Feb 12, 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.
Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:
Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.
The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.
Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.
The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.
In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.
On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.
In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.
Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.
To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.
They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.
The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.
They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.
These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.
Well, that wraps it up for our summaries. Now for our feature discussion.
For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.
Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.
Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found?
Dr. Jason Weatherald: This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.
We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective.
Dr. Carolyn Lam: Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them?
Dr. Kelly Chin: I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.
The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.
Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.
I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing.
Dr. Carolyn Lam: Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.
The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason?
Dr. Jason Weatherald: Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.
What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.
I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration.
Dr. Carolyn Lam: Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.
Kelly, what do you think are the real take home messages from this?
Dr. Kelly Chin: I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment.
Dr. Carolyn Lam: Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason?
Dr. Jason Weatherald: I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.
At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.
I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic.
Dr. Kelly Chin: I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.
But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization.
Dr. Carolyn Lam: Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment?
Dr. Jason Weatherald: Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening.
Dr. Carolyn Lam: And Kelly, what do you think should be next steps?
Dr. Kelly Chin: I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.
But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies.
Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in again next week.