Exercise Intolerance in Elderly Patients With HFpEF(Heart Failure With Preserved Ejection Fraction) (SECRET-II)

Study of the Effects Caloric Restriction and Exercise Training in Patients With Heart Failure and a Normal Ejection Fraction

The purpose of this study is to examine the effects of weight loss via hypocaloric diet (CR)and aerobic exercise (AT) compared to the effects of weight loss via hypocaloric diet (CR), aerobic training (AT)and resistance training (RT).

Study Overview

• Status: Completed
• Conditions: Obesity; Heart Failure, Diastolic
• Intervention / Treatment: Behavioral: dietary, and aerobic exercise; Behavioral: dietary, aerobic and resistance training

Detailed Description

Heart failure with preserved ejection fraction (HFPEF) is the most common form of HF, is nearly unique to the older population, particularly older women, and is increasing in prevalence. Exercise intolerance, with severe exertional dyspnea and fatigue, is the primary manifestation of chronic HFPEF and is a major determinant of these patients' severely reduced quality of life (QOL). However, its pathophysiology is poorly understood and its optimal treatment remains undefined.

Our recent data and others' indicate that in older HFPEF patients, both increased adiposity and abnormalities in skeletal muscle are major contributors to exercise intolerance and potential therapeutic targets. Obesity is one of the strongest risk factors for HFPEF, and is a robust predictor of physical disability in older persons. The investigator recently reported that in HFPEF compared to age-matched controls, percent total and leg lean mass are significantly reduced and independently predict exercise capacity.

Using MRI and needle biopsy of the thigh muscle, the investigators found increased fat infiltration, reduced capillary density and percent type I oxidative fibers, and trends for reduced muscle mitochondrial mass and function. Reduced exercise capacity was related to each of these muscle abnormalities, supporting their important role in HFPEF.

Diet, with or without aerobic exercise, can increase exercise capacity and quality of life in older obese persons with a variety of disorders, but usually results in significant loss of skeletal muscle mass, which could potentially have adverse long term consequences. The purpose of this trial is to determine if addition of resistance training to diet plus aerobic exercise training can improve skeletal muscle mass and function in HFPEF.

Multiple lines of evidence and our preliminary data indicate that resistance training (RT) may be an ideal addition to CR+AT for HFPEF, since RT reliably increases muscle mass, quality, strength, and function, significantly more than AT, and can prevent nearly 50% of the muscle mass loss during CR.

Therefore, the primary aim of the proposed study is to conduct a randomized, single-blinded 20-week intervention trial of RT added to CR+AT in 84 overweight / obese (BMI greater than 28 kg/m2), older (age greater than 60 years) HFPEF patients to test the following primary hypothesis:

The addition of resistance training to CR+AT will improve exercise capacity.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 60 years or older
2. Ejection fraction ≥ 50%
3. Left Ventricular Diastolic Dysfunction ≥ grade 1
4. BMI ≥ 28 kg/m2
5. HF symptoms/ signs by cardiologist review, using NHANES HF Clinical Score >/= 3 or Rich et al. criteria for HF

Exclusion Criteria:

1. Valvular heart disease as the primary etiology of CHF (congestive heart failure)
2. Significant change in cardiac medication or Heart Failure symptoms <6 weeks
3. Hospitalization or urgent care visit <6 weeks
4. Uncontrolled hypertension
5. Uncontrolled diabetes
6. Evidence of significant Chronic Obstructive Pulmonary Disease (COPD)
7. Recent or debilitating stroke
8. Cancer or other noncardiovascular conditions with life expectancy less than 2 years
9. Significant anemia (<10 g/dL Hgb)
10. Significant renal insufficiency (eGFR <30 mL/min/1.73m2)
11. Pregnant or of child-bearing potential
12. Psychiatric disease- uncontrolled major psychoses, depressions, dementia, or personality disorder
13. Plans to leave area within the study period
14. Refuses informed consent -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: dietary, and aerobic exercise; Intervention for diet-A hypocaloric diet will be developed to achieve a 2800 kcal/week deficit, which should produce about 0.4 kg (1 lb.) weight loss per week. Intervention for aerobic exercise-Based on initial evaluations and the stress testing results, (HR, VO2, RPE) an individual exercise prescription will be developed for aerobic training.	Behavioral: dietary, and aerobic exercise; hypocaloric diet individual prescription for aerobic training.
Active Comparator: dietary, aerobic and resistance training; Intervention for diet-A hypocaloric diet will be developed to achieve a 2800 kcal/week deficit, which should produce about 0.4 kg (1 lb.) weight loss per week. Intervention for aerobic exercise-Based on initial evaluations and the stress testing results, (HR, VO2, RPE) an individual exercise prescription will be developed for aerobic training. Intervention for resistance training- Additional weight resistant exercise will be added to this arm.	Behavioral: dietary, and aerobic exercise; hypocaloric diet individual prescription for aerobic training.; Behavioral: dietary, aerobic and resistance training; hypocaloric diet individual exercise prescription for aerobic training individual exercise prescription for resistance training.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Exercise Oxygen Consumption (VO2)	Peak exercise oxygen consumption (VO2) pre and post intervention	20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal Muscle Mass	Measure skeletal muscle mass in kg by DEXA analysis pre and post intervention.	20 weeks
Thigh Skeletal Muscle Mass	Measure skeletal muscle mass by MRI analysis pre and post intervention.	20 weeks
Thigh Muscle Composition	MRI skeletal muscle to intermuscular fat ratio	20 weeks
Muscle Strength	maximal isokinetic knee extensor strength (Newton-meters, Nm) using an isokinetic dynamometer (Biodex®)	20 weeks
Muscle Quality	knee extensor strength to thigh muscle area assessed by MRI (Nm/cm2).	20 weeks
Quality of Life Measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	The KCCQ Overall Summary Summary Score is a heart failure disease-specific quality of life measure encompassing domains of physical limitation, HF symptoms, quality of life, and social limitation scored on a scale of 0-100 with higher scores indicating better health status.	20 weeks
Quality of Life Measured by Short Form 36 Item Questionnaire (SF-36)	The SF-36 is a quality of life assessment with 2 component scores (Physical Composite Score and Mental Composite Score) ranging 0-100 with higher scores indicating better health status.	20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial Content	Porin citrate synthase pre and post intervention.	20 weeks
Mitochondrial Function	respiratory control ratio and mitofusin 2 concentration.pre and post intervention.	20 weeks

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Institute on Aging (NIA)

Publications and helpful links

General Publications

• Brubaker PH, Nicklas BJ, Houston DK, Hundley WG, Chen H, Molina MAJA, Lyles WM, Nelson B, Upadhya B, Newland R, Kitzman DW. A Randomized, Controlled Trial of Resistance Training Added to Caloric Restriction Plus Aerobic Exercise Training in Obese Heart Failure with Preserved Ejection Fraction. Circ Heart Fail. 2022 Oct 31. doi: 10.1161/CIRCHEARTFAILURE.122.010161. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): July 21, 2021
• Study Completion (Actual): July 21, 2021

Study Registration Dates

• First Submitted: December 9, 2015
• First Submitted That Met QC Criteria: December 18, 2015
• First Posted (Estimate): December 21, 2015

Study Record Updates

• Last Update Posted (Actual): July 15, 2022
• Last Update Submitted That Met QC Criteria: July 8, 2022
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Heart Failure; Elderly; Obesity; Diastolic heart failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic
• Other Study ID Numbers: IRB00032364; R01AG018915 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No