Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction

NCT03837470 | Completed Early Phase 1 FDA Drug

• 1 other identifier: IRB_00112270
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure (HF) affects 2-3% of the population, and is characterized by impaired sodium balance which results in fluid overload. Ejection fraction, a measure of systolic function, is reduced in only about half of all HF patients. Incidence of heart failure with preserved ejection fraction (HFpEF) has increased in the last 20 years making it a growing public health problem. Currently, most patients admitted to the hospital with heart failure have preserved rather than reduced ejection fractions. However, to date it remains unknown why patients with HFpEF retain salt and water. The hypothesis is that patients with clinical HFpEF have an impaired renal response to salt loading, intravascular expansion and diuretics. Characterization of the salt and water excretory renal response to intravascular salt, fluid and diuretic load in patients with HFpEF will provide insight into the pathophysiology of HFpEF, and may help in the development of novel strategies to target renal sodium handling in patients with HFpEF. This characterization is the primary objective of this pilot project.

Conditions

Heart Failure With Preserved Ejection Fraction

Outcome Measures

Primary Outcomes (2)

• Urinary Sodium Excretion

  Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls

  5 Hours

• Urine Volume

  Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls

  5 Hours

Secondary Outcomes (4)

• Change in NT-proBNP

  5 Hours

• Serum Aldosterone

  5 Hours

• Plasma Renin Activity

  5 Hours

• Plasma Nor-epinephrine

  5 Hours

Other Outcomes (1)

• Urinary Exosomes

  5 Hours

Study Arms (1)

Saline Loading and Diuretic Challenge

EXPERIMENTAL

Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg

Drug: 0.9% Sodium Chloride; Drug: Furosemide 40 mg

Interventions

0.9% Sodium Chloride DRUG

Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes

Also known as: normal saline

Saline Loading and Diuretic Challenge

Furosemide 40 mg DRUG

Bolus intravenous injection of 40 mg furosemide

Saline Loading and Diuretic Challenge

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• History of chronic (\> 6 months) heart failure with current New York Heart Association II-III symptoms
• Left ventricular ejection fraction \> 50% on a clinically indicated echocardiogram obtained within last 12 months
• Clinical compensated heart failure
• On constant medical therapy for heart failure; without changes in heart failure medication regimen (including diuretics) for previous 14 days and not expected to change in the next 2 days

You may not qualify if:

• Unable to comply with protocol or procedures
• Uncontrolled severe hypertension: systolic blood pressure \> 160 mmHg
• Significant renal impairment as defined by estimated glomerular filtration rate \< 30ml/min/1.73m\^2 determined by Chronic Kidney Disease - Epidemiology Collaboration equation
• Significant proteinuria (\> 0.5 g protein/daily protein or equivalent)
• Body Mass Index \> 40 kg/m\^2
• Acute coronary syndrome within last 4 weeks
• Coronary revascularization procedures (percutaneous coronary intervention or cardiac artery bypass graft) or valve surgery within 30 days of screening
• Cardiac resynchronization therapy, with or without implantable cardioverter defibrillator within 90 days of screening
• Clinically relevant cardiac valvular disease
• Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis, active myocarditis, active endocarditis, or complex congenital heart disease
• Cirrhosis of the liver
• History of known hydronephrosis
• History of adrenal insufficiency

Sponsors & Collaborators

• Adhish Agarwal: lead
• University of Utah Center for Clinical and Translational Science: collaborator

Study Sites (1)

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (24)

• Metra M, Teerlink JR. Heart failure. Lancet. 2017 Oct 28;390(10106):1981-1995. doi: 10.1016/S0140-6736(17)31071-1. Epub 2017 Apr 28.

  PMID: 28460827 BACKGROUND

• Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017 Oct;14(10):591-602. doi: 10.1038/nrcardio.2017.65. Epub 2017 May 11.

  PMID: 28492288 BACKGROUND

• Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul 20;355(3):251-9. doi: 10.1056/NEJMoa052256.

  PMID: 16855265 BACKGROUND

• Braunwald E. Heart failure. JACC Heart Fail. 2013 Feb;1(1):1-20. doi: 10.1016/j.jchf.2012.10.002. Epub 2013 Feb 4.

  PMID: 24621794 BACKGROUND

• Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet. 2011 Aug 20;378(9792):704-12. doi: 10.1016/S0140-6736(11)60894-5.

  PMID: 21856484 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

• Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013 Jul 23;62(4):263-71. doi: 10.1016/j.jacc.2013.02.092. Epub 2013 May 15.

  PMID: 23684677 BACKGROUND

• Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C, van Heerebeek L, Hillege HL, Lam CS, Navis G, Voors AA. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail. 2016 Jun;18(6):588-98. doi: 10.1002/ejhf.497. Epub 2016 Feb 10.

  PMID: 26861140 BACKGROUND

• Lam CS, Brutsaert DL. Endothelial dysfunction: a pathophysiologic factor in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2012 Oct 30;60(18):1787-9. doi: 10.1016/j.jacc.2012.08.004. Epub 2012 Oct 3. No abstract available.

  PMID: 23040569 BACKGROUND

• Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003 Feb 11;107(5):714-20. doi: 10.1161/01.cir.0000048123.22359.a0.

  PMID: 12578874 BACKGROUND

• Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009 Mar 31;53(13):1119-26. doi: 10.1016/j.jacc.2008.11.051.

  PMID: 19324256 BACKGROUND

• Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005 Feb;11(2):214-22. doi: 10.1038/nm1175. Epub 2005 Jan 23.

  PMID: 15665834 BACKGROUND

• Zamani P, French B, Brandimarto JA, Doulias PT, Javaheri A, Chirinos JA, Margulies KB, Townsend RR, Sweitzer NK, Fang JC, Ischiropoulos H, Cappola TP. Effect of Heart Failure With Preserved Ejection Fraction on Nitric Oxide Metabolites. Am J Cardiol. 2016 Dec 15;118(12):1855-1860. doi: 10.1016/j.amjcard.2016.08.077. Epub 2016 Sep 15.

  PMID: 27742422 BACKGROUND

• Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ, Hamdani N. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2016 Apr;4(4):312-24. doi: 10.1016/j.jchf.2015.10.007. Epub 2015 Dec 9.

  PMID: 26682792 BACKGROUND

• Oghlakian GO, Sipahi I, Fang JC. Treatment of heart failure with preserved ejection fraction: have we been pursuing the wrong paradigm? Mayo Clin Proc. 2011 Jun;86(6):531-9. doi: 10.4065/mcp.2010.0841. Epub 2011 May 16.

  PMID: 21576513 BACKGROUND

• Gladden JD, Chaanine AH, Redfield MM. Heart Failure with Preserved Ejection Fraction. Annu Rev Med. 2018 Jan 29;69:65-79. doi: 10.1146/annurev-med-041316-090654.

  PMID: 29414252 BACKGROUND

• Tschope C, Van Linthout S, Kherad B. Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. Curr Cardiol Rep. 2017 Aug;19(8):70. doi: 10.1007/s11886-017-0874-6.

  PMID: 28656481 BACKGROUND

• Gori M, Senni M, Gupta DK, Charytan DM, Kraigher-Krainer E, Pieske B, Claggett B, Shah AM, Santos AB, Zile MR, Voors AA, McMurray JJ, Packer M, Bransford T, Lefkowitz M, Solomon SD; PARAMOUNT Investigators. Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction. Eur Heart J. 2014 Dec 21;35(48):3442-51. doi: 10.1093/eurheartj/ehu254. Epub 2014 Jun 30.

  PMID: 24980489 BACKGROUND

• Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16281-6. doi: 10.1073/pnas.0707791104. Epub 2007 Oct 2.

  PMID: 17911245 BACKGROUND

• Volpe M, Magri P, Rao MA, Cangianiello S, DeNicola L, Mele AF, Memoli B, Enea I, Rubattu S, Gigante B, Trimarco B, Epstein M, Condorelli M. Intrarenal determinants of sodium retention in mild heart failure: effects of angiotensin-converting enzyme inhibition. Hypertension. 1997 Aug;30(2 Pt 1):168-76. doi: 10.1161/01.hyp.30.2.168.

  PMID: 9260976 BACKGROUND

• Nijst P, Verbrugge FH, Martens P, Dupont M, Tang WHW, Mullens W. Renal response to intravascular volume expansion in euvolemic heart failure patients with reduced ejection fraction: Mechanistic insights and clinical implications. Int J Cardiol. 2017 Sep 15;243:318-325. doi: 10.1016/j.ijcard.2017.05.041. Epub 2017 May 14.

  PMID: 28545850 BACKGROUND

• McKie PM, Schirger JA, Costello-Boerrigter LC, Benike SL, Harstad LK, Bailey KR, Hodge DO, Redfield MM, Simari RD, Burnett JC Jr, Chen HH. Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction. J Am Coll Cardiol. 2011 Nov 8;58(20):2095-103. doi: 10.1016/j.jacc.2011.07.042.

  PMID: 22051332 BACKGROUND

• Gaggin HK, Januzzi JL Jr. Biomarkers and diagnostics in heart failure. Biochim Biophys Acta. 2013 Dec;1832(12):2442-50. doi: 10.1016/j.bbadis.2012.12.014. Epub 2013 Jan 9.

  PMID: 23313577 BACKGROUND

• Damman K, Van Veldhuisen DJ, Navis G, Vaidya VS, Smilde TD, Westenbrink BD, Bonventre JV, Voors AA, Hillege HL. Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart. 2010 Aug;96(16):1297-302. doi: 10.1136/hrt.2010.194878.

  PMID: 20659949 BACKGROUND

MeSH Terms

Interventions

Sodium Chloride; Saline Solution; Furosemide

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds

Study Officials

• Adhish Agarwal, MD

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor, Nephrology

Study Record Dates

• First Submitted: February 8, 2019
• First Posted: February 12, 2019
• Study Start: May 6, 2019
• Primary Completion: February 20, 2020
• Study Completion: February 20, 2020
• Last Updated: April 19, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)