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Circulation on the Run

Nov 9, 2020

This week’s episode features author Kazuomi Kario and Associate Editor Wanpen Vongpatanasin as they discuss the article "Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP (Japan Ambulatory Blood Pressure Monitoring Prospective) Study."


Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its 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 Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, when is the best time to check your blood pressure if you have a home monitoring device? Morning? Afternoon? Nighttime? And what do those nighttime fluctuations infer? Well, we'll hear a lot more in our feature discussion today, but first let's grab a cup of coffee and jump into some of the other papers in the issue. I'm going to start first this week, and my first paper comes from Dr Joe Wu at Stanford University. Carolyn, a quiz. Are all endothelial cells alike?

Dr Carolyn Lam: Jeez, Greg. Okay, I'm going to hedge. I bet a lot of them share similarities, but there may be some differences.

Dr Greg Hundley: Yes, Carolyn. Dr Wu and his associates perform a series of elegant experiments involving mice, and they found that certain tissue-specific endothelial cells cluster strongly by tissue, like those in the liver or the brain, whereas others from, for example, adipose tissue or the heart have considerable transcriptomic overlap with endothelial cells from other tissues. They identified novel markers of tissue-specific endothelial cells and signaling pathways that may be involved in maintaining their identity, and sex was a considerable source of heterogeneity in the endothelial transcriptome.
In addition, they found that markers of heart and lung endothelial cells in mice were conserved in human fetal heart and lung endothelial cells and identified potential angiocrine interactions between tissue-specific endothelial cells and other cell types by analyzing ligand and receptor expression patterns.

Dr Carolyn Lam: So interesting, Greg. You especially had me at sex differences. So, what's the take home message?

Dr Greg Hundley: Right, Carolyn. So this group discovered a series of transcriptional networks that maintain endothelial cell heterogeneity, and that angiocrine and functional relationships exist between tissue-specific endothelial cells. These findings open the door for future studies that can manipulate these pathways and perhaps modify processes, like atherosclerosis, that impact the endothelium.

Dr Carolyn Lam: Wow, that's cool, Greg. Well, from your paper, I'm going to a mechanistic paper too, and the next study really aimed to define cardiac fibroblasts' heterogeneity during ventricular remodeling, as well as the underlying mechanisms that regulate their function, so important questions here. And co-corresponding authors, Drs Prósper and Lara-Astiaso from Clinica Universidad de Navarra in Pamplona in Spain, as well as Dr Lindner from Maine Medical Center Research Institute in Scarborough, Maine in the U.S., and their co-authors, basically characterized cardiac fibroblasts after myocardial infarction using a whole host of very novel techniques like single-cell and bulk RNA sequencing, ATAC sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing.

Dr Greg Hundley: Very intriguing. What did they find?

Dr Carolyn Lam: They identified and characterized a unique cardiac fibroblast subpopulation that emerged after myocardial infarction in mice. These activated fibroblasts exhibited a clear profibrotic signature expressing high levels of collagen triple helix repeat containing 1 and localized into the scar. Moreover, the absence of this regulator resulted in pronounced lethality due to ventricular rupture. Finally, a population of cardiac fibroblasts with a similar transcriptome was identified in a swine model of myocardial infarction, as well as in heart tissues from patients with myocardial infarction and dilated cardiomyopathy.

Dr Greg Hundley: Ah, so important information on how fibroblasts start the scar formation after infarction. So, Carolyn what's the take home message here for this research?

Dr Carolyn Lam: Well, this paper really provides important information on cardiac fibroblast heterogeneity, their dynamics during the course of myocardial infarction, and the authors also redefine the cardiac fibroblasts that respond to cardiac injury and participate in myocardial remodeling. This study identifies collagen triple helix repeat containing 1 as a novel regulator of the healing scar process, and as a target for future translational studies.

Dr Greg Hundley: Great, Carolyn. You're doing such a great job. This is an issue for double quiz. Have you ever heard of treatments for hypertension incorporating Chinese herbal formula gastrodia-uncaria granules?

Dr Carolyn Lam: What? Are you trying to speak Chinese, Greg?

Dr Greg Hundley: Yeah (affirmative) Okay.

Dr Carolyn Lam: I'm sure you're going to tell us about it.

Dr Greg Hundley: Right. So this study is from Professor Yan Li from Ruijin Hospital in Shanghai, Jiao Tong University School of Medicine. Gastrodia-uncaria granules Carolyn, is a mixture of Chinese herbs that dates back many years, I think thousands, and in this study was used in patients with masked hypertension. So in the study, patients with an office blood pressure of less than 140/90 millimeters of mercury, but a daytime ambulatory blood pressure of 135 to 150 millimeters of mercury systolic or 85 to 95 millimeters of mercury diastolic, were randomized one-to-one to receive the treatment of, and I'm going to abbreviate it, GUG versus placebo, 5 to 10 grams twice daily for four weeks. The primary efficacy variable was the change in daytime ambulatory blood pressure.

Dr Carolyn Lam: Ah. (affirmative), so did it work?

Dr Greg Hundley: Well, in their intention-to-treat analysis, daytime systolic-diastolic blood pressure was reduced by 5 and 3 millimeters of mercury in the GUG group, and 3 and 1.6 millimeters of mercury in the placebo group, respectively. The between group difference in blood pressure reductions was significant, 2.5 and 1.7 millimeters of mercury, and 24-hour blood pressure by 2 and 1.5 millimeters of mercury, but not for the clinic and nighttime blood pressures. The per protocol analysis in 229 patients produced similar results. Only one adverse event, sleepiness during the day was reported and no serious adverse events occurred. So Carolyn, a potentially inexpensive regimen found useful in China for patients with masked hypertension. To learn more of the results of this interesting study, listeners are suggested to review the article in this particular issue.

Dr Carolyn Lam: Wow, interesting Greg. Okay. So from hypertension to CABG. Now we know that approximately 15% of saphenous vein grafts occlude during the first year after coronary artery bypass graft surgery, or CABG, despite aspirin use. So can ticagrelor added to standard aspirin improve saphenous venous graft patency at one year after CABG? Now this is the question that Dr ten Berg from St. Antonius Hospital from Nieuwegein in Netherlands, and colleagues sought to answer in the popular CABG trial, which was an investigator-initiated randomized double-blind placebo-controlled multicenter trial of 499 patients with one or more saphenous vein grafts, who were randomly assigned after CABG to ticagrelor or placebo added to standard aspirin.
The primary outcome was saphenous vein graft occlusion at one year assessed with coronary CT angiography occurred in 10.5% of the ticagrelor group, versus 9.1% in the placebo group, so that's an odds ratio of 1.29, and it was not significant. The secondary outcome of one year saphenous vein graft failure, which was a composite of vein graft occlusion, revascularization, myocardial infarction in the myocardial territory supplied by the vein graft, or sudden death, well, that occurred in 14.2% of patients in the ticagrelor group, versus 11.6% in patients in the placebo group. Again, not a significant difference.

Dr Greg Hundley: So Carolyn, a negative study? What's our take home here?

Dr Carolyn Lam: In this randomized double-blind placebo-controlled trial, the addition of ticagrelor to standard aspirin after CABG did not reduce the rate of saphenous vein graft occlusions at one year. Now, this conclusion differs from some other studies that investigated this research question, and this is discussed in this editorial that you got to pick up. It's by Dr Goldman from the University of Arizona.

Dr Greg Hundley: Wow, Carolyn. Great job. Well, we've got a couple more articles in this issue, and I'll start by describing a research letter by Dr Daviet regarding heparin-induced thrombocytopenia in COVID-19, and then Carolyn there's a second research letter from our own Torbjørn Omland regarding established cardiovascular biomarkers provide limited prognostic information in unselected patients hospitalized with COVID-19. And then finally, from Dr Chonyang Albert, a case series entitled, The Enemy Within: Sudden Onset of Reversible Cardiogenic Shock with Biopsy-Proven Cardiomyocyte Infection by SARS-CoV2.

Dr Carolyn Lam: We've also got an ECG challenge by Dr Sreenivasan entitled, A Red Flag ECG, also known as, and have you heard of this, South African flag pattern. Okay, here's a hint. It's an important, but subtle ischemic ECG change. You got to look it up. There's an On My Mind paper by Dr Alexander on at risk of depriving patients’ life-saving cardiac surgery, and those are the implications of the ischemia trial for CABG. A Research Letter shared by Dr Susen entitled, Endotheliopathy is Induced by Plasma from Critically-ill Patients and Associated with Organ Failure in Severe COVID-19. And finally, in Cardiology News, Tracy Hampton reviews the most recent literature in top journals like Nature, Metabolism, Cell, Stem Cell, and Circulation Research. Wow. Bonanza issue. So cool, but I really want to hear about the different blood pressure patterns now. Let's go to our feature discussion, shall we?

Dr Greg Hundley: Absolutely. Here we go. Well, listeners we are excited to get to this feature discussion to learn more about the use of ambulatory blood pressure measures, particularly those that are collected 24 hours and during the nighttime. We have with us, Dr Kazuomi Kario from the Jichi Medical University in Japan, and our own Associate Editor, Dr Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas. Welcome to you both. And Kazuomi, could you start us off please and just describe some of the background that led you to perform this study? And what hypothesis did you want to address?

Dr Kazuomi Kario: The old guidelines management of the hypertension and now recommend instead of the office blood pressure, now the ambulatory blood pressure management. So for example, the ABPN and also home blood pressure monitoring, but the 24-hour blood pressure reduction is very much important, all prefer the values, but also our hypothesis took on the 24-hour blood pressure quantity reduction, but also, we should normalize our circadian rhythm. Usually blood pressure reduced by 10 to 20% at night during the sleep compared to the daytime. But the other group, is exhibited and predicated known six bars and also is either higher at night during the nighttime period compared to the daytime. And also home blood pressure variability, that hurts blood pressure in the morning. So circadian rhythm normalization and also, I recreate blood pressure variability especially is more precise.
It's important for the quality control over for the hypertension management. So my hypothesis is that blood pressure reduction, the other most blood pressure, and the normalized circadian rhythm, under agitate, to keep agitate among as such. All the three components I did try to optimize 24-hour blood pressure control, so I want to confirm our hypothesis. To optimize 24-hour blood pressure control consists of these three components, 24-hour pressure reduction, and the normalize circadian rhythm and the keeping the other keep such, it shouldn't be; I have, have you left your prevention or not? That's my hypothesis and background.

Dr Greg Hundley: So with our 24-hour ambulatory monitoring evaluating in this study, do we have the normal dip during the evening? Do we have a rise associated with the circadian rhythm? What is the variability of the blood pressure over time? Tell us what study population, and how did you design this study to address your hypothesis?

Dr Kazuomi Kario: This population is the hypertension patients, 90% or more on the out-patients who keep the adequate, the active daily readings, and they are medicated, or usually conventional hypertension medication is the effective to reducing the office blood pressure and they can. But the other hypotension treatment may not be sustained to be reducing the nocturnal blood pressure and next morning people are taking pills. So it may be that the picture of the nighttime blood pressure and the morning blood pressure. So our hypothesis targets is already mitigated hypotension patient, but we should find out control for the current hypotension treatment. It should be the nighttime and next morning.


Dr Greg Hundley: So we're addressing whether the efficacy of or any hypertensive medications are maintaining low blood pressures at night and avoiding a surreptitious rise in blood pressure when we wake up. So how many patients did you enroll and what were your study results?

Dr Kazuomi Kario: The total study population number is 6,359 patients or enrolls. And we find out, compared to the daytime. Daytime also where the risk of the nighttime blood pressure other age, was more the precise this predictor of cardiovascular events. So, cardiovascular events consist of the atherosclerosis cardiac events consists of stroke and coronary artery disease. And also the nighttime blood pressure associated with the risk of the heart failure. And very interestingly, disrupted circadian rhythm, it rises at night higher during the nighttime compared to the daytime, it was independent of risks for the cardiovascular event, especially for the heart failure. So even after controlling for the daytime, even on the nighttime blood pressure, this pattern nighttime riser was an independent risk, so very interesting results.

Dr Greg Hundley: So elevations of systolic blood pressure during nighttime, during sleep were associated with future atherosclerotic cardiovascular disease, as well as heart failure. And one more quick point, was there a particular magnitude of rise of that systolic blood pressure at night was important. And did you find similar results for men and for women?

Dr Kazuomi Kario: Yes, similar results for men and the women. Theo other factor was age was increased. The almost the higher during the nighttime or other age of the rising pattern was 10 allowed during the nighttime compared to the daytime.

Dr Greg Hundley: So even a 10% increase in systolic blood pressure at night relative to daytime was important for forecasting these adverse cardiovascular events. So Juan pen, can you help us take these results from this elegant ambulatory monitoring study and put those in the context of other study results that have evaluated 24 ambulatory monitoring of blood pressure?

Dr Wanpen Vongpatanasin: I think the notion of nighttime blood pressure as the independent predictor of cardiovascular outcome has been shown in other cohort, but usually not this large magnitude, that is an international registry. I had call that in different countries around the world that demonstrate this. But again, like I said, it compiled from a smaller dataset, there's even fewer data sets in the United States. There's a cohort from Jackson Heart, but again, it's less than a thousand and most of other cohorts have looked at mostly a target organ level, not at the heart CV outcome.
So I think this add to an important observation, and I think that the results from the nighttime it's similar, but extended from previously that look at individual outcome using a adjudicated data committee that also a very distinctive feature of the study that is a committee that look at this and look at a specific outcome rather than just a retrospective using the death index from different countries. The other part is slightly different perhaps, and they learn from reading it is the extreme dipping, also dropped a lot. Initially people think that it might be associated with the worst outcome, but even to me I wasn't sure what this mean, but in this study the most extreme dip, maybe not, not as much that shouldn't be worried as much compared to the actual nighttime blood pressure itself or not dipping itself.

Dr Greg Hundley: Kazuomi what do you see as the next study that needs to be performed in this area of research?

Dr Kazuomi Kario: Oh, it's the observational study of the current medical situations maybe kind of situations. So next step, we should focus on that nighttime blood pressure; regardless of the office and the daytime, so even there are controls, if we should target the nighttime blood pressure and the toxicity controls, organ damage should be decreased and the subsequent cardiovascular events should be decreased. So observational study targeting the nighttime blood pressure is the next topic.

Dr Greg Hundley: And Wanpen do you have anything to add to that?

Dr Wanpen Vongpatanasin:I'd like to see more large observational study from the US with the diverse population, because the salt consumption in Asia, particularly in Japan, are probably among the highest. So perhaps the nighttime blood pressure, it's
confounded by high sodium and something, and we're not too far behind obviously, but it'd be nice to know what it means in the US. And obviously they're targeting nighttime blood pressure, it's the hot topic and that's by itself is probably another 30 minutes to an hour of discussion. But I think that that's very important area of research.

Dr Greg Hundley: Listeners, what a really wonderful discussion. And in this study from Japan of over 6,000 individuals treated for high blood pressure, those with 24-hour monitoring and exhibiting a rise in systolic blood pressure during the nighttime was associated with future cardiovascular events and an increase in the risk of heart failure. Moving forward from these experts, performing additional observational studies to confirm these findings and other populations, and perhaps a randomized trial, trying to target therapeutic interventions that would lower nighttime blood pressure may be warranted. Thank you Dr Kario and Dr Vongpatanasin. We wish you a great week and we look forward to catching you on the run next week. This program is copyright The American Heart Association, 2020.