches and technical challenges related to surgical intervention for infective endocarditis Good morning. Thank you very much. Doctor Adams for the introduction. My only disclosure to you is that I'm not a historian of medicine. I have an interest in the history of medicine that I would like to share with friends and colleagues. So this is mostly a casual talk and feel free to interrupt me. I have a limited knowledge in the history of medicine, but I still try to share it with you with respect to infective in the card active, which is a topic of interest to all of us. As you might know, this is a very complex disease, and our understanding of the history of infective endocarditis has significantly changed over the centuries and one of the major contributor in our understanding of this disease is William Osler, who mentioned in his landmark lecture in 1885 that that was probably one of the most interesting diseases that he has had to deal with it in his life. This is our current knowledge, everybody knows how we diagnosed infective in the card itis, the importance of clinical symptoms which are mostly included in minor criteria of infective in the Iraqis and the major criteria which are either positive blood cultures or imaging finding with echocardiography including vegetation, abscesses and so forth. I'm not talking about what we know. This is very easy. We can open a textbook and learn a lot about in the card ideas. But what I would like to share with you is how we got there. What are the different steps? What are the major contributors in our understanding to get us to what we know today? So let me ask our residents, I don't know if they are there. Let me take a couple of minutes. If the history of infective in the car Darius was like a puzzle. What element would you like to see in this puzzle? Um The development of proper antimicrobials, antibiotics. Um The development of surgery for endocarditis, devolving indications facility of endocarditis, better diagnostic tools and Okay, so what you actually mentioned is mostly what we talk about for the last 50 years. That means The surgical tools because the surgery started in the second half of the 20th century's or imaging studies, which even started slightly later in the 1970s. I'm going to talk to you about history with the big eight. So I'm going to take you back almost 400 years and then you come forward. So when you talk about the history of medicine, you need to have the geography sources. And as morton signaled, one of the first uh authors who mentioned the importance of bibliography references is Sir William Osler who has its own classifications of bibliography references. So we use primary sources and the most significant one of the most respected one is the Garrison morton Garrison and martin work on the library of surgeon general of the United States, which later become the National Library of Medicine, which is the largest library of medicine in the world. And they use that as a source. Two describe bibliography references which includes the most significant contributors in the history of medicine in different fields. Uh this is the most respected sources. Are their mistakes in it? Yes. Are there authors missing in it? Yes. But still it remains a very respectable sources of information for those are interested about the history of medicine. There are of course secondary resources which are medical books in terms of history of cardiology, history of medicine or reviews that you see in different journals. So, these elements, when you look at them, they all get together at some point and you see the most important contributor in our understanding of different diseases in the history of medicine. So when we start to talk about infective endocarditis, obviously this is a term that was going later on but we have to go back very early in the history of medicine and one of the earliest contributor or the first description of a valvular disease which can relate to infective in the card. It is was done by Lhasa Riviera in 16 70 for for you to understand how the stock has been put together. So often you see the name of the altar on the top left side with the name of their book or their article below it. Then you have what we call the Frontiers piece or the cover of their book. And if there is any portrait available, I put the portrait on the right side of the screen and if you look carefully on the left side, you can see the evolution of the frontier space or the cover of these books over the centuries, which is interesting on its own. So last I revere reported a case and that's one of the first cases that has an autopsy analysis. So he basically correlated the clinical finding with postmortem examination reported case of a patient who presented with palpitation and irregular pulse. The patients worse than a few days ago, presented also with Disney to and swollen leg. And finally, later on where he was at the end of stage of his disease, you start having certifications and him up disease. And finally this patient dies. And when you look at the autopsy finding what he describes, it has been translated from latin is moreover in the left ventricle of the heart, around carbuncle. Look at the terminology were found like the substance of the lungs, the larger of which resembled the cluster of hazelnut and fill up the opening of the aorta. At that time again, the history of medicine was in a way that the theory of the disease was very obscure and there was a lot of discussion about human real changes to to describe the occurrence of diseases in human beings. And that's one of the first case is basically that he relates an atomic finding that correlate with pre mortem clinical symptoms and from historical point of view, that is considered the first case of aortic valve disease, which is compatible with aortic valve and the card itis. It goes almost 100 years without having significant publications in terms of aortic valve diseases which relate to in the card Itis. Now, we are on 1761 and we have this work of morgue Agni, which is considered the founding father of anathema pathology and one of the most respected physician in the history of medicine. He publishes large books, which is called on the siege and causes of the disease. Is and in this book he reports several cases of aortic valve disease. One of these cases out of the tree is in favor of erotic valve and the card itis. And here is the summary of the case. He described 36 year old may who president or who died basically from drops you off the torques that drops. It is a term that was using the equivalent of congestive heart failure that we use today. The patient has slow pulse and swollen legs and basically dies very rapidly. And this case has a very detailed uh autopsy descriptions of all the valve lesions and I summarized that you can read it faster than me, but I'm just going to read you the parts that are, have highlighted these Oregon translated from latin into english. All these valves is rolled out into short and unequal express seances by the lord of which being weighed down. When I examine each route in particular, I saw that the right had its border much shorter than usual or was become less transparently under the left was ruptured to the middle. The substance of all these valves was in part lacks and flaccid, very visible, very easily pulled away by the fingers and by the nails. So Again, this is the case that describes you the confusion which is going to last almost 140 years because here you have lesions which are compatible with in the car diabetes, but also you have lesions which are compatible with dramatic heart disease. None of these diseases was known at that time and hard work. We are going to see that over the decades and over the centuries probably distinguishes between different ideology of valvular heart disease. Then we get to the 19th century, between the work of more gag me and chor bizarre. There's almost no descriptions In terms of valvular lesions uh in the history of medicine. So here we are in 1806 and Corvis are published. His landmark work, which is on the organic diseases of the heart and the great vessels, chor bizarre. Was the physician of the napoleon and one of the most respected positions in Europe during the first two or three decades of the 19th century, and his contributions are the following in our understanding of infective endocarditis first and most of all, he coined the term vegetation To the term that we use today. The vegetation on the Echocardiography was first coined in 18 or six and one of the most important contributions of core bizarre was that he distinguished between two different types of valvular lesions. You talk about valvular and durations and calcifications that he called socios prosperity's, which is also used in english language in that time. And obviously, you know, these are in favor of rheumatic valve disease. And he also talked about vegetation which were soft lesions, which could be easily detached from the surface area of valve leaflets. Again, we didn't know anything about the ideology of this valve regions, but you can see on the page that are put on the left side, the word syphilis. He is one of the first author who mansions, who try to discuss the ideology of this valvular lesions and as they were similar to venereal lesions, he suggested that they may be of civility origin. Later on, one of his pupil disagreed with him and rejected this hypothesis. Here is one of the first cases that they were described by Chor Bizarre, is a 39 year old male. You have the text on the left side who presented with fever, Cough, Abdominal Pain, episode of one meeting and lower extremity edema. He also noted an enlarged liver. A few days later, patient died from drops you off the two racks of congestive heart failure, as you can see the clinical times a little bit more precise and most of them are compatible with infective endocarditis. And then then when these patients has a postmortem autopsy, here is the finding and the descriptions but core bizarre a large portion of the mitral valve which lies before the orifice of the aorta, held no longer by the tanginess threats. That is a cool enough for the rupture that we discussed today at its age become loose. Many species of very irregular and long vegetation were appended. So here you're facing the first description of mitral valve endocarditis, Which was reported by core resort in eight or 6. Then you have to go another decade to get to the work of heart. Stone. Hartson was the physicians in England who was very respected and very wealthy. I published treaties on the diseases of the arteries and the veins, which was published in 18 15. Hartson was known for his work about the aortic aneurysms and he has a great interest in a different portion of the aorta and basically discussed significantly, a standing aortic aneurysm and arch aneurysm and less about valvular heart disease. The report, the first case of aortic valve in the car bodies, which was complicated with peripheral embolization. But interestingly, this work went unnoticed because it was not of interest to him and he wasn't known for it. And this report, this case report actually was noticed in 20th century. So he has very limited impact of in our knowledge because that's one of the main the signs of infective endocarditis, which is peripheral embolization, but that wasn't noticed at that time here, the first text books in english. So I put you the original text and we can read it together and here the way it leaves A young man about 18 years of age, six weeks before his death was afflicted with violent pain in the head and constant vomiting. His pulse was unusually strong and hard, and a quick vibrato re pulsation was observed on the left side of the abdomen. The right leg was cold and no politician could be discovered in its arteries. This patient goals and dies from heart failure. And the second paragraph that is highlighted is about the autopsy finding two of the seven million or valves of the Ortho Evra lacerated and from their edges spouted numerous world light express senses immediately below the valves. And at the origin of these experiences was an extensive ulcer which had penetrated deeply into the walls of the ventricle at the root of the aorta. And later on the third paragraph that is highlighted, described the peripheral embolization the right femoral artery, together with the propaganda at the origin of the ladder were filled with the firm white substance similar in structure to that of the express senses which grew from the valves of the aero top. So, as I said, Hartman was a very rich physician in England, and he published an atlas along with his book, as you might know at that time. Most these books are published with the money of the physician because they were reporting their own experiences don't have to pay for the publications and including medical illustrations was very expensive. So most these medical books don't have any illustration. He published a large atlas which is about 100 page and has the multiple, you know, medical illustration. And this is the first illustration of the case of valvular in the car diet is as you can see, there is perforation and lacerations of the aortic valve with this altar that he described, that it extends to the left ventricle. We also highlight this word of fungus that he used and we will see that through the decades later on. Some other authors also use this fungus, you know, outgrowth, which looks like words like extra senses which is described in this text. Then we go on later and we get to 1819, this is lion neck and Lionel was one of the pupils of Core Resort, And his book was published in 1819, which is mostly focusing on Cardiac Diseases and also made it as quotations. And here are some of the most important contributions of lining Clinic invented this. The telescope in 1816. The distinguishes not two types of vegetation, and he called them vegetation is very close and vegetation is global, or the second one is early description of Trumbo's incurred in cardiac chamber, so we are not focusing on them. And he goes on to say that these vegetation is the varicose one were mostly located on the left side of the heart and the right side of the valves are really involved. And the way he described it in his autopsy findings were that these vegetation are often small, didn't obstruct the orifice of the valves. Does explaining the reality of founding at ostentation. Which can be true in some cases. Here is the case that was described by aligning the 25 year old may who present with this not dizziness, palpitation and homeostasis. And at Oscar rotations, he founds bello sounds and that pal patients who found thrilled at the pericardial regions. These are the first findings that you have that the clinical examinations before a patient dies. We start finding some signs that can lead us to a disease. So this is the first case of a valvular in the car diaries that is compatible that has clinical descriptions and Oscar rotations findings. And a few days later this patient's also dies. And when he does his autopsy finding, he sees cardio Meagley called the rupture of the mitral valve multiple vegetation on the free margin of the mitral valve. And he noted that this vegetation were numerous irregular, different in size and shape, often long and thin and very fragile. Then he goes on to 1835, and that is one of the most important contributors in our understanding and our early understanding of valvular heart disease. His name is john Bettis bubo, and what did he do video in the introduction of his work, introduced the term and a card and the inflammation on the undercard, which he called endocarditis. But, as you may know on the left side, is in the pre phase of his book. And some of the authors at that time, if they have any major findings, rather than going to in their textbook and reading hundreds of pages, they were introducing them in the preface of their book and later on they were expanding on the topic over pages and pages. But the term of endocarditis was first coined in 1835 and was related to the inflammation of the inner layer of the heart. But then there is a chapter which is the general history of endocarditis and Boy Oh describes three periods in the development and progressions of anatomical alterations of endocarditis. I read them quickly for you. The first one is period of sanguinary congestions of soft landing of alteration and separation. As you can see, this is really in favour of infective in the car diaries, then cover the second period of organization of secreted products, which is the formations of vegetation. The 3rd 1 is period of cardiac pathologies, oceans or cal Karius in duration of the undercard job. And this one is in favour of rheumatic heart disease. So there is a mixture of description of lesions, which is very confusing and what is that? Because at that time we didn't know anything about the germ theory of the disease. The fact that microorganism put impact value, color or valves wasn't known at that time. And even we were at earlier stage to know that rheumatic fever can cause valvular heart disease. So One of the second most important contributions of Budo is that he has studied about 200 patients who had rheumatic fever and associated valvular heart disease. And he wrote this landmark textbook in 1840, which is a book about acute articular rheumatism, with the development of valvular heart disease. And do you believe that in the great majority of cases of accurate articular rheumatism with fever, there exists in a variable degree a rheumatism of the thorough fibrous tissues of the heart. And he called that the law of coincidence, that was a major work and a major contribution because for the first time, we have a known ideology, which was acute articular rheumatism, causing valvular heart disease. And you can see that we are going to see that throughout the next five or six decades. How much this concept of uh inflammations not only contributed, but also confused our understanding of other challenge of valvular heart disease. And the reason of this confusion is here because we have dramatic valve disease that has a specific legions. We have infective endocarditis, which has his own lesions, which are mostly vegetation. But you had also patient with dramatic valve disease, that this valvular heart disease was complicated with infective in the card ideas. That's why you have this mixture of description of legions throughout the history until the 19th century, because most patients have both together and there's this overlapping area that creates the confusion. Now, you have this earlier stage of symptoms, the clinical symptoms, the constitutional one are well described. We know about the vegetation. People start using our school stations to see if patients with valvular heart disease are have findings and I'm not going to go through the description, our understanding of Oscar rotation that also takes on its own about five centuries, five decades. But now we have to Get to the second part of the 19th century. And here we have more descriptions of clinical picture which are specific endocarditis. And one of the first authors is William curves and as you can see, the title of his of work is very long and I'm sure no editor today would accept to publish an article which is such a long title and the title of his work is on some of the principal effects resulting from the detachment are fibrous deposits from the interior of the heart and their mixture with the circulating blood. That was published in 1852. And in this work, works emphasised two aspects of our current understanding of infective endocarditis, Which is one peripheral embolization, and the second one is the systemic manifestation, which he called poison state of the circulating blood. And as I said, if you remember, the first case of embolization was described by Hudson, but that was unnoticed and 37 years later it's curved that brings to the attention this aspect which is a specific to end the card. It is and relate to peripheral embolization in terms of pay for embolization, eric said, if of large size and only loosely adherent as they often are want or more masses of even considerable magnitude may at any time we detached from the valve and convey with the circulating blood until arrested with some arterial canal, which may be completely plugged up by it. And he says that that can lead to a fatal events. And also you mentioned that if these fibrous material are very small, they can obstruct capillary and cause organ dysfunctions. He also wrote that the effects produced on the organ affected will be the chairman by the side of the heart. He mentioned that there are mostly located on the left side of the heart and if the impact, brain, brain and kidney, because they are largely and directly supplied with blood from the left side of the heart. In his article, Kerik's describes four case of endocarditis which affect the left sided valves. The mitral valve was involved in all of them, and he described also the clinical signs of his patients, including fever, profuse sweating, joke allegiance, and three of these patients died from stroke. An autopsy he describes multiple vegetation. Zwiers noted on the lifted after of the mitral valve that these there were multiple embolization involving several large arteries, including right middle, several artery and multiple emboli were also observed in the kidneys and spleen. So this work impacted a lot of physicians at that time. And as you can see when Osler gives his lecture in 1885 mentioned that our current understanding toward the end of 19th century were coming from this article because that's the article that focuses on one of the primary signs of infective endocarditis, which is peripheral embolization. The second aspect of the work is what I highlighted on the text on the left side is the poison state of the circulating blood or circulating fluid. And in this article in this paragraph, thanks mentioned that the masses of phi brain may soften and break up, and this mingling and circulating with the blood may give rise to various disturbances indicated of the contaminated the state of this fluid poison blood producing symptoms very similar to those observed what they were calling at that time. Typhus, which is the equivalent of septicemia of today. And that's very important because that's the first time that alters are hypothesizing that there is something going on in the blood that can cause a fatal event very quickly, which we call today septicemia, although they were not able to find any other material on the valves or any other solid organs. A few years later, almost 18 years later, after works of uh Kurds, Wilkes published this article which is titled capillary embolism or are chillier petit mia. And he expends more on the systematic manifestations of a disease which today we call infective and the card itis. So he mentioned that the occurrence of arterial pay email and its attendant constitutional symptoms of fever, rigor, and arthritic pain, which was also associated with enlargement of the spleen and liver and neurological alterations and will believe that the systemic manifestation of blood poisoning were more often the cause of death and the primary valvular lesion. And he mentioned that the arrangement of the valvular apparatus was scarcely sufficient to cause death. These are among his observation, and he postulated that in many cases the fibrous deposits may have occurred from a primary change in the blood itself. Things often there is no proof of the existence of a primary and the card itis. In these cases it is possible that the first symptoms which attract attention will be the constitutional one and then highlighted on the left side. And he recommends to use the word septicemia. And again, this blood poisoning that these authors are describing corresponds to basically bacteria MIA and septicemia, with all the general symptoms that we see in our patients. But these are the two major contributions in the middle of the 19th century of our understanding of a disease that today we call infective endocarditis, which are every friday mobilizations and septicemia, which is due to the infectious nature of this disease. Now, how do we get to determine there is infection within the card. Obviously at that time we need to do some significant development in the field of microbiology. And before we go to the our understanding of the infective nature of endocarditis. Let me just briefly summarize for you in order to give you a perspective about the major milestones in microbiology. The term bacteria was coined in 1838 by German naturalist. The gem theory of the disease was described in 1861 by Lou Pastor and he suggested that there are microorganism that can affect our bodies and that can cause diseases. And we will see that not in the stock that luke Pastor and contributed significantly in the development of the microbiology and identifying organism that causes multiple infections in the body. The gram stain things were more frequently performed in 1880s and Christian Graham from Norway published his work in 1884. tissue cultures were more commonly performed toward the end of the 19th century, although they were not very reliable. You have a lot of false positive and false negative and the blood cultures are more commonly performed at the First decade of the 20th century. But knowing this timeline, let's see how our understanding of infective nature of the card that is developed to one of the main contributor is ring and he published this case report and he called that Mikos is Endo card. In this case report Finger described a 42 year old male who presented with toe injury that was complicated. The local upstairs. Later on the patient developed fever, chills, sweating, this and delirium and he died from blood poisoning, which is the equivalent of septicemia. At autopsy on the aortic valve and track a spit valve, he discovered cauliflower vegetation which contained posts and here a detailed descriptions of the microscopic examination of the valvular legions and he stopped parasitic vegetation, which were short rod shaped or round bodies. And later on basically, he sentenced a specimen to work out which was one of the most respected physician in Germany, was one of the finding, father of him, mythology and he confirmed his finding. And in the conclusion of his work, he said, as my eye, I must say for certain that this is not a postmortem artifact, but that's the first time that we have a case of. They were taken to a hospital valves in the car. Daddy's with microscopic examinations and identification of some microorganisms That takes us to 1869. Three years later Heiberg published a similar article and similarly he called that also active endocarditis and referred to it as Mikos is in the Cardi. And this is a 22 year old female who dies basically after childbirth with substance and fever, articular pain and skin legions. And at autopsy you find mitral valve alternative endocarditis with multiple vegetation. And when he does microscopic examination you find parasitic organisms when she called little tricks. And he named this affection. Microsd Mikos is endo Cardi, but these are the two articles that identify microorganisms. An autopsy examination with microscopic examinations of vascular tissue. At that time, one of the founding founder of Microbiology Edwin clubs postulated that all the so called forms of endocarditis, our of my aquatic nature. That was extremely controversial and a lot of authors didn't agree with that because they were basically privileging the inflammations of the valuable allegiance over ineffective nature of valvular lesion. Then I put this textbook for you. This is one of the most popular textbook which was used in europe and the United States. There is no original contribution in these textbooks, but it has a very good review used in most medical schools and summarized as well. Our understanding of what we call on their multiple name, also active in Al Qaeda is or if derek and a car that is and so forth. And here are the terminology that are used in these books. And they referred to the same pathology but they were calling them septic endocarditis. Also writing in the card itis infect appears in the card itis, the heretic and the card itis and the car that is malignant or arterial petit mia. And Brownsville described well this disease, but again he favor the acute inflammation of the indycar job. He gives some credit to infectious nature, but again he says the primary is inflammation of the indycar job. And he described found great vegetation on the pathology. He described alteration of the undercard um and then he goes and described quiet well, the clinical symptoms which were known at that time. This textbook has also some illustration which describes wells the valvular lesions on the left side. You see aortic valve in the card at ease with vegetation and perforations of them, or two valve. The second on the left side, you have an aneurysm of the Ontario leaflet of the mitral valve, which was known as one of the most common lesions affecting the mitral valve. On the bottom pictures. The second one you see perforation and aneurysm on the, of the ensure lifted of the mitral valve and the third pictures from the left, you can see, he described dilatation and hypertrophy of the left ventricle associated with mitral regurgitation. You have some microscopic examination of the heart at the base of the aortic valve. These are magnification at 10 times and on the bottom. Again, that's the paragraph that he give some credit to the infectious nature of this disease. And he refers to ball lock masses of micro cox. I. And that was coming from Osler studies As you can see, this is almost 140 years old. It's quite similar to our textbooks of today. Obviously there is no sections on imaging studies and there's not many sections about therapeutics, but otherwise they have a good understanding of clinical symptoms and barbara lesions were very well known. We were at the earliest stage of microscopic examinations and we have a better understanding of infect shoes nature of this disease. Then comes the man who basically clarified everything toward the end of the century and he published multiple articles, including the most important article in the field of infections in the card itis. And this is Sir William Osler. His first publications relating to this disease is Came out in 1881 and it is called on some points in the etiology and pathology of alternatives and the card itis In this work, which is about eight pages. He summarizes our understanding Of uh of this disease based on the literature. He also brings his early experience, which has, I think about 12 patients. But the reason I put him here is that things even for us, there were not cleared at that time. The Oslo recognize certain role to micro cracks in the pathogenesis of endocarditis. He, however, expressed the opinion that these agents may not be the primary responsible for all cases of new car dieting. And here is a paragraph by paragraph from his book, what determines the precise for the undercard that is, we don't know by the soft in the cardinal vegetation form a suitable notice for the development of micro cock style. Again, here, the confusion comes from the predominant role of inflammation and Australia is similar to other authors thought that there is inflammation. The inflammations of valves due to rheumatic or other causes Can lead to vegetation, as was described by Boucheron 1835, and that these vegetation were in night us for the micro cock side as we know today. Obviously the vegetation czar caused by the infectious agent in most cases. So this is a quote from Peter Fleming regarding Osler early work saying that Osler was puzzled by the idea that disease of all degrees of severity and Cronus city could be caused by organism. This disease, as I mentioned in my first slide, was of great interest to Osler. Our very short period of time. Osler developed a large experience in the management and in basically handling of patients with infective endocarditis. And his landmark paper comes later, but his understanding evolved in a short period of time, came from extensive culture studies that he performed and in terms of experimental models of endocarditis and this model of in the car that his credit goes to a few Russian authors that used animal model, mostly dogs, and they were using the crowded approach to cause tears in the aortic valve to see if that leads to any aortic valve in the card at ease. And once the technique of cultures developed and they were able to basically have uh infectious agents available, they were injecting, you know, stripped of cox i in these valves Received at least two infected and the card ideas. And these two aspects that happened over a period of 15 years led to the confirmation of infectious etiology of endocarditis. and these are the elements that significantly impacted the understanding of infectious nature of this disease. For Osler, So, William Osler published his major work on malignant endocarditis. In long set they recalled the Palestinian lecturers, these three articles that were published, I think over a period of one month, And it goes to the personal experience of Osler, which included more than 200 patients. And this is the distribution of the valvular lesions, The aortic valve in 53 patient Mitral 77, The double Valve 41 and the right side involved in 34 patients. And here, the main contribution of us there is basically he cleaned up the entire field. He brought his own logic. He clarifies our understanding of, of bacterial endocarditis. And, for example, he suggested a simpler classification which was based on clinical presentation. And he rejected terms which were based on an atomic feature. No more alternative in the car. That is no more value because in the car that is. He introduced chronic forms versus acute form. And he designated temple forms, will have mostly the subsequent forms that have a more favorable evolution versus malignant form. He had a great understanding and there's almost two or four page about the clinical symptoms of endocarditis, which we all know. You can read them very easily. But he also defines subclinical groups except this ethnic group, the cardio group and the cerebral group. And this is almost what we do today. Like one of the indications for surgeries, patients who have uncontrolled sepsis. And he described this patient with septicemia which have a very early fatal events because the blood poisoning or the septus emmick event could not be controlled. The cardiac groups are the patients who have significant thermodynamic compromise after their value or endocarditis. And that's also one of the criteria that we use for surgical indications if you have a patient with natural regurgitation or aortic regurgitation most often that cannot be managed you know, properly. There is an early indication for surgery. So he defines these high risk groups there and the several groups basics, our patients have multiple embolization that they couldn't be managed very effectively and they were dying very early on during the evolution of their disease. He also performed a lot of microscopic analysis. He's one of the first that reported that blood products and blood platelets and fibrin were included in the vegetation. He stressed the fact that micro cock side with constant elements in the vegetation and that gram staining was the most satisfactory. Committed to identify them. In the conclusion of his third lecture, he wrote the story of accurate and the card itis which at present prevails and the only one to which I shall refer is that it is in all its forms and essentially Micah tick process. This very attractive theory can be adjusted meet every requirement of the case And that really set our understanding of the undercard itis for the 20th century. Now he also described the chronic form of infective endocarditis and then I'm going to just go with the last two of Forest lied very quickly. One of the contributors was Hugo scott Mueller from Germany that also identify for the first time after significant in a culture study, a strip to cook very dance as the microorganism that was involved in the subsequent form of endocarditis. These findings were further confirmed by Lippman and Seller in 1910, that also reported their own uh series with culture and identify a streptococcal, very dense uh in the ideology of sub acute endocarditis. Uh For those who don't know, lippman was the chair of cardiology at Mount Sinai for several decades, during In the early decades of 20th century, and also another american author, George Bauer, that describes very in detail the glomeruli legions of Slovakia pin the card itis and the report that in the kidneys of nearly all individuals dying during the course of subsequent back to run the card itis. There exists a pathological lesion with affect one or more loops of a variable proportion of the kilometer right. And he did extensive histological studies that have just put my interest for those who would like to read more about that finding. And it So again, we are set toward at this point, early 20th century and there is a good understanding of infective endocarditis. The cultures are practiced more often in terms of diagnosis in patients who are living. The autopsy findings often leads to micro microscopic examination and the culture tissue also allows to identify the microorganism involved in this disease. But unfortunately, there is nothing regarding the treatment of this condition and the early development in terms of treatment of patients with endocarditis. First was the use of cell phone. Um It these are the first anti bacterial agents which were used in the third decade of the 20th century that had limited efficacy in the treatment of endocarditis, The first treatment with antibiotics. But with penicillin, as you know, Fleming discovered penicillin in 1928 And that was the most commonly used medication during the Second World War. The first report of the treatment of a patient with infective endocarditis. Alfred penicillin was reported in 1940 for the second aspect of the treatment is surgical therapy. And as you know, uh cardiac surgery was introduced with the development of the heart lung machine by Gibbons in 1953. And the first cases of valvular replacement were described in 1960s. Stop I hope I didn't disappoint some of my younger colleague because I didn't focus on the last 50 years, because that's something you can find in any textbooks. But what I was focusing was mostly our the centuries, our understanding of infective and the card at ease, uh you know, evolves from early descriptions with post mortem findings, were more specific descriptions of the legions of this disease, identification of microorganism and infective and the card itis. And until we get a good picture of This disease toward the early 20th century, this is the end of my talk and I hope you enjoyed it and if you have any questions, I'll be happy to answer them.