Carolyn Lam, MBBS, PhD

Circulation May 25, 2021 Issue

Circulation May 25, 2021 Issue

Please join editorialist Padma Kaul and Associate Editor Karol Watson as they discuss the original research article "Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study" and the editorial "Pregnancy as Oracle: What it Augurs for Women's Health." 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: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Oh Greg, today's feature paper is really important. It's about preterm delivery and the long-term risk of stroke in women. A very, very important cardiovascular risk factor that we don't talk about. This is important data from the national cohort and co-sibling study. So hang on, look out for it. But first, how would you take us through some of your spotted original papers? Dr. Greg Hundley: So Carolyn, my first paper comes to us from Dr. Guido Claessen from University Hospitals in Leuven. Exertional intolerance, Carolyn, is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension, and traditionally, the etiology has been attributed to central factors, including ventilation, perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. So pulmonary endarterectomy and balloon pulmonary angioplasty provides substantial improvement of functional status and hemodynamics. However, despite normalization of these pulmonary hemodynamics, exercise capacity often does not return to age-predicted values. So by systemically evaluating the oxygen pathway, these authors aim to elucidate the causes of functional limitations of chronic thromboembolic pulmonary hypertension patients before and after these pulmonary vascular interventional procedures. Dr. Carolyn Lam: So very interesting. Tell us more, what did they find, Greg? Dr. Greg Hundley: Yeah, well Carolyn, they utilize cardiovascular magnetic resonance, as you know, one of my big interests, but guess what? They also did it with exercise and simultaneous invasive hemodynamic monitoring. The authors in doing so, sought to quantify the steps of the oxygen transport cascade from the mouth to the mitochondria in patients with this pulmonary hypertension. So they had 20 subjects with pulmonary hypertension and they compared those to 10 healthy individuals. Furthermore Carolyn, the authors evaluated the effect of pulmonary vascular intervention procedures, both endarterectomy or balloon angioplasty, on the individual components of the cascade in 10 of those 20 individuals. Dr. Greg Hundley: So what did they find? They found that in this chronic thromboembolic pulmonary hypertension condition, these patients, they have significant impairments of all steps in the oxygen utilization cascade, resulting in markedly impaired exercise capacity, the thick equation uncoupled. And pulmonary vascular interventions increased, peak VO2, by partly correcting the oxygen delivery, but having no impact on abnormalities in peripheral oxygen extraction. Dr. Greg Hundley: So Carolyn, this suggests that the current interventions only partially address patient's limitations and that additional therapies may improve functional capacity, such as improvement in skeletal muscle function and metabolism. So maybe one of your faves, cardiac rehab, perhaps could work on some of those peripheral factors in these patients. So, really interesting, very well accomplished study. Dr. Carolyn Lam: Nice, elegant and clinically impactful. Very nice. Well, the next paper is the same. We know that prenatal detection has benefits for infants with hypoplastic left heart syndrome and transposition of the great arteries. Well, this next paper describes the largest multicenter study to evaluate whether social economic quartile, public insurance, race or ethnicity, rural residence and distance from the residence are associated with the prenatal detection of critical congenital heart diseases in North America. This study is from Dr. Krishnan from Children's National Medical Center in Washington, DC and colleagues. Basically, what they found was that lower socioeconomic position, Hispanic ethnicity, and rural residence were all associated with decrease prenatal detection rates of hypoplastic left heart syndrome and transposition of the great arteries. Dr. Greg Hundley: Wow Carolyn, so social determinants of health, interesting. So how do we, as clinicians, apply these results? Dr. Carolyn Lam: Well, clinicians can use the findings of the study to focus efforts on improving overall prenatal detection rates for congenital heart disease. They can specifically improve health equity in prenatal detection and timing of prenatal detection by improving linkages between tertiary care centers and these populations and regions that were identified in this study. Dr. Greg Hundley: Very nice Carolyn. Well, I'm going to turn to the world of aortic aneurysms and this next paper comes to us from Dr. Maria Mittelbrun from Centro de Biología Molecular Severo Ochoa. Carolyn, it involves Marfan syndrome, which you know, is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene, encoding a large glycoprotein in the extracellular called fibrillin one. The major complication, again as you know, of this connective disorder is the risk to develop thoracic aortic aneurysms. To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are surgery. So here, the authors studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm dilation, and mitochondrial boosting strategies as a potential treatment to manage these aneurysms. Dr. Carolyn Lam: Wow, that's really fascinating. So what did they find? Dr. Greg Hundley: So Carolyn, just like in circulation, these wonderful translational basic science studies, the research here by these authors was performed in both mice and in patient samples from Marfans patients. So mitochondrial function of vascular smooth muscle cells was found to be controlled by the extracellular matrix and drive the development of aortic aneurysm in the Marfan syndrome. Interestingly, restoring mitochondrial metabolism with the NAD precursors nicotinamide riboside rapidly reversed aortic aneurysm in the fibrillin positive mice. Thus Carolyn, the clinical implications are that by potentially targeting vascular metabolism, a new available therapeutic strategy for managing aortic aneurysms associated with these genetic disorders, such as Marfan syndrome, may become available. Really interesting new development in the world of managing aortic aneurysm dilation in patients with Marfan syndrome. Dr. Carolyn Lam: Oh my goodness, that would be paradigm shifting. Wow, hope that's going to be pursued further. Well, this next one is from the preclinical world and this study really uncovered a metabolic transcriptional axis that explains how dividing cells coordinate metabolism with gene regulation in pulmonary arterial hypertension. So this is from Dr. Rabinovitch and colleagues from Stanford University School of Medicine who applied RNA sequencing to pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension with and without a BMPR2 mutation compared to control pulmonary artery smooth muscle cells, basically to uncover genes required for their heightened proliferation and glycolytic metabolism. The assessment of differentially expressed genes establish metabolism as a major pathway. The most highly up-regulated metabolic gene was aldehyde dehydrogenase family 1 member 3, an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular smooth muscle cells, but now demonstrated in pulmonary arterial hypertension. Isn't that cool? Dr. Carolyn Lam: The findings were basically like this, an increase in this particular aldehyde dehydrogenase family 1 member 3, underlined the heightened proliferation and glycolysis of pulmonary artery smooth muscle cells in patients with both idiopathic and hereditary pulmonary artery hypertension, while promoting survival of their endothelial cells under stress. The authors further uncovered the way this molecule interacted with genetic factors in doing so and then finally demonstrated that transgenic mice with the deletion in smooth muscle cells did not develop chronic hypoxia-induced pulmonary hypertension. Dr. Greg Hundley: Wow Carolyn, really new, inventive material from the world of basic science. So what's the take-home message? Dr. Carolyn Lam: So these findings really suggest that selectively disrupting the pivotal role of aldehyde dehydrogenase family 1 member 3 in pulmonary artery hypertension smooth muscle cells, note that was smooth muscle cells, not the endothelial cells, may be a important therapeutic consideration in patients. Dr. Greg Hundley: Very nice. Dr. Carolyn Lam: So Greg, let me tell you about some other articles in today's issue. There's an exchange of letters between Drs. Pengo and Kario 00:10:36 regarding the article Nighttime Blood Pressure Phenotype And Cardiovascular Prognosis, A Practitioner-based Nationwide JAMP Study. Dr. Greg Hundley: Great Carolyn, well also in the mail bag, we have a perspective piece from Professor Chang entitled Trial By Wildfire, The Need To Expand The Framework Of Environmental Determinants Of Cardiovascular Health From Climate Change To Planetary Health. Also, there's a primer from Professor Miano entitled The Fate And State Of Smooth Muscle Cells And Atherosclerosis. Then lastly, we have another article from the world of basic science, a research letter from Dr. Ieda entitled Overexpression Of GATA4, MEF2C and TBX5 Generates Induced Cardiomyocytes Via Direct Reprogramming And Rare Fusion In The Heart. Well, Carolyn, how about we get to the world of preterm delivery and onto that feature article? Dr. Carolyn Lam: I'm there already, let's go. Dr. Greg Hundley: Well, listeners. Now we are turning to our feature discussion and we're so excited today to have with us our editorialist for this article, Dr. Padma Kaul and our own associate editor, Dr. Karol Watson and we'll be discussing today, a paper related to preterm delivery and long-term risk of stroke in women. Padma, I'd like to start with you. Describe for us a little bit, the context for this study, and then what were the authors' study population and study design? Dr. Padma Kaul: So Greg, this is a study, which is a retrospective cohort study from Sweden and they looked at women who had given birth over a pretty long period of time, from 1973 to 2015. In over two million women, they looked at the association between preterm birth and the long-term development of stroke in the mothers. It's a really interesting study. What they did find is that preterm birth was associated with a higher hazard ratio for stroke, over 48 million person years of follow-up. The authors also did an interesting co-sibling analysis to supplement what the overall primary analysis. This was by looking at a subset of women who had at least one sibling in the cohort. The point of that was to assure that the association between preterm birth and stroke risk remained, even after you account for familial or genetic environmental factors. They do find that it was demonstrated even in the subset. Dr. Greg Hundley: Very nice, just a couple quick clarifying points. Were these ischemic strokes, were they hemorrhagic strokes? And then give me a little bit of definition. How did they define preterm? Dr. Padma Kaul: So preterm was in less than 37 weeks of gestation, and they looked at both hemorrhagic as well as ischemic strokes in the women. So they did an overall stroke endpoint as well as looked at whether these two types of strokes, whether the relationship stayed. Dr. Greg Hundley: And was there any particular age at which these strokes occurred? Dr. Padma Kaul: That's an excellent point. As I told you, that the time period of the study is pretty long. So they did stratify the follow-up period into 10 year segments, and they found that higher risk in the early part of the 10 and the 10 to 20 time periods. It stayed in the latter periods as well, but it was more so associated with a higher hazard in the early time periods, the 10 and the 20. Dr. Greg Hundley: Thank you so much, Padma. Well now listeners, we're going to turn to our associate editor, Dr. Karol Watson from UCLA. Karol, I know working on the editorial board at Circulation, you see many papers come across your desk. What attracted you to this particular manuscript? And how would you put the results from this study in the context of other studies that have really evaluated women's health in this situation? Dr. Karol Watson: That's a fabulous question. I think really so many great manuscripts come in and there are important features of many of them, but this one caught my eye for a couple of reasons. It was so incredibly well done. This is a huge, huge cohort of over two million women and it's from Sweden, where they keep really exquisite records, so we had so much data on this population. So we really got to know all about these soliton deliveries in Sweden, over a 40 year period. So the great cohort that was really well characterized, the really long follow-up. I love the co-sibling analysis that they talked about, they really did control for so many things, shared familial factors, shared genetic factors, covariates. So they just did a fabulous study. Dr. Karol Watson: So, in the whole realm of women's health, we are understanding that pregnancy is a great window into a woman's vascular future. So we now know so many things, we know that preterm delivery is amongst those pregnancy outcomes that we have to look for. So we have to look for pregnancy-induced hypertension, gestational diabetes, but also preterm delivery and pregnancy loss. So all of these things are telling us that a woman's vascular system is under stress and we have to do things to make sure they have good outcomes, because we know they're at greater risk. Dr. Greg Hundley: Very nice. So as leading experts in the era, Padma first to you, and then I'll come back to Karol. Padma, tell us, what do you think is the next area of research that needs to be explored in this topic area? Dr. Padma Kaul: I think that this is an observational study. So one of the things we have to recognize is how do we add to the evidence that this study has provided us? That I think, is to see if in other cohorts, similar pregnancy birth cohorts with longitudinal data, whether we observe the same patterns that we ever observed in Sweden. Sweden is actually quite unique in terms of the makeup of the population and these are historical trends. We do know that the characteristics of the mothers who are giving birth are changing over time. Women are delaying childbirth, they are getting heavier, they may have preexisting conditions. So I think to keep monitoring the health of the mothers and pregnancy factors is what is needed to move the field forward. Dr. Greg Hundley: Very nice, and Karol? Karol, would you like to add anything? Dr. Karol Watson: Yeah, I agree completely with what Padma says. The beauty of the Swedish cohort is how well characterized it is, but one of the limitations is it's a fairly homogenous cohort. So I would love to see similar data in other racial or ethnic groups. We'd also like to see, again, as Padma said, this is observational cohort study, so we don't know truly the causal validy here, although this is a really good study to identify this trend. I would love to think of ways why this might be, we really don't have a good handle on the pathobiology. We can surmise some things endothelial dysfunction, et cetera, but we just don't know for sure. The other thing I'd like to think of is ways we might address mitigating risk. If this truly is a risk factor, how are we going to help these women have better vascular outcomes. But again, a great study to start all these questions. Dr. Greg Hundley: Well, thank you Karol and Padma and listeners. We certainly want to thank both Drs. Kaul and Watson for their time today and also the author group under the direction of Dr. Casey Crump for submitting this article to us at Circulation reporting on this large cohort of women from Sweden, identifying a preterm delivery and long-term risk of both ischemic and hemorrhagic stroke. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you 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.  

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