Sep 1, 2021
This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Kypros Nicolaides and Associate Editor Karol Watson as they discuss the article "Pravastatin versus Placebo in Pregnancies at High Risk of Term Preeclampsia."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We are your co-hosts, 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, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
We have a really important feature discussion today. It's on pravastatin versus placebo in pregnancies at high risk of term preeclampsia. Very important condition. And I'm just so glad that we will be discussing this issue, coming right up. But first, I want to start on the other papers in this issue. And this first study, which is the first study to assess the effects of aerobic exercise training with and without caloric restriction on changes in the proximal aortic stiffness using cardiovascular magnetic resonance imaging. Now the corresponding author is Dr. Brinkley from the Sticht Center of Healthy Aging and Alzheimer's Prevention in Wake Forest School of Medicine. But guess what? Our very own Dr. Greg Huntley is a co-author. So whether you know it or not, Greg, we're going to do a mini feature, right now. So Dr. Huntley, could you please give us some background to your study, it's so cool?
Dr. Greg Hundley:
Oh, Carolyn, thank you so much. It's quite a privilege to be, actually being interviewed by you. So about the paper. Aortic stiffness is really a prominent manifestation, as we know, of vascular aging. And it's an independent predictor of cardiovascular events and mortality. And risk factors such as hypertension, diabetes, obesity, they can promote vascular changes that lead to accelerated vascular aging. Now, on the other hand, lifestyle factors such as healthy diet, regular physical activity, they may attenuate age related increases and aortic stiffness.
Dr. Greg Hundley:
And both cross-sectional and longitudinal studies indicate that exercise is associated with lower aortic stiffness. However, some data suggests exercise alone may not be sufficient to improve aortic stiffness in certain subpopulations of older adults. And so what Tina did, she worked in combination with all the co-authors and determined the effects of aerobic exercise training, with and without moderate to high caloric restriction on the structure and function of the proximal aorta in a 160 older, so 65 to 79 year old men and women with obesity that had a body mass index of 30 to 45 kilograms per meter square.
Dr. Carolyn Lam:
Wow. Okay, cool. But how do you assess this by MRI? Isn't that part of the novelty of the study, right?
Dr. Greg Hundley:
Right, Carolyn. So kind of two ways magnetic resonance imaging assesses aortic stiffness. First is to look at the distensibility. What is this distensibility? That's the change in the area of the aorta, relative to the distending pressure. And you can't measure that distending pressure noninvasively. So what we do is use a surrogate, your cuff pressure at your brachial artery. So that's one measure. Area change divided by basically the pulse pressure indexed for the resting area. And the second is pulse wave velocity. And for the listeners, remember pulse wave velocity, the faster the blood moves around through the aorta, the stiffer the artery is. And so we measured both aortic distensibility and pulse wave velocity.
Dr. Carolyn Lam:
I love it. You're such a good decentral educator. Okay. So what are the results real quick?
Dr. Greg Hundley:
Thanks Carolyn. So there were significant treatment effects for descending aortic distensibility and strain. And aortic arch pulse wave velocity with the aerobic exercise training plus the moderate caloric restriction group, having a 21% increase in distensibility, and an 8% decrease in pulse wave velocity. And none of the aortic stiffness measures changed significantly in the aerobic exercise training. Only, or in the aerobic exercise training plus very intensive caloric restriction.
Dr. Carolyn Lam:
So how do you put that all together? What does this mean for us clinically?
Dr. Greg Hundley:
Right, Carolyn. So I think the findings that Tina and everyone here in this group are showing, they suggest that exercise alone, that is in the absence of significant weight loss, has minimal effects on proximal aortic stiffness in older adults with obesity. Second, although obesity likely blunts the beneficial effects of regular aerobic exercise on aortic stiffness in older adults, these data support a growing number of studies indicating that intentional weight loss can be safe for older adults with obesity. And then finally, Carolyn, the addition of moderate caloric restriction appears to maximize improvement in aortic stiffness. Whereas higher intensity caloric restriction may not be necessary or even really advised. And that has important indications for weight loss recommendations to improve cardiovascular disease risk among older adults.
Dr. Carolyn Lam:
Oh, wow. Thanks Greg. And congratulations to you and your co-authors on this beautiful paper. Well, in the next paper, we switch to the preclinical world and I'm going to tell us about the WW domain containing E3 ubiquitin protein ligase 1. And I'm not going to be able to say that again. So I'll call it WWP1. We know that this is an important regulator of aging related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload induced cardiac remodeling and heart failure is yet to be determined. So this next paper looks at that with co-corresponding authors, Dr. Li and Ling from the State Key Laboratory of Space Meds and Fundamentals and Application, China Astronaut Research and Training Center in Haidian district in Beijing. Now the authors use WWP1 Knockout Mice, and adeno associated virus, serotype nine, carrying cardiac troponin T promoters driven by small hairpin RNA targeting WW1. And in these special mice, found that WW1 regulated cardiac hypertrophy induced pressure overload by stabilizing disheveled segment polarity proteins, or DVLs.
Dr. Greg Hundley:
Carolyn. So disheveled segment polarity proteins. So what are those?
Dr. Carolyn Lam:
Well, the DVLs, which include DVL one, two, and three are important cytoplasmic mediators, involved in canonical and non-canonical WNT signaling. And these are pivotal in cardiac remodeling. The authors demonstrated that WWP1 interacts with DVL2, and stabilizes it through an atypical ubiquitin type modification. And thus WWP1 has the potential as a therapeutic target for cardiac hypertrophy and heart failure.
Dr. Greg Hundley:
Excellent, Carolyn. Boy, what a fantastic summary. Well, my next paper comes from Dr. Zhao Wang from University of Texas Southwestern Medical Center. And Carolyn, as we know, metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. And the elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, it's role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully understood. And so these authors aim to dissect the role of cardiac pyruvate kinase muscle iso enzyme 1 in glucose metabolic regulation and cardiac response under pressure overload.
Dr. Carolyn Lam:
Oh. Wow. So what were the results?
Dr. Greg Hundley:
Right, Carolyn. So they found that pyruvate kinase muscle iso enzyme 1, so let's call that PKM1 expression, is reduced in failing human and mouse hearts. And importantly cardiomyocytes specific deletion of PKM1 exacerbated cardiac dysfunction and fibrosis in response to pressure overload. Now inducible over expression of PKM1 and cardiomyocytes protected the heart against TAC induced cardiomyopathy and heart failure. And at the mechanistic level PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration and ATP production under pressure overload. And furthermore deficiency of PKM1 caused a defect and cardiomyocytes growth and a decrease in pyruvate dehydrogenase complex activity at both the in vitro and in vivo levels. So, Carolyn, in summary, these findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.
Dr. Carolyn Lam:
Oh, nice, Greg. Well, let's go on to what else is in this issue? There's a Research Letter by Dr. Aguib on a new variant with a previously unrecognized mechanism of pathogenicity in hypertrophic cardiomyopathy.
Dr. Greg Hundley:
And, Carolyn, I've got three papers. First, there's an ECG Challenge from Professor Gunnaseelan [Rajendran], “Not All Waves Are Factual.” There's a nice On My Mind piece from one of our associate co-editors Torbjørn Omland entitled “Cardioprotective Therapy in Cardio-Oncology: Quo Vadis?” And finally, there's an In-Depth article from Dr. Brilakis entitled the “Saphenous Vein Graft failure From Pathophysiology to Prevention and Treatment Strategies.” Well, Carolyn, how about we head off to the feature discussion, and learn a little bit more about pravastatin versus placebo in pregnancies at high risk of term pre-eclampsia.
Dr. Carolyn Lam:
Let's go.
Dr. Mercedes Carnethon:
Well, welcome to Circulation On the Run. I'm pleased to be one of your hosts today. My name is Mercedes Carnethon. I'm an epidemiologist and professor at the Northwestern University's Feinberg School of Medicine, and one of the associate editors of the journal. I'm really excited to participate in the podcast today with our featured guests. We have a paper led by Dr. Nicolaides, Kypros Nicolaides, from the University of Exeter in the United Kingdom. And we have the associate editor, Dr. Karol Watson, who handled the piece for the journal.
Dr. Mercedes Carnethon:
So I'm really pleased to have each of you with me today and good morning.
Dr. Karol Watson:
Good morning. Thank you for having us.
Dr. Mercedes Carnethon:
Well, thank you. So why don't we jump right in? So the title of today's piece is pravastatin versus placebo in pregnancies at high risk of term preeclampsia. A really exciting read that I think provides important insights to us as well as emphasizes what we can learn from negative trials and negative studies. And so I'll jump right in and rather than me providing a summary, I'll turn it over to you. Kypros. Tell me a little bit about your inspiration for carrying out this work and why you pursued this topic.
Dr. Kypros Nicolaides:
Thank you. Well, preeclampsia is one of the major causes of death and handicap for the mother, and the fetus, and the baby. We have been trying for many decades to develop a method of identifying a high risk group of women that would develop preeclampsia. And we succeeded in doing so. And five years ago, we carried out a major trial at 12 weeks where we gave aspirin to the high risk group. And that study was very successful. We managed to reduce the rate of preterm pre-eclampsia by about 60%. And it was published in the New England Journal of Medicine.
Dr. Kypros Nicolaides:
However, screening at 12 weeks was not very effective in identifying women that deliver with pre-eclampsia term. And aspirin was not effective in preventing term preeclampsia and although preterm preeclampsia individually has more serious complications than term preeclampsia. Because three quarters of preeclampsia happen at term, the overall contribution of term preeclampsia is actually higher than that of preterm preeclampsia.
Dr. Kypros Nicolaides:
So that was the rationale, the background of having to do something to first identify the high risk group for term preeclampsia. And secondly, see whether we could do something to prevent it. So we, in this study involving about 30,000 women carried out in several hospitals in England, essentially, and Belgium, we screened at 35 to 56 weeks. We identified that 10% of the population at high risk. And then we randomized 1,120 women in trial with pravastatin 20 milligrams against placebo. Why pravastatin? Because a study from the United States by Constantine in a preliminary study, 10 women that were randomized to try the pravastatin or placebo starting from 12 weeks showed extremely promising results. So pravastatin studies are very commonly used for the treatment or prevention of hypertensive disease outside pregnancy preeclampsia and hypertensive disease are very closely related. So we felt that perhaps pravastatins given at this late stage would prevent the development of preeclampsia. Unfortunately, we found that that was not the case.
Dr. Mercedes Carnethon:
You know, your final point, there is one that we often lecture about and talk about with students. What do you do when you have a negative trial? I noticed that you said, unfortunately, you found that wasn't the case. But tell us about the value of the negative trial. I think part of the reason why this is so compelling and important is you may have ruled something out. So tell us a little bit about your findings. Did they surprise you? What do you make of them?
Dr. Kypros Nicolaides:
I can divide the findings into two, Mercedes. Firstly, the ability to screen in a multicenter study using our method, it was a method of validating our previous model. And we had found that we could identify 75% of the women that would develop term preeclampsia for a screen positive rate of about 10% and I think that that was very important. And I think that Karol Watson that was editing and dealing with the article identified that as being an important component of the article. And to me, that is very much so. We found, we have now a method of identifying a very high proportion of women that will develop term preeclampsia.
Dr. Kypros Nicolaides:
We failed. The drug, it was disappointing. But we have a background method with which we can identify the high risk group to try new methods of intervention that perhaps would be helpful. I think that I will have, in a sense, great success with aspirin in the first semester. And to a great extent, elimination of preterm preeclampsia forced us to move with optimism of preventing term preeclampsia. But perhaps giving pravastatin starting from 35, 36 weeks was perhaps too late. We should have perhaps started giving treatment before that. But we couldn't be because we did not have a good method of identifying the high risk group. So as far as I am concerned, we learned that pravastatin is unlikely to be beneficial, even if we try it every year, because we cannot identify the high risk group.
Dr. Karol Watson:
I'm so sorry for interrupting, but I just -
Dr. Kypros Nicolaides:
I'm glad you did.
Dr. Karol Watson:
This was such an important trial in so many respects. I think you under sell it a little bit. This was phenomenal to be able to identify this high risk group. As you say, just phenomenal. You know, 35,000 women screened, identifying this high risk group, and then to do a randomized trial of statin therapy in pregnancy. That is landmark. That was really very, very prescient, thoughtful, and really important to study. And I'm so grateful that you guys did.
Dr. Kypros Nicolaides:
Carol, thanks very much for your kind words and for accepting our paper for publication. Thank you.
Dr. Mercedes Carnethon:
You know, Kypros, this is really exciting. And I'm glad that you jumped in, Carol. You know, it stands out to me that part of why I will love having this as a potential paper to add to cases where we teach people, how to understand, how to carry out a study and how to respond when your primary hypothesis isn't born out. However, even if your primary hypothesis wasn't born out, you did learn something. And it sounds as though you learned a strategy to identify high risk individuals. And it is informing your next steps in your next study. Carol, you are obviously very involved. It was great to hear your feedback. What are your thoughts about what the lessons are for the practicing cardiologist?
Dr. Karol Watson:
Well, there are several that I took away from this. One is, I mean, I think building on your prior work with aspirin, that was landmark. As you know. And the first time we actually had a viable therapy for preventing preeclampsia. So we can prevent preeclampsia. That's the really important thing that we found out. And then there was a really good theoretic basis for thinking pravastatin might work. I mean, the rationale for this study was so solid and so important. I think the timing issue is, I think it's still an answered whether treating with pravastatin earlier might've helped. I don't know.
Dr. Karol Watson:
But again, we'd have to be able to identify people at risk, which is what your group is so good at doing. But I also think it was brave and very important that you guys decided to treat pregnant women with statin therapy. As you know, there was an FDA contra-indication to that until about a week ago when they removed, or a month ago when they removed it. So you guys had to say, we have the data, we know this seems to be safe, certainly in this time period, and we want to do this. And that was a really important thing to do. This is just such a rare and important trial. The randomized controlled trial of statin therapy in pregnancy. We just don't see that. You guys are groundbreaking
Dr. Kypros Nicolaides:
And, Carol, on that point for those that are still, I know that in the United States, people are planning new trials, starting from the first trimester. But as you said, they were stopped by the FDA. We provided further evidence of the potential safety of the drug. It was not published in the journal, but as part of the trial, we were collecting from some women cord blood. And it had shown that there were no adverse biochemical events. And also there were no significant differences in adverse events between the placebo and the pravastatin group. So in that respect, it is a good starting point to encourage those that want to do studies everywhere only in pregnancy.
Dr. Karol Watson:
So important, so important.
Dr. Mercedes Carnethon:
Thank you so much, Kypros. And I'm really excited that we're featuring this in Circulation On the Run because it means that we can get word out beyond our core audience of cardiologists. This is really an important piece as well for the obstetrician gynecology community to hear about given the steps that they will, how they'll consider using these data. Certainly, and you both touched on a really important point, which is that it isn't as common that we do intervention studies in vulnerable groups and protected groups. And pregnant women typically are. You enrolled 1,100 people into this trial. That is really impressive. Can you share with our audience a little bit, to the extent, a little bit about that process. How did you convince the team of the safety and were women enthusiastic and how did they respond? I look forward to using your responses to discuss with my trainees, how we go about carrying out this important work.
Dr. Kypros Nicolaides:
One of the issues about trials, Mercedes, is to have the background method of identifying a high risk group. In the United States, unfortunately, there is no method of routine screening in pregnancy during the first trimester. In very few cultures, if I take ultrasound scanning, for example, a few decades ago I was instrumental in introducing a 12 week scan. Because I have noticed that increased nuchal translucency is a marker of chromosomal abnormalities and so on. And that created a 12 week routine assessment in many countries of the world. It was at the back of that assessment that we introduced first trimester screening for preeclampsia. That led to the aspirin trial and the successful results of prevention. We have pioneered, in my hospital, the series of hospitals that I have under my influence, because they are run by ex research fellows of mine, a routine 36 weeks scan in pregnancy.
Dr. Kypros Nicolaides:
I call three scans in pregnancy important. One at 12 weeks, we find out whether the woman is truly pregnant or not, whether she carries one baby or not, whether the babies are generally all right. Whether we can screen at that point for chromosomal and other abnormalities, and now screening for preeclampsia. At 20 weeks scan, where we look for the fetal anatomy again, and then the development of the baby. In the third trimester scan, which I call it the delivery scan. At 36 weeks, we can tell whether the baby is developing normally or not. Whether the baby's in the right position cephalic or breach. And now whether the baby's too big or too small. And now whether you can identify they're high risk group for preeclampsia. So you need that background of routine screening of the whole population. And then of course we are quite experienced in recruiting women into our studies.
Dr. Kypros Nicolaides:
I deliberately call my center—although it is a routine, national health center institution—I call it an institute of research in fetal medicine. The ideology of the center is research. There are so many things that we do not know. And women have understood the value arriving in a research institute. They accept the ideology that if you participate in research, you will benefit or others will benefit or you will benefit your next pregnancy. So I think a successful recruitment into trials is the projection that you have a center that is actively being involved in research. And research is an integral part of providing a good clinical service. That's all I can say as a general point.
Dr. Mercedes Carnethon:
That is wonderful. You know, Kypros, I've really appreciated the time you spent with us. And I just want to end by calling on my colleague, Carol. Any final words or comments as we wrap up today?
Dr. Kypros Nicolaides:
I just thought from soup to nuts, beginning to end, this study was so informative and illustrative. We were able to, thanks to you and your group, Kypros, to understand that you can identify this high risk group. That you can treat pregnant women with statin therapy, with safety. And that you can get information out of a neutral study. And I just think all of those are so important and I am really looking forward to your next step. Because I think your group has just been groundbreaking in so many levels.
Dr. Mercedes Carnethon:
Well, thank you so much, Kypros, Carol. I think we've had a really exciting discussion this morning and our listeners from the cardiology community, to even the more broad research community, and the OB GYN community have learned a great deal from your work. So this is Mercedes Carnethon, one of the associate editors at Circulation and the happy host of the Circulation On the Run podcast. So thank you very much.
Dr. Karol Watson:
Thanks so much.
Dr. Kypros Nicolaides:
Thank you.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also wish everyone a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.