Mark S. Lesney

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

SAN DIEGO – The Society of Thoracic Surgeons Predicted Risk of Mortality score is a well-validated predictor of mortality during the first 30 days after cardiac surgery. The PROM score’s role in predicting longer-term survival, however, has not been investigated, according to Dr. John D. Puskas.

To fill this void, Dr. Puskas and his colleagues from Emory University, Atlanta, undertook a study to statistically validate PROM at 1, 3, 5, and 10 years after cardiac surgery. He presented the study’s results at the annual meeting of the Society of Thoracic Surgeons.

The investigators found that the STS PROM algorithm accurately predicted mortality both at 30 days and during 12 years of follow-up with almost equally strong discriminatory power. "This may have profound implications for informed consent as well as for longitudinal comparative effectiveness studies," Dr. Puskas stated in an interview.

"The STS Predicted Risk of Mortality models are probably underutilized and underappreciated in their power to predict short and long-term outcomes for our patients. The STS provides this service free of charge, and it is available online 24/7. I am hopeful that this newfound ability to predict longer-term survival after cardiac surgery will find utility in comparative effectiveness research and ultimately in shaping health policy," he added.

Dr. Puskas and his colleagues evaluated the survival rates for 24,222 patients who underwent cardiac surgery at a single academic center between Jan. 1, 1996, and Dec. 31, 2009. Long-term, all-cause mortality was determined by referencing the national Social Security Death Master File. Logistic and Cox survival regression analyses were used to evaluate the long-term predictive utility of PROM. The AUROC (area under the receiver operator characteristic) curve measured the discrimination of PROM at 1, 3, 5, and 10 years. Kaplan-Meier curves were stratified by quartiles of PROM risk to compare long-term survival. All analyses were performed for both the whole sample and 30-day survivors.

The investigators found an overall 30-day mortality rate of 2.78%.

Among all patients and 30-day survivors, AUROC values for PROM at 1, 3, 5, and 10 years were remarkably similar to the 30-day end point for which PROM is calibrated.

Moreover, PROM was highly predictive of Kaplan-Meier survival, even when this analysis was restricted to patients surviving beyond 30 days, he added.

Among 30-day survivors, each percent increase in PROM score was significantly associated with a 9.6% increase in instantaneous hazard of death (P less than .001).

Dr. Puskas and his colleagues reported no relevant disclosures with regard to their study.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

Left ventricular unloading in patients with end-stage heart failure has been shown to improve with the use of a left-ventricular assist device, according to the results of several recent clinical studies. This improvement includes favorable changes in myocardial structure and function, including beta-adrenergic responsiveness and myocyte contractility.  

Several molecular and genetic mechanisms have been correlated with these changes and might provide the basis for improvements in device behavior, as well as indications for potential targets for new therapeutic drugs and altered regimens for existing drugs. Such new treatments might have the potential to benefit not only patients who have received LVADs, but also heart failure patients as a whole, as reported in a "state-of-the-art" article published in the Feb. 8 issue of the Journal of the American College of Cardiology.

The LVAD population presents a unique and valuable opportunity to obtain myocardial tissue of patients with end-stage heart failure (HF) at the time of implantation, and often at the time of heart and/or LVAD explantation, after a period of unloading, according to Jennifer L. Hall, Ph.D., of the University of Minnesota, Minneapolis, and her colleagues in the United States and Europe. These tissue samples allow paired comparisons of before and after changes in molecular, genetic, and cytologic markers indicative of improvements that occur with the reverse remodeling of the human heart seen in response to LVADs. Key pathways involved include beta-adrenergic signaling, calcium handling, cytoskeleton proteins and integrins, various metabolism and growth-factor related genes, and natriuretic peptides and chromogranin A, all of which show positive responses in the normalizing heart.

The researchers supported their conclusions with a review of recent clinical trials and assembled data from a report by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) covering the years 2006-2009, which included the introduction of continuous-flow technology as well as the original pulsatile flow devices (J. Am. Coll. Cardiol. 2011;57:641-52).

Mechanical improvements in failing hearts treated with LVADS have been characterized by partial recovery of the contractile performance of myocytes. This includes improvements of the magnitude of shortening in isolated myocytes in response to beta-adrenergic agonists, of basal relaxation, and in the rise and fall in tension in trabecular muscle preparations.

Relevant markers and pathways found to be improved or normalized by LVAD support included:

• Beta-adrenergic signaling. Improvements in developed tension with LVADs have been shown to be associated with an increased beta-adrenergic receptor density. Because a novel combination of LVAD support and pharmacologic therapy – including the selective beta-2 agonist clenbuterol – showed promise in restoring ventricular function in patients with heart failure, investigators performed microarray analysis on six paired human heart samples isolated at the time of LVAD implantation and at the time of LVAD explantation due to sufficient myocardial recovery. Significant changes to a number of genes in the beta-adrenergic signaling pathway occurred in recovering hearts.

• Calcium handling. Although improvements in basal relaxation rates with LVADs have not been definitively linked to changes in calcium handling, the largest improvements in action potential and sarcoplasmic reticulum calcium content occurred in patients who achieved clinical recovery in response to LVADs and pharmacological therapy. However, improvements in calcium handling and contractility appear time dependent, with patients with shorter durations of support (less than 115 days) showing improvement, which reverted back to failing levels in patients with longer durations of support.

• Metabolism and growth factor–related genes. Several genes that regulated metabolism were found to change their expression during LVAD-supported recovery. These included arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, which was significantly down-regulated after unloading in the recovered hearts, returning to normal levels, in direct contrast to the up-regulation of AGAT seen in patients with heart failure. Insulin growth factor was elevated in patients at the time of LVAD explantation due to recovery. This was thought to aid in limiting atrophy and apoptosis during reverse remodeling and to promote repair and regeneration.

• Natriuretic peptides and chromogranin A. Unloading a failing heart with an LVAD was associated with a decrease in natriuretic peptides (which are activated during heart failure) and reestablishment of the local responsiveness of a key enzyme to cardiac atrial natriuretic peptide. Research by authors of the review showed that chromogranin A, which is known to be co-stored with natriuretic peptides in patients with dilated cardiomyopathy, was significantly increased in patients with congestive heart failure, compared with healthy controls, and decreased by ventricular support.

But all is not perfect in the LVAD-supported heart. In one study, there was a significant increase in total and cross-linked collagen in the myocardium, compared with nonfailing and medically managed patients with heart failure, which correlated with increased left ventricular stiffness. "Interestingly, the majority of [these] LVAD patients after implantation were not on ACE inhibitors, which have been demonstrated to improve fibrosis and remodeling." A subsequent retrospective cohort study of the same group, comparing LVAD patients who did and did not receive ACE inhibitor therapy after implantation, showed a significant decrease in collagen content and myocardial stiffness in the cohort with LVADs and ACE inhibitors. "These findings support the hypothesis that maximizing optimal medical management after ventricular unloading with LVADs may promote myocardial recovery." Furthermore, they provide a good example of the benefit of tissue studies on understanding the processes going on with these patients.

"Recent clinical trials have shown that both pulsatile and continuous-flow LVADs significantly improve the quality of life and functional capacity of patients with heart failure," the researchers concluded. "Identification of the biomarkers and factors that will aid in risk stratification for patients with LVAD therapy will help move this field forward and enhance patient care."

The study was sponsored by the National Institutes of Health, the American Heart Association, and the National Institutes for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust, and Imperial College London. Several of the authors reported receiving research support and/or honoraria or speakers fees from Thoratec, Heartware Inc., and Medtronic, all manufacturers of LVADs.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Since 2007, the use of preoperative beta-blockers has been a quality standard for patients undergoing coronary artery bypass graft surgery. However, a study by Dr. William T. Brinkman of the Cardiopulmonary Research Science and Technology Institute, Dallas, and his colleagues found no evidence that perioperative beta-blocker usage before CABG was beneficial.

Using data from the STS National Database for the period from 2000 to 2008, Dr. Brinkman and his colleagues compared outcomes between two propensity-matched groups obtained from their overall study group. These propensity-matched groups comprised 4,474 patients who received preoperative beta-blockers and 4,474 who did not.

In the propensity-matched groups, there was no difference between event rates in patients treated with beta-blockers and those who were not. However, significantly more beta-blocker-treated patients required intraoperative blood product use. Calculating the adjusted odds ratios showed that in the propensity-matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality, Dr. Brinkman said January 31 at the annual meeting of the Society of Thoracic Surgeons.

In the remaining unmatched cohort from the overall group study patients, only deep sternal infection (0.3% vs. 0.5% without beta-blockers), pneumonia (1.9% vs. 2.4% without beta-blockers) and intraoperative blood usage (37.2% vs. 34.1% without beta-blockers) reached statistical significance.

"We were unable to substantiate any benefit to routine use of preoperative beta-blocker therapy. Our findings do not support continued use of preoperative beta-blockade as a quality indicator for CABG," Dr. Brinkman said in an interview.

"This illustrates the importance of cardiac surgeon participation in decisions regarding quality and value in cardiac surgery."

Dr. Brinkman reported being on the speakers bureau of the Medicines Company; all authors had an ownership interest in the Heart Hospital Baylor Plano. Some of the authors had a financial relationship with heart device companies

Discussant Dr. David M. Shahian, chair of the STS National Database Workforce – which has advocated beta-blocker use as a quality control measure, stated that he disagreed with the conclusions of Dr. Brinkman’s study. "There are now almost 30 randomized clinical trials that demonstrate on average a 60% reduction in the odds of postoperative atrial fibrillation with the use of perioperative beta-blockade," he said.

Because of this and other benefits for patients with various heart conditions, the use of these drugs has had long-standing support, unless contraindicated. "For beta–blockade naive patients, beginning therapy as far in advance of surgery as possible, and titration to optimal heart rate, are the safest and most efficacious strategies," Dr. Shahian added.

An audience member pointed out – and Dr. Brinkman concurred – that the issue is not the value of beta-blockade as a therapy but its use for all patients as a quality indicator. This is especially problematic because there are no controls as to whether beta-blockade is properly used (as Dr. Shahian described) and administered to appropriate patients, as opposed to simply being part of a checklist of necessary prescriptions. Dr. Brinkman advocated further study of the issue before making blanket recommendations.

Dr. Shahian had no relevant disclosures regarding his comments.

SAN DIEGO – Although the right internal thoracic artery is biologically identical to the left internal thoracic artery, it is rarely used in coronary artery bypass grafting. In a study comparing the use of different graft sources for coronary artery bypass grafting (CABG), Dr. James Tatoulis and his colleagues found that the right internal thoracic artery (RITA) showed equivalent results to using the left internal thoracic artery (LITA).

Dr. Tatoulis of the Royal Melbourne Hospital and his colleagues evaluated consecutive RITA graft angiograms performed between 1986 and 2008. Patency was examined over time, by coronary territory, and by whether in situ or free RITA, and was compared with other coronary conduits, according to the study, which was presented January 31 at the annual meeting of the Society of Thoracic Surgeons.

A total of 5,766 patients had a RITA graft, usually as part of bilateral internal thoracic artery CABG. The operative mortality was 1.1%, and the rate of deep sternal infection was 1.5%. Of the nearly 7,800 coronary conduits studied, 991 RITA conduits were examined at a mean of 100 months postoperatively.

The overall 10-year RITA patency was 90%. RITA graft patency to the left anterior descending artery (n = 149) was 95% at 10 years and 90% at 15 years. Ten-year RITA patency to the circumflex marginal artery was 91% (n = 436); to the right coronary artery (RCA), 85% (n = 199); and to the posterior descending artery (PDA), 86% (n = 207). Ten-year RITA and LITA patencies to the left anterior descending artery were identical.

In situ RITA (n=451) and free RITA (n=540) had similar 10-year patencies, 89% vs. 91% respectively.

RITA patency was found to be significantly better than radial artery and saphenous vein grafts for both, circumflex marginal, and RCA/PDA. The 10 year survival of patients with RITA and LITA for triple vessel coronary disease were identical at 89%.

Dr. Tatoulis and his colleagues stated that late patencies of RITA are excellent, equivalent to the LITA for identical territories, and always better than radial artery and saphenous vein grafts.

"Unfortunately, less than 10% of all coronary artery surgery worldwide is performed with two internal thoracic arteries," Dr. Tatoulis said in an interview.

He added that the use of this technique could improve patient outcomes and could offer an even better revascularization alternative to stents, particularly for triple-vessel coronary disease.

Dr. Tatoulis and his colleagues reported that they had no relevant disclosures.

SAN DIEGO – Although the right internal thoracic artery is biologically identical to the left internal thoracic artery, it is rarely used in coronary artery bypass grafting. In a study comparing the use of different graft sources for coronary artery bypass grafting (CABG), Dr. James Tatoulis and his colleagues found that the right internal thoracic artery (RITA) showed equivalent results to using the left internal thoracic artery (LITA).

Dr. Tatoulis of the Royal Melbourne Hospital and his colleagues evaluated consecutive RITA graft angiograms performed between 1986 and 2008. Patency was examined over time, by coronary territory, and by whether in situ or free RITA, and was compared with other coronary conduits, according to the study, which was presented January 31 at the annual meeting of the Society of Thoracic Surgeons.

A total of 5,766 patients had a RITA graft, usually as part of bilateral internal thoracic artery CABG. The operative mortality was 1.1%, and the rate of deep sternal infection was 1.5%. Of the nearly 7,800 coronary conduits studied, 991 RITA conduits were examined at a mean of 100 months postoperatively.

The overall 10-year RITA patency was 90%. RITA graft patency to the left anterior descending artery (n = 149) was 95% at 10 years and 90% at 15 years. Ten-year RITA patency to the circumflex marginal artery was 91% (n = 436); to the right coronary artery (RCA), 85% (n = 199); and to the posterior descending artery (PDA), 86% (n = 207). Ten-year RITA and LITA patencies to the left anterior descending artery were identical.

In situ RITA (n=451) and free RITA (n=540) had similar 10-year patencies, 89% vs. 91% respectively.

RITA patency was found to be significantly better than radial artery and saphenous vein grafts for both, circumflex marginal, and RCA/PDA. The 10 year survival of patients with RITA and LITA for triple vessel coronary disease were identical at 89%.

Dr. Tatoulis and his colleagues stated that late patencies of RITA are excellent, equivalent to the LITA for identical territories, and always better than radial artery and saphenous vein grafts.

"Unfortunately, less than 10% of all coronary artery surgery worldwide is performed with two internal thoracic arteries," Dr. Tatoulis said in an interview.

He added that the use of this technique could improve patient outcomes and could offer an even better revascularization alternative to stents, particularly for triple-vessel coronary disease.

Dr. Tatoulis and his colleagues reported that they had no relevant disclosures.

SAN DIEGO – Although the right internal thoracic artery is biologically identical to the left internal thoracic artery, it is rarely used in coronary artery bypass grafting. In a study comparing the use of different graft sources for coronary artery bypass grafting (CABG), Dr. James Tatoulis and his colleagues found that the right internal thoracic artery (RITA) showed equivalent results to using the left internal thoracic artery (LITA).

Dr. Tatoulis of the Royal Melbourne Hospital and his colleagues evaluated consecutive RITA graft angiograms performed between 1986 and 2008. Patency was examined over time, by coronary territory, and by whether in situ or free RITA, and was compared with other coronary conduits, according to the study, which was presented January 31 at the annual meeting of the Society of Thoracic Surgeons.

A total of 5,766 patients had a RITA graft, usually as part of bilateral internal thoracic artery CABG. The operative mortality was 1.1%, and the rate of deep sternal infection was 1.5%. Of the nearly 7,800 coronary conduits studied, 991 RITA conduits were examined at a mean of 100 months postoperatively.

The overall 10-year RITA patency was 90%. RITA graft patency to the left anterior descending artery (n = 149) was 95% at 10 years and 90% at 15 years. Ten-year RITA patency to the circumflex marginal artery was 91% (n = 436); to the right coronary artery (RCA), 85% (n = 199); and to the posterior descending artery (PDA), 86% (n = 207). Ten-year RITA and LITA patencies to the left anterior descending artery were identical.

In situ RITA (n=451) and free RITA (n=540) had similar 10-year patencies, 89% vs. 91% respectively.

RITA patency was found to be significantly better than radial artery and saphenous vein grafts for both, circumflex marginal, and RCA/PDA. The 10 year survival of patients with RITA and LITA for triple vessel coronary disease were identical at 89%.

Dr. Tatoulis and his colleagues stated that late patencies of RITA are excellent, equivalent to the LITA for identical territories, and always better than radial artery and saphenous vein grafts.

"Unfortunately, less than 10% of all coronary artery surgery worldwide is performed with two internal thoracic arteries," Dr. Tatoulis said in an interview.

He added that the use of this technique could improve patient outcomes and could offer an even better revascularization alternative to stents, particularly for triple-vessel coronary disease.

Dr. Tatoulis and his colleagues reported that they had no relevant disclosures.

WASHINGTON – Breakthroughs in human genetics, combined with funding from the Affordable Care Act, have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the meeting, Dr. Collins shared his excitement at the state of human genetics in the postgenomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled the NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money(between $40 and $50 billion dollars a year) and yet in spite of that, [Food and Drug Administration] approvals of new molecular entities – that is, genuinely new drug therapeutics, not 'me-toos' – have been dropping steadily over the last 15 years,” he said.

The reasons are complex, he added, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which the NIH is and can be very much involved.

The NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is available to help to modify HTS hits to enable compounds to become more druglike and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage in the last 4–5 years; more than half are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” Dr. Collins said, “because this is where projects often go to die.”

The NIH can now assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009. The agency also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed clinical center, Dr. Collins said.

“And we have 50 and soon we will have 60 clinical and translational science awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” he added.

This new direction in research funding has involved unprecedented cooperation with the FDA, he said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS

WASHINGTON – Breakthroughs in human genetics, combined with funding from the Affordable Care Act, have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the meeting, Dr. Collins shared his excitement at the state of human genetics in the postgenomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled the NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money(between $40 and $50 billion dollars a year) and yet in spite of that, [Food and Drug Administration] approvals of new molecular entities – that is, genuinely new drug therapeutics, not 'me-toos' – have been dropping steadily over the last 15 years,” he said.

The reasons are complex, he added, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which the NIH is and can be very much involved.

The NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is available to help to modify HTS hits to enable compounds to become more druglike and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage in the last 4–5 years; more than half are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” Dr. Collins said, “because this is where projects often go to die.”

The NIH can now assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009. The agency also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed clinical center, Dr. Collins said.

“And we have 50 and soon we will have 60 clinical and translational science awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” he added.

This new direction in research funding has involved unprecedented cooperation with the FDA, he said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS

WASHINGTON – Breakthroughs in human genetics, combined with funding from the Affordable Care Act, have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the meeting, Dr. Collins shared his excitement at the state of human genetics in the postgenomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled the NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money(between $40 and $50 billion dollars a year) and yet in spite of that, [Food and Drug Administration] approvals of new molecular entities – that is, genuinely new drug therapeutics, not 'me-toos' – have been dropping steadily over the last 15 years,” he said.

The reasons are complex, he added, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which the NIH is and can be very much involved.

The NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is available to help to modify HTS hits to enable compounds to become more druglike and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage in the last 4–5 years; more than half are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” Dr. Collins said, “because this is where projects often go to die.”

The NIH can now assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009. The agency also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed clinical center, Dr. Collins said.

“And we have 50 and soon we will have 60 clinical and translational science awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” he added.

This new direction in research funding has involved unprecedented cooperation with the FDA, he said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS

Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.

In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.

Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.

He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.

Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).

Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.

Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.

Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years' follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.

Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel versus 7 months in the case of distal occlusion - a significant difference, Dr. Katsanos said.

He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.

"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).

"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.

Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.

In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.

Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.

He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.

Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).

Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.

Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.

Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years' follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.

Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel versus 7 months in the case of distal occlusion - a significant difference, Dr. Katsanos said.

He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.

"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).

"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.

Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.

In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.

Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.

He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.

Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).

Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.

Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.

Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years' follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.

Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel versus 7 months in the case of distal occlusion - a significant difference, Dr. Katsanos said.

He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.

"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).

"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.

WASHINGTON — Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not 'me-toos,' have been dropping steadily over the last 15 years,” Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” according to Dr. Collins, “because this is where projects often go to die.”

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

“And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” Dr. Collins added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS

WASHINGTON — Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not 'me-toos,' have been dropping steadily over the last 15 years,” Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” according to Dr. Collins, “because this is where projects often go to die.”

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

“And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” Dr. Collins added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS

WASHINGTON — Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.

Speaking with enthusiasm to those he addressed as his “peeps” at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.

This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.

Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.

“There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. … Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not 'me-toos,' have been dropping steadily over the last 15 years,” Dr. Collins said.

The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.

NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.

With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are “poised to go to the next step” of preclinical trials in animals, or the “Valley of Death,” according to Dr. Collins, “because this is where projects often go to die.”

NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.

NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.

“And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities,” Dr. Collins added.

This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.

Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping “de-risk” the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick disease type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).

If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.

Dr. Collins reported having no financial conflicts of interest with regard to his presentation.

Despite annual investments of up to $50 billion by the drug industry, FDA approvals of new entities have dropped steadily.

Source DR. COLLINS