Cover Story

Adults with congenital heart disease present challenges, rewards for cardiologists

Physicians and patients in the United States have seen outstanding progress in the treatment and care of congenital heart disease during the past 50 years. If a child was born with congenital heart disease in the 1960s, the chance of survival to adulthood was estimated to be less than 20%. If a child is born with congenital heart disease today, the chance of survival to adulthood is estimated to be higher than 90%.

Carole Warnes, MD, was involved with guidelines on the care of adults with moderate to complex congenital heart disease.

Carole Warnes, MD, was involved with
guidelines on the care of adults with moderate
to complex congenital heart disease.

Photo: Matthew Meyer, Mayo Clinic.

Many factors are behind the progress observed thus far. Some of the drivers include advances in cardiac surgery and interventional techniques; the advent of the ICU; developments in the care of vascular disease and arrhythmia disorders; progress in imaging; and improvement in the education of medical caregivers.

“Before cardiac surgery and the tools we have available now, about 25% of children born with congenital heart disease would die in the newborn period and about 60% would die in the first year. A minority, approximately 15%, would ever survive beyond puberty,” Carole Warnes, MD, director of the Adult Congenital Heart Disease Clinic at Mayo Clinic, told Cardiology Today.

Treatment of congenital heart disease in childhood has been so successful that there are now more than 1 million adults in the United States living with congenital heart disease, and the population is growing by an estimated 5% per year.

The rising numbers of adults with congenital heart disease have presented another set of challenges, as adults with congenital heart disease have different, and often more complex, needs than adults with acquired heart disease. In addition, there are not enough subspecialists and staff trained in the management of adult congenital heart disease to provide adequate care for the growing number of patients in that demographic, according to experts Cardiology Today interviewed.

A study by Jared M. O’Leary, MD, and colleagues published in JAMA in 2013 indicated that the annual number of congenital heart disease hospitalizations for adults increased faster than for children from 1998 to 2010. Adult admission volume was 87.8% higher during the latter years of the study compared with the earlier years, whereas the corresponding increase in annual admission volume for children was 32.8% (P<.001).

However, 2015 is shaping up to be a landmark year for management of adult congenital heart disease. In 2012, the American Board of Medical Specialties approved the creation of physician certification for the subspecialty of adult congenital heart disease, and the first board exam will be given in October 2015. Also in 2015, a process driven by the Adult Congenital Heart Association to accredit centers for treatment of adult congenital heart disease will begin, and the Accreditation Council for Graduate Medical Education will commence accrediting training programs for this subspecialty.

“The model of care that we have always espoused is one in which specialty centers should be set up so you get high-quality care,” Yuli Kim, MD, medical director of the Philadelphia Adult Congenital Heart Center at the Hospital of the University of Pennsylvania and Children’s Hospital of Philadelphia, said in an interview. “This accreditation process is key for our patients to ensure that they get high-quality care by establishing benchmarks which can enable us to examine outcomes.”

Challenges, risks

The care of patients with adult congenital heart disease is particularly challenging for a number of reasons. One, these patients not only have structural disease that may or may not have been repaired, but also are at higher risk for adult-onset comorbidities compared with people of the same age.

“Our patients [with adult congenital heart disease] are much older than stated age,” Mike Landzberg, MD, director of the Boston Adult Congenital Heart and Pulmonary Hypertension Group at Brigham and Women’s Hospital and Boston Children’s Hospital, told Cardiology Today. “If they have 40 years of chronologic age, their bodies behave in many ways as if they are 60-year-olds. Their kidneys, livers and brains may have potential for diseases that the typical 60-year-old sees.”

Patients with adult congenital heart disease may also be at risk for hypertension, hyperlipidemia, diabetes, obesity, atherosclerotic disease, chronic kidney disease and other adult-onset conditions, Kim said. “When you add all of these on top of a structurally abnormal heart, it creates a unique physiology, essentially,” she said. “It really requires an adult congenital subspecialist to manage it; someone who is trained in congenital heart disease, but also in how these factors interplay with each other.”

What the adult congenital heart disease community has learned in recent years, Kim added, is that there is no such thing as “fixed” congenital heart disease. That inaccurate assumption has led to a number of adults with congenital heart disease not being as healthy as they could be because they were not followed all their lives, she said. According to Landzberg, once as many as 90% of children with congenital heart disease were lost to follow-up by specialists as adolescents and/or adults, and today the figure likely remains more than 50%.

“Many patients who were repaired in prior years were told that they were actually corrected and repaired, and that they didn’t need to come back anymore,” Kim said. “We are now finding that these patients are coming back to our hospitals and clinics with serious problems because they were never told to follow-up. We need to focus on better ways of educating practitioners, patients and families that patients need lifelong congenital heart care, because it is not just a problem that you fix and are done with. We know that patients who are lost to care can suffer from adverse events that may have been preventable.” This can also occur in adults with congenital heart disease who were never diagnosed until adulthood, experts said.

Curt J. Daniels, MD

Curt J. Daniels

Curt J. Daniels, MD, director of the Columbus Ohio Adult Congenital Heart Disease and Pulmonary Hypertension Program and professor of internal medicine and pediatrics at The Ohio State University Medical Center and Nationwide Children’s Hospital, agreed.

“Patients fall between the cracks,” he said in an interview. “They ‘graduate,’ so to speak, from pediatric cardiology and then do not have a home in terms of who can care for them. It is somewhat a contributing factor to the patients having poorer outcomes than we ever would have anticipated. We have a tremendous gap in terms of care models for the patients and in research that has led to specific therapies for patients.”

Richard Krasuski, MD

Richard
Krasuski

In addition, adults with congenital heart disease have often undergone multiple surgeries and/or catheter-based procedures, and may be living with scar tissue or complications from those procedures, according to Richard Krasuski, MD, director of adult congenital heart disease services at Cleveland Clinic.

“For instance, they can have problems with blood-vessel supply to different limbs,” Krasuski said. “They can have problems with the draining veins and they can have varicose veins, which are not often seen in young people. There can be rhythm disturbances, pulmonary hypertension and HF. We do not normally expect young people to have problems with inadequate blood flow to their arterial circulation or venous congestion, but young people with congenital heart disease are more prone to this.”

Because of the structural differences of the hearts in patients with congenital heart disease, treatments for these conditions that work in patients with acquired heart disease may not work in adults with congenital heart disease, or may be more difficult to implement, Warnes said. “For example, for the congenital heart patient, something as relatively simple as needing a pacemaker may be particularly difficult because their anatomy is such that you cannot safely access the heart intravenously. They might require cardiac surgery to place an epicardial pacemaker.”

The optimal timing and placement of pacemakers and implantable cardioverter defibrillators in adults with congenital heart disease has not been studied, but this is a crucial research gap, Daniels said. “We have a population with a relatively high incidence of sudden cardiac death, felt to be arrhythmia-related, but we still do not have a good handle on who is best for certain types of therapies, which has been well worked out in acquired heart disease,” he said.

Prevention, education

Prevention strategies are crucial for the patient with congenital heart disease and go hand-in-hand with educational strategies, Landzberg said.

“A 20-year-old with congenital heart disease may face a high arrhythmia, HF, liver or kidney burden if they [participate in] life behaviors that a typical 20-year-old might be able to get away with,” he said. “They need to learn and understand the changing nature of their condition, how it can affect them at different phases of their life and also the ramifications of not getting care. It’s almost as if they have diabetes; it can lead to a superb life, but things can happen that interfere with that, and people need to be educated about what those things are. These patients not only need to know that they need lifelong care, but they need to have coordination of their care.”

An American College of Cardiology/American Heart Association guideline published in 2008, written by a panel chaired by Warnes, recommended that care of adults with moderate or complex congenital heart disease be guided by or in collaboration with clinicians trained in treating adults with congenital heart disease.

However, a survey of pediatric cardiologists published in 2012 determined that, in many cases, adults with congenital heart disease were still being seen by pediatric cardiologists. Barriers identified to adult congenital heart disease care included emotional attachment of parents to the pediatric cardiologist (identified by 87% of respondents), emotional attachment of the patient to the pediatric cardiologist (86%), clinician attachment to the patient/family (70%) and a lack of qualified adult congenital heart disease care providers (76%).

Selected conditions seen in adults with congenital heart disease

When to transfer care

Debate surrounds whether institutions should mandate an age at which patients with congenital heart disease transfer from pediatric care to adult care.

“I think the best care is given by someone who has done the training and has the expertise [in adult congenital heart disease]. If that care is available, then there should be some cut-off where pediatric cardiology hands off that patient to an adult center,” Warnes said. However, determining the “right” age should be an individualized process and depends on when the patient is emotionally and physically ready to be transitioned and transferred, according to Warnes.

Daniels noted that the most important aspect is not a specific age, but rather the presence of a plan for appropriate long-term care. “My personal belief is that all patients should transition and transfer care at some point, but you can develop a plan that can work for the patient, the parents and the providers,” he said. “It is beneficial to have a transition plan that is individualized based on development, based on the needs of the patient, and executed in a way where the change is not a shock to the system.”

Given a shortage of specialists trained in adult congenital heart disease care, it is important for those in the subspecialty to “get the message out to the cardiology community about the special needs of these patients,” Krasuski said.

“It is unrealistic at this point [to believe] that we can handle every single patient out there,” he said. “It is important for physicians in the community to recognize which are the most complicated patients and ensure that they are seen by specialists, and yet also recognize what some of the complications with the simpler lesions are and how to look for them. For instance, with a simple shunt, it is important to recognize that when a patient undergoes an echocardiogram, to look at the right ventricle to ensure that it is not becoming larger, that the velocity of blood across the tricuspid valve is not increasing, which would suggest that pulmonary hypertension may be developing. When in doubt, refer; we are always happy to be of assistance. But also recognize that this is a vastly growing population.”

Management of adults with congenital heart disease also requires subspecialists to consider issues that cardiologists usually do not need to in those with acquired heart disease, Warnes said. For example, they need to help counsel female patients on which kinds of contraception they can use and whether they can have a baby, and they need to counsel patients on risks they may face if undergoing noncardiac surgery.

Without that, “they may get no advice or incorrect advice about all these issues that are very important,” Warnes said. “They have unique needs.”

Goals, progress

The treatment of adults with congenital heart disease has vastly improved from what it was a few decades ago, and if the new certifications and accreditations achieve their desired long-term effects, treatment in a few decades could be vastly improved from what it is now. Experts in the subspeciality are already thinking about the next steps.

“The next thing we need to achieve is a more programmatic approach to the patient,” Daniels said. “Today, pediatric cardiology and adult cardiology centers around the country are organized in a complete systematic way. A systematic improvement of the care team is our next major hurdle and hopefully our next major potential accomplishment. This is by developing programs for adult congenital heart disease that do not just concern the board-certified cardiologist, but the support services around them such as nurses and technicians. We know that when complications or problems occur, it may not be because of one single event, but it has to do with the entire hospital system.”

Everyone in the field, however, is relishing how much better patients’ lives are than they used to be.

“I have been blessed to have seen this field mature,” Landzberg said. “We are practicing on foundations laid by people who have built medicine and cardiology over the past 100 years so that we can see our patients enjoy their lives so much more than others have before. Every single person I take care of is a hero to me and a hero to our group. They have faced unbelievable challenges in their lives, and each one of them has adapted in a unique fashion. Yet, I think we are just at the surface of the innovation we are going to see in terms of the health care for our patients and the rising improvement in survival.” – by Erik Swain

Fernandes SM. J Am Coll Cardiol. 2012;60:2411-2418.
O’Leary JM. JAMA. 2013;309:984-986.
Warnes CA. J Am Coll Cardiol. 2008;52:143-263.
Curt J. Daniels, MD, can be reached at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205; email: curt.daniels@nationwidechildrens.org.
Yuli Kim, MD, can be reached at 3400 Civic Center Blvd., East Pavilion, Philadelphia, PA 19104; email: yuli.kim@uphs.upenn.edu.
Richard Krasuski, MD, can be reached at J2-4, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: krasusr@ccf.org.
Mike Landzberg, MD, can be reached at BACH Group, Department of Cardiology, Brigham and Women’s Hospital and Children’s Hospital, 300 Longwood Ave., Boston, MA 02115; email: mlandzberg@partners.org.
Carole Warnes, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: warnes.carole@mayo.edu.

Disclosures: Krasuski reports consulting for Actelion and Bayer. Landzberg reports working on trials funded by Actelion, Gilead and Pfizer. Daniels, Kim and Warnes report no relevant financial disclosures.

Physicians and patients in the United States have seen outstanding progress in the treatment and care of congenital heart disease during the past 50 years. If a child was born with congenital heart disease in the 1960s, the chance of survival to adulthood was estimated to be less than 20%. If a child is born with congenital heart disease today, the chance of survival to adulthood is estimated to be higher than 90%.

Carole Warnes, MD, was involved with guidelines on the care of adults with moderate to complex congenital heart disease.

Carole Warnes, MD, was involved with
guidelines on the care of adults with moderate
to complex congenital heart disease.

Photo: Matthew Meyer, Mayo Clinic.

Many factors are behind the progress observed thus far. Some of the drivers include advances in cardiac surgery and interventional techniques; the advent of the ICU; developments in the care of vascular disease and arrhythmia disorders; progress in imaging; and improvement in the education of medical caregivers.

“Before cardiac surgery and the tools we have available now, about 25% of children born with congenital heart disease would die in the newborn period and about 60% would die in the first year. A minority, approximately 15%, would ever survive beyond puberty,” Carole Warnes, MD, director of the Adult Congenital Heart Disease Clinic at Mayo Clinic, told Cardiology Today.

Treatment of congenital heart disease in childhood has been so successful that there are now more than 1 million adults in the United States living with congenital heart disease, and the population is growing by an estimated 5% per year.

The rising numbers of adults with congenital heart disease have presented another set of challenges, as adults with congenital heart disease have different, and often more complex, needs than adults with acquired heart disease. In addition, there are not enough subspecialists and staff trained in the management of adult congenital heart disease to provide adequate care for the growing number of patients in that demographic, according to experts Cardiology Today interviewed.

A study by Jared M. O’Leary, MD, and colleagues published in JAMA in 2013 indicated that the annual number of congenital heart disease hospitalizations for adults increased faster than for children from 1998 to 2010. Adult admission volume was 87.8% higher during the latter years of the study compared with the earlier years, whereas the corresponding increase in annual admission volume for children was 32.8% (P<.001).

However, 2015 is shaping up to be a landmark year for management of adult congenital heart disease. In 2012, the American Board of Medical Specialties approved the creation of physician certification for the subspecialty of adult congenital heart disease, and the first board exam will be given in October 2015. Also in 2015, a process driven by the Adult Congenital Heart Association to accredit centers for treatment of adult congenital heart disease will begin, and the Accreditation Council for Graduate Medical Education will commence accrediting training programs for this subspecialty.

“The model of care that we have always espoused is one in which specialty centers should be set up so you get high-quality care,” Yuli Kim, MD, medical director of the Philadelphia Adult Congenital Heart Center at the Hospital of the University of Pennsylvania and Children’s Hospital of Philadelphia, said in an interview. “This accreditation process is key for our patients to ensure that they get high-quality care by establishing benchmarks which can enable us to examine outcomes.”

Challenges, risks

The care of patients with adult congenital heart disease is particularly challenging for a number of reasons. One, these patients not only have structural disease that may or may not have been repaired, but also are at higher risk for adult-onset comorbidities compared with people of the same age.

PAGE BREAK

“Our patients [with adult congenital heart disease] are much older than stated age,” Mike Landzberg, MD, director of the Boston Adult Congenital Heart and Pulmonary Hypertension Group at Brigham and Women’s Hospital and Boston Children’s Hospital, told Cardiology Today. “If they have 40 years of chronologic age, their bodies behave in many ways as if they are 60-year-olds. Their kidneys, livers and brains may have potential for diseases that the typical 60-year-old sees.”

Patients with adult congenital heart disease may also be at risk for hypertension, hyperlipidemia, diabetes, obesity, atherosclerotic disease, chronic kidney disease and other adult-onset conditions, Kim said. “When you add all of these on top of a structurally abnormal heart, it creates a unique physiology, essentially,” she said. “It really requires an adult congenital subspecialist to manage it; someone who is trained in congenital heart disease, but also in how these factors interplay with each other.”

What the adult congenital heart disease community has learned in recent years, Kim added, is that there is no such thing as “fixed” congenital heart disease. That inaccurate assumption has led to a number of adults with congenital heart disease not being as healthy as they could be because they were not followed all their lives, she said. According to Landzberg, once as many as 90% of children with congenital heart disease were lost to follow-up by specialists as adolescents and/or adults, and today the figure likely remains more than 50%.

“Many patients who were repaired in prior years were told that they were actually corrected and repaired, and that they didn’t need to come back anymore,” Kim said. “We are now finding that these patients are coming back to our hospitals and clinics with serious problems because they were never told to follow-up. We need to focus on better ways of educating practitioners, patients and families that patients need lifelong congenital heart care, because it is not just a problem that you fix and are done with. We know that patients who are lost to care can suffer from adverse events that may have been preventable.” This can also occur in adults with congenital heart disease who were never diagnosed until adulthood, experts said.

Curt J. Daniels, MD

Curt J. Daniels

Curt J. Daniels, MD, director of the Columbus Ohio Adult Congenital Heart Disease and Pulmonary Hypertension Program and professor of internal medicine and pediatrics at The Ohio State University Medical Center and Nationwide Children’s Hospital, agreed.

“Patients fall between the cracks,” he said in an interview. “They ‘graduate,’ so to speak, from pediatric cardiology and then do not have a home in terms of who can care for them. It is somewhat a contributing factor to the patients having poorer outcomes than we ever would have anticipated. We have a tremendous gap in terms of care models for the patients and in research that has led to specific therapies for patients.”

Richard Krasuski, MD

Richard
Krasuski

In addition, adults with congenital heart disease have often undergone multiple surgeries and/or catheter-based procedures, and may be living with scar tissue or complications from those procedures, according to Richard Krasuski, MD, director of adult congenital heart disease services at Cleveland Clinic.

“For instance, they can have problems with blood-vessel supply to different limbs,” Krasuski said. “They can have problems with the draining veins and they can have varicose veins, which are not often seen in young people. There can be rhythm disturbances, pulmonary hypertension and HF. We do not normally expect young people to have problems with inadequate blood flow to their arterial circulation or venous congestion, but young people with congenital heart disease are more prone to this.”

Because of the structural differences of the hearts in patients with congenital heart disease, treatments for these conditions that work in patients with acquired heart disease may not work in adults with congenital heart disease, or may be more difficult to implement, Warnes said. “For example, for the congenital heart patient, something as relatively simple as needing a pacemaker may be particularly difficult because their anatomy is such that you cannot safely access the heart intravenously. They might require cardiac surgery to place an epicardial pacemaker.”

PAGE BREAK

The optimal timing and placement of pacemakers and implantable cardioverter defibrillators in adults with congenital heart disease has not been studied, but this is a crucial research gap, Daniels said. “We have a population with a relatively high incidence of sudden cardiac death, felt to be arrhythmia-related, but we still do not have a good handle on who is best for certain types of therapies, which has been well worked out in acquired heart disease,” he said.

Prevention, education

Prevention strategies are crucial for the patient with congenital heart disease and go hand-in-hand with educational strategies, Landzberg said.

“A 20-year-old with congenital heart disease may face a high arrhythmia, HF, liver or kidney burden if they [participate in] life behaviors that a typical 20-year-old might be able to get away with,” he said. “They need to learn and understand the changing nature of their condition, how it can affect them at different phases of their life and also the ramifications of not getting care. It’s almost as if they have diabetes; it can lead to a superb life, but things can happen that interfere with that, and people need to be educated about what those things are. These patients not only need to know that they need lifelong care, but they need to have coordination of their care.”

An American College of Cardiology/American Heart Association guideline published in 2008, written by a panel chaired by Warnes, recommended that care of adults with moderate or complex congenital heart disease be guided by or in collaboration with clinicians trained in treating adults with congenital heart disease.

However, a survey of pediatric cardiologists published in 2012 determined that, in many cases, adults with congenital heart disease were still being seen by pediatric cardiologists. Barriers identified to adult congenital heart disease care included emotional attachment of parents to the pediatric cardiologist (identified by 87% of respondents), emotional attachment of the patient to the pediatric cardiologist (86%), clinician attachment to the patient/family (70%) and a lack of qualified adult congenital heart disease care providers (76%).

Selected conditions seen in adults with congenital heart disease

When to transfer care

Debate surrounds whether institutions should mandate an age at which patients with congenital heart disease transfer from pediatric care to adult care.

“I think the best care is given by someone who has done the training and has the expertise [in adult congenital heart disease]. If that care is available, then there should be some cut-off where pediatric cardiology hands off that patient to an adult center,” Warnes said. However, determining the “right” age should be an individualized process and depends on when the patient is emotionally and physically ready to be transitioned and transferred, according to Warnes.

Daniels noted that the most important aspect is not a specific age, but rather the presence of a plan for appropriate long-term care. “My personal belief is that all patients should transition and transfer care at some point, but you can develop a plan that can work for the patient, the parents and the providers,” he said. “It is beneficial to have a transition plan that is individualized based on development, based on the needs of the patient, and executed in a way where the change is not a shock to the system.”

PAGE BREAK

Given a shortage of specialists trained in adult congenital heart disease care, it is important for those in the subspecialty to “get the message out to the cardiology community about the special needs of these patients,” Krasuski said.

“It is unrealistic at this point [to believe] that we can handle every single patient out there,” he said. “It is important for physicians in the community to recognize which are the most complicated patients and ensure that they are seen by specialists, and yet also recognize what some of the complications with the simpler lesions are and how to look for them. For instance, with a simple shunt, it is important to recognize that when a patient undergoes an echocardiogram, to look at the right ventricle to ensure that it is not becoming larger, that the velocity of blood across the tricuspid valve is not increasing, which would suggest that pulmonary hypertension may be developing. When in doubt, refer; we are always happy to be of assistance. But also recognize that this is a vastly growing population.”

Management of adults with congenital heart disease also requires subspecialists to consider issues that cardiologists usually do not need to in those with acquired heart disease, Warnes said. For example, they need to help counsel female patients on which kinds of contraception they can use and whether they can have a baby, and they need to counsel patients on risks they may face if undergoing noncardiac surgery.

Without that, “they may get no advice or incorrect advice about all these issues that are very important,” Warnes said. “They have unique needs.”

Goals, progress

The treatment of adults with congenital heart disease has vastly improved from what it was a few decades ago, and if the new certifications and accreditations achieve their desired long-term effects, treatment in a few decades could be vastly improved from what it is now. Experts in the subspeciality are already thinking about the next steps.

“The next thing we need to achieve is a more programmatic approach to the patient,” Daniels said. “Today, pediatric cardiology and adult cardiology centers around the country are organized in a complete systematic way. A systematic improvement of the care team is our next major hurdle and hopefully our next major potential accomplishment. This is by developing programs for adult congenital heart disease that do not just concern the board-certified cardiologist, but the support services around them such as nurses and technicians. We know that when complications or problems occur, it may not be because of one single event, but it has to do with the entire hospital system.”

Everyone in the field, however, is relishing how much better patients’ lives are than they used to be.

“I have been blessed to have seen this field mature,” Landzberg said. “We are practicing on foundations laid by people who have built medicine and cardiology over the past 100 years so that we can see our patients enjoy their lives so much more than others have before. Every single person I take care of is a hero to me and a hero to our group. They have faced unbelievable challenges in their lives, and each one of them has adapted in a unique fashion. Yet, I think we are just at the surface of the innovation we are going to see in terms of the health care for our patients and the rising improvement in survival.” – by Erik Swain

Fernandes SM. J Am Coll Cardiol. 2012;60:2411-2418.
O’Leary JM. JAMA. 2013;309:984-986.
Warnes CA. J Am Coll Cardiol. 2008;52:143-263.
Curt J. Daniels, MD, can be reached at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205; email: curt.daniels@nationwidechildrens.org.
Yuli Kim, MD, can be reached at 3400 Civic Center Blvd., East Pavilion, Philadelphia, PA 19104; email: yuli.kim@uphs.upenn.edu.
Richard Krasuski, MD, can be reached at J2-4, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: krasusr@ccf.org.
Mike Landzberg, MD, can be reached at BACH Group, Department of Cardiology, Brigham and Women’s Hospital and Children’s Hospital, 300 Longwood Ave., Boston, MA 02115; email: mlandzberg@partners.org.
Carole Warnes, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: warnes.carole@mayo.edu.

Disclosures: Krasuski reports consulting for Actelion and Bayer. Landzberg reports working on trials funded by Actelion, Gilead and Pfizer. Daniels, Kim and Warnes report no relevant financial disclosures.