Apr 4, 2022
This week, please join author Zdenka Pausova and Associate Editor Svati Shah as they discuss the article "Circulating Metabolome and White Matter Hyperintensities in Women and Men."
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 cohosts. 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.
Dr. Carolyn Lam:
Greg, have you ever wondered what white matter hyperintensities in a brain are made of? Well, guess what? The feature discussion is going to give us a little clue. Believe it or not from the circulating metabolome, interesting, huh? Well, I'm going to keep you in suspense, as we first discuss other papers in the issue. And I want to go first, may I?
Dr. Greg Hundley:
Absolutely, but let's all grab a cup of coffee.
Dr. Carolyn Lam:
All right. You got yours. And here goes. This first paper reviews the results of endovascular aneurysm repair in patients from the Japanese Committee for Stent Graft Management registry, to determine the significance of persistent type II endoleak and the risk of late adverse events, including aneurysm sac enlargement.
Dr. Greg Hundley:
Ah, Carolyn, a very clinically relevant question. So what did this study show?
Dr. Carolyn Lam:
Of more than 17,000 patients who underwent endovascular aneurysm repair for abdominal aortic aneurysm from 2006 to 2015, 29% had persistent type II endoleak. The cumulative incidence rates of abdominal aortic aneurysm related mortality, rupture, sac enlargement, and reintervention were higher in patients with persistent type II endoleak. Specifically, the cumulative incidence rates of rupture and abdominal aortic aneurysm related mortality increased to 2% at 10 year follow up, which is dissimilar to the previously reported frequency of only about 1%. Cox regression analysis revealed older age, female sex, proximal neck diameter, and chronic kidney disease as independent, positive correlates of sac enlargement.
Dr. Carolyn Lam:
So these wonderful results are from Dr. Hitoshi Matsuda and colleagues from the National Cerebral and Cardiovascular Center in Osaka Japan, and really suggests that persistent type II endoleaks are not always benign.
Dr. Greg Hundley:
Beautiful summary, Carolyn. Well, my paper comes from the world of pre-clinical science. And Carolyn, in most eukaryotic cells, the mitochondrial DNA is uniparenterally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mitochondrial DNA. All copies are therefore, nearly identical or, as we would call homoplasmic.
Dr. Greg Hundley:
Now Carolyn, the presence of more than one mitochondrial DNA variant in the same cytoplasm can arise naturally or as a result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH.
Dr. Greg Hundley:
Now Carolyn, these investigators led by Professor Jose Enriquez from the Centro Nacional de Investigaciones Cardiovasculares hypothesized that DNPH is maladaptive and usually prevented by the cell.
Dr. Carolyn Lam:
Wow, that's really interesting, investigations from the world of preclinical science. What did the investigators find?
Dr. Greg Hundley:
Right, Carolyn. So, the investigative team engineered and characterized divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, as we've talked about before, mice throughout their lifespan. The authors found that DNPH impair mitochondrial function with profound consequences in critical tissues that did not resolve heteroplasmy, particularly within cardiac and skeletal muscle. Progressive metabolic stress in these tissues led to severe pathology results, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. And finally, Carolyn, symptom severity was strongly modulated by the nuclear context.
Dr. Greg Hundley:
So in conclusion, Carolyn, these findings suggest that medical interventions that could generate divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, so to address potential incompatibility between donor and recipient mitochondrial DNA.
Dr. Carolyn Lam:
Oh wow. That is fascinating. Well guess what? My next paper is also about mitochondria, but this time looking at the role of the mitochondrial calcium uniporter. So we know that calcium is a key regulator of energy metabolism and impaired calcium homostasis damages mitochondria, resulting in cardiomyocyte death, pathological hypertrophy, and heart failure.
Dr. Carolyn Lam:
This study by Dr. Wang from University of Washington and colleagues investigated the regulation and the role of the mitochondrial calcium uniporter in chronic stress induced pathological cardiac remodeling. In a series of elegant experiments in the mitochondrial calcium uniporter knockout or transgenic mice infused with isoproteronol, the authors found that the mitochondrial calcium uniporter is up regulated in the stressed heart to orchestrate mitochondria sarcoplasmic reticulum, and cytosolic calcium handling, preventing cytosolic calcium overload induced cardiomyocyte death.
Dr. Carolyn Lam:
Lack of mitochondrial calcium uniporter mediated mitochondrial calcium uptake is detrimental. Whereas, transgenic over expression is beneficial to the heart during chronic beta adrenergic stimulation. The nuclear translocation of calcium/ calmodulin kinase II delta beta via calcineurin mediated dephosphorylation of serine 332 activates CAMP response element binding protein to promote mitochondrial calcium uniporter gene expression in adult cardiomyocytes.
Dr. Greg Hundley:
Well, Carolyn, what's the take home here? What are the clinical implications?
Dr. Carolyn Lam:
Ah, thought you might ask. Well, this study indicates that enhancing mitochondrial calcium uptake could be a new approach to prevent chronic beta adrenergic stimulation induced heart remodeling. Targeting this cam kinase two delta beta KREB mitochondrial calcium uniporter pathway could be a therapeutic option for pathologic cardiac remodeling associated with chronic adrenergic stress.
Dr. Greg Hundley:
Excellent description, Carolyn, and thank you for walking us through that wonderful paper. Well, we've got some other papers in the issue and from the mail bag, Professor Lusis has a Research Letter entitled Identification of DNA Damage Repair Enzyme, ASK II as Causal for Heart Failure with Preserved Ejection Fraction. And Carolyn there's a cardiovascular case series from Professor Barrett entitled, “The Unrepairable Infant Mitral Valve, an Unexpected Case of Decompensated Heart Failure.”
Dr. Carolyn Lam:
Interesting. There's an exchange of letters between Doctors Matrougui and Wang regarding the article, “Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control” and a Perspective piece by Dr. Fatkin on “Fishing for Links between Omega-3 Fatty Acids and Atrial Fibrillation.” Wow. Super cool. Greg, let's go on now to a feature discussion, shall we?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
For our feature discussion today, we are talking about white matter hyperintensities. Now that's the most common brain imaging marker of small vessel disease. That may be known, but there's a lot more to it. For example, what are they made of? Well, you're going to so enjoy today's feature paper, and I'm so proud to have the corresponding author with us, Dr. Zdenka Pausova from Hospital for Sick Kids in Toronto, Canada, as well as our associate editor, Dr. Svati Shah from Duke University. So welcome ladies. And Zdenka, if I could start with, could you explain the rationale for your study and what you did?
Dr. Zdenka Pausova:
Yeah. Thank you. Thank you for having me. Well, we were thinking that it is important to know what the metabolic variables that associate with white matter hyperintensities might be, simply because we know that there are other studies that have shown that whatever circulates in blood is in some way related to brain health. For example, different lipids associated with Alzheimer Disease, cognitive functioning and with structural properties of the brain. So we were wondering what the metabolics that are associated with white matter hyperintensities might be, simply because we would like to know a little bit more about the pathogenesis of the disease, because that's what metabolomic profiling can provide. And also if one can identify biomarkers that potentially could be used in the clinical setting.
Dr. Carolyn Lam:
Wow. Thank you. And Zdenka, this may be a very basic question, but we hear a lot about the metabolome and sometimes it's not very clear what metabolome profiling actually is. And could you just say a little bit about the technique and your study population and then your findings? Thanks.
Dr. Zdenka Pausova:
Yes. Sure. So we actually studied over 9,000 individuals from eight different population based studies and all of those individuals had metabolomic assays done with two main platforms. It's mass spectrometry and nuclear magnetic spectroscopy. Mostly these platforms are actually commercially available and altogether across all platforms, there were over 2,200 different metabolites. And from those we could study about 1200 that we had at least in two populations. And what the metabolites are, these are different metabolites of lipids, sugar, proteins, amino acids that people put on those platforms or that designers put on the platforms, in order to test some of their hypotheses, that they were actually these metabolites of interest for different sorts of diseases, including cardiovascular and cerebrovascular disease.
Dr. Carolyn Lam:
Wow. So this is really large scale, massive, big data, if I may, and if I'm not wrong, it's the first large scale study to identify circulating metabolomic measures associated with white matter hyperintensities. So could you please summarize the main findings?
Dr. Zdenka Pausova:
Well, overall we actually found that there were 416 metabolites that were nominally associated with white matter hyperintensities, but as it is in epidemiology, you have to correct for multiple comparisons. So when we did DR correction, there were only 30 variables associated with white matter hyperintensities. And when we wanted to check whether those associations are independent of the risk factors for white matter hyperintensities, such as hypertension, type two diabetes, smoking, obesity, we actually ended up with seven markers, seven metabolites that were significantly associated in the fully adjust model.
Dr. Zdenka Pausova:
And the main one was actually a derivative of amino acid hydroxyphenol that probably is a marker of ischemia in the brain. And what actually I am coming to is, and one of the main findings was, that many of those metabolites were associated with white matter hyperintensities in a sex specific manner. That is that they were detected in the pool sample, but essentially the signal came from only one of the sexes. And so this one that was the most significant was detected only in males essentially, and not really in females.
Dr. Zdenka Pausova:
And that I think is an interesting, one of the most interesting findings that we can expect that there are really sex specific pathways, biochemical pathways, that accompany white matter hyperintensities.
Dr. Carolyn Lam:
Wow. Zdenka, thank you so much. I have to bring Svati in right now to share some perspective, Svati, especially to put these findings into context, please.
Dr. Svati Shah:
Yes. Dr. Pausova, really wonderful paper. This is an incredible study, if you think about it. The largest scale study that really is trying to understand metabolic by biomarkers, but the biomarkers actually tell us about the potential biology of what's going on with these white matter hyperintensities. We know that these hyperintensities in the brain are associated with increased risk of stroke, increased risk of cognitive decline, but we don't really understand stand what the risk factors are. There's been some studies suggesting that there's genetic risk factors, but this is really the first large scale study to say, "Hey, what's in the blood that we can measure?" And just to be clear, these technologies are measuring these biomarkers that are very, very, very low levels in the blood, really granular snapshot of what's going on with the human being.
Dr. Svati Shah:
And by looking at these blood markers that the authors were able to find biomarkers that are associated with these brain abnormalities, but really highlighting some of the important biology as Dr. Pausova started to talk about. So I think what it gets us to is we get to have our cake and eat it too. We get to learn about biomarkers that might have clinical utility, but we also have discovered, they've discovered new biology that could lead to new therapies, for example, and a better understanding of the mechanisms of why some people develop these hyperintensities as they age. And some people do not.
Dr. Carolyn Lam:
Wow, Svati, you put that so eloquently and just to put it out there for everyone, that significant metabolite hydroxyphenol pyruvate explain 14% of the variants of white matter hyperintensity volumes in males. Whereas, the proportion of variants explained by hypertension is only 1% or type two diabetes is only 1 to 3%, or smoking is even less than 0.1%. So this is, as you said, Svati, it's a significant discovery as well. Zdenka, though, how do we apply this clinically?
Dr. Zdenka Pausova:
Well, it could be a marker that is measured in circulation and it is a marker that can be measured in blood and can indicate early stages of white matter hyperintensities. But I think before we get there, it would be of high value to actually carry out some longitudinal studies, because it would be really interesting to know if it is an early marker before the white matter hyperintensities extent is enlarged. And so that would one thing. But other than that, I think if that would be the case, we can just measure it in blood and see how predictable it is.
Dr. Carolyn Lam:
Can I ask what about the women? Did anything predict it in women?
Dr. Zdenka Pausova:
That's a good question. There was only actually one variable. To our surprise, only one variable that was significantly associated with white matter hyperintensities in women. And it is really surprising because the sample size was the same. The extent, the volume of white matter hyperintensities was quite similar. They were of similar age, similar adiposity. So there were no huge differences, yet we could not actually detect too many metabolized associated with white matter hyperintensities in women. Really surprising. And I don't have a good answer for it now.
Dr. Carolyn Lam:
Wow. Thank you. Svati, did you have further thoughts on the clinical applications and implications of these tremendous data?
Dr. Svati Shah:
Yeah. I think the ability to have a biomarker as Dr. Pausova nicely articulated that would potentially prevent people from having to get an MRI. And we would be able to identify people hopefully at an earlier stage in the process. In this lovely study, they were looking at biomarkers in people who already had the hyperintensities. I think the next step as Dr. Pausova outlined to be able to identify whether these predict high risk people who will develop them in the future and then try to target therapies. A potential advance in precision medicine in the neurologic space, that we could use this biomarker to say, "You need this particular medication."
Dr. Svati Shah:
Some of the biomarkers that Dr. Pausova's group discovered were actually just cholesterol measures. So maybe we need to be instituting more aggressive cholesterol therapies in these patients who are at high risk. I'm not saying we can do that yet, but these provocative results suggest that this could lead to a more personalized approach to high risk individuals who may have consequences and develop these white matter hyperintensities.
Dr. Carolyn Lam:
And Zdenka, did you have anything to add to that?
Dr. Zdenka Pausova:
Perhaps one interesting aspect of the study that I actually was nicely surprised at the end of the study that the markers, one could the different lipids or the different derivatives of amino acids, the literature provided actually a possible pathways, how those could be involved in the development of white matter hyperintensities. Some of them actually, we could possibly link to impairment of myelination of a neuronal axons, or actually the axons themselves could be the metabolized could reflect damage of those axons.
Dr. Zdenka Pausova:
And also, one suspicious pathway or one pathway that is suspected to be big part of the development of white matter hyperintensities is the disruption of blood brain barrier and some of the markers could be actually linked to that vascular dysfunction.
Dr. Carolyn Lam:
Aw, that's wonderful. Thank you so much, Zdenka, for publishing this beautiful work with us in Circulation. And thank you, Svati, for taking this paper through and inviting this beautiful editorial. In fact, it quite summarizes our discussion. It's entitled, What Turns White Matter White? Metabolic Clues to the Origin of Age-Related White Matter Hyperintensities and it's by Dr. Eric Smith from University of Calgary and I invite everyone to read this.
Dr. Carolyn Lam:
So thank you once again for joining us today on Circulation on the Run. From Greg and I, it's been wonderful having you. Don't forget to join us again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. 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, please visit ahajournals.org.