What can you tell us about your facility/practice at Washington University School of Medicine?
The facility and practice at Washington University are both large, experienced, and very successful. A primary emphasis has been on research projects; therefore, it is tied in significantly with government funding through the NIH. It also has a very large and vibrant clinical in-service practice that allows us to train and maintain the fourth largest cardiology fellowship in the US and provides a variety of high-risk and clinically complex patients to work with. All around, it is an advantageous situation for faculty, fellows, and patients.

What is the current focus of your research energy?
My current research is focused mostly on translational research and new clinical applications, both in devices and pharmaceutical agents. Our research positions also allow us to develop internal projects with the framework, research nurses, and ancillary help to perform clinical research.

Individually, my own research encompasses drug-eluting stents, issues involving thrombosis, and a particular focus on structural heart disease, including atrial septal defect/patent foramen ovale (ASD/PFO) closure and many of the valvular projects, such as the MitraClip (eValve, Inc., Menlo Park, CA) and the Edwards Sapien percutaneous aortic valve (Edwards Lifesciences, Irvine, CA).

Which areas of coronary artery and structural heart disease need the most attention from industry and physicians in the next several years?
There are several pressing issues. We still have concerns about very late stent thrombosis in drug-eluting stents. Even though they are small in number, they can have devastating consequences. The major thrust should be in trying to reduce this particular component, while at the same time working toward reducing the absolute need for long-term thienopyridine use, such as clopidogrel, and the upcoming prasugrel. Although they have effectiveness over the initial year of use when a patient presents with an acute coronary syndrome, we would like to have the leeway of reducing their use in patients who face considerable medical risk for long-term administration or have difficulty with compliance. This is actually a joint, overlapping project in the sense that anything that will reduce inflammation or allow for more rapid endothelial growth and stent strut coverage should also allow for an inherent reduction in the need for dual-antiplatelet therapy.

With regard to structural heart disease, we would like to see the development of a number of rapid iterations in percutaneous aortic valve replacement. Although currently effective, percutaneous aortic valve therapy only applies to the minority of high-risk aortic stenosis patients due to the large (22–24 F) sheath sizes required.

With regard to the mitral valve, we have seen one very capable technology (ie, the MitraClip) applied to a very select portion of patients with mitral regurgitation to perform repair. However, mitral regurgitation has a multiplicity of different types of problems involving the mitral apparatus, in which one situation does not fit all. This area needs to undergo rapid development in solving the other components of mitral regurgitation, whether through a coronary sinus approach, a combined coronary sinus/mitral valve approach, or the actual replacement of the valve itself in certain circumstances. These types of projects have moved much slower than their aortic counterparts that were initially lagging but which have now moved ahead in terms of development and clinical applicability.

What recent developments in coronary artery and structural disease have had the greatest impact in successful outcomes?
The most recent development in coronary artery disease has clearly been drug-eluting stents, including the newest iterations, which are much more flexible and easier to deliver. These improvements have helped simplify our lives to some extent and have hopefully reduced the complication rates that we sometimes see with more complex interventions. I believe they have a significant impact on how we treat patients and in broadening our ability to treat more complex anatomies. We have also seen a number of significant trials conducted that have demonstrated the safety of drug-eluting stents, particularly in patients who can stay on dual-antiplatelet regimens for prolonged periods of time. It has been reassuring to see that we can approach so-called off-label indications safely and effectively, while maintaining efficacy and a reasonable safety profile.

In structural heart disease, the greatest impacts have been from two trials involving the Evalve MitraClip and the Edwards Sapien transfemoral valve. These technologies have provided us with significant options in a select group of patients, allowing them to achieve significant improvements in valve function without undergoing major surgery. With particular regard to the transfemoral aortic valve, the two cohorts of patients include either those who are surgically inoperable or those who have very high morbidity and mortality rates. We have seen revolutionary patients who have had little to no quality of life with perhaps the expectation of not living through the next year or 2, have their lives turned around dramatically due to their ability to withstand the procedure, go home at an early time point, and achieve a dramatically better functional status.

What is the next step in technology for PFO closure? What is your take on the connection between PFO and migraine?
The next step in technology for PFO closure largely depends on completing the long-standing randomized trials' hope to show that PFO closure can be as good as, if not better than, medical therapy for paradoxical embolization in strokes. Paradoxical embolization may be one of the major reasons that young people experience stroke or minor stroke/transient ischemic attacks (TIAs) when we can find no other apparent cause. There is a significant percentage of people younger than 55 years who have a PFO and presumptive clot in their venous system that ended up crossing the PFO, causing a stroke. The data have been a long time in coming, since we initially started with registries and then had to convert to a randomized trial traversing an entire decade. It now appears that these trials will come to a conclusion in the very near future; establishing the PFO link and determining exactly what the case is. Migraines have been more challenging.

In the initial registries, migraines could be eliminated in 50% of patients who had a PFO closure for suspected paradoxical embolization. In other words, they had a neurologic event, and they just happened to have migraines before the closure took place. In this population, we found dramatic improvements (a 50% reduction and an additional 20% reporting significant improvement in migraine frequency). Unfortunately, those patients have been excluded from the three randomized trials recently attempted, two of which were discontinued.

I have often said that eliminating the CVA/TIA patients secondary to paradoxical embolization in the PFO treatment of migraines is like testing an antiplatelet drug in acute coronary syndrome patients and eliminating the troponin positives. The patients with thrombus benefitted most from antiplatelet agents, and thus, improvement in their outcomes. Similarly, eliminating the patients who may have had paradoxical embolization basically eliminates the highest-risk population.

The inclusion criteria for these studies were patients who had refractory migraines, were on multiple medications, and were having migraines at a frequency that qualified them for the study (migraines on multiple days per month). The exclusion criteria was the presence of a definitive neurological event (such as CVA or TIA). The expectation was a 50% elimination of migraines and perhaps another 20% or so that had significant improvements. That expectation was based on multiple registries (and our unreported results supporting this) demonstrating PFO closures in patients closured for paradoxical embolization resulted in the stated 50% elimination of migrations. Since this group has been eliminated from the study, why would the outcomes be expected to be as good as those that were originally reported? It may take many years to sort out this relationship.

You have served as principal investigator on several trials. What can you tell us about your experiences, and what have you learned about the process?
What I have learned from being a principal investigator is interesting. When I was a junior faculty member, I naively assumed that being in a study primarily meant that I had to go out and recruit patients and then, by following the guidelines, apply the treatments for whatever I was studying, and that would pretty much be it. I found out that this is a much more labor-intensive process than I could have ever imagined. The implantation of a new device or the testing of a new drug is the fun part of all this, but the majority of the work is in the approval process from both the human study committee and the Investigational Review Board to get the protocol up and running and in the extensive amount of rigorous follow-up and monitoring that take place after the drug or device has been utilized. By far, actually conducting the protocol itself is the easy part, but the preparation and the follow-up are much more time- and labor-intensive.

The net result, however, is a very rewarding experience that often opens up a brand new field. The collective experiences in a multicenter, multi-investigator trial often enrich and enhance our understanding of an area far beyond what a textbook can provide. As has often been said, a new study raises more questions than it answers. But in all respects, it can change our whole perspective on a certain field.