Exercise and Cognitive Retraining to Improve Cognition in Heart Failure.
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional

Summary: 
      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. In addition, we have an optional sub-study that
      participants may participate in order to further our understanding of biomarkers of
      inflammation and gen e expression before and after exercise.
    

Detailed description: 
      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.
    

Intervention name(s): Exercise and Cognitive retraining; Exercise Only; Stretching and Flexibility
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): Walking 5 times per week at moderate intensity; cognitive retraining one-hour 2 times per week.
Other intervention name(s): Aerobic exercise; walking and computerized cognitive retraining program
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Heart failure; Exercise; Cognitive training