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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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Jul 31, 2018

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.

                                                Does measuring baseline BNP add prognostic information in patients undergoing revascularization for left main coronary artery disease? Well, to find out the answers, you have to stay tuned and listen up for our feature discussion coming right up, after these summaries.

                                                The first original paper this week reports a new role for bone morphogenetic protein 9, or BMP9, as an endogenous inhibitor of cardiac fibrosis. Now, we are familiar with transforming growth factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis. TGF-β1 also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. BMP9 is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1.

                                                In the current paper from first author Dr Morine, corresponding author Dr Kapur, from Tufts Medical Center in Boston, and their colleagues. The authors examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. They utilized the thoracic aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. The authors’ results identified a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload. They further showed that treatment with either recombinant BMP9 or inhibiting a high affinity receptor for BMP9 known as endoglin promoted BMP9 activity and limited cardiac fibrosis in heart failure. Thus, this provides a potential novel therapeutic approach for patients with heart failure.

                                                The next paper shows that endothelial C-type natriuretic peptide, or CNP, regulates microcirculatory flow and blood pressure. First author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues from University of Würzburg in Germany analyzed whether vasodilating response to CNP changed along the vascular tree. In other words, whether the guanylyl cyclase–B receptor was expressed in microvascular types of cells. The authors used novel gene-modified mouse models to show that guanylyl cyclase–B cyclic GNP signaling in parasites diminished microcirculatory resistance and arterial blood pressure. In contrast, endothelial, or macrovascular smooth muscle cell guanylyl cyclase–B signaling was not involved. This indicated that CNP participated in the local cross talk between endothelial cells and parasites, thus playing an important role in the maintenance of normal microvascular resistance and blood pressure. Thus, pharmacological augmentation of endogenous CNP signaling in parasites may provide a useful therapeutic tool to combat increased vascular resistance and hypertension.

                                                Has the rapid and exponential growth in transcatheter aortic valve replacement, or TAVR, demand overwhelmed capacity, thus translating to inadequate access and prolonged wait times? Well, the next paper provides some answers. First author, Dr Elbaz-Greener, corresponding author Dr Wijeysundera, from University of Toronto, evaluated temporal transient TAVR wait times and the associated clinical consequences in their population-based study of all TAVR referrals from April 2010 to March 2016 in Ontario, Canada. Their study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusions of the study.

                                                For patients who underwent a TAVR, the estimated median wait time in the post reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability at 80 days of wait-list mortality was 2% and of heart failure hospitalization, 12%, with an increase in events with increased wait times. Thus, post reimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting that the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access.

                                                The final paper shows that patients with type 2 diabetes and a history of heart failure are particularly likely to benefit from treatment with the SGLT2 inhibitor canagliflozin. First author, Dr Rådholm, corresponding author Dr Figtree, from Royal North Shore Hospital in Australia, and colleagues, studied more than 10,000 participants with type 2 diabetes and high cardiovascular risk in the CANVAS Program who were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. Participants with a history of heart failure at baseline constituted 14.4% of the study population and were more frequently women, white, and hypertensive, with a history of prior cardiovascular disease. The benefit of canagliflozin on cardiovascular death and hospitalized heart failure was greater in patients with a prior history of heart failure compared to those without heart failure at baseline with a p for interaction of 0.02. The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in patients with and without heart failure at baseline. Effects were apparent across a broad range of participant subgroups, including those using established treatments for the prevention of heart failure, such as renin-angiotensin-aldosterone system inhibitors, diuretics, and beta-blockers. Thus, patients with type 2 diabetes and a history of heart failure may be particularly likely to benefit from treatment with canagliflozin. The beneficial effects of canagliflozin on heart failure outcomes unlikely to be accrued on top of other therapies for heart failure management.

                                                And that brings us to the end of this week's summaries, now for our feature discussion.

                                                In patients with left main coronary artery disease who are undergoing revascularization, could BNP assessment be that precision medicine tool to aid us in our clinical decision making? Well, I am just so excited to discuss this very topic with the corresponding author for this feature paper, Dr Gregg Stone from Columbia University Medical Center, as well as our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo.

                                                Gregg, it was a super smart idea to look at circulating BNP and how this may associate with outcomes, as well as therapies in the EXCEL trial. Please tell us what inspired you to do this and please tell us what you found.

Dr Gregg Stone:                As everybody knows, BNP has been identified as an important prognostic factor in patients with heart failure and ischemic heart disease. It correlates with both cardiovascular and noncardiovascular mortality. Patients with left main disease are among the highest-risk patients that either interventional cardiologists or cardiac surgeons treat because of the amount of myocardium at risk, they often present in heart failure, and even if they're not in overt heart failure, they can be prone to large severe left ventricular dysfunction. So first we wanted to establish the prognostic utility of BNP in this patient population and then we were interested to see if it might have a role in helping differentiate which patients might have a better prognosis with either PCI or coronary artery bypass graft surgery.

                                                EXCEL is the largest trial to date of left main PCI versus CABG in a randomized format with 1905 enrolled patients. And overall, we found that PCI and CABG had similar rates of deaths, large myocardial infarction, or stroke in 3 years. But of course, there are high risk-patients and low-risk patients buried within those overall aggregate outcomes, and BNP was an important prognostic predictor of overall mortality in the trial. Both cardiovascular and noncardiovascular, but not of any other ischemic end points interestingly. Not myocardial infarction, stent thrombosis, graft occlusion, bleeding, revascularization. But definitely, mortality. Even independent of left ventricular ejection fraction and heart failure status.

                                                Now, when we looked at the outcomes of PCI versus bypass surgery, we actually found a very powerful interaction, such that at relatively lower BNP levels, patients who underwent PCI had a better prognosis and tended to have lower mortality. Where patients with high baseline BNP levels tended to have a better prognosis after surgery.

Dr Carolyn Lam:                You know, Torbjørn, I love your editorial where you contextualize these findings so nicely. Could you do that for us now?

Dr Torbjørn Omland:      First, I would like to congratulate Gregg and his team with this very interesting and very well-done study, and I think Circulation is very fortunate to be able to publish papers like this. We have known for quite a long time that BNP is a strong prognostic indicator across the spectrum of cardiovascular diseases and it seems to be particularly strongly associated with risk of heart failure events, cardiac arrhythmias, and risk of death. And, as shown in the EXCEL trial, the association with left ventricular ejection fraction is actually quite weak, and also the association with ischemic events. So, these findings fit very well with previous observations. The really novel and intriguing finding of this study is the very strong interaction between procedural BNP levels and the effect of the randomized therapies and, as you alluded to, all the investigators have tried to look at this in other more low-risk populations like in the LIPID trial but actually failed to find any significant interaction. It's really a novel and important finding.

Dr Carolyn Lam:                That's true. Does it bring up the question are the natriuretic peptides just a better EF measurement? You mentioned that there was a correlation, what do you think, Gregg?

Dr Torbjørn Stone:          Well, you know, there was a weak correlation between BNP and ejection fraction and history of heart failure but the prognostic utility of BNP in this study and its ability to differentiate between the outcomes of PCI versus CABG in patients with low versus high BNP was actually strongly independent of both congestive heart failure history and acute left ventricular ejection fraction. So, I think the BNP is giving a useful independent information. It's a strong reflector of both atrial and ventricular pressures and volume status, but it also reflects myocardial hypoxia, it may be involved in glycolysis and lipid peroxidation, and other mechanisms that we don't fully understand. There may be elements of diastolic dysfunction that we have not measured in this study and other mechanisms related to prognosis in these patients. So, while EXCEL was not set up to truly differentiate and delve deeply into the mechanisms of our observations, statistically these were strong associations that may prove clinically useful.

Dr Carolyn Lam:                Right, I thought that was so intriguing as well, just the points that you brought up. First, let's just clarify for the audience that when you say low and high you were using a cutoff of 100.

Dr Gregg Stone:                We did use a cutoff of 100 pg per mL as is common, but we also modeled BNP as a continuous measure. And actually the relationships were even stronger when modeled as a log hazard ratio continuous measure, both for mortality and for the primary end point.

Dr Carolyn Lam:                Yeah, that's so cool. And Torbjørn, you talked about this in your editorial as well and I thought your point about the distributions of the ejection fraction versus the distribution of natriuretic peptide, that was very revealing, too. Would you like to explain your thoughts there?

Dr Torbjørn Omland:      I found it very interesting that all of this is clearly a high-risk operation overall. More than 90% actually had what we regard a normal, or at least not a reduced ejection fraction. Whereas the distribution of BNP values were more widely distributed so that actually about 40% of participants had BNP levels above this ratio of 100 pg per mL. And that probably shows that in this population, BNP provides additional and independent information about the status of the myocardium that is not revealed by angiography or ejection fraction measurements.

Dr Carolyn Lam:                That's true, and that's an important point because it added above the SYNTAX score, too, right Gregg?

Dr Gregg Stone:                That's right, it was an independent predictor, and in fact the SYNTAX score and the severity of left main coronary disease did not vary, according to BNP levels, that is. High versus low BNP were equally distributed, not related to the anatomic extent and complexity of coronary artery disease. So, BNP is clearly reflecting a different state of the myocardium in a way that we can't measure with any other available test and that makes it quite a useful biomarker.

Dr Carolyn Lam:                Exactly, so I think I'd like to wrap up with asking you both, you can already see what the potential clinical implications are, right? Which means that perhaps in a similar type of patient where there's equipoise of the revascularization method and has left main disease, maybe we should be using natriuretic peptides to guide our clinical decision making. What do you think are next steps before this is prime time?

Dr Gregg Stone:                Well I can mention that when one makes a decision of the best revascularization modality for patients with extensive multi-vessel or left main coronary artery disease, there are many factors that go into that determination, both clinical, anatomic, is the patient a good candidate for one versus the other revascularization modality, what are the patient's preferences, what's the surgeon's or interventionalist's likelihood of being able to safely get the patient through the procedure and achieve complete revascularization.

                                                The SYNTAX score makes a difference, as does gender and age and kidney disease and COPD and ejection fraction and many other factors. So I think we can now add to that list BNP, although I will say this was a post-hoc study, we only had BNP available in approximately 60% of the patients, and while the outcomes were similar in the patients who we did not versus who we did have BNP, this has to be looked at as hypothesis-generating analysis, and we would love to also see this type of finding replicated in other large datasets. That being said, there are no other large left main or new multi-vessel disease trials that are planned right now to my knowledge, and I think given the breadth of this dataset and its size and scope, I do think that these findings are robust enough to use BNP as one of the clinical factors to consider in revascularization decisions.

Dr Torbjørn Omland:      I actually agree with that and I think ideally, we would, of course, like to see external validation in another dataset and even retrospective randomized study comparing conventional versus BNP-guided strategy but that may not be realistically undertaken. So, I think these are clearly the best data we have and as clinicians need to integrate this in our overall evaluation in making this important decision.

Dr Carolyn Lam:                Yeah, I mean Gregg, could I ask you, do you apply this clinically already?

Dr Gregg Stone:                We have not been before this, although I believe we will now. I believe BNP should be a biomarker that we more routinely measure in patients with ischemic heart disease as well as those with overt congestive heart failure. And again, use as one of the factors of many when making revascularization decisions. And I think it's important to note also that the PCI patients tended to preferentially benefit, in fact with even lower mortality when BNP was lower. Where the surgical patients tended to benefit when BNP was higher. So, it's one factor, not the only factor, but I think it's one additional piece of the puzzle.

Dr Carolyn Lam:                Yeah, I have to say too I mean, after reading this, after reading this awesome editorial, it's hard not to think I should be applying this clinically because it's going to be really hard and take a long time to prove this with more prospective data, for example. Although, external validation and other datasets may be better, this is the largest trial already to show this and show it so clearly with a significant interaction. I think that is striking to me.

                                                Torbjørn maybe I've put you on the spot with the last word, does this change your clinical practice?

Dr Torbjørn Omland:      I agree with Gregg. This will be one of maybe several other factors but I think it's ready for being taken into account when making this sometimes very difficult decision.

Dr Carolyn Lam:                Thank you so much Gregg and Torbjørn for joining me today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

 

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