Apr 19, 2021
For this week's Feature Discussion, please join author Marco Vinceti and Associate Editor Wanpen Vongpatanasin as they discuss the article "Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, co-host and Associates Editor, Director of the Pauley Heart Center, Richmond, Virginia, VCU Health
Dr. Carolyn Lam:
Dr. Greg, today's feature paper, super, super exciting. Everyone has to listen to it because it's about blood pressure and sodium intake. But you think you've heard it all? You haven't. You have to listen to this feature discussion, and I'm sure you'll learn a lot, just like I did. Seriously. But before that you got your copy, I got mine. Let me tell you all about microRNA. Shall I?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
MicroRNA, we know, have a remarkable influence on the physiology of the heart and the remodeling of diseased hearts through canonical RNA interference mechanisms. Now, the authors of today's paper, co-corresponding authors, Dr. Fu and Deschênes from Ohio State University in Columbus, Ohio, investigated if microRNA one or mir-1 specifically binds with cardiac plasma membrane proteins, and they revealed an evolutionarily-conserved direct binding between this mir-1 and an inward rectifier potassium channel called cure 2.1. Now, this is endogenously existing in cardiomyocytes.
Dr. Carolyn Lam:
Now, the authors then used inside out and wholesale patch clamp recordings to show the biophysical modulation of cardiac electrophysiology by mir-1. They further studied the mechanism of this physical interaction and investigated its pathophysiologic relevance by using mir-1 deficient transgenic mice. In total, their study demonstrated a novel mechanism of microRNA ion channel biophysical modulation that regulates cardiac arrhythmia risk.
Dr. Greg Hundley:
Wow, Carolyn really sophisticated work involving the pathophysiology of some of these arrhythmias. What are the take home message?
Dr. Carolyn Lam:
Ah, I'm glad you asked. Let me circle back to what I said earlier. Cardiac electrophysiology is regulated by microRNAs. We knew about the canonical RNA interference mechanisms, but that needs hours to days to regulate gene expression. But now we have the newly discovered biophysical mechanism that quickly, and that is within seconds or minutes, modulates the function of the ion channels. These microRNAs could prevent or trigger arrhythmias through biophysical modulation of the ion channels, even before its RNA interference regulation of protein expression occurs in diseased hearts.
Dr. Greg Hundley:
Wow, Carolyn. Really interesting new basic science. Such an asset for our journal. Well, I'm going to switch and talk a little bit about really, really high coronary artery calcium scores, something that sometimes we see. The work comes from Dr. Michael Blaha from Johns Hopkins University in Baltimore, Maryland. Carolyn, as you know, there are limited data on the unique cardiovascular disease and non-cardiovascular disease and mortality risk of primary prevention individuals with very high coronary artery calcium scores. What do we mean by very high? These are scores greater than or equal to a thousand. That's especially true in comparison to rates observed in secondary prevention populations. In this study, the investigators compared the hazard ratios for coronary artery calcium scores greater than a thousand in comparison with calcium scores of zero, those from 400 to 999, and they looked at this for those with cardiovascular disease, non-cardiovascular disease, and also evaluated mortality outcomes.
Dr. Carolyn Lam:
Oh, wow. That's interesting and those are very high coronary artery calcium score. What did they find?
Dr. Greg Hundley:
Thanks, Carolyn. After full adjustment, coronary artery calcium scores greater than or equal to a thousand demonstrated a 4.7 to a seven and a half increase in the hazard ratio for outcomes compared to individuals with calcium scores of zero, a 1.6 to 1.3 four-fold increase compared to those with calcium scores in the 400 to 999 range. Carolyn, with increasing coronary artery calcium scores, the hazard ratios increased for all event types with no apparent upper coronary artery calcium threshold. For example, a coronary artery calcium of a thousand correspond to an annualized 3-point MACE rate of 3.4 per a hundred person years and that's similar to that of a for EA population of 3.3 and higher than lower risk for EA subgroups.
Dr. Greg Hundley:
Carolyn, these results raise the thought that as we're thinking and putting together future guideline statements, should we consider a less distinct stratification algorithm between primary and secondary prevention patients for these very high coronary calcium scores? The high scores in the primary prevention group for this study really mirrored those four EA scores that you see in patients that are undergoing secondary prevention. They've already had a heart attack. Should we start thinking about for these very high scores, really aggressive preventive pharmacotherapy, just like we would in a patient that was undergoing secondary prevention?
Dr. Carolyn Lam:
I like that explanation. Thanks, Greg. Well, this next one really speaks to my favorite topic, sex differences in cardiovascular physiology and disease outcomes. Greg, here's the quiz question. Do you think progesterone receptors in cardiac cells play a role in determining the difference between you and me? Co-corresponding authors Dr. Porrello from Murdoch Children's Research Institute in Melbourne, Australia and Dr. Hudson from the Berghofer Medical Research Institute in Brisbane, Australia, and their colleagues, hey performed single nucleus RNA sequencing to capture transcriptional changes across multiple cardiac cell populations during the human heart development from fetal stages to adulthood. Their data revealed six specific transcriptional mechanisms governing maturation of multiple cell types in the heart, including a previously unrecognized role for the progesterone receptor in human cardiomyocyte maturation. These data really provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.
Dr. Greg Hundley:
Oh, great, Carolyn. Very nice. Well, Carolyn, my next paper really involves an assessment of air pollution. As you know, many of the studies today have really focused on short-term exposures to air pollution. But this group headed by Dr. Yazdi at the Harvard T.H. Chan School of Public Health began to evaluate long-term or chronic exposure to air pollution. Carolyn, the study examined the relationship between the long-term exposure to find particulate matter with an aerodynamic diameter of less than 2.5. micrometers also from nitrogen dioxide and from ozone, and they evaluated all three of those relative to hospital admissions for four cardiovascular and respiratory outcomes: myocardial infarction, ischemic stroke, the development of atrial fibrillation or flutter, and the development of pneumonia. They looked at this in the Medicare population within the United States.
Dr. Carolyn Lam:
Hmm, interesting. What did they find?
Dr. Greg Hundley:
Okay, Carolyn, so a couple things. First, long-term exposure to that fine particulate matter was associated with an increased risk of all outcomes with the highest effect seen for those that incurred a stroke. The findings translated to 2,536 cases of hospital admissions with ischemic stroke per year, which can be attributed to each one unit increase in fine particulate matter levels among the study population. Also, the nitrogen dioxide was associated with an increase in the risk of admission for stroke and atrial fibrillation. Then, the ozone was associated with an increase in the risk of an emission for a pneumonia.
Dr. Greg Hundley:
Carolyn, what this study showed, at lower concentrations, a chronic exposure, long over time of all these pollutants, were consistently associated with an increased risk for all of the study-related cardiovascular and cardiopulmonary studied outcomes. New important information regarding long-term as opposed to short-term exposure of these pollutants.
Dr. Carolyn Lam:
Yikes, yikes. Important to pay attention to. Thanks, Greg. Let me now go to the other articles in today's issue. There is a beautiful Perspective piece by Dr. Shah titled Transcatheter Closure of the Patent Foramen Ovale: Not Always an Open or Shut Case. There is a Research Letter by Dr. Davis on engrafted human induced pluripotent stem cell derived cardiomyocytes undergoing clonal expansion in vivo.
Dr. Greg Hundley:
Great, Carolyn. I've got two publications to discuss. First, Dr. Ransom has an EKG challenge entitled Palpitations in the Clinic. Then, finally, our own editor in chief, Dr. Joe Hill has a wonderful in memoriam to Dr. Jim Willerson, a prior editor-in-chief of circulation, and really a guiding light for many of us in cardiovascular diseases for much of his life. Well, Carolyn, on that note, how about we now transfer to that feature discussion and learn a little bit more about sodium intake and high blood pressure.
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Carolyn Lam:
Now, most of us would agree that dietary sodium has a role in the modulation of blood pressure levels. That we've agreed on. However, we still debate over the magnitude of the effect, who it applies to, and the importance of sodium-driven blood pressure changes for global disease burden. Well, today's feature paper does a lot to address many of the remaining questions that are revolving around sodium intake and blood pressure. I'm so pleased to have with us the corresponding author of the feature paper, Dr. Marco Vinceti from University of Modena and Reggio Emilia in Italy, as well as our associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern. Welcome both. Marco, if I may and begin with you, please, could you tell us the inspiration for your study and what you did?
Dr. Marco Vinceti:
Thank you by the way, for inviting me and good morning to everybody. Our inspiration was being aware that as you already say, there may be an association, there is an association between sodium intake and blood pressure, but that maybe not all the details about such relation are being explored and carefully investigated, also for the lack of adequate statistical tools. Also, because we know that health endpoints and exposures, both dietary and environmental factors, I mean, may have a relation that is not linear, that is, just has some kind of different shape, U-shaped curve, J-shaped curve, and so on. Our thought was to investigate better this relation between sodium intake and blood pressure, even in a category of people which is wide. Also, there isn't such a large consensus about the relation; that is, people without high blood pressure and to shape that association using new statistical tools in non-linear fashion, if appropriate.
Dr. Carolyn Lam:
Very nice. Could you tell us what was special about your study design? Because it is true that the methodology you used was very unique and then perhaps the top line of what you found.
Dr. Marco Vinceti:
We took advantage of from a recent, let's say, discovery. I don't know if the term is correct, but we consider it like a discovery, of a colleague of ours at the Karolinska Institute of Stockholm. He is a statistician named Nicola Orsini. He published it in 2019. A new tool, a new approach, call it a one stage dose response meta-analysis that is able to shape the relation between exposures, in this case, sodium intake, and health endpoints or outcomes. We're talking here of continuous endpoint such as blood pressure. We can maybe talk about an outcome, almost outcome hypertension, even in the whole range of exposure from very low intake up to a high intake.
Dr. Marco Vinceti:
Until recently the only meta-analysis that you could perform was just comparing high versus low sodium intake across trials or observational studies. But in each trial, the high exposure category is different from another trial so you are comparing across trials categories that are not the same categories, are not corresponding each other. This is a major limitation. So far, there are no publication able to shape the entire range of exposure, the result of experimental studies. For experimental studies, I mean the gold standard in medical research, in human medicine that are randomized controlled trials.
Dr. Carolyn Lam:
I love that. That is really spot on, I think, of what makes your meta-analysis so important. Could you maybe then now tell us about the results?
Dr. Marco Vinceti:
Well, yes, the results, if I go back to one last detail about our statistical approach, if I can add, in addition to what I said before, we also wanted to use extensively what in 2016, the American Statistical Association just declare it, that to avoid the systematic use of p-values and statistical significant testing, just a black and white approach or something which is statistically significant or not statistically significant, and to shape the relation in a smooth, in a different way, looking graphically their religion and not having a dichotomous black and white approach, exactly as recommended by the American Statistical Association in it's very important statement in 2016.
Dr. Marco Vinceti:
About the results. I think that the main results were that the relation was, unfortunately, I will say linear. Because we were looking at non-linear association and that we tried in any way to find out if there was some kind of non-linearity in the association and I'm saving unfortunately only because we used a tool that is suitable to test a non-linear association. But we found evidence confirming here at previous meta-analysis and previous studies that say that there is a linear association between intake, that is exposure to sodium, and blood pressure. But this association also holds for people without hypertension, participant in these trials without high blood pressure. This put there that this consensus is not exactly well established all over the world; that there are investigators claiming that in people without hypertension, there is no relation, particularly for diastolic blood pressure and sodium intake. Our analysis showed, in my opinion clearly, that such association exists also, even if it is slightly weak, let's say in terms of strength compared with people with hypertension, with at least a high blood pressure.
Dr. Marco Vinceti:
There is an association for people with and without high blood pressure for diastolic and systolic blood pressure, and it exists across the entire range of usual exposure in the Western world. Because we were talking about mainly Western population. Most studies were carried out in Europe, in Australia and North America. The large majority or the 85 trials, which is the largest amount of trials ever analyzed in meta-analysis so far, were carried out in Western population. In those populations, the relation exists and is really detectable across the entire range of association even at very low intakes.
Dr. Carolyn Lam:
Wow, thank you. Thank you so, so much, Marco. So indeed a large, extremely well done meta-analysis, 85 trials, basically showing a positive and approximately linear association between dietary sodium consumption and blood pressure. Wow!
Dr. Carolyn Lam:
Wanpen, please. I mean, Marco is so just delightful in sort of saying that we'd look really hard for that J and U shape that everyone else talks about. We didn't find it, but that's exactly, I think, why we editors found this paper so, so important. Wanpen, I know you can express this better than me, so please.
Dr. Wanpen Vongpatanasin:
Sure. I agree. This is a very important study for the precision in comparing different levels of sodium intake and what it means for blood pressure. Also, I liked the paper that examine the different cutoffs that for example, the paper has a project in blood pressure that recommend by the American Heart at different levels of 1,500 milligrams a day was just the usual American diet about 3.5 grams a day, and in some subgroups even more. We can get pretty good idea and what it's translate into a blood pressure reduction.
Dr. Wanpen Vongpatanasin:
The thing that I particularly like is there's no threshold. I think that's fascinating and I think that's really important. The data, at least part of, I think, inertia in the public too, at least for me as a physician, I saw many remarks saying, "Oh, if it's part of the problem we had before, without these type of techniques, we usually give a general blanket. Sodium restriction, lower blood pressure by a few millimeters. Why do we even bother? But here you can see a dose response relationship without plateau. It really tells us that the more you eat, the more you're going to get into this kind of problem. I think this is really important and perhaps we'll push the certain population that address and consume a lot of salt to rethink about it.
Dr. Carolyn Lam:
Wanpen that was just really, really nicely put. I know that Marco was just nodding and appreciating as well. I know you had some questions from Marco too. Would you like to ask them?
Dr. Wanpen Vongpatanasin:
Yes. Based on the information from your study, would you give a recommendation a little bit differently, or how would you ... you've changed your view in terms of preexisting guidelines from European or from the United States?
Dr. Marco Vinceti:
I think that our results are really strengthening the most recent guidelines from both the U.S. and in Europe. I'm talking about the American Health Association guideline of limiting sodium intake below or at least at 1.5 gram per day, about the national recent sodium dietary allowance reference values of coming not beyond the 2.3 gram, and the European Food Safety Authority it's not just a recommendation, it's a risk assessment of indicating 2 gram per day the ideal intake of sodium. I would say the AHA was absolutely right in pointing out the opportunity to reduce to 1.5 gram and even lower, I would say. It's not a general assessment that we're one of the sodium and the Human Health Association. It's not a general risk assessment of sodium, but we know that hypertension, high blood pressure is a major, probably the major driver of all cardiovascular diseases. In our opinion, keeping this threshold, let's say, and even attempting to go below, we know how difficult it is in public health. That is absolutely correct.
Dr. Carolyn Lam:
I completely agree. That's the amazing public health message of this very important paper. As you said, it supports the guidelines, but it also suggests, I mean, should we just be saying, go as low as you can? We don't see a threshold so that's really, really fascinating.
Dr. Carolyn Lam:
Oh, may I ask maybe, cheekily, I recall, you mentioned Marco, that you had a lot of press about this paper and the publication and circulation. We would love to hear about that. Could you share with the viewers?
Dr. Marco Vinceti:
I can tell you that this is not to use or to ask, to be able to publish in such a top journal and you are not only the according to Web of Science, number one journal in the world in the cardiovascular community, let's say, but everybody. Even in the journal of medicine. I mean, I'm a public health physician, and anybody in my world, in Italy, and of course, not only Italy, I'm talking about my country, well knows this journal and what is publishing in such a journal is like some kind of an endorsement of what you are telling.
Dr. Marco Vinceti:
We received a lot of attention not only in my medical school, in my university, but also for the local press. From the national press a lot of people call me and ask for interview and even from the media. This is something that, particularly in this period of what everybody, I'm a public health physician is talking about COVID-19 and this is the emergency of course. Having the capacity to look at usual traditional disease but so important, that probably haven't received enough attention during the last months, I think is very important because I hope we are not forgetting that these are the major health issues, even in this period that is so difficult for an effect of disease for the COVID-19 outbreak.
Dr. Carolyn Lam:
Thank you so much Marco. I mean, I wish the whole audience could see the smiles you have put on all of our faces. Really, the credit all goes to you and your team for fantastic work done. We are privileged to have published this very important paper in circulation. And so thank you very, very much once again, to both of you for being on the show and to the audience for listening in today.
Dr. Carolyn Lam:
From Greg and I, you've been listening to Circulation on the Run. Thank you for joining us today.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.