Exercise and Cognitive Retraining to Improve Cognition in Heart Failure.

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. 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. 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. Further, if CI is detected, there are
currently no effective or evidenced-based guidelines to help restore or improve cognition in
this population.Despite the aging population and projected rise of CI in HF, only 2 small
intervention studies have been documented, indicating a critical need for further research in
this area.

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.Clinical studies
have shown that CI is improved after cardiac transplantation and is modifiable with standard
therapies that improve cardiac output, oxygenation, fluid overload, and systemic and cerebral
perfusion; these findings are inconsistent and anecdotal. 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.

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. Less is known about the effect of exercise on cognitive function. Animal
research has provided the most compelling evidence that exercise positively affects neuronal
growth and the neural systems involved in learning and memory. Similar human findings have
emerged; recent advances in neuroimaging support that participation in regular exercise leads
to specific changes in brain structure and function. Exercise is also thought to enhance
brain plasticity. BDNF appears to play a crucial role in this process: when BDNF levels
increase following exercise, cognitive function improves. The association between exercise,
BDNF and cognitive function has not been previously reported in HF. 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. 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. Animal studies show that, like exercise, learning tasks and performing
cognitively stimulating activities also increase BDNF levels and improve learning and memory.
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, whereas CT appears to promote cell survival,suggesting a synergistic
relationship may exist with greater benefit obtained when both are used together. 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, 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.

Inclusion Criteria:

men and women between the ages of 40 and 75; English speaking; live independently within a
60 mile radius of Atlanta; 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) have a computer with internet connection; documented medical diagnosis of
NYHA class II or III systolic. Left ventricular ejection fraction (LVEF) ≥ 10% that is
documented within the last year by echocardiogram, cardiac catheterization ventriculography
or radionuclide ventriculography; Receiving medication therapy for HF according to American
College of Cardiology (ACC) American Heart recommendation guidelines for at least 8 weeks
prior to study enrollment.

Exclusion Criteria:

NYHA class I or IV; change in HF therapy within 8 weeks; worsening HF symptoms within last
5 days; unstable angina; renal insufficiency (serum creatinine > 3.o mg/dL); fixed rate
pacemaker; uncontrolled hypertension; not involved in any structured exercise program or
exercising 3 or more times per week for a minimum of 30 minutes and; not hospitalized
within the last 30-days; not diagnosed with any neurological disorder that may interfere
with cognitive function; Beck Depression Inventory II (BDI-II) score greater than 25; any
disorder interfering with exercise participation.