This is Anne Dubin. I'm from Stanford University. I'm going to be talking today about cardiac resynchronization and right ventricular resynchronization. I have no disclosures to make. When we talk about Tetralogy of Fallot and right bundle branch block, it's important that we all be speaking the same language. Tetralogy of Fallot consists of an anterior malaligned ventricular septal defect, which results in pulmonary outflow tract stenosis and a non-restrictive VSD. Patients with Tetralogy of Fallot often have right bundle branch block. This right bundle branch block can be either secondary to a surgical intervention and or to right ventricular enlargement or fibrosis. Long-term complications of Tetralogy of Fallot repair include pulmonary regurgitation and right ventricular enlargement and dysfunction. The relationship between the conduction delay and ventricular dysfunction has been well established in studies of patients with structurally normal hearts. Resynchronization therapy has been shown to have a significant benefit, including decreasing mortality in these patients. So the question arises, are Tetralogy of Fallot patients with interventricular conduction delay and ventricular dysfunction candidates for resynchronization therapy? And if so, do we resynchronize the right ventricle alone or is biventricular resynchronization needed? So in order to try and figure this out, we decided to start several years ago looking at the acute reaction of the Tetralogy of Fallot patient to pacing. We performed acute catheterization study in patients with right bundle branch block and RV dysfunction in seven of these patients. And we measured cardiac index, RVDPDT, and QRS duration in multiple sites. Pacing was optimized for maximum fusion and narrowest QRS duration. And what we found was in the vast majority of patients, we had an improvement in cardiac index from a baseline state to an improvement with pacing. And we also saw improvement in the RVDPDT from a baseline state, a preferential pacing situation. This work was then further performed by Janoshek's group in 2017, where they looked at 28 patients with Tetralogy of Fallot or double outlet right ventricle following a full repair. A triggered RV free wall pacing was performed for maximal fused QRS. And if you look here, we can see we had a nice narrow QRS when they were pacing the ventricle. And when they turned off pacing, the underlying right bundle branch came out. They paced all these patients for over five minutes. And then they looked at arterial blood pressure, CVP, pulse pressure, cardiac index, and DPDT. And even just looking at this one tracing, you can see with pacing the arterial blood pressure is higher. And as they turn off pacing, that decreases. So what they found was number one, they were able to actually decrease the QRS duration electrically resynchronized and from 110 milliseconds down to 70 milliseconds. And they found that systolic blood pressure, pulse pressure, DPDT, and cardiac index all improved both at one minute and five minutes of pacing while central venous pressure decreased. They then furthered this work in 2019 by not looking at the acute situation, but looking more chronically at RV resynchronization. And what they did was they took six symptomatic RV dysfunction patients with a mean age of 13.6 and years. And all these patients had right bundle branch block in RV dysfunction. They again performed RV free wall pacing at the latest activation site so that they could achieve a QRS duration that was 85% of native. So they were all able to shorten the QRS duration across the board and use the AV delay to achieve maximal fusion. What they found was improvement in the New York Heart Association class. They found improvement in their NT pro BNP measurements and the RV fractional area change increased substantially. Also of note with just RV pacing, they did not see any decrease in the LV ejection fraction, which sometimes can be seen with RV only pacing. So they were able to actually improve RV function, but not decrease LV function by doing this. However, they were very, very conscientious and took a lot of time to make sure that they were having this maximal fusion situation and the narrowest QRS that they could achieve. But it can be difficult to optimally pace the right ventricle. Stevenson looked at the patients who had an ICD in place within the RV and found that when they paced the QRS, their paced QRS was significantly higher than the native QRS. So they had careful programming of the AV and to try and achieve maximal fusion, but this was not a static process and would change over time with changing physiologic AV delays. So that using an ICD that was in place already would not allow them to chronically RV resynchronize their patients. And there is also the additional question of could the right bundle branch block be masking LV disfunction and LV electrical delay in some of these patients? And which would lead us to thinking, well, would biventricular pacing therefore be more efficacious in this disease? In order to try and look at this a little bit closer, Thambo's group did electroanatomical mapping of several patients with Tetralogy of Low and these were all adult patients. And what they found was that one size does not fit all in this scenario and that while patients may have a very similar looking right bundle branch block on their surface EGG, what's actually happening electrically may be quite different. If we look at this first panel, we see two patients being represented. Patient number one is showing us that indeed they have early activation of the left side of the heart and the entire right side of the heart is activating later with as would be expected with the right bundle branch blocks. And so this is proximal right bundle branch block with delay across the entire right ventricle. However, in patient number two, who also had a right bundle branch block, the conduction delay was really only limited to the right ventricular outflow tract. Again, the red is earlier, the blue and green are later. You can see the left ventricle is activating early, but so is a great percentage of the right ventricle and the only really late areas are up in the outflow tract itself. So you would imagine therefore that trying to resynchronize each of these patients, you might need a very different kind of therapy. They looked at pacing from the RV alone in this first patient and found again that, yes, everything seemed a bit later that there was some early from the pacing site, but that we got later across. But when they bi-ventricularly paced, they got a bit more synchrony and a bit more homogeneity in the activation sequence. So it really depends on where the area of conduction delay is as to what might be the optimal way of thinking about this. So how does varying areas, we've really been talking mostly about electrical synchrony and then the resulting hemodynamics, but that has to somehow or another translate to mechanical synchrony in order to have that functional binding. And there's been a lot of work that has looked at this. And again, there is that heterogeneity across the board. Mechanical synchrony is linked to electrical synchrony, but it can have very differing patterns. You can see late activation of the RV free wall, or you can sometimes see late activation of the RV outflow track. It just depends on the patient. We do know that between 50 and 90% of patients with tetralogy will have LV dyssynchrony seen as well when you look by echo measurements. And we know that increased cure restoration is associated with reduced strain in the lateral and septal LV walls, as well as a decreased LVEF. So multiple studies really have shown this link between LV dyssynchrony and long-term RV dyssynchrony. So when we're thinking about tetralogy, it may be a more complex scenario than just trying to improve the function on the right side. We may also need to, especially as patients get older, think about the left side more. So this has led people to thinking about, well, should we be considering biventricular pacing in these tetralogy patients in order to resynchronize them? And one of the first papers to look at this was a study that came out in 2014, where these were adult patients, there were 10 tetralogy patients, who were either upgraded from an RV-only pacing scenario to biventricular pacing, or had de novo CRT pacing placed at the time. Interestingly, and I point this out, when they did this, they did not actually cause electrical synchrony. They did not decrease the QRS duration. Prior to pacing, in the patients who did not have a pacing system in place, the QRS duration was a mean of 167 milliseconds, and it actually got longer after CRT. The upgraded patients who already had a pacemaker in place, they didn't really narrow them either, and I think that may explain some of the findings that they found in this study. As I said, these patients were an average age of 44, and they had poor LV function with a baseline LVEF of 24%. They followed these patients for close to five years, and they found an initial improvement in the ejection fraction from 21% up to 32%. However, this was not sustained long-term, and fell back down to 26.7%. But I think that it is important to take this study with a bit of a grain of salt, because it doesn't seem that they really actually achieved what the initial plan was, which was the narrowing of the QRS itself. And so it's not clear whether these patients really did undergo resynchronization. However, this did show that we could do this, and led to further studies looking at long-term CRT in Tetralogy of Fallot patients. And this is a study that just came out this year, which was a 12-center retrospective cohort, and looked at longitudinal data, including New York Heart Association LV ejection fraction, as well as QRS duration. They analyzed the data at three months, one year, and greater than two years follow-up, and they had 44 patients, which for a congenital heart disease study is a pretty good-sized study. Average age here was 40.3, plus or minus 19.2 years. 66% of these patients were paced prior to CRT, and so they were upgraded, as opposed to the other patients who actually had a de novo system placed. And in this study, what they found was that the LVEF improved from 32% at baseline to 42% at early follow-up, and remained stable in the intermediate and late follow-up epics. Here, the QRS duration decreased from 180 milliseconds down to 152 milliseconds at early follow-up, and remained decreased throughout the entire study. So here they were able to electrically resynchronize the patients, and you could see the resulting improvement in the infraction that was sustained. Not only was the LV function improved, but the RV function also improved. They found that the patients had an ejection fraction of 38% at early follow-up, but at late follow-up, went up to 55%. Transplant-free survival in this group at three years was 85%, five years, 79%, and at eight years was 73%. It's important to be thinking about this piece of the study, the transplant-free survival. Adult studies in adult patients with structurally normal hearts have shown, and it is well-known, that it actually can improve mortality in this patient group. For a very long time, because of heterogeneity of patients, and because of issues of having adequate sample size, we weren't able to really show improvement in mortality. However, this also has recently changed, and Henry Chubb has recently shown in a five-center propensity match study of pediatric and congenital heart disease patients, which included Tetralogy of Fallot, that in patients who had a systemic ventricular ejection fraction of less than 45%, had heart failure, and a QRS duration that was greater than three Z-scores above baseline, that they did actually have a better survival rate with resynchronization than if they did not pace these patients. The hazard ratio for transplant-free survival with CRT was 0.44, and as you can see in this Kaplan-Meier, that these are the patients who were resynchronized, these are the patients who were propensity matched, so the same diagnoses, the same age, same epochs, same ejection fractions, who did not receive pacing, and there was a significant difference between these two groups. This paper has then led for us to consider CRT for congenital heart disease and in pediatric patients who do have an ejection fraction less than 45% and a wide QRS. So if we are able to do CRT, and it does seem to be helpful in this group, and we do know that if we look at the larger group of congenital heart disease patients, that yes, indeed, we have been able to improve mortality, what are the issues? Why aren't we using it more? Often, especially in younger children, we are concerned more about the need for additional leads in this group and the complexity of trying to place a resynchronization device into a somewhat younger child. This thinking is now changing with the introduction of conduction system pacing. This is conduction system pacing, which is pacing within the HISS bundle or near the HISS bundle in the Parisian region is just starting to be employed in pediatric and congenital heart disease patients. And the advantage here, again, is that it is less pacing leads within the heart itself. The majority of studies really are now just really looking at feasibility of technique, but there was a seven-center retrospective propensity match study of conduction system pacing versus conventional pacing with 65 total cases of conduction system pacing. In this group, the tetralogy of flow was represented in 19%, which was the largest group. And again, they found similar improvement with conventional resynchronization therapy to conduction system pacing, both for injection fraction and the improvement in QRS duration. So it does appear that this may be quite promising for the future for us in thinking about how do we resynchronize these patients that we may not need a true biventricular resynchronization device, but may be able to have the same kind of results with conduction system pacing. So in conclusion, patients with tetralogy of flow have varying patterns of both electrical and mechanical dyssynchrony, which could affect the RV, the LV, or both ventricles. Acutely, RV pacing, primarily in the free wall alone, improves hemodynamics. However, true fusion pacing really can be difficult to achieve. Many patients with tetralogy of flow and right bundle branch block have underlying mast LV dyssynchrony and result in poor LV function as well. These patients can benefit from conventional CRT pacing and patients with congenital heart disease, prolonged QRS duration, and decreased EF will show a mortality benefit. Conduction system pacing is a potentially promising and complex means of resynchronization in this patient, but really is still in its early phase. Thank you very much. ♪

cardiac resynchronization

Tetralogy of Fallot

right bundle branch block

biventricular pacing

conduction system pacing