ACE2 in Obstructive Hypertrophic Cardiomyopathy & COVID-19

A few weeks ago an article came out saying that patients with heart disease had worse outcomes if they were infected with Tsarskoe v2 and had Kovan 19, that their outcomes were worse, and of course that caused a lot of anxiety throughout my community of patients and families. . with a genetic heart disease with a variety of genetic heart diseases such as long QT syndrome CP VT,

hypertrophic

cardiomyopathy

, etc., and I wonder if I belong to that group where Cova 19 will be worse in me because I have heart disease. Hi, I'm Mike. Ackerman, a genetic cardiologist here at Mayo Clinic in Rochester Minnesota and director of the Mayo Clinic Winland Smith Rice Genetic Heart Rhythm Clinic and the Winland Smith Rice Sudden Death Genomics Laboratory and on behalf of the team of researchers here at Mayo Clinic and of researchers from all over the world.

I am very excited to share with you some highlights from our article published in the Mayo Clinic Proceedings. Our article is titled Marked regulation of a stew in hearts of patients with

hypertrophic

obstructive

cardiomyopathy

. Implications for Tsarskoe v2-mediated kovat 19. This work is long. The work on its manufacture actually dates back 20 years, to the first snap-frozen surgical myectomy specimen by dr. Hartzell Schaaf and Dr. Joe de Rainey for the surgical operation of our patients with hypertrophic

obstructive

cardiomyopathy and septal reduction therapy. Surgical myectomy is the gold standard for treating our patients with obstructive hypertrophic cardiomyopathy, and we see more cases here at Mayo Clinic than probably anywhere else in the world.

Worldwide, this also provided us with a tremendous research opportunity by removing a sample of snap-frozen cardiac muscle from patients' hearts to relieve their symptoms of left ventricular outflow tract obstruction and, over the course of 1999 to 2010, we were able to archive and build a repository of frozen tissue from the surgical myectomy less at the time the hearts were removed, the heart muscle tissue was removed at the time of surgery and we received a master's thesis from one of our former cardiology trainees, Dr. Virginia Hebel was analyzing the transcriptome with my research team and published his master's thesis from this work in 2012 under the direct mentorship of the first author of this article, Dr.

Chief Martin, we didn't know exactly how to tell the story back then, we were looking at genes that were upregulated and transcripts that were downregulated and looking at these differentially regulated genes and some upregulated, some downregulated, some sideways and definitely different from normal tissue that we knew. that more than 20% of the human transcriptome was being differentially regulated up and down by the disease process of obstructive hypertrophic cardiomyopathy or HCM and that's where it plateaued, but that was so BC before Crona because about six weeks ago when we started to learn. more and more about covin 19 mediated by SARS Co v2 and the corona virus pandemic we are in, we are starting to hear things about how this corona virus hijacks a particular protein to enter the heart muscle cells and enter the lung tissue and that sequesters The receptor protein is called ace two that rang a bell, a memory, and in fact, we had a flashback at the same time as one of the co-senior authors, dr.

Frank Burrows of itch, a colleague of mine here in our cardiovascular medicine department at Mayo Clinic. I think we emailed each other almost at the same time. It was not so to transcribe an upregulation in our frozen myectomy samples with HCM and now. you say the rest of the story, Martin Boss jumped into the data set, looked at what we had put together back then, and in fact, of all the transcripts in the human transcriptome, there are probably 20 to 25,000 genes, probably from order of 50 to 200 thousand unique transcripts and of all the transcripts in the human transcriptome, the most regulated transcript was the ACE 2 transcript, which was kind of an aha moment where divided lemons make lemonade and we looked at our data set and we confirm it. with quantitative PCR and that transcription is the most regulated and, most importantly, it was demonstrated by Western blotting that it measured the protein itself, not only the gene or the transcribed gene product of transcription but the translated product, the protein and, of fact, the level of h2 protein in cardiac tissue. at the time of the surgical myectomy it was five times higher than normal tissue now there was a story to tell, a really exciting story, it is higher regardless of what brought the heart to that level of obstructive HCM, whether it was the HCM of myosin heavy chain or myosin junction. protein C HCM or obstructive HCM without identifiable genetic cause these two levels protein levels are higher and, in fact, are higher in women with obstructive hypertrophic cardiomyopathy, approximately 30% higher than in men with obstructive hypertrophic cardiomyopathy, so , What does this all mean? aha moment, we think that for the And under what we call heart diseases there are hundreds of different heart diseases and we know that if you have long QT syndrome, if you have CP V T, if you have Brugada syndrome, you are not at greater risk of having a bad outcome by Kovat 19. than me without any particular heart disease if you are otherwise young and healthy, but what types of heart diseases may actually be at higher risk?

Well, I think the answer has come are those heart diseases where the disease process is causing an accentuation and an increase. in ACE protein levels, and now we see that it is not just obstructive hypertrophic cardiomyopathy; There's a little article published last month about eight patients, eight patients with heart failure, a different type of heart disease where the pump doesn't push very hard. well, it's weak in eight patients with heart failure, ACE two levels were higher, we see it now in this collection in over a hundred patients with obstructive hypertrophic cardiomyopathy, so what's going on? Well, ace two didn't increase because the coronavirus was going to arrive one day.

Think and others think that increasing a stew is a way. Oh, response reaction, it's the heart's way of citing, healing yourself or trying to counteract the stress and threat of the HCM obstructive disease process and, as we show in figure three, the normal purpose of increased levels of ACE as the reaction of the heart is to try to counteract the bad protein if you want of angiotensin 2 and Angie intense and two fibrotic effects pro hypertrophic effect a vasoconstrictor effect ace to that protein that enzyme that receptor converts angiotensin 2 into a polypeptide protective angiotensin 1-7 and angiotensin 1-9 and that converted polypeptide has an antifibrotic effect an antihypertrophy effect a vasodilator effect Latorre makes sense so isn't it that the heart is trying to compensate?

It is a path through a response reaction, but that was also BC before Corona because now we have a different problem with ACE 2 that accentuates pathological processes such as obstructive hypertrophic cardiomyopathy and perhaps heart failure. This five-fold increase we have seen in ACE 2 protein levels provides 5 times the amount of receptors. for the virus to take over and use to steal entry to the heart muscle cells, perhaps that is why these types of patients with these types of heart diseases may be at higher risk. This is also why it is incredibly important for heart disease patients taking ACE inhibitors like lisinopril or angiotensin receptor blockers like losartan to continue taking those medications as recommended by all major heart societies for now and perhaps indefinitely as we learn more because, in fact, we may learn that it is not dangerous to take them. which can actually be very important and protective to continue taking them because an angiotensin receptor blocker then blocks and prevents the Tencent motor from also starting its process of fibrotic process hypertrophic process process of vasoconstriction of the veins a process that will be easier in these patients that not only do they have five times higher levels of ACE for the virus to steal entry, but when the virus steals entry to those cells, it takes that ace to the protein and therefore we lose our counterbalance of the effects harmful effects of excess angiotensin to stay on their medications we will learn a lot, for now we think we have connected the dots, as we show in figure four, of why certain patients with heart disease may be more vulnerable to a cardiac reaction due to infection by coronavirus and if there are elevated levels of a stew in the lung in these patients, if not demonstrated, that may explain why they have a more severe respiratory injury.

There is a lot of work to be done for sure, we don't know if this applies to all patients with hypertrophic cardiomyopathy, there is only the subset with obstructive hypertrophic cardiomyopathy. Cardiomyopathy is only a subset, we do not yet know if after performing surgical myectomy and relieving left ventricular outflow tract obstruction, protein levels decrease. We do not know if this applies to patients with non-obstructive HCM or apical HCM. patients, we don't know what other heart diseases are, like to accentuate heart diseases where the levels of ACEs for transcribing and ACEs for proteins increase, we are working on that and we will soon learn if this is true in hypertension, our two protein levels in the heart.

The higher this is true in dilated cardiomyopathy our two higher protein levels we will learn that and we will learn if this is the common denominator in terms of the answer behind the question of why certain patients with certain heart diseases do worse when get infected with Tsarskoe v2 we think this is the answer, so what do we do about it? What do our patients do about it? Who could have an ace? Marked heart disease such as hypertrophic obstructive cardiomyopathy. Several things first. Without fear. Knowledge is power. There is no need to be anxious. Stay. your treatment program this, if anything, will do the latter, it will give you more vigilance and incentive to follow all the precautionary measures that work, do not slack on the safety measures, remember the physical distance that is observed at six feet, Hold on and don't let go. on that wash your hands with soap and water don't slack off on that take your temperature don't skimp and get carried away thinking that this coexistence with Tsarskoe v2 is no big deal, it's a big deal stay alert stay alert stay masked in public use social masking no change your medications on your own stay on them if you have been prescribed medications to treat your heart just know and be encouraged that the community of scientists, doctors and medical scientists around the world are dedicated to your heart diseases and we are dedicated to trying to find the answers to why and here we believe we find at least part of the answer.

Thank you very much for joining me today and I hope you enjoy this article from the Mayo Clinic proceedings that summarizes over twenty years of work on this topic, take care everyone, we hope you found this presentation of website content valuable. The mission of our magazine is to promote the best interests of patients by advancing the knowledge and professionalism of the medical community if you are interested in more information about us, our home page is WWE Women's, not only there you will find access to information for our social media content, such as additional videos on our youtube channel or magazine updates on Facebook, you can also follow us on Twitter, more information about healthcare, Mayo.

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