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Circulation on the Run

Oct 19, 2020

This week's episode includes author Daniel Lackland and Associate Editor Mercedes Carnethon as they discuss the article "Forty-year Shifting Distribution of Systolic Blood Pressure with Population Hypertension Treatment and Control."


Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley associate editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature is good news. What do I mean by good news? It's going to be a tale of how hypertension has evolved in the Southeastern United States. And it's going to review how that's progressed its treatment efficacy in both those of white, and men and women of black race. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in this issue.

Dr Carolyn Lam: Man, you got my attention, Greg. You definitely got my attention.

Dr Greg Hundley: Very good. Well, Carolyn, my first paper is from the world of basic science, and it's from Dr Maya Kumar from Stanford University School of Medicine. This group maps the step wise remodeling of pulmonary arteries in a robust chronic inflammatory mouse model of pulmonary hypertension. A model that demonstrates pathologic features of human disease, including right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation and perivascular inflammation, all of those combined. And the author sought to define the cell behaviors underlying each stage of vascular remodeling, and identified a pathway required for neointima formation with the premise being that this understanding could be pivotal in modulating progression of disease in pulmonary hypertension.

Dr Carolyn Lam: Nice. So what did they find?

Dr Greg Hundley: Well, Carolyn, they found surprisingly. The neointima arises from smooth muscle cells and not the endothelium. Medial smooth muscle cells proliferate broadly too thick in the media, after which a small number of smooth muscle cells are selected to establish the neointima. These neointimal founder cells subsequently undergo massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery smooth muscle cell population is heterogeneous, and the authors identify a Notch3-marked minority subset of smooth muscle cells as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension, thus perhaps providing a new mechanism from which to test therapies to thwart the progression of disease in those with pulmonary hypertension. Very interesting basic science work.

Dr Carolyn Lam: Yeah. And very important too. Thanks Greg. Well, I've gotten another basic science paper too. First, let me ask you, do you think of DNA methylation much?

Dr Greg Hundley: We hear a lot about that, Carolyn. Methylation and changing DNA and how it might be transcribed. Tell us more.

Dr Carolyn Lam: DNA methylation is indeed a mechanism of gene transcription regulation. It's recently gained a lot of attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, the authors Dr Stenzig from University Medical Center, Hamburg-Eppendorf and colleagues knocked out the main de novo DNA methyltransferase in cardiomyocytes. Also, called DNMT3A in human induced pluripotent stem cells. They then assess the functional consequences of DNA methylation deficiency under control and stress conditions in human engineered heart tissue from these knockout derived cardiomyocytes.

Dr Greg Hundley: Wow, Carolyn. So what did they find here?

Dr Carolyn Lam: Three main consequences of DNMT3A knockout. Number one, there were gene expression changes of contractile proteins, such as higher atrial gene expression. Number two, there was ever an activation of the glucose lipid metabolic regulator PPAR gamma, which was associated with accumulation of lipid vacuoles in these knockout cardiomyocytes. And number three, HIF-1 alpha protein instability occurred, which was associated with impaired glucose metabolism and lower glycolytic enzyme expression rendering the knockout engineered heart tissues sensitive to metabolic stress such as serum withdrawal and restrictive feeding. So in conclusion, these results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.

Dr Greg Hundley: Wow, Carolyn. That was really fascinating, especially helping us understand how DNA methylation is operative, great summary there, and it's just organized so well. Learned a lot from that. I'm going to switch back and move into the world of clinical science on this next article. And it really fascinating, projecting outcomes using some biomarkers that I hadn't heard of previously. This paper is from Dr Alan Maisel from University of California, San Diego School of Medicine, and it evaluated the utility of advanced biomarkers for discriminating type one versus type two MI in patients presenting to the emergency room. In the study, two cardiologists adjudicated type one and type two MIs and six biomarkers were analyzed cardiac troponin I, copeptin, mid-regional pro-atrial natriuretic peptide, C-terminal proendothelin-1, mid-regional pro-adrenal Mendelian, and finally procalcitonin. And the prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular events or mace included the composite of acute MI, unstable engine of petrous, re-infection, heart failure, and stroke at 180 days of follow-up.

Dr Carolyn Lam: So what did they find with these very interesting biomarkers, Greg? Were they able to distinguish type one from type two MI?

Dr Greg Hundley: Great question, Carolyn. So among 2,071 patients type one MI and type two MI were adjudicated in 94 and 176 participants, respectively. Patients with type one MI had higher levels of cardiac troponin I while those with type two MI had higher baseline levels of all of the other biomarkers. Next, combining all the biomarkers resulted in a similar accuracy to a model using clinical variables and cardiac troponin I, and the addition of the biomarkers to the clinical model yielded the highest AUC, under the curve. Next, other biomarkers, but not cardiac proponent was associated with mortality and mace at 180 days among all the patients with no interaction between the diagnosis of type one or type two MI. Then conclusion, Carolyn, the assessment of these new biomarkers, reflecting pathophysiologic processes occurring with type two MI may help differentiate it from type one MI. Additionally, all the biomarkers measures except cardiac troponin I were significant predictors of prognosis regardless of the type of MI, both type one and type two.

Dr Carolyn Lam: That's really cool, Greg. Thanks. I'm going to end with a clinical paper too, and maybe ask you, Greg, you know so much about AI playing a role in cardiac MRI. Do you think it could do that in echo too?

Dr Greg Hundley: Leading question, Carolyn. Now, you have expertise in this area as well. I bet it could be helpful. Tell us what you've got in this paper.

Dr Carolyn Lam: Well, automated interpretation of echocardiography with deep neural networks and AI could support clinical recording and improve efficiency. Now while prior studies evaluated spatial relationships using still frame images and echo these authors who were led by Dr Tsai from National Cheng Kung University Hospital and college of medicine in Taiwan, these author's aim was to train and test a deep neural network for video analysis by combining spatial and temporal information to automate the recognition of left ventricular regional wall motion abnormalities on echo.
So they collected a series of transthoracic echocardiogram examinations performed between July 2017 and 2018 in two tertiary care hospitals. Regional wall abnormalities were defined by experienced physiologists and confirmed by train cardiologists. First, the authors developed a 3D convolutional neural network or CNN model for view selection to ensure stringent image quality control.
Second, a unit model segmented the images to annotate the location of each left ventricular wall, and third, a final 3D CNN model evaluated echo videos from four standard views before and after segmentation and calculated a wall motion, abnormality confidence level for each segment.

Dr Greg Hundley: Very nice, Carolyn. So a lot going on to identifying the wall and then performing analysis on those walls' segments. So what did they find?

Dr Carolyn Lam: So when a series of more than 10,600 echoes, their view selection model identified 6,454 or 61% of exams with sufficient image quality. The external validation was performed in 1,756 exams from an independent hospital. The final model recognizes regional wall motion abnormalities, and the cross validation and external validation datasets with an area under receiver operating characteristic curve of impressive now 0.91 and 0.89 respectively. In the external validation dataset, the sensitivity was almost 82% and specificity also almost 82%. And so in echo exams of sufficient image quality, it is feasible from this work for deep neural networks to automate the recognition of regional wall motion abnormalities using temporal and spatial information from moving images, further investigation is required to optimize the model performance and evaluate clinical application.

Dr Greg Hundley: Sounds very exciting. Helping facilitate the identification of regional wall motion abnormalities. Well, how about if we jump into some of the other articles in the issue, would you like to go first?

Dr Carolyn Lam: I'd love to Greg. There's Research Letter from Dr Wu on patient-specific induced pluripotent stem cells and how they implicate intrinsic impaired contractility in the hypoplastic left heart syndrome. There's an In-Depth paper by Dr McEvoy on lifelong aspirin for all in secondary prevention of chronic coronary syndrome. Is this still sacrosanct or is reappraisal warranted? In our Cardiovascular Case Series, Dr Grodin talks about an uncommon disease in a rare location, the mystery of the rapidly progressive cardiomyopathy. A very interesting one. You have to read it. We have a Research Letter from Dr Golbus on changes in type of temporary mechanical support device use under the new heart allocation policy. There's an ECG challenge by Dr Choxi entitled entitle, 􀍞􀁞how me the P wave.􀍟 Very interesting title. You got to pick it up. And there's an On My Mind paper by Dr Thibodeau on telehealth for uptight titration of guideline directed medical therapy and heart failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got a couple of letters. First, there's an exchange of Letters to the Editor regarding the article 􀍞􀀾ow Attenuation Noncalcified Plaque to Predict Myocardial Infarction: Are We There Yet?􀍟 And it's from Dr Alfonso and then a response from Dr Williams, and finally, a Research Letter entitled The Effectiveness of Deep Sedation for Patients with Intractable Electrical Storm Refractory to Antiarrhythmic Drugs. And it comes from Dr Raphaël Martins. Well, Carolyn, how about we move on to that feature article and learn more about hypertension in the Southeastern United States?

Dr Carolyn Lam: You had me waiting right from the start, Greg. Let's go.

Dr Greg Hundley: Well, listeners, welcome to our feature discussion today. And we're going to be reviewing a paper regarding hypertension and with us, we have Dr Daniel Lackland from Medical University of South Carolina and our own associate
editor, Mercedes Carnethon from Northwestern University. Welcome to you both. Well, Dan let's get started with you. Can you tell us a little bit about the background information pertaining to your paper? And then what was the hypothesis that you wanted to test?

Dr Daniel Lackland: For decades, we've known that the Southeastern portion of the United States is a disadvantaged area, but a great geographic diversity where you had these great rates of disease. In 1960, there was NIH-supported the Charleston Heart Study and the Evans County Georgia Heart Study. And these were two databases that were trying to actually look for some type of a factor that was in this population that was leading to the great risk, we became the custodians of this database. And then the regard study focused in or structured around 2000 began to also look at areas of the Southeast. And so the question that we had was using these cohorts, looking at 40 years, have we seen a difference in blood pressure? We did see a difference in outcomes, but have we seen also the difference in blood pressure in this high-risk group?

Dr Greg Hundley: It sounds like your hypothesis was to determine whether blood pressure had diminished. And you've told us a little bit about your study design, but perhaps can you describe a little more of the study population.

Dr Daniel Lackland: In the Charleston Heart study, Charleston, South Carolina, it was basically the County and there was a random sample SLED it in that area and Evans County, Georgia Friday it was just everybody that was in the County. Curtis Hames was the individual at that time and put together these two nice cohorts. These were individuals, obviously in 1960 a time before we were treating blood pressure and recognizing pressure. So there was a blood pressure measurement, there was a cholesterol measurement and basically, a general overall assessment that was having in both of these cohorts in 1960. These individuals again were followed, and then when the regard study was started in the late 1990s, it did also again, blood pressure measurements, but with a focus in the Southeastern portion of the United States. And so you were able to see this population. So it was an opportunity to look at some cohorts that were readily available and using them for a unique way to consider it in this particular high-risk area.

Dr Greg Hundley: Very good. And so how many total subjects did you have?

Dr Daniel Lackland: In the Charleston Heart Study and Evans County, Heart Study you were looking at several thousand and you were comparing it to a slightly higher group from the regards where you're looking at 5,000 or so.

Dr Greg Hundley: So what did you find, Dan?

Dr Daniel Lackland: We found some wonderful things. Certainly, the blood pressures had come down just like national studies have shown. The top of the list was these excessive blood pressures, these severe blood pressures of where 10% of the African-American men and women in 1960 had systolic blood pressures greater than 2000. These were virtually eliminated. We didn't see this later on 40 years later, I think a wonderful accomplishment. The other piece is that while all the blood pressures came down, blood pressures came down significantly greater for African-American men and women and all facets. So those blood pressures that we would have considered high 140, whatever, those all came down there, and they came down greater than we saw among white men and women. We were seeing the gap that was so huge in 1960. The racial gap, starting to come together with a very positive type of sign.
The other piece excitingly, we saw the blood pressures in the lower percentiles coming down suggesting that maybe some of the lifestyle that we've been implementing around the country were also being implemented successfully in this high-risk Southeastern population.

Dr Greg Hundley: Very good. So Dan, in 1960, 10% of the men and women had systolic blood pressures greater than 200 millimeters of mercury. And you saw mark declines after the year 2000, and then also you saw declines for those that had mild elevations in blood pressure, systolic blood pressures in the 140-millimeter mercury range. And one quick question, was this true for both men and women?

Dr Daniel Lackland: Yes, indeed. Both men and women, everybody's blood pressure came down.

Dr Greg Hundley: So Mercedes, let's turn to you help us put this paper in the context with other manuscripts that we review at circulation, but also the world's literature.

Mercedes Carnethon: I'm really excited about the opportunity to feature these findings and circulation, because I think they provide a very unique contribution to the literature about the population trends and levels in blood pressure, in the United States and around the world. And one thing that's really important is we don't often talk about our population level successes. And as we know, hypertension is one of the leading drivers of cardiovascular disease. And particularly when we think about reasons for disparities in some of the diseases that Dan mentioned earlier, heart failure, renal disease, hypertension as a primary driver of this, as well as stroke.
I certainly can't leave that out. And so to hear that over time a population levels of blood pressure are shifting downward or are certainly shifted downward is really heartening news. It does back certain questions. We certainly still see disparities in blood pressure levels between blacks and whites in this country, but are most likely a primary driver of the disparities that we see in stroke, in renal failure, in certain cardiovascular diseases, and as well as heart failure.
And so it's wonderful to see this. And I asked Dan and his colleagues, this particular study data was from the baseline of the regard's cohort and extremely well-designed study that's captured individuals from across the United States. I have two questions, Dan. One is, were you able to tease out any
differences in blood pressure between those in rural versus more urban areas in the Southeast and the second, because this ended in 2005, what do you project would happen today? Do you think these trends are holding? Have we gotten better? Where do we stand?

Dr Daniel Lackland: That's wonderful questions. As far as the rural urban, in one sense or certainly Evans County, Georgia is all rural. And if you compared a little bit teasing out, as you've suggested, the Evans County rates were just exceptionally higher than the of the urban sides. If you will allow me for a moment to call Charleston, South Carolina is somewhat urban community. You did see some differences, but they were relatively subtle. Where we are today, if we look at the clinical data, it looks like the top of the list, those excessive, severe blood pressures that particularly we saw in black men and women in 1960 are gone. Now we're working on the moderate blood pressures that Greg had referred to. And I think that, that's fun on that. Those are also coming down. The exciting piece though, although also those lower blood pressures that you refer to, so that in that prevention side of it, those blood pressures are coming down. And that lifestyle, maybe our messages are gradually getting there to all of the population.
Dr Greg Hundley: Very good. Let me ask you here in closing, maybe 30 seconds for each of you, what do you think is the next study that needs to be performed in this particular area? Dan, we'll start with you.

Dr Daniel Lackland: I think we know that the interventions work for everybody. So I think we're one of the pieces. Again, is to look at the groups that we've been referring to now with the new guidelines and the new classifications of hypertension, looking at those people that we used to call prehypertension and now have become stage one hypertension, and also elevated blood pressure. Can we implement lifestyle interventions and get down a lower blood pressure? The other piece on the global side that we have mentioned, I think there are global populations around the world that actually unfortunately were similar to what 1960 South Eastern populations are. And I think this is a good model to make sure that we can take what we've done here and take it to other populations around the world.

Dr Greg Hundley: Very good, Mercedes?

Mercedes Carnethon: What I'm most curious about going forward is what proportion of this decline is due to pharma-cotherapies and what proportion is due to shifts in lifestyle behavior? As a data type of person, I would be very interested in teasing this out because there are multiple contributions to high blood pressure, some of which need to involve interventions at the individual level and others that can be implemented on a population scale. And those population scale interventions, for example, reducing sodium and certain foods have the potential to reach all populations, including vulnerable populations, and are less dependent on one's ability to adopt lifestyle changes individually. And so I would be most curious about trying to tease that out so that we can appropriately target resources that will reach the largest and most vulnerable populations.

Dr Greg Hundley: Well, listeners we're most appreciative to have this opportunity to speak with Dan Lackland from Medical University of South Carolina and Mercedes Carnethon from Northwestern University. And listen to them describe these very encouraging results from the regard study, showing that there have been detriments in both severe and mild to moderate hypertension over the last 40 years in the Southeastern United States. So on behalf of both Carolyn and myself, we wish you a great week, and we'll catch you next week on the run. This program is copyright the American Heart Association, 2020.