Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

Heart failure with preserved ejection fraction is the fastest growing form of heart failure,
is almost exclusively found in older persons, particularly older women, and is associated
with a high morbidity and mortality rate. The primary chronic symptom in HFpEF patients is
severe exercise intolerance measured objectively as decreased peak exercise oxygen uptake
(peak VO2). A consequence of the reduced exercise tolerance is that activities of daily
living require near maximal effort, resulting in further deconditioning and reduced quality
of life. The majority of work to date has focused on cardiac limitations, showing impaired
cardiac output and marked diastolic dysfunction. Although these findings have provided
important insight into the pathophysiology of HFpEF, drug therapies targeting cardiac
function do not improve peak VO2, quality of life, or survival in HFpEF patients.

Older HFpEF patients have multiple skeletal muscle abnormalities including reduced skeletal
muscle oxidative capacity and capillary-to-fiber ratio resulting in increased anaerobic
metabolism during low-level exercise. Importantly, accumulation of anaerobic metabolites
within the exercising muscles are known to activate skeletal muscle afferent fibers (called
metaboreceptors), that elicit a reflex-mediated increase in efferent muscle sympathetic
(vasoconstrictor) nerve activity (MSNA). The investigators here propose a novel paradigm of
exercise intolerance in older HFpEF patients whereby skeletal muscle abnormalities lead to
overactivation of the muscle metaboreflex and MSNA mediated vasoconstriction that limits
delivery of oxygenated blood to the active muscles. Further, exercise training mediated
improvements in skeletal muscle function will alleviate the metaboreflex, thereby reducing
MSNA and improve oxygen delivery to the contracting muscles.

To test this novel paradigm, the investigators will first perform an initial cross-sectional
comparison of older (≥60 years) HFpEF patients (N=24) with age and sex-matched healthy
controls (N=24), and then enter the HFpEF patients into a randomized, controlled, single
blind, trial of exercise training to test the following hypothesis: (i) that MSNA is elevated
in older HFpEF patients compared to healthy controls, and is associated with reduced peak
VO2, physical functional performance, aerobic endurance, muscle blood flow, and quality of
life; and (ii) Exercise training will attenuate MSNA compared to attention control, and will
correlate with improved peak VO2, physical functional performance, aerobic endurance, muscle
blood flow, and quality of life in older HFpEF patients.

Inclusion Criteria for Heart Failure Preserved Ejection Fraction Patients:

- ≥60 years of age, male or female.

- Documented heart failure diagnosis.

- Left ventricular ejection fraction ≥50%.

- Clinically stable (no heart failure hospitalization within prior month).

Inclusion Criteria for Healthy Controls:

- ≥60 years of age, male or female (matched to the age and sex of HFpEF patients).

- No cardiac medications except for statins.

- Sedentary (exercise three days per week or less).

Exclusion Criteria for Heart Failure Preserved Ejection Fraction Patients:

- Greater than moderate valvular disease or congenital heart disease.

- New York Heart Association class IV.

- Any orthopedic or medical condition that would limit exercise testing or training.

- Development of signs and symptoms of myocardial ischemia (1 mm ST segment depression
on EKG), or unstable hemodynamics/rhythm, or systolic/diastolic blood pressure
>240/110 mmHg during baseline cardiopulmonary (peak VO2) testing.

Exclusion Criteria for Healthy Controls:

- Chronic medical condition (e.g. self reported hypertension, or diabetes, or chronic
obstructive pulmonary disease or heart disease)

- Abnormal history or cardiovascular physical exam.

- Segmental wall motion abnormalities or structural valvular abnormalities.

- Left ventricular ejection fraction <50%.

- Any orthopedic or medical condition that would limit exercise testing.

- Development of signs and symptoms of myocardial ischemia (1 mm ST segment depression
on EKG), or unstable hemodynamics/rhythm, or systolic/diastolic blood pressure
>240/110 mmHg during baseline cardiopulmonary (peak VO2) testing.