Cardiologist Clifton Watt, MD, offers new insights on the pathogenesis of heart problems resulting from COVID; breaks down the evidence on whether novel treatments – neutralizing antibodies and antivirals – have therapeutic or preventive value; then presents a risk-benefit analysis for the available vaccines, incorporating new data from a heart MRI study.
Thanks everyone for being able to attend. I'm going to talk a little bit about Covid 19. Uh and cardiology updates. Pertinent to Covid 19. So obviously a very pertinent topic. Um And I'll go ahead and get started. I have no disclosures for this topic. And so um just for my outline I'll talk a little bit about where we started regarding the COVID-19 pandemic, where we've gone. Um We'll talk obviously about variants which are very you know pertinent. Um um even to the present time Um we'll talk about what learnings we've gotten about cardiac pathogenesis of COVID-19. We'll go over some of the treatment data um cardiovascular safety of vaccines. This is a big topic that I get confronted with almost everyday from my patients and long covid and cardiac issues with long covid. Um So there's a lot to cover. Um I'll try, I'll go ahead and get started. Um So you know, started going back to, you know, this has almost been you know, two years Um since we had the first case of COVID-19. Um You know what what has been commonly thought was that the first cases Of COVID 19. Um you know, were discovered around December 2019 January 2020. Um one I wanted to bring up this this paper Which actually uh did an analysis using extinction models um in conservation science looking at some of the earliest cases of COVID-19. And actually based on estimates from this model. Uh I looked and saw that potentially the earliest cases came from potentially October or November 202019. So a little bit earlier than we even expected, originating from, from probably China. Sure, alright, so this is a screenshot from the johns Hopkins website. Just a little bit of an overview, you know, we're all sort of inundated by some of this data, but Just for the present time snapshot as of November 30 um you know, we, we've seen a lot of cases and you know, unfortunately a lot of deaths. Um, this is uh, this is data regarding the last month of cases in red. You can see that um, europe probably is now considered the epicenter if you will, of the, of the newest cases, all those red dots clustered in europe. Um um what I, what I can point out is, you know, the more recently, um, you know, if you can look at the right side, you know, weekly cases here, um you can see that, you know, there was sort of a lull, you know, decrease in cases over the summer overall locally, but as you can see, you know, july um you know, you know, starting late late summer, you know, we can see, we've seen the number of cases start to pick up um so, so that's a little bit of snapshot across the United States. Um you know, this is total cases, you know, you can see in dark red or burgundy the case is um, you know, overall have been clustered around the major metro areas. Um this is in California um um by county um um you know at the top of the L. A. County, Los Angeles County with the largest percentage of cases but if you see you know where we are, where I am located in SAn Francisco County um you know, even though san Francisco obviously is a lot a lot smaller than L. A. Um You know you see you see a much smaller percentage of of of cases of the state's cases as well as a smaller number of deaths which probably has been attributed to the high vaccination rate in SAn Francisco. Alright, so that's a little bit about sort of landscape now moving on to variants. Um So you know I was doing research and and you know found that you know, there there is a group, a federal group called the SARS COv two interagency group that basically whose job it is to monitor variants and to group variants into categories um and categories based on how dangerous or how not dangerous they are. So the first category variants being monitored, you know, that's just a general category of of variants that are sort of on the list um of total variants. You know, being sort of monitored by the by the CDC variants of interest may be more transmissible, may have more disease severity variants of concern. Those are the variants that have shown um evidence of either increased transmissibility, more severe disease reduced effective effectiveness of vaccines or treatments. Um Delta the delta variant is the one variant on this list um um you know, this is a very you know recent obviously change omicron um has not been added to this list but we'll see what happens more and more on that in a bit and then variants. Finally the variants of high consequence, you know, these are variants that are clearly proven to have more severe disease and are more difficult to treat. Fortunately no variants are on this list at this point. So this is from from the C D C a list of all the variants um that are on the variants being monitored list. So this is these are variants that were discovered early on and basically were thought to be you know, not not of major concern. And so you can see they're all V. B. M. Variants being monitored. Um But what's more relevant, much more relevant today is, you know, this is a graph of the variance in the United States. And as you can see these large orange bars are variants um represent the variant B16172, which is the delta variant. So, you know, by far and away, you can see, you know, over 99% of cases in the United States are Delta. So of course I cannot have a covid talk without talking about omicron. So this is very up to date. I just added this slide about 10 minutes ago. um um there's a lot I would say you know there's a lot of hearsay and a lot of speculation about omicron um at this point um if you look at the CDC website the statement is quote, we are working with other U. S. And global public health and industry partners to learn more about this variant. I think there's just not enough data that's available to us to make a decision about about it. You know I know that there's a lot of media coverage about how it may be more contagious and we don't know about the disease disease severity. There's just we just don't know enough. Um this last bar here you know I just I just added it to my slide you know five minutes ago. Um it looks like the first confirmed us case of a micron was detected in California and the sequence that act actually at UCSF. So this is really hot off the press. Alright so that's variants some more to come. But Now moving on to pathogenesis of COVID-19 so That we we have um you know, learned um uh more about how COVID-19 causes disease. So I think it's pretty generally thought that um early in the clinical course of disease the disease is mainly active replication of the virus. It's so it's the viruses replicating its you know um you know in attacking cells invading cells and that's how it's causing um you know the disease however later in the course um you know, as we as we know, you know, there's inflammatory storm, you know, cytokine release and and the disease sort of changes from more of a you know, viral replication to more of a you know immune dis dis regulation. And so that's where some of these treatments target different parts of the disease spectrum. Um So some of the new learnings that we have. Um So I think initially there was a lot of emphasis on on on how the virus, the SARS cov two virus can attack the the heart cells the cardiac maya sites directly and and cause damage to the heart however, um and I'll show some of this data now it's thought more that the heart is probably less of a direct target of the virus and and more of what we call an innocent bystander. Um and so you know, mechanisms for the disease, you know, with regards to the heart um may include supply demand, mismatch, um demand ischemia is something that we invoke frequently could be related to hypoxia, tachycardia um and thrombosis. Um um and we just see lots of, you know, as I mentioned earlier, you know, general inflammation, inflammatory storm and that can that can just lead to myocardial injury. Um as I mentioned, you know, initially it was thought that myocarditis was a very you know, specific disease uh and potentially very commonly related to covid but I think we've seen we've seen less covid related myocarditis than we um than we expected initially and again. I'll show you data about that. Um uh moreover we we tend to check proponents in in patients for whom we you know suspect myocardial injury um in COVID-19. And um certainly Troponin elevated proponents carry prognostic significance um but may not be an independent marker of disease outcomes and I'll show you that. So this is a study actually performed in Germany of autopsy. Um um it was an autopsy study of 39 cases of COVID-19. Um and the end of these 39 autopsy cases Um 61% of these cases SARS Kobe two virus was detected inside the heart. Um And what was done in this study was the patients with the highest viral load um were compared with the patients with no viral load in the heart. And what was found was that the patients with the highest virus in their heart showed a much higher amount of inflammatory side of kinds. Um you know I'll I'll six etcetera um compared to the patients with no viral no virus in their hearts. So that sort of makes sense. However, what was interesting um was that um in the patients with high viral load um these patients actually did not have high numbers of um inflammatory cells or Lucas sites that were expected um Typically when we see patients with myocarditis. Um they have high leukocyte counts inside the heart um inflammatory cells and that was not found. So that was sort of an interesting um finding. So the thought was you know maybe this is not a classic myocarditis that we usually um see or are expected to see with covid 19. Um certainly um pathologically, you know um path wise, you know, it behaves differently based on this autopsy study. Um In terms of the proponents um um this was a study that was done um last year looking at covid patients who were intubated. Um and uh in the hospital obviously so these hospitalized intubated patients proponents were checked which is routinely done. Um 51% of these intubated COVID patients had abnormal troponin levels. Um as we might expect, mortality was much higher in the patients with very high proportions compared with mortality and normal. So 61% in intra opponents In patients with your opponents 10 times greater than 10 times upper limit of normal. So not too surprising. However, what was a little bit surprising was that when adjusting for confounding factors, when you tried to associate elevated troponin as an independent marker for mortality, um there was no statistically significant difference or association, I should say so in this study, you know, proponents, um we're not an independent marker for mortality. They just told us that patients were sicker and and uh and had higher rates of mortality. Um What also was done in the study was um a. R. D. S. Patients were kind of taken from this cohort and they were compared to a separate cohort of non covid 19 A. R. D. S. Patients and proponents were looked at in both cohorts. And actually what was interesting was myocardial entry iii troponin elevation was actually less common in the covid areas patients than in the non covid um Various patients. So again just uh you know maybe a little bit surprising given our expectation that you know covid um affects the heart and and enters the heart. So so certainly hypothesis generating. Um um So moving on from pathogenesis to treatment. So this is I think an important important topic that I've I've encountered. Um which is you know anti thrombin attic therapy um in patients with COVID-19 is prophylactic antibiotic therapy helpful. Um and and and of course this question has been raised because we know that COVID-19 patients have higher rates of DVD arterial and venous thrombosis. So should we anti coagulate them prophylactically? Um if they're high risk. So this trial looked at this this population of Outpatient COVID 19 patients so patients who were covid positive had mild symptoms did not need to be hospitalized and they were randomized to a pixel ban high and low dose as well as aspirin for prevention. Again these were not patients who had thrombosis but um were thought to be potentially higher risk for thrombosis. Um And what was found was that the trial was actually stopped early because actually there was so few events in all groups um So events being you know mortality um arterial venous thrombosis, embolism, my stroke hospitalization again for our patients. Um So the conclusion was was that you know these covid 19 covid 19 patients who are outpatients with mild symptoms. Um There's really no clear indication for prophylactic anti thrombin attic therapy because the event rates are so low. Um So this is this is something that was studied um recently. Okay so moving on to more treatments um so you know we we can sort of group um treatments now into you know the neutralizing antibodies, monoclonal antibodies. Um These are currently under emergency use authorization. Um and so there are three sort of anti a antibody regimens with difficult to pronounce names. Um Each of them are intravenous. Um And we'll talk about those the other major group are the antivirals which are which we're hearing more about there just to be clear investigational at this point um They're being evaluated by the FDA. Um These are oral and typically you know a five day course. Um So we'll talk about it. I mean these uh you know I included a picture of these clinics walk in clinics of people who just walk in and go get infusions. Um This is a picture from florida where where I understand it's a it's a sort of a big thing there so I'll go over some of the data a little bit quickly. Um This is one of the earlier studies involving caso rhythm ab and and devon ab by re general. And this was a study looking at outpatients with COVID-19 and looking at in terms of efficacy. How um treatment with this cocktail would Reduced viral load from baseline of COVID-19 As well as looking at um what they called a medically attended visit through the 1st 30 days after diagnosis of COVID-19. So what what happened was, you know, obviously these these patients were randomized between placebo and the antibody group. And and they were stratified between serum antibody initially serum antibody negative and serum antibody positive groups. Also obviously viral load was looked at. Um So while I know this is a busy slide but what I'll, what I'll point out to you, you know, if you look at sort of the upper right hand corner um here you can see the group the serum antibody negative here on the on the left and the serum antibody positive on the right meaning, you know the patients. Um we're talking about obviously SARS quickly to in the body. Um you can see how these graphs and the Y axis is change in viral load and you can and all of these actually these graphs are all all about viral load change. And you can see how you you know there is a difference between the antibody group which is the the the green and the blue dotted lines and placebo in terms of you know a bigger drop in viral load with the antibody group. Um in the antibody negatives group here on the left um You don't see that you don't see the lines actually cross here in the serum antibody positive group. Um So that's interesting. Right? I mean we can speculate and say well in the patients potentially who are who are you have not been immunized or have not been exposed potentially. This antibody cocktail can be very effective in reducing the viral load. Um We also see a difference in how the antibody cocktail works with regards to baseline baseline viral load. So you know if you see here on the right side these are the patients with baseline, highest number of virus at baseline versus on the left side, the lowest number of of virus. And you can see how you know you see the biggest difference and um in in change in viral load in the high baseline virus group whereas in the lower group you know the lines actually cross. So it's it's interesting I mean it's it's to me you know the um you know I'm not sure how uh you know convincing the data is here especially in this this low lower virus slowed group but in any case this is the data that I got um this cocktail um emergency use authorization. Um And this is um data from that same study and that same cocktail looking at um um the medically attended the percentage of medically attended visits. Um So that means you know any clinic visit er urgent care telehealth visit after after the diagnosis of covid. Um And what was notable was you know in the treatment group and the antibody cocktail group. 3% of the Those patients have had at least one medically attended visit within the first month Whereas in the placebo group there was six So 3 3% vs 6%. Um Again I mean you can sort of judge as you wish. You know how convincing this data is for you and I question you know how how useful this medically attended visits data point is. But in any case this is what what led to you a for for this cocktail. But it's more to me more interesting is this study which was more recent in august of this year. Looking at how this particular same cocktail Regeneron cocktail can actually prevent potentially prevent covid. So this study was done um um in by looking at patients who were um recently you know just diagnosed, we're sorry. Um this study was done in patients who had a close contact who was recently diagnosed with COVID-19 um and looked at the actual contact and looked at rates of symptomatic and asymptomatic infection. Um So again looking at the point of this is can can using this cocktail um prevent covid in someone who has a close contact with covid. Um So this is a busy slide but but if you look at the top um this is the end point was actually hospitalization and and um I'm sorry, I'm sorry this this endpoint was infection rate of infection. Symptomatic infection um in in the group. Um and the group in the red dotted or dashed line is the antibody group and the blue solid line is the placebo group and you actually can see a pretty clear separation of lines. The Regeneron cocktail group had a lower incidence of both symptomatic infection which is represented here as well as asymptomatic infection which you can see here on the on the bars and you also the bar graphs, you also see, you know, shorter duration of symptoms um in the patients in the Regeneron cocktail group. Um anybody so very interesting to me how potentially this could be, could be used for that purpose. Obviously, you know, getting an intravenous infusion for this, you know, lots of questions about, you know, is this a good use of healthcare resources etcetera. I won't talk about that. Um moving on to another cocktail, you know, very similarly conducted study looking at second cocktail bam land nova mob and tests and tests seven ab um again in outpatient covid patients um again looking at viral load and um you know hospitalization and mortality and you can see the, you know the the yellow orange line is the antibody group showing lower viral load um over time and lower rates of hospitalization and mortality in the antibody group. Um So so this this antibody cocktail is also has also been granted eu away for emergencies to use and then this is the final um neutralizing antibody. So trump and have um again looking at hospitalization and death rates and and you can see you know very very uh significantly lower endpoint or outcome break in the antibody group compared to placebo. So you know that's led to this the NIH guidelines. This is a busy slide but I'll just point out that this you know there are slides or websites on the NIH site um that are I think nice and succinct regarding what what you can do for outpatients with covid 19. Um And it's basically you know what you follow this sort of flow chart where you know if you see a patient who doesn't need oxygen who doesn't need hospitalization um You know these this would be this cohort of patients and you know that's that's uh that's this this panel here where potentially these patients could be um um could benefit from the antibody um treatments. And then there are others obviously these are patients who are hospital discharges. And there's other language about how they should not receive, you know, you know steroid dexamethasone zone um um And I'll let you look at that on your own time. Um This is actually so those were the inpatient outpatient recommendations. These are the inpatient recommendations. I won't spend too much time on this but I'll just point out that you know there's also a flow chart here where you know if you have a hospitalized patient who needs oxygen um then you know you treat you may treat that person differently versus um you know if you the patient does not need oxygen. So so against something that you can look look at on online, moving on to antivirals again very new this is from This is a press release from October one. so a couple of months ago and I think it's more and more in the news, Merck Merck has develop this antiviral medication called mullen appear beer um which is an antiviral medication. Um There's there's no um published data. This is all just from the company. Um But they they have released this press release saying that You know, it looks certainly looks very impressive if you look at the headline, you know, reduction of risk of hospitalization or death by by 50%. Um um And so this this was an interim analysis and so currently where we are is the FDA is is reviewing this data. Um Probably some of you have heard about in the news about how there may be um risks of of this drug in terms of fetal toxicity. Um um So that's certainly going to be a risk benefit analysis that that some of us may need to make when we when we when we use this medication or if we use this medication and then the other antiviral medications called the packs loaded, which is also an investigational protease inhibitor, which is in combination with Rihanna beer, which is a known antiviral. Um which again actually had even more impressive results. If you look at the press release again, this is just press release. No published data. No peer reviewed data Showing significant 89 reduction of risk of hospitalization or death compared to placebo. Um So, but we'll see because this is all just a press release um interim interim analysis data. Um So now moving on to vaccines which which are the huge, you know tool in our armamentarium for for covid 19 as we all know, you know, we all know that the M. RNA vaccines have shown very significant efficacy. Um and when they were approved, initially approved anyway, there were no specific safety concerns. Um um and then, you know, also with the johnson and johnson Um vaccine also showed slightly lower but still, you know, greater than 60% overall efficacy. Um There were there was a pause in the J and J vaccine, as some of us may remember because of several cases of central venous sinus thrombosis. So, so venus thrombosis. Um And so the Sandia vaccine was paused at some point in time, but it was resumed because it was thought that the benefits of the vaccine that weighed the risks and that's true in general. I would I would say all of the vaccines that three of the three vaccines that we have in this country um in the United States, that typically the benefits of vaccination tend to outweigh the risks. Um So as a cardiologist I get this question asked me quite often, which is, you know, um you know, what's the risk to my heart with with the M. RNA vaccines? Because what about this myocarditis? A lot of my patients are are very well versed in what myocarditis is. And so and this comes from um you know, reports um you know, it's it's definitely true that patients with or after having gotten that M. RNA vaccines have developed myocarditis. Um And so 11, a lot of the cases have been noted to be in patients who have either already had covid 19 and they developed symptoms after the first shot or they have not had infected COVID-19 infection but had um symptoms after their second shot of of the M. RNA vaccines. So, so hence the thought being, you know, perhaps prior immune exposure could have set someone up for um you know, some sort of an auto immune um reaction to a subsequent shot um leading to myocarditis. I mean, I think this is speculation it's not been proven But this is potentially a hypothesis for why my own part. I just can happen in these patients. Um It's still a pretty low incidence, you know, between 10, 10 to 20 cases of myocardial this per million shots um in individuals 12 to 39 years of age, I think we we've heard that it's myocarditis um related to M. R. And A. Vaccines have been more common in young men Under the age of 30 symptoms, symptoms typically start 2-4 days after vaccination. And really typically the patients have mild symptoms and they recover on their own. So this is something that if you ever encounter this with your patients, you know, you can sort of give them this data that it's pretty pretty infrequent. And patients, even if patients do develop myocardial visits typically mild. And in fact, you know, this was an article from the journal circulation um actually discussing the risk benefit of of myocarditis with vaccination versus the potential benefit of vaccination. And you know, for example, if you sort of look at the highest Um you know, highest rates of myocarditis in the in the males 12-17 years of age here in this block here. So Um you know, 56-69 um cases for every million second dose vaccination. Um So that's the risk, right? That's one side of the pendulum. But then if you look at the benefit in that same group. You can see how potentially um with the vaccinations. You could prevent 8500 covid cases, you could prevent 183 hospitalizations, 38 iCU admissions and one death. Um So you know it's sort of certainly something to discuss with your patients. But certainly if you look at the american College of Cardiology, the languages, you know, the benefit of vaccination should typically outweigh the risk of something like my own car bikes. Um And and this is just uh you know october this quickly. This is a paper from Um an imaging paper imaging journal looking at one of these patients with myocarditis after COVID-19 vaccination. And and you see a pattern of of late gadolinium enhancement in the infra lateral wall here which is consistent with a non ischemic um injury. Pretty classic for my own car Vegas. And this was a younger female who recovered from her myocarditis. Well okay so then moving on to another sort of complication of vaccination which is um this is actually a complication from the J. And J. Vaccine which is called vaccine induced traumatic thrombosis opinion. And these patients um um developed both thrombosis and thrombosis santa pina at the same time. And this typically occurs in this unusual location such as the cerebral veins in the brain. Um They develop antibodies against the platelet factor for Hepburn complex which if that looks familiar. It's because it's actually the same complex um that is found in heparin induced homicide opinion or hit. Um. Again this is this is associated with the J. And J. Vaccine or the astrazeneca vaccine which is not found here in the United States but not with the M. RNA vaccines. It's actually quite rare, you know, .9 per million um cases or per million shots. Um it's shown to occur anywhere from 5 to 28 days after vaccination. Um There's no clear evidence that patients have who have had hit before or thrombosis before before are at higher risk of this. But what what is recommended is that if you have a clinical suspicion um um You know, let's say a patient of yours had the J. And J. Vaccine, you know, a week prior and started to develop a headache. Um And what you would probably do is you would if you had enough suspicion, of course you you would get a cbc to look at the plate account. Um You might look at um you know, get a ct venogram of the brain to look at the sinuses or the cerebral veins. If you find both thrombosis and thrombosis Dapena, then these patients really should be hospitalized. Again, this is a pretty rare phenomenon from what we've seen. Okay, this is my last slide um Moving on, you know, too long carpet which is something that I've I have multiple patients um with with long covid or sort of post acute sequelae of um covid 19. So we know that these patients have can have a variety of symptoms, fatigue, shortness of breath, chest pain palpitations, autonomic dysfunction, tachycardia. Um You know, we still don't know why um these patients have have this. I mean there there are certainly lots of speculation whether this is an autonomic dysfunction, whether it's sort of a persistent um um immune dis regulation whether it's kind of low levels of virus still persisting in the body. Um But you know, I think time will tell um you know what what what this the pathology of this is as far as an and in addition treatment. Um what was sort of noted early on earlier on in the pandemic was um that these patients with Long Covid chronicled long covid chronic Covid um had MRI's of their heart um showing persistent abnormalities. Um For example, you know, inflammation um adama and late gadolinium enhancement showing potential fibrosis in the heart um even long after recovery from their clinical illness. Um So it was thought, well, you know, maybe Covid has persistent damages causing persistent damage to the heart. Um But subsequent memory studies have really sort of made it seem like this is less of an issue. And in fact there was one study more recently looking at cardiac M. R. E. S. Um comparing Cardiac Mri's between. COVID-19 survivors and healthy patients healthy controls six months after their diagnosis of COVID and they're this study showed that there are these M. R. E. S. Between the covid 19 survivors and the controls. We're no different. There was no significant difference in the M. R. I. S. So you know I think well we still have yet to learn about Um what the long term sequelae of COVID-19 um is in terms of the heart. Um But I think we've we've done more learning. Um and perhaps you know, the damage to the heart from covid may not be as significant um as we may have thought initially. Um So just take some points, you know, um delta variants really has changed their ability to to fight covid 19. I could add on the crown in this point. Um um second point potentially there's less myocarditis and less direct cardiac injury from COVID-19 than we thought. Maybe it's more of an inflammatory process of general inflammatory process. They're a bunch of new treatments on the horizon. And I would say, you know, if you have something to tell your patients, it's vaccination, vaccination, vaccination which whose benefits tend to outweigh the risks. So that's my talk. Um Just you know, shout out to my team, my cardiology colleagues here at UCSF. Um Thank you very much for listening. This is a way to contact me mm hmm
