Circulation April 18, 2017 Issue

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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. Our feature paper this week discusses the very important patient group with myocardial infarction and non-obstructive coronary artery disease, a paper that we will be digging deep into right after these summaries.

The first paper identifies a novel therapeutic target in pulmonary arterial hypertension, and that is nicotinamide phosphoribosyltransferase, a cytozyme which regulates intracellular NAD levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis.

This is a paper from first author Dr. Chen and co-corresponding authors Dr. Machado from University of Illinois Chicago and Dr. Garcia from the University of Arizona. The authors found that plasma and mRNA and protein levels of nicotinamide phosphoribosyltransferase were all increased in the lungs and the isolated pulmonary arterial endothelial cells from patients with pulmonary arterial hypertension.

They were also increased in the lungs of rodent models of pulmonary hypertension. Nicotinamide phosphoribosyltransferase deficient mice were protected from hypoxia mediated pulmonary hypertension; whereas, enhanced activity promoted human arterial smooth muscle cell proliferation via paracrine effect and inhibition of activity attenuated pulmonary hypertension in rats.

This paper, therefore, provides evidence that nicotinamide phosphoribosyltransferase plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

The next study suggests that high sensitivity cardiac troponin T may be an early biochemical signature for clinical and subclinical heart failure. In this study from first author Dr. Seliger, corresponding author Dr. deFilippi, and colleagues from Inova Heart and Vascular Institute, the authors measured high sensitivity cardiac troponin T at baseline among almost five thousand participants in the multi-ethnic study of atherosclerosis MESA cohort, who were initially free of overt cardiovascular disease.

Cardiac magnetic resonance imaging was performed at baseline and repeated 10 years later among 2,831 participants who remain free of interim cardiovascular disease events, among whom 1,723 also received gadolinium enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Results showed that a mild elevation of high sensitivity cardiac troponin T identified subjects at highest risk for an increase in left ventricular mass and end diastolic volume over the next 10 years.

Higher levels also associated with an increased incidence of replacement fibrosis, but with no differentiation between ischemic or non-ischemic fibrosis patterns. For the more high levels remained an independent predictor for incident heart failure, coronary heart disease events and cardiovascular events, independent of underlying left ventricular hypertrophy or ejection faction.

The implications are that myocyte injury, measured with a highly sensitive cardiac specific troponin assay may ultimately be an important early signal used to target therapy to prevent or delay left ventricular remodeling and progression to heart failure.

Does maintenance of cardiovascular risk factors at target eliminate the excess risk of mortality in cardiovascular diseases associated with type 1 diabetes? Well, this question was addressed in the next paper by Dr. Rawshani and colleagues of the Swedish National Diabetes Register in Gothenburg Sweden. The authors compared more than 33,300 patients with type 1 diabetes to more than 166,500 match controls without diabetes from the Swedish National Diabetes Register. They found that patients with type 1 diabetes, with five selected cardiovascular risk factors at target, demonstrated a non-significant access risk of death compared to controls.

These five risk factors included glycated hemoglobin, blood pressure, albuminuria, smoking, and LDL cholesterol. Nonetheless, despite having all risk factors at target, persons with type 1 diabetes still had 82% to 97% elevated risk of myocardial infarction and heart failure respectively. For every incremental risk factor not at target, the excess risk of death in cardiovascular outcomes increased in a graded fashion.

In conclusion, there was a steep graded association between decreasing number of cardiovascular risk factors at target and major adverse cardiovascular outcomes with patients with type 1 diabetes. While achievement of current evidence based target levels of five cardiovascular risk factors markedly reduced or even potentially eliminated the excess mortality risk, these patients remained at higher risk of myocardial infarction and heart failure compared with controls.

The final paper suggests that hemodynamic guided heart failure management may be beneficial in general clinical practice and not just in the context of controlled trials. In this study by Dr. Heywood and colleagues from Scripps Clinic Torrey Pines in La Jolla, California, the authors examined the first 2,000 patients implanted with the novel Pulmonary Artery Pressure Sensor, CardioMEMS, in the general cardiology practice setting.

They found that patients uploaded information an average of every 1.2 days, and that pressures were significantly reduced by remote monitoring using the Pulmonary Artery Sensor where patients with the highest mean pulmonary artery pressures had the highest reduction in pressures. Furthermore, they found that these general use patients experienced a greater reduction in pulmonary artery pressure over time compared to those in the pivotal CHAMPION clinical trial.

The results from this large observational study, therefore, demonstrates hemodynamic heart failure management may be effective in U.S. clinical practice with high rates of patient adherence and effective pressure management.

This paper is accompanied by an excellent editorial by Drs. Gorter, Rienstra, and van Veldhuisen from University Medical Center, Groningen, Netherlands, which really places this paper in the clinical context of heart failure and particularly patients with heart failure and preserved ejection faction

Well that wraps it up for your summaries. Now for our feature discussion.

We're discussing a hugely important emerging issue today. And it's MINOCA, a myocardial infarction with non-obstructive coronary arteries, and a very important paper in today's issue, which really provides the first insight into potential long-term medical therapy in the management of MINOCA.

However, now this issue of MINOCA is quite new and I'm sure new to many of those listening on the line. So, I am with the first and corresponding author of the paper, Dr. Bertil Lindahl from Uppsala Clinical Research Center in Sweden. Welcome.

Dr Bertil Lindahl: Thank You.

Dr Carolyn Lam: And also the associate editor who managed this paper, Dr. Gabriel Steg from Hospital Bichat in Paris, France. Welcome back.

Dr Gabriel Steg: Hello.

Dr Carolyn Lam: Now, we need to start by first understanding what we're talking about. MINOCA ... give us a good definition of what you mean by MINOCA. And does it include the non-coronary causes of AMI, or non-obstructive disease? Does it include myocarditis? Does it include the non-cardiac causes, like pulmonary embolism?

Dr Bertil Lindahl: Our definition of MINOCA used in this paper is that you received the ICD code for acute myocardial infarction. If you have a clinically clear case of myocarditis or Takotsubo and were not included in this analysis. But we know if we look into patients that have got the diagnosis of myocardial infarction ... if you performed, for instance, MRI afterward, you can see that a portion of the patients experience ... between 10 and 30 percent of the MINOCA patients, have evidence of myocarditis, although it was not clinically expected.

So this is a heterogeneous population ... initial diagnosis was myocardial infarction.

Dr Carolyn Lam: Thank you for clarifying what you used in your study. Gabriel, could I just, you know, bring you in on this because you invited an excellent editorial that accompanies this paper. And, basically, it helps to get us past all this terminology you know, MINOCA now. Could you maybe just clarify the overall perspective of what it means?

Dr Gabriel Steg: Yeah. This area is fairly new and we still have a major nomenclature problem. Clearly it's been recognized for many years that patients who have a clinical syndrome of myocardial infarction do not necessarily have obstructive coronary artery disease. At least severe obstructive coronary artery disease. Many patients have mild lesions and some patients apparently have no lesion at all.

Now, over the last few years we've understood that this is really a syndrome. And that under that big umbrella, there are patients who have non-cardiac causes of troponin elevation and chest pain. These should be excluded from MINOCA. If you have pulmonary embolism, this is not MINOCA. This is pulmonary embolism.

The second aspect is there are more subtle distinctions to be made with fairly new entities such as Takotsubo. When this study was started, Takotsubo was an emerging disease concept. And so the authors were not able to properly rule out the Takotsubos and probably a few myocarditis from their data set. We now have learned over the past few years that MRI is an excellent tool to screen MINOCA patients and flush out patients who have myocarditis or Takotsubo, which are not rare. Actually it's a substantial portion of that entity.

And then we're left with what I call the true MINOCA. Now what's fascinating in the study here is really that ... first of all I want to say this is another great study from our Swedish colleagues leveraging their data collection tools, which are remarkable. Really an example to the world.

The second thing is they have collected ten years of data on MINOCA. And they're able to tease out which are the agents that should be using secondary prevention in that population. Elegantly demonstrating with sensitivity analysis and positive and negative controls what are the agents associated with improved outcomes and what are the agents that apparently do not impact outcomes.

So even though at the time they were not able to rule out myocarditis and Takotsubo properly, still the sheer size of their study, long term follow up, and the careful statistical analysis that they've done are remarkable.

Dr Carolyn Lam: I couldn't agree more. And more so in an area that is really emerging in importance. And for which we don't have any prospective clinical trials. I'm correct in saying that, right ? So Bertil, this would be a great point for you to let us know what are the main findings from your study please.

Dr Bertil Lindahl: The main findings are that statins are associated with a beneficial effect on the cardiac event. And also, ACE inhibitors or ARBs , while we were not able to show statistically things you can affect with beta blockers and similarly not with dual anti-platelet treatment. So that's basically the main findings of the study.

Dr Carolyn Lam: May I ask how have these findings personally impacted your clinical practice or do you think the next steps are gaps that need to be addressed first?

Dr Bertil Lindahl: I think that's an ongoing discussion in Sweden now and in our hospital on how this should be applied to clinical practice. Nothing. It will have an effect that statins and ACE Inhibitors or ARBs will be used. I'm not sure whether we still can say that we should not use beta blockers or dual antiplatelet treatment. But I think also that we are now discussing we should do a randomized clinical trial to really tease out whether we should use beta blockers or not or also verifying the findings regarding ACE Inhibitors and ARBs.

So, I think there's always a discussion whether we can really use observation studies for treatment decision. But I think since we don't have any better trials so far I think that this is the best that we can get. So I think it will be used and applied in clinical practice.

Dr Carolyn Lam: Indeed. I really agree with what Gabriel said this is the best available evidence we have now. And my personal take home message was to pay more attention to the statins and the ACE Inhibitors. So congratulations on this great study.

Gabriel, what do you think? What are next steps? I mean, MINOCA's not even in the guidelines now. Our guidelines talk about type 1, type 2, AMI ...how does it all fit in?

Dr Gabriel Steg: Well, we've seen a sea change in the concepts regarding myocardial infarction over the last fifteen years with the advent of troponin and the ability to diagnose new patients that previously we wouldn't even label as an MI.

The second aspect is we've recognized over the years that there are some genuine MI's that don't have severe obstructive coronary artery disease. Now what's interesting is that some of them may have apparently mild obstructive disease. Which presumably is related to coronary dissections, embolism, plaque rupture with thrombosis that disappeared in the interim. And some of them may have actually "clean" coronary arteries and have myocardial infarction related to other mechanisms such as micro vascular mechanisms. What's interesting, and I'd like to ask the opinion of Dr. Lindahl is, these three types of diseases; mildly obstructive disease, coronary dissection, and microvascular angina are all more frequent among women. And I wonder whether you have any insights regarding gender differences in your registry.

Dr Bertil Lindahl: In this study, in the sub-group analysis we saw no significant interaction between gender and the effects. But unfortunately we don't have the registry information between , let's say completely "normal coronary arteries" versus "mildly obstructed coronary arteries". And that's a clear limitation of this study. It will be very interesting to see whether these effects are similar in these two sub-groups.

It seems from other studies that approximately fifty percent of the MINOCA patients that have normal coronary arteries and fifty percent that have mild aortic disease. So this is a limitation of this study and I think that's just something we have to look for in the future. And I hope that we will have in the registry onwards, data on whether this normal or mild coronary artery disease.

Dr Carolyn Lam: Really appreciate that and really appreciate the insights you gentlemen have shared. Any final words or concluding remarks, Gabriel?

Dr Gabriel Steg: Well, again congratulations on the great study. I would refer our readers to the excellent editorial of John Beltrame that accompanies this paper, which reviews the concepts of MINOCA, the nomenclature, and some of the remaining and lingering questions that plague the field. And delineates way forward for studies.

I think it's a fascinating area. I'm sure we're going to hear a lot more, both from the Swedish Heart Registry as well as other data sources. I think we all need to stay tuned to this important area. The prognosis of these patients is not so good, so we need to pay attention to that entity.

Dr Carolyn Lam: Wonderfully put. Well, thank you listeners for joining us this week. Please share this episode with all of your friends. So thank you and join us next week.

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