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Circulation on the Run

Sep 23, 2019

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 Gregory Hundley:       I'm Greg Hundley, also associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Greg, what do you think is the association between preeclampsia and hypertensive diseases of pregnancy and cardiovascular disease and future? Well, we're going to find out in a large U.K. pregnancy cohort of linked electronic health records, the CALIBER Study, but that's a feature discussion that's coming right up.

                                                I think we need to start by discussing this week's hot issue. For the first paper, we know that the incidents of acute cardiovascular complications are highly dependent on the time of day. Greg, have you ever wondered what mechanisms drive the rhythmicity of ischemic vascular events?

Dr Gregory Hundley:       You know what, Carolyn, I had a dream about that and I think that somehow maybe it might be something to do with leukocytes.

Dr Carolyn Lam:                Good guess, Greg. Well, Dr Christoph Scheiermann and his colleagues from University of Geneva looked at this and they examined the role of rhythmic leukocyte adhesions and what those play in different vascular beds. They did this by evaluating leukocyte recruitment in vivo with real time, multichannel fluorescence intravital microscopy of a TNF alpha induced acute inflammation Murine model.

                                                Now, they also used ablation of sympathetic nerves or adrenergic receptors to assess their relevance for these rhythmic leukocyte adhesions. Basically what they found was that leukocytes adhere to arteries and veins following a circadian rhythm in mice, with adhesion peaking in the arteries in the morning and in the veins at night.

                                                These peaks in leukocyte adhesion at different times in the two vascular beds were associated with increased vascular inflammation and shortened times to local basal occlusive events occurring out of phase between the arteries and the veins. The differences in cell adhesion molecules and leukocyte adhesions were ablated when disrupting the sympathetic nerves, thus demonstrating their critical role in this process and the importance of beta2-adrenergic receptor signaling. Neat, huh?

Dr Gregory Hundley:       Really neat. It's interesting how that ties together sympathetic nerve activity and leukocyte adhesion.

Dr Carolyn Lam:                You got a paper?

Dr Gregory Hundley:       I've got a paper to discuss and it's from Dr John Cooke at the Houston Methodist Research Institute. It's involving nuclear S-nitrosylation and how that defines an optimal zone for inducing pluripotency, the ability to generate induced pluripotent stem cells or I.P.S.C's from somatic cells as it enhanced the field of regenerative medicine.

                                                It has facilitated studies of development in differentiation, promoted insights into pathobiology, and generated a novel platform for drug discovery and testing. In fact, work in this area has been sufficient to induce nuclear reprogramming to pluripotency and galvanized our whole scientific community. Recently in 2012, this work was recognized by the Nobel Prize for physiology or medicine.

Dr Carolyn Lam:                Wow. What did this week's paper show in this area?

Dr Gregory Hundley:       Well, Carolyn, in this study, the team identified an optimal zone. They call it the Goldilocks zone of innate immune activation for nuclear reprogramming to pluripotency. The authors believe that this Goldilocks zone for nuclear reprogramming may have broad relevance for epigenetic control, for regenerative processes, and for the pathobiology of cancer and even other diseases.

                                                Consequently, the results from this study may help to develop methods that identify whether a patient or tissue is in an optimal zone of inflammatory signaling to improve surgical and medical therapies. In addition, they may provide a method to detect early inflammatory signaling and DNA accessibility and thereby reverse these processes to guide cancer prevention.

Dr Carolyn Lam:                Oh wow, Greg. It sounds like a real landmark paper. Everyone, you've got to pick that one up. As with this next paper, it is the first randomized trial comparing internal cardioversion by commanded shock and external cardioversion in patients with ICD's who present in atrial arrhythmias.

                                                Dr Lüker and colleagues from University Hospital Cologne randomized 230 consecutive patients with ICD's undergoing elective cardioversion for atrial arrhythmias at 13 centers and they randomized them to either internal or external cardioversion. The primary safety endpoint was a composite of lead or device malfunction and conversion of the atrial arrhythmia to sinus rhythm was the primary efficacy endpoint. Myocardial damage was studied by measuring troponin release in both groups.

Dr Gregory Hundley:       I really like where this study's going. What did they find?

Dr Carolyn Lam:                They found that external cardioversion was superior for the restoration of sinus rhythm, with shock efficacy of 93% in the external cardioversion group compared to 65% in the internal cardioversion group. There were three cases of preexisting silent lead malfunction that were unmasked by the internal shock resulting in lead failure. Troponin release did not differ between the groups.

                                                In summary, these findings suggest that external cardioversion may be considered as the first line approach to electrical cardioversion in patients with ICD's and atrial fibrillation. Because silent lead malfunction may be present in some ICD patients, internal cardioversion may be considered in select patients to detect it and with no difference in adverse events associated with internal or external shocks. That's a good sign but needs to be evaluated in larger randomized trials.

Dr Gregory Hundley:       Oh, very nice, Carolyn. Well, my next paper is entitled the Androgenic Effects on Ventricular Repolarization and it's a translational study from the International Pharmacovigilance Database to iPSC-cardiomyocytes. The corresponding author is Dr Joe-Elie Salem from Vanderbilt University Medical Center.

                                                Male hypogonadism arising from a range of ideologies, including androgen deprivation therapies and other things, has been reported as a risk factor for acquired long QT syndrome, as well as torsade de pointes. The authors searched the International Pharmacovigilance Database, VigiBase, for men and they had 6,560,000 plus individual case safety reports presenting with long QT syndrome, torsade de pointes, or sudden death associated with androgen deprivation therapies.

                                                In cardiomyocytes derived from induced pluripotent STEM cells from men, they also studied the electrophysiological effects of androgen deprivation and dihydro testosterone.

Dr Carolyn Lam:                That's super interesting. What did they find, Greg?

Dr Gregory Hundley:       It's one of these combinations of a clinical study as well as basic science. Of the 10 androgen deprivation therapies examined, seven had disproportional association reporting odds ratios of one four to four seven with long QT syndrome, torsade de pointes, and sudden death. The minimum medium times to sudden death were from 0.25, a quarter of a day, to 92 days respectively. The androgen receptor antagonist, enzalutamide was associated with more deaths than any other androgen deprivation therapy used for prostate cancer.

                                                In the basic science experiment, in induced pluripotent STEM cells acute and chronic enzalutamide at 25 micromolar, a. Significantly prolonged action potential durations, b. Generated after depolarizations and activity, c. Inhibited delayed rectifier potassium currents, and d. Chronically enhanced late sodium currents.

                                                Interestingly, dihydrotestosterone at 30 nanomolar reversed the enzalutamide electrophysiologic effects on these induced pluripotent STEM cells.

Dr Carolyn Lam:                Again, really interesting approach from this Pharmacovigilance Database as well as bench work and clinical work, but what do we do with this information?

Dr Gregory Hundley:       Couple of key points, Carolyn. One, men receiving androgen deprivation therapy are at increased risk for drug induced QT prolongation and torsade de pointes. Two, in men developing acquired long QT syndrome or torsade de pointes, a diagnostic workup might include evaluation of testosterone blood levels, androgen deprivation therapy intake, and evaluation for endocrine conditions associated with hypogonadism. Three, in men treated with androgen deprivation therapy for example, for prostate cancer, other risk factors for torsade de pointes should be sought and corrected to avoid any accumulation of risk. And finally number four, in men treated with androgen deprivation therapy, the role of electrocardiographic monitoring to detect QT prolongation really requires an additional study.

Dr Carolyn Lam:                Cool, Greg. What else in the journal did you find cool?

Dr Gregory Hundley:       Yeah, this is great, Carolyn. We're going to start now with sort of a new format where we go through all the other wonderful information. We're just going to trade back and forth.

                                                The first one I'm going to tell you about is a letter from James Tisdale who is from the College of Pharmacy at Purdue University, and he demonstrates in a small randomized controlled trial that transdermal testosterone attenuates drug induced QT lengthening in older men. Really kind of links back to that study I just told you about.

Dr Carolyn Lam:                Nice. Well, I want to highlight an on my mind paper and it's entitled, Chronic Severe Aortic Regurgitation, Should we Lower Operating Thresholds? This is from Dr Desai at Cleveland Clinic and he considers newer EchoMRI methods to assess the severity of aortic regurgitation and determine suitability for valve intervention. It's a large study and just a really nice read of a short on my mind paper.

Dr Gregory Hundley:       Excellent. Well, you know we also highlight excellent reviews in circulation and the one I'm going to discuss briefly is from Schuyler Jones from Duke and he revisits the role of primary aspirin for primary prevention of cardiovascular disease.

                                                He talks about the indications, that there are really few indications for aspirin in those with diabetes mellitus, community dwelling elderly individuals, and patients without diabetes who are at intermediate risk for atherosclerotic events. Also, he discusses the role of aspirin and reviews very nicely the role of aspirin in primary prevention including the optimal drug formulations, different dosing schedules, weight-based dose selection, and the interplay between sex and treatment response. It's a great review.

Dr Carolyn Lam:                Ah, and then from a nice in-depth review we also have a perspective, a nice short read. This one is from Dr Simari from Kansas who discusses diversity in clinical trials and you know, his title is actually a question, when will clinical trials finally reflect diversity? Really lovely paper. He points out that to increase the diversity of enrollment, we need to consider expanding the diversity of investigators. So, a nice piece there, too. Thanks, Greg. That was a super chat. Shall we go on to our feature discussion now?

Dr Gregory Hundley:       Absolutely. Welcome everyone to discussion of our featured article focusing on hypertensive disorders in pregnancy, and then the subsequent long-term outcomes related to that. For our author discussion, we have Fergus McCarthy from Ireland and the Irish Center for Fetal and Neonatal Translational Research at Cork. Then, we also have our associate editor, Sharon Reimold.

                                                Fergus, could you tell us a little bit about what was your thinking behind starting this study? What type of questions were you trying to answer? And then after that, tell us a little bit about the study design.

Dr Fergus McCarthy:       I'm an obstetrician by trade and we have this funny paradox where a lot of us know that pregnancy is not just about the nine-month periods that a woman is pregnant and then ultimately delivers, that what happens in pregnancy can influence long-term maternal health. But despite this, we have this paradox whereby a woman becomes pregnant, the pregnancy may be complicated by hyper pressure in pregnancy, the woman delivers her baby, goes home and often doesn't see a healthcare practitioner for possibly another 10, 20 years.

                                                Even though we know if a pregnancy is affected by high blood pressure, we don't really do a huge amount about it and we deal with this funny situation. We know that high blood pressure in pregnancy affects two to 8% of pregnancies, depending on the population studied. What we wanted to do was examine specifically the impact of hypertension or high blood pressure in pregnancy on long-term maternal health.

                                                But importantly, what we also wanted to try and determine was is there any factor that may be modifiable that may be ultimately able to improve or reduce the long-term morbidity associated with having hyper pressure in pregnancy? So, if you have high blood pressure in pregnancy, is that it or is there anything that we maybe could make women aware of that may ultimately improve their long-term health?

                                                Also as I said, despite research documented in the association between preeclampsia, which is high blood pressure in pregnancy and major cardiovascular disorders later in life, but we felt also that there was a lot of limitations with the evidence that's there.

                                                Firstly, a lot of the evidence is focused on more composite endpoints and secondly, over the past several decades, the pattern of initial presentation of cardiovascular disease has changed significantly. And thirdly, a lot of the studies that are out there have been unable to adjust for post-pregnancy factors such as hypertension. We wanted to see whether that was a significant factor. But that's the thought process behind why we undertook this study.

                                                Then we had a great opportunity with the collaboration with the Fire Institute in London and University College London, whereby we were able to use a database which is called CALIBER. What CALIBER stands for is cardiovascular research using linked bespoke studies and electronic health records, bit of a mouthful. But what CALIBER is, is basically it's a combination of the GP database in the U.K., which is called the Clinical Practice Research Database, hospital episodes, statistics, and the Office for National Statistics cause specific mortality records. What that does is basically it combines a lot of pregnancy data with long-term really well phenotyped cardiovascular disease.

                                                In particular, what CALIBER is very strong for is they have phenotypes, 12 cardiovascular phenotypes, in an extremely strong robust way. So, we were able therefore to examine the impact of pregnancy using the GP database, using the CPRD with these 12 cardiovascular phenotypes as our outcomes.

Dr Gregory Hundley:       Tell us a little bit about your study population and what were some of the results of your study?

Dr Fergus McCarthy:       What we did was we used electronic health records from a period of 1997 to 2016 and we looked at a U.K. population core of about 1.3 million women. The mean age of delivery of these women was about 28 years of age and they had about just under 2 million, 1.9 million completed pregnancies.

                                                Over the 20-year study period, we were able to observe just over 18,000 cardiovascular disorders, 65% of which had occurred in women under the age of 40. Again, this was quite surprising because using cardiovascular disease, you think a much older group, and when we looked at the pregnancies that were affected by hypertension in pregnancy, we were able to see that compared to women without hypertension in pregnancy, women who had one or more pregnancies affected by preeclampsia had increased hazard ratio for stroke, atherosclerotic events, heart failure, atrial fibrillation, cardiovascular death, and for chronic hypertension.

                                                What was particularly interesting was that the differences in the cumulative incidence curves that we were able to see. According to preeclampsia, we were able to see these differences within one year of the first index pregnancy. So again, this was quite fascinating from our point of view because I think prior to this study, maybe we thought that it was happening a bit earlier than we thought in women's lives, but actually, to see something so soon occur after pregnancy was quite interesting.

                                                The other thing that, and one of our motivations to do this was to say, okay, well is there anything we can do about it? Is there anything that might be modifiable here? What we were able to do within our study was we were able to examine, is this just because women are leaving hospitals with high blood pressure and this high blood pressure is not being treated? What we were able to do was we were able to adjust into our models this concept of having postpartum hypertension. If we were able to adjust for the mediating effect of post-pregnancy hypertension, we observed a 35% reduction in the point estimates of the hazards ratio for any cardiovascular disease event.

                                                One of the things I think that this study shows is that it is critically important that women have appropriate medical follow-up after their pregnancy. It's a very difficult period. People have young babies, they may be going home to more children at home, and often the neglected person in this situation is the mother. What we're saying is that actually even if we could focus on that one factor which is post-pregnancy adequate control of hypertension, we may be able to reduce the hazards ratio of developing a cardiovascular disease by approximately 35% is what the study is suggesting.

Dr Gregory Hundley:       Really interesting results, Fergus. Sharon, I wanted to turn to you a little bit. How do the results of this study change for us the way we might practice in terms of managing this patient population?

Dr Sharon Reimold:         This study, I think, is very interesting because of the large population and the significant number of unfortunately adverse outcomes and the ability to compare those with and without preeclampsia and hypertension. I think that we end up with two or three different issues or ways that we think about dealing with them.

                                                First of all, just as Fergus alluded to is we need to make sure that we take hypertension seriously in pregnancy and since it's a small, but significant number of women leave the hospital and will remain hypertensive, we need to assure that they are getting care. The other thing that I think is important in this group, but you would never be able to capture in the current study is my approach is also to think about, well, what other risk factors does this woman have other than just high blood pressure? Is she at risk to be a diabetic? Does she smoke? Is she getting enough exercise? What other things can we do to modify their long-term risks?

                                                This points out a method to identify those patients pretty easily. Are they hypertensive early post-pregnancy, and then it's up to the medical community to really develop strong guidelines and training that emphasizes using prevention in the outpatient setting.

                                                The two things I found very interesting about this work, first of all, the rapid separation of these curves. I know that they had some very young women that gave birth and then some obviously women of what I guess would be termed advanced maternal age. But we do think of a woman who has a child at 30 maybe being at higher risk when she's 50 or 60, but the risk is much earlier, and patients are really not aware of this.

                                                Then, the ultimate thing is how do we identify these women early in their pregnancy or before they're pregnant, so we can help avoid these complications altogether? I guess the take home message is if somebody has hypertension or they're going home hypertensive, they need early follow-up and we need to be aggressive about their treatment.

Dr Gregory Hundley:       Both of you have emphasized the point that this paper makes of early identification of hypertension. In the paper, it talks about hypertensive disorders of pregnancy. I think many of us understand about preeclampsia or eclampsia and relatively high blood pressures, HELLP syndrome, et cetera. Are there other issues that we need, like what blood pressure ranges are we thinking about?

                                                If I'm picking up a chart of a woman in their early forties, late thirties what should I be looking back for retrospectively in terms of blood pressure levels? Do I follow the new guidelines and I'm looking for blood pressures above 120 systolic? Can either of you give us some guidance on what to look for, how I would set up a program, what the timing would be, when I need women to come back? Just practical things like that.

Dr Sharon Reimold:         I believe that is still in the obstetric world that the older guidelines are really what are used and whether those shift over time to lower thresholds for the diagnosis of hypertension is not clear, but usually it's 140 over 90. You want to try to get the patient history and differentiate between those people that perhaps were hypertensive prior to their pregnancy, people who had isolated short-term hypertension during their pregnancy, and those people who then left pregnancy remaining hypertensive. But I'll ask Fergus since he deals with this a lot more than I do with the pregnancies, what they use as the cutoff in the U.K.

Dr Fergus McCarthy:       In general, we had the CHIPS Study, which was published several years ago. That advocated, certainly during pregnancy, that a tighter control of blood pressure was associated with an improved pregnancy and improved maternal outcome. That type of control generally aimed for a systolic blood pressure of under 135. In general, when we are managing our patients, that's usually what we're aiming for, to keep the systolic blood pressure under 135.

                                                I think the other thing that is becoming apparent from a lot of the work that's been done is that it's maybe not just about the pre-eclamptic woman, which is generally the woman with hypertension and proteinuria that gestation and hypertension, which often is nonproteinuric by definition, is also playing a significant part.

                                                Certainly, when you look at populations where I previously worked in the U.K. and London, women with chronic hypertension, pregnancy is becoming a huge issue, both with increasing obesity and certain ethnic groups, and with advanced maternal age women coming into pregnancy with chronic hypertension is really becoming a major issue for us, as well, and is associated with a much worse pregnancy outcome. But to answer the question, that's usually where we're aiming for and we're trying to, where possible, run as tight a control of blood pressure as possible.

Dr Gregory Hundley:       Thank you very much, and we look forward to talking and discussing with you with Carolyn next week.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.