Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. The new ACC/AHA hypertension guidelines are hotly discussed. So much so that we have invited perspectives of these new guidelines from around the world and authors will be discussing this right here on Circulation on the Run. Stay tuned, as it's coming right up after these summaries.
The first original paper this week is a translation study suggesting that the parasympathetic system may be a novel therapeutic target in pulmonary arterial hypertension. Co-corresponding authors Dr. Handoko and de Man from University Medical Center Amsterdam used heart rate recovery after maximal cardiopulmonary exercise testing as a surrogate for parasympathetic activity, and assessed white ventricular ejection fraction in 112 patients with pulmonary arterial hypertension. They found that patients with a lower right ventricular ejection fraction had a significantly reduced heart rate recovery compared to patients with a higher right ventricular ejection fraction.
Furthermore, they looked at tissues from the right ventricle of 11 patients undergoing heart-lung transplantation, and found that there was increased expression of nicotinic receptors with no difference in muscarinic receptor expression compared to controls.
Finally, in a rat model of pulmonary hypertension, they showed that chronic pharmacologic sympathetic stimulation by pyridostigmine, which is an acetylcholinesterase inhibitor, improved surviving right ventricular function and reduced pulmonary vascular remodeling.
In summary, the study shows that right ventricular dysfunction is associated with reduced systemic parasympathetic activity in patients with pulmonary arterial hypertension, with an inadequate adaptive response of the cholinergic system in the right ventricle. Furthermore, enhancing the parasympathetic activity in these patients may be a novel therapeutic strategy.
Dr. Carolyn Lam: The next study unveils a new mechanism by which pericardial adipose tissue coordinates immune cell activation and outcomes following a myocardial infarction. First author Dr. Horckmans, corresponding author Dr. Steffens, and colleagues from Institute of Cardiovascular Prevention in Munich identified larger B-cell clusters in epicardial adipose tissue of human patients with coronary artery disease compared to controls without coronary artery disease. Furthermore, they showed that infarcted mice had larger pericardial clusters, and a 3-fold up regulator numbers of GM-CSF producing B-cells within the pericardial adipose tissue, but not in the spleen or lymph nodes. This was associated with higher dendritic cell and T-cell counts in the pericardial adipose tissue.
Further experiments show that activated dendritic cells migrated from infarcts into the pericardial adipose tissue. Cytokines and growth factors released locally within the pericardial adipose tissue as well as systemically promoted immune cell proliferation and emergency granulopoiesis after myocardial infarction.
Finally, the enhanced fibrosis and worsened ejection fraction in mice was limited by removal of the pericardial adipose tissue.
In summary, these pre-clinical data suggest that pericardial adipose tissue may be a central compartment for innate and adaptive immune responses, which regulate post-myocardial infarction healing.
Dr. Carolyn Lam: The next study reports for the first time in a large, comprehensive national cohort study, the incidence of atrial fibrillation in children and young adults with congenital heart disease. First and corresponding author Dr. Mandalenakis and colleagues from University of Gothenburg in Sweden used data from the Swedish Patient and Cause of Death registers to identify all patients with a diagnosis of congenital heart disease who were born between 1970 and 1993. Each patient with congenital heart disease was matched by birth year, sex, and county with ten controls from Sweden. Follow-up data were collected until 2011.
The authors found that the risk of atrial fibrillation in children and young adults with congenital heart disease was 22 times higher than that in matched controls. Up to the age of 42 years, one in 12 patients with congenital heart disease had developed atrial fibrillation and one in 10 patients with congenital heart disease with atrial fibrillation had developed heart failure. In particular, patients with the most complex congenital malformations, conotruncal defects, had the highest risk to develop atrial fibrillation. These patients should be considered for targeted monitoring.
Dr. Carolyn Lam: The next study provides a novel and simple risk score for right-sided heart failure in adults undergoing Left Ventricular Assist Device implantation with the current mainstream devices. First and corresponding author Dr. Solomon and colleagues from University Medical Center Rotterdam studied almost 3000 adults who underwent continuous flow Left Ventricular Assist Device implantation in the largest EU registry of mechanical circulatory support devices. They derived and validated a right-sided heart failure prediction model that out-performed several published scores and well-known hemodynamic and echocardiographic individual markers of right-sided heart failure.
This prediction model included the following risk factors: need for three or more inotropic agents, inter-agency registry from mechanically-assisted circulatory support class one through three, severe right ventricular dysfunction on semi-quantitative echo cardiography, ratio of right atrial to pulmonary capillary wedge pressure of more than 0.54, and a hemoglobin level of less than 10 grams per deciliter.
These findings offer a step towards improving prediction of the risk of right-sided heart failure to target future optimal strategies aiming at early and intension right-sided heart failure management for the highest risk subgroups of patients undergoing Left Ventricular Assist Device implantation.
Dr. Carolyn Lam: Now, sharing a patient-level clinical trial data has been widely endorsed, but just how extensively have these data been used for cardio metabolic diseases? The final study this week attempts to answer this question. First and corresponding author Dr. Vaduganathan and colleagues from Brigima Women's Hospital extracted data from clinicalstudydatarequest.com, a large, multi-sponsored data sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.
They found that the median time from study completion to data availability was more than six years. Most data requesters of cardio metabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Only 15% of these trials had been accessed by investigators thus far, and few findings have reached publication. Most requests for shared data access focused on new hypothesis generating questions rather than validation of the original study findings. These data may allow anticipation of barriers to effective system implementation and shared data consumption in cardiology.
Well, that wraps it up for our summaries this week. Now for our feature discussion.
Dr. Carolyn Lam: We are having a truly global conversation today on a really global problem. That is hypertension. From Canada, we've got Dr. Ernesto Schiffrin from McGill University, from Europe we've got Dr. Giuseppe Mancia from university of Milano, from the United States we have Dr. Wonpen Vongpatanasin from UT Southwestern, our dear associate editor and regular voice on this podcast, and then of course from Asia, that's me. You know what we're talking about? It is the global impact of the 2017 ACC/AHA hypertension guidelines. So many novel aspects about these guidelines, including new definitions of hypertension and it's stages, new thresholds and goals of treatment, consideration of the global risks and treatment decisions, addition of classes of recommendations and levels of evidence. So much to talk about, and let's start right now.
Wanpen, you were the brainchild of suggesting these global perspectives. Perhaps say a few words about the ACC/AHA new guidelines first.
Dr. Wonpen Vongpatanasin: Yeah, so I think that this is the guidelines that actually incorporating the more recent evidence and trials, particularly SPRINT, and applying this into the threshold and the blood pressure goal across the board. There's three comprehensive guidelines, and obviously ... The first time, the threshold was lower across the board, and that leads to a lot of discussion and concern and trying to see how we're implementing this or is it appropriate to all the population? Particularly not just in the US and around the world. I guess that leads to us reaching out to many hypertension leaders across the globe and really get very interesting and very insightful feedback from the global experts, two of which is on podcast today. I'm really thankful and excited to have some more in depth insight from them.
Dr. Carolyn Lam: Yeah, exactly. The buzz has really been worldwide, I can see that even from where I'm sitting here in Asia. But maybe Ernesto, I'm just gonna jump straight to the core questions. How are these guidelines different from the hypertension Canada guidelines, and frankly do you think that the ACC American guidelines are going to impact hypertension care in Canada?
Dr. Ernesto Schiffrin: Well, there are quite a few differences. The definition of hypertension remains the classical one in Canada. We have different thresholds and goals, and interestingly, the hypertension Canada guidelines have adopted a SPRINT-based recommendation for high cardiovascular risk patients in contrast to the AHA/ACC hypertension guideline. Although it has intensified the goals for treatment, it has lowered ... Has introduced as you mentioned a category of elevated blood pressure, a new definition of hypertension equal to or above 130 over 80 in contrast to ours equal to or above 140 over 90. It has not really introduced a SPRINT-based recommendation. As well, I think that one of the major questions remains the measurement of blood pressure. In Canada, we have adopted the AOBP, the Automated Office Blood Pressure measurement, at least for high risk, SPRINT like individuals. In the AHA/ACC hypertension guidelines, there is emphasis on standardized blood pressure measurement, but the SPRINT-like measurement of blood pressure has not been adopted.
Dr. Carolyn Lam: Very interesting. In Canada, with the AOBP, how do you translate that? I suppose you estimate it as lower than what would otherwise be labeled?
Dr. Ernesto Schiffrin: That is indeed a problem, because the evidence for the relationship between the AOBP carried out in the absence of a health care professional and the standardized oscillometric measurement, or the osculatory manual measurement, is unclear. The evidence is weak. So we have not really provided a guideline or recommendation with respect to these differences.
In contrast, AHA/ACC provides at least a pragmatic expert-based recommendation on what the differences are between office blood pressure and out-of-office blood pressure measurement. But, as I mentioned, there is no recommendation regarding the SPRINT-like measurement of blood pressure, and that's important because there may be major differences in the order of ten or even 15 millimeters of [inaudible 00:13:32] systolic blood pressure. However, as I see it, the committee for the ACC/AHA hypertension guideline has adopted a prudent and pragmatic approach, and actually simplified thresholds and goals to 130 over 80, and in my view this is a prudent approach.
Will it impact Canada? I think in Canada, most physicians follow the hypertension Canada guidelines, and they are recommended as best practice by governments across the country, provincial and federal. I think that physicians will be aware, but will still carry out their practice following the hypertension Canada guidelines.
Dr. Carolyn Lam: I like that. Aware but perhaps not so practice-changing in Canada. Let's shift to Europe though. Giuseppe, do you agree with that? How do you think these American guidelines may impact physicians in Europe?
Dr. Giuseppe Mancia: The American guidelines have been received with interest, lots of interest. But also there has been some criticism. For example, the question of the SPRINT [inaudible 00:14:55], you read the question of how blood pressure was measured as professor Schiffrin mentioned. It was measured at least in large number professions, why they were [inaudible 00:15:10], I'm not sure. This means that values have lower worth than those obtained by conventional office blood pressure measurement. How much room is still debated, but it could be 10, 15 millimeter mercury, which means that you could compare these SPRINT-like values to conventional office blood pressure values. Probably the SPRINT values are not much lower than 140 millimeters to the mercury systolic.
Then there is the question that can SPRINT mutually [inaudible 00:15:50] at the start. Most of them with two hypertensive charts. So if it's difficult to decide the bounds of threshold to treatment, lower these pressures to the high-low of blood pressure range, less than 140 millimeters mercury systolic when you have patients already treated, because their original blood pressure was probably higher than 140 millimeters of mercury. This [inaudible 00:16:15], however there are other data suggesting that, at least in high-risk individuals, one might indeed start treatment when blood pressure is in the 140 millimeter of mercury. You'll see what the European guidelines will recommend ... They are going to be published in June ... But perhaps this fraction of the population will be a candidate for treatment.
One last point, however, collecting the data from SPRINT is what you wish for in this regard, is that there should be a definite reduction in the threshold blood pressure for treatment in the elderly. In Europe, this was about 160 millimeters mercury based on randomized trials but probably in the future it will be about 140 millimeters mercury. So a large fraction of the elderly population will be involved in [inaudible 00:17:14].
Dr. Carolyn Lam: You know a question I always get though, is what about the side effects? We talk about the benefits of lowering it further, but what about the side effects. I don't know, does anyone have any thoughts on that?
Dr. Ernesto Schiffrin: I would say that, when you look at SPRINT, although there were increased side effects in the intensive treatment group, actually side effects were relatively rare. Some of them were important, such as acute renal failure and hyperkinemia, and so on, and other electrolyte abnormalities and syncope. But they were rare, and when we are recommending intensified treatment for the elderly, for example, which is SPRINT based in the hypertension Canada guidelines, we do say that this approach should be a gentle and progressive one, very aware that particularly in the elderly orthostatic hypertension may occur. One has to be very careful about this intensification of treatment, but yet we believe that if using automated office blood pressure measurement unobserved, you are able to reach lower blood pressures and they are well tolerated around or below 120 systolic, this will benefit these patients as shown in the SPRINT trial.
Dr. Carolyn Lam: Yeah, indeed. That's very nicely put, and just brings up the gaps that we still need to answer, like the way blood pressure is measured, standardization. We may be accounting more about risk versus benefits, patient subgroups. Wanpen, have I missed out anything else? What is the other buzz that you've heard?
Dr. Wonpen Vongpatanasin: I think that we really need to do a better job in measuring blood pressure in basic clinical practice, particularly in the US where we allow only 20 minutes to see your follow-up patient. I don't think that it will be possible to do an AOBP in the US, but I think one thing that makes the issue a little bit murkier is the SPRINT group. I actually just had an abstract presentation at the last HA meeting, that said only half of that site measure in the intended way on AOBP.
Actually, at UT Southwestern we also SPRINT site and we actually did not use AOBP, and when that stratified the treatment side by using AOBP versus non-AOBP, the outcomes was still the benefit of intensive blood pressure reduction for what it's worth. I think that the AOBP story is still controversial, but I think that I agree that we hardly have patient, sit down quietly, for five minutes before we do the measurement. I think that's first and foremost, we need to be able to do that, and do at least two measurements. We'd be lucky if we'd get one measurement after sitting down immediately, that's what we usually get in clinical practice. I definitely agree with Dr. Schifferin that when we ... Particularly the elderly, we have to be careful about orthostatic hypertension. Particular in the SPRINT trial, they actually exclude anyone who had standing systolic blood pressure less than 110. These people who are high risk of having [inaudible 00:20:35] never get into those trials to begin with.
Dr. Carolyn Lam: I can't thank you enough, everyone, for joining me in this chat around the world. It has been a learning conversation for me, as I'm sure it has been for our listeners as well.
Listeners out there, you've been listening to Circulation on the Run. Thank you for joining us today.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. This week’s issue is the Go Red for Women issue, my favorite discussions of the year happened during this podcast.
Today, I am so delighted to have with me, our Editor-in-Chief himself, Dr. Joe Hill, from UT Southwestern, as well as, of course, the editor that made this issue possible, Dr. Sharon Reimold, also from UT Southwestern. Joe, would you like to tell us a little bit about this year’s Go Red issue? From the birds eye view.
Dr. Joseph Hill: Well Carolyn, I share your enthusiasm. This is our second annual Go Red for Women issue and it is fantastic. It has generated great interest in the community. We had a number of papers coming in, unsolicited. Our frame of reference-type content. Original research articles. State of the art.
We clearly touched a nerve with this issue. As we will discuss further, we shine a bright light here on some of the very best science, focusing on sex-based differences in the biology of heart disease, the presentation of heart disease, how women function, and are treated in the academic environment. The ways in which they are impacted by psychological stress. It's an absolute bonanza of science, in this issue.
Dr. Carolyn Lam: You took the words out of my mouth. It is a bonanza issue. I mean, we had seven original articles. Lots of new stuff, but lots of good, important papers on plain old ischemic heart disease. What I really liked was that, three of these original papers focused on myocardial infractions, in the young, and their risk factors, prevention, and so on. Sharon, shall we go through those? I mean, there was the one on genetics, lifestyle, and LDL in young women.
Dr. Sharon Reimold: That would be great. That manuscript looked at, sort of, a distribution of lipids, in women, that would have otherwise expect to be healthy. They sorted them out by individuals that had extremely low LDL levels and those that had high LDL levels. They pointed out that the individuals with high LDL levels. Ended up having hypercholesterolemia heritable, but they also found genetic variance of related to those with low LDL levels. I think this manuscript points out the importance of screening younger women for lipid disorders and incorporating those data into their clinical management.
Dr. Carolyn Lam: Absolutely. Then, there was that paper that, again, talked about young women experiencing myocardial infarction, and the sex differences in their presentation, and perception. That was super cool. From the Virgo trial.
Dr. Sharon Reimold: There are several other papers, that are published, demonstrating that women tend to have multiple symptoms when they present with symptoms of ischemia. That's true for both myocardial infarction, as well as for other unstable syndromes. They certainly have more symptoms than men.
But what was very interesting about this particular paper, is that when women presented with multiple symptoms, providers were less likely to think that the symptoms were due to a cardiac etiology. So even when women are trying to tell their providers what is going on, sometimes, they're not taken seriously, because they have multiple symptoms. So I'm hoping that this resonates with our providers, clinical providers, and we think about this. Whether we're cardiologist, or emergency room providers, or even EMTs.
Dr. Carolyn Lam: Exactly. Then, the third original paper in these young women, kind of scary, mental stress induced myocardial ischemia.
Dr. Sharon Reimold: Right. So there's been a lot of interest in the myocardial infarction without obstructive coronary disease, in the last year or two. Because a lot of those individuals, even thought, they don't have typical atherosclerotic pathologies, they don't have good outcomes. So this article looks at the role that mental stress plays in inducing ischemia, by EKG, in these individuals.
I think we still need to understand more about how this contributes to the biology, and outcomes, in these individuals. Also, get a better understanding if this is also true in older women, who have ischemic heart disease.
Dr. Carolyn Lam: Exactly. You know, but speaking of the older women, it's not like the issue left out the older women this time either. I did think that the study on the metabolic predictors of incident ischemic events, in postmenopausal women, was really interesting, as well. Basically, the authors identified a cluster of novel metabolites, that were related to oxidative stress, that added to. you know?
They weren't correlated with the traditional biomarkers. Really suggesting that there may be a whole area of metabolites, and other biomarkers, that we may be needing to check, and to understand better, for risk prediction. At least, in older women. But, of course, in men as well. Then, finally, there was the data on sex differences from the STICH trial, on surgical revascularization. What did you think of that one?
Dr. Sharon Reimold: Well, I thought that this was a very important addition to the cardiology literature. Because we are accustomed to thinking of women as having poor outcomes, after they have cabbage revascularization surgery. Certainly, the STICH trial enrolled patients who were more sick than the average patient, with their underline LV dysfunction. They found that sex did not influence the outcomes in this trial.
So the importance of that, for the medical community, is obviously we should not consider sex as a barrier to sending women to surgery, even if they're at high risk, because they can have equally good outcomes.
Dr. Carolyn Lam: Exactly. Important message. Important paper. Then, moving from ischemic heart disease. We also had a paper focusing on stroke, which I thought was a really intriguing one, talking about atrial fibrillation, and questioning if being a woman is a risk modifier, or a risk factor. Do you want to elaborate on that one?
Dr. Sharon Reimold: So instead of the using the CHA2DS2–VASc algorithm they use the CHADS2-VA program and then looked to see how well that predicted risk, and how much the S and C, the gender actually influenced outcome. I think this is an important issue. I'll say it's for women, perhaps. because as a woman, you know, without doing anything, you start out with a risk factor of one. Then, once you get to a certain age you have a risk factor of two. That's even for somebody who has no other disease processes.
Dr. Carolyn Lam: Yeah.
Dr. Sharon Reimold: So I think it's a little different way to look at how the risk is modified. They propose that if your CHADS2-VA score is two, or greater, certainly, your risk goes up if you're also female. They propose, then, that you would treat those patients more intensively. It's just a little twist on the CHA2DS2–VASc and maybe will provide us different ways to refine our knowledge about outcomes in atrial fibrillation.
Dr. Carolyn Lam: Yeah. I love that paper, too, because it's quite different from the papers that we had in the first Go Red issue. Isn't it? But in the first Go Red issue, we had lots of papers on pregnancy. The current issue certainly has those papers as well.
Dr. Sharon Reimold: Yes. There are increasing number of pregnancy related complications. Both maternal, and offspring, complications that predict increased cardiac risk, down the line. This issue has a series of women who had, had preeclampsia during pregnancy, and found that 17% of their women had a coronary artery calcium score of greater than 95th percentile. While that doesn't entirely get you from the biology, in between those two, it at least gives you an idea of where to start going back, and taking a look at what's going on.
Dr. Carolyn Lam: What about the one in rheumatic mitral valve disease? Pregnancy outcomes in women with those?
Dr. Sharon Reimold: So rheumatic heart disease and pregnancy outcomes, you know, we don't see much written about it anymore. because most of the active disease is in certain areas, in the world. But obviously, these women can have symptoms related to their mitral stenosis and/or their regurgitation during their pregnancy, with heart failure being the most common presenting cardiovascular complication. While some of that is much more quantitative, than perhaps, it was in the past, which is useful.
I think that the take-home message from this particular trial is that you need to talk to these patients, and screen them, prior to pregnancy, if possible, to help achieve the best possible outcome. I think that the risk of heart failure was a little bit less than 2% during the trial, which is obviously much higher than the average woman's cardiovascular risk during pregnancy.
Dr. Carolyn Lam: this is still definitely an important issue, in many other parts of the world. I really appreciate that you invited this editorial, that gave that global perspective. The editorial, by Athena Poppas and Katharine French, really beautiful work there. You know, I have to say that one of my favorite papers, in this issue, was that in depth paper, regarding gender versus sex, as a social determinant of cardiovascular risk. I found that so intriguing, the first time I read it, and just love it.
Dr. Sharon Reimold: Social determinants of health is a hot topic, in a lot of different areas of medicine these days. But they point out some really interesting things, that I don't think I had thought about. One is the fact that, when you are a child, you know maybe 10 or 12, that boys are encouraged more to be physically active. Athletics and other sorts of activities. Whereas many girls, don't have the opportunity or are not as interested. Perhaps we set up an abnormal social situation very early in most people's lives.
Dr. Carolyn Lam: Yeah, that represents cardiovascular risk. I know. That stuck out to me too.
Dr. Sharon Reimold: Obviously, how and where people live, as children, can influence outcome. That can be influential for both boys and girls. But I think bringing the idea back to cardiovascular diseases, and risk, are really long term, lifelong processes, that we can make changes in, from a preventative standpoint, even in young people.
Dr. Carolyn Lam: Something we don't usually think about and I just love the way it was presented, so clearly, and I just love it. Now, to an area that really cuts close to the heart. Pun intended. That is the bias in research grants, bias in manuscript authorship. Joe you mentioned that, right from the introduction, I would love your comments on those papers.
Dr. Joseph Hill: The reality, that we all are aware of, is, in many countries, including the United States, 50% of medical students now are female. But as we move through the ranks, into the different subspecialties, and up the career ladder of academic cardiology, we see a thinning of female representation. Arguably, it's been improving, over the last number of years.
But the reality is, that there remains a bias against representation of women, in terms of extra mural grant funding, authorship on high-profile papers. This article digs into that, and analyzes those numbers, takes a snapshot of what it looks like at the present time. In some ways, I believe it's a call to arms on how we must do a better job of recognizing this and rectifying it, going forward.
Dr. Carolyn Lam: Sharon, did you have comments to add?
Dr. Sharon Reimold: Yeah. I mean, I think, I wholeheartedly agree with Joe about those sorts of things. I mean, we see the same types of issues in clinical cardiology as well as in the research components of what we do. we need to figure out how to do this better, so that we all can be productive, going forward.
Dr. Carolyn Lam: You know it's just such a beautiful issue. So rich, in so many ways. Was there anything else you might want to highlight to our listeners?
Dr. Joseph Hill: I might add that Sharon and I kicked off the issue with a brief introduction. Pointing out that the reality is, that one and four women will die of heart disease. Most women don't know that. Most healthcare providers don't know that. Many Cardiologist don't know that.
When you compare that to the realities of breast cancer, it's 1 in 40. It's 10 times different. Now, that community has done a fantastic job. The Susan G. Komen program, in the United States. The pink ribbons, that we see all around the world. That community has done a fabulous job of getting the message out about that grievous disorder.
We have to do better. We have to do better educating ourselves, educating the lay public, about the realities of heart disease in women. 1 in 4, around the world. We also have to do a better job of digging into the science. That's where this issue does an especially good job.
That the reality is that heart disease is different in men and women. It presents differently. It presents at a different age. The way in which women respond to therapies, can differ from men. So there's work to be done, in terms of awareness. There's work to be done, in terms of the underline biology. This is an especially exciting time in this arena.
Dr. Carolyn Lam: I couldn't agree more. I'd add to it, even sex differences and the perceptions about own symptoms, and that of women versus men with chest pain. Then, the whole gender, social element to it. Oh, just so much to discuss, so much to learn from.
Well, listeners you heard it right here. I want you to please send this episode, share it with as many other women as you can think of. Do help us to spread this message, it's such an important one.
Thank you so much, Joe and Sharon, for joining me today. Thank you, listeners, as well. Tune in again next week.
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.
Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:
Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.
The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.
Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.
The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.
In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.
On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.
In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.
Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.
To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.
They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.
The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.
They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.
These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.
Well, that wraps it up for our summaries. Now for our feature discussion.
For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.
Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.
Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found?
Dr. Jason Weatherald: This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.
We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective.
Dr. Carolyn Lam: Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them?
Dr. Kelly Chin: I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.
The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.
Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.
I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing.
Dr. Carolyn Lam: Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.
The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason?
Dr. Jason Weatherald: Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.
What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.
I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration.
Dr. Carolyn Lam: Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.
Kelly, what do you think are the real take home messages from this?
Dr. Kelly Chin: I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment.
Dr. Carolyn Lam: Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason?
Dr. Jason Weatherald: I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.
At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.
I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic.
Dr. Kelly Chin: I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.
But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization.
Dr. Carolyn Lam: Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment?
Dr. Jason Weatherald: Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening.
Dr. Carolyn Lam: And Kelly, what do you think should be next steps?
Dr. Kelly Chin: I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.
But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies.
Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in again next week.
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. In today's feature discussion, we are talking about external validation of the DAPT score, a discussion that's going to take us all the way to east Asia, but for now, here are your weekly summaries.
In this week's journal, two studies are presented which compare ductal stenting to surgical shunts in the current era of ductal dependent pulmonary blood flow. As background, infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt between the subclavian artery and either pulmonary arteries. This modified Blalock–Taussig shunt allows progress through early life to an age and weight at which repair or furthermore stable palliation can be safely achieved. However, these modified Blalock–Taussig shunts continue to present concern for post-procedure instability and early mortality.
Duct stenting has emerged as an alternative with potential for greater early stability and improved survival. In the first study, first and corresponding author Dr. Bentham from Yorkshire Heart Centre reviewed data from the National Congenital Heart Audit, comparing the outcomes of 171 neonates who underwent a modified Blalock–Taussig shunt and 83 who underwent attempted ductal stenting, all in the setting of duct dependent pulmonary blood flow between 2012 and 2015. They found that stenting the arterial duct was preferable over the modified Blalock–Taussig shunt in terms of survival to next stage surgery, early post-procedure hemodynamic stability and shorter intensive care and hospital stay. There was a high failure rate both early, with the inability to stent the duct and late, with a greater need for re-intervention on the stented duct compared to the surgical shunt.
The second study originated from four North American pediatric cardiology centers representing the Congenital Catheterization Research Collaborative. First and corresponding author, Dr. Glatz from Children's Hospital of Philadelphia performed a retrospective cohort study reviewing all infants with ductal dependent pulmonary blood flow under a year of age, having either a ductal stent or a modified Blalock–Taussig shunt between 2008 and 2015. Although the observed risks of the primary outcome of death or unplanned re-intervention to treat cyanosis was higher in the surgical shunt group, there was no significant difference between groups after adjusting for patient level factors. Furthermore, after adjusting for patient factors, other outcomes favored the stent group, including fewer procedural complications, shorter intensive care unit length of stay, less frequent need for diuretics and larger and more symmetric pulmonary arteries at last follow up.
These companion papers are discussed in an elegant editorial by Drs. Benson and Van Arsdell from Hospital for Sick Children in Toronto.
The next study tells us that there may be a higher risk of vascular dementia in patient who survive a myocardial infarction. First and corresponding author, Dr. Sundbøll from Aarhus University Hospital in Denmark performed a nationwide, population based study including almost 315,000 patients with myocardial infarction and found that the risk of vascular dementia was higher compared to a matched general population comparison cohort. The risk of vascular dementia was incrementally higher in patients who suffered stroke or developed severe heart failure during the first year after myocardial infarction and in patients who underwent coronary artery bypass grafting. There was no association with all caused dementia, Alzheimer's disease or other dementia sub-types. Take home message is that among one year survivors of myocardial infarction, attention should be placed to persistently higher risk of vascular dementia.
The next study identifies a novel mechanism whereby the RNA binding protein, fragile X mental retardation autosomal homologue one or FXR1, directly regulates gap junction remodeling, leading to dilated cardiomyopathy. Co-first authors Drs. Chu and Novak, corresponding author Dr. Gregorio and colleagues from University of Arizona studied human left ventricle dilated cardiomyopathy biopsy samples as well as mouse models of dilated cardiomyopathy. They found that FXR1 expression was significantly increased in human and mouse dilated cardiomyopathy. Up regulation of FXR1 in the heart altered the location and distribution of gap junctions, subsequently leading to ventricular tachycardia in mice.
Mechanistically, FXR1 associated with intercollated discs and directly interacted with integral gap junction proteins to regulate their expression in cardiomyocytes. Finally, loss of FXR1 in the heart led to dilated cardiomyopathy. Together, these results provide a novel function of FXR1, namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. Thus, the authors concluded that FXR1 may be a promising target for therapeutic strategies to improve gap junction function in dilated cardiomyopathy.
Well everyone, that wraps it up for our summaries. Now for our feature discussion.
The dual anti-platelet therapy or DAPT score is widely used everywhere to estimate bleeding versus ischemic risk in patients undergoing percutaneous pulmonary intervention. However, very few studies have provided external validation of its utility. Well we have a very important paper in this week's journal that addresses just that in a Japanese population. So pleased to have with us the corresponding author, Dr. Takeshi Kimura from Kyoto University Graduate School of Medicine. Not just him, but also the editorialist for this paper, Dr. Shinya Goto, also an associate editor of Circulation from Tokai University of Japan and last but not least of course, our dear Senior Associate Editor of Circulation, Dr. Laura Mauri from Brigham and Women's Hospital. What an important topic. Takeshi, would you mind to please tell us about your study to start?
Dr Takeshi Kimura: Actually we thought about the utility of the DAPT score provided from the DAPT study in Japanese patient population. In a full cohort of three studies that are conducted in Japan, we compare the risks for ischemic and bleeding risks from 13 to 36 months after a PCI between patients with DAPT score (high-DS) and DAPT score <2 (low-DS) in patients in the Japanese population. We evaluated 12,223 patients. There were 1,344 patients with high DAPT score, 8,279 patients with low DAPT score. The cumulative incidence of primary ischemic end point myocardial infarction or stents from both is significantly higher in the high DAPT score group than in the low DAPT score group.
One of the cumulative incidence of the primary bleeding end point tended to be lower in high DAPT score than in the low DAPT score group, therefore the DAP score has successfully stratified ischemic and bleeding risks in Japanese patients. We've externally validated DAPT score successfully.
Dr Carolyn Lam: Thank you so much Takeshi. Shinya, you wrote an excellent editorial to this paper. Could you let us know why it was so important to validate this in the Japanese population?
Dr Shinya Goto: It's quite homogenous in one way and the other way in the world is heterogeneous. Some may say the risk of thrombotic and the bleeding event in Japanese or East Asia might be different from other regions of world. Dr. Kimura’s paper is the first validation of the DAPT score in the East Asian patient. Original attempts to study didn't include patients from East Asia. This is the real first validation of the DAPT score in that East Asian population. The world is quite homogeneous. It is very important message.
Dr Carolyn Lam: Yes, yes, I agree. Could I just ask maybe a cheeky question. What would you have thought may be any differences?
Dr Shinya Goto: Indeed, previous global trial and also global registry showed relatively low risk of ischemic event. Maybe not many of the US reader doesn't know we are using relatively low dose over anti-coagulant agent for preventing stent thrombosis. Dr. Kimura's paper provides very important insight. DAPT score is predictable for that event but even in the population with lower use of anti-coagulant agent like standard dose of prasugrel in Japan is just 3.75 milligram. Maybe that thrombogenicity in Japanese populations is lower as compared to the global population. Still that’s quite predictable for the ischemic event. That's very important message.
Dr Carolyn Lam: I agree and I have to tell you, practicing in Asia too, I have a tendency to think the bleeding risk may be underestimated by existing scores. We also tend to use lower doses, so it's so important to show objective data such as these. Laura, what are your thoughts coming from the US?
Dr Laura Mauri: Well I think it's very important. I want to congratulate Takeshi, it's a wonderful study, very large randomized data set and very important. I think in the grand scheme of things we do randomized trials, we can't represent every single population in every study. The DAPT study was done in the US, Europe, as well as in Australia and New Zealand, but it's true. We weren't able to also include sites in Asia just from practical reasons. I think it's very exciting to see, looking at this question of the DAPT score in patients in Japan.
I think in general, it matters a lot to understand the generalizability of our randomized trial results across different populations. I think Shinya's mentioned some of the important sources of variability. It may be this great interest in understanding genetics and how they relate in different populations, but there are also clear differences in medical practice across the world. Doing this type of study where one looks at different populations is quite important and I think it's also one of the reasons that circulation in terms of the editors are really seeking to expand the international scope of the randomized trials and secondary studies from randomized studies such as this that really impact patient care across the world.
Dr Takeshi Kimura: I think one of the difference from the DAPT studies in this Japanese closed study is the proportion of the high DAPT score versus low DAPT score is a little bit different. In the Japanese study population, the low DAPT score patients are dominant and also ischemic event risk are lower. However, the DAPT score clearly differentiates that, stratifies the bleeding and the ischemic risks so we should see both the bleeding and ischemic risk and also the difference of absolute event rates in each geographic ischemic population. I think it's important message from this paper.
Dr Carolyn Lam: That is such a great point, Takeshi. In other words, there may be some heterogeneity around the world in baseline risks, as Laura said, baseline practice patterns and I'm talking about baseline both ischemic and bleeding risks. What your paper definitely shows is that the DAPT score however, performs similarly and as we've said so many times, that's such an important message. Shinya, what do you think? What's your message to all the audience out there in Japan and abroad?
Dr Shinya Goto: As Takeshi told me and also how Laura pointed out, if we try to find the difference in the world, there is a difference and if we try to find the similarity, there is a similarity. Dr. Kimura paper shows similarity in the risk factor determining the ischemic and bleeding event. Matched, absolute event risk is low. Background medication is not the same. Majority of the patient taking [inaudible], 200 milligrams a day. [Inaudible] is a bad drug already in the world, but still in Japan, the doctor is still using. Clopidogrel, 75 milligram is also very widely used. The prasugrel dose is just 3.75 milligrams. That is different from the world. Ticagrelor with the dose similar to the world was not successful in the clinical trial in East Asia.
There is a similarity and heterogeneity. Dr. Kimara beautifully demonstrated both in his registry.
Dr Carolyn Lam: Indeed. Laura, looking at this now with these new data, do you think clinical trials should be done any different? Should we be doing multiple small trials maybe in different parts of the world now? Should we power trials to look at regional differences? This trial business is really hard, isn't it?
Dr Laura Mauri: That's a great question. It does come up practicality, whether we should do the same clinical trial in multiple different countries. I don't think it's the six answer, I think that as Shinya, I think, was alluding to, I think that patients responses worldwide are more similar than they are different. That doesn't mean when we plan our trials we shouldn't think about what the differences are and how they might impact the results and whether we might need to make confirmations across the world. I think this study is quite important because it finds the commonality across different populations even though there may be underlying differences that Takeshi mentioned in the baseline rate. I think a similar approach worldwide where we go in with a hypothesis about where things may be consistent or different to determine whether trials need to be replicated elsewhere is useful to have.
Dr Carolyn Lam: Thanks so much, Laura. I don't think any of us could have said it better.
Thank you all for joining me on the show today and thank you ladies and gentlemen throughout the world for listening in today. You've been listening to Circulation on the Run, don't forget to tune in again next week.