Circulation October 20, 2020 Issue

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."

TRANSCRIPT BELOW

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,