Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

Heart Failure, Diastolic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03111017
• Other study ID #: 1R15NR016826-01
• Status: Completed
• Phase: N/A
• Start date: April 17, 2017
• Est. completion date: December 12, 2019

Study information

• Verified date: February 2020
• Source: The University of Texas at Arlington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: December 12, 2019
• Est. primary completion date: December 12, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Diastolic

Intervention

Other:
• Exercise Training
HFpEF patients randomized to either 16 weeks of exercise training or attention control group.

Locations

Country	Name	City	State
United States	University of Texas at Arlington	Arlington	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas at Arlington

Country where clinical trial is conducted

United States, 

References & Publications (24)

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Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, Kass DA. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006 Nov 14;114(20):2138-47. Epub 2006 Nov 6. — View Citation

Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010 Sep;3(5):588-95. doi: 10.1161/CIRCHEARTFAILURE.109.930701. Epub 2010 Jun 11. — View Citation

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Haykowsky M, Brubaker P, Kitzman D. Role of physical training in heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2012 Jun;9(2):101-6. doi: 10.1007/s11897-012-0087-7. Review. — View Citation

Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol. 2011 Jul 12;58(3):265-74. doi: 10.1016/j.jacc.2011.02.055. — View Citation

Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky S, Eggebeen J, Kitzman DW. Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass. J Gerontol A Biol Sci Med Sci. 2013 Aug;68(8):968-75. doi: 10.1093/gerona/glt011. Epub 2013 Mar 22. — View Citation

Haykowsky MJ, Kouba EJ, Brubaker PH, Nicklas BJ, Eggebeen J, Kitzman DW. Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol. 2014 Apr 1;113(7):1211-6. doi: 10.1016/j.amjcard.2013.12.031. Epub 2014 Jan 15. — View Citation

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Liao L, Jollis JG, Anstrom KJ, Whellan DJ, Kitzman DW, Aurigemma GP, Mark DB, Schulman KA, Gottdiener JS. Costs for heart failure with normal vs reduced ejection fraction. Arch Intern Med. 2006 Jan 9;166(1):112-8. — View Citation

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Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016 Jan 26;133(4):e38-360. doi: 10.1161/CIR.0000000000000350. Epub 2015 Dec 16. Erratum in: Circulation. 2016 Apr 12;133(15):e599. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.