Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: October, 2019
Oct 28, 2019

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 Center and Duke National University of Singapore.

Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results.

Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers.

Dr Carolyn Lam:  So... What did they find?

Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients.

Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized.

Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP.

Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes.

Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study?

Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more.

Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells.

Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find?

Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart.

Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy.

Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them?

Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer.

Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap.

Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece.

Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter.

Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock.

Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy.

Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study?

Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer.

Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population?

Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk.

Dr Greg Hundley: And who did you include in this study?

Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention.

Dr Greg Hundley: And how many subjects were in your study? Was this a large study?

Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations.

Dr Greg Hundley: So what did you find? What were your results?

Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis.

To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis.

Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis.

Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women?

Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding.

Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies?

Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer.

And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear.

Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation?

Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial.

Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years?

Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier?

Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy.

And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week.

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

Oct 21, 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 Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article?

Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm.

Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first?

Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm.

Dr Greg Hundley:             Interesting. What did they find, Carolyn?

Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery.

Dr Greg Hundley:             Fantastic, Carolyn.

                                                Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension.

Dr Carolyn Lam:                Huh. What did they find Greg?

Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients.

Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.

                                                Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry.

Dr Greg Hundley:             Carolyn, what did they find?

Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag?

Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.

                                                First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal.

Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion.

Dr Greg Hundley:             You bet.

                                                Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods.

Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.

                                                I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation.

Dr Greg Hundley:             What was your overall study design and your study population?

Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important.

Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms?

Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan.

Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF?

Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.

                                                The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.

                                                We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes.

Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct?

Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well.

Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works?

Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?

                                                And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion.

Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy.

Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients.

Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that?

Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses.

Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week.

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


Oct 14, 2019

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 Center and Duke National University of Singapore.

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

                                                Well, Carolyn, we've got a great feature article to discuss later in our interview today. We're going to compare surgical versus percutaneous aortic valve replacement, but now with coronary artery revascularization. So, very exciting results from the SURTAVI trial.

                                                So, Carolyn, do you have a couple papers to discuss?

Dr Carolyn Lam:                For sure. Actually, it's exactly a couple, and it's a couple of GWAS papers. The first is a GWAS of the cardiac magnetic resonance imaging derived left ventricular phenotypes of the UK bio bank. It comprises almost 17,000 European-UK bio bank participants without prevalent myocardial infarction or heart failure. So this was led by professors Petersen and Monroe from Queen Mary University of London, and colleagues who found that prognostically important left ventricular imaging phenotypes were highly heritable, with a heritability of 22 to 39%. A total of 14 genetic susceptibility low PSI, eight of which were unique, enriched in the cardiac developmental pathways and regulation of contractile mechanisms were discovered, and the polygenic risk scores of left ventricular phenotypes were predictive of heart failure events independently of clinical risk.

Dr Greg Hundley:             Well, Carolyn, knowing me and MRI, something I really am interested in. So tell us a little about what are the clinical implications?

Dr Carolyn Lam:                Well, the findings not only enhance our understanding of the genetic basis of prognostically important left ventricular phenotypes in the general population, but they also underscore the intricate genetic relationship between these endo phenotypes and the pathogenesis of heart failure. The prioritized genes in the genome whites significant load size should be followed up in the functional studies to aid the development of potential novel therapies in future. The polygenic risk scores of left ventricular phenotypes may have a role in personalized risk stratification. But this, of course, is dependent on further validation of the clinical robustness in future studies.

                                                I want to skip onto my second GWAS paper, and this time dealing with bicuspid aortic valve. So, first a little reminder that bicuspid aortic valve disease is a congenital defect that affects 0.5 to 1.2% of the population, and is associated with comorbidities including ascending aortic dilatation and calcific aortic stenosis. To date, while a few causal genes have been identified, the genetic basis for the vast majority of bicuspid aortic valve cases remains unknown. Today's paper from Dr Lipschultz from Medical University of South Carolina reports novel human genetic based models, which developed bicuspid aortic valve and aortic stenosis with high penetrance.

Dr Greg Hundley:             Very interesting. So, how did the authors do this, Carolyn?

Dr Carolyn Lam:                Yeah, it is interesting. What they did is they performed a GWAS and replication study using cohorts of more than 2,000 patients with bicuspid aortic valve and more than 2,700 controls, which identified the primary Celia genes as associated with the bicuspid aortic valve phenotype. Specifically the most associated snips were identified in or near genes that are important in regulating Ciliogenesis through the exocyst, which is a shuttling complex that chaperone Celia cargo to the membrane. Genetic dismantling of this exocyst resulted in impaired Ciliogenesis through the XO CIS, disrupted Ciliogenic signaling, and resulted in a spectrum of cardiac defects in zebra fish and aortic valve defects including bicuspid aortic valve, valve stenosis, and Velveeta calcification in murine models as well. So this data really supports that the exocyst is required for normal Ciliogenesis during aortic valve morphogenesis and really implicates the disruption of Ciliogenesis, and its downstream pathways may contribute to bicuspid aortic valve and its associated comorbidities.

Dr Greg Hundley:             Wow. Very interesting. Learning more and more about bicuspid valves through our journal. I'm going to shift Carolyn and talk about an article from Dr Marc Sabatine from the TIMI study group at Brigham and Women's hospital. This study performed a systematic review and a trial level meta regression analysis of three classes of lipid lowering therapies that reduce triglycerides to a greater extent than they do LDLC. Fibrates, Niacin, and Marine derived Omega-three fatty acids and key inclusion criteria were a randomized, controlled trial that reported on major vascular events. The study also incorporated data from a previous Meta-regression of 25 Statin trials, and the main outcome measure was the risk ratio for major, vascular events associated with absolute reductions in lipid parameters.

Dr Carolyn Lam:                Oh, very interesting. So did the study show that it was beneficial to lower triglycerides or not?

Dr Greg Hundley:             Let me tell you a little more about it. The study encompass 374,358 patients that sustained 46,180 major cardiovascular events, and in their multi-variable Meta-regression model, that included terms for both LDLC and triglyceride surrogates for LDL and VLDL. The risk ratio was 0.8 per one millimole per liter reduction in LDLC, and 0.84 per one millimole liter reduction in triglycerides. Therefore, a reduction in non-HDLC, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid lowering drug class, and triglyceride lowering is associated with a lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction then with LDLC. Interesting, Carolyn one study reduce it and impacted the study results, and nearly all non-statin trials did not achieve significant non-HDLC lowering to detect a clinical difference in major vascular events. Now how about in regards to Omega- three dose?

                                                Well, each one gram per day of EPA administered was associated with a 7% relative risk reduction in major vascular events, whereas there was no significant reduction in major vascular events with DHA. So the benefits of Marine-derived Omega-three fatty acids, particularly high dose EPA, appear to exceed their lipid lowering effects.

Dr Carolyn Lam:                Wow. Interesting. So Greg, take it home for us. What should we do clinically about this information?

Dr Greg Hundley:             Carolyn, developing drugs that achieve large reductions in VLDL and triglycerides and are targeting patients with high baseline levels of triglycerides would likely increase the probability of showing a meaningful clinical benefit, and fibrates could be considered in patients needing further non-HDLC lowering, being mindful of side effects, as they should offer clinical benefit proportional to the degree of non-HDLC lowering, and if a disproportionate relationship between lipid lowering and cardiovascular risk reduction is validated in ongoing high dose Omega-three fatty acid trials, it will support the hypothesis that confers a unique benefit of this class of agents beyond simply their lipid lowering.

                                                How about that?

Dr Carolyn Lam:                Very nice Greg and I think very balanced and good clinical take home messages. Tell us what else is in the mailbag.

Dr Greg Hundley:             We have so many interesting articles in Circulation and let me just run through a quick list of those that are also in this issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the 50th anniversary of the Dallas Bedrest Study that involve five 20-year-olds that underwent several weeks of bedrest, and he discusses how this informs many of our thoughts regarding the benefits of activity today, and one of his major coauthors is Dr Ben Levine. Our own Josh Beckman reviews the ongoing efforts of physicians to understand the role of paclitaxel coated stents for those undergoing peripheral arterial interventions. Dr Berlinde von Kemp, in our case series, identifies that not all cardiomyopathy, after delivery, is simply postpartum cardiomyopathy. In another article, Dr Anurag Agrawal discusses what's on their mind regarding the use of spirometry as a cardiovascular disease risk assessment tool, should it be incorporated into existing cardiovascular disease risk models.

                                                Then, we have a great letter back and forth discussion from Dr Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three separate letters that discussed the relevance of age of onset for type two diabetes relative to cardiovascular risk. Then, finally our own Carolyn Lam reviews the role of biomarkers in heart failure and preserved ejection fraction.

Dr Carolyn Lam:                Let's hop on to our feature discussion, shall we?

Dr Greg Hundley:             Absolutely.

Dr Greg Hundley:             Welcome everyone to the discussion of our featured article today where we're going to review an excellent study comparing TAVR versus SAVR in patients with aortic stenosis, but also now considering simultaneous coronary artery revascularization. Discussing our article today we have Dr Thomas Engstrøm and then our own associate editor, Dharam Kumbhani. Well Thomas, welcome to our podcast featured article discussion. I wonder if you could start us off with a little background regarding your study. What were your hypotheses, and then tell us a little about your study population and your methods.

Dr Thomas Engstrøm:     Now, as you know, up to 50% of patients that are treated for aortic stenosis have coronary artery disease, and this may be considered as a bystander disease to develop disease, but definitely also adds to the prognosis for the patients. A priority guideline recommends that if you do SAVR, you'll also have significant coronary artery disease. What we don't know is if the complete percutaneous approach is as good as a surgical approach. Maybe do TAVR plus PCI comply with fiber plus CABG. That's the background for the study.

                                                Now, the population involved in this study is the population from the search TAVR trial, which as you know compared TAVR to SAVR in patients that were clinically at intermediate risk and in patients that had severe aortic stenosis. If patient had additional coronary artery disease with a syntax called Bob 22, they were excluded from the trial. We are talking about intermediate risk patients with low syntax score. Of the patients in the TAVR trial, 20% had additional coronary artery disease and were resterilized. In the paper, we compare TAVR plus PCI versus SAVR plus CABG in those patients with significant coronary artery disease.

Dr Greg Hundley:             How did you define the presence or absence of coronary disease? Just real quickly before we get to your results.

Dr Thomas Engstrøm:     This was at the discretion of your operator to define where the patients had coronary artery disease or not. In the paper, patients were defined as having significant diseases. More than 70% of stenotic lesions were present in one or more coronary arteries.

Dr Greg Hundley:             And so can you tell us, Thomas a little about the results of your study?

Dr Thomas Engstrøm:     First of all, the patients that had additional coronary artery disease had a poor prognosis than those that only had valve substitution, which is probably not a surprise. Within those that also had coronary artery disease, TAVR plus PCI appeared to be as good as CABG plus SAVR in terms of the primary endpoint, which was all because mortality or disabling stroke after two years. Then, if you dive more deeply into the endpoint and the number of secondary endpoints were pre-specified, there were no differences regarding any stroke myocardial infraction and in total no differences between what you could call major heart end points. If you look more into detail of the secondary endpoint, there are subtle differences. Patients that were in the SAVR plus CABG had more atrial fibrillation as they also had more acute kidney injury following that treatment. Whereas, in the TAVR plus PCR, more patients had vascular complications and of course had the need for pacemaker implantation. There are differences between the outcome in the two groups, but not in regard of pre-specified primary and more important secondary endpoints.

Dr Greg Hundley:             Dharam, I was wondering if you could help us think about what this means for the field in terms of both from aortic valve replacement, and then also the concomitant management of coronary disease in patients that require aortic valve replacement.

Dr Dharam Kumbhani:   As Thomas just pointed out, I think this is a very important question. This comes up all the time in patients with severe aortic stenosis, being evaluated for best options, and the guidelines have stayed true to this that if somebody has concomitant coronary artery disease, then the guidelines typically would recommend SAVR as the first option because then they can have CABG at the same time. This study really seeks to address a very important knowledge gap in the field, and as he very well pointed out, this does restrict itself a little in terms of the population, because they couldn't have a high syntax score, actually an intermediate or high syntax score, and they need in the trial...I think the main syntax score was eight or nine. I think that is important, but having said that, more than 50% of the patients had multi-vessel disease, and it was really impressive that nearly 15 or 17% still had three vessel PCI even in this arm.

                                                I think it's important for people to recognize that although this was the lowest syntax score, multivessel PCI was still pursued. I think that's definitely an important takeaway from the strike. It's a really important trial. It's one of the very few pieces of information that we have that is prospectively done under the auspices of a big trial like SURTAVI, and with low risk approval in and what this means for patients going forward I think will be very exciting to see how this few devolves.

                                                Thomas, as this field matures, could you walk us through, in terms of did you do the valve first and then the coronaries, or where the coronaries worked on first and then the valve? That's sort of the first question. Can you walk us through how you make those decisions?

Dr Thomas Engstrøm:     It was up to the discretion of the operator whether to do a concomitant procedure, both PCI and TAVR, or to state the procedures in that way that PCI was done first, and this could be done up to seven days before the TAVR. If you compare those two groups, and now numbers become a little bit few, so we can't be conclusive here. It appears that patients that had stage procedures did poorer than those that had concomitant procedures done. Of course, it raises some questions. The prioritization as to do it in one way or the other was that through concomitant procedure, you may introduce too much of stress to the patient. Otherwise, if you do a stage procedure, it's best to do the PCI first, because the actual appearance of the valve may make it more difficult and cumbersome to address the coronary arteries. To sum this up, in the patients that we have, it appeared that a concomitant procedure is safe.

Dr Greg Hundley:             Dharam, tell us, what do you think is the next step forward for this field? What do see as the next study moving forward here?

Dr Dharam Kumbhani:   I think this study really sets the stage for, I think future trials where perhaps we would have... So I'm doing this in this trial. The stratification was done based on whether or not they need to revascularization. I think going forward, again with LOTUS approval here and proliferation of the number of TAVR procedures that are being offered everywhere, I think it will be helpful. This study would set the stage for future studies, where I think you would prospectively have patients with needing an aortic valve replacement and perhaps even complex revascularization, and how that was kind of actually the randomization, which is the stratification strategy, which again was very helpful. These are really among the first few data that we have of this, but I think this kind of sets the stage for future investigations in this space. And then as I briefly alluded to, I think this may help evolve or this may help in the evolution on the guidelines as well.

                                                Thomas, would you like to add anything to that?

Dr Thomas Engstrøm:     Yeah, I completely echo that. Going back to the old syntax trial, it would be very interesting to see if PCI holds through, even in high tunes, syntax scores with newer drug eluting stents, and also of course the question of the diabetics is totally unsolved in this cohort. CABG plus SAVR may turn out to be the best solution, but we still are waiting to see data that can support any of the two strategies in those patient cohorts.

Dr Greg Hundley:             We want to thank Thomas Engstrøm and also our own Dharam Kumbhani. We look forward to seeing you next week.

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


Oct 7, 2019

Dr James de Lemos:        My name is James de Lemos. I'm the executive editor for Circulation and I'll be filling in today for Carolyn Lam and Greg Hundley, and delighted to host the podcast for the annual cardiac surgery themed issue. I'm joined today by Tim Gardner from the University of Pennsylvania who leads the surgical content in Circulation year-round, as well as by Dr Marc Ruel, who's the guest editor for this issue and the Chief of Cardiac Surgery at the University of Ottawa and has really led the development of this issue. Marc, Tim, welcome.

Dr Timothy Gardner:      Thank you.

Dr Marc Ruel:                    Thank you. Good afternoon.

Dr James de Lemos:        And Marc, thanks for all you've done to bring this issue home again this year. It's really wonderful to see this thing develop. Why don't you start us off and tell us how this issue came together and what the purpose of this is? Why do we publish a specific issue focused on cardiac surgery?

Dr Marc Ruel:                    We're really delighted that Circulation has taken the stance as the cardiovascular community's premier cardiovascular journal. I think as an important piece of this is the fact that cardiovascular surgery already has a resurgence intermediate with importance despite new percutaneous options and medical therapies available. There's more and more patients who find himself in need advance path if you will, of an advanced cardiovascular disease and surgery can be performed with safer and better outcomes constantly.

                                                So, I think this issue obviously aims to gather the very best of cardiovascular surgery, not only including cardiac surgery, but also there's actually one of the papers on peripheral vascular surgery.

Dr James de Lemos:        We'll start Tim with you if you don't mind. I'd like to talk about two papers. One from Stanford that focuses on inter-facility transfer of Medicare patients with Type A dissection and then a research letter that studies hospital volume effects with abdominal aortic aneurysm surgery from Salvatore Scali and colleagues at the University of Florida. Can you walk our readers through these papers and lead the discussion on these?

Dr Timothy Gardner:      The first paper focused on inter-facility transfer of Medicare recipients with Type A dissections. First off, underlines the fact that this is a very difficult, serious condition with mortality rates in this series there ranging between about 22 and 30%. And the purpose of the study was to analyze how these Medicare patients with acute aortic Type A aortic dissections are managed and whether the effect of high or low volume hospital experiences influences the mortality. As I think we might expect, patients who receive care at high volume aortic surgery centers have a lower mortality. Then the question is, what is the effect of transfer from a low volume or from a hospital without aortic surgery capabilities? What is the net effect there? The benefit of care and a high volume hospital is pretty clear. The mortality rate is significantly lower and the need to transfer or the actual fact of transfer does not increase the risk to the patient.

                                                It's an interesting challenge because we do know that patients with acute aortic dissection, if their repair or surgery is delayed, we'll have a predictable accumulating mortality. However, what this study shows is that the benefit of transfer and the importance of experience with this complicated aortic surgery. And it really brings up this very challenging issue of regionalization, of acute care or specialized care.

                                                We really struggle with this in so many aspects of surgical care, medical care in general, but especially procedural care. We realize that we need to be able to provide emergency care in many areas and we don't want to suggest that that smaller hospitals may not be able to care for patients with acute complex illnesses. But on the other hand, if transfer can be accomplished and if the availability of high volume experience can be achieved, that this is something that we really need to look at carefully. I think that this study brings that into pretty good view.

Dr Marc Ruel:                    James, I think that Tim has already captured the essence of this paper. The results are impressive in this excellent series and the really carefully led analysis. This is an important paper and it's very thought provoking.

                                                There’re two clans among surgeons. Those that believe that every cardiac surgeon who was named as such should be able to perform safely aortic dissection repair and another client and somewhat sustained or supported by the data from this paper that says that this is a special expertise that should be or regionalized and put through centers of excellence. So this paper would support the latter theory.

Dr James de Lemos:        The next paper, which was a research letter, sort of adds fuel to this fire of regionalization, doesn't it? At least insofar as we're talking about the more complex procedures.

Dr Timothy Gardner:      Yes, this paper studies the hospital volume effects on surgery for abdominal aortic aneurysms, an even more common and somewhat less lethal, but very morbid condition. And this analysis of center volume for care of these patients is complicated even a little bit more because as we know, endovascular repair of abdominal aortic aneurysms is now the most common form of treatment.

                                                Interestingly, in looking at the outcomes in a variety of centers with varying volume procedural volumes, there was no difference in outcomes when endovascular repair was done, but there was inverse relationship between volume and outcomes after classical surgical repair. This really highlight a change that's occurring in vascular surgery where, with endovascular repair being done more commonly, surgeons are having less exposure unless experience with open repairs. This is particularly a challenge for training programs where you have a surgical resident or fellow for two years and he or she may experience relatively few open repairs.

                                                So, this again, the data seems to suggest that higher volume vascular surgery centers, where the numbers of open repairs are done, have better results and that this is not nearly as much, in fact, it wasn't an issue for endovascular treatments, but it again highlights the procedure of volume outcomes relationship. I think this is something we're going to have to deal with both in terms of optimizing patient care, even considering when we're training new or young avascular surgeons, they may have to move to different centers to ensure that they have the kind of exposure to classical surgical treatment for those complex patients who are not candidates for endovascular repair.

Dr James de Lemos:        Let's change gears. We've been talking about two systems of care issues, but let's get back to the complicated patient themselves and talk about a paper Mark from Kato and Pellikka from Mayo Clinic, focusing on hemodynamic and prognostic impact of concomitant mitral stenosis in patients undergoing surgery or TAVR for Aortic Stenosis.

Dr Marc Ruel:                    As you say, this is an intricate clinical problem that we not uncommonly meet when we provide care for patients who have severe aortic stenosis. These are not young patients. These patients in this particular series of 190 patients with severe aortic stenosis, they also had some significant degree of mitral stenosis. These are patients that had a mean age of 76 years. I think we've all encountered these patients estimations, so someone has severe aortic stenosis and has some form of calcific mitral stenosis. And indeed in this series, more often than not, the vast majority of those patients had calcific MS as opposed to a Rheumatic MS. So, a different type of pathology probably to what we see in the elderly patients coming in with some degree of inflow obstruction.

                                                So, the authors took their 190 patients, mostly from the Mayo clinic, but also from Tokyo, about five patients contributed from Japan, and matched in one to two with some controls who also had the same degree of severe aortic stenosis, the same age, same gender, same left ventricular ejection fraction, but didn't have mitral stenosis. And then compare their fate over a couple of years. Essentially, what the authors found is that in patients with severe MS, which was defined as a trans-mitral gradient of equal or higher than four millimeters of mercury, the midterm survival was decreased. The hazard of death was increased by about 90% or so. And there was also a classification, the sub classification based on the fate of the patient with regards to the echocardiographic findings, as to whether the patient truly had mitral stenosis at the time of presentation. So prior to the aortic valve replacement or whether the patient had pseudo-mitral stenosis. How the authors classify this, is those patients in whom the mitral valve area remained less than two centimeters square before and after aortic valve replacement were classified as having true mitral stenosis.

                                                The authors provide a number of maybe predictors, if you will, or correlates perhaps a more appropriately termed as such, of patients who would be generally believed as having true mitral stenosis. And these included, for instance, in the mitral valve area was less than 1.5 centimeters square at the time of presentation, if calcium involved at both the anterior and the posterior leaflet on echo. And there was also the concept of Andler excursion. So, basically the distance between the apex and the analyst of the mitral Valve, half of the patients had true mitral stenosis and the other half saw an increase in the mitral valve area above two centimeters squares after aortic valve replacement.

                                                I think still that we don't have an answer to the question as to whether the mitral valve should already be intervened upon in this series. It was an observational series, so there's no arm where the mitral valve was actually intervened on, and we know that often this intervention is not easy to do if it's by TAVR, there's not a lot we can do on the aortic valve and if it's at surgery, often these patients may have extensive mitral annular calcification, which is not an easy undertaking to fix at the time of surgery.

                                                So, whether these patients, even the ones with true MS are better served by just addressing the aortic valve or adding a mitral valve intervention in addition to the AS treatment still remains an unresolved or unanswered question. But I think this paper helps tremendously with regards to identifying patients who may have the true mitral stenosis concomitant problem at the time of presentation with a severe AS.

Dr James de Lemos:        This was news for me actually. The high prevalence of pseudo MS in this context, I think many of us are very familiar with this with aortic stenosis and low output, but to see this in the context of serial valve lesions was really instructive for me. Tim, what are your thoughts?

Dr Timothy Gardner:      I think this is a really important observation to remind ourselves of in this TAVR era. If you have the heart open and you're doing the aortic valve replacement and you notice this, you can get a picture of this severity of the mitral stenosis or the mitral valve involvement, but I think that in the TAVR era, this finding, this possibility of significant mitral stenosis related to a more severe aortic stenosis has to be accounted for and taken into account.

Dr James de Lemos:        Excellent. The next paper I'd like to talk about is another original article from Shudo and Joe Wu at Stanford. Remarkable series really of almost a thousand heart-lung transplants that were done and reported in UNOS. Tim, can you walk us through this paper and its implications?

Dr Timothy Gardner:      heart-lung transplantation was done first at Stanford and actually by one of my close colleagues. Bruce Reitz in 1981. It was a really an operation and in the tradition of the innovation there in transplant surgery at Stanford. The operation, primarily for patients with end stage lung and heart disease, was done reasonably often at adventuresome and well-experienced transplant centers in the eighties and nineties and it's used less often today because we found that even in patients with end stage lung disease and concomitant ventricular failure that many of those patients can be treated successfully with double lung transplantation.

                                                So, that has resulted in a decline in use of heart-lung block transplantation. The other problem is that as they mentioned in the article that a donor becomes available and you can get two or three patients treated by taking the individual lungs and the heart for three recipients rather than using the whole block for one. That's been another reason why it's been harder to get these heart-lung blocks. But for some patients with end stage heart disease and irretrievable lung disease, this is a great option. There's a few patients with end stage congenital heart disease who have developed irretrievable Eisenmenger's complex with severe pulmonary irreversible form of hypertension who are still candidates for this, but this analysis of the 30 year experience at Stanford and using the UNOS database as well is very interesting and shows the importance of donor selection as a really significant effector of outcomes.

Dr James de Lemos:        Yeah, well I was also struck by the recipient factors too. It looks like selection in both directions is so important. The group that was remarkable to me was the markedly poor outcomes in the group that had heart-lung transplant after ECMO, that five times increase in mortality. That really struck a chord, particularly given what we're seeing now with ECMO accelerating somebody's status on wait lists. I don't know Mark or Tim, do you want to comment?

Dr Timothy Gardner:      That's a very useful observation and where an individual patient ends up on the acuity list as a potential recipient with UNOS rules, it is ECMO support does get them to a higher level of urgency and yet, as is shown in this series, the morbidities or co-morbidities associated with a patient who requires ECMO support prior to transplantation is pretty consequential. And as you said, those were the features of the recipient, the degree of co-morbidities or co-morbidity complications also impact the outcome.

                                                We're still struggling to find the best way to deal with rescue patients both with mechanical support and with transplantation, organ transplantation, and even in the case of heart failure, with destination therapy with mechanical devices, we're still struggling in an area where the challenges are high, and the best practices are not always as well clarified as we would like.

Dr Marc Ruel:                    And I would echo those concerns. I think the prohibitive results that we see after ECMO reflect the reality that there's not a lot of intermediate therapies available for patients who require heart-lung transplants. We have them for the heart now. We can move from ECMO and not go directly to an LVAD or to a transplant because we have implantable axial devices that can be put in percutaneously and basically can arrest the inflammatory response and the major cascade derangements that we see with ECMO.

                                                Unfortunately that is not available to replace both the heart and lungs, so I think there's still some medical advances, surgical advances that are necessary to bridge the gap because that gap right now is real and it's not a gap, it's a cliff.

Dr James de Lemos:        Great discussion gentlemen. Let's talk next Marc, about a research letter that was a case series from Cleveland Clinic from Donnellan and Desai, focusing on a fairly large group of individuals that had received mediastinal radiation therapy previously and then underwent valve surgery for radiation-induced valve disease.

Dr Marc Ruel:                    We were happy to receive this research letter from the Cleveland Clinic because clearly that institution, and maybe a few others around the world, have a special expertise in dealing with the uncommon, but very, very challenging issue of patients with the surgical radiation-induced mitral valve disease. And in fact, radiation-induced carditis. On average, these were patients who were seen about 17 years after their chest irradiation and I guess the main message that can be seen from this paper is that there's often multiple cardiac issues in those patients. They don't just have, for instance, a single valve, in this case the mitral valve, being affected. But the vast majority all tolled of around 80, 85% of patients required not only either another valve, but valve plus bypass or bypass surgery to be performed as well.

                                                So, there are clearly patients where there's been a lot of physical/irradiation damage, not only to the mitral valve, but to the entire heart. It's also, when you look at this series of these 146 patients, you can see that many had an increase in the right ventricular systolic pressure on echo and probably some degree of RV dysfunction as certainly we've seen episodically in our practices.

                                                So, hospital mortality outcomes are pretty good, but the results are humbling. 51% mortality at 2.8 years. And these patients were on average 60 years of age. So looking at U.S. life tables, when someone's 60 years, I've made it to 60, they usually have at least another 20 years on average to live. But these unfortunate patients, despite their cardiac operation performed, having been performed safely, have about an 18% death rate per year.

                                                I think the jury's still out as to which are clear indications to offer these patients surgeries with the humbling results that we see even at a center of excellence by the Cleveland Clinic. But I think this is a foray into a very difficult cardiac problem for which there was limited literature before and certainly that's something that's very relevant as we refer to very advanced cardiac surgical therapies for patients with advanced disease.

Dr James de Lemos:        Mark, you're actually a coauthor on our State-of-the-Art piece, evaluating arterial grafts and CABG, reviewing after the publication of art and radial. What were the main conclusions from your review and interpretation?

Dr Marc Ruel:                    Essentially, there's a discrepancy right now with regards to the use of multiple arterial grafting. The observational series have almost uniformly showed that patients who receive multiple arterial grafts live longer and do better, et cetera, but I think this has to be taken for what it is. There's an inherent indication bias or confounding by indication that goes into allocating that therapy to patients who are perceived to have the potential to do well in the long-term. There may also be an expertise bias at the institutions that provide this and those patients may be receiving better secondary medical therapy or guidelines directed medical therapy, etc. So, maybe a halo effect that comes into play.

                                                In counterpart, the randomized control trials of which the latest was the arterial revascularization trial. Now available with data at 10 years, have shown essentially very little difference which regards to the use of multiple arterial grafts on long-term outcomes. Even looking at cardiac-specific outcomes like myocardial infarction. Actually the more compelling data came from their Radial Alliance, also led by Mario Gaudino who is the author of this, State of the Art paper.

                                                The conclusion of the article is that we need a trial and we need to include the radial artery. The answer may not necessarily lie with the use of mammary arteries, but it may be that the radial artery is more user friendly and more robust. So the new ROMA trial has been designed with that in mind. Comparing one arterial graft versus as many arterial grafts, as long as it's more than one in the test group that the surgeon wants to use. And the surgeon, she or he can use the right internal thoracic artery or radial artery in order to complete the revascularization.

                                                That trial is ongoing. Enrollment is on track and hopefully should provide answers to this very relevant question.

Dr James de Lemos:        You know that discussion about the limitations of clinical trials, Tim, I think leads really nicely into the frame of reference you received from Eugene Blackstone and Cleveland Clinic, doesn't it?

Dr Timothy Gardner:      Yeah, and it was really an article worth everybody reading. It's a short opinion piece and he points out the fact that we really have competing standards for choosing therapy. Sort of the standard traditional evidence based medicine, evidence-based medical care versus precision medicine which focuses on individual patients risk factors and so on. It's sort of the average treatment effect that we may be able to demonstrate well in randomized clinical trials versus real world experience with various therapies based on the risk profile of the patient. It's a really excellent article and as many of us know Gene Blackstone is a very thoughtful student of statistics in surgery and this is, I think, an excellent article. I'm really grateful for his doing this opinion piece for us.

Dr James de Lemos:        The last opinion piece we have is from Mike Farkouh in the group in Toronto. Can you just give the readers and listeners a bullet about what they might expect in that piece?

Dr Marc Ruel:                    I think it's one of the remaining big questions, if you will, in myocardial revascularization as to what should be done with diabetic patients in multi-vessel coronary artery disease who have an acute coronary syndrome and require revascularization. A very well written piece and certainly that instructs what probably the next five years we'll see in terms of big study questions in coronary REVASC.

Dr James de Lemos:        First I'd like to recognize Sarah O'Brien from the Circulation Editorial Office for her tremendous work for pulling this issue together. She's really the glue that brings this issue together every year and thank as well Marc, for your leadership again of this effort and Tim for your ongoing leadership at circulation with our cardiac content and vascular content as well as liaisoning with our surgical colleagues.

                                                Dr Marc, you get the last word. Can you please summarize the thoughts you'd like to leave our listeners with?

Dr Marc Ruel:                    Thank you, James, for your generous comments and also for your support of cardiovascular surgery in and of the team issue. I think again, we have a fantastic issue this year and we really want to gather the very best of cardiovascular surgery and we want to get the highest impact papers. Circulation is home for the best data, the best outcome, say the most interesting answers to important clinical questions that are around cardiovascular surgery.

                                                There's definitely an editorial desire to help with the best of cardiovascular surgery science. And I think I want to again launch a call to cardiac surgical investigators and cardiovascular and surgical investigators in general to consider circulation as your home.

Dr Timothy Gardner:      Yes. And if I could just add to that, not only are we interested in a surgery-themed issue annually that really highlights some of the best articles that we have to publish, but we also want some of the best surgery science during the course of the year. And just remind our surgeon colleagues that the particular advantage to having a paper published in circulation is the exposure of that study to a broad cardiovascular community. Not just surgeons, the predominant readership obviously of circulation, or cardiologists and other cardiovascular specialists. So that's the big advantage you get by having your best work published in circulation. We'd love to see more of it.

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