[1] It’s a pleasure to talk to you today. I’ve been involved with this therapy for, I think, eight years now and it continues to fascinate me for a lot of different reasons. It’s always a challenge or at least it often is a challenge even though we have all these great tools and experience helps tremendously. It still is challenging and that variation from patient to patient is a part of the major part of that challenge. The other thing about it is that sometimes we just see spectacular improvements, but then again there’s a substantial amount of response rate. So trying to understand what that’s all about and maintain as high as possible response, I think, is the motivation for what I’m going to talk about, which is trying to optimize the therapy. These are my disclosures. [2] So why optimize? Well, unfortunately, there about 30% of folks that don’t respond so I’m going to spend some time talking about that and the mechanisms and then focus a lot of my talk on how to optimize the timing intervals which are variables that are under our control. And, then spend the last piece of my talk highlighting a particularly challenging case where we used an interesting novel technology that many of you may now have access to that uses a magnetic guide wire. [3] So this is a slide from the miracle trial; one of the first multi-center, randomized, prospective trials of CRT. And, it just highlights the fact that’s now come to be well known in all of the subsequent trials that a substantial portion of patients don’t respond here if you total the patients who had either no change or actually got worse it was 42% in this particular trial and subsequent trials had similar rates of non-response. [4] So, why don’t people respond to this therapy? Well, there are probably a lot of reasons one being that the disease that they have is progressive and that although this may be somewhat helpful it’s not helpful enough and the progression is a steady downward course. Another very reasonable hypothesis is that a substantial amount of myocardial scar exists that inheritantly disynchronous and it doesn’t respond to CRT and that doesn’t change once the pacing leads are in. But, the things that we do have under our control that probably affect response rate are the stimulation site as the prior showed the middle of the lateral wall probably on average is the best place to be and that’s about the resolution of our information at the present time. And, also there seems to be a substantial effect on the response of the AV or, now, VV timing. And, so taking advantage of that is the way to maximize the response we can see in our patients. [5] So this is an example of how deranged AV timing in the heart can be in patients with, that are a candidate for CRT and this is actually not a CRT patient, but it was a, it’s a fantastic slide in which left atrial pressure is measured at the same time as LV pressure and a right heart cath to measure cardiac output and simultaneous with that, transmitral. So that’s fairly spectacular. Here’s a measurement; what you can see here is this patient has a tremendously long AV delay and so that the time the mitral valve is open is really fairly tiny. You don’t see any A-wave and immediately after that mitral shuts passively there begins to be diastolic mitral regurgitation so that’s actually squandering diastolic filling of the LV and then as soon as the LV starts then that becomes systolic mitral regurgitation. Now if you pace with a very short AV delay, which at one point was thought to be a reasonable thing for heart failure patients, but now we know really isn’t helpful on average. You can see the A wave but the price to be paid is that the left atrial pressure can be high and you still see a substantial mitral regurgitation envelope. Now with echo optimization it is possible to achieve an optimal timing of ventricular stimulation so that you have a nice A wave and that the diastolic filling time is maximized. And, if you can see here on the pressure tracing LV systole sits exactly right on top of the apex of the left atrial pressure curve so that’s what we understand to be an optimal. [6] The best hemodynamic data we have for AV optimization came from the past CHF trials mentioned previously and in a separate publication from the one that was shown. Auricchio and colleagues looked at what the optimal time interval should be between the beginning of LV systole and an impulse in the left ventricular pressure curve due to the left atrial contribution. Now this sort of pattern was seen in the majority of patients they studied, 19 of 27, there was thought to be responders based on their improvement and their pressure pulse of greater than five percent and but also in non-responders had this as well. So in those patients what they saw, and let me go back to that, so if this were truly the pattern you might expect that if AV delay is optimized there might actually be an improvement, an increase in the left ventricular endiastolic pressure. The reason that left ventricular diastolic pressure’s falling in here is because of that diastolic mitral regurgitation. So the LV is depressurizing backwards up into the left atrium. That’s why its, [7] so it’s reasonable to expect that that’s not at all what they saw. What they saw with progressive shortening of the AV delay there was no significant change in the LV endiastolic pressure until a certain point at which time that pressure actually decreased because diastole was being impeded by premature closure due to LV systole. [8] A fascinating thing about the measurements they made is that there was a very acute relationship between the maximum change and the pulse pressure that’s the systolic benefit of CRT and that interval that they measured between the apex of the left atrial impulse and the left ventricular impulse. And, this is in the responder group. [9] However, in the non-responder group it was a very different pattern. And, the other thing about this is that it is possible in these non-responders to make things worse by CRT. So that’s an important consideration. So just by putting a device in out of the box unfortunately we’re faced with the substantial number of non-responders. We may actually make matters worse by not paying attention to what sort of magnitude we, [10] improvement we get. So what sort of optimization techniques can we have at our, to use? Well, one is sort of the out of the box setting and a reasonable estimate of what might be optimal on average is an atrial sense, ventricular stimulated and VDD, AV delay of 120 milliseconds on average or the companion trial used a method that’s calculated based on intraventricular timing intervals. I’ll show you that in a moment. The aortic VTI is a popular echo method that we prefer. There’s also a mitral inflow method or also called the Ritter method, the author that proposed it initially. And, then the hemodynamic measurements that I’ve shown, pulse pressure, LV, DPDT max. Now there are also new ideas about acoustic measurements, whether S3 intensity or ejection period; that remains to be seen whether or not those will be useful. [11] So this was presented in abstract form. Hopefully it will be coming out in a major publication so we all can look carefully at the data but what they saw in the companion, this is from the past CHF data set again, but what they use to drive this is that in patients with a QRS duration of greater than a 150 milliseconds, 70% of the native A sense to V sense intervals, so these are intracardiac measurements minus 55 milliseconds, put patients on average at the apex of the AV delay. And, if you QRS duration was less than 150 milliseconds then a different calculation was appropriate. [12] So we were interested in comparing this sort of out of the box 120 millisecond setting to spending a lot of time with the iterative aortic VTI method that requires a dedicated echocardiographer and probably about 30 minutes on average to do the AV delay optimization. We wanted to see whether or not that actually paid any sort of clinical benefit long term that we could measure. [13] So to do that we did a randomized prospective trial of 40 patients who had their device implanted and then got this aortic VTI measurement. And, then they were randomized to either receive the optimal AV delay setting or to get the empiric 120 millisecond. Then we looked at three months at clinical follow-up which we include a six minute walk, New York Heart Association Class, hospitalizations, and a Minnesota Living with Heart Failure questionnaire [14] for quality of life. So a typical population of CRT patients, refractory heart failure symptoms, low EF, wide QRS duration, [15] good medical therapy; the principle of the aortic VTI method is that this is a non-invasive measurement of the stroke volume. So in my mind that’s probably as good as you can do to look at the systolic benefit of CRT is to actually measure the stroke volume. And, the principle is that by integrating the aortic continuous wave Doppler envelope you get a measurement in centimeters and you multiply that by the outflow track area in centimeters squared. You get the stroke volume. [16] This is the intra-observer variation in our labs which just makes a point that if you are very careful with the technique in spite of the physiologic variation you can see and particular respiratory affects are important in beat to beat variation in the aortic VTI but also position of the echo. In spite of those things with some skill you can get a very good intra-observer performance with the technique. [17] So what we saw was that on average that a 120 millisecond AV delay setting is actually not bad, but the trouble is there’s a tremendous number of outliers going from very short AV delays all the way up to the longest AV delay that we looked at. [18] The immediate acute systolic difference between the two methods was that we had almost a two-fold or more than a two-fold improvement in the stroke volume and ejection fraction by going that extra nine yards to ten yards to get the aortic VTI optimization. [19] The other thing about that that was very interesting was that that acute systolic improvement predicted the clinical benefit long term and if we used a ten percent change as a cut-off that actually captured all but one of the patients who went on to have a systolic [20] benefit. But the more important piece that we’re interested in is that long term that difference in the acute systolic benefit between the two techniques also translated into the clinical things that we saw. So it was a much higher improvement in New York Heart Association Class, quality of life, [21] and a reduction in hospitalizations. [22] So an alternative method that’s been used in some of the trials is this Ritter method and it’s based on measurements made in patients with complete heart block who received dual chamber pacemakers. And, the principle is an interesting one which is to say that if you allow an AV delay long enough to permit the natural course of the A wave to finish you can get some estimate of what ideal diastole should be. Now the exception here is in patients with severe diastolic dysfunction who just don’t have an A wave, but if you could, if there were no electromechanical delay just decreasing the AV delay by that amount A would allow the systole to occur right at the natural conclusion of the A wave, but the reality is that there is an electromechanical delay and to get a handle on that you can program a very short AV delay and get premature truncation of the A wave and that using those two measurements together you can calculate an AV delay with just two single AV delay settings during the measurement. [23] So that’s the idea. We compared that method with our method, the aortic VTI in each patient, which just shows the response in each of the patients we compared. You can see that in every case there as a better improvement with the aortic VTI method. [24] And, interestingly there was no correlation between the predictions of the two measurements. So that was a scatter plot. [25] Okay, so I want to just illustrate a particularly difficult case I had recently and we used a guide wire. So this is a typical venogram. It looks like there’s a nice big lateral branch here with a couple of sub branches here; one that swings out onto the middle of the lateral wall, one that stays relatively posterior lateral. But, unfortunately, [26] in the RAO view things don’t look quite so nice. So, what you can see here is a very highly angulated take off. It basically turns back on itself like a 180 degrees and on top of that there’s a valve right across the ostium. So this is a particularly challenging thing to deal with from a lot of different perspectives. Number one getting a wire across that valve and into the side branch and number two to actually get a lead to track over it are two challenges. [27] This is a subselection catheter that I found incredibly useful for these highly angulated sub branches. It’s actually from interventional radiology. It’s Rausch inferior mesenteric catheter. I’m using a five French here. I don’t know if any of you’ve any experience with that, but I highly recommend it for these highly angulated side branches. So that rim catheter allowed me to basically get across that valve and into the side branch and then I’ve introduced my 0.014 wire. Now this particular wire is a magnet tip wire. I’m going use [28] that as a stereo taxis system. Now the stereo taxis system principle is that you steer the tip of the guide wire with magnetic fields. So the magnet that’s on the tip of the guide wire responds to the prevailing magnetic field and with the stereo taxis system you can manipulate that magnetic field and use that to guide yourself down into side branches. With highly angulated branches and multiple secondary branches it’s hard to have control of standard guide wires to get into places you want to be and this just simplifies matters. So that’s the principle and [29] this shows what the stereo taxis system looks like. This is now, I think, the fifth generation of the system. It’s based on this particular system, on permanent magnet arrays that are located on armatures on each of these cowlings on either side of the patient and manipulation of the armature generates a magnetic field that you can manipulate any projection in three-dimensional space. And, the other piece is a cockpit basically with a lot of screens and a software interface that is really useful for this [30] particular application. What you can do with that software interface is extract the three-dimensional anatomy of the side branch that you want. Here we’ve actually drawn along the branch that we’re interested in, identified the two target sites, and the computer interface integrates that into three-dimensional space, and you can manipulate this into virtual space and get a sense of what the take off is and what angulation is and for the sake of navigation we can manipulate the magnetic field to allow you to go in those branches. [31] So in this kind of particular case we got the lead into the upper of the two branches and it worked nicely. [32] So I just want to summarize that I think AV delay optimization is an important way to improve the response that you see in your patients. At least in our hands, we had about a 50%, I mean a two-fold greater improvement in that response compared to sort of an out of the box programming method. Of the techniques that we’ve looked we think the aortic VTI iterative method is the best and I’m excluding the LV DPDT measurement. I think that’s probably best but it’s an invasive technique and we’re not doing it routinely. And, I think in part the stimulation site is a major issue for how to improve your response rate. Trying to get to the mid lateral wall may not be the best. Hopefully the new imaging studies will give us more insight into that, but for now that’s our, this should be our best target I think. I’ll take any questions. [33]

Mitchell Faddis Ballroom E CRT Optimization How to Successfully Implant CRT: From Lead Placement to Programming