 Thank you, Jim. A pleasure to be here to talk about something new and improved, something funny or interesting or confusing for many. We would like to reassess the subject, this little chapter in cardiology, because I think we are almost ready to make sense and create a mature culture in a field that has been confusing to many and possibly important, possibly mild and irrelevant. Let's see if we can start with an idea that comes from pathologists because they have the best pictures and comment on this typical autopsy of a patient that dies of cytokinesic death and has an unusual amount of trabiculation around the apex, but obviously also hypertrophy of the heart, 15 versus 6 at this point. This is what in clinical grounds we call non-compaction. The pathologists tend to disregard the trabiculation. They say they are irrelevant most of the time. But this is the question that we want to address today and we want to touch the subjects from several different sources. One is the main source that brought me and our group interested in this field. It is what Dr. Willison was mentioning, the screen to prevent study or the screening of several kids in a study of a large population in Houston that came up with an incredible prevalence of this condition in the general population. Then we'll talk about embryology because this is obviously something that is decided during an abnormal behavior in embryos. Then we'll talk about comparative anatomy. Many animals live with the hypertrobacular heart and we'll see how frequent it is, how it affects their lives. Finally, we'll talk to the subject of the spectrum of presentations as seen from the pathology point of view. I have been working and Dr. Max Bouya is here with the pathologist here trying to see several different issues in the autopsies and when we discussed the incidence of non-compaction in autopsies I was told that no, we don't really have a name for that nor a criteria to identify and it doesn't look to be so important at this point. Let's see if we can improve that background culture on this subject. We'll come to describe in more detail what we called the garden variety of non-compaction and ventricle and we'll differentiate it from non-compaction cardiomyopathy. We'll talk in detail of the findings of the MRI study showing the spectrum of forms and finally some elaboration of the possibility of evolution of a non-compaction congenital condition into a cardiomyopathy because of what we do in life, not only because of growth but because of exercise, aggressive exercise. First the data from this study of ours, 5,243 students in the middle school basically but age 11 to 19 years of age, a group of people that were tendentially asymptomatic and involved in sports at the very early stage. 70 people were found to have high risk cardiovascular conditions, 1.3%. And out of this condition that we don't want to describe at this time, we found 992 patients, 18.73% for the whole group, they had non-compaction ventricle by the criteria we'll discuss here. The preference of non-compaction is established by the Peterson criteria. Peterson in radiology with MRI has proposed and widely this is the standard for definition of non-compaction that the heart has non-compaction to compaction ratio of more than 2.3 is 2.1 is a non-compaction ventricle, cardiomyopathy is still debatable. By echo this is different is more than 2.0 in insistently why this is endiastomy. This makes a lot of difference obviously and the frequency of non-compaction in the CAT lab until recently I don't know if there is any large statement at this regard on prevalence but in the echo labs they say that 0.14 or 0.1% of the echoes have non-compaction. Non-compaction criteria will tell us that the majority of our patient or candidates for sports have more than 40% ejection fraction, 100%. No one has severe cardiomyopathy but mild cardiomyopathy is seen in 10% of these kids. It's interesting that our candidates 3,200 or 60% reported working out more than six hours a week with the equivalent of running. Let's see what embryology can tell us. Embryology is obviously where the action is and where the problem starts. Initially during the first week the heart is a straight tube and is composed in its wall by a monolayer of myocytes inside the cardiac jelly. In the inside of the heart there is an endothelium that has an origin from the bone marrow and the external wall of the heart is naked at this time. It's only later on during the first month of life the proepicardial organ, a group of cells coming from the south of the border below the diaphragm, from Mexico probably, from the liver. They bring the blood, the cells, the population of cells that eventually will form the basic structures of the coronary arteries. From a single layer of myocytes the heart develops a thicker, gradually more obvious, especially at the level of the apices of the heart, trabeculations that develop from the origin of myocytes. At the end of the first month a dramatic event occurs in the life of a human embryo which is the closure of the septum between the aorta and pulmonary artery and the formation of the aortic valve. That valve is essential for the development of coronary arteries or proper function because a high diastolic pressure is the condition to have a diastolic predominantly blood flow to the myocardium. At the same time the ventricle septum structure is completed and the coronary arteries that were in the subepicardium cells form some channels and eventually touch the aortic sinuses and start the circulation. Let's see in the section of the heart that this is a drawing coming from the website of somebody, this is the only notion that I have of the origin. The thickening of the heart tube brings the heart to have pouches of the prospective right ventricle and left ventricle with a thick myocardium, compact myocardium outside and trabecular heart with opening into the main cavities in the upper portion. It is normal for the embryo to have more than two to one, usually it's five to one ratio between non-compaction and compaction, so this is an embryologic non-compaction. If you make a cut a few millimeters from the apex you see a lot of trabeculations they have myocytes but no function of myocardium, the ventricular septum starts composing, there is a very thick layer of cells, the proepicardium they form the coronary arteries, but in a few days you see something so tremendously different in the structure of the myocardium of the left ventricle but also the right ventricle where the outside little layer of the compact muscles is now added as a continuous space, muscle with a great number of inter-muscular spaces, they are covered by endothelium, it is very likely but it was never demonstrated that this is the way the intramiocardial coronary arteries, septals and not are formed. Eventually the myocardial trabecule disappear gradually and almost totally inhuman to leave some 10% of the space occupied but the majority of the heart is compacted and wins the myocardial vessels and it is impossible for the heart to form back the non-compaction, there are several papers in the literature saying appears and disappears of non-compaction in adults, don't believe a single word of this. In animals it's interesting to see that many animals live with non-compaction hearts, this is a study recently published by Jensen and associates in Amsterdam, it shows that warm blood animals may have or may not have in adult heart trabeculations but many especially in the lower cold blood animals have trabeculation in the adult stage and they seem to be working very well including elephants, giraffe pigs with some level of trabeculations. They describe trabeculations as abnormal hyper-trabecular being this one by designing a sort of a border between the space between the trabecule and the popular muscles and the thick compact myocardium. They decide that 35% or more defines hyper-trabeculated or non-compacted hearts just a few examples, this is the full spectrum of patterns of myocardium, pigs have no trabeculations at all, human have some trabeculations, the normal is about 15 to 20% of the space occupied by trabecular, mouse which is an animal frequently used for experimental embryology has some trabeculations but sharks for example have mainly trabeculated coronary arteries only in the outflow tract and by the way this is continuous pressure is post the brankial system blood flow so it's a very inefficient way if you want to run away from a shark swim very fast for the first 100 meters it will give up my prediction is. This is a comparison between human and other animals basically in the more dramatic case in chicken before the separation of the artery, the appearance of the coronary arteries the 80% of the space inside the heart this is the point described by MRI is trabeculated at the end of hatching the muscle is compact pretty much all over experiment and embryology has been very interesting in trying to reproduce in animals the non-compaction studying the mechanism by which poor development eventually develops into a definitive mature heart and non-compaction the majority of the studies affected the activation of the not system the not system is an organizing system of local growth factors they are activated by molecules like MIB1 silencing these activators the heart develops non-compaction this is a molecules that is a mutation in several families with non-compaction cardiomyopathy in humans so it's a very interesting model that was tested with four different kind of experiments to give you an idea this is the normal wild type mouse control and this is the non-compacted left ventricular results of inducing a bed mutation. As you see this is a heart that is quite different than this this is this section of the heart this one is this section of the heart this is organizing compact myocardium on top of the pre-existent compact myocardium and it has this structure that again suggests that the inter trabecular spaces eventually gives vessels inter myocardial vessels. That this is a correct definition of non-compaction comparable to the human is shown by this picture this is the wild animal and this is the animal treated with this MIB1 mutation obviously is very similar to what we see in human. To give an idea of the organization in space of the non-compaction trabeculae you see with high definition electron microscopy the non-compact myocardium and the compact myocardium in such a detail that doesn't leave any doubt that these are not functional segments of the heart is pumping organ this is not a functioning myocardium this is more what Dr. Uribe represented with the name of La Barbita it's a decoration is not structural muscle. Conclusion embryologically early trabeculations are present in every human embryo and many with all animals embryos then compact muscle in human is the norm and highly trabeculated hearts may or may not function normally in different animal species. Let's see what pathologist have seen there are three mentions here of important pathologist that they showed a typical example of non-compaction this is Bill Roberts with the heart that I don't know by the history but apparently is an early adult age death or ex-planted without coronary disease severe cardiomyopathy and you see how complicated is the mesh of trabecular tissue at different level it gradually comes down to cover most of the periapical territory. Talking about the spread of possible manifestation on compaction this is a fairly frequent but usually irrelevant or asymptomatic case of a localized non-compaction where the myotrabecular apotrabecular mesh up here is accompanied by a deep penetration of intertravaculars spaces that goes to a minimal thickness of the compound myocardium at this point there's a little bulging here we never saw in the literature described in aneurysm from this in part because probably the non-travaculations of this bands of fibrous tissue or muscle protect from expansion because this is a very solid part of the structure if not able to contract is able to prevent dilatation. This is what we call the garden variety this is in a paper by Augustinia an Italian pathologist in Pavia where she uses the same criteria that we use in the cardiac MRI and more of the 2.3 to 1 thickness of the non-compact versus complex myocardium and a pretty preserved level particular function and size. If we try to place in terms of frequency and in terms of the number of periapocardium the number of no compaction in human the garden variety isolated and no compaction is a great spread of thickness of the non-compaction ratio and can go from 1 to 5. One is pretty much normal 5 is the most extreme case of development of apotravacular space the standard is now to add more than 2.3 to 1 and this is about 97% of the total number of non-compaction lead ventricle. The localized kind is very rare the proliferative kind that we'll show you in the next slides is also very rare. Hypertrophic hydromyopathy with non-compaction implies different genes without probability but we're not sure that exercise can also lead to the same condition. Different than the isolated non-compaction the ventricle is the rare 1% or slightly more of non-compaction associated with neuromuscular dystrophy congenital heart diseases interesting that the most frequent congenital heart disease in human with non-compaction is Epstein malformation a typical disease caused by poor elaboration of the compact and non-compact layers. Also in hypertrophic obstractic hydromyopathy we are seeing cases of non-compaction. This is the anatomic idea of case A hypertrophic non-compaction very thick cells not clear if this is related to exercise or a different genes that promotes thickening of this tissue but definitely always with a very regular shape and most likely this is non-functional myocardium but nobody knows exactly what happens there if there is ischemia is also a question. This level of hyper development of proliferation of non-compaction bands this is bilateral this is only leventricular this is what we call the proliferative hypertrophic and restrictive cardiomyopathy only transplants can take care of these cases and these are extremely rare. In the literature there are only two cases of sudden cardiac death accompanying pretty innocent non-compaction that ventricle. It is not clear how serious is this problem of arrhythmias. The impression that we are studying now with Anna Maria is that the Purkinja system doesn't reach the edges of this tissue that is muscular but is not probably functional and is very slow in activation. Potentially there is a background for reentry phenomenon but is not very well treated. In the literature several times it has been reported that it is difficult to pace these patients because the myocardium touched by the electrode is not communicating with the rest of the myocardium. This is fibrolastosis of the leventricle. In our experience some facts that they are very important is in this case the the thickness of the non-compacted the ratio between non-compaction and compaction is an easy simplification of the scripture that is more complex. If you look here the thickness of the trabeculations in millimeters you can go up to 16 or 1.6 centimeters and the average is 9 millimeters. So there is a large spread if you look at the compact myocardium and this is the most important part in describing the functional result of non-compaction leventricle. The thickness of the compact myocardium can be as low as less than 2 millimeters. The most frequent is between 2 and 3 but there are some that have very large almost normal leventricle compact. This is where it applies the Peterson criteria 2.321 is really able to identify most of the cases in non-compaction. Very few have labarbita. These trabeculations they are excessive but it's rare. 17 cases of 600 cases they were studied by short axis MRI. The great majority have a variable level of ratio but definitely above 2.321. Here very important is the ejection fraction. At the end what you measure is the function of the heart as a pump to see the relevance clinically of this anomaly of structure. And this is comparing in black and white and this is comparing in black and white and this is comparing in black, race, Hispanic, white and others. We have a pretty large spread of the population in our study but all of the kids had a pretty normal mean leventricle ejection fraction in the range of 61 percent. In this period 11 to 19 or in this slide is only 11. 11 to 16 we see that there is a major development of the leventricular mass. The leventricular mass in this four years of life increases by 30 percent. And it is where the heart responds the most to overload the aesthetic or systolic overload and eventually developing to myocardiopathies they may or may not disappear. The presence of non-compaction cardiomyopathy leventricle is not clear but probably affects especially the probability of occurring in the form of cardiomyopathy, dilated cardiomyopathy. I want to show you very dramatic pictures in motion by MRI that shows you the function of the non-compaction. You see non-compaction stays there inside the contraction of the compact myocardium. The intertubecular space is decreased and the space in systolic decreases in the non-compaction area but there is no active motion of the wall because of the motion of the trabeculae. This is another projection in the leventricular off-road tract view. Very clearly these are by standards the work is done by the compact myocardium. This case had a sudden onset of congestive heart failure and shock. It was very sick. It was published eventually with a different name but the initial author opinion was that this was a case of appearance in an adult of dilated cardiomyopathy because of non-compaction. In reality by echo that was the idea by MRI that I asked insistently to show there was not the compact myocardium, a normal myocardium but still a thin compact in a lot of non-compaction bands. The improvement was obvious but there is no appearance in adult of non-compaction. This is an athlete, very active, more than six hours a week of exercise athlete that had this as a routine not because of any symptoms. The leventricular free wall had a diastolic thickness of 2.8 but insistently this is typical of athletes. The thickness increases dramatically is not the typical case and it seems like exercise is good for this heart but this is a very typical non-compaction leventricular with this type of numbers. Another observation comparing MRI and CAT scan and geography the anatomy of the leventricular is much better studied in detail by CAT scan and geography but it is important to take pictures in the diastolate and then insistently not enough to take it only in insistently and it will show you not only the thickness of the wall much better than MRI but especially the subtle change in the construction of the popular muscles. Popular muscles in non-compaction leventricular are not implanted over the free wall of the left ventricle but on the non-compaction layers on the trabeculine and it is interesting and it is patterno-monic is sign of non-compaction. So what is the function of non-compaction leventricular? The non-compaction segment of the heart is variable in amount is 25 to 50 percent of the leventricular end diastolic volume and also up to 50 percent of the circumference of the leventricular profile. It is consistently incapable of structurally contributing to the leventricular systolic action of the ejection. The trabeculae are weak, especially disorganized, the blood in the inter trabecular spaces is compressed from the outside compact myocardium that is not in itself contracting to move the wall of the leventricular. It may be that the non-compaction especially in the adult where there is a fibroelastosis of the upper part of the non-compaction there is an action of a fairly favorable nature whereby the expansion of the heart that you would expect with the thinning of the compound myocardium is prevented because this muscle may work as cordae. It is still too early but we are going to know very quickly by pathologists if or not there are Pukinje fibers in the trabeculation, hyper trabecular spaces and if or not the EKG is normal, abnormal in non-compactual leventricular is now perfectly clear. Dr. Lopez has reviewed pretty much everything we needed to see. There is no increase in intraventricular conduction defects, it is not leventricular hypertrophy, it is not drive-ventricular hypertrophy, there are no bundle branch block typical of this condition and no T-way inversion that has sometimes reported but is related to athletes' heart or additional mutations. Complications of non-compactual leventricular, very rare in isolated leventricular that basically should not be called in itself cardiomyopathy but it may become cardiomyopathy and most of the time it will be because of additional mutations that we need to understand. Arithmias is difficult to see, we never saw in this 5000 people or especially in the 982 that had the non-compactual, a single PVC but I am not sure about that data, we need to do halter and treadmills and thank you Dr. Wilson is an expert on this, he has seen some athletes and is pretty reassured by the lack of significant arrhythmias with the maximum exertion. Aneurysm is never, the late-academiopathy increases steadily in our population, doubles between the less than 14 and more than 15 years of age, so there is a tendency that needs to be monitored. Potentially clinical consequence is very interesting to mention to a clinical audience. The fact that there is a thin myocardium means that there is like a scar by leventricular myocardial scintigraphy, so a positive stress test, a nuclear stress test is to be expected in many of these 982 kids that go or adult that remain with non-compaction with thin myocardium. Straight pattern is something that Juan Carlos is going to study with us hopefully and we will see also if Legadolinium enhancement, there was reported recently as a sign of non-compaction is really ischemia or scar or just a different amount of muscle that may or may not behave like a functional muscle in this context. The association with genetic mutation needs to be studied specifically, and this is for AJ, in people that don't have cardiomyopathies, there should be a typical mutation, probably many less than what was suggested by the experimental pathology in Imbraeus, suggesting 19 percent to have normal leventricular function should have some genetic mutation, they are probably different than the ones that come to the observation of the doctor because of congestive failure. So all this needs to be studied, but in conclusion in my mind at least in human non-compaction leventricular is generally a frequent anomaly of the leventricular architecture, not intrinsically a cause of dilated cardiomyopathy. Occasionally it may be complicated by cardiomyopathy, most likely by additional mutation associated with it, strenuous exertion, especially pressure related, main use, progressive dilatation of the ventricle that is thinner than normal in the free wall. And this is pretty much the group of enthusiastic collaborators that help with this, both radiologists, administrators, and a lot of fellows. Thank you very much.