The Feasibility of Exercise and Cognitive Retraining to Improve Memory, Attention and Concentration in Heart Failure.
Phase: NA
Conditions: Heart Failure
Sponsor: Emory University

 
 
Study Protocol and Statistical Analysis Plan  
 
Unique Protocol ID:  IRB00060752 
 
NCT02151266 
 
Feasibility of Exercise and Cognitive Retraining to Improve  
Memory, Attention and Concentration in Heart Failure. 
 
Principal Investigator 
Rebecca Gary, PhD 
 
08/03/2015 
 
 

 
Title: Feasibility of Exercise and Cognitive Retraining to Improve Cognitive Impairment in Heart Failure. 
Abstract.  Cognitive impairment (CI) is a prevalent problem in persons with HF heart failure (HF) and is 
associated with adverse clinical outcomes, higher mortality and poorer quality of life. Studies designed to 
attenuate or alleviate CI in persons with HF are limited, and evidenced based guidelines for screening and 
provision of care are practically nonexistent. Improvement in cognition has been reported following some 
therapies in HF and is thought to be the consequence of enhanced cerebral perfusion and oxygenation, 
suggesting that CI may be amenable to intervention in this population. Exercise is documented to increase 
cerebral perfusion and oxygenation by promoting neuroplasticity and neurogenesis, and, in turn, cognitive 
functioning.  Brain derived neurotrophic factor (BDNF) is a key mechanism underlying the effect of exercise, 
but most studies of BDNF have not included individuals with CI or chronic illness populations, and its 
relationship to cognitive outcomes in HF is unknown. Cognitive retraining techniques, originally developed to 
treat traumatic brain injury, have also shown efficacy in broader neurologically-affected conditions and may 
provide added benefit to that of exercise.  Animal studies suggest exercise and plasticity-based cognitive 
training could act synergistically through different neural mechanisms to have a more pronounced and positive 
impact on cognitive outcomes than either approach alone; but this has not been previously tested as an 
intervention to improve CI. The proposed feasibility study is designed to test the acceptability and limited 
efficacy of a combined exercise (Ex) and cognitive training (CT) program to improve CI in stable NYHA class II 
and III HF patients compared to either exercise alone or a no-intervention, attention-control group. Findings will 
be used to support the development of a future, large scale study to test the efficacy of this intervention to 
improve cognitive functioning, quality of life, and physiological markers of improved brain function in HF. 
 
Specific Aims.  Persons with heart failure (HF) have a four-fold greater likelihood of developing cognitive 
impairment (CI) than their age matched healthy counterparts, placing them at high risk for adverse clinical 
outcomes, poorer quality of life (QOL) and higher mortality.1-6 CI is a subtle but measurable deficit in one or 
multiple cognitive domains; it is a deficit greater than cognitive losses associated with normal aging.5 The few 
studies that have documented CI in HF are inconsistent. Few have used standard neuropsychological testing, 
and little is known about change in cognitive function over time in HF. 5,7-10 Further, if CI is detected, there are 
currently no effective or evidenced-based guidelines to help restore or improve cognition in this population.3,5-
7,11-14 Despite the aging population and projected rise of CI in HF, only 2 small intervention studies15-16 have 
been documented, indicating a critical need for further research in this area.5-6 
    The etiology of CI in HF is not fully understood, but several underlying mechanisms are consistently 
reported: reduced cerebral perfusion and oxygenation, brain structural changes (i.e., hippocampal damage, 
atrophy, loss of gray matter), and micro emboli.5,7,11,14,17-22 Clinical studies have shown that CI is improved after 
cardiac transplantation23-24 and is modifiable with standard therapies that improve cardiac output, oxygenation, 
fluid overload, and systemic and cerebral perfusion; these findings are inconsistent and anecdotal.5,8,13-14,25-27 
The ability to positively influence cognitive function has important implications for patient adherence to a 
complex self-care regimen and the development of interventions that may partially reverse CI.5-6 
     Exercise improves clinical outcomes in HF by altering the deleterious peripheral and central mechanisms 
that contribute to HF exacerbations, worsen symptom severity, and lead to poor clinical outcomes.28-38 Less is 
known about the effect of exercise on cognitive function.15,39-43 Animal research has provided the most 
compelling evidence that exercise positively affects neuronal growth and the neural systems involved in 
learning and memory.49-51 Similar human findings have emerged;17,52-55 recent advances in neuroimaging 
support that participation in regular exercise leads to specific changes in brain structure and function. 56-57 
Exercise is also thought to enhance brain plasticity. BDNF appears to play a crucial role in this process: 52-53,58-
60 when BDNF levels increase following exercise, cognitive function improves.52-53,58 The association between 
exercise, BDNF and cognitive function has not been previously reported in HF.53 This feasibility study will 
clarify these important relationships and increase the potential for improving clinical outcomes in a future trial. 
     Neurogenesis and neuroplasticity are means for the brain to recover from poor perfusion and oxygen 
deprivation such as that occurring in HF.5,50,52 Animal studies again provide the strongest evidence to date for 
using cognitive training (CT) to promote better cognitive functioning and provide a rationale for why a combined 
exercise and CT approach may be superior to monotherapy.50,52 Animal studies show that, like exercise, 
learning tasks and performing cognitively stimulating activities also increase BDNF levels and improve learning 
and memory.15,16 The effect of BDNF on brain function due to exercise however, is thought to be different from 
that occurring with CT.  Exercise increases the proliferation and division of neuronal cells through BDNF,61 
whereas CT appears to promote cell survival,62-63 suggesting a synergistic relationship may exist with greater 

benefit obtained when both are used together.50,52-53 The combination of exercise and plasticity-based CT has 
not been previously tested in HF or in other populations as an intervention for improving cognitive 
outcomes,50,64-66 but may be most optimal for targeting the underlying mechanisms for CI in HF.  The proposed  
feasibility study is designed to test the acceptability, implementation and limited efficacy  of a combined 
exercise (Ex) and cognitive training (CT) intervention in stable NYHA class II and III heart failure patients with 
cognitive impairment. A total of 60 participants will be randomized to one of three study arms: Ex/CT (N=20), 
Ex-alone (N=20), and attention control (N=20).  The study aims are: 
 
Aim 1: To evaluate the feasibility of a 3-arm intervention (ExCT, Ex, AC) in heart failure patients with CI. 
   Aim 1a. To test the acceptability and implementation of each study arm. 
Aim 2: To ascertain limited efficacy of the 3-arm intervention on changes in cognitive abilities 
Aim 3: To ascertain limited efficacy of the 3-arm intervention to improve cerebral oxygenation, physiological 
status, physical function and QOL.  
A. Significance.  Approximately 670,000 individuals are diagnosed with HF annually in the United States,67-70 
and over one million hospitalizations occur each year due to HF, especially among adults 65 years of age and 
older.71-73 As many as 60% of persons with HF experience cognitive impairment, (CI); this number increases 
proportionately as HF worsens.5-6,10,74-76 Increased age and depression are independent predictors of more 
severe CI in persons with HF.5-6,77-82 CI often interferes with the ability to engage in effective self-management 
of HF; this leads to more frequent hospitalizations and contributes to the cost burden on the health care system 
and reduced quality of life.6,74-75,83 To reduce these burdens, we propose a nurse-led exercise and cognitive 
training intervention that targets underlying mechanisms that contribute to CI in persons with HF.  
Exercise. Over 130 smaller studies, as well as the recent large, multi-site Heart Failure: A Controlled Trial 
Investigating Outcomes of Exercise Training (HF-Action) trial,28 have established the safety and efficacy of 
moderate-intensity aerobic exercise in stable HF. The effect of exercise on cognitive outcomes in HF however, 
remains largely unknown.5,44-45,52-53 One small study examining the effect of exercise on cognitive functioning 
and cerebral perfusion in HF revealed significant improvements in 2 cognitive domains (attention and psycho-
motor speed) but no changes in cerebral perfusion; the low dose exercise regimen and lack of a true 
comparison group also interpretation.15 Evidence from other populations, including those with disabilities and 
chronic illness, (e.g. renal failure, Parkinson’s Disease, multiple sclerosis, stroke, Alzheimer’s Disease) 
suggests that exercise improves cognition via several biological processes: its impact on increased cerebral 
blood flow and oxygen delivery; its influence on BDNF (thought to enhance neurogenesis); and its effect on 
certain neurotransmitters.52-53,58-63 Exercise is reported to improve cerebral oxygenation following moderate 
intensity aerobic exercise, but few studies have examined clinical populations or the impact on cognitive 
functioning.86  Recent meta-analyses also provide strong evidence of a positive and significant effect size for 
aerobic exercise on cognitive function, despite methodological limitations.39,41,87 Importantly, the effect of 
exercise is much greater on selected cognitive processes, especially executive function; this suggests that 
executive function may be amenable to intervention.52-55 This finding has important implications for persons 
with HF whose executive functioning is particularly affected by the underlying pathological changes associated 
with HF.82,84 Moreover, because executive functioning is necessary to effectively manage HF disease, it is not 
surprising that poor cognitive functioning is a significant predictor of mortality in this population.82 
     Cognitive training. The type of CT that produces the best cognitive function outcomes is unknown since 
many studies have enrolled predominately healthy, well-educated white individuals with no CI.64-66 Research in 
adults with CI are inconclusive and have considerable limitations; few randomized trials are available.64-66,88 
Several recent studies suggest that computer-based plasticity interventions may be advantageous, e.g. in 
memory training.89-91 Plasticity-based training interventions hinge on the understanding that targeted, repeated 
cognitive exercises can rebuild and re-organize function through neuronal generation, dendritic sprouting, and 
axonal sprouting.  The only study to date to incorporate plasticity-based cognitive training in HF found that it 
significantly increased list learning, delayed recall memory, psychomotor speed, and performance of IADLs; 
participant adherence and satisfaction were high.16 In another study of community dwelling older adults without 
CI, improvement in memory and attention was significantly greater in the group that received the plasticity-
based cognitive training intervention than in those receiving a program of general cognitive stimulation.  
     Combined exercise and CT.  Evidence of exercise improving cognitive function is robust; and similar 
changes on cognition are noted with plasticity-based CT; the effects of these two approaches are different yet 
synergistic, and suggest the effect on cognitive functioning may be more pronounced when the two are used in 
combination versus alone; this provides a strong rationale for the proposed intervention. 52-66 This feasibility 
study will evaluate the acceptability of the intervention(s), adherence to the intervention protocols, the scope of 

recruitment efforts to identify acceptable cases, potential dose responses gleaned from differing amounts of 
intervention compliance, and estimates of effect sizes to optimize a subsequent, large-scale efficacy trial.  
 PRELIMINARY STUDIES. We have tested strategies to maximize physical function, reduce psychological 
distress, and maintain optimal physiological status in persons with HF.94-100 Our interdisciplinary team 
published results of one of the largest non-pharmacological trials demonstrating the effectiveness of exercise 
and CBT to reduce depression in HF patients,96 using a similar design as the one proposed here, and 
demonstrating the ability to recruit and retain highly complex HF patients. We have expertise in the design of 
home-based exercise studies using self-monitoring strategies to increase adherence to exercise (e.g. exercise 
testing and prescription, HR monitors, pedometers, logs).  In our prior work, we collected, stored and analyzed 
a variety of biomarkers (hsCRP, tumor necrosis alpha and BNP) and findings showed a trend for significance, 
similar to previous research. This preliminary study will expand our previous work by exploring the influence of 
exercise and CT on novel biomarkers (BDNF, cerebral oxygenation) not previously examined in HF. 
Conceptual framework.  The conceptual model for this study, portrayed in Figure 1, is based on the 
substantial literature of the underlying physiological mechanisms that contribute to CI in HF.75,93 Heart failure 
by definition is a state of hypo-perfusion that contributes to poor cerebral perfusion, poor oxygenation and, in 
turn, CI.93 The proposed intervention (exercise and CT) is designed to positively alter these underlying 
physiological processes that contribute to CI in persons with HF.  This model aligns well with that of the Center. 
 
 
 
 
 
 
Figure 1. Conceptual framework 
B. Innovation: Available evidence to guide care for persons with HF who are cognitively impaired is 
nonexistent. Our preliminary work using exercise and cognitive behavioral strategies 94-100 has shown improved 
physical, psychological and QOL outcomes in persons with HF. The proposed study will expand this work and 
provide important insight on an innovative intervention strategy (exercise and CT) and novel biomarkers (BDNF, 
cerebral oxygenation) in a diverse population of HF with CI.  No study has documented whether exercise 
improves cerebral oxygenation in persons with HF; the one study measuring cerebral oxygenation in persons 
with HF found a significantly reduced cerebral oxygenation level using near infrared spectography (NIRS), 
despite a normal peripheral oxygen saturation.101 Combination physical exercise and cognitive training have 
never been evaluated in HF to improve CI. This dual process may provide a synergistic, additive benefit through 
different yet complementary mechanisms of recovery. This feasibility study will provide essential information to 
optimize the potential success of a future, large scale research trial.  
 
C. APPROACH.   
Design. A pre-post randomized controlled design will be used to measure study aims. Sixty participants will be 
randomized to receive ExCT 
(N=25), Ex-alone (N=25), or 
attention control (N=25) 
intervention conditions for 3 
months. Assessments will 
take place at baseline, 
intervention completion (3-
months) and 6 months post-
intervention. Outcomes of interest include cognitive functioning, peak oxygen consumption (peak V02), BDNF, 
and Kansas City Cardiomyopathy Questionnaire (KCCQ; HF specific quality of life instrument). After a 4-5 month 
start-up for hiring and training, enrollment will begin. Recruitment/enrollment will take place over 18 months; the 
final follow-up appointment in month 30. This will leave 6 months for data analysis and dissemination.                                                   
 
Setting and Sample:  Patients will be recruited from the Centers of Heart Failure Therapy of Emory University 
Hospitals (EUH) and clinics, Emory University Hospital Midtown (EUHM), and Grady Health Systems (GHS). A 
full description of the ethical recruitment of participants is described in the Human Subjects section of this 
proposal. The Atlanta Cardiomyopathy Consortium (TACC) and HF Network databases at EUH will enable us to 
rapidly identify HF patients who meet our eligibility requirements. In 2009, over 4,000 inpatient admissions to 
EUH or EUHM were due to HF, and excluding those for transplant, 5377 local patients with HF were seen in the 
Antecedents 
Age 
Depression 
Co-morbidities  
SES 
Medications
Heart failure 
    Severity (NYHA, LVEF) 
    Duration  
 
    Hypoperfusion, oxygenation 
Intervention 
Ex/CT 
Ex Only 
AC control 
Outcomes 
Cognitive function 
Cerebral oxygenation 
Physiological status 
Physical function 
QOL

Center for HF Therapy; 42% are women and 31% African American.  The patients at GHS reflect a more 
ethnically homogeneous group: 51% are women, 94% African-American, and most are low socioeconomic 
status.  Because the regional population is estimated to be 35% to 40% African American, this range will be 
used as the recruitment goal. See Human Subjects for sample characteristics and rationale.   
STUDY CONDITIONS. All 3 groups will receive Usual Care (UC) + group assignment (attention control 
stretching, EX/CT or EX only) after undergoing baseline measures conducted at the Clinical Integration Network 
(CIN) clinic of the Atlanta Clinical Translational Science Institute (ACTSI). UC includes pharmacologic therapy 
according to ACC guidelines 102-103 and patient education and self-management (i.e., low sodium diet, 
medication instructions, symptom and weight monitoring).  All study patients will be given standard printed 
educational materials (Heart Failure Society of America [HFSA] Modules 1 and 3) regarding HF.103  Group 
assignments, 
schedules and 
procedures are 
outlined in Table 1.  
Education, flexibility 
and stretching will 
provide control for 
the possible 
confounding variable of receiving attention from a healthcare professional.  Instruction on stretching and 
flexibility movements is also expected to reduce attrition and patient dissatisfaction and to better ensure 
concealment of group allocation. These time-equivalent, flexibility/stretching movements have been previously 
piloted and will serve as the “placebo exercise condition.” In pilot evaluations they were well received, but were 
not strong enough to influence outcomes. The AC education placebo component will be delivered as soon as 
feasible after baseline (T1). The first 2 weeks of the intervention phase will include 2 home visits to demonstrate 
stretching and flexibility movements and to discuss educational materials. Weekly telephone calls will then be 
made for the next 10 weeks to discuss educational materials and to answer questions about stretching 
movements. An appointment will be made for participants to come to the ACTSI to collect T2 measures; this will 
occur at weeks 13 and 14. From weeks 15-24 bi-monthly telephone contact will be used to encourage continued 
adherence to the AC intervention.  At the end of 24 weeks, a final visit to the ACTSI will be arranged and T3 
measures will be taken.  For ethical and cardiovascular health reasons, the AC group will be advised to 
exercise, but will not be provided with an exercise prescription or self-monitoring equipment since these have 
been shown to influence exercise adherence and exercise self-efficacy and may confound study outcomes.104-105   
 
Groups 2 and 3 Exercise Prescription. Groups 2 & 3 will receive the same exercise prescription using a 
progressive moderate intensity aerobic protocol. To ensure that participants achieve adequate training stimulus, 
dose-specific exercise will be 
based on maximum heart rate 
(HR) obtained during symptom 
limited, modified Balke treadmill 
tests106-107 conducted by an 
exercise physiologist and 
supervising cardiologist in the 
CIN. Target heart rate (THR) using the 60% to 70% of maximum HR achieved on the cardiopulmonary exercise 
test (CPET) will be used to monitor the intensity and training response for aerobic exercise.  Each participant will 
be provided with an individualized THR zone based on CPET results.107 Under the supervision of a research 
nurse, participants will begin the walking sessions at 60% of THR and increase to 70% by week 5 as shown in 
Table 2.  In our pilot with HF patients, a progressive moderate intensity level exercise program yielded positive 
outcomes with no adverse events, was appealing to participants and adherence rates were 80% or higher. 
Group 2: EX/CT (UC + aerobic exercise + cognitive training) The first 2 weeks of the study will consist of 2 
consecutive weekly home visits by the research nurse to demonstrate use of the HR monitor, pedometer and 
the CT program, Brain Fitness (Posit, San Francisco, CA detailed below).  The research nurse will supervise 
one walking session during the first 2 weeks to ensure the safety of the participant and that he/she understands 
how to use the Polar HR monitor and pedometer and how to complete the walking logs. During the first 2 weeks, 
the research nurse will also provide training and demonstrate how to use the Brain Fitness computerized 
cognitive training program designed to be completed in 40 sessions over 12 weeks. We expect that participants 
will require additional time (at least 30 minutes each time) in the first 2 weeks to learn how to use and access 
the Brain Fitness program.  The weekly schedules are provided in table 1. 

Brain Fitness Computer Training: is based on the principles of positive brain plasticity and designed for use by 
adults. The training program (“Brain Fitness”) is focused on speech reception to strengthen an individual’s 
memory for speech. It has 6 modules names Hi-Lo, Tell Us Apart, Match It, Listen and Do, Sound Replay and 
Story Teller. Research to date has found: 1) participants with limited or no computer experience were capable of 
learning to perform the training exercises, 2) the training was safe and well tolerated by participants, and 3) 
healthy participants who trained on Brain Fitness showed on average a 1/3 standard deviation of improvement 
in memory, concentration and cognition, and 4) it has been tolerated well in patients in HF in a prior study.16 
Group 3: Ex only group (UC + aerobic exercise). The same exercise protocol will be used as above without the 
computer training.  
Exercise adherence. To be 100% adherent for exercise sessions, participants in both groups 2 and 3 must 
document walking weekly at the prescribed intensity/duration on the exercise log.  Participants will record on a 
calendar provided: maximum HR achieved; rate of perceived exertion (RPE) during walk; and number of steps 
walked during the walking sessions.  Polar HR monitors and pedometers (described in instruments) will be used 
to objectively document exercise intensity (i.e., maximum HR and RPE achieved), duration, walking adherence 
and progression. The Polar HR monitor and pedometer data will be downloaded during each home visit during 
the first 2 weeks to track exercise duration and steps walked.  At T2, data collected from the HR monitors and 
pedometers will also be downloaded to document exercise adherence.  A total summary adherence score will 
be calculated by summing and dividing weekly adherence scores by total number of weeks walked.  
CT adherence.  The total number of minutes for the full Brain Fitness program is approximately 2400 minutes 
over 8 weeks.  Patients will be considered adherent if they meet or exceed 80% of the required minutes for the 
intervention.  Total number of minutes can be accessed from the program to monitor adherence.   
 
VARIABLES, DEFINITIONS AND MEASURES. Variables, operational definitions and methods are described 
below and in Table 3.  Questionnaires will be administered at the time of the visit by a trained research assistant 
blinded to group allocation.  Core services and Center activities will greatly enhance the success of this study. 
Through training and monitoring in administration and scoring of the core test battery, regular consultation with 
the BMC to monitor implementation issues, systematic data management and analysis, and support in using 
these findings to prepare an RO1 application, this study will achieve its aims and further the goals of this Center. 
Sociodemographic and clinical variables will be obtained from self-report and medical records. The Charlson 
Comorbidity Index (CMI)108 will quantify the cumulative risk of death.  Mini Mental Status Examination102 will 
be used to screen for study inclusion for mild to moderate cognitive impairment (score of 20 for 8-9 yrs of 
schooling; 22 for 10-12 yrs of schooling; 23 for >12 yrs) 102 and has excellent specificity at this cut-off point.5  
The Beck Depression Inventory-II (BDI-II)109 has been widely used in the HF population. Scores will be used 
as an effect modifier and explored as a potential outcome variable. Cognitive Function. We will use the 
Center’s core neuropsychological testing battery of well-established and validated instruments that are 
described in the Biobehavior and Methods Core (BMC) portion of this application. The BMC will provide training 
on test administration and scoring and will aid in data management and interpretation.  Cerebral tissue 
oxygenation will be assessed in the CIN by a cerebral oximeter sensor (Casmed, Blanton, CT) using near 
infrared spectography (NIRS). NIRS is widely used and validated in a variety of fields to assess cerebral tissue 
oxygenation.86,101 
 
  Table 3.   Variables, measures, instruments and time of evaluation 
Variable 
Measure/Instrument 
# of items/time 
Time of 
Evaluation 
Antecedents 
Participant  Demographics 
& Clinical information: Co-
morbidity, Cardiac Fx, Meds 
Mild-moderate cognitive 
impairment 
Depressive symptoms 
Age, gender, education, marital status,  
Charlson comorbidity Index (CMI) LVEF, NYHA 
class, length of time with HF & etiology, 
Medications  
MMSE 
 
BDI-II 
Chart review & 
questionnaire 
Questionnaire 
 
30 item/10 minutes 
 
21 item/15 minutes 
Baseline 
(BL) 
 
 
BL only 
 
BL only 
Cognitive function 
   Repeatable Battery for the Assessment of        
   Neuropsychological Status (RBANS) 
Controlled Oral Word Association Test 
Color Trails 1 & 2  
WAIS-III Digit Span/Letter Number Sequence  
Stroop Test  
Ruff 2 & 7 Test  
Rey Auditory Verbal Learning Test 
30 minutes 
 
5 minutes 
10 minutes 
10 minutes 
5 minutes 
5 minutes 
10 minutes 
BL, 3 and 
6 months 

Physical function 
Peak oxygen consumption (Modified Balke) 
20 minutes 
BL & 3 
mos 
Physiological status 
BDNF 
NA 
BL & 3 
mos 
Cerebral oxygenation 
Near infrared spectography,  
30 minutes 
BL & 3 
mos 
Quality  of Life 
KCCQ  
23 items /15 
minutes 
BL, 3 and 
6 months 
Exercise Adherence 
 
 
CT adherence 
Polar HR (intensity, duration and frequency), 
walk calendars, pedometer, nurse telephonic 
log 
Brain Fitness program, nurse telephonic log 
10 minutes 
 
 
NA 
3 and 6 
months 
 
Physical Function will be assessed using the modified Balke maximal treadmill test 106-107 to determine peak 
oxygen consumption (peak Vo2), maximum HR for exercise prescription and to screen for cardiac 
contraindications to exercise according to the (AHA/ACC) guidelines.102 Physiological status. The serum 
biomarker BDNF will be collected in the CIN by a research nurse or phlebotomist, the assays will be stored at -
80 degrees until processed by the ACTSI biocore lab using the manufacturer’s ELISA guidelines.  
QOL. The Kansas City Cardiomyopathy Questionnnaire (KCCQ)110 is a reliable and well validated 23-item, 
disease specific questionnaire that quantifies physical function, symptoms, social function, and HRQOL in 
HF.111-112 
Adherence. Step counts will be indirectly assessed using the Omron HJ-7201ITC pedometer to count daily 
steps.113-117  The 15 point (6-20) Borg Rate of Perceived Exertion (RPE) Scale118 will be used to measure 
participants’ subjective perception of effort. Target heart range (THR) 107 using the HR reserve method will be 
used to monitor the intensity and training response to walking.  Polar Beat  Watch (FT4)119 will be used to 
monitor intensity and duration of walking.120-121 Actual adherence to intervention protocols and study attrition 
rates will be included in an intent-to-treat analysis (CT & Ex). 
Acceptability. During post-baseline visits and phone contacts, participant’s opinions about the intervention, e.g. 
perceived usefulness, ease of use, barriers to adherence, perceived improvements in health, cognition, mood, 
quality of life will be collected. The PI will use content analytic techniques to assess acceptability and to identify 
themes suggesting possible revisions or alterations in the interventions that might improve acceptability. 
Procedures  Recruitment, Screening and Enrollment of participants will occur through physician and other 
health care provider referrals and patient self-referral. These methods have proved successful in our prior work.  
The recruitment nurse will arrange a time for laboratory, and treadmill tests at the CIN. Baseline (T1) measures 
will be taken in the CIN by a trained data collector blinded to group assignment.  All participants will be given the 
same measures, in the same sequence at each time point.  Questionnaire completion should take 30 minutes or 
less, the neuropsychological testing is anticipated to take 75 minutes. Laboratory samples will be taken prior to 
the treadmill test. The BDNF samples will be stored at -80 in the CIN until processed. After the laboratory work is 
completed, the modified Balke treadmill test will be conducted by an exercise physiologist; emergency 
equipment, doctors and nurses are available.  After BL, participants will be randomized to study groups by 
computerized sheet prepared by the study statistician. At 3 and 6 months we will follow the same procedures 
used at Evaluation 1.  After Evaluation 3, participants will be discharged from the study, and all participants 
provided with study results. A $50 honorarium will be provided at each measurement time point, to total 
$150/patient for completing the study.  Intervention process measures (evaluation, attendance) will be tracked 
and evaluated to maintain internal validity.  Protocol adherence will be calculated for both groups.  
Data Management and Analysis.  The Biobehavioral and Methods Core (BMC) will coordinate the collection, 
integration, and analysis of biological and psychosocial data for this study. Data will be analyzed using both 
descriptive and inferential test statistics. We will build multivariable statistical models to examine the relationship 
between an Ex/CT intervention to exercise alone and attention control (AC) on cognitive functioning (P-30 
Neuropsychological Battery), cerebral oxygenation (NIRS, 3 months only), physiological status (BDNF), physical 
function (peak V02) and QOL (KCCQ) in HF at BL, 3 and 6 months controlling for but not limited to age, gender, 
SES, depression, social support, NYHA class, medications and comorbidities. 
     Since the intent of this study is exploratory; hypothesis testing will not be the primary focus of the statistical 
analysis. Rather, we will analyze data with the specific intent of establishing population parameters (e.g., effects 
sizes) for the variables being investigated. Confidence intervals will be calculated for all effect sizes associated 
with the predictor variables, other significant outcome effects, and for changes over time. These effect size 
estimates will be used to design the future R01 study. Given the relatively small sample size of n=60 at 80% 
power, and α=.05, we will have the ability to detect a moderate (d=.5) to large effect size (d=.8). We will use 

general linear and/or mixed models as the main modeling framework for analyses of the outcome measures in 
the projects. We will build full factorial models to test for interactions and review estimated marginal means. We 
will use Using G*Power 3, to estimate actual power for the GLM analysis both a priori and post hoc.  
 
E.    HUMAN SUBJECTS RESEARCH 
Inclusion criteria: (a) 75 outpatient men and women between the ages of 40 and 75; (b) English speaking; (c) 
live independently within a 60 mile radius of Atlanta; (d) meet education corrected cut-offs on the MMSE 
indicating cognitive impairment (score of 20 for 8-9 yrs of schooling; 22 for 10-12 yrs of schooling; 23 for >12 
yrs) 102; (e) have a computer with internet connection;(f) documented medical diagnosis of NYHA class II or III 
systolic. (g) Left ventricular ejection fraction (LVEF) ≥ 10% that is documented within the last year by 
echocardiogram, cardiac catheterization ventriculography or radionuclide ventriculography; (h) Receiving 
medication therapy for HF according to American College of Cardiology (ACC) American Heart 
recommendation guidelines103for at least 8 weeks prior to study enrollment. Exclusion criteria: a) NYHA class I 
or IV; (b) change in HF therapy within 8 weeks; (c) worsening HF symptoms within last 5 days; (d) unstable 
angina; (e) renal insufficiency (serum creatinine > 3.o mg/dL); (f) fixed rate pacemaker; (g) uncontrolled 
hypertension; (h) not involved in any structured exercise program or exercising 3 or more times per week for a 
minimum of 30 minutes and; (i) not hospitalized within the last 30-days; (j) not diagnosed with any neurological 
disorder that may interfere with cognitive function; (k) Beck Depression Inventory II (BDI-II) score greater than 
25; and (l) any disorder interfering with exercise participation.  
It is anticipated that approximately 50% of patients approached regarding the study will be eligible and will 
agree to participate. Based on the PI’s earlier studies, a retention rate of 85% is expected. The actual 
acceptance and retention rates will be included as part of the information gleaned from this feasibility study to 
inform the design and methods for a subsequent, large scale efficacy trial. 
Rationale for sample characteristics. The age range was selected to avoid confounding effects of age and 
sarcopenia with outcomes such as aerobic capacity, BDNF and HRQOL; participants below the age of 40 
years are likely to have HF for other reasons than the majority of the general HF population. Older age (>75) is 
associated with reduced exercise capacity and age related cognitive decline which may confound physical 
function cognitive outcome measurement. In addition, persons over the age of 75 are at higher risk for adverse 
events during exercise testing and with aerobic exercise.  Although we anticipate most participants to be 
receiving optimal medication therapy, treatment decisions regarding individual care will be based on patient's 
clinician; evidence-based care will be encouraged.  If any participants are not being treated with what is 
considered optimal medication therapy according to ACC guidelines, the reason (eg, intolerance) will be 
recorded and tracked by group and statistically controlled as a covariate. We recognize that both resting and 
exercise heart rates are influenced by beta-blockers, which is considered optimal therapy for HF patients. For 
both exercise testing and training we will use the heart rate reserve method which takes into account the 
patient’s resting heart rate, thereby reducing the effect of beta-blockade. We will attempt to schedule patients 
for their exercise testing and training a minimum of 3 hours after taking beta blockers.28-29  For patients who are 
unable to schedule exercise during this time frame or exercise up to the prescribed heart rate, Borg’s 6-20 rate 
of perceived exertion scale (RPE) between 12-15, will be used to guide exercise intensity, consistent with a 
moderate intensity level exercise. Patients with an ICD may be enrolled if their heart rate limits are set to be 
higher than the target heart rate for the exercise regimen.  In our last preliminary study, approximately 90% 
had an ICD; there were no firings during exercise or any increase in adverse events.  Although unlikely to 
occur, participants with a fixed rate pacemaker would not be able to participate because heart rate may be set 
at a lower rate than required to achieve prescribed target heart rate.  Participants who have recurrent angina, 
more severe symptoms have uncontrolled hypertension will be excluded due to the higher risk for adverse 
cardiovascular events during exercise testing and the walking intervention.  Because moderate to severe 
depressive symptoms are a major predictor of exercise attrition and more severe CI, participants will be 
excluded who have a BDI-II score of 25 or higher.  These severely depressed subjects will be evaluated for 
suicidal risk, and referred to psychiatric care. Because the benefit of exercise is being evaluated, participants 
who are currently enrolled, or were recently enrolled in an exercise program for the past 8 weeks, currently 
exercising at regular intervals (more than twice per week for 30 minutes) will not be eligible for the study. 
     Based on the practice patterns at enrolling institutions, we expect the recruitment pool to be approximately 
35% African American, with very small numbers of Hispanic/Latino, Asian/Pacific Islander or American Indian 
racial/ethnicity groups. We anticipate our recruitment to represent this population (Tables 3 and 4).  Subjects 

will not be excluded due to race or ethnicity.  Based on our prior experience with this population, we anticipate 
most participants will have computer access.  
 
Sources of research material will include responses to questionnaires obtained at baseline, 3 and 6 
months; data will also be obtained at these time points in the form of laboratory serum samples, treadmill and 
neuropsychological tests.  Polar HR monitors and pedometers will be downloaded weekly during the first 2 
weeks to obtain data on adherence to prescribed exercise intensity and duration and at 3 and 6 months.  
Calendar walking logs will be used to obtain data on exercise adherence for the exercise sessions.  The 
participant’s medical history, medication history and sociodemographic information will be obtained from the 
medical record.  It is expected to take approximately 30 minutes for the participants to complete the 
questionnaires at each time point. The neuropsychological tests are anticipated to take approximately 75 
minutes.  Each participant is anticipated to spend approximately 3 hours at each time point for data collection 
purposes.  A trained research assistant blinded to study group assignment will administer the questionnaires at 
the ACTSI at each visit in the same sequence for each time point.  All data will be obtained specifically for 
research purposes and in the same order and sequence at each testing period.  Participants in each group will 
have 2 home visits during the first 2 weeks of the study followed by weekly telephone contact from 3-12 weeks 
and bi-monthly telephone contacts from 15-24 weeks.  Participants randomized to the exercise/CT and 
exercise only group will have one supervised walking sessions to establish safety, explain use of pedometers, 
HR monitors and calendars. Participants randomized to the exercise/CT group will have 2 home visits during 
the first 2 weeks to explain and review how to use the Brain Fitness program (in combination with one 
supervised walk session). The AC group will also have 2 home visits in the first 2 weeks to demonstrate 
stretching and flexibility exercises and to review HF educational materials.  At the end of 12 weeks, the 
participants will undergo T2 measures at the ACTSI at weeks 13 and 14 (3 months evaluation).  At the end of 
the 6 months, T3 measures will be scheduled at weeks 25 and 26.  Printed education materials will be 
standardized across all groups. The total participation time over 12 weeks is anticipated to be 40 hours for the 
exercise only and AC groups, including testing time.  The total estimated time for the exercise and CT group is 
anticipated to be approximately 80 hours including testing time. 
  
After a 4-5 month start-up for hiring and training, enrollment will begin. Recruitment/enrollment will take 
place over 18 months; the final follow-up appointment in month 30. This will leave 6 months for data analysis 
and dissemination.                                                                                                                                                                 
 
Participants will be recruited through two mechanisms following HIPPA guidelines- health provider 
referral and self-referral.   We will track method of referral and examine this in relation to demographic and 
outcome variables.  Physicians, physician assistants, and nurse practitioners working in the HF clinics of the 
enrolling sites will identify patients who meet eligibility criteria and provide them a brief letter describing the 
study and asking if they are interested to hear more about the study. If interested, the patient will either be 
briefed at that time by a member of the research team if available, or be asked to provide his or her phone 
number at the bottom of the letter, and a member of the research team will pick up such forms at the end of 
each week and will follow-up by phone with each potential subject within 48 hours.  Recruitment flyers, posters, 
and print/media advertisements will be placed in strategic places for patient access, with a phone number to 
call if they are interested in participating. The Atlanta Cardiomyopathy Consortium (TACC) database and NIH 
funded HF network at EUH will also be used to identify potential participants. Those who are identified as 
eligible using the TACC or HF network database will be mailed letters with research team contact information 
for them to call if they are interested in participating or want further information about the study. Recruitment 
fairs may also be held in areas where HF patients are likely to be present, such as HF patient education 
conferences and congregate housing facilities.  Community-sponsored events such as health fairs and cardiac 
support groups are also potential venues to elicit study participants. Once eligibility has been established via 
phone or in person, the study will be fully explained and written informed consent will be obtained from each 
participant by a member of the research team. Prior to beginning the study, recruitment materials will be 
reviewed and approved by the Institutional Review Board (IRB) of Emory University, which serves as the 
oversight committee for each of the enrolling institutions.  IRB approval for the overall study will be obtained 
prior to participant recruitment or enrollment.   
 
Potential Risks are expected to be minimal since participants will be referred from an academic health 
sciences center under the care of a cardiologist and receiving optimal medication and device therapies.  In 
addition, excluding patients who are over the age of 75 years, NYHA class IV and have a LVEF < 10 will 
reduce risk of adverse cardiac events.  The cardiologist will be contacted and agree that potential participants 
are eligible for the exercise program.  We will conduct a brief history and physical examination before aerobic 

capacity tests (modified Balke) are conducted at the ACTSI.  If a participant becomes fatigued and does not 
wish to continue, they will be rescheduled for an additional appointment to complete the remainder of the tests. 
     The risks associated with administering the modified Balke treadmill tests are anticipated to be minimal but 
may include: atrial and ventricular arrhythmias, sudden death, angina, ICD firings, adverse blood pressure 
changes (high or low), dyspnea, fatigue, falling orthopedic/musculoskeletal complaints, dizziness, and 
electrocardiographic evidence of ischemia. We will administer the modified Balke, a symptom limited treadmill 
test, in the ACTSI by an exercise physiologist and under the sponsorship of the study cardiologist according to 
the ACC/AHA guidelines.123  The treadmill test will be performed with commercially available equipment 
(VMAX Spectra 29 CPET Instrument, Yorba Linda, CA) according to the recommendations of the ACC/AHA 
guidelines.123 Before the exercise testing, each participant will undergo spirometry and remain seated for 2 min 
to obtain resting oxygen consumption (VO2); and will walk for 1 min to warm up to avoid potential muscle 
soreness. Emergency equipment, medical and nursing staff are immediately available should the participant 
have any adverse response.  A continuous electrocardiogram and blood pressure readings every 1 minute will 
be recorded.  If ST elevation or multiple ventricular ectopy occur the treadmill test will be stopped immediately.  
The participant will be continuously monitored during the treadmill test and VS taken every 1 minute for 5 
minutes after the test, then every 5 minutes.  If there are any untoward vital sign changes such as lower or 
higher BP, arrhythmia, chest pain or dizziness the study cardiologist (Dr. Butler) will be notified.  Data from the 
HF-ACTION study provides evidence of the safety of symptom limited exercise tests.  Of the 4,411 symptom-
limited exercise tests during 5 years, no deaths and only 2 nonfatal, major CV events occurred (0.45 
events/1,000 tests). There were also no test-related ICD discharges requiring hospitalization.  It was concluded 
that in NYHA class II-IV patients with severe left ventricular systolic dysfunction, that symptom-limited exercise 
testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests123  
     The potential risks associated with the walking intervention are anticipated to be minimal.  Any potential 
cardiovascular (CV) events that poses risk to the participant is anticipated to be detected during the modified 
Balke maximal treadmill test.  In addition, the duration of walking will be limited to 30 minutes during the first 2 
weeks and at an intensity level (60%) that is not likely to result in any adverse CV events; if necessary 
participants can rest as needed until the 30 minute duration of walking is completed. Participants will wear a 
Polar HR monitor so that HR and intensity level can be closely monitored. Participants will undergo 2 
supervised walking sessions prior to walking at home unsupervised; the risk associated with the unsupervised 
session therefore, is anticipated to be minimal.  Participants in the study will be provided with detailed 
instructions on self-monitoring HR, BP and symptoms associated before, during and after walking.  Each 
participant will be provided with a target heart rate range to stay within during the study period.  Participants 
will be instructed to wear the Polar HR monitor during each exercise session.  The participants will take their 
HR, and BP (if machine available) and weight prior to and after each walking session and record it in their 
walking calendar. Participants will be instructed to call the research nurse if their BP or HR is outside their 
normal range.  If participants are symptomatic, experience increased shortness of breath or have a greater 
than 2 pound weight gain over the previous 24 hours, they will be instructed not to exercise. The participants 
will be instructed to take their medications as usual prior to exercise and instructed on proper attire for 
exercising.  Demonstrations and return demonstrations of the Polar HR monitor will ensure they know how to 
wear the monitor around the chest as well as trouble shoot when the monitor does not display a HR.  They will 
be instructed that if their HR approaches within 5-10 beats of the target HR range to slow the walking pace 
down. The will also be instructed if they have an ICD, to keep their HR 15 beats below the firing range at all 
times (usually set at higher than 170 beats per minute, so it is unlikely to interfere with training stimulus).  In 
addition, they will be instructed to monitor their RPE using the Borg 6 to 20 scale, and to keep their RPE at 12-
13 during the initial weeks and to gradually progress with instructions to 15 as stipulated in the protocol.  
Participants in the intervention groups will be advised to carry a cell phone when they walk at home in the 
event of an emergency or sudden event.  Specifically, participants will be instructed to slow their pace if their 
HR increases to near THR as previously noted or if they become short of breath. Participants who have 
ischemic heart disease and prescribed nitroglycerin (NTG) will be instructed to carry their NTG with them 
during each walking sessions. If chest pain occurs during exercise, the participants will be told to stop 
exercising and to take a NTG as directed by their cardiologist. The participant will also be instructed if the chest 
pain continues to sit down and to call a relative or friend and to take another NTG if the chest pain does not 
subside.  If the chest pain continues and is not relieved by NTG within 10 minutes they will be instructed to call 
911.  If the participant becomes moderately to severely dyspneic where they cannot talk while walking they will 
be instructed to stop walking until the dyspnea subsides.  If the dyspnea continues once they have stopped 
walking for several minutes they will be instructed to call a relative or friend; if not dissipated they will be 

instructed to go the nearest emergency room.  If a participant becomes dizzy while walking they will be asked 
to sit down and to get up slowly once the dizziness passes. If an ICD fires, the participant will be instructed to 
call 911 if symptoms are present; to notify their cardiologist if no symptoms for possible evaluation.  In our 
preliminary work, 90% of participants had an ICD and there were no ICD shocks using a very similar protocol.   
If symptoms are present at current intensity level or duration of walking the participant will not be progressed 
until exercising at current level with RPE at 15 or below for 45 minutes.  This will better ensure the participant 
is not progressed too rapidly. 
      The potential risk to participants in the CT is anticipated to be minimal.  Participants will be taught how to 
use the computerized CT program by a research nurse. It is possible that some participants may have 
additional stress or anxiety related to participation in the CT.  The 2 home visits that will be used to review the 
CT program are anticipated to alleviate any unusual stress or concern about participation in CT.  In addition, 
the research nurse will be contacting the participant on a weekly basis to discuss any concerns or issues 
related to CT from weeks 3-12.  In a prior study that used the same CT program in persons with HF, Brain 
Fitness (Posit, San Francisco, CA), there were no adverse events, and satisfaction and adherence were 
reported to be high.16 
     The potential risk to participants in the AC control stretching/flexibility movement group is anticipated to be 
minimal.  Participants will be taught how to use stretching and flexibility movements by a research nurse who is 
not involved with the intervention groups. In our preliminary work, participants enjoyed this placebo exercise, 
but it was not strong enough to influence outcomes.  Although some participants did experience a better QOL 
from contact with the research team but this was not as strong as the intervention, and it was of shorter 
duration.   
       Potential risks related to questionnaire completion include the possibility of distress after the instrument 
administration or teaching session.  Based on the preliminary work and patient responses to these types of 
questionnaires and interventions, we anticipate this risk to be minimal.  The intervention should not increase 
distress over usual care.  We also observed no increase in patient depressive symptom scores over time in 
other studies suggesting that the intervention did not introduce greater distress. However, if participants do 
indicate significant symptoms of depression by their responses on the BDI-II, mental health referral information 
will be provided and they will be asked if they would like a research team member to assist them in setting up a 
referral.  If at any time a participant indicates serious depressive symptoms or an intent to hurt him or herself, a 
family member will be informed (as agreed in the Informed Consent form) and/or their primary care provider (or 
cardiologist) alerted (again as agreed to in the Informed Consent).  Other risks that occur are increased burden 
of participating in the intervention or attention control follow up calls and clinic visits.  The blood sample will be 
collected by a research nurse or laboratory assistant in the ACTSI at each time point.  The needles and 
syringes will be disposed in appropriate biohazard containers.  The BDNF sample will be labeled by participant 
identification number, time point and stored in the ACTSI at -80 degrees until analyzed using the 
recommended ELISA procedures by the manufacturer.  All laboratory specimens will be run twice to ensure 
reliability of blood tests. Slight bruising at the site of the venipuncture is possible. For participants on 
anticoagulant therapy, additional pressure to site will be applied. 
 
     The study was designed to minimize and protect against potential risks by careful training of staff, emphasis 
on confidentiality, and efforts to increase convenience to the subject for each study activity. To reduce anxiety 
and emotional responses to the intervention, we will address these concerns as part of the sessions.  In the 
rare event that subjects experience emotional distress, they will be referred to their provider, a clinical 
psychologist or clinical nurse specialist available to HF patients.  The total BDI-II will be reviewed as part of 
screening and those with moderate to severe depressive symptoms will be excluded.  If BDI-II scores reveal 
that moderate depression (BDI-II>25) is present, the participant will be informed and asked for permission to 
share this information with their primary physician because of the established increased CV risk as a 
consequence of depression in this patient population. This will be a part of the study explanation prior to 
informed consent.  It is important to note that the BDI-II does not confer a diagnosis of clinical depression but is 
a useful screening tool for those needing further assessment by a clinical psychologist or psychiatrist.  
     All patient records will be kept in a locked file cabinet in the research office and will be accessible only to 
the PI and the research team.  All data will be coded by subject identification number, and no identifying 
information will be recorded on the data collection forms.  The master list that will connect the codes to 
identifying information will be secured in the research project office.  All data maintained in the computerized 
database will be accessible only with a login and protected, encrypted password.  After the study is completed, 
all data will be kept according to regulations in a locked file.   

 
The potential risks to subjects are anticipated to be minimal, and the anticipated benefits to patients 
enrolled in the study are potentially high.  The majority of those who participate in combined exercise and 
exercise only are expected to show an improvement in cognitive function, physiological status, aerobic 
capacity and QOL.  Because CI and physical inactivity contributes to physical function decline and poor clinical 
outcomes in persons with HF, improvement of physical function has the potential to significantly reduce the 
burden associated with this disorder and has potentially cost savings benefits. Based on our previous 
experience, we anticipate that the AC stretching/flexibility group may have an improvement in psychological 
functioning and QOL as a result of the contact with the research team members, but it will likely be of shorter 
duration than the intervention groups, and have no benefit on any of the other outcome variables.  In addition, 
potentially AC education only participants may improve in HF self-care behaviors based on the additional 
knowledge and education provided in the education sessions.  The potential knowledge to be gained from this 
study includes a better understanding of the underlying mechanisms that contribute to CI and the influence of a 
combined exercise and CT program on cognition, aerobic capacity and novel biomarkers.  We will provide 
funds to cover transportation and parking costs associated with laboratory and physical function testing.  In 
addition, costs for travel, parking and membership at the ACTSI will be provided. A payment of $50 will be 
used at each measurement time point to total $150/patient for completing the study.   
 
Inclusion of Women 
Based on the practice patterns of the enrolling institutions, we expect 60% of the HF patients to be male. 
Enrollment targets are set for 40-50% of the HF patient sample to represent women.  This is congruent with the 
population at the enrolling sites and will result in data generalizable to the overall population of HF patients. We 
will over sample women at all sites to assure attainment of the gender distribution.  We will monitor the gender 
of enrolled HF patient subjects and alter recruitment strategies to increase the representation of women if 
needed.  In our pilot studies we were able to recruit 47% women.   
 
Inclusion of Minorities 
The greater Atlanta area census data reflects that approximately 35% of the population is African American. 
Based on the practice patterns at the enrolling institutions, we expect the minority recruitment pool of HF 
patients to be approximately 35% to 40% African American, with very small numbers representing 
Hispanic/Latino, Asian/Pacific Islander or American Indian racial/ethnicity groups.  Enrollment targets are set 
for at least 30% of the enrolled HF patients sample to represent minorities, primarily African Americans, which 
will be congruent with the populations of the enrolling sites and the greater Atlanta area.  We will monitor 
minority enrollment for HF patient subjects and alter recruitment strategies to increase the representation of 
minorities if needed. In our previous studies 39%-52% were African American HF participants.  We have been 
diligent in selecting the sites for this study for their access to potential minority participants.   
 
Inclusion of Children   
Children are excluded from this study. This is due to the low prevalence of HF under the age of 21 years, the 
difference in the etiology, disease process and self management behaviors in children and the extraordinary 
scientific effort and financial resources that would be essential to include children in this study.   
 
Data and Safety Monitoring Plan.  A data and safety monitoring plan will be developed and implemented 
following the guidelines of the Institutional Review Board and the ACTSI of Emory University.  The plan will 
include anticipation of adverse risks, monitoring of study progress and safety of patients, assurance of 
compliance with requirements regarding reporting of adverse events, and plans for performing data reviews 
and it will incorporate a data safety and monitoring board (DSMB).  This board will be composed of Dr. Monica 
Parker, Chairperson, Dr Andrew Lee Smith, cardiologist and Director of the Heart Failure Therapy Center, 
Emory University School of Medicine, Dr. Ann Rogers, Professor at Emory University School of Nursing; this 
board will be supported by Dr. Amita Manatunga, PhD, biostatistician in the School of Public Health.  Each of 
the DSMB members have extensive experience serving on a DSMB and are well qualified to serve in this 
capacity. 
 
The PI will assume responsibility for developing and implementing the data and safety monitoring plan.  
This study is considered to present minimal risks to participants.  Adverse events, that is, unfavorable or 
unintended symptoms temporarily associated with the intervention or evaluation, are expected to be minimal.  
Possible mild adverse events could include shortness of breath, fatigue, chest pain, dizziness, or rapid beating 
heart beat during the symptom limited modified Balke treadmill test and muscle strength testing.  Subjects will 

be informed of these and will be asked to notify the research staff if any of the symptoms occur; they will also 
have telemetry in place during the tests to detect any heart rhythm changes, blood pressure will be monitored 
as well before and after these tests.  The risks for the adverse events during the home based walking and 
resistance intervention are also anticipated to be minimal.  If symptoms occur during the home-based 
intervention, participants will be counseled on ameliorating strategies and asked to contact their provider. 
Before the modified Balke, all participants will receive a brief history and physical by a cardiology fellow or 
advanced practice nurse, and will be asked if they feel well enough to perform the test.  If they experience any 
untoward symptoms, the treadmill test or muscle strength testing will be stopped and the participant seated 
and evaluation of symptoms performed by the ACTSI, nursing research team member or study cardiologist.  If 
symptoms persist, the person will be taken to the Emergency Department for further evaluation and treatment.  
All adverse events will be reported to the IRB, ACTSI and DSMB for review.   
 
The research team will meet periodically to review screening, enrollment and randomization data and to 
identify any human subject issues that arise.  All staff will be trained in the protection of human subjects 
according to university and NIH regulations, and will be required to be certified in human subject’s research in 
accordance with the Emory University IRB procedures.  We will conduct random and periodic audits of 
research records to ascertain that informed consents are signed, witnessed and complete for each subject, 
and that confidentiality procedures are being maintained.   
 
The DSMB will meet with the PI and study team at the beginning of the trial, after 30 patients have been 
enrolled and completed the study, as well as annually or as needed to review the conduct of the trial, including 
accrual, recruitment and retention, violations in protocols, adverse events, breaches in confidentiality, or other 
data related to protection of human subjects. The first meeting of the DSMB will review and make 
recommendations about consent procedures, and situations within which confidentiality may be broken, for 
example, if a participant indicates suicide tendencies on the BDI-II.  The primary role of the DSMB will be to 
ensure data integrity and the safety of participants.  They will have the power to recommend termination of the 
trial if significant negative trends emerge.  In the highly unlikely event that serious risks occur, they will also 
have the power to recommend termination of the trial.  In addition, study recruitment, and retention procedures 
will be examined for timeliness, practicality, safety, and protection of all human subjects.   
 
At subsequent regular annual meetings, the DSMB will review adherence to the goals for recruitment and 
retention; adherence to study protocols; cumulative data for evidence of study related adverse events; quality, 
completeness, and timeliness of the data collected; factors that could affect the outcome or compromise 
participant/data confidentiality; and other factors outside the study (e.g., therapeutic developments, agency 
related policies) that could impact the safety of participants or the ethical conduct of the study.  General 
recommendations the DSMB may include these: continuation of the study without change; modifications to the 
study protocol; suspension or early termination; alternative approaches to consider. Formal minutes and 
reports of the DSMB will be maintained and made available to NIH as required.  All materials, discussions and 
reports of the DSMB are considered confidential and will be treated as such in the maintenance of records.   
 
    
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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