Chapters Transcript Limitations of the Coronary Angiogram: More than Meets the Eye – Cardiology Grand Rounds William Fearon, MD, of Stanford University Medical Center presents Limitations of the Coronary Angiogram: More than Meets the Eye. WILLIAM FEARON: I'll start off just showing my conflicts of interest of pertinence, particularly to this talk, is that I received grant support from Saint Jude Medical, which is one of the makers of the coronary pressure wire, which I'll be talking a lot about. I thought I'd start with this little vignette. Those of you have kids, little kids in particular, may recognize this series of stories by Ian Falconer, one of the cartoonists for The New Yorker magazine, about this pig, Olivia, and her various misadventures. And in this particular story, she's searching on a dark and stormy night for her favorite missing toy. And she hears some noise coming from an adjacent room. And she goes to investigate. And she sees this ferocious shadow on the wall, which is quite scary. But then on further investigation, she realizes that the source of it is her harmless pet dog, and that he's chewed her toy to bits. And the reason I show this is because as an interventional cardiologist, in the cath lab on a daily basis we're seeing these shadows, the coronary angiograms. And we have to try to figure out which ones are the ferocious ones and which ones are the benign ones. And for example, in this case, you see sort of a moderate-looking LAD lesion there on the left and a more severe right coronary lesion. And the question is, which one's the culprit for this 66-year-old's angina? And we can use adjunctive techniques like the coronary pressure wire to measure fractional flow reserve. And in this case, that right coronary lesion has an FFR of 0.85. And we'll talk about what that means. But it's not significant. And that lesion can be managed medically very safely and doesn't need a stent, whereas this LAD, which may not have looked quite as severe based on the angiogram is quite significant based on FFR assessment at 0.68. And therefore would likely do better with revascularization, as we'll discuss. So what I'd like to go through in the next 40 minutes or so, briefly talk a little bit about coronary flow reserve, and then spend more time on fractional flow reserve, and then finish up talking about something we've been working on for the past decade or so called the index of microcirculatory resistance. So for the fellows, as a little bit of a review, when we're talking about coronary physiology, the at rest, there is some basal resting tone. The microvasculature, the pre-arterials, and arterials have the ability to dilate and constrict at a moment's notice, depending on the perfusion pressure and the metabolic milieu, and to regulate blood flow to myocardium. During exercise or after administering invasive dilator, we have maximal dilation of the microvasculature and blood flow increases. And that increase in blood flow, the ratio of the peak flow to the resting flow, is called the coronary flow reserve, or CFR. And normally, it's well above two, in the three, four, or five range. When you have a diseased epicardial vessel, you can have a drop in pressure. And this drop in perfusion pressure, the microvasculature responds by partially vasodilating to allow improved blood flow to the myocardium, such that then when you exercise or give a vasodilator, the increased flow from the further vasodilation is blunted. And so your coronary flow reserve is less, in this case around 1.5 or so. Now, coronary flow reserve can be measured noninvasively. In the cath lab, we can also measure it with a Doppler wire. Because velocity is proportional to flow. And this is an example from our animal lab. It's actually from a pig, where we have the peak flow on the right hand side and the resting flow. And it's 45 over 16 equals 2.9. And that's the coronary flow reserve. So that has been around for many years. But there are a number of limitations of CFR. In particular, there isn't a clearly defined value. So below two is generally considered abnormal. But in one patient, a CFR of three may be normal. And in another patient, it may be five. And that limits its clinical applicability. It's also affected by resting hemodynamics. Because resting flow is part of the equation, if you measure CFR in a patient one day. And the patient's heart rate is 60 and then the next day it's 100, you can get very different values because the resting flow will be different. Same thing with blood pressure and contractility. It can be technically difficult, particularly with the Doppler wire in the cath lab, to get good signals. And probably most importantly, CFR interrogates the entire circulation. And that can be helpful in some cases. But in the cath lab, if you're, for example, interested in whether or not the epicardial vessel is the culprit for the patient's ischemia and symptoms, you can be misled by CFR. Because if there's diabetes, or hypertension, or previous MI, you can have microvascular dysfunction, which will affect your CFR and give you a lower value. And it may not be due to the epicardial vessel. So for a number of reasons, including ones I just showed, about 20 years ago, Nico Pijls and Bernard de Bruyne, two European cardiologists, derived and defined fractional flow reserve. It's defined as the maximum flow down the vessel in the presence of a stenosis, compared to the maximum flow in the hypothetical or theoretical absence of the stenosis. And this is how it looks in equation form. If you think of coronary flow being equal to pressure divided by resistance, and if we give nitroglycerin and adenosine to dilate the epicardial and microcirculation and minimize resistance, and sort of take it out of the equation, then coronary flow becomes proportional to pressure. And our equation for FFR can be the coronary pressure in the presence of the stenosis, compared to the pressure and the theoretical absence. If we look at this cartoon, this is the aorta, the epicardial vessel, the microcirculation and venous system. One key concept is that in a normal epicardial vessel, there's very little loss of pressure down the vessel. So the distal pressure is equal to the proximal pressure. And the reason this is important is because then in a diseased vessel when we want to calculate FFR, we want to look at the distal pressure in the presence of the stenosis and compare it to what the distal pressure would be in the absence of the stenosis. Well, that's difficult to do without treating the lesion. But you can estimate what the distal pressure would be by measuring the proximal pressure. Because it's a reflection of what the distal pressure would be if the stenosis weren't there. And so FFR simply becomes the PD, or distal pressure divided by PA, or the aortic or proximal pressure, again, during maximal hyperemia. And so it's the fraction of flow that's getting to the heart compared to what should be getting there. How we do this in the cath lab, we use a miniaturized pressure sensor on a regular angioplasty guidewire, place that in the distal vessel. And in this case, there's a small resting gradient. And then adenosine is administered intracoronary. There's increase in flow and an increase in the gradient. And you look at the mean distal pressure here, 60 divided by the mean proximal pressure of heart, 100. So the FFR is 0.60, meaning 60% of the flow that should be getting to that part of the heart is actually getting there. So how does FFR different from CFR? Using this analogy of a wine bottle, where the bottleneck represents the epicardial stenosis, and our ability to tilt the bottle and pour it represents the health of the microvasculature, you see that CFR, again, is hyperemic flow, or peak flow divided by resting flow. So it incorporates both your ability to tilt the bottle-- you know, how healthy is microcirculation-- as well as the bottleneck. FFR, on the other hand, is the hyperemic flow in the presence of the bottleneck, or stenosis, compared to the hyperemic flow in the theoretical absence. And so because both are measured at hyperemia, the impact of the microcirculation is taken out of the equation. And we're just looking at the effect of the bottleneck, or the epicardial stenosis. So FFR is specific for the epicardial vessel. It's, in a sense, independent of the microcirculation, whereas CFR interrogates the entire system. Other unique things about FFR is that it has a clearly defined normal value of 1.0 in every patient and every vessel, which is an advantage. It also has a narrow ischemic threshold between 0.75 0.80, which we'll talk a little bit about. It's not affected by resting hemodynamics. So you can change heart rate and blood pressure and that doesn't have an effect on it. And it's relatively easy to perform. The landmark study validating FFR was performed by Nico Pijls and Bernard De Bruyne and published in the New England Journal in 1996. And in this study, they interrogated 45 patients who had intermediate single vessel coronary disease. And one of the questions was, well, what do we use as a gold standard for diagnosing ischemia? And to get around the fact that no noninvasive test is perfectly accurate, they used three different noninvasive tests. And using Bayes' theorem, if each has an 80% accuracy and you rely on all three, any one of them has to be positive, you can increase your accuracy to over 95%. And they found that if the FFR was below 0.75, at least one test was abnormal, meaning ischemia was present in every case. So there's 100% specificity. And there is a very high sensitivity. After this study, a number of other studies came along and showed that you could increase that cut off value to 0.80 without really affecting the specificity too much, and with increasing your sensitivity. So there's a bit of a gray zone. In general, if it's above 0.80, we think there's no significant ischemia, and below 0.75 we know there is, and then a little gray zone for clinical judgment in between. So one of the next key questions was, well, can we rely on this technique to safely decide not to intervene on a lesion? Meaning if you have a 60% stenosis and the FFR is above the cutoff value, is it OK to leave it alone and treat it medically? That's hard for interventional cardiologists who like to put in stents. The first big study looking at this was the DEFER trial, which was a randomized trial including 181 patients, all of whom had intermediate lesions that were not hemodynamically significant based on FFR 0.75 or greater. And they randomized the patients to either performance of PCI anyway or medical therapy. And this slide shows the five year death and MI rate. And you see that they're not significantly different. But numerically, the defer group had a lower than-- or less than half the rate of death and MI compared to the perform group. So this was very reassuring, that it looks like it's safe to defer these lesions. So why do we need FFR in the cath lab when we have noninvasive tests? I think the key thing is that we want to identify which lesions are causing ischemia, and then try to relieve the ischemia, both from the symptom standpoint for the patient, but also from the prognostic standpoint. And this slide shows how nuclear perfusion scans in 718 patients, the death and MI rate is clearly affected by the severity of ischemia that's present. It's interesting, though, that more recent data, these are just coming out in press in JACC Interventions, this is from the COURAGE study group, again looking at nuclear perfusion scan results and showing that, at least in their cohort, the severity of the ischemia didn't seem to correlate well with future events. And this may be because there are more multivessel disease patients included. And we've seen this. This is a sub study we did from the FAME trial, which we'll talk about in more detail, where we compared in patients with multivessel disease, the result of the nuclear scan to FFR. And what you see is that there are a significant minority of nuclear scans that appear to be normal in a certain territory, yet the FFR of the vessels attending that region is abnormal or ischemic. Likewise, there are some areas where the FFR is not ischemic, yet it's a region that shows up as being reversible ischemia. And I think many of us who are in the cath lab see this on a daily basis, where the nuclear scan may be abnormal. And that brings a patient to the lab. But it doesn't necessarily guide us as to which area is the culprit for the patient's symptoms. And we need more specific tests to do that. Some people say, well, I can just rely on the angiogram. You know, once the patient's in the cath lab, the angiogram will tell me which way to go. But you see there's plenty of studies like this one in 213 patients who have intermediate left main, where two experienced operators were asked to say, is that left main significant or not? And then FFR was measured. And the results were compared. And you see how poorly the operators performed at their ability to predict which lesion would be significant. So we can't rely on our eyeball. Even using quantitative techniques like quantitative coronary angiography isn't very useful. Certainly, if you have a very mild stenosis, less than 30%, or a very severe one, you know, 80, 90% or greater, there's a good correlation between the stenosis severity and at the FFR value. But most of the lesions that we encounter fall in that intermediate range. And there it's really dealer's choice which one will be significant and which one won't. So another reason why we need FFR came from the results of the FAME trial. Fame stands for fractional flow reserve versus angiography for multivessel evaluation. And in this study, was a multi-center international study, where we looked at patients who had at least two or three vessel coronary disease, meaning you had to have 50% or greater narrowing. And the operator had to feel that those lesions required stenting based on the angiographic appearance, as well as any noninvasive data. Then the patient was randomized to either angio-guided PCI, which was the way of doing things at the time, where the operator would go ahead and stent whichever lesions had been identified based on angiogram or to FFR-guided strategy, where FFR was first measured. And only if it was below 0.80 or less than or equal to 0.80 would stenting be performed. The primary endpoint was a composite of death, MI, and repeat revascularization at one year. About 1,000 patients were included. And there were about three lesions per patient. The first main finding was that the FFR-guided group received significantly fewer stents compared to the angio-guided group, primary because these lesions weren't physiologically significant. Even though they had FFR measured, the procedure time was no different. So you end up spending a little more time measuring FFR. But you save time by avoiding unnecessary stenting. The cost of the procedure, or excuse me, the amount of contrast used. And the costs were significant less. And there tended to be a shorter hospital stay. When we look at the primary outcome, major adverse cardiac events at one year, you see that it was significantly reduced in the FFR-guided patients. And this was due to a relative reduction across all components of the composite. And if you look at just death and MI alone, just hard endpoints, that was also significantly reduced. And the reason behind this is thought to be that, again, only the ischemic lesions were getting stented. So you can maximize the benefit of your stent. And the nonischemic ones could be treated medically. And you could avoid the downside or the risk of unnecessary stents. When you look at the two year outcomes, there continues to be separation of the curves. And the death and MI rate continue to be significantly reduced. One of the questions that you might ask, sort of like what was shown in the DEFER trial, is well, what about those lesions that looked significant that the operator then decided not to treat? And in the FFR-guided patients, there were about 500 lesions that fell into that category that were deferred. And over two years, there were nine late myocardial infarctions. Eight of them turned out to be due to a previously place stent, or to actually a new lesion that hadn't been identified at the original angiogram. So only one myocardial infarction was due to an originally deferred lesion, or 0.2%. So again, reassuring data that these hemodynamically insignificant lesions can be safely managed, at least in the short term, with medical therapy. Another important component of FAME was the cost effectiveness analysis. And the pressure wire certainly costs money, as does adenosine. But again, by avoiding unnecessary drug-eluting stents, FFR-guided PCI saved over $2,000 per patient. Also, because of fewer adverse events, there is savings. So that the strategy is one of those unique ones that not only improves outcomes, but also saves money and falls into this bottom right hand quadrant of the bootstrap analysis. Another concept that we're learning about from FAME is this difference between anatomic and functional coronary disease. Of course, because it was multivessel disease patients, there were a large number who had angiographic three vessel disease. But then after FFR is measured, you see that the majority actually only have one or two vessel functional CAD. This becomes important when we decide about which patients we're going to refer, for example, to bypass surgery versus PCI. We rely to some degree on scoring systems, like the SYNTAX score, which basically gauges how severe or complex the disease is based on the angiographic appearance of the lesions. But because these scoring systems are angiography-based, they're inherently limited by the accuracy of the angiogram. And even so, they have been shown to have some predictive value and are making their way into appropriate use criteria and guidelines. For example, here you see patients who have a high SYNTAX score above the lowest tertile, above 22 or higher. CABG is recommended over PCI, whereas lower SYNTAX score, you might consider PCI. So we wondered whether or not we could enhance the SYNTAX score by incorporating FFR into it and calculating the so-called functional SYNTAX score. And this might convert high or medium risk patients to a lower risk group. And it might improve our risk stratification of patients with multivessel disease undergoing PCI. And I'll show an example of a case where this can be applied. This is a patient with exertional angina, stable angina. And again, you see this very high grade LAD, proximal ostial LAD disease. You don't need FFR to determine whether or not that's significant. That's clearly a problem. However, the patient also has occlusion of the mid circumflex, shown there on the left hand panel. And then the right coronary, there are tandem lesions, with the distal one involving this bifurcation of the right coronary here. So when we calculate the SYNTAX score, it comes out somewhere around 26, in the middle tertile. And you might consider bypass surgery in a patient like this. However, we measure FFR on that right coronary artery. And a bit surprisingly, it's almost normal, 0.91, but clearly above the ischemic threshold. So if we subtract the right coronary from the SYNTAX score to calculate the functional SYNTAX score, it turns out to be lower, around 18 or 19, so kind of in the lowest tertile. And in this case, we elected to just go ahead and stent that proximal LAD. And the patient had relief of his symptoms and has been doing well after that. So in the study that Chang-Wook Nam, who is a South Korean interventional cardiologist doing research with us for a while, led, he calculated the SYNTAX score in the 500 or so patients in the FFR-guided arm of FAME and divided them up into a high, medium, and low SYNTAX score tertiles without taking into account FFR, and then recalculated the functional SYNTAX score, subtracting any lesions that had FFRs that were not ischemic. And as you can see, over a third of patients moved from a higher risk group to a lower risk group. But I think what's more important is that when we look at the predicted value of this functional SYNTAX score for discriminating the risk for death and MI, it outperformed the classic SYNTAX score. And importantly, the percent that fell into the high risk category decreased. And the amount that fell into the lower risk increased. And so again, this suggests that we can shift patients that are higher risk to lower risk. And perhaps manage these patients with a percutaneous route, as opposed to sending them to bypass. We're going to now test this strategy prospectively in the FAME three trial, which is looking at patients with three vessel disease and randomizing them to FFR-guided guided PCI with current generation drug-eluting stents, versus bypass, kind of a redo of the SYNTAX study, but instead using FFR and using current generation stents. One of the criticisms of the FAME trial was that there wasn't a medical therapy arm. Now, FAME did include unstable patients. About a third had acute coronary syndromes. And there's not as much debate there about using percutaneous intervention. But in stable patients, we all are familiar with the COURAGE trial, which showed that medical therapy seems to perform just as well as PCI with respect to the rate of death and MI during follow up. But one could argue that if the PCI in COURAGE had been guided by FFR, as opposed to by angiography, maybe there would've been lower death and MI rates, like we saw in the FAME trial. And so that served as the basis for the FAME two study, to compare whether or not in stable patients with single or multivessel coronary disease, using an FFR-guided approach would improve outcomes. And the key difference between FAME two and studies like COURAGE is that FFR was measured up front in all of the target lesions. And this is important. Because if all lesions had FFR above 0.80, then the group went into a registry. And this turned out to be about a quarter of patients. And these are patients who had angiographic disease that likely would have been enrolled in studies like COURAGE. But these are also patients that we know do very well with medical therapy. Because their lesions aren't hemodynamically significant. On the other hand, if the patient had at least one stenosis with an FFR of 0.80 or lower, then the patient went into the randomized portion of the study and was randomized to either PCI or medical therapy. And in this way, the population was enriched with truly ischemic disease, and to perhaps optimize the benefit of, or if there is any benefit, of PCI. The primary endpoint was death, MI, and urgent revascularization at two years. This is a case that we enrolled, just as an example, a patient with moderate to severe sort of proximal mid LAD disease, and moderate right coronary disease, and some apical ischemia. In this case, FFR was measured. And that right coronary, which again in some other studies would have likely been stented, had an FFR of 0.89. And so that was treated medically, whereas the LAD highly significant, 0.51. This patient ended up being randomized to stenting, or to the PCI arm, and so had PCI of the LAD. FAME two was stopped early by the DSMB because of a significantly higher rate occurring in the medical therapy arm of the composite endpoint. And what we see when we look at the Kaplan-Meier curve is that the registry group, so these are patients who had angiographic disease, but none of the lesions had significant FFRs. And they were all managed medically. They did very well. They had a low event rate. And a fairly similar group of patients who also had angiographic disease but was physiologically significant based on FFR. So they had significant ischemia. They were also treated medically in the randomized portion of the study. And they had a much higher event rate. The patients who are identical to the red line, they had FFR-positive lesions, but underwent PCI, had a bit of a blip early on from periprocedural events, but then a very flat curve that ended up mimicking the non-ischemic registry patients. So once the ischemia was relieved, their even rate was very similar. Now this was driven by a much higher rate of urgent revascularization. The differences in death and MI were not significant between two groups, the medical therapy and the PCI arm. And that's been one of the criticisms of FAME two. Because urgent revascularization is considered a bit of a softer endpoint. When we look at the reasons for urgent revascularization, about half were due to a very objective finding, such as a myocardial infarction or acute coronary syndrome with EKG changes. The other half were due to unstable angina. Now, this was adjudicated in a very strict fashion by a clinical events committee with narratives about each patient that they reviewed to determine whether or not it was truly unstable. And they were blinded to the treatment assignment. But if you subtract those out, because they might be considered more subjective, there's still a highly significant difference in the rate of urgent revascularization between the two groups. Now, another interesting finding from FAME two, this is just looking at the medically treated patients, those in the registry, as well as those in the randomized portion. And you see this relationship between how severe the FFR is, or how much ischemia there is, and the target lesion failure rate, so the rate of death, MI, or ischemia-driven revascularization. And you see that there is this a clear correlation. The more severe the ischemia, the higher the event rate. So this sort of supports the hypothesis that if we can identify the truly ischemic lesions, those are the ones that might benefit the most from revascularization. Another sub study or analysis from FAME two is this landmark analysis, looking at just the rate of death and MI. And this starting at seven days, meaning we subtract all the events that occur during the first week, the periprocedural MIs primarily that occur from the PCI arm, and then look at future events. And you see that the PCI arm has a very flat event rate. But the medical therapy patients continued to accrue primarily spontaneous MIs, such that at one year, there's almost a significant difference between the two arms. And the reason I show this is because there are data to suggest that it's these spontaneous MIs that are they dangerous ones and not the periprocedural MIs. This is a study from ACUITY trial, where over 7,000 patients, looking at the independent predictors of subsequent mortality, and you see that periprocedural MI was not a significant predictor. But the spontaneous occurring MIs really were. Because there wasn't any dramatic difference in death and MI between the two arms, the cost effectiveness of the strategy becomes even more relevant. And we just looked at this in the FAME two trial. And as you would imagine, early on there's a significant difference in cost because of the cost of drug-eluting stenting. But during the first year, there's a catch up from the medical therapy arm because of the events occurring, such that at one year, the difference in cost is less than half what it was at baseline. And when you look at the quality of life improvement that the PCI arm gets from symptom relief and fewer adverse events, and then put that into the equation to calculate the cost effectiveness and perform this bootstrap simulation, you see that about 80% have a value that falls below the $50,000 quality of life year willingness-to-pay threshold, and almost 100% below the $100,000 quality threshold, so a fairly attractive finding for FFR-guided PCI compared to medical therapy in these patients. Now, there are a number a limitations of FFR, which I haven't really discussed. It's invasive. It assumes that microvascular resistance is minimal and constant. So in the setting, for example, of an ST elevation MI, where there is stunning and changes in the microvasculature, FFR is not recommend to be used. There is this gray zone, which I talked about, which can be problematic at times. And there are potential pitfalls, technical issues, which I haven't really gone into, but you need to be aware of. So we focused a lot on the epicardial artery. And the remainder of the talk, I wanted to now spend a little time on the microvasculature. Because it's been an interest of mine and something that we've been working on for the past 10 years or so. Because of the issues I mentioned with CFR, it seemed apparent that it would be nice to have an index in the cath lab that's specific for the microvasculature. And so we've been working on this Index of Microcirculatory Resistance, or IMR. The idea behind this is that it would be readily available in the cath lab. It would be specific for the microvasculature, independent of the epicardial vessel, quantitative, and reproducible, and predictive of outcomes. And the theory behind this stems from the fact that the pressure wire, with the appropriate software, the pressure sensor can also act as a thermistor. And this was first tested as a way to measure coronary flow reserve using a thermodilution technique. You can inject room temperature saline and a thermodilution curve is created. And you can calculate the mean transit time of that saline down the vessel. And that's a reflection of coronary flow. It's inversely proportional to coronary flow. And so we applied that concept to derive IMR, which is basically looking at resistance in the microvasculature. So we look at the change in pressure, the distal coronary pressure minus the venous pressure, divided by the flow across the microvasculature. Now in general, the venous pressure is negligible compared to distal coronary. So to simplify things, we eliminate that from the equation. And flow we can estimate using this thermodilution technique. So we can measure IMR by taking the distal coronary pressure measured with the pressure wire and dividing it by the inverse of the mean transit time. We're multiplying it by the transit time. And we do this during maximal hyperemia, again to avoid the effect resting hemodynamics, and also to calculate the minimum achievable resistance. Because we think that's a reflection of the health of the microcirculation. And the way it's done is fairly simple. You use the same set up to measure FFR, but you also inject three times room temperature saline and calculate a resting time, and then do it during hyperemia. And taking the resting and hyperemic time, you can calculate the CFR, if you're interested in it. And you can also calculate the IMR by taking the hyperemic time and multiplying it by the distal pressure. In this case, it's 33. And we and others have found that less than 25 is generally considered a normal IMR. And above 25 or so is abnormal. We first looked at this in our animal lab, where we took an open chest pig model. And we put a flow probe around the LAD to calculate the true flow and true microvascular resistance. And we had an occluder to create variable epicardial stenoses to see if it was independent of the epicardial vessel. And we embolized microspheres down the LAD to create microvascular disruption. And we found that IMR did increase with microvascular disruption. And the true microvascular resistance also increased in a similar fashion. When we looked at the impact of an epicardial stenosis, the percent change after disruption of the microcirculation was no different between true IMR, or true microvascular resistance and IMR. And also, it didn't matter really whether a stenosis was present or not. The next question was, how reproducible is this technique? And Martin Ng, who was one of our interventional fellows, led this study, where we take about 15 or 20 patients who had lesions that we were interrogating. And we measured FFR as well as IMR and CFR at baseline, and then rapidly paced the right ventricle 110 beats per minute and recalculated the indices. And you see that CFR dropped significantly, whereas IMR and FFR were stable. We also gave nitroprusside to change blood pressure. And again, CFR tended to decrease. IMR and FFR were stable. And we gave dobutamine to increase contractility. And CFR dropped really significantly in this case. But IMR and FFR stayed the same. And so this was reassuring that IMR seems to be very reproducible and independent of the changes in hemodynamics. But why do we even care? Why do we need something to look at the microcirculation? Well, we're learning that the microcirculation is important in predicting outcomes in some patients. For example, this study from the [INAUDIBLE] group looked at 189 women who had chest pain and normal-appearing coronaries, and measured CFR using a Doppler wire, and found that those patients with a lower CFR had a higher, significantly higher event rate compared to those with a more normal microvascular function. So it could be important to identify these patients. But as I mentioned, there's issues with CFR. And so we're interested in whether IMR may be a better predictor. I'll show a few examples of patients that you encounter on a daily basis in the cath lab. This is a 65-year-old man with risk factors, chest pain, and an abnormal stress echo. His LAD here is somewhat tortuous. But there's no real fixed stenosis that's apparent. When we look more closely, we see that the IMR is normal at nine. So there doesn't seem to be microvascular dysfunction. The CFR is normal at 5.3. And the FFR is above the ischemic threshold. So in this case, you might conclude that it's a false positive stress test, and reassure the patient, and avoid unnecessary further testing or medical therapy. Now, this patient, also a middle-aged man with risk factors who gets chest pain with emotional stress and has septal ischemia on a nuclear scan. Again, a fairly unimpressive LAD without any real fixed stenosis. When we measure IMR in this case, however, it's quite high at 53. The CFR is kind of in the borderline range, 2.9. And the FFR is above the ischemic threshold. So this would suggest that the epicardial vessel is OK. But there is microvascular dysfunction. And you might be more aggressive with statin therapy, or perhaps ACE inhibitor or other measures that you think improve microvascular dysfunction. And you can also tell the patient that we think we found out what's causing your symptoms, as opposed to just saying, oh, you've got normal coronaries. You know, it's in your head or anxiety. And here's another case, 68-year-old man, multiple risk factors, with actually a negative noninvasive test but increasing classic angina. Here, you might argue that the mid LAD has some irregularity. But again, there's no critical-appearing stenosis. When we measure IMR, it's completely normal at eight. The CFR is sort of in that borderline range, 2.7. The FFR, however, is quite abnormal, 0.53, suggesting that there is significant epicardial disease. We can do a slope pullback of a pressure wire, which can be quite useful to determine whether or not there's a focal step up in the gradient, or whether it's just diffuse disease. And what you see here, the yellow line represents the sort of beat-to-beat FFR. There's no real jump. It's just a gradual loss of the pressure gradient, suggesting diffuse disease. And when we do intravascular ultrasound, we see just that. This dark spot represents the probe. And then the vessel is outlined here. And then in here, this is around three to six o'clock, is some eccentric plaque, which isn't really compromising the lumen. But it's diffuse throughout the vessel. It becomes a little more concentric as the probe is pulled back more proximally. But again, you see that the lumen is preserved. So the angiogram looks OK. Yet, there's this moderate diffuse disease throughout that's likely causing the ischemia in the patient's symptoms. So again, you can tell the patient, you know, we found out. You may not want to put a full metal jacket of stent in. You could consider putting a LIMA to the LAD. But anyway, you can figure out exactly what the problem is. So Jennifer Tremmel, who is one of my interventional colleagues, has been spearheading this study, where we've been looking at a series of patients with chest pain and often abnormal stress tests who are found to have normal-appearing coronaries. And in these cases, we measure FFR, IMR, CFR, perform IVUS, and also look at endothelial function with the acetylcholine down the LAD, all part of a research study. The findings so far that these are generally younger patients, predominantly women. They do have the typical array of risk factors. When we look at the average IMR, it's around 20. About a fifth of patients have abnormal microvascular function. And these patients more commonly have typical angina, and more commonly have a positive stress test. And the predictors of microvascular dysfunction are age, the older patients having it more often, BMI, and having typical angina. Only a small percent, about 4%, had an abnormal FFR. I actually thought this might be a little higher, that we'd have more patients with diffuse disease. 44% had evidence of endothelial dysfunction based on vasoconstriction with acetylcholine. 44% had a myocardial bridge, defined by IVUS. I think probably the most important finding is the group that didn't have any of these abnormalities, so 42% percent had a, basically a normal FFR, normal IMR, and no endothelial dysfunction. And about a third had none of those and no bridge. And I think this is important. Because these are the patients who might continually come back and visit us in the ER or the cath lab. And once we've done this analysis, we can say, you know, your coronaries are OK. This is not coming from the heart, and focus on other areas of treatment. So that's one area where I think the microvasculature is important. Another area that's emerging are patients who are stable that were performing PCI. And it turns out that IMR can identify those that are likely to have a periprocedural event. This is one study where IMR was measured in patients. They were basically looking at direct stenting versus conventional stenting. This was a study by Bernard de Bruyne. And they found that IMR after a PCI correlated with troponin release. So if you had a higher IMR, you were more likely to have an elevated troponin afterwards. We looked at this in a slightly different way, where the idea was that perhaps these patients who have elevated IMR before PCI are more susceptible to periprocedural events. So they have microvascular dysfunction for whatever reason, and are less able to tolerate the embolic phenomena that occurs during PCI. And so we found that those patients who had periprocedural MI had a significantly higher IMR before the intervention, compared to those who didn't have a periprocedural MI. And the IMR was the only independent predictor of periprocedural MI on multivariate analysis. Finally, I'd like to finish up with another area where clearly the microvasculature plays a big role. And that is in patients who've had STEMI. We've known for a number of years from other methods that if you have microvascular dysfunction after a STEMI, or the worse your microvascular dysfunction, the worse your outcome. Again, I'd like to show a couple of cases that were interesting from a study that we did. This is a 65-year-old man, hypertension. He came in with recurrent chest pain and persistent ST elevation in his anterior leads after receiving lytics at an outside hospital. And so he was taken urgently to a cath lab. This was about 5 and 1/2 hours after the onset of his symptoms. And what you see, he does have flow down his LAD. But he's got this thrombotic, high grade, proximal LAD lesion and some sort of diffuse mid LAD disease. So we went ahead and stented the proximal LAD, and then as part of this research study, measured IMR and found that it was quite high at 50. And the peak CK was on the higher side as well, 3,700. All these patients had an echo at baseline and then at three month followup. And you see that the EF was low, 37%. And it didn't improve during followup. Now, in this second case, a 52-year-old man with hypertension and dyslipidemia also had recurrent chest pain and persistent ST elevation in his anterior leads after failed lytics at an outside hospital. And so he was taken emergently to the cath lab about eight hours after his symptom onset. A similar angiographic finding, he's got this high grade, proximal LAD lesion. But he does have flow down the LAD and some moderate diffuse disease. Again, just the proximal LAD was focally stented and IMR was measured. In this case, it was almost normal. It was lower at 27. The peak CK was only 1,000. And although the initial EF was low, over the three months, the EF essentially normalized. And so we looked at this in about 30 patients. And we found that the median value of IMR in this setting was 32. So half the patients had a value below that and half above it. And those that were in the lower half had a significantly lower peak CK, compared to those with the higher IMR. And when we look at the wall motion score, so derived by echo. So the lower the score, meaning the better the LV function, at baseline both groups, the low IMR and the higher IMR, had similar wall motion scores. But you see that the patients with the low IMR, in general, all of them had improvement in their wall motion score over time, so that it was statistically significant. Whereas in the higher group, there was a mix. Some improved. And some got worse. And some stayed the same. So overall, there was no significant change or improvement in LV function. When we compare IMR to other measures that have been used, like the TIMI myocardial perfusion grade, CFR, ST segment resolution, or TIMI frame count, IMR was the strongest predictor of the peak CK and the improvement in left ventricular function over time. It's been gratifying to see some other groups reproduce these findings. Hyeong-Seok Lim, who's an interventional cardiologist in South Korea, did this study looking at 40 patients with STEMI and comparing IMR to PET scanning, and finding, again, a fairly similar median value of 33. And those patients who had lower IMRs had significantly fewer nonviable segments on the PET scan. So it seems to correlate, the IMR does, with the amount of damage to microvasculature based on the PET imaging. This was also looked at by a group in Scotland, led by Keith Oldroyd, comparing IMR to cardiac MR in 57 patients with STEMI. And if microvascular obstruction was present based on cardiac MR, the IMR was significantly higher right after the primary PCI, compared to those where it's absent. So you might conclude that this is a technique that we can use in the cath lab to determine exactly how much damage there's been to the microvasculature. They also found a similar value around 35, which is a reassuring that it appears that this IMR is fairly reproducible across patient populations. We've just finished this multi-center registry of 253 STEMI patients, where we looked at clinical outcomes, hard endpoints, and found that, in this case, the mean value was 40. And we used that to divide patients. And those with a higher IMR above the mean value had a significantly lower survival free from death or rehospitalization for heart failure, compared to those with a lower IMR. Again, this is measured at the time of the initial presentation. When you look at just death alone, there was also a significantly worse survival in those patients with higher IMR, compared to those with a lower IMR. So, I've tried to show some potential advantages to this technique. Of course, there are some limitations. The main one may be that it's invasive, which hampers our ability to do it easily, as well as to do serial measurements over time. There may be some issues with interpatient or intervessel variability, you know, right coronary versus LAD. This is a estimate of microvascular resistance. We're not actually measuring. The sensor distance, we haven't found that small changes, you know, a centimeter or two here or there doesn't make a big difference. But clearly, if you're only halfway down the vessel, your transit time will be different. And that can affect your value. Also, I kind of glossed over the independence from the epicardial disease. We've done a lot of work looking at this. If you do have a very tight epicardial lesion, that'll affect coronary flow. And it can affect your IMR. And so you need to measure the wedge pressure, which is a reflection of collateral flow, in order to accurately estimate microvascular resistance. But in general, when we're measuring IMR, it's in patients who don't have critical epicardial disease. But that is a limitation to be aware of. So with respect to IMR itself, there's a few take home messages. I think the microvasculature can be assessed easily and reliably by measuring IMR. In stable patients with normal coronary arteries, the simultaneous assessment of FFR and IMR can guide therapy. And IMR predicts outcomes in acute MI. And emerging data suggests its utility in stable patients as well. So in conclusion, I think in many cases, assessing coronary physiology improves one's interpretation of the coronary angiogram. In particular, measuring FFR in patients with multivessel coronary disease improves outcomes and saves resources. And measuring IMR in certain patients subsets can help guide treatment decisions. Thanks for your attention. [APPLAUSE] Created by Presenters William Fearon, MD Professor of Medicine (Cardiovascular Medicine) at the Stanford University Medical Center View full profile
