I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Supplement Editor:
Marc S. Penn, MD, PhD

Contents

Depression and Heart Disease

The Bypassing the Blues trial: Collaborative care for post-CABG depression and implications for future research
Bruce L. Rollman, MD, MPH, and Bea Herbeck Belnap, Dr Biol Hum

Type D personality and vulnerability to adverse outcomes in heart disease
Johan Denollet, PhD, and Viviane M. Conraads, MD, PhD

Biofeedback in the treatment of heart disease
Christine S. Moravec, PhD, and Michael G. McKee, PhD

Device-Based Therapies

Electrical vagus nerve stimulation for the treatment of chronic heart failure
Hani N. Sabbah, PhD, FACC, FCCP, FAHA

Treatment of chronic inflammatory diseases with implantable medical devices
Ralph J. Zitnik, MD

Pioneer Lecture

New frontiers in cardiovascular behavioral medicine: Comparative effectiveness of exercise and medication in treating depression
James A. Blumenthal, PhD

Depression and Inflammatory Signaling in Alzheimer Disease

Depression: A shared risk factor for cardiovascular and Alzheimer disease
Dylan Wint, MD

Inflammatory signaling in Alzheimer disease
Robert Barber, PhD

Vascular signaling abnormalities in Alzheimer disease
Paula Grammas, PhD; Alma Sanchez, PhD; Debjani Tripathy, PhD; Ester Luo, PhD; and Joseph Martinez

Stress in Medicine

Stress in medicine: Strategies for cargivers, patients, clinicians—The burdens of caregiver stress
Michael G. McKee, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Promoting better outcomes with stress and anxiety reduction
A. Marc Gillinov, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Addressing the impact of clinician stress
M. Bridget Duffy, MD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback in the treatment of stress
Richard N. Gevirtz, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Biofeedback for extreme stress: Wounded warriors
Carmen V. Russoniello, PhD

Stress in medicine: Strategies for cargivers, patients, clinicians—Panel discussion

Annual Review of Key Publications in Heart-Brain Medicine

Key 2010 publications in behavioral medicine
Laura D. Kubzansky, PhD, MPH

Novel Findings in Heart-Brain Medicine

Imaging for autonomic dysfunction
Stephen E. Jones, MD, PhD

Neurohormonal control of heart failure
Gary S. Francis, MD

Poster Abstracts

Abstract 1: Biofeedback in coronary artery disease, type 2 diabetes, and multiple sclerosis
Matt Baumann, BS; Dana L. Frank, PhDc; Michael Liebenstein, PhD; Jerry Kiffer, MA; Leo Pozuelo, MD; Leslie Cho, MD; Gordon Blackburn, PhD; Francois Bethoux, MD; Mary Rensel, MD; Betul Hatipoglu, MD; Jim Young, MD; Christine S. Moravec, PhD; and Michael G. McKee, PhD

Abstract 2: Biofeedback in heart failure patients awaiting transplantation
Dana L. Frank, PhDc; Matt Baumann, BS; Lamees Khorshid, PsyD; Alex Grossman-McKee; Jerry Kiffer, MA; Wilson Tang, MD; Randall C. Starling, MD; Michael G. McKee, PhD; and Christine S. Moravec, PhD

Abstract 3: Prevalence of anxiety and type D personality in an outpatient ICD clinic
Leo Pozuelo, MD; Melanie Panko, RN; Betty Ching, RN; Denise Kosty-Sweeney, RN; Scott Bea, PhD; Karen Broer, PhD; Julie Thornton, MS; Kathy Wolski, MPH; Karl-Heinz Ladwig, MD; Sam Sears, PhD; Suzanne Pedersen, PhD; Johan Denollet, PhD; and Mina K. Chung, MD

Abstract 4: Sudden unexpected death in epilepsy: Finding the missing cardiac links
Lara Jehi, MD; Thomas Callahan, MD; David Vance, MD; Liang Li, PhD; and Imad Najm, MD

Abstract 5: Low levels of depressive symptoms predict the combined outcome of good health-related quality of life and no cardiac events in patients with heart failure
Kyoung Suk Lee, Terry A. Lennie, Sandra B. Dunbar, Susan J. Pressler, Seongkum Heo, and Debra K. Moser

Abstract 6: Spectral HRV and C-reactive protein in a community-based sample of African Americans
Larry Keen II, MS

Abstract 7: Symptoms of depression and anxiety determine fatigue but not physical fitness in patients with CAD
Adomas Bunevicius, Albinas Stankus, Julija Brozaitiene, and Robertas Bunevicius

Abstract 8: Depression, cardiovascular symptom reporting, and functional status in heart failure patients
Andrew J. Wawrzyniak, Kristie M. Harris, Kerry S. Whittaker, Nadine S. Bekkouche, Sarah M. Godoy, Willem J. Kop, Stephen S. Gottlieb, and David S. Krantz

Abstract 9: Cardiotopic organization of the functionally associated axons within the cervical vagus nerves that project to the ventricles of the cat heart
E. Adetobi-Oladele, S.E. Ekejiuba, M. Shirahata, S. Ruble, A. Caparso, and V.J. Massari

Abstract 10: Significance of carotid intimal thickening in hypertensive patients
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 11: Lacunar infarcts in a hypertensive population and their correlation with systemic vascular resistance
Shashi K. Agarwal, MD, and Neil K. Agarwal

Abstract 12: Age-matched attenuation of both autonomic branches in chronic disease: I. Hypertension
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 13: Age-matched attenuation of both autonomic branches in chronic disease: II. Diabetes mellitus
Aaron I. Vinik, PhD, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 14: Age-matched attenuation of both autonomic branches in chronic disease: III. Coronary artery disease
Rohit R. Arora, MD; Samanwoy Ghosh-Dastidar, PhD; and Joseph Colombo, PhD

Abstract 15: Age-matched attenuation of both autonomic branches in chronic disease: IV: HIV/AIDS
Patrick Nemechek, DO; Sam Ghosh Dastidar, PhD; and Joe Colombo, PhD

Abstract 16: The existential dilemma of coronary artery disease: Nurse as agent of change in the emerging field of behavioral cardiology
Patricia Baum, RN, BSN

Abstract 17: Phantom shocks as markers of underlying PTSD and depression
Ana Bilanovic, Jane Irvine, Adrienne Kovacs, Ann Hill, Doug Cameron, and Joel Katz

Abstract 18: Psychologic markers of stress, anxiety, and depression are associated with indices of vascular impairment in women with high stress levels and advanced coronary artery disease
U.G. Bronas, R. Lindquist, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik

Abstract 19: Personality dimensions and health-related quality of life in patients with coronary artery disease
Juste Buneviciute, Margarita Staniute, and Robertas Bunevicius

Abstract 20: Behavioral stress results in reversible myocardial dysfunction in a rodent model
Fangping Chen, Sherry Xie, and Mitchell S. Finkel

Abstract 21: Perceived stress, psychosocial stressors, and behavioral factors: Association with inflammatory, immune, and neuroendocrine biomarkers in a cohort of healthy very elderly men and women
Grant D. Chikazawa-Nelson, PhD; Kenna Stephenson, MD; Anna Kurdowska, PhD; Douglas Stephenson, DO; Sanjay Kapur, PhD; and David Zava, PhD

Abstract 22: Prognostic significance of PD2i in heart failure patients
Iwona Cygankiewicz, MD, PhD; Wojciech Zareba, MD, PhD; Scott McNitt, MS; and Antoni Bayes de Luna, MD

Abstract 23: Sympathovagal imbalance assessed by heart rate variability correlates with percent body fat and skeletal muscle, independent of body mass index
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 24: Trajectory of depressive symptoms in patients with heart failure: Influence on cardiac event-free survival
Rebecca L. Dekker, PhD, ARNP; Terry A. Lennie, PhD, RN; Nancy M. Albert, PhD, CCNS; Mary K. Rayens, PhD; Misook L. Chung, PhD, RN; Jia-Rong Wu, PhD, RN; and Debra K. Moser, DNSc, RN

Abstract 25: Autonomic modulation of ankle brachial index assessed by heart rate variability in healthy young male and female volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 26: Toward uncovering key factors in adherence in a post–heart transplant population: A project in the making
Flavio Epstein, PhD, and Parag Kale, MD

Abstract 27: Sympathovagal tone assessed by heart rate variability is directly related to body mass index, percent body fat, and skeletal muscle in healthy male and female young volunteers
David Martinez Duncker R., MD, PhD; Martha Elva Rebolledo Rea, MD, MSc; Ernesto González Rodríguez, MD, MSc; David M. Duncker Rebolledo, MD; and Martha E.M. Duncker Rebolledo, MS

Abstract 28: Biofeedback training to promote ANS resilience in Army ROTC cadets
M. Haney, MS; K. Quigley, PhD; B. Batorsky, PhD; LTC J. Nepute; S. Moore, BS; A. Uhlig, MS; and L. Zambrana, BA

Abstract 29: Trait hostility is associated with endothelial cell apoptosis in healthy adults
Manjunath Harlapur, MD; Leah Rosenberg, MD; Lauren T. Wasson, MD, MPH; Erika Mejia, BA; Shuqing Zhao, MS; Matthew Cholankeril, BA; Matthew Burg, PhD; and Daichi Shimbo, MD

Abstract 30: Vascular depression impairs health-related behavior
K.K. Hegde, B.T. Mast, and P.A. Lichtenbeg

Abstract 31: Detection of acute mild hypovolemia by nonlinear heart rate variability
Pamela L. Jett, MD; James E. Skinner, PhD; Jerry M. Anchin, PhD; Daniel N. Weiss, MD; Douglas E. Parsell, PhD; and James J. Hughes, MD

Abstract 32: Metabolic pathway perturbation of patients with chronic heart failure and comorbid major depressive disorder
Wei Jiang, MD; David Steffens, MD; Edward Karoly, PhD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Christopher M. O’Connor, MD; Ranga Krishnan, MD; and Rima Kaddurah-Daouk, PhD

Abstract 33: Headache: An unusual presenting symptom of Guillain-Barré syndrome
Kanchan Kanel, Aisha Chohan, Reza Vaghefi hosseini, Murray Flaster, and Hesham Mohamed

Abstract 34: Effect of stress reduction using the BREATHE technique on inflammatory markers and risk factors for atherosclerosis
John M. Kennedy, MD, FACC, and Donna J. Miller, MSN, FNP-C

Abstract 35: The lite HEARTEN study: How exercise and relaxation techniques affect subclinical markers of heart disease in women: Patterns of change and effect sizes to power future studies of treatment efficacy
R. Lindquist, U. Bronas, A. Leon, Y. Song, D. Windenburg, D. Witt, D. Treat-Jacobson, E. Grey, W. Hines, and K. Savik,

Abstract 36: Cardiovascular effects of spinal cord stimulation in hypertensive patients
Shailesh Musley, Xiaohong Zhou, Ashish Singal, and David Schultz

Abstract 37: Screening for depression and anxiety in patients admitted for coronary artery bypass graft: Comparison of nurses’ reports vs hospital anxiety and depression scale
Ali-Akbar Nejatisafa, Nazila Shahmansouri, and Sina Mazaheri

Abstract 38: Hormonal heart-mind connections: Clinical and research implications
Jan B. Newman, MD, MA, FACS, ABIHM

Abstract 39: Gender differences in longevity and sympathovagal balance
Edward Pereira, MD; Scott Baker, MD; Robert Bulgarelli, DO; Gary L. Murray, MD; Rohit R. Arora, MD; and Joseph Colombo, PhD

Abstract 40: Neuroendocrine, inflammatory, and immune biomarkers associated with body composition, depression, and cognitive impairment in elderly men and women
Jean P. Roux, PhD; Kenna Stephenson, MD; Sanjay Kapur, PhD; David Zava, PhD; Robert Haussman, PhD; Christine Gély-Nargeot; and Courtney Townsend

Abstract 41: Short-term heart rate complexity determined by the PD2i algorithm is reduced in patients with type 1 diabetes mellitus
James E. Skinner, Daniel N. Weiss, Jerry M. Anchin, Zuzana Turianikova, Ingrid Tonhajzerova, Jana Javorkova, Kamil Javorka, Mathias Baumert, and Michal Javorka

Abstract 42: Heart rate variability biofeedback and mindfulness: A functional neuroimaging study
Paula Sigafus

Abstract 43: Heart, brain, and the octopus connection
Nirmal Sunkara

Abstract 44: Relationship between depressive symptoms and cardiovascular risk factors in black individuals
Ali A. Weinstein, PhD; Preetha Abraham; Stacey A. Zeno, MS; Guoqing Diao, PhD; and Patricia A. Deuster, PhD

Abstract 45: History of depression affects patients’ depression scores and inflammatory biomarkers in women hospitalized for acute coronary syndromes
Erica Teng-Yuan Yu, PhD, RN, ARNP

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Coronary artery bypass graft (CABG) surgery is one of the most common and costly medical procedures performed in the United States.¹ However, up to one-half of post-CABG patients report significant increases in mood symptoms following surgery,² and these individuals are more likely to report poorer health-related quality of life (HRQoL) and worse functional status,³ and to experience higher risk of rehospitalizations⁴ and death⁵ despite a satisfactory surgical result.

Strategies to detect and then manage depression in CABG patients and in cardiac populations are of great interest given the potential for depression treatment to reduce cardiovascular morbidity.

In recognition of the prevalence and excess burdens associated with this condition, a recent American Heart Association (AHA) Science Advisory has advocated regular screening and treatment of cardiac patients for depression.⁶ Yet, the Advisory has been controversial,^7,8 as most depression treatment trials conducted in patients with cardiac disease have had less-than- anticipated impact on mood symptoms,^7,9–14 cardiovascular morbidity,^7,9,10,14 or mortality.^{7,9–11,13–15} Possible explanations include: (1) dependence solely on single antidepressant agents^9,14 that, in general, are often ineffective,¹⁶ untolerated, or otherwise discontinued by patients¹⁷; (2) reliance on psychologic counseling in elderly, medically ill populations who may be either unwilling or unable to adhere to successive face-to-face encounters with a therapist^10,13; (3) inadequate consideration of patients’ preferences for type and location of treatment^18,19; (4) insufficient treatment adherence^20,21; (5) perceived stigma of depression²²; (6) brief duration of treatment and followup^9,13,14; and (7) higher-than-expected spontaneous remission rates for depression.^10,14

Reprinted, with permission, from Effective Clinical Practice (Wagner EH. Eff Clin Pract 1998; 1:2-4). Copyright 1998 American College of Physicians. All rights reserved.

Over the past 15 years, numerous trials have supported use of the flexible real-world collaborative care approach to improve outcomes for depression^27,28 as well as a variety of other chronic medical conditions^29–32 and at a lower total cost of care.^33,34 This strategy is supported even outside the framework of a trial.^35,36 Moreover, collaborative care was the clinical framework³⁷ for a Robert Wood Johnson Foundation program to realign clinical and financial incentives for providing sustainable high-quality depression treatment in primary care.^38–41 It is also embraced by depression improvement initiatives supported by the MacArthur (http://www.depression-primarycare.org/)⁴² and Hartford (http://impact-uw.org/)⁴³ Foundations. In recognition, a National Heart Lung and Blood Institute–sponsored working group on the assessment and treatment of depression in patients with cardiovascular disease endorsed testing of collaborative care strategies for treating depression in combination with “usual cardiologic care” as a method to improve clinical outcomes.²³ Collaborative care has also emerged as an integral part of the “patient-centered medical home” model presently advocated by leading professional organizations to organize and reimburse PCPs for providing high-quality chronic illness care.⁴⁴

Despite this interest in collaborative care, to date, only the “Bypassing the Blues” (BtB) trial has reported the impact of this depression treatment strategy on the clinical outcomes of a population with cardiac disease.⁴⁵ In an effort to help disseminate collaborative care more broadly into routine practice as envisioned by the AHA Science Advisory, we pre sent the key design elements and main outcome findings from BtB, along with our efforts to improve upon and expand the model for testing in other cardiac conditions.

STUDY OVERVIEW

IDENTIFICATION OF DEPRESSION

Applying the two-step Patient Health Questionnaire (PHQ) depression screening strategy recently endorsed by the AHA Science Advisory,⁶ BtB recruited medically stable post-CABG patients prior to hospital discharge from seven Pittsburgh-area hospitals between 2004 and 2007. To support our recruitment efforts, we developed press releases, wall posters, newsletter articles, and brochures to inform physicians, hospital staff, patients and their families about the impact of depression on cardiovascular disease and our study (available for download at: www.bypassingtheblues.pitt.edu).

Study nurse-recruiters obtained patients’ signed informed consent to undergo screening with the two-item PHQ-2²² (“Over the past 2 weeks have you had: little interest or pleasure in doing things or “felt down, depressed, or hopeless?”).⁴⁷ We defined a positive PHQ-2 depression screen as patient endorsement of one or both of its items (90% sensitive and 69% specific for major depression among patients with cardiac disease when measured against the “goldstandard” Diagnostic Interview Schedule⁴⁸).

The psychologic and physical symptoms of depression often overlap with the post-CABG state (eg, fatigue, sleeplessness) and these elevations in depressive symptoms frequently remit spontaneously. Therefore, we administered the nine-item PHQ-9⁴⁹ over the telephone 2 weeks following hospital discharge to confirm the PHQ-2 screen. We required that patients score at least 10 to remain protocol-eligible, a threshold that signified at least a moderate level of depressive symptoms⁴⁹ and has been described as “virtually diagnostic” for depression among patients with cardiac disease (90% specific).⁴⁸

ASSESSMENT AND OUTCOME MEASURES

Upon confirmation of all protocol-eligibility criteria prior to randomization, we conducted a detailed baseline telephone assessment that included the SF-36⁵⁰ to determine mental (MCS) and physical (PCS) HRQoL, the 12-item Duke Activity Status Index (DASI)²⁶ to determine disease-specific physical functioning, and the 17-item Hamilton Rating Scale for Depression (HRS-D)²⁷ to track mood symptoms. Telephone assessors blinded as to randomization status readministered these measures at 2, 4, and 8 months’ followup and routinely inquired about any hospitalizations and mental health visits patients may have experienced since their last telephone assessment. Whenever they detected a potential “key event,” we requested a copy of relevant medical records from the hospital where the event occurred. These were then forwarded to a physician adjudication committee that was blinded as to the patient’s depression and intervention status to classify the nature of the event (cardiovascular, psychiatric, or “other”).

COLLABORATIVE CARE INTERVENTION

Following randomization, a nurse care manager telephoned each intervention patient to: (1) review his or her psychiatric history, including use of any prescription medications, herbal supplements, or alcohol to self-medicate depressive symptoms; and (2) provide education about depression, its impact on cardiac disease, and basic advice for managing the condition (eg, exercise, sleep, social contact, alcohol avoidance); and (3) assess the patient’s treatment preferences for depression.

Using a shared decision-making approach, patients then selected one or more of the following treatment options: (1) a workbook designed to impart self-management skills for managing depression⁵¹; (2) antidepressant pharmacotherapy, primarily a selective serotonin-reuptake inhibitor (SSRI) chosen according to patient preference, prior usage, and insurance coverage, but prescribed by the patient’s PCP⁴⁶; (3) referral to a local mental health specialist in keeping with the patient’s insurance coverage; and (4) “watchful waiting” if the patient’s mood symptoms were only mildly elevated and he or she had no prior history of depression.

Afterward, the nurse care manager telephoned the patient approximately every other week during the acute phase of treatment to practice skills imparted through workbook assignments, monitor pharmacotherapy, promote adherence with recommended care, and suggest adjustments in treatment as applicable. Depending upon the patient’s motivation to complete workbook assignments and whether he or she accepted antidepressant pharmacotherapy, these followup contacts typically lasted 15 to 45 minutes and continued for 2 to 6 months. The patient subsequently transitioned to the “continuation phase” of treatment, during which the care manager contacted him or her less frequently until the end of our 8-month intervention.

WEEKLY CASE REVIEW

Following discussion, the clinical team typically formulated one to three treatment recommendations that the nurse conveyed to the patient via telephone. As PCPs were responsible for prescribing all medications and dosage adjustments, we conveyed pharmacologic recommendations to them via telephone or fax. PCPs could accept or reject these recommendations at their discretion. If the patient demonstrated little response, had complex psychosocial issues (eg, impending divorce), or had an uncertain diagnosis (eg, bipolar disorder), we typically recommended referral to a mental health specialist. At quarterly intervals and at the end of the 8-month intervention, we mailed the PCP a summary of the patient’s progress that included antidepressant dosages, PHQ-9 scores, and other pertinent information.⁴⁶

PROMOTING MEDICATION ADHERENCE

To promote adherence with our treatment recommendations, our nurse care managers offered to call in antidepressant prescriptions to patients’ pharmacies under their PCP’s verbal orders, and then forwarded an order sheet for the PCP to sign and return to document it.

Some patients agreed to a trial of antidepressant pharmacotherapy but then declined or quickly discontinued it because of cost, side effects, or concerns about dependence, safety, or stigma. In these instances, particularly if the patient remained symptomatic, care managers attempted to overcome the patient’s reluctance using various motivational interviewing approaches. Care managers also provided educational materials, including the workbook,⁵¹ to mitigate any concerns, and emphasized they would monitor the patient’s clinical status closely and report back to the clinical team and the patient’s PCP for ongoing guidance. The care manager also informed the PCP of the patient’s reason(s) for nonadherence, raising the possibility that the clinician could help overcome the patient’s resistance.

OUTCOMES

Self-reported measures

PROCESSES OF CARE

Of the 150 patients randomized to our collaborative care intervention, 146 (97%) had one or more telephone care manager contacts and 83% had three or more contacts by the 4-month followup. At the 8-month conclusion of our intervention, the median number of care manager contacts per patient was 10 (range: 1–28). The proportion of intervention patients using antidepressants also increased from 15% at baseline to 44% by 8 months, and 4% reported a visit to a mental health specialist. In comparison, 31% (P = .05) and 6% (NS) of usual-care patients, respectively, were using an antidepressant or saw a mental health specialist during this period.⁴⁵

HEALTH SERVICES UTILIZATION

Depressed patients reported a similar 8-month incidence of all-cause (33% intervention vs 32% usual care) and cardiovascular-cause (15% vs 18%) rehospitalizations by randomization status. However, male intervention subjects tended to have a lower incidence of cardiovascular-cause rehospitalizations than men randomized to usual care (13% vs 23%; P = .07) and one that was similar to that of nondepressed BtB male post-CABG patients (13%). Notably, we did not observe a similar pattern among female patients enrolled in BtB. To better examine the “business case” for treating post-CABG depression, we are presently analyzing claims data from Medicare and from two large western Pennsylvania insurance providers and hope to report these analyses shortly.

DISCUSSION

BtB was the first trial to examine the impact of a real-world collaborative care strategy for treating depression in post-CABG patients or in any other cardiac population. The generalizability of our treatment strategy is enhanced by multiple design features including: (1) use of a brief, validated, two-stage PHQ depression screening procedure that was endorsed by the AHA and can be routinely implemented by nonresearch clinical personnel; (2) a centralized telephone-delivered intervention; (3) reliance on a variety of safe, effective, simple-to-dose and increasingly generic pharmacotherapy options, a commercially available workbook, and community mental health specialists to deliver step-up care; (4) consideration of patients’ prior treatment experiences, current care preferences, and insurance coverage when recommending care; (5) use of trained nurses as care coordinators across treatment delivery settings and providers across state lines; and (6) an informatics infrastructure designed to document and promote delivery of evidence-based depression treatment, care coordination, and efficient internal operations.

The ES improvement in HRS-D we observed in the BtB trial was at the upper end of a meta-analysis of 37 collaborative care trials for depression involving 12,355 primary care patients (ES: 0.25; 0.18–0.32).²⁷ It compared favorably with the improvements reported by the ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) randomized trial (ES: 0.22; 0.11–0.33),¹⁰ the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (ES: 0.14; −0.06–0.35),⁹ and the citalopram arm of the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) trial (ES: 0.29; 0.05–0.52).¹³ However, our ES improvement was smaller than those generated by the more laborintensive and face-to-face interventions provided by Freedland et al’s trial of cognitive behavioral therapy (CBT) for post-CABG depression (ES: 0.73; 0.29–1.20; N = 123),¹⁵ the COPES (Coronary Psychosocial Evaluation Studies) trial of problem-solving therapy (ES: 0.59; 0.18–1.00) that was the first to report a significant reduction in major adverse cardiac events from treating depression,^15,56 or a recent meta-analysis of psychologic treatments in patients with medical disorders (ES: 1.00; 0.57–1.44).⁵⁷

Although the BtB intervention focused on depressed post-CABG patients, it is also generalizable to patients with other cardiovascular conditions. Moreover, the model can be readily adapted into practices at a variety of integrated health care delivery systems.⁵⁸ Therefore, we believe collaborative care interventions such as ours will become more widespread as elements of the 2010 Affordable Care Act are phased in.

FUTURE DIRECTIONS

Despite positive outcomes on HRQoL and mood symptoms generated by BtB and other recent trials,^15,56 it remains unclear whether effective depression treatment can reduce cardiovascular morbidity and mortality. Given the trend toward a reduced incidence of rehospitalization for cardiovascular causes among depressed male patients in BtB and findings from COPES⁵⁶ and other trials,⁷ we believe a comparative effectiveness trial of reasonable size (N < 2,000 study subjects) and cost will require an intervention capable of producing an ES reduction in mood symptoms of at least 0.50. Furthermore, because of declines in morbidity and mortality over the past decade following CABG surgery and myocardial infarction,¹ we also believe heart failure remains the only prevalent cardiovascular disorder for which to conduct this future comparative effectiveness trial.

Because an improvement of at least 0.50 ES in mood symptoms is higher than the ES improvements presently generated by collaborative care treatment approaches, it is critical to develop new interventions that blend the scalability and patient acceptability of telephone-delivered collaborative care with the greater efficacy of more intensive face-to-face counseling strategies. To address this need, we are investigating how best to incorporate Internet-delivered computerized cognitive behavioral therapy (CCBT) and other online strategies for treating depression into the BtB model. CCBT is a new and evolving technology that can improve patients’ access to personalized, convenient, and effective treatment for depression.⁵⁹ Used primarily in the United Kingdom, Australia, and the Netherlands, CCBT has attracted growing interest by US investigators.⁶⁰ Importantly, some CCBT programs are able to produce the ES improvements in mood symptoms needed to potentially demonstrate a reduction of cardiovascular morbidity⁶¹ and do so reliably, at scale, and at low cost compared with more labor-intensive methods of care.^62–64 Still, pilot testing of this innovative treatment approach is necessary to evaluate: (1) whether CCBT will be as effective among depressed patients with cardiovascular disease as among those recruited from primary care settings; (2) how best to integrate CCBT within a collaborative care program linked to cardiovascular patients’ usual sources of cardiac and primary care; and (3) whether incorporating Internet-delivered CCBT into a “traditional” collaborative care program that provides active follow-up, pharmacotherapy monitoring, and mental health specialty referral as options provides either no additional benefit (ES ∼0.30), benefit approaching that of CCBT alone (ES: ∼0.60),⁶¹ or an additive or synergistic benefit approaching face-to-face CBT (ES: ≥ 0.80).^15,65 Findings from these studies could also have profound implications for changing the way both cardiovascular and mental health conditions are treated⁶⁶ and direct further attention to the emerging field of e-mental health by other US investigators.⁶⁰

Depression has been studied extensively in relation to cardiovascular disease.^1–3 In addition to depression, anger⁴ and anxiety⁵ also may promote coronary artery disease (CAD), suggesting that emotional distress in general may be related to increased cardiovascular risk. Evidence indicates that the general distress shared across depression, anger, and anxiety predicts CAD, even after controlling for each of these specific negative emotions.⁶

THE CONCEPT OF TYPE D PERSONALITY

Lately, there is a renewed interest in broad individual differences in general distress and heart disease.⁷ Since psychologic factors often cluster together in individual patients, biobehavioral research may benefit from the identification of discrete personality subtypes.⁸ This focus on the identification of psychologically vulnerable patients who are at increased risk for adverse outcomes has led to the introduction of the distressed⁹ or type D¹⁰ personality profile in cardiovascular research. This personality construct is defined as follows:

“The type D (distressed) personality profile refers to a general propensity to psychological distress that is characterized by the combination of negative affectivity and social inhibition.”¹⁰

Negative affectivity, or the tendency to experience negative emotions across time and situations, is a major determinant of emotional distress in cardiac patients.^9,10 Patients who score high on this trait frequently report feelings of dysphoria, worry, and tension. Social inhibition, or the tendency to inhibit the expression of emotions or behavior, is a major determinant of social distress.^9,10 Patients who score high on this trait tend to avoid negative reactions from others.

Both traits define psychologically vulnerable patients and can be assessed with the type D scale (DS14).¹⁰ This brief measure consists of a seven-item negative affectivity subscale (eg, I often feel unhappy) and a seven-item inhibition subscale (eg, I am inhibited in social interactions), and has a clear two-factor structure and good reliability (Cronbach’s α = .88 and .86). Patients are classified as type D if they score 10 or higher on both DS14 subscales.¹⁰ The prevalence of type D personality ranges between 20% and 40% across different types of cardiovascular conditions.

The type D construct was designed for the early identification of chronically distressed patients. This article reviews (1) the risk of adverse events associated with type D, (2) the extent to which type D is distinct from depression, (3) the biologic pathways of type D, and (4) the implications of the type D personality profile.

RISK ASSOCIATED WITH TYPE D

The relationship between type D personality and adverse events has also been investigated in other cardiovascular conditions. Type D has been associated with poor prognosis in patients with peripheral arterial disease,¹⁷ but evidence for the prognostic role of type D in patients with chronic heart failure is mixed. In a study of patients with heart failure following myocardial infarction, type D predicted cardiac death independent of disease severity¹⁸; in a study of heart failure patients who underwent cardiac transplantation, type D was associated with early allograft rejection and increased mortality.¹⁹ However, type D was not associated with cardiac death in a recent, larger heart failure study.²⁰ The link between psychologic factors and heart failure is complex³ and may be less obvious than the type D-CAD link.²⁰ Type D has also been associated with the occurrence of life-threatening arrhythmias following implantable cardioverter defibrillator (ICD) treatment,²¹ and it has been shown to predict an increased risk for mortality in ICD patients, independent from shocks and disease severity.²²

The wide range in odds ratios and confidence intervals indicates disparity in data across these type D studies (Table 1). We recently performed a metaanalysis of prospective studies between 1996 and 2009 to provide a more reliable estimate of the risk associated with type D. In this analysis, type D was associated with a threefold increased risk of adverse events²³; the confidence interval of this pooled odds ratio ranged from 2.7 to 5.1. In addition, type D personality was associated with a threefold increased risk (range, 2.6 to 4.3) of emotional distress over time.²³ From the recent studies that were not included in this meta-analysis, one reported negative findings²⁰ and three others positive findings^16,21,22 on the risk associated with type D.

COMPARING DEPRESSION AND TYPE D

Clinical evidence shows that, after adjustment for depression, type D remained a predictor of adverse cardiac events in CAD.^16,24,25 Following ICD implantation, anxious type D patients were at risk of ventricular arrhythmias, whereas depression did not predict arrhythmias.²¹ Type D also exerts an adverse effect on patients’ health status following coronary bypass surgery,²⁶ heart failure,²⁷ or myocardial infarction,²⁸ adjusting for depressive symptoms. Type D is related to biomarkers of increased stress levels independent of depression^29–31 and, unlike depression, type D is not confounded by the severity of cardiac disorder.³²

Following myocardial infarction, only one of four distressed patients met criteria for both type D and depression; most had one form of distress but not the other.³² Research in healthy³³ and in cardiac³⁴ populations confirmed that items from depression and type D scales reflect different distress factors. After adjustment for depression at baseline, type D also predicted the incidence,³⁵ persistence,³⁶ and severity^37,38 of depression and anxiety. However, these findings do not imply that depression and type D are antonymous perspectives or that one perspective is better than the other in predicting outcomes; rather, we would like to argue that both constructs represent complementary perspectives that have added value.²³

BIOLOGIC PATHWAYS OF TYPE D

Other studies found that type D was associated with inflammatory dysregulation. In healthy adults, type D has been related to higher concentrations of C-reactive protein.⁴¹ In heart failure patients, type D is associated with increased plasma levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α and its soluble receptors 1 and 2.^46,47 Increased TNF-α levels may cause suppression of bone-marrow–derived endothelial progenitor cells (EPCs) that play an important role in maintaining vascular integrity. The negative affectivity component of type D has been shown to predict decreased circulating EPC counts in healthy individuals⁴⁸; another study found that these EPC numbers were reduced by more than 50% in heart failure patients with a type D personality.⁴⁹ Type D personality is also associated with an increased oxidative stress burden in patients with chronic heart failure.²⁹ Studies on genetic linkage⁵⁰ and heritability⁵¹ further support biologic underpinnings of the type D construct.

Regarding pathways that may explain the effect of type D, some issues are of special interest. First, genetic factors contribute to stability in type D personality, but environmental factors may induce changes in type D characteristics over time.⁵¹ Hence, given this role of environmental influences over time, behavioral intervention would be feasible and useful in type D patients. Second, type D can promote heart disease indirectly through behavioral pathways. Type D has been associated with a sedentary lifestyle,^41,52 an unhealthy diet,⁵³ and a passive coping style.^54,55 Poor adherence to medical treatment^56,57 and reluctance to consult clinical staff⁵⁸ may jeopardize the working relationship with type D patients in clinical care. Intervention may focus on the management of these behavioral risk factors in type D patients. Third, many of these biologic^{40–43,48,50,51} and behavioral^41,52–54 pathways have also been documented in healthy type D individuals, which suggests that these associations cannot be explained away by the confounding effect of underlying cardiovascular disease.

CLINICAL IMPLICATIONS OF TYPE D

The findings from type D research have a number of clinical implications. Type D is associated with an increased risk of adverse events,²³ chronic distress,^35–38 and suicidal ideation.⁵⁹ Type D may also have an adverse effect on the outcome of invasive treatment.^{14,19,21,22,24,26,60}

Type D was associated with mortality and morbidity at 9 months¹⁴ and 2 years²⁴ following coronary artery stenting, and with impaired health status 1 year following bypass surgery.²⁶ Type D also predicted mortality and allograft rejection following heart transplantation,¹⁹ and an increased risk of ventricular arrhythmia²¹ and mortality²² in ICD patients. Researchers from the Cleveland Clinic have shown that type D is a risk factor for anxiety in ICD patients.⁶⁰

Regarding the DSM-IV classification by the American Psychiatric Association,⁶¹ type D qualifies for the diagnosis “psychological factors affecting medical condition” (Section 316). In keeping with this classification, the diagnostic category type D affects (1) the course of cardiovascular conditions,²³ (2) the treatment of these conditions,^56,57 and (3) the working relationship with medical staff.⁵⁸ At present, no clinical trial has examined whether intervention for distress among type D patients alters their risk for adverse events. Nevertheless, some have argued that it is plausible for type D patients to learn new strategies to reduce their level of general distress.⁶² Previous research with patients experiencing symptoms like those of type D patients suggests that psychotherapy, social skills training, stress management, and relaxation training may reduce stress in these patients and improve their ability to express their emotions to others.⁶² Others have suggested that stress management training, including communication skills and problem-solving, may further improve the risk profile and health in cardiac patients.⁶³

It is possible that type D patients may benefit from close monitoring of their clinical condition and from aggressive management of their risk factor profile to prevent adverse clinical events. Cardiac rehabilitation is an effective approach to treating risk factors and enhancing well-being in CAD.^63,64 A few studies have examined the effect of cardiac rehabilitation in type D patients. One study found a significant decrease in the social inhibition component of type D following cardiac rehabilitation, but there was no change in the prevalence of type D at 1-year follow-up.⁶⁵ Although the type D profile tends to remain stable during rehabilitation,^65,66 evidence shows that type D patients who participate in cardiac rehabilitation improve in physical and mental health status.⁶⁶ Cardiac rehabilitation may also ward off further deterioration in negative affect,⁶⁷ which, in turn, has been associated with better survival in patients who participated in rehabilitation.⁶⁸ Future studies need to examine the effect of cardiac rehabilitation and other personalized approaches to treatment in type D patients.

CONCLUSIONS

General distress shared across negative emotions^6,23 may partly account for the role of depression, anxiety, and anger in cardiovascular disorders.^1–5 Some cardiac patients are more likely to experience distress than others. Type D may identify these psychologically vulnerable patients who tend to experience general distress.²³ This propensity to general distress differs from depression, predicts adverse outcomes, is linked to plausible biologic pathways, and highlights the chronic nature of psychologic distress in some cardiac patients.

After adjustment for depression, type D remains significantly associated with an increased risk of adverse events in patients with CAD.^16,24,25 However, this association is less obvious in patients with heart failure, and type D did not predict survival in one heart failure study.²⁰ Although initial findings suggest a number of plausible biologic and behavioral pathways, more research is needed to explain the adverse effect of type D on cardiovascular outcomes. Future research also needs to investigate whether type D patients may benefit from close monitoring of their risk factors and a more personalized approach to behavioral and cardiac treatment.

Overall, the current understanding of type D indicates that general distress should not be ignored in the link between mind and heart, and that cardiovascular patients who have a type D personality profile are particularly vulnerable to the adverse clinical effects of general distress. The DS14¹⁰ is a brief, well-validated measure of type D that could be incorporated into clinical research and practice to identify patients who are at risk of chronic distress and poor prognosis.

Depression has been studied extensively in relation to cardiovascular disease.^1–3 In addition to depression, anger⁴ and anxiety⁵ also may promote coronary artery disease (CAD), suggesting that emotional distress in general may be related to increased cardiovascular risk. Evidence indicates that the general distress shared across depression, anger, and anxiety predicts CAD, even after controlling for each of these specific negative emotions.⁶

THE CONCEPT OF TYPE D PERSONALITY

Lately, there is a renewed interest in broad individual differences in general distress and heart disease.⁷ Since psychologic factors often cluster together in individual patients, biobehavioral research may benefit from the identification of discrete personality subtypes.⁸ This focus on the identification of psychologically vulnerable patients who are at increased risk for adverse outcomes has led to the introduction of the distressed⁹ or type D¹⁰ personality profile in cardiovascular research. This personality construct is defined as follows:

“The type D (distressed) personality profile refers to a general propensity to psychological distress that is characterized by the combination of negative affectivity and social inhibition.”¹⁰

Negative affectivity, or the tendency to experience negative emotions across time and situations, is a major determinant of emotional distress in cardiac patients.^9,10 Patients who score high on this trait frequently report feelings of dysphoria, worry, and tension. Social inhibition, or the tendency to inhibit the expression of emotions or behavior, is a major determinant of social distress.^9,10 Patients who score high on this trait tend to avoid negative reactions from others.

Both traits define psychologically vulnerable patients and can be assessed with the type D scale (DS14).¹⁰ This brief measure consists of a seven-item negative affectivity subscale (eg, I often feel unhappy) and a seven-item inhibition subscale (eg, I am inhibited in social interactions), and has a clear two-factor structure and good reliability (Cronbach’s α = .88 and .86). Patients are classified as type D if they score 10 or higher on both DS14 subscales.¹⁰ The prevalence of type D personality ranges between 20% and 40% across different types of cardiovascular conditions.

The type D construct was designed for the early identification of chronically distressed patients. This article reviews (1) the risk of adverse events associated with type D, (2) the extent to which type D is distinct from depression, (3) the biologic pathways of type D, and (4) the implications of the type D personality profile.

RISK ASSOCIATED WITH TYPE D

The relationship between type D personality and adverse events has also been investigated in other cardiovascular conditions. Type D has been associated with poor prognosis in patients with peripheral arterial disease,¹⁷ but evidence for the prognostic role of type D in patients with chronic heart failure is mixed. In a study of patients with heart failure following myocardial infarction, type D predicted cardiac death independent of disease severity¹⁸; in a study of heart failure patients who underwent cardiac transplantation, type D was associated with early allograft rejection and increased mortality.¹⁹ However, type D was not associated with cardiac death in a recent, larger heart failure study.²⁰ The link between psychologic factors and heart failure is complex³ and may be less obvious than the type D-CAD link.²⁰ Type D has also been associated with the occurrence of life-threatening arrhythmias following implantable cardioverter defibrillator (ICD) treatment,²¹ and it has been shown to predict an increased risk for mortality in ICD patients, independent from shocks and disease severity.²²

The wide range in odds ratios and confidence intervals indicates disparity in data across these type D studies (Table 1). We recently performed a metaanalysis of prospective studies between 1996 and 2009 to provide a more reliable estimate of the risk associated with type D. In this analysis, type D was associated with a threefold increased risk of adverse events²³; the confidence interval of this pooled odds ratio ranged from 2.7 to 5.1. In addition, type D personality was associated with a threefold increased risk (range, 2.6 to 4.3) of emotional distress over time.²³ From the recent studies that were not included in this meta-analysis, one reported negative findings²⁰ and three others positive findings^16,21,22 on the risk associated with type D.

COMPARING DEPRESSION AND TYPE D

Clinical evidence shows that, after adjustment for depression, type D remained a predictor of adverse cardiac events in CAD.^16,24,25 Following ICD implantation, anxious type D patients were at risk of ventricular arrhythmias, whereas depression did not predict arrhythmias.²¹ Type D also exerts an adverse effect on patients’ health status following coronary bypass surgery,²⁶ heart failure,²⁷ or myocardial infarction,²⁸ adjusting for depressive symptoms. Type D is related to biomarkers of increased stress levels independent of depression^29–31 and, unlike depression, type D is not confounded by the severity of cardiac disorder.³²

Following myocardial infarction, only one of four distressed patients met criteria for both type D and depression; most had one form of distress but not the other.³² Research in healthy³³ and in cardiac³⁴ populations confirmed that items from depression and type D scales reflect different distress factors. After adjustment for depression at baseline, type D also predicted the incidence,³⁵ persistence,³⁶ and severity^37,38 of depression and anxiety. However, these findings do not imply that depression and type D are antonymous perspectives or that one perspective is better than the other in predicting outcomes; rather, we would like to argue that both constructs represent complementary perspectives that have added value.²³

BIOLOGIC PATHWAYS OF TYPE D

Other studies found that type D was associated with inflammatory dysregulation. In healthy adults, type D has been related to higher concentrations of C-reactive protein.⁴¹ In heart failure patients, type D is associated with increased plasma levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α and its soluble receptors 1 and 2.^46,47 Increased TNF-α levels may cause suppression of bone-marrow–derived endothelial progenitor cells (EPCs) that play an important role in maintaining vascular integrity. The negative affectivity component of type D has been shown to predict decreased circulating EPC counts in healthy individuals⁴⁸; another study found that these EPC numbers were reduced by more than 50% in heart failure patients with a type D personality.⁴⁹ Type D personality is also associated with an increased oxidative stress burden in patients with chronic heart failure.²⁹ Studies on genetic linkage⁵⁰ and heritability⁵¹ further support biologic underpinnings of the type D construct.

Regarding pathways that may explain the effect of type D, some issues are of special interest. First, genetic factors contribute to stability in type D personality, but environmental factors may induce changes in type D characteristics over time.⁵¹ Hence, given this role of environmental influences over time, behavioral intervention would be feasible and useful in type D patients. Second, type D can promote heart disease indirectly through behavioral pathways. Type D has been associated with a sedentary lifestyle,^41,52 an unhealthy diet,⁵³ and a passive coping style.^54,55 Poor adherence to medical treatment^56,57 and reluctance to consult clinical staff⁵⁸ may jeopardize the working relationship with type D patients in clinical care. Intervention may focus on the management of these behavioral risk factors in type D patients. Third, many of these biologic^{40–43,48,50,51} and behavioral^41,52–54 pathways have also been documented in healthy type D individuals, which suggests that these associations cannot be explained away by the confounding effect of underlying cardiovascular disease.

CLINICAL IMPLICATIONS OF TYPE D

The findings from type D research have a number of clinical implications. Type D is associated with an increased risk of adverse events,²³ chronic distress,^35–38 and suicidal ideation.⁵⁹ Type D may also have an adverse effect on the outcome of invasive treatment.^{14,19,21,22,24,26,60}

Type D was associated with mortality and morbidity at 9 months¹⁴ and 2 years²⁴ following coronary artery stenting, and with impaired health status 1 year following bypass surgery.²⁶ Type D also predicted mortality and allograft rejection following heart transplantation,¹⁹ and an increased risk of ventricular arrhythmia²¹ and mortality²² in ICD patients. Researchers from the Cleveland Clinic have shown that type D is a risk factor for anxiety in ICD patients.⁶⁰

Regarding the DSM-IV classification by the American Psychiatric Association,⁶¹ type D qualifies for the diagnosis “psychological factors affecting medical condition” (Section 316). In keeping with this classification, the diagnostic category type D affects (1) the course of cardiovascular conditions,²³ (2) the treatment of these conditions,^56,57 and (3) the working relationship with medical staff.⁵⁸ At present, no clinical trial has examined whether intervention for distress among type D patients alters their risk for adverse events. Nevertheless, some have argued that it is plausible for type D patients to learn new strategies to reduce their level of general distress.⁶² Previous research with patients experiencing symptoms like those of type D patients suggests that psychotherapy, social skills training, stress management, and relaxation training may reduce stress in these patients and improve their ability to express their emotions to others.⁶² Others have suggested that stress management training, including communication skills and problem-solving, may further improve the risk profile and health in cardiac patients.⁶³

It is possible that type D patients may benefit from close monitoring of their clinical condition and from aggressive management of their risk factor profile to prevent adverse clinical events. Cardiac rehabilitation is an effective approach to treating risk factors and enhancing well-being in CAD.^63,64 A few studies have examined the effect of cardiac rehabilitation in type D patients. One study found a significant decrease in the social inhibition component of type D following cardiac rehabilitation, but there was no change in the prevalence of type D at 1-year follow-up.⁶⁵ Although the type D profile tends to remain stable during rehabilitation,^65,66 evidence shows that type D patients who participate in cardiac rehabilitation improve in physical and mental health status.⁶⁶ Cardiac rehabilitation may also ward off further deterioration in negative affect,⁶⁷ which, in turn, has been associated with better survival in patients who participated in rehabilitation.⁶⁸ Future studies need to examine the effect of cardiac rehabilitation and other personalized approaches to treatment in type D patients.

CONCLUSIONS

General distress shared across negative emotions^6,23 may partly account for the role of depression, anxiety, and anger in cardiovascular disorders.^1–5 Some cardiac patients are more likely to experience distress than others. Type D may identify these psychologically vulnerable patients who tend to experience general distress.²³ This propensity to general distress differs from depression, predicts adverse outcomes, is linked to plausible biologic pathways, and highlights the chronic nature of psychologic distress in some cardiac patients.

After adjustment for depression, type D remains significantly associated with an increased risk of adverse events in patients with CAD.^16,24,25 However, this association is less obvious in patients with heart failure, and type D did not predict survival in one heart failure study.²⁰ Although initial findings suggest a number of plausible biologic and behavioral pathways, more research is needed to explain the adverse effect of type D on cardiovascular outcomes. Future research also needs to investigate whether type D patients may benefit from close monitoring of their risk factors and a more personalized approach to behavioral and cardiac treatment.

Overall, the current understanding of type D indicates that general distress should not be ignored in the link between mind and heart, and that cardiovascular patients who have a type D personality profile are particularly vulnerable to the adverse clinical effects of general distress. The DS14¹⁰ is a brief, well-validated measure of type D that could be incorporated into clinical research and practice to identify patients who are at risk of chronic distress and poor prognosis.

Depression has been studied extensively in relation to cardiovascular disease.^1–3 In addition to depression, anger⁴ and anxiety⁵ also may promote coronary artery disease (CAD), suggesting that emotional distress in general may be related to increased cardiovascular risk. Evidence indicates that the general distress shared across depression, anger, and anxiety predicts CAD, even after controlling for each of these specific negative emotions.⁶

THE CONCEPT OF TYPE D PERSONALITY

Lately, there is a renewed interest in broad individual differences in general distress and heart disease.⁷ Since psychologic factors often cluster together in individual patients, biobehavioral research may benefit from the identification of discrete personality subtypes.⁸ This focus on the identification of psychologically vulnerable patients who are at increased risk for adverse outcomes has led to the introduction of the distressed⁹ or type D¹⁰ personality profile in cardiovascular research. This personality construct is defined as follows:

“The type D (distressed) personality profile refers to a general propensity to psychological distress that is characterized by the combination of negative affectivity and social inhibition.”¹⁰

Negative affectivity, or the tendency to experience negative emotions across time and situations, is a major determinant of emotional distress in cardiac patients.^9,10 Patients who score high on this trait frequently report feelings of dysphoria, worry, and tension. Social inhibition, or the tendency to inhibit the expression of emotions or behavior, is a major determinant of social distress.^9,10 Patients who score high on this trait tend to avoid negative reactions from others.

Both traits define psychologically vulnerable patients and can be assessed with the type D scale (DS14).¹⁰ This brief measure consists of a seven-item negative affectivity subscale (eg, I often feel unhappy) and a seven-item inhibition subscale (eg, I am inhibited in social interactions), and has a clear two-factor structure and good reliability (Cronbach’s α = .88 and .86). Patients are classified as type D if they score 10 or higher on both DS14 subscales.¹⁰ The prevalence of type D personality ranges between 20% and 40% across different types of cardiovascular conditions.

The type D construct was designed for the early identification of chronically distressed patients. This article reviews (1) the risk of adverse events associated with type D, (2) the extent to which type D is distinct from depression, (3) the biologic pathways of type D, and (4) the implications of the type D personality profile.

RISK ASSOCIATED WITH TYPE D

The relationship between type D personality and adverse events has also been investigated in other cardiovascular conditions. Type D has been associated with poor prognosis in patients with peripheral arterial disease,¹⁷ but evidence for the prognostic role of type D in patients with chronic heart failure is mixed. In a study of patients with heart failure following myocardial infarction, type D predicted cardiac death independent of disease severity¹⁸; in a study of heart failure patients who underwent cardiac transplantation, type D was associated with early allograft rejection and increased mortality.¹⁹ However, type D was not associated with cardiac death in a recent, larger heart failure study.²⁰ The link between psychologic factors and heart failure is complex³ and may be less obvious than the type D-CAD link.²⁰ Type D has also been associated with the occurrence of life-threatening arrhythmias following implantable cardioverter defibrillator (ICD) treatment,²¹ and it has been shown to predict an increased risk for mortality in ICD patients, independent from shocks and disease severity.²²

The wide range in odds ratios and confidence intervals indicates disparity in data across these type D studies (Table 1). We recently performed a metaanalysis of prospective studies between 1996 and 2009 to provide a more reliable estimate of the risk associated with type D. In this analysis, type D was associated with a threefold increased risk of adverse events²³; the confidence interval of this pooled odds ratio ranged from 2.7 to 5.1. In addition, type D personality was associated with a threefold increased risk (range, 2.6 to 4.3) of emotional distress over time.²³ From the recent studies that were not included in this meta-analysis, one reported negative findings²⁰ and three others positive findings^16,21,22 on the risk associated with type D.

COMPARING DEPRESSION AND TYPE D

Clinical evidence shows that, after adjustment for depression, type D remained a predictor of adverse cardiac events in CAD.^16,24,25 Following ICD implantation, anxious type D patients were at risk of ventricular arrhythmias, whereas depression did not predict arrhythmias.²¹ Type D also exerts an adverse effect on patients’ health status following coronary bypass surgery,²⁶ heart failure,²⁷ or myocardial infarction,²⁸ adjusting for depressive symptoms. Type D is related to biomarkers of increased stress levels independent of depression^29–31 and, unlike depression, type D is not confounded by the severity of cardiac disorder.³²

Following myocardial infarction, only one of four distressed patients met criteria for both type D and depression; most had one form of distress but not the other.³² Research in healthy³³ and in cardiac³⁴ populations confirmed that items from depression and type D scales reflect different distress factors. After adjustment for depression at baseline, type D also predicted the incidence,³⁵ persistence,³⁶ and severity^37,38 of depression and anxiety. However, these findings do not imply that depression and type D are antonymous perspectives or that one perspective is better than the other in predicting outcomes; rather, we would like to argue that both constructs represent complementary perspectives that have added value.²³

BIOLOGIC PATHWAYS OF TYPE D

Other studies found that type D was associated with inflammatory dysregulation. In healthy adults, type D has been related to higher concentrations of C-reactive protein.⁴¹ In heart failure patients, type D is associated with increased plasma levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α and its soluble receptors 1 and 2.^46,47 Increased TNF-α levels may cause suppression of bone-marrow–derived endothelial progenitor cells (EPCs) that play an important role in maintaining vascular integrity. The negative affectivity component of type D has been shown to predict decreased circulating EPC counts in healthy individuals⁴⁸; another study found that these EPC numbers were reduced by more than 50% in heart failure patients with a type D personality.⁴⁹ Type D personality is also associated with an increased oxidative stress burden in patients with chronic heart failure.²⁹ Studies on genetic linkage⁵⁰ and heritability⁵¹ further support biologic underpinnings of the type D construct.

Regarding pathways that may explain the effect of type D, some issues are of special interest. First, genetic factors contribute to stability in type D personality, but environmental factors may induce changes in type D characteristics over time.⁵¹ Hence, given this role of environmental influences over time, behavioral intervention would be feasible and useful in type D patients. Second, type D can promote heart disease indirectly through behavioral pathways. Type D has been associated with a sedentary lifestyle,^41,52 an unhealthy diet,⁵³ and a passive coping style.^54,55 Poor adherence to medical treatment^56,57 and reluctance to consult clinical staff⁵⁸ may jeopardize the working relationship with type D patients in clinical care. Intervention may focus on the management of these behavioral risk factors in type D patients. Third, many of these biologic^{40–43,48,50,51} and behavioral^41,52–54 pathways have also been documented in healthy type D individuals, which suggests that these associations cannot be explained away by the confounding effect of underlying cardiovascular disease.

CLINICAL IMPLICATIONS OF TYPE D

The findings from type D research have a number of clinical implications. Type D is associated with an increased risk of adverse events,²³ chronic distress,^35–38 and suicidal ideation.⁵⁹ Type D may also have an adverse effect on the outcome of invasive treatment.^{14,19,21,22,24,26,60}

Type D was associated with mortality and morbidity at 9 months¹⁴ and 2 years²⁴ following coronary artery stenting, and with impaired health status 1 year following bypass surgery.²⁶ Type D also predicted mortality and allograft rejection following heart transplantation,¹⁹ and an increased risk of ventricular arrhythmia²¹ and mortality²² in ICD patients. Researchers from the Cleveland Clinic have shown that type D is a risk factor for anxiety in ICD patients.⁶⁰

Regarding the DSM-IV classification by the American Psychiatric Association,⁶¹ type D qualifies for the diagnosis “psychological factors affecting medical condition” (Section 316). In keeping with this classification, the diagnostic category type D affects (1) the course of cardiovascular conditions,²³ (2) the treatment of these conditions,^56,57 and (3) the working relationship with medical staff.⁵⁸ At present, no clinical trial has examined whether intervention for distress among type D patients alters their risk for adverse events. Nevertheless, some have argued that it is plausible for type D patients to learn new strategies to reduce their level of general distress.⁶² Previous research with patients experiencing symptoms like those of type D patients suggests that psychotherapy, social skills training, stress management, and relaxation training may reduce stress in these patients and improve their ability to express their emotions to others.⁶² Others have suggested that stress management training, including communication skills and problem-solving, may further improve the risk profile and health in cardiac patients.⁶³

It is possible that type D patients may benefit from close monitoring of their clinical condition and from aggressive management of their risk factor profile to prevent adverse clinical events. Cardiac rehabilitation is an effective approach to treating risk factors and enhancing well-being in CAD.^63,64 A few studies have examined the effect of cardiac rehabilitation in type D patients. One study found a significant decrease in the social inhibition component of type D following cardiac rehabilitation, but there was no change in the prevalence of type D at 1-year follow-up.⁶⁵ Although the type D profile tends to remain stable during rehabilitation,^65,66 evidence shows that type D patients who participate in cardiac rehabilitation improve in physical and mental health status.⁶⁶ Cardiac rehabilitation may also ward off further deterioration in negative affect,⁶⁷ which, in turn, has been associated with better survival in patients who participated in rehabilitation.⁶⁸ Future studies need to examine the effect of cardiac rehabilitation and other personalized approaches to treatment in type D patients.

CONCLUSIONS

General distress shared across negative emotions^6,23 may partly account for the role of depression, anxiety, and anger in cardiovascular disorders.^1–5 Some cardiac patients are more likely to experience distress than others. Type D may identify these psychologically vulnerable patients who tend to experience general distress.²³ This propensity to general distress differs from depression, predicts adverse outcomes, is linked to plausible biologic pathways, and highlights the chronic nature of psychologic distress in some cardiac patients.

After adjustment for depression, type D remains significantly associated with an increased risk of adverse events in patients with CAD.^16,24,25 However, this association is less obvious in patients with heart failure, and type D did not predict survival in one heart failure study.²⁰ Although initial findings suggest a number of plausible biologic and behavioral pathways, more research is needed to explain the adverse effect of type D on cardiovascular outcomes. Future research also needs to investigate whether type D patients may benefit from close monitoring of their risk factors and a more personalized approach to behavioral and cardiac treatment.

Overall, the current understanding of type D indicates that general distress should not be ignored in the link between mind and heart, and that cardiovascular patients who have a type D personality profile are particularly vulnerable to the adverse clinical effects of general distress. The DS14¹⁰ is a brief, well-validated measure of type D that could be incorporated into clinical research and practice to identify patients who are at risk of chronic distress and poor prognosis.

BIOFEEDBACK: WHAT IS IT?

The term “biofeedback” refers to the instrumentation or training process that allows biologic information to be recorded, displayed, and communicated back to an individual, allowing the individual to make adjustments in physiologic processes that may enhance health or performance. The biofeedback display is analogous to a mirror, in which physiologic processes can be observed and adjusted much as one might adjust a hairstyle or a tie.

In our work with cardiovascular disease patients, biofeedback is a training process that involves a subject or patient, a biofeedback coach or therapist, and state-of-the-art biofeedback equipment. For biofeedback training to be effective, the subject who is trying to learn the skill must be engaged and willing to practice, the coach must be trained in psychophysiology, and the equipment must display accurate readings in real time, allowing the subject to monitor and change physiologic reactions appropriately. The coach teaches the subject about the physiologic parameters, establishes target ranges, and helps the subject learn how to move the physiologic parameters in the right direction.^1,2

Training often begins with a session in which a brief mental stress test is followed by a period of relaxation while physiologic parameters are recorded and displayed. This process helps the subject to understand the link between mental processes and physiologic arousal.

Biofeedback training can involve a number of physiologic modalities, including those that reflect autonomic nervous system arousal, such as skin conductance and heart rate variability, and those that are not strictly correlated with autonomic activity, such as surface muscle tension. Each physiologic parameter is recorded by a specific sensor, and all sensors are noninvasive. Sensors feed signals into a computer, where they are processed and amplified, and subjects are able to view the output on a computer screen.

Typically, in our work, there is one screen for the subject, on which a single parameter can be displayed, observed and discussed, and another screen for the coach, on which all parameters are displayed simultaneously. During a single session of biofeedback training, the coach may choose to work on a single parameter or switch between parameters, depending on how much progress is being made with each. In our work with patients, we generally train to simple parameters first, such as respiratory rate, finger temperature, and skin conductance, moving on to surface muscle tension, heart rate, and eventually heart rate variability, which is a more complex concept and more easily understood later in the training process.

It is important that the subject receive positive reinforcement for changing the physiologic parameters, and if the subject struggles too long with one parameter, it is generally useful to go back to a different parameter, where success may be more easily experienced. Ideally, by the end of six to eight training sessions, the subject will be able to make progress on all physiologic parameters, which will track together over time.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT

Pure biofeedback training consists of operant conditioning. That is, the subject learns to regulate his or her physiology in the right direction because of the feedback, which can be as simple as a pleasant image appearing on a computer screen or as complicated as a car moving faster around a racetrack; pure biofeedback involves changing physiology in response to positive reinforcement of some sort.

In practice, we generally employ biofeedback-assisted stress management (BFSM) rather than pure biofeedback. With BFSM, the subject learns to change physiology in the direction of health and wellness by learning techniques of stress management. The coach teaches the subject various relaxation techniques, such as slow and rhythmic breathing, guided imagery, progressive muscle relaxation, mindfulness, assertiveness, and how to change negative thought patterns. With regular practice, the subject learns to change the physiologic parameters by relaxing the body. For example, instead of instructing the subject to “increase your finger temperature” and assume that the subject will achieve this because doing so will make the light bulb on the screen glow more intensely, the BFSM coach may instead talk with the subject about eliminating stressful thoughts, learning to relax, and the fingers warming in response to the body relaxing.

We distinguish between techniques of stress management, some of which are mentioned above, and psychotherapy, which can certainly be effectively combined with biofeedback, but which we do not provide in our research studies. Coupling stress management techniques with biofeedback helps the subject change physiologic parameters in the direction of wellness and acquire tools that can be used in everyday life when stressful events arise. The objective of BFSM training is not just to change physiology, but also to change the way subjects respond to stressful events in daily life; ie, react to fewer events, react less intensely when they do react, and recover more quickly.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT IN CARDIOVASCULAR DISEASE

We are currently studying the effects of BFSM in patients with cardiovascular disease, including both heart failure and stable coronary artery disease. Patients with cardiovascular disease often are functionally limited, and they also experience psychologic distress related to physical limitations and other life stressors. Both the physical limitations and the psychologic distress impact quality of life. We hypothesize that BFSM will teach our patients techniques of stress management, both mental and physiologic, that will help relieve their psychologic distress and improve their quality of life. BFSM will also potentially decrease the overactivation of the sympathetic branch of the autonomic nervous system, which is common in cardiovascular disease, and correspondingly upregulate the contribution of the parasympathetic branch of the autonomic nervous system, which should be beneficial.³

A PROMISING TECHNIQUE IN HEART FAILURE

We are currently studying the effects of BFSM in patients with end-stage heart failure who are awaiting heart transplant at Cleveland Clinic.⁴ As noted in a recent review, biofeedback is a promising technique in heart failure that patients may be able to use to consciously regulate their autonomic nervous systems.⁵ We hypothesize that BFSM training will interfere with the overactivation of the sympathetic nervous system that is characteristic of heart failure, and that this will reverse the cellular and molecular remodeling that occurs in the failing human heart.

To date, we have enrolled 25 patients; 10 are being studied in our National Institutes of Health–funded Clinic Research Unit and 15 are inpatients. All 25 patients are listed as heart transplant candidates and have given consent for us to study their hearts when they are explanted.

Each patient receives eight sessions with a certified biofeedback therapist. The first and last sessions include mental stress tests, while the remaining six are BFSM training sessions. Patients are assessed at the beginning and end of the study using the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and measurement of plasma catecholamines.

The primary end point of the study is the measurement of cellular and molecular markers that have been shown to be altered in the failing human heart, testing the hypothesis that these markers will be reversed in the direction of normal in the BFSM therapy group. These markers are measured in the explanted failing heart when the patient receives a heart transplant.

It is too early to report the results of this study, since only seven patients have undergone transplantation to date. We are encouraged by several early findings, however, and hope these will be validated when the entire group is analyzed.

In early analysis, scores on the Kansas City Cardiomyopathy Questionnaire are improved in the last session compared with the first; patients have shown the ability to learn a slower breathing rate; and they are able to regulate their heart rate variability, as measured by the standard deviation of the N-to-N interval, or SDNN. Most important, measurements in the first seven hearts indicate that there is a degree of biologic remodeling of the failing heart after BFSM that is similar to what we have observed with left ventricular assist devices—hemodynamic pumps that take on the workload of the heart, permitting the heart to rest and recover while the patient is waiting for a transplant.^6,7 If BFSM could produce changes in the cellular and molecular properties of the heart that are equal in magnitude to those produced by a mechanical pump, this would be a revolutionary finding in the field of heart-brain medicine.

It should be noted that we are not the first group to study BFSM in patients with heart failure. Moser and colleagues first observed that a single session of skin temperature biofeedback could have significant functional effects in patients with heart failure.⁸ Bernardi and coworkers showed that merely teaching patients to breathe six times per minute (a large component of BFSM training) improved oxygen saturation and exercise tolerance.⁹ Swanson and colleagues in 2009 demonstrated that patients with heart failure were able to regulate their heart rate variability, although they observed this only in patients with a left ventricular ejection fraction greater than 30%.¹⁰ Our preliminary data demonstrate regulation of heart rate variability in patients with lower ejection fractions, which is promising, but we have also added the biologic component of studying the explanted heart, allowing us to test the hypothesis that BFSM could potentially impact the remodeling process and thus have important therapeutic implications.

TRIAL UNDER WAY IN CORONARY ARTERY DISEASE

In addition to our studies of BFSM in heart failure, we have begun a randomized clinical trial of patients with stable coronary artery disease, type 2 diabetes, or multiple sclerosis. These three patient populations were chosen because evidence from numerous studies suggests that they all involve autonomic nervous system dysregulation as well as an inflammatory process.

It has already been mentioned that BFSM can interfere with overactivation of the sympathetic nervous system and potentially upregulate the contribution of the parasympathetic nervous system, which usually exists in juxtaposition to the sympathetic nervous system. Based on the work of Tracey,^11,12 upregulating the parasympathetic nervous system should be antiinflammatory. Thus, we hypothesize that by decreasing both sympathetic nervous system activation and inflammation, BFSM should have an impact on patients with one of these disease states, resulting in improved quality of life and clinical status, reduced anxiety and depression, and changed disease-specific indicators of severity.

We are currently enrolling patients who have coronary artery disease, type 2 diabetes, or multiple sclerosis and randomizing them to groups that will receive either BFSM or usual care. Outcome variables that will be assessed in all patients include heart rate variability; the response of temperature, skin conductance, respiratory rate, and heart rate variability to mental stress; plasma catecholamine levels; plasma C-reactive protein levels; and tumor necrosis factor alpha levels. At the first and last visits, all patients will complete the SF-36, the eight-item Patient Health Questionnaire depression scale (PHQ-8), the Generalized Anxiety Disorder seven-item scale (GAD-7), and a visual analog pain scale. We will also assess disease-specific variables, including heart rate recovery after exercise, plasma lipids, and myeloperoxidase in patients with coronary artery disease; the Multiple Sclerosis Functional Composite (MSFC) test and the Modified Fatigue Impact Scale (MFIS) will be administered to patients with multiple sclerosis; and plasma glucose and hemoglobin A1C will be assessed in patients with type 2 diabetes.

Results of this study will provide data on the potential of BFSM to decrease common markers of autonomic nervous system activation and inflammatory cascades and the effect of those alterations on three specific disease states. To our knowledge, such a randomized study has not been conducted previously; our findings will add significantly to the literature on the mechanism of action of biofeedback-type interventions.

POTENTIAL IMPACT ON DEPRESSION IN CARDIOVASCULAR DISEASE

Depression is increasingly recognized as a component of many cardiovascular diseases; this raises the question of what effect BFSM therapy in cardiovascular disease patients will have on their depression. Of particular importance to this discussion, heart rate variability has been shown to be decreased both in cardiovascular disease and in depression, and BFSM is one treatment that can be used to regulate heart rate variability. Heart rate variability biofeedback has been shown to be useful in treating depression.

Work from Karavidas and colleagues showed that 10 weeks of heart rate variability biofeedback in patients with depression led to significantly improved scores on the Hamilton Depression Scale and the Beck Depression Inventory. Improvement was observed by the fourth week of training, with concurrent increases in the SDNN.¹³ Siepmann and colleagues also used heart rate variability biofeedback in depressed subjects and demonstrated significant improvement in scores on the Beck Depression Inventory, as well as a concomitant decrease in anxiety.¹⁴ In related work, Uhlmann and Fröscher used electroencephalographic biofeedback (also called neurofeedback) in epilepsy patients with depression and measured an increased sense of self control and a decrease in external locus of control; they postulated that biofeedback training provided an important opportunity for success, and thus increased internal control and decreased depression.¹⁵

Evidence suggests that BFSM should have an impact on depression in addition to impacting the cardiovascular disease itself, and both should work together to improve quality of life. For this reason we have added a depression inventory to our randomized trial of BFSM in patients who have coronary artery disease, diabetes, or multiple sclerosis.

BIOFEEDBACK: WHAT IS IT?

The term “biofeedback” refers to the instrumentation or training process that allows biologic information to be recorded, displayed, and communicated back to an individual, allowing the individual to make adjustments in physiologic processes that may enhance health or performance. The biofeedback display is analogous to a mirror, in which physiologic processes can be observed and adjusted much as one might adjust a hairstyle or a tie.

In our work with cardiovascular disease patients, biofeedback is a training process that involves a subject or patient, a biofeedback coach or therapist, and state-of-the-art biofeedback equipment. For biofeedback training to be effective, the subject who is trying to learn the skill must be engaged and willing to practice, the coach must be trained in psychophysiology, and the equipment must display accurate readings in real time, allowing the subject to monitor and change physiologic reactions appropriately. The coach teaches the subject about the physiologic parameters, establishes target ranges, and helps the subject learn how to move the physiologic parameters in the right direction.^1,2

Training often begins with a session in which a brief mental stress test is followed by a period of relaxation while physiologic parameters are recorded and displayed. This process helps the subject to understand the link between mental processes and physiologic arousal.

Biofeedback training can involve a number of physiologic modalities, including those that reflect autonomic nervous system arousal, such as skin conductance and heart rate variability, and those that are not strictly correlated with autonomic activity, such as surface muscle tension. Each physiologic parameter is recorded by a specific sensor, and all sensors are noninvasive. Sensors feed signals into a computer, where they are processed and amplified, and subjects are able to view the output on a computer screen.

Typically, in our work, there is one screen for the subject, on which a single parameter can be displayed, observed and discussed, and another screen for the coach, on which all parameters are displayed simultaneously. During a single session of biofeedback training, the coach may choose to work on a single parameter or switch between parameters, depending on how much progress is being made with each. In our work with patients, we generally train to simple parameters first, such as respiratory rate, finger temperature, and skin conductance, moving on to surface muscle tension, heart rate, and eventually heart rate variability, which is a more complex concept and more easily understood later in the training process.

It is important that the subject receive positive reinforcement for changing the physiologic parameters, and if the subject struggles too long with one parameter, it is generally useful to go back to a different parameter, where success may be more easily experienced. Ideally, by the end of six to eight training sessions, the subject will be able to make progress on all physiologic parameters, which will track together over time.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT

Pure biofeedback training consists of operant conditioning. That is, the subject learns to regulate his or her physiology in the right direction because of the feedback, which can be as simple as a pleasant image appearing on a computer screen or as complicated as a car moving faster around a racetrack; pure biofeedback involves changing physiology in response to positive reinforcement of some sort.

In practice, we generally employ biofeedback-assisted stress management (BFSM) rather than pure biofeedback. With BFSM, the subject learns to change physiology in the direction of health and wellness by learning techniques of stress management. The coach teaches the subject various relaxation techniques, such as slow and rhythmic breathing, guided imagery, progressive muscle relaxation, mindfulness, assertiveness, and how to change negative thought patterns. With regular practice, the subject learns to change the physiologic parameters by relaxing the body. For example, instead of instructing the subject to “increase your finger temperature” and assume that the subject will achieve this because doing so will make the light bulb on the screen glow more intensely, the BFSM coach may instead talk with the subject about eliminating stressful thoughts, learning to relax, and the fingers warming in response to the body relaxing.

We distinguish between techniques of stress management, some of which are mentioned above, and psychotherapy, which can certainly be effectively combined with biofeedback, but which we do not provide in our research studies. Coupling stress management techniques with biofeedback helps the subject change physiologic parameters in the direction of wellness and acquire tools that can be used in everyday life when stressful events arise. The objective of BFSM training is not just to change physiology, but also to change the way subjects respond to stressful events in daily life; ie, react to fewer events, react less intensely when they do react, and recover more quickly.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT IN CARDIOVASCULAR DISEASE

We are currently studying the effects of BFSM in patients with cardiovascular disease, including both heart failure and stable coronary artery disease. Patients with cardiovascular disease often are functionally limited, and they also experience psychologic distress related to physical limitations and other life stressors. Both the physical limitations and the psychologic distress impact quality of life. We hypothesize that BFSM will teach our patients techniques of stress management, both mental and physiologic, that will help relieve their psychologic distress and improve their quality of life. BFSM will also potentially decrease the overactivation of the sympathetic branch of the autonomic nervous system, which is common in cardiovascular disease, and correspondingly upregulate the contribution of the parasympathetic branch of the autonomic nervous system, which should be beneficial.³

A PROMISING TECHNIQUE IN HEART FAILURE

We are currently studying the effects of BFSM in patients with end-stage heart failure who are awaiting heart transplant at Cleveland Clinic.⁴ As noted in a recent review, biofeedback is a promising technique in heart failure that patients may be able to use to consciously regulate their autonomic nervous systems.⁵ We hypothesize that BFSM training will interfere with the overactivation of the sympathetic nervous system that is characteristic of heart failure, and that this will reverse the cellular and molecular remodeling that occurs in the failing human heart.

To date, we have enrolled 25 patients; 10 are being studied in our National Institutes of Health–funded Clinic Research Unit and 15 are inpatients. All 25 patients are listed as heart transplant candidates and have given consent for us to study their hearts when they are explanted.

Each patient receives eight sessions with a certified biofeedback therapist. The first and last sessions include mental stress tests, while the remaining six are BFSM training sessions. Patients are assessed at the beginning and end of the study using the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and measurement of plasma catecholamines.

The primary end point of the study is the measurement of cellular and molecular markers that have been shown to be altered in the failing human heart, testing the hypothesis that these markers will be reversed in the direction of normal in the BFSM therapy group. These markers are measured in the explanted failing heart when the patient receives a heart transplant.

It is too early to report the results of this study, since only seven patients have undergone transplantation to date. We are encouraged by several early findings, however, and hope these will be validated when the entire group is analyzed.

In early analysis, scores on the Kansas City Cardiomyopathy Questionnaire are improved in the last session compared with the first; patients have shown the ability to learn a slower breathing rate; and they are able to regulate their heart rate variability, as measured by the standard deviation of the N-to-N interval, or SDNN. Most important, measurements in the first seven hearts indicate that there is a degree of biologic remodeling of the failing heart after BFSM that is similar to what we have observed with left ventricular assist devices—hemodynamic pumps that take on the workload of the heart, permitting the heart to rest and recover while the patient is waiting for a transplant.^6,7 If BFSM could produce changes in the cellular and molecular properties of the heart that are equal in magnitude to those produced by a mechanical pump, this would be a revolutionary finding in the field of heart-brain medicine.

It should be noted that we are not the first group to study BFSM in patients with heart failure. Moser and colleagues first observed that a single session of skin temperature biofeedback could have significant functional effects in patients with heart failure.⁸ Bernardi and coworkers showed that merely teaching patients to breathe six times per minute (a large component of BFSM training) improved oxygen saturation and exercise tolerance.⁹ Swanson and colleagues in 2009 demonstrated that patients with heart failure were able to regulate their heart rate variability, although they observed this only in patients with a left ventricular ejection fraction greater than 30%.¹⁰ Our preliminary data demonstrate regulation of heart rate variability in patients with lower ejection fractions, which is promising, but we have also added the biologic component of studying the explanted heart, allowing us to test the hypothesis that BFSM could potentially impact the remodeling process and thus have important therapeutic implications.

TRIAL UNDER WAY IN CORONARY ARTERY DISEASE

In addition to our studies of BFSM in heart failure, we have begun a randomized clinical trial of patients with stable coronary artery disease, type 2 diabetes, or multiple sclerosis. These three patient populations were chosen because evidence from numerous studies suggests that they all involve autonomic nervous system dysregulation as well as an inflammatory process.

It has already been mentioned that BFSM can interfere with overactivation of the sympathetic nervous system and potentially upregulate the contribution of the parasympathetic nervous system, which usually exists in juxtaposition to the sympathetic nervous system. Based on the work of Tracey,^11,12 upregulating the parasympathetic nervous system should be antiinflammatory. Thus, we hypothesize that by decreasing both sympathetic nervous system activation and inflammation, BFSM should have an impact on patients with one of these disease states, resulting in improved quality of life and clinical status, reduced anxiety and depression, and changed disease-specific indicators of severity.

We are currently enrolling patients who have coronary artery disease, type 2 diabetes, or multiple sclerosis and randomizing them to groups that will receive either BFSM or usual care. Outcome variables that will be assessed in all patients include heart rate variability; the response of temperature, skin conductance, respiratory rate, and heart rate variability to mental stress; plasma catecholamine levels; plasma C-reactive protein levels; and tumor necrosis factor alpha levels. At the first and last visits, all patients will complete the SF-36, the eight-item Patient Health Questionnaire depression scale (PHQ-8), the Generalized Anxiety Disorder seven-item scale (GAD-7), and a visual analog pain scale. We will also assess disease-specific variables, including heart rate recovery after exercise, plasma lipids, and myeloperoxidase in patients with coronary artery disease; the Multiple Sclerosis Functional Composite (MSFC) test and the Modified Fatigue Impact Scale (MFIS) will be administered to patients with multiple sclerosis; and plasma glucose and hemoglobin A1C will be assessed in patients with type 2 diabetes.

Results of this study will provide data on the potential of BFSM to decrease common markers of autonomic nervous system activation and inflammatory cascades and the effect of those alterations on three specific disease states. To our knowledge, such a randomized study has not been conducted previously; our findings will add significantly to the literature on the mechanism of action of biofeedback-type interventions.

POTENTIAL IMPACT ON DEPRESSION IN CARDIOVASCULAR DISEASE

Depression is increasingly recognized as a component of many cardiovascular diseases; this raises the question of what effect BFSM therapy in cardiovascular disease patients will have on their depression. Of particular importance to this discussion, heart rate variability has been shown to be decreased both in cardiovascular disease and in depression, and BFSM is one treatment that can be used to regulate heart rate variability. Heart rate variability biofeedback has been shown to be useful in treating depression.

Work from Karavidas and colleagues showed that 10 weeks of heart rate variability biofeedback in patients with depression led to significantly improved scores on the Hamilton Depression Scale and the Beck Depression Inventory. Improvement was observed by the fourth week of training, with concurrent increases in the SDNN.¹³ Siepmann and colleagues also used heart rate variability biofeedback in depressed subjects and demonstrated significant improvement in scores on the Beck Depression Inventory, as well as a concomitant decrease in anxiety.¹⁴ In related work, Uhlmann and Fröscher used electroencephalographic biofeedback (also called neurofeedback) in epilepsy patients with depression and measured an increased sense of self control and a decrease in external locus of control; they postulated that biofeedback training provided an important opportunity for success, and thus increased internal control and decreased depression.¹⁵

Evidence suggests that BFSM should have an impact on depression in addition to impacting the cardiovascular disease itself, and both should work together to improve quality of life. For this reason we have added a depression inventory to our randomized trial of BFSM in patients who have coronary artery disease, diabetes, or multiple sclerosis.

BIOFEEDBACK: WHAT IS IT?

The term “biofeedback” refers to the instrumentation or training process that allows biologic information to be recorded, displayed, and communicated back to an individual, allowing the individual to make adjustments in physiologic processes that may enhance health or performance. The biofeedback display is analogous to a mirror, in which physiologic processes can be observed and adjusted much as one might adjust a hairstyle or a tie.

In our work with cardiovascular disease patients, biofeedback is a training process that involves a subject or patient, a biofeedback coach or therapist, and state-of-the-art biofeedback equipment. For biofeedback training to be effective, the subject who is trying to learn the skill must be engaged and willing to practice, the coach must be trained in psychophysiology, and the equipment must display accurate readings in real time, allowing the subject to monitor and change physiologic reactions appropriately. The coach teaches the subject about the physiologic parameters, establishes target ranges, and helps the subject learn how to move the physiologic parameters in the right direction.^1,2

Training often begins with a session in which a brief mental stress test is followed by a period of relaxation while physiologic parameters are recorded and displayed. This process helps the subject to understand the link between mental processes and physiologic arousal.

Biofeedback training can involve a number of physiologic modalities, including those that reflect autonomic nervous system arousal, such as skin conductance and heart rate variability, and those that are not strictly correlated with autonomic activity, such as surface muscle tension. Each physiologic parameter is recorded by a specific sensor, and all sensors are noninvasive. Sensors feed signals into a computer, where they are processed and amplified, and subjects are able to view the output on a computer screen.

Typically, in our work, there is one screen for the subject, on which a single parameter can be displayed, observed and discussed, and another screen for the coach, on which all parameters are displayed simultaneously. During a single session of biofeedback training, the coach may choose to work on a single parameter or switch between parameters, depending on how much progress is being made with each. In our work with patients, we generally train to simple parameters first, such as respiratory rate, finger temperature, and skin conductance, moving on to surface muscle tension, heart rate, and eventually heart rate variability, which is a more complex concept and more easily understood later in the training process.

It is important that the subject receive positive reinforcement for changing the physiologic parameters, and if the subject struggles too long with one parameter, it is generally useful to go back to a different parameter, where success may be more easily experienced. Ideally, by the end of six to eight training sessions, the subject will be able to make progress on all physiologic parameters, which will track together over time.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT

Pure biofeedback training consists of operant conditioning. That is, the subject learns to regulate his or her physiology in the right direction because of the feedback, which can be as simple as a pleasant image appearing on a computer screen or as complicated as a car moving faster around a racetrack; pure biofeedback involves changing physiology in response to positive reinforcement of some sort.

In practice, we generally employ biofeedback-assisted stress management (BFSM) rather than pure biofeedback. With BFSM, the subject learns to change physiology in the direction of health and wellness by learning techniques of stress management. The coach teaches the subject various relaxation techniques, such as slow and rhythmic breathing, guided imagery, progressive muscle relaxation, mindfulness, assertiveness, and how to change negative thought patterns. With regular practice, the subject learns to change the physiologic parameters by relaxing the body. For example, instead of instructing the subject to “increase your finger temperature” and assume that the subject will achieve this because doing so will make the light bulb on the screen glow more intensely, the BFSM coach may instead talk with the subject about eliminating stressful thoughts, learning to relax, and the fingers warming in response to the body relaxing.

We distinguish between techniques of stress management, some of which are mentioned above, and psychotherapy, which can certainly be effectively combined with biofeedback, but which we do not provide in our research studies. Coupling stress management techniques with biofeedback helps the subject change physiologic parameters in the direction of wellness and acquire tools that can be used in everyday life when stressful events arise. The objective of BFSM training is not just to change physiology, but also to change the way subjects respond to stressful events in daily life; ie, react to fewer events, react less intensely when they do react, and recover more quickly.

BIOFEEDBACK-ASSISTED STRESS MANAGEMENT IN CARDIOVASCULAR DISEASE

We are currently studying the effects of BFSM in patients with cardiovascular disease, including both heart failure and stable coronary artery disease. Patients with cardiovascular disease often are functionally limited, and they also experience psychologic distress related to physical limitations and other life stressors. Both the physical limitations and the psychologic distress impact quality of life. We hypothesize that BFSM will teach our patients techniques of stress management, both mental and physiologic, that will help relieve their psychologic distress and improve their quality of life. BFSM will also potentially decrease the overactivation of the sympathetic branch of the autonomic nervous system, which is common in cardiovascular disease, and correspondingly upregulate the contribution of the parasympathetic branch of the autonomic nervous system, which should be beneficial.³

A PROMISING TECHNIQUE IN HEART FAILURE

We are currently studying the effects of BFSM in patients with end-stage heart failure who are awaiting heart transplant at Cleveland Clinic.⁴ As noted in a recent review, biofeedback is a promising technique in heart failure that patients may be able to use to consciously regulate their autonomic nervous systems.⁵ We hypothesize that BFSM training will interfere with the overactivation of the sympathetic nervous system that is characteristic of heart failure, and that this will reverse the cellular and molecular remodeling that occurs in the failing human heart.

To date, we have enrolled 25 patients; 10 are being studied in our National Institutes of Health–funded Clinic Research Unit and 15 are inpatients. All 25 patients are listed as heart transplant candidates and have given consent for us to study their hearts when they are explanted.

Each patient receives eight sessions with a certified biofeedback therapist. The first and last sessions include mental stress tests, while the remaining six are BFSM training sessions. Patients are assessed at the beginning and end of the study using the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and measurement of plasma catecholamines.

The primary end point of the study is the measurement of cellular and molecular markers that have been shown to be altered in the failing human heart, testing the hypothesis that these markers will be reversed in the direction of normal in the BFSM therapy group. These markers are measured in the explanted failing heart when the patient receives a heart transplant.

It is too early to report the results of this study, since only seven patients have undergone transplantation to date. We are encouraged by several early findings, however, and hope these will be validated when the entire group is analyzed.

In early analysis, scores on the Kansas City Cardiomyopathy Questionnaire are improved in the last session compared with the first; patients have shown the ability to learn a slower breathing rate; and they are able to regulate their heart rate variability, as measured by the standard deviation of the N-to-N interval, or SDNN. Most important, measurements in the first seven hearts indicate that there is a degree of biologic remodeling of the failing heart after BFSM that is similar to what we have observed with left ventricular assist devices—hemodynamic pumps that take on the workload of the heart, permitting the heart to rest and recover while the patient is waiting for a transplant.^6,7 If BFSM could produce changes in the cellular and molecular properties of the heart that are equal in magnitude to those produced by a mechanical pump, this would be a revolutionary finding in the field of heart-brain medicine.

It should be noted that we are not the first group to study BFSM in patients with heart failure. Moser and colleagues first observed that a single session of skin temperature biofeedback could have significant functional effects in patients with heart failure.⁸ Bernardi and coworkers showed that merely teaching patients to breathe six times per minute (a large component of BFSM training) improved oxygen saturation and exercise tolerance.⁹ Swanson and colleagues in 2009 demonstrated that patients with heart failure were able to regulate their heart rate variability, although they observed this only in patients with a left ventricular ejection fraction greater than 30%.¹⁰ Our preliminary data demonstrate regulation of heart rate variability in patients with lower ejection fractions, which is promising, but we have also added the biologic component of studying the explanted heart, allowing us to test the hypothesis that BFSM could potentially impact the remodeling process and thus have important therapeutic implications.

TRIAL UNDER WAY IN CORONARY ARTERY DISEASE

In addition to our studies of BFSM in heart failure, we have begun a randomized clinical trial of patients with stable coronary artery disease, type 2 diabetes, or multiple sclerosis. These three patient populations were chosen because evidence from numerous studies suggests that they all involve autonomic nervous system dysregulation as well as an inflammatory process.

It has already been mentioned that BFSM can interfere with overactivation of the sympathetic nervous system and potentially upregulate the contribution of the parasympathetic nervous system, which usually exists in juxtaposition to the sympathetic nervous system. Based on the work of Tracey,^11,12 upregulating the parasympathetic nervous system should be antiinflammatory. Thus, we hypothesize that by decreasing both sympathetic nervous system activation and inflammation, BFSM should have an impact on patients with one of these disease states, resulting in improved quality of life and clinical status, reduced anxiety and depression, and changed disease-specific indicators of severity.

We are currently enrolling patients who have coronary artery disease, type 2 diabetes, or multiple sclerosis and randomizing them to groups that will receive either BFSM or usual care. Outcome variables that will be assessed in all patients include heart rate variability; the response of temperature, skin conductance, respiratory rate, and heart rate variability to mental stress; plasma catecholamine levels; plasma C-reactive protein levels; and tumor necrosis factor alpha levels. At the first and last visits, all patients will complete the SF-36, the eight-item Patient Health Questionnaire depression scale (PHQ-8), the Generalized Anxiety Disorder seven-item scale (GAD-7), and a visual analog pain scale. We will also assess disease-specific variables, including heart rate recovery after exercise, plasma lipids, and myeloperoxidase in patients with coronary artery disease; the Multiple Sclerosis Functional Composite (MSFC) test and the Modified Fatigue Impact Scale (MFIS) will be administered to patients with multiple sclerosis; and plasma glucose and hemoglobin A1C will be assessed in patients with type 2 diabetes.

Results of this study will provide data on the potential of BFSM to decrease common markers of autonomic nervous system activation and inflammatory cascades and the effect of those alterations on three specific disease states. To our knowledge, such a randomized study has not been conducted previously; our findings will add significantly to the literature on the mechanism of action of biofeedback-type interventions.

POTENTIAL IMPACT ON DEPRESSION IN CARDIOVASCULAR DISEASE

Depression is increasingly recognized as a component of many cardiovascular diseases; this raises the question of what effect BFSM therapy in cardiovascular disease patients will have on their depression. Of particular importance to this discussion, heart rate variability has been shown to be decreased both in cardiovascular disease and in depression, and BFSM is one treatment that can be used to regulate heart rate variability. Heart rate variability biofeedback has been shown to be useful in treating depression.

Work from Karavidas and colleagues showed that 10 weeks of heart rate variability biofeedback in patients with depression led to significantly improved scores on the Hamilton Depression Scale and the Beck Depression Inventory. Improvement was observed by the fourth week of training, with concurrent increases in the SDNN.¹³ Siepmann and colleagues also used heart rate variability biofeedback in depressed subjects and demonstrated significant improvement in scores on the Beck Depression Inventory, as well as a concomitant decrease in anxiety.¹⁴ In related work, Uhlmann and Fröscher used electroencephalographic biofeedback (also called neurofeedback) in epilepsy patients with depression and measured an increased sense of self control and a decrease in external locus of control; they postulated that biofeedback training provided an important opportunity for success, and thus increased internal control and decreased depression.¹⁵

Evidence suggests that BFSM should have an impact on depression in addition to impacting the cardiovascular disease itself, and both should work together to improve quality of life. For this reason we have added a depression inventory to our randomized trial of BFSM in patients who have coronary artery disease, diabetes, or multiple sclerosis.

Autonomic imbalance characterized by sustained sympathetic overdrive and by parasympathetic withdrawal is a key maladaptation of the heart failure (HF) state. This autonomic dysregulation has long been recognized as a mediator of increased mortality and morbidity in myocardial infarction and HF.^1,2 Sympathovagal imbalance in HF can lead to increased heart rate, excess release of proinflammatory cytokines, dysregulation of nitric oxide (NO) pathways, and arrythmogenesis. Diminished vagal activity reflected in increased heart rate is a predictor of high mortality in HF.^3,4 Sustained increase of sympathetic activity contributes to progressive left ventricular (LV) dysfunction in HF and promotes progressive LV remodeling.^5,6 Pharmacologic agents that reduce heart rate, such as beta-blockers and, more recently, specific and selective inhibitors of the cardiac pacemaker current If, have been shown to improve survival and prevent or attenuate progressive LV remodeling in animals with HF.^4,5,7,8

During the past two to three decades, the emphasis on modulation of neurohumoral activition for treatment of chronic HF gave rise to angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers, and aldosterone antagonists. In recent years, renewed interest has emerged in modulating parasympathetic or vagal activity as a therapeutic target for treating chronic HF. An alteration in cardiac vagal efferent activity through peripheral cardiac nerve stimulation can produce bradycardia and can modify atrial as well as ventricular contractile function.^9,10

Electrical vagus nerve stimulation (VNS) was shown to prevent sudden cardiac death in dogs with myocardial infarction and to improve long-term survival in rats with chronic HF.^11,12 VNS has also been shown to suppress arrhythmias in conscious rats with chronic HF secondary to myocardial infarction.¹³

This article focuses primarily on the effects of chronic VNS on LV dysfunction and remodeling in dogs with HF produced by multiple sequential intracoronary microembolizations¹⁴ or by high-rate ventricular pacing¹⁵ and on the safety, feasibility, and efficacy trends of VNS in patients with advanced HF.¹⁶

VNS IN DOGS WITH MICROEMBOLIZATION-INDUCED HEART FAILURE

Courtesy of BioControl Medical, Ltd., Yehud, Israel

Monotherapy with VNS

Long-term VNS therapy also elicited improvements in indices of LV diastolic function. VNS significantly decreased LV end-diastolic pressure (Table 1), increased deceleration time of rapid mitral inflow velocity, tended to increase the ratio of peak mitral inflow velocity during early LV filling to peak mitral inflow velocity during left atrial contraction (PE/PA), and significantly reduced LV end-diastolic circumferential wall stress, a determinant of myocardial oxygen consumption (Table 1). These measures suggest that VNS can reduce preload, improve LV relaxation and improve LV function without increasing myocardial oxygen consumption.

The effects of VNS in combination with beta-blockade were examined in dogs with HF. Dogs with LV ejection fraction of approximately 35% were randomized to 3 months of therapy with a beta-blocker alone (metoprolol succinate, 100 mg once daily, n = 6) or to metoprolol (100 mg once daily) combined with active VNS with CardioFit (n = 6). As with the monotherapy study, the CardioFit VNS system was operated in the feedback on-demand heart rate responsive mode. Dogs were started on oral metoprolol therapy 2 weeks prior to randomization to VNS therapy. After randomization, all dogs continued to receive metoprolol succinate once daily for the duration of the study.¹⁸

The improvements in LV systolic and diastolic function with combination therapy were associated with important changes in heart rate. Twenty-four–hour ambulatory ECG Holter monitoring studies showed no differences in minimum and average heart rate between dogs treated with metoprolol and those treated with combination therapy with VNS. Maximum heart rate, however, was significantly lower in dogs treated with the combination therapy (114 ± 12 vs 149 ± 8 beats/min, P < .05). These observations suggest that preventing heart rate escape at the high end may further improve LV systolic function compared with beta-blockade alone. This added benefit of the combination of VNS and beta-blockade was likely the result of reducing the adverse impact of increased cardiac workload and increased myocardial oxygen consumption elicited by the heart rate increase.

VNS and left ventricular remodeling

VNS and proinflammatory cytokines, nitric oxide, and gap junction proteins

Nitric oxide (NO) is formed by a family of NO synthases (NOS). The three isoforms of NOS identified to date are endothelin NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). The three isoforms have differing characteristics and roles:

eNOS. NO produced by eNOS plays an important role in the regulation of cell growth and apoptosis²² and can enhance myocardial relaxation and regulate contractility.^22,23

iNOS. Overexpression of iNOS in cardiomyocytes in mice results in peroxynitrite generation associated with fibrosis, LV hypertrophy, chamber dilation, cardiomyopathic phenotype, heart block, and sudden cardiac death.²⁴

nNOS. nNOS has been shown to be upregulated in the human failing heart and in rats following myocardial infarction.²⁵ In rats with HF, inhibition of nNOS leads to increased sensitivity of the myocardium to beta-adrenergic stimulation,²⁶ suggesting a role for nNOS in the autocrine regulation of myocardial contractility.²⁶

In dogs with coronary microembolization-induced HF, mRNA and protein expression of eNOS in LV myocardium is significantly downregulated compared with normal dogs; therapy with VNS significantly improves the expression of eNOS (Table 3).²⁷ Both iNOS and nNOS are significantly upregulated, and their expression tends to be normalized by long-term VNS therapy.²⁷

Gap junction proteins or connexins are reduced or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases, including HF.²⁸ This so-called “gap junction remodeling” is considered highly arrhythmogenic. In mammals, gap junctions exclusively contain connexin-43 (Cx43). Reduced expression of Cx43 occurs in the failing human heart and has been shown to result in slowed transmural conduction and dispersion of action potential duration with increased susceptibility to arrhythmia and sudden cardiac death.^29,30 In dogs with coronary microembolization-induced HF, mRNA and protein expression of Cx43 in LV myocardium was shown to be markedly downregulated compared with normal dogs, and long-term therapy with VNS was associated with a significant increase in the expression of Cx43 in LV myocardium (Table 3).³¹

VNS IN DOGS WITH RAPID PACING–INDUCED HEART FAILURE

Electrical VNS as a potential therapy for HF was examined in dogs with HF secondary to high-rate ventricular pacing using the Cyberonics VNS system (Cyberonics Inc., Houston, TX), which does not operate on a negative feedback mechanism.¹⁵ In this study, VNS therapy was delivered continuously for the duration of the study with a duty cycle of 14 seconds on and 12 seconds off. VNS signals were delivered to the right cervical vagus nerve at a frequency of 20 Hz and a pulse width of 0.5 msec.¹⁵ Dogs were randomized to control (n = 7) or to monotherapy with VNS (n = 8) and followed for 8 weeks. All measurements were made approximately 15 minutes after temporarily turning off the ventricular pacemaker and the vagus nerve stimulator.¹⁵ VNS therapy resulted in a significant decrease in LV end-diastolic and end-systolic volumes and a significant increase in LV ejection fraction compared with controls.¹⁵ This improvement was associated with significant reduction in plasma levels of norepinephrine, angiotensin II, and C-reactive protein. The study also demonstrated the effectiveness of VNS in restoring baroreflex sensitivity, thus improving cardiac autonomic control.¹⁵ Because rapid pacing was maintained throughout the study except for short periods when measurements were made, one can argue that the benefits of VNS therapy in this model of HF are independent of heart rate.¹⁵

SAFETY AND TOLERABILITY OF VNS IN PATIENTS WITH ADVANCED HEART FAILURE

In patients with HF, reduced vagal activity is associated with increased mortality.¹ Vagal withdrawal has also been shown to precede episodes of acute decompensation.³² In a recently published study, De Ferrari et al, on behalf of the CardioFit Multicenter Trial Investigators, examined the safety and tolerability of chronic VNS in 32 patients with symptomatic HF and severe LV dysfunction using the CardioFit system.¹⁶ The CardioFit system used in this study differed from that used in dogs with microembolization-induced HF in that it did not operate on a negative feedback principle. A bradycardia limit causing interruption of VNS was set at 55 beats/min. A 3-week uptitration period was used to maximize current amplitude and duty cycle based on patient sensation. The intensity of the stimulation reached 4.1 ± 1.2 mA at the end of the titration period.¹⁶

This multicenter, open-label, phase 2 trial involved 3 to 6 months of followup with an optional 1 year followup. The results suggested that VNS may be safe and tolerable in HF patients with severe LV dysfunction. Trends for efficacy were also favorable, bearing in mind the nonrandomized and unblinded nature of the study design. The study showed significant improvements in New York Heart Association HF classification, 6-minute walk test, LV ejection fraction, and LV systolic volumes.¹⁶

CONCLUSIONS

A wealth of preclinical and clinical studies supports the concept that electrical VNS can favorably modify the underlying pathophysiology and course of evolving HF. In animals with HF, VNS improves LV function, attenuates LV remodeling and may prevent arrhythmias that provoke sudden cardiac death. VNS derives these potential clinical benefits from multiple mechanisms of action that include reduced heart rate and normalization of sympathetic overdrive. VNS also appears to have a favorable impact on other signaling pathways that are likely to elicit beneficial effects in patients with HF. These include restoration of baroreflex sensitivity, suppression of proinflammatory cytokines, normalization of NO signaling pathways, and suppression of gap junction remodeling. At present, there is no evidence to implicate a single mechanism of action for the benefits derived from VNS. Instead, it is likely that all of the mechanisms listed above act in concert to elicit the global benefit seen with VNS. In humans with HF, VNS may be safe, feasible, and apparently well tolerated. Full appreciation of its efficacy in treating chronic HF must await completion of pivotal randomized clinical trials.