Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

Study Overview
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Brief Summary
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Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure with a high morbidity and mortality rate, and is associated with severe exercise intolerance. The mechanisms responsible for the reduced exercise tolerance remain poorly understood. The investigators propose a novel paradigm shift, focusing on peripheral limitations to exercise. In particular, the investigators will test the hypothesis that muscle sympathetic nerve activity (MSNA) is elevated in older HFpEF patients compared to healthy controls, and is associated with reduced exercise tolerance. The investigators will also test whether 16-weeks of exercise training will lower MSNA compared to attention control, and correlate with improved exercise tolerance in older HFpEF patients.

Detailed Description
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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.

Official Title
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Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients With Preserved Ejection Fraction

Conditions
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Heart Failure, Diastolic

Intervention / Treatment
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* Other: Exercise Training


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise Training<br>Subjects will perform continuous endurance exercise (arm and leg cycle on Schwinn AD6 Airdyne ergometer, treadmill walking) 3 days per week. During the first 4-weeks, the exercise intensity will be set at 60%-70% of heart rate reserve and will increase by 5% per month. The initial exercise duration be 30 minutes and will gradually increase by 10 minutes every month. A 5-minute warm up and cool-down will precede and follow the aerobic conditioning phase. After the aerobic training phase is completed, patients will also perform unilateral handgrip exercise at an initial intensity of 50% maximal voluntary contraction for 1 set of 10 repetitions, and the intensity and sets will increase by 5% and 1 set, respectively each month. | Other: Exercise Training<br>* HFpEF patients randomized to either 16 weeks of exercise training or attention control group.<br>|
| No Intervention: Attention Control<br>These subjects will be asked to continue with normal activity and will not be given any exercise training. The subjects will be contacted by the study coordinator at pre-arranged times and dates once a month and involve inquiry regarding overall well-being of the subject. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle sympathetic nerve activity (MSNA) assessed by direct microneurography | Standard microneurographic procedures will be used to directly measure MSNA, at rest and during handgrip exercise and post-exercise cuff occlusion, using the peroneal nerve. | Change from Baseline MSNA at 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Oxygen Uptake (Peak VO2) assessed by gas exchange indirect calorimetry | Peak VO2 will be measured as the highest oxygen uptake during a peak cycle exercise test on an upright cycle ergometer. | Change from Baseline Peak VO2 at 16 weeks. | 
| Physical functional performance assessed by Short Physical Performance Battery (SPPB) Test | The Short Physical Performance Battery consists of 3 subtasks: standing balance, walking speed, and time to raise from a chair 5 times. | Change from Baseline physical functional performance at 16 weeks. | 
| Aerobic endurance assessed by six-minute walk distance | The six-minute walk test is a validated measure of aerobic endurance in patients with heart failure that measures the distance covered in a 6 min period. | Change from Baseline aerobic endurance at 16 weeks. | 
| Muscle blood flow assessed by brachial artery Doppler Ultrasound | Measurement of brachial artery diameter and blood velocity via Doppler Ultrasound to calculate blood flow. | Change from Baseline muscle blood flow at 16 weeks. | 
| Quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) | The KCCQ is a valid, reliable and responsive health status measure for patients with heart failure. | Change from Baseline quality of life at 16 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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muscle sympathetic nerve activity, exercise tolerance, exercise training, peak oxygen uptake