 Hi, I'm Stephanie Coulter, and I'm the Assistant Medical Director here at the Texas Heart Institute. I also serve as the Director of the Center for Women's Heart and Vascular Research. And I also run the Cardiovascular Disease Fellowship here at Texas Heart Institute at Baylor St. Luke's Medical Center. I have here is my esteemed colleague and guest, Dr. Zvonimir Krazier, who's going to help me in this discussion about COVID-19 and the cardiovascular complications therein. Welcome, Dr. Krazier. Thanks for coming. Thank you, Stephanie. Dr. Krazier is an interventionalist cardiologist at the Texas Heart Institute at Baylor St. Luke's Medical Center. He serves as the Program Director for Peripheral Vascular Intervention at THI, is a clinical professor of medicine at the Baylor College of Medicine, and is the immediate past president of the International Society of Endovascular Specialists. Today, we are going to discuss our understanding of COVID-19, and we're going to talk about its diagnosis, its prevention, and treatment, which is rapidly evolving. Without a risk model for cardiac complications, healthcare providers on the front line, such as us, have had to work to understand the clinical variables and cardiovascular complications in order to identify best and predict various response to treatment and the modalities that we should use. In response to the evolving COVID-19 pandemic, the Texas Heart Institute dedicated its technology and techniques education series to provide perspective to the healthcare community, taking care of cardiovascular patients and facilities in which COVID-19 patients are receiving treatments. The discussion that follows today is really a compendium of all the discussions that Dr. Krazier and others have had over the last really 12 weeks where we've had, Dr. Krazier, how many have we had so far? I think we have done 11. 11 series where we look at state-of-the-art discussions as the literature and not the literature as podcasts have evolved. The first series that we conducted was in reference to a paper that one of our former fellows put out, which looked at the effects of the coronavirus on the cardiovascular system in late March of 2020, and we had a discussion with Dr. Majid on that day. And really, at this point, we really had very limited information that was really coming from China, which looked at how did the virus work, that it was a single-strand RNA virus, that it attached itself to the angiotensin converting enzyme 2 receptor, which is really the way the bug invades the body. So it has been known to invade the epithelial cells of the respiratory system, and more important, and in more recent findings, we discovered that the virus directly invades the endothelial cells of the vascular system, which has led to a whole extra lot of complications that have really been elucidated through the observational studies that have gone on in America from both Seattle and to New York. And very interesting. We also know now that from series from both China, from Seattle, and from New York, that there are predictors of in-hospital death due to COVID-19, most importantly, age over 65, male sex, history of coronary artery disease, a history of heart failure, a history of diabetes, which is not included on this, a history of hypertension or even carotid artery disease, have all been determined to be risk factors for in-hospital death. But in addition to this, some important cardiovascular therapies have been shown to be protective, and that includes patients who have hypertension or heart failure or heart disease that are taking ACE inhibitors, and those that are taking statins have been shown, as you can see in this slide, to have a protective advantage from dying in hospital from COVID-19. Again, you can see in another multivariate model where they looked at race, and then they looked at additional modifiers and looked to see if it changed the model. And still race being a black individual was a greater risk than being white, age in five-year increments, male sex, comorbidity index, as well as living in more close contacts. So in denser areas such as New York and in inner city locations have also been shown to be at put people at greater risk of developing the virus or contracting the virus and also from dying from the virus. Patients that had medical insurance that were more expensive fared better and certainly obesity played a role as well. Dr. Crazier, can you tell us more broadly what are these potential effects that the coronavirus has on the cardiovascular system? Thank you, Stephanie. We have learned so much in the last three to four months about the effects of COVID on the human body, not only on the cardiovascular system, but in general. As you have mentioned, the virus typically enters through the respiratory system, through the nasal pharyngeal sites and then through the respiratory tract. And from that point on, it disseminates in certain scenarios, particularly in patients that are at high risk, patients with comorbid conditions, throughout the vascular system. And it not only affects the heart, but also affects the whole vascular system, because as you have mentioned, it affects and it has affinity to the arterial system and it causes arterial dysfunction, destruction and inflammation. So heart is full of ACE2 receptors and they are present not only in their vasculature, but also in the myocardium. So as we can see here in this Dr. Majid's publication, very elaborate scheme of all the cardiac effects of COVID-19, we can see that it can cause obstruction, thrombosis, acute myocardium infarction. It can affect the epicardial or major vessels, but also it can affect the microvascular and elevates troponin, which is significantly elevated in great majority of patients with COVID-19 infection. But it also affects the myocardium and can cause myocarditis and then secondary due to obstructive disease in the coronaries or due to inflammatory process in the myocardium, it can cause malignant ventricular arrhythmias. So those are all the modalities where we can see how this virus affects the cardiovascular system. So it's starting to look like COVID-19 is a vascular disease because most of the injury and death rates are related really to patients that have risk factors for heart disease and evidence of heart inflammation or thrombosis in some blood vessel. Because the ratio of dying in patients that have elevated troponins is really significant. So the hazard ratio for an elevated troponin is at least four. And in patients that died of heart related deaths due to COVID, 51% of the deaths were in patients that had elevated troponin, as opposed to patients that had normal troponin. The rate of death in a big study out of China was only 4%. So it appears that troponin is a significant discriminator of risk. Absolutely. Now, one important thing is there are so far at least 12 or 13 coronaviruses that have been identified. And most of them are relatively benign. However, there are three of them that have shown serious effects as far as the cardiovascular system is concerned. One of them that was previously published was SARS Covirus. And after that, the MERS Covirus and then more recently SARS Covirus 2 that we're dealing with at the present time. As we can see from this particular publication from Majid and Jama, we can see that the other two viruses were significantly more malignant as far as mortality and morbidity is concerned. However, SARS Covirus 2 truly was presented in a large epidemic. And that is probably one of the major concerns that we are dealing with at the present time because of the extent of the infection that occurred worldwide. As we can see, as far as mortality is concerned, it is significantly lower with the SARS Covirus 2 than it has been in SARS Covirus or MERS virus. But of course, the numbers are significantly higher. We were successful in reducing the rapid distribution of infection with the other viruses while we were not as effective with SARS Covirus 2. Well, Dr. Crazier, certainly the asymptomatic and pre-symptomatic spread of this virus with its long incubation period certainly contributed to the speed with which this virus was able to spread silently through our population and contributes to the excess mortality that we're seeing across the world at this time. Can you tell us more about the thrombotic and embolic complications that we're seeing now in the patients in the US that are suffering, that are hospitalized with COVID-19, Dr. Crazier? Certainly, as we have already previously mentioned, since the COVID-19 virus has affinity towards the endothelium or the vasculature, we can certainly expect serious complications and problems such as thrombosis, infarcts, and embolization. Now, as far as risk factors are concerned, in general, related to the thrombosis, we have acquired factors and we have hereditary factors. Acquired factors include advanced age, as we already mentioned, patients that are inactive, patients that have some other inflammatory process, patients that are pregnant, obesity, cancer, hormonal replacement therapy, diabetes, sickle cell anemia, antifosphorylipid syndrome, and prolonged travel certainly within activities plays a role. Patients that have a significant heart failure, hit or myeloproliferative disorders, history of AIDS and the history of DVT are certainly at risk. Those are acquired factors. Now, there are numerous hereditary factors that lead to propensity to develop thrombosis in the vasculose system, such as bacterial or venous system, such as Factor V Leiden deficiency, thrombin-21-2-1-0-A, protein C and protein S deficiency, elevated factors 8, 9, and 11, elevated homocysteine, and also this fibrinogenemia, and 9-10 thrombin deficiency. Those are all the factors that lead to a propensity to develop thrombosis, typically in the venous system, less in arterial system. Now, another important thing is when we talk about SARS-CoV-2 and the vascular injury, that the effect of SARS-CoV-2 by affecting the endothelium and entering into AC2 sites, they stimulate inflammatory substances such as interleukin-6 and other ones to be very active, and that causes further endothelial dysfunction, and then also it affects a Pi-1 that increases tremendously, and by that effect, thromboplastin drops significantly, and all of those lead to thrombosis. Now, the excessive amount of inflammatory markers such as interleukin-6 and also Pi-1 can lead to cytokine storm that causes frequently irreparable damage as far as not only vascular system, but also multi-organ failure. So when we look at the early reports on thrombosis in COVID-19 patients, we can see that incidence is relatively high. It occurs between 30 to 35% of patients, and it can manifest itself in many different ways. What has been discovered that a lot of those patients have a micro thrombi or micro emboli in the pulmonary vascular chair, but they also have a hypercoagulable state by clotting IV lines, CVV HD lines, and we have learned that routine prophylaxis was not always used, unfortunately, and that led to more complications and more problems. Further changes were then initiated once we learned about those mistakes, but even with the proper anticoagulant treatment, the problems continued, particularly in patients that were in so-called cytokine storm. So then we adjusted the anticoagulant dose, and that was certainly helpful in certain subset of patients. One interesting thing is that it's important related to the use of anticoagulants, that the incidence of bleeding in patients with COVID-19 was relatively low and has been on an average reported to be roughly at 1%. Well, that's certainly some good news, Dr. Crazier, but we've also seen patients developing large vessel strokes in young people without any evidence of previous vascular injury. So patients that had no plaque development, no vascular risk factors, and suddenly presented actually in Wuhan, we had patients here in our medical center, young patients that presented with acute large vessel stroke that required treatment with mechanical thrombectomy and the interventional radiology suite. So we think that these patients that have acute COVID-19, that these are just more manifestation of the direct effect on the vasculature by the virus which has also been shown in an autopsy series recently from Mount Sinai where they did as quick, as fresh autopsy as you can get after a patient's death. Viral particles were seen in the endothelial cells in the vasculature upon death in patients that were overwhelmed with severe viral infection. You know, Stephanie, if I may add, so the virus can enter in the CNS system in the brain in several ways. One is through the vascular dissemination. Another one is through the respiratory or actually through the oral route and olfactory channels enters the brain and actually can affect the brain tissue, not only the vasculature but the brain tissue per se and that could also cause irreparable damage that is very frequently manifested with a lot of different scenarios and a lot of patients that actually recovered from the COVID-19 CNS side effects might have still some residual side effects such as seizure disorder, memory deficiency and a lot of other problems related to COVID-19 infection. It's amazing how much we learn as we go. The guidelines for venous thromboembolism, prophylaxis and monitoring have been updated and coagulation testing on presentation is recommended in all patients with COVID-19 that require hospitalization, PT, PTT, D dimer, fibrinogen, platelet count, CRP, ferritin, CBC and basic metabolic panel are all recommended and these individual labs are useful because they are going to help us delineate who are in the highest risk categories and are helpful also for stratification for clinical trials because some clinical trials are only available to patients with very elevated CRP, D dimer, ferritin levels. Clearly patients with elevated fibrinogen and D dimer levels over a thousand indicate a worse outcome and need for admission and careful monitoring. Thrombosis, prophylaxis and treatment recommendations are as follows. All hospitalized patients should receive pharmacologic prophylaxis according to risk stratification. If the creatinine clearance is normal or greater or is better than moderate, we recommend low molecular weight heparin with weight-adjusted regimens, but if the creatinine clearance is less than 30, we recommend unfractionated heparin with weight-adjusted. The monitoring of the PT, the D dimer, the fibrinogen, the platelet count, the creatin and LDH, which is important. The liver function tests are also recommended. But in patients with elevation of D dimer and in those with multiple organ failure, we recommend therapeutic dosage of unfractionated heparin over low molecular weight heparin, because it's easier to control. So, Stephanie, what we have learned in the last few months, really as far as COVID-19 is concerned, that we are building the ship as it sails, there was so much of unknown and there is so much that we have learned in the last few months. It's absolutely amazing how much has been achieved in such a short period of time. We're going to talk a little bit about preparedness, because obviously we're in a large medical center here and we've had to literally shake and roll as we prepared ourselves for the coming increase in caseload. Because COVID-19 is a new pandemic with enormous impact on hospitals, intensive care units, staff and equipment. We had to work to improve the safety of both our patients and our staff. We've learned that we had to think about the way that we optimize patient flow and isolation. We had to prepare special protocols for procedures knowing where and when do we bring the patients to the cath lab or to the echo lab or should we keep them quarantined in a COVID unit. We had to work on staff surging protocols because we didn't know and we didn't want to become overwhelmed by the virus. And we really literally had only 30 intensive care unit doctors who were available on our faculty and literally Dr. Krazier and I worked to help prepare a backup plan, which included cardiovascular ICU type physicians to man COVID units if it became necessary. We also had to work with testing as it became more available and more accurate and we had to streamline surveillance protocols for hospital personnel to make sure that the asymptomatic spread of the virus wasn't occurring in our hospital. So we went to special staffing models where we had half the doctors come in at one time and then while off we had surveillance protocols for testing to make sure that patients weren't given the doctors the virus and that the doctors weren't spreading it and to this day we have had a surveillance program here where we've looked at 700 personnel, both doctors and medical personnel and I can report that at this point we really did a great job Dr. Krazier and we only had three positive patients in that 700 member protocol. So we think that we did a really good job with prevention measures that we implemented because we were lucky because we were in the middle of the country so we had an opportunity to listen to our colleagues both from Louisiana, from California, from Washington state and mostly from New York and as well from Europe and from the Milan area or Bergano area in Italy so that we could plan and to use our resources in the best way we can. So we were very concerned that the safety of our team was threatened and at the beginning of the epidemic those that were helping to plan were worried that we were going to run out of PPE and we were careful to use our PPE but it was the safety of our medical personnel that we were the most concerned with because if your medical personnel go out sick and many others become quarantine the rate limiting factor on medical care is really your medical team. So keeping our team safe and healthy was really one of our strongest desires. So we made sure that we used our PPE properly, we canceled all elective cases and we really were on basically non-elective care for the cardiac community here in Houston for really close to, I'm thinking close to eight to ten weeks. We renovated our telemetry admission criteria and we renovated how we used the Echo Lab and how we utilized our equipment and we also looked at changing how we use the interventional catheterization labs and how we manage STEMI cases. So Dr. Coulter, can you tell me what has been done in Echo Lab as far as COVID-19 precautions are concerned and what is the optimal way to use the Echo Lab during this pandemic? Well, Dr. Crazier, the Echo Lab turned out to be more important than we knew because we didn't understand that COVID-19 was going to have such cardiovascular manifestations. So in patients that have shortness of breath, you know, the echocardiogram is one way to identify other comorbidities. So we tried a lot of things but what we really did was we tried to keep the COVID patients that were either presumed or positive out of the Echo Lab because we wanted to keep the Echo Lab relatively clean. So we decided that we would use designated areas that COVID-19 patients would stay in their designated areas and we'd use designated equipment for those areas. We had a specialized team that went through the hospital. It was an advantage we'd really been looking for and had the hospital buy about 40 of these point of care ultrasounds that could be used on location and completely enclosed in plastic to obtain portable studies with pretty good accuracy. So we implemented this into the ICUs of the COVID units and they became very helpful. Full echocardiograms could be performed but TEEs in high-risk patients because they are an aerosolizing procedure were quite a risk to all the healthcare workers. So TEEs in COVID or COVID suspected patients were highly censored and we only performed a few. All healthcare workers that were involved in TEEs of any patient were required to wear proper PPE which includes an N95 and a facial shield, gown and gloves. We also limited the number of healthcare workers in the rooms during TEEs because of the risk of aerosolization and the risk of spreading virus in asymptomatic patients. How accurate are tests that we have available at the present time in diagnosing COVID-19 infection? Well testing has improved dramatically during the beginning of the epidemic for patients that we knew for sure must have COVID-19. We were taking six days to get a positive test but as our hospital system became available we started doing more quick turnaround times and I think we can get a turnaround COVID PCR type test in four to six hours. We are not submitting cultures for viral culture because of the risk of infecting our virology lab but we're also recommending that patients that are suspected to have COVID-19 have a flu test and other tests that may be reasonable. We've only also just started doing serology testing. It's important because the PCR tests have about 85% sensitivity. So in patients that you are really, really concerned have COVID-19 and if the first test comes back negative we certainly recommend that a second test be performed as well as other kind of confirmatory blood work like a low lymphocyte count but as more immunologic tests or serologic tests become available we hope that a PCR test with an IgM test will be available in the near future to help improve the sensitivity of the PCR tests. Certainly IgG tests are now more routinely available to help describe whether or not a patient has had exposure at least seven days before to COVID-19. We're still not clear if the IgG test affords any immunity in the future. We are interested also in review of the treatments because when the pandemic first began we were really without any medical treatment except for supportive care and over the last really short amount of time, six weeks, we've had a lot of trials that have come forward. Dr. Kreiser, would you like to comment about this? Yes. As a matter of fact as you can see here in this information that was published in JAMA in March of 2020 actually. We can see that even at that time which is several months from past we can see that there were more than 30 studies that were ongoing with a variety of different antiviral and other medications and since then additional studies have been initiated. So we already have some answers but yet we're still waiting for additional information that I believe will be appearing relatively soon. Now as far as information that is available at the present time one of the very promising trials using Remdesivir showed kind of mixed results. Remdesivir is inhibitor or viral RNA replication with a specific activity against SARS and MERS and that has been a very effective drug for those coronaviruses that are no longer of a serious concern. The first clinical trial was marginally effective what it actually showed that the hospitalization time and the time of respiration and artificial respiration was shortened but there were no dramatic differences as far as mortality is concerned. The second trial that was a significantly larger trial AC-TT trial with over a thousand patients there were patients that were hospitalized with COVID and also pneumonia also used Remdesivir and this particular study lasted longer and showed significantly better results than the previous study with trends towards lower mortality with 7% mortality in patients that were treated with Remdesivir versus 12% of patients that were treated with placebo so there is at least a trend of benefit over Remdesivir in this subset of patients. What other treatments are we looking at Dr. Prezier for the treatment for COVID-19? Some of them that have been already shown to show preliminary promising results were Lupinavir and Retinavir which has been approved for treatment of HIV and of course interleukin and of course highly publicized use of chloroquine and hydroxychloroquine certainly is one of them that has been extensively studied maybe I should mention a few things about chloroquine and hydroxychloroquine hydroxychloroquine and chloroquine have been used for a very long period of time for treatment and prevention of malaria parasitic infection and also they are used for inflammatory processes such as rheumatoid arthritis and lupus and have been shown to be very effective. Now those drugs have been shown to be useful in inflammatory arthritis or inflammatory processes such as lupus but the drug has been used in relatively low doses. Now here when this drug was used in clinical trials for treatment of COVID-19 infection significantly higher doses were used. Another important factor when we talk about chloroquine and hydroxychloroquine is concerned a lot of patients with this type of infection also have significant cardiac effects. I'm talking about myocardial infarction, elevation of the troponin, affecting microvascular chain in the heart, myocarditis, pericarditis and also a lot of those patients might have actually ventricular tachyuritimias already due to infection with COVID-19 virus. Now when you enter using a drug that belongs to the QT interval and causes prolongation of the repolarization and dispersion of repolarization you add another component of ritmogenicity and propensity towards developing malignant ventricular erythmias and it has been actually discovered that in patients that were treated with hydroxychloroquine a significant number of them developed ventricular acardias or so-called torso de poins type of erythmias that are the most malignant type of ventricular tachyuritimias and as we can see on this study that actually there is no benefit from extensive clinical trial that were carried on in several countries with the use of hydroxychloroquine in decreasing mortality and morbidity using hydroxychloroquine. As a matter of fact there is a certain increased risk as far as cardiac morbidity and mortality is concerned so we have to keep this in mind. This drug is not safe to be used in patients with COVID-19 infections. So Dr. Krazier, the other treatment trials that are ongoing include the interleukin-6 inhibitors which are injectable monoclonal antibodies that target cytokine storm. There are two chemical preparations that are already approved for use in rheumatologic inflammatory conditions. So Tosalizumab and Saralumab have strict criteria for inclusion in clinical trials so we're encouraging all the patients that are very ill to be part of these clinical trials so that we can collect the data because these drugs are really expensive. They're monoclonal antibodies so they're not easily and readily produced for mass huge production and they do increase the risk for bacterial and supra infection with fungal etiology so they have to be more carefully targeted. So the only other treatment trials that are ongoing use convalescent serum which is the plasma where we used and infused the plasma with antibodies from recovered COVID patients and thousands of patients have been treated at this point with convalescent serum because in places where they're overwhelmed with COVID-19 infection there was really no treatment available outside of a study and convalescent serum could be collected at the institution and we've been using it as well. Dr. Crazier can you tell us about vaccine development? Well we're in very early stages as far as vaccine development concerns and we have to realize that to do a proper job there has to be a proper study done and from our previous experiences I'm talking about major vaccines that have been developed it took sometimes up to a decade to develop a safe and reliable vaccine and at the present time there is a tremendous enthusiasm in doing research as far as potential vaccines and to the best of my knowledge there are close to 100 potential vaccines that are currently being developed and analyzed. Of course very few of them will be eventually shown to be very effective and the reason for it is that to do a proper job you have to go to the exploratory phase you have to go through the preclinical phase you have to go through a phase one trial with maybe 100 or less patients phase two trial with a larger number of patients and then eventually phase three trial and all of those steps require time and effort to make sure that we don't have a significant side effect morbidity and mortality related to the vaccines and also that they are effective and doing a proper job so that's the most important factor the second important factor is are we going to be dealing with a significant genetic mutation we know that SARS-CoV-2 already is mutating and at least there are 13 strains that have been identified and whether all those vaccines that are currently being evaluated whether they are going to be effective for all those mutations it's certainly unknown at the present time and the other thing we don't know is whether or not the vaccine itself can cause hyperimmune enhancement which can lead to ARDS or a Guillain-Barre syndrome so we want to be careful before we unleash a vaccine that could cause healthy people to become disabled or sickened by a vaccine that's meant to prevent a disease now one thing that's positive as far as vaccines are concerned that we are in a certain degree ahead of previous vaccine developments for other illnesses for other viral illnesses that SARS-CoV-2 and MERS are very similar in design there are coronaviruses and have a similar genetic structure in a certain degree so a certain evaluation as far as testing for vaccines for SARS and MERS have been already initiated a decade ago or so on so we can certainly expedite this process and objectively the experts believe that probably we can get a vaccine that's relatively safe within the next few years or so well the whole world is watching and waiting as we're held hostage to this virus at this time outside of vaccine development Dr. Crazier there's still a lot of unanswered questions about COVID-19 how to test, how to treat but there are certainly some known things that we know about COVID-19 can you walk us through this slide it is not a typical viral pneumonia when we talk about COVID-19 infections and it's not a typical ARDS that we see with viral pneumonia so we have learned that using PEEP or high pressure on artificial respiration could be detrimental in this type of scenarios we have also learned that COVID-19 has a specific affinity to ACE2 receptors in the respiratory system and also in the vasculature ACE2 receptors are less developed in children we have learned that and less prominent in women and they are more prominent in men and they are more prominent in patients with hypertension and with other comorbid conditions we also have learned that COVID-19 is predominantly a systemic vascular disease or vascular injury that affects the endothelial system and causes endothelial dysfunction and that is manifesting the lungs, heart and other vascular systems causing organ failure, plaque disruption that leads to thrombosis and embolization it can also cause myocarditis and eventually causes cell destruction that can lead eventually to multi-organ failure COVID-19 causes also profound hypoxia and a lot of time it's not diagnosed early enough and this can then lead to serious consequences where the patient eventually ends up on a respirator in a scenario where this could have been prevented we also have learned how much we don't know about the COVID-19 disease and we still don't know what the most effective diagnostic test for COVID-19 or what a combination of tests might yield us we haven't really figured out who should be screened should the population be screened only sick in the beginning of the pandemic we only had very limited testing and we were only testing very sick and very symptomatic people certainly that was allowing people to spread the bug asymptomatic and pre-symptomatically we don't know anything about the risk of COVID-19 reinfection we don't know what the presence of IgG antibodies mean long term whether or not you can be reinfected if immunity is available we don't know how long it lasts we're not sure if COVID-19 will mutate and change the direction of vaccine development we don't really know what combination treatments are going to be available and which treatments are going to have the best outcomes and certainly we know relatively little what the long term sequelae for these patients will be so we have a lot to learn so we're left at the end of the day at the very beginning of a pandemic with a lot of interesting new knowledge and a lot of unanswered questions so we're going to continue to learn and we're going to learn as a medical community and these webinars that we've been making are hopefully helpful to our community to help us spread the word what we know what we don't know and what knowledge we can impart to our community I'd like to thank the participants of the Perfusion Conference as you know the Perfusion School is one of the oldest in America Perfusion was developed here literally on the grounds of this hospital so we're very proud to be part of your conference for those of you in the audience who are interested in more detailed information the Texas Heart website including TexasHeart.org has a series of more detailed lectures for your availability thank you so much for participating and Dr. Crazier thank you for helping me get through this again today it was a lot of fun thank you my pleasure