COMMENTARY

Coronary Microvascular Dysfunction: Common Finding in HFpEF

PROMIS-HFpEF

Ileana L. Piña, MD, MPH; Carolyn S.P. Lam, MBBS, PhD

Disclosures

September 25, 2018

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña from the Albert Einstein College of Medicine in [the Bronx,] New York, and Montefiore Medical Center, also in the Bronx. Today I am at the European Society of Cardiology (ESC). We are starting to wind down this incredibly busy meeting and we are all talking about pacing ourselves. But Dr Carolyn Lam has been generous enough to give us a little time to talk about her study. Carolyn is professor of medicine at the Duke National University in Singapore. She is very involved in our clinical trials—we see each other more often in clinical trial land. Carolyn, welcome, and congratulations on getting your paper accepted.

Carolyn S. P. Lam, MBBS, PhD: Thank you, Ileana. Frankly, this is what I've been waiting for. I'm a fan of your series. Thank you for having me.

Piña: Thank you. We really try to get the good information out.

We've had sessions in my blogs about heart failure with preserved ejection fraction (HFpEF). I've talked about how frustrating it is to take care of these patients because I don't think it's one disease and we keep thinking about it as if it were one disease and all the patients are the same. I don't think that's true, and I think you and I share that concept of it. Tell us about your study and then we can go into more questions.

PROMIS-HFpEF

Lam: One unifying hypothesis that has been put forth is that microvascular dysfunction gives rise to underlying nitric oxide reduction in bioavailability in the endothelium and then a reduction in cyclic guanosine monophosphate (cGMP) by cardiomyocytes and that, etc., leads to left ventricular diastolic function. But a lot of the data behind that Paulus and Tschöpe paradigm of HFpEF[1] actually come from preclinical data or from clinical data that are largely indirect or done in selected prospective referral populations. PROMIS-HFpEF[2] is the first prospective, multicenter, multinational study to show that coronary microvascular dysfunction is really prevalent in prospective HFpEF.

Piña: This is coronary; we are not looking at periphery.

Lam: This is coronary. But it is associated with systemic endothelial dysfunction; we measured that with peripheral arterial tonometry and there is a correlation. It's also related to heart failure severity, indicated by NT-pro BNP (N-terminal pro B-type natriuretic peptide) and related to strain measurements of cardiac dysfunction.

I think this is important because this is the clinical evidence we need to say that coronary microvascular dysfunction or microvascular dysfunction in general is very common and seems to at least be associated with all of the markers of bad disease that we know in HFpEF. Because that then opens the door to treatment options that may be new.

Piña: What did you find in your population?

Lam: First, 75% of them had coronary microvascular dysfunction.

Piña: This is routine HFpEF, with EF > 40%.

Lam: But this was not just routine HFpEF. It was carefully collected prospectively across a few countries: Sweden, Finland, United States, Singapore. We fulfilled all of the major criteria of HFpEF, including raised natriuretic peptide levels. You want the population that really has HFpEF and not just have comorbidities in there.

Piña: But they have comorbidities anyway, don't they?

Lam: They do. One question that comes up, I suppose, is, is this all related to comorbidities? Because that is how the hypothesis came about. We didn't actually find that the comorbidities were independently related to coronary flow reserve (CFR). But I think that's because we actually lacked a comorbidity matched control group. So we only had HFpEF and they all have comorbidities, so it's hard to see that association there. But other studies have included a comorbidity match such as hypertension or diabetes, and they have shown then that HFpEF has more microvascular dysfunction.

Piña: At the end, [CFR] was 75%. Tell us about the testing. You did tonometry, but in the echo you also looked at strain. I happen to be a fan of speckle strain patterns, but our audience may not be as familiar. Tell us a little bit about that and left atrial measurements.

Coronary Flow Reserve

Lam: I will back up to the echo. Echo is how we determined CFR, so that's kind of neat too. It's a validated transthoracic Doppler echo way you can actually pulse the velocity of the left anterior descending artery. The acoustic window needed for that is quite small, but it's even highly feasible in the obese because it's shallow. It's not deep, it's just there. We measure that coronary flow velocity at rest and with adenosine. The blunted increase in velocity we defined as coronary microvascular dysfunction.

We measured it that way, so it's highly feasible that we could do it in this large cohort, and then we also looked at strain. Strain lets us see things that our eyes can't see. It basically indicates that at the myocyte level, things may not be doing so well, even though the entire chamber is still doing okay.

Piña: We know this from cardio-oncology.

Lam: Exactly. You can detect subtle or preclinical changes in its systolic function. The cool thing is that CFR was related to worse left ventricular, right ventricular, and left atrial strain. It really is a promising composite risk marker in HFpEF.

Piña: How hard is it? How long does it take to do an echo like this? We do tons of echos all the time and you know the technicians take their time. But when you're doing these very precise measurements, they take a little longer, I would think.

Lam: They do take a little longer and it's a bit intimidating when you first hear about it. But honestly, we had five sites, and with a bit of training, everybody was doing it without problems. It's actually not that difficult.

Piña: It just takes a little extra training and the techs were doing them. Phenomenal.

[W]e often don't think about heart failure as an inflammatory state and it probably is.

Heart Failure as an Inflammatory State

Piña: We talk about endothelial dysfunction and we talk about cGMP. Do you think that some of the newer drugs that are looking down the pike of cGMP [will work?] Hydralazine and nitrates didn't work.

Lam: I know. I'm going to stick my neck out on the line because all of these trial results are going to come out and then I may have to eat my words. But yes. That sort of legitimizes our approach to maybe raise cGMP, for example. Angiotensin receptor neprilysin inhibitors (ARNIs) are postulated to work that way, too, through particulate guanylate cyclase. The PARAGON-HF trial has finished recruiting and now we're waiting for results. A soluble guanylate cyclase stimulator, vericiguat, is being tested now in VITALITY-HFpEF. So it kind of says, "All right. There may be something there." But perhaps it also opens up anti-inflammatory approaches.

Piña: I find that very tantalizing because we often don't think about heart failure as an inflammatory state and it probably is.

Lam: Yes, and thanks to Paul Ridker’s work and the CANTOS trial,[3] that field is really much alive right now.

Piña: We have all of these conversations about iron deficiency. A lot of my HFpEF patients are also iron deficient. In the appropriate patient, I've been giving intravenous iron because I don't think they absorb it. But I've also been getting ferritins and transferrins. I'm looking for that inflammation. Very often it's there—not that I know what to do with it.

I think we have to strip apart this HFpEF issue. And there may be buckets of patients who respond to one thing and not to something else. Obesity is also an inflammatory state.

Lam: That's right. In my mind I think there are mainly two types. One is the cardiometabolic/diabetic milieu. They tend to be the younger patients. And what we showed in our ASIAN HF registry is that the other kind is the older hypertensive with atrial fibrillation. I think in that bucket it's more fibrosis, hard arteries, hardened heart—that sort of thing.

Piña: Do you think endothelial dysfunction is worse in them?

Lam: I think that has reached fibrosis so it's [already beyond]. And the inflammatory ones I feel [are early].

Piña: It's so interesting that there are more women with this syndrome and women with endothelial dysfunction, and even angina. There has been a lot of talk in this meeting about microvascular changes. What's next for you?

Next Steps

Lam: Next we will address the limitations and the further steps that need to be done. We didn't have outcomes and so on.

Piña: Are you tracking the patients for outcome?

Lam: We'll look at that. Microvascular dysfunction is a bit of a bucket. With a high filling pressure you may get some; with inflammation you may get some. So we're going to look more closely at biomarkers to maybe try to tease that apart. And then, of course, maybe we'll do some pilot trials. Let's look at the ones that are coming up, and I think there are a lot more [agents] in the pipeline. Once we know that, that is the pathway.

Piña: Well, it's an opening. Thank you so much for your time. I wish you lots of luck and I'm sure I'll be seeing you very soon.

And that's it for us today. I want to thank Prof Lam for being with us. I hope this helps you in your practice. Take a look at these patients—it's not just one group. Try to tease apart some of these other issues that an individual patient may be going through, and maybe you can apply therapies to those individual patients.

'Til next time, this is Ileana Piña, signing off. Thank you for being with me.

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