 Okay, well good morning and thank you very much to the organizers of the conference for inviting me. It's a great pleasure to be here. And Stephanie, that was a great talk. It was taking a really complicated topic in which we're all sort of operating in the dark and sort of making it manifest and the number of people that come into clinic wanting to discuss estrogen and low T are huge. I was, I'm giving a talk today on peripartum cardiomyopathy and the first part of it is going to be fairly standard and then I'm going to deviate a little bit into some interesting immunology and some speculative data that should just be a little bit of an appetizer again for things to come. First of all, I need to tell you that maternal mortality in the United States is actually rising substantially and this is a very frightening statistic. In many, many countries the maternal mortality has decreased but the United States unfortunately is a glaring exception and I know that, you know, there's a mantra in the United States we have the best healthcare system in the world, we have the best healthcare system in the world but if you think about maternal mortality as an important reflection of that we are really not doing so well. A recent report by McDormand et al. found a baseline mortality rate of 18.8 maternal deaths per 100,000 live births in 214. If we contrast this data to Germany or the United Kingdom they are both reporting 6.7 maternal deaths per the same 100,000 live births and I think it's also really important to underscore the fact that African American women have a maternal mortality rate that is double that of Caucasian counterparts and this was actually detailed even as early as 2007 by a Texas legislative report. To put that graphically this is a fairly, this is comparing maternal mortality rates between 1990 and 2013 in a number of different countries and as you see we are not really doing so well our maternal mortality is sharply rising, we are doing far worse than New Zealand, Canada, Netherlands, Australia, Denmark, Singapore, Norway and Switzerland. Now if we delve into this a little bit further and we say what's going on it's still not entirely clear but we seem to be doing a little bit better in hemorrhages, obstructive labor a little bit more, sepsis a little better, hypertension about the same and then we have these sort of murky categories of indirect, late and other direct which are not, which seem to be sort of a grab bag of other causes that are contributing to this. So I think first of all we need to put this peripartum cardiomyopathy data into this context that we are not doing a good job for our mothers and for the children of these mothers at the moment and I think that this is almost, I mean this needs to be a real call to action. So let me talk to you a little bit about peripartum cardiomyopathy because this is a very interesting and very tragic disease, I mean this is, I saw my first case of peripartum cardiomyopathy when I was at UCSF working with Nora Gulchlocker and we were taking care of a young African-American woman who developed this terrible heart failure shortly after having her first baby, unfortunately she did die of this disorder leaving an orphan child and so this is the kind of illness that when you lose a young mother it has echoes in the family and in the child's life forever and so it really is a multiplicative tragedy. We have a recently revised definition and that is this is an idiopathic cardiomyopathy presenting with heart failure that becomes manifest towards the end of the pregnancy and in the months following delivery where no other cause of heart failure is identified. So it's a diagnosis of exclusion and when you see these people we have to take a careful family history and we have to think is there a family history of cardiomyopathy in the family? Did the stress of the pregnancy seem to unmask that cardiomyopathy? Is there lupus or are there other causes? Was the mother hypertensive and so you really have to go down the laundry list and you know have they been diabetic for 10 years what and so this is really a diagnosis that is reserved for people who get very very sick out of the blue in the pregnancy with no recognized risk factors. So what is the incidence and in fact the incidence varies very widely so there seems to be a genetic predisposition for this it may be other things as well. One in 100 live births in Africa women experience are diagnosed with peripartum cardiomyopathy. One in 100 live births also in Haiti. One in 3,000 live births in the United States and one in 6,000 live births in Japan. And recently an increase in the incidence of peripartum cardiomyopathy has been recorded in the United States. Now we're thinking it's closer to 8.5 to 11.5 for 10,000 live births. So why is this and we don't know all this data is pretty hand-wavy and speculative. We think that you know people say it's due to the increase in maternal age it's increased it's I'm sorry maternal age as opposed to just yeah gestational age increased multifetal pregnancy incidence because we're having we're using more reproductive technology and improved diagnostic capability but at the end of the day we don't know we don't know. What are the risk factors well really for risk factors have been defined African American descent and older maternal age multi-fetal births and hypertensive disorders during pregnancy. Those are the four things that have really and again that have really come out as being risk factors. So what is the clinical course of this disease and again it's widely variable. The old teaching used to say and it's probably not really too different than the old teaching a third, a third and a third. A third of them get worse. A third stay the same which is usually bad and a third get better. So again you know it's really an all bets are off situation. Some of these women do with medical management and good good good care really get back to a fairly normal ejection fraction. Some have persistent left ventricular dysfunction and some progress to cardiogenic shock requiring you know assisted technologies such as L-vads or they also may require transplantation. So again it's a scary disease. So again it's a scary disease. Multiple mechanisms have been proposed in the literature and again it's a potpourri of things. People have implicated low selenium, they've speculated about viral infections, the usual round up the usual suspects, stress activated cytokines, inflammation although that there's less evidence for that autoimmune and alloimmune interactions which I'm going to actually talk about a little bit later and vascular disease associated with the hormonal changes of pregnancy and then you get into these really speculative explanations, unbalanced oxidative stress or pregnancy leading to angiogenic imbalance and impaired cardiomyocytes that you know those kinds of explanations that are a little short on details. The other thing that you should know is there is an association with peripartum cardiomyopathy and preeclampsia and I'll get to that a little bit later as well. So clinical recognition and again it's often delayed as when you're seeing a young healthy woman going through pregnancy it's not the first thing that you think of when you have somebody who says you know I'm pregnant I'm short of breath. There is a condition called dyspnea of pregnancy which is thought to be hormonal. There is also the issue of when you have a big baby in a little person there is some impairment of your respiratory function but one of the things that happens is these women don't get diagnosed in a prompt matter because there are sort of these other explanations. Well, you're just tired, you're pregnant, what do you expect and they look at it as part of sort of some of the you know the normal pregnancy so it can get missed. The typical for these women the presentation of congestive heart failure is fairly typical. There can be EKG changes, there can be pulmonary congestion on exam and on radiographic studies. If they do get echoed you can start seeing left ventricular systolic function and for this definition an EF of less than 45% is required you can see elevated biomarkers so BNPs and tropononemias and the prognosis is it carries sort of a not so great prognosis. There is a mortality of 19% in the general population and in the African cohorts up to 30% and whether it's a slightly different disease in that group of people or whether it's a function of the medical care is less good it's hard to say there as well. So in the recently published IPAC study which is Investigations of Pregnancy Induced Cardiomopathy for and they looked at 100 patients the one year mortality was 4%. By year one 13% of women had experienced life-threatening events and that would include either death, requirement for transplant, LVAD or persistently low ejection fraction and heart failure. The event free survival was 93% and the event free survival was much worse than the women that had the very low quartile ejection fractions. I had a patient that I've taken care of since 2008 at the time of diagnosis her ejection fraction was 11%. She's now sort of, she gets by but she's never fully recovered now seven years later we're managing her and her ejection fraction is about 40 to 45% but she's had arrhythmias, other complications and is still on lots of medication to try and maintain that recovery. Spontaneous recovery occurs in about 33 to 72% of cases but even women who are recovered and in fact we don't really even anymore so much think about these people who improve their ejection fractions so much as a recovery because I think it's probably a misnomer and it leads people to think everything's fine is more of a remission okay. So we can have these people that are very sick with cardiomopathy you take care of them with all your the tools in your armamentarium and they have a remission and they can improve their functional status but underneath it they probably still have a cardiomopathy and the reason that that semantic is important is because if we say that they've recovered they often go out to the GPs or see other doctors and they'll say the notes say you're recovered why do you need all this medicine let's stop it and that's a little bit of a sporting thing and we've all seen patients like this come back very sick again when someone is just sort of spontaneously stopped all of their evidence-based medication. So recurrence can occur and subsequent pregnancies are inadvisable. Whenever a woman is diagnosed with peripartum cardiomopathy we strongly caution them please do not fall pregnant again. Now that's a pretty tough thing to tell a young woman and we have a girl right now in the ICU who was very young girl very nice girl she had a pregnancy her ejection fraction she was very sick her ejection fraction improved to about 30% and unfortunately she had an unplanned second pregnancy which she carried to term and she's now upstairs on a balloon pump with an ejection fraction of about 11% and you know her young family you know she's got two young children now less than three years old a baby and this young child she's got a young husband I mean you can imagine the stress of the situation. In what we call recovered women again I don't love that term but it's in the literature 21% of women will reduce their ejection fraction by another 20% with a with a subsequent pregnancy and in unrecovered women 44% will suffer further reductions in their ejection fraction. The mortality in this unrecovered group is significantly higher overall a one-third of women will suffer further deterioration with another pregnancy and so I really try and counsel women in the strongest possible terms and I plead with them and say it's really important to be around for the baby that you have and I you know I try to appeal to them on all sorts of but people are very reluctant to be told that they can't have more children it's it's it's something it's part of our biologic thing. Now I'm going to start and I'm just going to sort of take a little you term because that's about what we know about peripartum cardiomyopathy and what I want to do is I want to sort of tantalize you just a little bit with some with the fact that pregnancy we don't even though we're pretty sophisticated in 2016 we really don't know that much about it frankly and I got very interested in alloimmunity or the immune responses that were involved with pregnancy because I had a son my second son was born in 1994 I'm sorry 1998 that's Daniel and he had hemolytic disease the newborn from something called anti-cal antibody. Now my my husband has an antigen on his red cells he's a hematologist so I always say this is all his fault but he has an antigen on his red cells called anti-cal called cal and it only about four percent of the population has this and so it's very analogous to the anti-D which you probably learned about in medical school so your first pregnancy so I'm cal negative my husband's cal positive our first son was cal positive and during that pregnancy I was exposed to his fetal cells and I made I had a huge it's an extremely antigenic thing this glycoprotein on the red cell and I made these huge amount of antibodies I didn't know it who would know and then when I had a second pregnancy we did fortunately discover that I had this because then the antibodies that I made then attack the second pregnancy because of course the second baby also inherited the anti-cal from his dad now this is a really interesting antibody because what it does is it cuts off the fetal cell erythropoiesis at the progenitor level so the granulocytes are okay the platelets are okay but these babies stop making red cells it's the weirdest thing we don't know why they do it we don't understand it but so Daniel was born in 1998 he was called the miracle baby when we were living in Australia we had to treat him with intrauterine cord transfusions and remember the cord is really little when they're like 20 weeks old his hemoglobin was three he was in high output heart failure his liver filled up his whole abdomen on the ultrasound so it was a pretty hairy deal this is Daniel at born at 34 weeks he was about four pounds we decided at this age the risk of transfusion because every time you transfuse the cord you can clot it off so we decided that the we delivered him early because of the attendant risks this is Daniel now he's a Shakespearean acting student in New York so he's obviously done very well but I got very interested in all this aloe this auto this immune response that women have to pregnancy and I think there's something really interesting here and I'm just going to give you a little primer this morning about pregnancy and immunity because it's super interesting and I think you'll be seeing more on this in the next few years so humans are you theory and that means that we're placental animals and this is allowed in internal organ which is the uterus to protect and nourish fertilized eggs and allow for the birth of a highly developed offspring now the real question is why don't we reject our babies the way that we would any other foreign tissue and I'm a transplant doctor so this is also interesting for me in that respect so our fetuses are semi allergenic meaning half like mom half like dad immune tolerance is mediated by by the placenta which is made up of two love layers of baby so fetal trophoblast cells and one layer of mom which is the maternal deciduous and graphically that sort of looks like this this part the deciduous is is mom and here are the spiral arteries and then these two layers are baby and this is the part that leads to the this is the umbilical vein and arteries so this is a very interesting structure again we don't know that much about it so let me just give you a little bit of immunology about pregnancy because it's super interesting trophoblast trophoblast cells form the interface between the fetus and the mom they escape aloe recognition okay so recognition of this baby is a foreign object because they lack HLA class 1 and class 2 molecules which are how which is the basis for recognizing self versus non-self any aloe immune response must be carefully mediated to keep a pregnancy in homostasis it's very important stuff the trophoblast plays a permissive role in allowing a bi-directional exchange of traffic at the maternal fetal interface and remember the baby is immune naive but the mother is immune mature okay so there are going to be different responses to these shared cells so the exchange of cells gives rise to maternal micro chimerism and the fetal circulation so the baby gets the mother cells circulating and the fetus and the mother has fetal micro chimerism we have women who've had babies have fetal cells circulating and this is a really cool area both types of micro chimerism last well beyond the pregnancy itself so ladies your children are still with you fetal micro chimerism in the mother may begin at seven weeks of gestation and may remain in the circulation up to 27 years postpartum and interestingly there is some emergent data suggesting that it's this fetal micro chimerism which may partially explain why women actually live longer because you get this bolus of stem cells at when you have babies maternal micro chimerism in fact may be lifelong owing to the immature state of the fetal immune system so your your your children may always have their mother's cells with them okay maternal immune cells may become sensitized to these inherited paternal antigens okay so once once you have a baby it's half like you half like dad this fetal cells are circulating in the maternal circulation and that means that you can make an alloimmune response to these cells that are half different than you and those are called inherited paternal antigens and this can be reflected in the formation of anti HLA antibodies in a significant proportion of women that have babies we run into this all the time in transplant where we have women who have had children and they have very high levels of panels of reactive antibodies because of this exposure to these inherited paternal antigens so these fetal derived chimeric cells which are circulating in mom remember we can find them at least up to 27 years they can induce these alloantibodies autopsy studies of pregnant women have located these these chimeric cells in the on these are women who've unfortunately died when they were pregnant in lungs, spleens, livers, kidneys and hearts to a greater extent than non-pregnant females to make the story even more complex women often harbor micro chimeric cells from their own mother so the grandmother of the baby your own mother for your lifetime so those are called non-inherited maternal antigens so it's a complicated immunologic milieu so there is a bi-directional cell movement of cells during a normal pregnancy this is associated with the development of the fetal immune system so they need those cells to start priming the the naive fetus there have there is the development of tolerance mechanisms which are associated with maintaining a healthy pregnancy there's also the idea that fetal cells have some role in tissue repair or in create or in autoimmune disease and immune surveillance now if tolerance is not established towards a pregnancy this can result in fetal wastage during the pregnancy via a maternal immuno immunologic response directed towards the fetus which is semi allogeneic so what I'm trying to say here is that there's a delicate balance between immunologic priming and immunologic tolerance in a normal pregnancy mothers and babies are different clearly chimeric cells acquired from the mother during the fetal life occurs again when the fetus is immune naive and in the fetal cells as an immature immune system and so there's not going to be much of an immunologic response on the other hand chimeric cells that enter the maternal circulation are encountered by a fully mature maternal immune system so this is I'm going to take one more little turn here and I'm sorry if this is I hope everybody's had their Starbucks because this immunology stuff is a little out there the adaptive immune system is what we refer to when we talk this is evolved so that we recognize and remember a unique diversity of antigens the cells of the adaptive immune system are educated and instructed as our marine system develops not to mount a harmful response towards antigens that are encoded by our own genome so in other words this is how we don't destroy ourselves in humans this is all mediated by the major histo compatibility complex and this is called the HLA complex so and there are two types and I'll get into that in a minute the HLA or MHC complex consists of genes that includes cell surface glycoproteins that are required for antigen presentation to see T cells and antigen presentation of other pathogenic like viruses and bacteria and things like that each individual has a specific MHC and HLA protein and it functions just like an immunologic fingerprint this will help your immune cells distinguish its own cells from foreign cells transplant rejection and I'm jumping into that because it's related to this remember you know a transplant we match these organs but they're not a hundred percent like the the donor and recipients and transplant are not haplo identical unless you have an identical twin that gives you a kidney or something which is fabulous but in most cases that's not the case never in transplants for hearts transplant rejection occurs because the immune system recognizes the transplanted tissue as foreign due to an HLA mismatch and the immune response is similar to that directed towards any other foreign particle I will get back to pregnancy in a minute the MHC genes and code proteins are involved in antigen presentation to T cells and T cell receptors and the outstanding feature of the eight MHC molecules is their extensive polymorphism which is critical so there is a huge amount of variability and there is a huge repertoire so that we can fine tune this immunologic reaction that distinguishes self versus non-self there are some differences between MHC one and two MHC one is encoded by all nucleated cells in the body they are encoded on two different several different genes and they are structurally somewhat different than MHC two and the MHC two the MHC one is involved in cell mediated immunity and MHC two is involved in these antigen presentations to T cells now there are several different pathways and you don't have to remember all the details of this but immune responses occur mainly against MHC one and MHC two genes there are a direct and indirect and a semi direct pathway I don't expect you to remember the details of all of this but they have different time frames which in the transplant world is really interesting T cells are critical to the strategy that is involved to suppress immune reactivity to fetal antigens that are foreign to mothers just like occurs in the transplant literature and again remember guys that we didn't know anything about T cells until the HIV epidemic we didn't know we knew nothing until the 1980s so this research and our understanding of this work is still in its infancy I mean the HIV epidemic as horrible as it was it really elucidated all of the mechanisms by how T cells work because of course HIV you know attacks the T cells so the T cells or T lymphocytes play a central role in the cell mediated immunity they can just T cells can be distinguished from other lymphocytes such as B cells and natural killer cells by the presence of the T cell receptor on the cell surface okay and there are different types again I don't think we have to go into a lot of detail about this there's CD4 cells which is refers to a glycoprotein found in the T helper cells monocytes macrophages and dendritic cells and CD8 cells that are cytotoxic cells that are involved with this the T cell receptor binding to MHC so all of these are implicated in this very complex process again there's a direct and indirect and semi direct pathway and again I'm not going to expect you to know the details but one of the really interesting things if you look at these little graphs down here at the bottom and they're small but they're really interesting you can see that in this is in the kidney transplant literature that the direct pathways and the semi direct pathways are very important early in transplant and this is where we see the highest levels in early transplant when we were talking about rejection and we have to immunosuppress people the most heavily right after they've had a transplant of foreign tissue however one of the things I tell patients all the time when I try and explain to them why a transplant doesn't last as long as a regular organ is that we can fool mother nature some of the time but we can't fool her all the time and this is really red and this is really reflected in this indirect pathway which you can see gets upregulated and probably is more important over time and it's probably the reason that you know we get coronary vasculopathy in a transplanted organ it's the reason we get coronary we get can or nephropathy in a renal transplant so it's the reason it doesn't last as long as a normal organ would because of this low-level aloe immune response okay we are going to get back to pregnancy remember pregnancy is unique the fetus harbors antigens that the immune maternal immune system has not been exposed to a key strategy that's evolved to mediate this maternal fetal tolerance is this T regulatory cell and it specifically suppresses immune reactivity to fetal antigens that are far into the mother and these these cells are the cornerstone of immunologic tolerance during pregnancy and in in a normal pregnancy there's a specific regulation towards NEMA on the fetal side so non-inherited maternal antigens the mom stuff that the baby sees and towards the inherited paternal antigen the stuff from the baby that is far into mom that the mom sees so what is the evidence that peripartum cardiomyopathy involves aloe immune and autoimmune dysregulation well it's actually increasing and we're in the early days of looking at this and findings that auto antibodies against the adenosine nucleotide translocator ant and remember ant is like the last step in creating ATP in your mitochondria against a branched chain alpha keto acid dehydrogenase and against cardiac myosin were found to be significantly higher in patients with peripartum cardiomyopathy compared to pregnant controls recent reports also suggests that they're significantly higher beta one adrenal receptor and myosin or in other adrenal receptors auto antibodies and peripartum cardiomyopathy patients compared to controls and that the titers of these antibodies are actually correlated to the severity of cardiac dysfunction and negatively correlated with ejection fraction so and I'm gonna just say one other thing because I mentioned to you earlier in a previous slide that it appears that preeclampsia has a relationship now preeclampsia is thought to be a problem directed at those spiral arteries connecting mom and baby some sort of dysregulation there I mean there are a lot of theories about that as well I won't go into that but there is a relationship between these two illnesses again preeclampsia is responsible for 15 to 20% of maternal mortality so it's contributing to that excess mortality that I showed you in the first in the second slide there's an 11-fold increase in hypertensive moms and the preeclampsia the incidence is doubled in African-American women compared to Caucasians recent studies show increasingly that preeclampsia is associated with poor trophoblastic invasion as a result of altered production of immune regulatory cytokines and angiogenic factors so this is something we need to really understand a lot better and in this disease they've able been able to find very high levels of anti-angiotensin antibodies against and they're present in 70 to 95 percent of preclamping patients and there is a very strong correlation with disease severity so I'm just sort of throwing that out there to give you a little you know pregnancy immunology 101 because I think this is going to be where the money is going to be at in this peripartum cardiomyopathy and probably even in preeclampsia maternal mortality rates are increasing we need a lot more attention to this area we need to understand something that's so basic to how we survive as a human race we need more basic studies we need good registries for both peripartum cardiomyopathy and preeclampsia including bio banking and you know serum from moms looking at antibodies DNA from babies remember a lot of times and we don't know the role of having lots of different fathers which would also expose you to different inherited paternal antigens that's something registry data could probably shed some light on and we certainly need a more concerted societal effort if we're going to prevent maternal and fetal mortality so I'm just going to close this by saying mothers lives matter so thank you very much