Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

NCT03111017 | Completed

• 1 other identifier: 1R15NR016826-01
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Heart Failure, Diastolic

Keywords

muscle sympathetic nerve activity; exercise tolerance; exercise training; peak oxygen uptake

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Peak Oxygen Uptake (Peak VO2) assessed by gas exchange indirect calorimetry

  Change from Baseline Peak VO2 at 16 weeks.

• Physical functional performance assessed by Short Physical Performance Battery (SPPB) Test

  Change from Baseline physical functional performance at 16 weeks.

• Aerobic endurance assessed by six-minute walk distance

  Change from Baseline aerobic endurance at 16 weeks.

• Muscle blood flow assessed by brachial artery Doppler Ultrasound

  Change from Baseline muscle blood flow at 16 weeks.

• Quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)

  Change from Baseline quality of life at 16 weeks.

Study Arms (2)

Exercise Training

EXPERIMENTAL

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

Attention Control

NO INTERVENTION

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.

Interventions

Exercise Training OTHER

HFpEF patients randomized to either 16 weeks of exercise training or attention control group.

Exercise Training

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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).
• ≥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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• The University of Texas at Arlington: lead

Study Sites (1)

University of Texas at Arlington

Arlington, Texas, 76019, United States

Location

Related Publications (24)

• Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, Borlaug BA. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail. 2013 Jul;15(7):776-85. doi: 10.1093/eurjhf/hft026. Epub 2013 Feb 20.

  PMID: 23426022 BACKGROUND

• Bhella PS, Prasad A, Heinicke K, Hastings JL, Arbab-Zadeh A, Adams-Huet B, Pacini EL, Shibata S, Palmer MD, Newcomer BR, Levine BD. Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail. 2011 Dec;13(12):1296-304. doi: 10.1093/eurjhf/hfr133. Epub 2011 Oct 5.

  PMID: 21979991 BACKGROUND

• 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. doi: 10.1161/CIRCULATIONAHA.106.632745. Epub 2006 Nov 6.

  PMID: 17088459 BACKGROUND

• 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.

  PMID: 20543134 BACKGROUND

• Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, Redfield MM. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010 Sep 7;56(11):845-54. doi: 10.1016/j.jacc.2010.03.077.

  PMID: 20813282 BACKGROUND

• Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014 Sep;11(9):507-15. doi: 10.1038/nrcardio.2014.83. Epub 2014 Jun 24.

  PMID: 24958077 BACKGROUND

• Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006 Oct;27(19):2338-45. doi: 10.1093/eurheartj/ehl250. Epub 2006 Sep 8.

  PMID: 16963472 BACKGROUND

• Fisher JP, Young CN, Fadel PJ. Autonomic adjustments to exercise in humans. Compr Physiol. 2015 Apr;5(2):475-512. doi: 10.1002/cphy.c140022.

  PMID: 25880502 BACKGROUND

• Gottdiener JS, Arnold AM, Aurigemma GP, Polak JF, Tracy RP, Kitzman DW, Gardin JM, Rutledge JE, Boineau RC. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol. 2000 May;35(6):1628-37. doi: 10.1016/s0735-1097(00)00582-9.

  PMID: 10807470 BACKGROUND

• Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep 6;362(9386):772-6. doi: 10.1016/S0140-6736(03)14284-5.

  PMID: 13678870 BACKGROUND

• 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.

  PMID: 21737017 BACKGROUND

• 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.

  PMID: 22430146 BACKGROUND

• 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.

  PMID: 23525477 BACKGROUND

• 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.

  PMID: 24507172 BACKGROUND

• Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002 Nov 6;288(17):2144-50. doi: 10.1001/jama.288.17.2144.

  PMID: 12413374 BACKGROUND

• Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, Haykowsky M. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol. 2014 May;306(9):H1364-70. doi: 10.1152/ajpheart.00004.2014. Epub 2014 Mar 21.

  PMID: 24658015 BACKGROUND

• 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. doi: 10.1001/archinte.166.1.112.

  PMID: 16401819 BACKGROUND

• Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Dec 4;359(23):2456-67. doi: 10.1056/NEJMoa0805450. Epub 2008 Nov 11.

  PMID: 19001508 BACKGROUND

• Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92. doi: 10.1056/NEJMoa1313731.

  PMID: 24716680 BACKGROUND

• Redfield MM. Heart failure--an epidemic of uncertain proportions. N Engl J Med. 2002 Oct 31;347(18):1442-4. doi: 10.1056/NEJMe020115. No abstract available.

  PMID: 12409548 BACKGROUND

• Redfield MM. Understanding "diastolic" heart failure. N Engl J Med. 2004 May 6;350(19):1930-1. doi: 10.1056/NEJMp048064. No abstract available.

  PMID: 15128890 BACKGROUND

• Shimiaie J, Sherez J, Aviram G, Megidish R, Viskin S, Halkin A, Ingbir M, Nesher N, Biner S, Keren G, Topilsky Y. Determinants of Effort Intolerance in Patients With Heart Failure: Combined Echocardiography and Cardiopulmonary Stress Protocol. JACC Heart Fail. 2015 Oct;3(10):803-14. doi: 10.1016/j.jchf.2015.05.010.

  PMID: 26449998 BACKGROUND

• Writing Group Members; Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez 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. No abstract available.

  PMID: 26673558 BACKGROUND

• Yamamoto K, Origasa H, Hori M; J-DHF Investigators. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. 2013 Jan;15(1):110-8. doi: 10.1093/eurjhf/hfs141. Epub 2012 Sep 14.

  PMID: 22983988 BACKGROUND

MeSH Terms

Conditions

Heart Failure, Diastolic

Interventions

Exercise

Condition Hierarchy (Ancestors)

Heart Failure; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Mark Haykowsky, PhD

  University of Texas at Arlington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor & Moritz Chair in Geriatrics, College of Nursing and Health Innovation

Study Record Dates

• First Submitted: March 25, 2017
• First Posted: April 12, 2017
• Study Start: April 17, 2017
• Primary Completion: December 12, 2019
• Study Completion: December 12, 2019
• Last Updated: March 3, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)