Circulation November 13, 2018 Issue

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.

                                                This week's feature discussion focuses on first and man pilot study results of pericardiotomy and its influence on left ventricular diastolic reserve with volume loading. Very fascinating implications for heart failure with reserved ejection fraction, coming right up after these summaries.

                                                Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. But what are the underlying mechanisms and potential therapeutic approaches to this? Well, in today's paper from co-first authors Drs Sun and Yao, corresponding author Dr Chang, and colleagues from UT Southwestern Medical Center, the authors examine the status of cardiac autophagy and its role during sepsis pathogenesis using a rodent lipopolysaccharide-induced sepsis model. They've found that forced overexpression of Beclin-1 in the heart promoted autophagy and mitophagy, protected mitochondria, improved cardiac function, and alleviated inflammation and fibrosis after a lipopolysaccharide challenge. Whereas, haplosufficiency for Beclin-1 resulted in the opposite effects. For the more injection of a cell permeable Tat-Beclin-1 peptide improved outcomes in lipopolysaccharide-challenged animals. Thus promoting Beclin-1-dependent signaling may be a novel and effective intervention to alleviate organ dysfunction caused by maladaptive autophagy during severe sepsis.

                                                The next paper presents important experimental data that causes us to consider the potential cardiovascular hazards of anti B-cell activating factor immunotherapy, which is currently approved for the treatment of autoimmune systemic lupus erythematosus. You see, genomic data has shown that B-cell activating factor receptor pathway is specifically essential for the survival of conventional B lymphocytes, which is a key driver of coronary heart disease. However, in today's paper from co-first authors, Drs Tsiantoulas and Sage, corresponding author Dr Binder and colleagues from Medical University of Vienna, the authors reported an unexpected finding that B-cell activating factor neutralization increased atherosclerotic plaque size and complexity despite efficient depletion of mature, conventional B lymphocytes. Furthermore, the authors provided evidence suggesting a novel B-cell independent anti-inflammatory property of B-cell activating factor. They showed that the expression of the alternative B-cell activating factor binding receptor, transmembrane activator and CAML interactor in myeloid cells limited atherosclerosis thus showing novel atheroprotective pathways. Thus, these results introduce a new perspective with respect to the potential cardiovascular hazards that may be associated with the long term blockade of B-cell activating factor in chronic inflammatory settings. There is a need for more refine therapeutic approaches targeting the B-cell activating factor pathway.

                                                Vascular smooth muscle cells are known to possess remarkable plasticity undergoing fundamental phenotypic switches from a differentiated to a dedifferentiated state in response to vascular injury or remodeling. However, what are the underlying cellular processes by which vascular smooth muscle cells maintain their cell identity? Well, in today's paper from co-first authors Dr Yao, Yu and Li, corresponding Dr Wang from Fu Wai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking University Medical College. The authors applied single cell RNA sequencing to analyze disease human arteries and identified histone variant H2A.Z as a key histone signature that maintains vascular smooth muscle cell identity. H2A.Z occupied genomic regions near vascular smooth muscle cell marker genes and it's occupancy was decreased in vascular smooth muscle cells undergoing dedifferention. H2A.Z expression was dramatically reduced at both messenger RNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescued injury-induced loss of vascular smooth muscle cells identity and new intima formation. Together, these data introduced dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions and implied that H2A.Z may be a potential intervention known for vascular diseases.

                                                What is the causal role of body mass index and cardiovascular health in young adults? In the next paper from first and corresponding author Dr Wade from University of Bristol in United Kingdom and her colleagues. The authors used a combination of conventional multivariable regression analyses, Mendelian randomization and subsample recall by genotype methodologies. Recall by genotype is a novel approach that exploits the random assortment of alleles through meiotic cell division at conception to inform genetically base recall and enables the collection of precise phenotypic measures in smaller studies while maintaining statistical power and ability for causal inference. The authors use these methods to estimate the causal effect of body mass index on gross level and detail cardiovascular health in healthy participants from the Avon longitudinal study of parents and children at age 17 years as well as in an independent sample from the same cohort study at age 21 years.

                                                Their results showed that higher body mass index was likely to cause worse cardiovascular health specifically higher blood pressure and higher left ventricular mass index even in youth. Higher body mass index also resulted in increased cardiac output in the recall by genotype study which appeared to be solely driven by stroke volume, as neither the Mendelian randomization nor the recall by genotype analyses suggested a causal effect of body mass index on heart rate. These consistent results support efforts to reduce body mass index from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using a recall by genotype methodology.

                                                Older adults undergoing aortic valve replacement are at risk for malnutrition, however, what is the association between pre-procedural nutritional status at midterm mortality? First author, Dr Goldfarb, corresponding author Dr Afilalo from McGill University in Montreal, Quebec, reported results of the FRAILTY-AVR prospective multicenter international cohort study conducted between 2012 and 2017 in 14 centers in three countries. This study included patients 70 years and older who underwent transcatheter aortic valve replacement or surgical aortic valve replacement. The mini nutritional assessment short form was assessed by trained observers pre procedure with scores seven or less out of 14 being considered to be malnourished. The short performance physical battery was simultaneously assessed to measure physical frailty. The authors found that malnutrition was associated with higher one-year mortality and 30-day adverse events following aortic valve replacement via a transcatheter or surgical approach. While malnutrition and frailty were interrelated, the integration of nutritional assessment resulted in improved predictive value for frail patients. Clinical trials are needed to determine whether pre and post procedural nutritional interventions can improve clinical outcomes in these vulnerable patients.

                                                Do newer generation ultra-thin strut drug-eluding stents improve clinical outcomes over contemporary thicker strut stents? First and corresponding author, Dr Bangalore from New York University's School of Medicine and colleagues search PubMed, Embase and Central and identified 10 trials that randomized more than 11,650 patients and evaluated three newer generation ultra-thin strut drug-eluding stents, that is defined as a strut thickness less than 70 microns, versus thicker strut second generation drug eluding stents and reported clinical outcomes. They found that newer generation ultra-thin strut drug-eluding stents were associated with a 16% reduction in target lesion failure, which was a composite of cardiovascular death, target vessel myocardial infarction or ischemia-driven target lesion revascularization evaluated at one year follow-up. Ultra-thin strut drug-eluding stents reduced the risk of target-lesion failure driven by a reduction in myocardial infarction and also a qualitatively lower rate of stent thrombosis compared to contemporary thicker strut second generation drug-eluding stents.

                                                Ambient air pollutants are known to be associated with increased cardiovascular morbidity and mortality, however, what is the association between air pollution and cardiac structure and function? First and corresponding author Dr Aung from Queen Mary University of London and colleagues performed a cross-sectional analysis of a large population free of preexisting cardiovascular disease in the UK Biobank population study. They found that higher past exposure to fine particulate matter and nitrogen dioxide were associated with larger cardiac biventricular volumes. Proximity to major roads, a surrogate for chronic air pollution exposure, was additionally associated with higher left ventricular mass. These associations between ambient air pollution and at first cardiac phenotypic changes, in individuals without prevalent cardiovascular disease, suggest that air pollution should be recognized as a major modifiable risk factor which needs to be targeted by a public health measures.

                                                The final original paper this week is the first study to demonstrate a causal link between atrial fibrillation and the NLRP3 inflammasome, which is an innate inflammation signaling complex. Co-first authors, Drs Yao and Veleva, corresponding author Dr Li from Baylor College of Medicine and colleagues assessed MLRP3 inflammasome activation by immunoblot in atrial whole tissue lysates and cardiomyocytes from patients with paroxysmal or long-standing persistent atrial fibrillation. They found that NLRP3 inflammasome activity was increased in these patients. To determine whether cardiomyocytes specific activation of NRLP3 was sufficient to promote atrial fibrillation, they established a cardiomyocyte specific knock in mouse model which expressed constitutively active NLRP3. These mice developed spontaneous premature atrial contractions, an inducible atrial fibrillation, which was attenuated by a specific NLRP3 inflammasome inhibitor. Cardiomyocyte-specific knockdown of NRLP3 suppressed atrial fibrillation development in these mice. Thus, these results establish a novel pathophysiological role for cardiomyocyte NLRP3 inflammasome signaling with a mechanistic link to the pathogenesis of atrial fibrillation, and suggests that inhibition of NLRP3 may be a potential novel atrial fibrillation therapy approach.

                                                And that brings us to the end of our summaries.

                                                Now for our feature discussion.

                                                Is pericardiotomy going to be our next treatment for heart failure with preserved ejection fraction or HFpEF? I have the first and corresponding author of a very intriguing research letter. Dr Barry Borlaug from Mayo Clinic in Rochester, Minnesota, joining me today to tell today about his great paper. Barry, welcome back to the show. You are amazing. Congratulations on yet another wonderful publication. So, could you set us up. Those of us who don't think about this every day. The hemodynamics of what pericardiotomy does. Tell us what was the rationale of doing this study?

Dr Barry Borlaug:              You know, it's interesting. We think about intracavitary pressures on the left side ventricle and the left atrium causing congestion and pulmonary hypertension. We think that this is all related to left ventricular issues, but about 30 or 40% of the pressure is actually related to external restraint on the heart as mediated by the right ventricle across the septum and the pericardium and external pericardial contact restraints. In animals, we've known since back in the late 1970s, that with the chest open, if you open up the pericardium, which we know in HFpEF, on average, is shifted up and to the left. It's stiffer. This effect really comes into play more at higher heart volumes. It doesn't have as much of an affect at lower heart volumes like might be absorbed with rest. It's even been rumored that in some species like greyhounds, illicit dog racers, would actually cut away the pericardium so these dogs could race better. It's actually been shown that they can experimentally, in a paper in the 1980s, that they can exercise the higher peak VO2. They have a higher cardiac output response, because the heart is better able to utilize the Frank-Starling relationships to augment ventricular filling and ejection at fuller pressures.

Dr Carolyn Lam:                Oh my goodness. I didn't know that latter fact about the racing dogs. Could I ask you something? We've talked about this before back in the day. When you say the left side the filling pressures go up when there's pericardial restraint, remember we used to talk about a parallel shift upwards versus true intrinsic stiffening ... diastolic stiffening. You still do mean that parallel shift upwards, right?

Dr Barry Borlaug:              That's right. If it was purely an increase in stiffness, we would expect it to sort of rotate, pivot from the bottom left up, but what we see, and in human data, we published a number of years ago, most of the increase in LV end-diastolic pressure is a parallel shift upward in the diastolic pressure volume relationship. That really suggests that there's an increase in restraints on the heart. That's why we think that that's an important target and it's possibly more remediable to treatment since we're having such tough luck changing the viscoelastic properties of the left ventricle, not that we shouldn't be doing that, but this might be something different that we could do that might give us a little bit more of a benefit in terms of filling pressure reduction.

Dr Carolyn Lam:                True. True. But the way you describe it too, it does mean that we may be talking about, I hate to say this but, specific subsets or types of HFpEF, where that may play a bigger role and I'd just like to bring the audience to your incredible paper that I think that I've cited a gazillion times already on the obese HFpEF phenotype. Do you want to remind everyone about that because I think there you really [inaudible 00:16:30], didn't you that ventricular interdependence played a big role.

Dr Barry Borlaug:              So, in people with obese HFpEF, which is now becoming by far one of the most dominant. Oh God. We did a study that compared them to non-obese and we see that the obese patients have a bit more plasma volume expansion, a bit more cardiac remodeling, right heart enlargements, increase of LV mass and an increase in epicardial fat. What all this does is increases the total heart volume in the pericardial space. Because the pericardium doesn't appear to grow as much as the heart volume, this increases the coupling between the right and left heart. Some people, perhaps like the obese phenotype of HFpEF, might be more poised to derive benefit from approaches to therapeutically remove this excess pericardial restraint.

Dr Carolyn Lam:                Okay, now you just have to get down to telling us what you did. This was a first in man pilot study. Drum roll everybody. You gotta listen up. This was so cool.

Dr Barry Borlaug:              This physiology just got us thinking that maybe we could do this to help our patients with HFpEF. First we tested this in dogs, then with pigs with features of HFpEF and it seemed to work there so the next step was to show that it might work in people. We took people that were already going to get their pericardium open, so people that were referred for cardiac surgery. We wanted to choose people that had risk factors for HFpEF and diastolic dysfunction but maybe not necessarily diagnosed HFpEF.

Dr Barry Borlaug:              We took people who were referred for aortic valve replacement for AS, coronary artery bypass grafting or both and consented them ahead of time, put catheters into them to measure hemodynamics and then we measured resting hemodynamics with the chest open, but pericardium intact, because the changes that we see occur predominantly when there's an increase in volume load to the heart, we then had to stress the system. Now we can't have them exercise cause they're under general anesthesia with an open chest. You achieve that by elevating their legs and giving them a little saline bolus, so we had a pressure at rest, pressure with saline load.

                                                Then we asked our surgeons to open the pericardium, which they do obviously to gain access to the heart for cardiac surgery and we repeated the same assessments and intervention. What we saw was that the resting filling pressures, again these people did have diastolic dysfunction, the resting pulmonary wedge pressure was about 16. With the volume load maneuver, it increased to 25 when the pericardium was intact. After we had opened the pericardium, the increase in wedge pressure, which was our primary endpoint, was reduced from an increase in nine millimeters of mercury down to an increase of only three millimeters of mercury. So that verified our hypothesis that the pericardium contributed and that we could prove total cardiac diastolic reserve, if you will, just by removing that pericardial restraints.

Dr Carolyn Lam:                Wow. I love the figures, by the way, that you've drawn as always they illustrate that so beautifully. And listeners, this is a research letter, so there's that one central figure that you must get your hands on right away. Now Barry, I think the first question is this wasn't really HFpEF patients right? Let's be very clear with the audience who these were though and then you did a subset analyses though, a further analysis that showed this may apply more to people with higher wedge at rest. Could you elaborate?

Dr Barry Borlaug:              Absolutely. While these people, and Carolyn, I think you know as well, I think a lot of people probably have HFpEF that they have a sort of occult HFpEF, that's not been diagnosed maybe because unfortunately, not everybody else thinks about this diagnosis. When you look at the charts very carefully, and found out about 13 of the 19 patients complained of significant dyspnea based on chart review. Of those 13, 10 had other indicators that according to current criteria would give them the diagnosis. When we looked at this at this very post hoc, sort of exploratory subset, we actually saw that these patients, even though they didn't necessarily have a clinic diagnosis of HFpEF, that these patients actually responded even more favorably to the effects of pericardiotomy in their greater reduction in the increase in wedge pressure. When we plotted in the figure that you mentioned, we plotted the change in the increase in wedge pressure, it was really the patients that had the greatest increase with volume loading initially that derived the most benefit. That makes sense because those were the people where the pericardium and the restraint is the becoming most operative, when the heart is most distended and congested.

Dr Carolyn Lam                 Maybe one quick last question. What next Dr Borlaug? Gosh, you just keep coming up with one thing after another with the animals. I noticed that it was a non-invasive pericardiotomy. I'm reading between the lines here. What are you going to do next? Do you think this is ready for prime time?

Dr Barry Borlaug:              As usual, you're reading correctly between the lines. We have filed a patent awhile back for this and we have a device that can achieve a pericardial modification or an anterior pericardiotomy without the need for open heart surgery, so that you don't crack the sternum. It's done from a subxiphoid approach and we've actually just received some funding to start doing this under an IDE, which we will need to work with the FDA. We hope to do and start testing this in patients that have HFpEF and then look at the acute hemodynamically affects. Then we'll also begin to explore the safety and potential efficacy using other indices like imaging, exercise capacity and things like that.

Dr Carolyn Lam:                That is just so cool. I think that one of the immediate take home messages for me now though is when we see patients who we think have HFpEF, have a low threshold to look for evidence of constriction. I would say that we may miss the diagnosis of people who legitimately have constrictive pericarditis and may need to benefit from this. I think it's one of those hidden diagnosis, so that's one thing. And then the next thing, if I could just ask you, are there any patient populations that you say should not undergo this? And I say this because I remember back in the day again, when we were experimenting with dog models, this is just gestalt okay, but I thought that the dogs who had right-sided heart failure, severe right-sided heart failure, needed that pericardium to lean on, and if you released it, the dilatation on the right side would just be inexorable because there is no pericardium to rein them in. Do you get what I mean? I don't know. I'm just curious if you have any patient population right now that you're already thinking I'm not going to include in my trial.

Dr Barry Borlaug:              Yeah. That's a very important point, Carolyn. We would not want to apply or test initially certainly this therapy where eccentric cardiac remodeling is a problem because we know that there is a little bit of eccentric dilatation even in people after a regular cardiac surgery with pericardiotomy. Marty Molenter showed that, in a paper back in the 1980s, you have a patient who already has some dysfunction, we would hypothesize that they may get a bit worse, so we would not want to test this in people with the right ventricular dysfunction, right ventricular enlargement phenotype of HFpEF. We would not want to give this to people with HFrEF. Remember with HFrEF, we wanted to do just the opposite. We tested this years ago with the ACORN trial or older studies wrapping the latissimus dorsi around the heart to cause reverse remodeling so this is really something that would maybe work more for people with smaller stiff hearts, HFpEF, where that concern that they're going to dilate and get low EF heart failure either on the left or on the right side. We would want to focus more on the small hearts and away from those people with dilation.

Dr Carolyn Lam:                That is so great. Thanks so much Barry for letting us under the hood. Congratulations once again. These are just great papers. Keep them coming. Well listeners. I'm sure you enjoyed that as much as I did. Don't forget to tune in again next week.