Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction
NCT ID: NCT03837470
Last Updated: 2021-04-19
Study Results
Results pending
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Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
EARLY_PHASE1
Total Enrollment
14 participants
Study Classification
INTERVENTIONAL
Study Start Date
2019-05-06
Study Completion Date
2020-02-20
Brief Summary
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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.
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Detailed Description
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In patients with heart failure with reduced ejection fraction (HFrEF), poor renal perfusion and neuro-hormonal activation cause renal salt and water retention. In contrast to HFrEF, patients with HFpEF have blunted neuro-hormonal activation, and other mechanisms likely cause fluid overload. Investigators have proposed several mechanisms including inflammatory state, endothelial dysfunction, decreased vascular compliance, pulmonary hypertension, and reduced nitric oxide (NO) bioavailability. However, the etiology and pathophysiology of fluid overload in HFpEF patients remains controversial.
Renal dysfunction is common in patients with HFpEF, and is associated with cardiac remodeling. HFpEF is associated with coronary microvascular endothelial activation and oxidative stress, which through reduction of NO dependent signaling contributes to the high cardiomyocyte stiffness and hypertrophy. Plasma sodium stiffens vascular endothelium and reduces NO release. Thus, renal sodium retention may play a pivotal role in the pathophysiology of HFpEF. Patients with HFrEF indeed have abnormal renal sodium excretion in response to salt load; however, it remains unclear if patients with HFpEF also have an impaired renal sodium excretion in response to a salt load, volume expansion or diuretics.
Since (as noted above) renal sodium retention may play an important role in the pathophysiology of HFpEF, it may be critically important to characterize renal sodium handling in patients with clinical HFpEF in response to salt loading, intravascular expansion and diuretic challenge. Impaired sodium excretion has been previously demonstrated in response to volume expansion in pre-clinical systolic and diastolic dysfunction, but not in patients with clinical HFpEF. Further, it is of note that this impairment in renal sodium excretion is rescued by exogenous B-type natriuretic peptide (BNP), which is a natriuretic peptide that is increased in most patients with HFpEF. It is possible, although not reported, that baseline BNP \[which is commonly assessed by N-terminal prohormone of BNP (NT-proBNP)\] levels affect renal sodium handling in HFpEF patients in response to salt and volume load, or diuretic challenge. It is also unknown if baseline kidney function, measured by estimated glomerular filtration rate (eGFR), affects natriuresis in patients with HFpEF after salt loading or diuretic challenge. Renal tubular function may also have important effects on salt retention in HF patients.
Characterization of the natriuretic response to intravascular salt and volume load and diuretic challenge, and of tubular function, 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.
Renal dysfunction is common in patients with HFpEF, and is associated with cardiac remodeling. HFpEF is associated with coronary microvascular endothelial activation and oxidative stress, which through reduction of NO dependent signaling contributes to the high cardiomyocyte stiffness and hypertrophy. Plasma sodium stiffens vascular endothelium and reduces NO release. Thus, renal sodium retention may play a pivotal role in the pathophysiology of HFpEF. Patients with HFrEF indeed have abnormal renal sodium excretion in response to salt load; however, it remains unclear if patients with HFpEF also have an impaired renal sodium excretion in response to a salt load, volume expansion or diuretics.
Since (as noted above) renal sodium retention may play an important role in the pathophysiology of HFpEF, it may be critically important to characterize renal sodium handling in patients with clinical HFpEF in response to salt loading, intravascular expansion and diuretic challenge. Impaired sodium excretion has been previously demonstrated in response to volume expansion in pre-clinical systolic and diastolic dysfunction, but not in patients with clinical HFpEF. Further, it is of note that this impairment in renal sodium excretion is rescued by exogenous B-type natriuretic peptide (BNP), which is a natriuretic peptide that is increased in most patients with HFpEF. It is possible, although not reported, that baseline BNP \[which is commonly assessed by N-terminal prohormone of BNP (NT-proBNP)\] levels affect renal sodium handling in HFpEF patients in response to salt and volume load, or diuretic challenge. It is also unknown if baseline kidney function, measured by estimated glomerular filtration rate (eGFR), affects natriuresis in patients with HFpEF after salt loading or diuretic challenge. Renal tubular function may also have important effects on salt retention in HF patients.
Characterization of the natriuretic response to intravascular salt and volume load and diuretic challenge, and of tubular function, 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.
Conditions
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Heart Failure With Preserved Ejection Fraction
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
BASIC_SCIENCE
Blinding Strategy
NONE
Study Groups
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Saline Loading and Diuretic Challenge
Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg
Group Type
EXPERIMENTAL
0.9% Sodium Chloride
Intervention Type
DRUG
Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes
Furosemide 40 mg
Intervention Type
DRUG
Bolus intravenous injection of 40 mg furosemide
Interventions
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0.9% Sodium Chloride
Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes
Intervention Type
DRUG
Furosemide 40 mg
Bolus intravenous injection of 40 mg furosemide
Intervention Type
DRUG
Other Intervention Names
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normal saline
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
Exclusion Criteria
* 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
* 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
Minimum Eligible Age
21 Years
Maximum Eligible Age
80 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
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University of Utah Center for Clinical and Translational Science
UNKNOWN
Sponsor Role
collaborator
Adhish Agarwal
OTHER
Sponsor Role
lead
Responsible Party
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Adhish Agarwal
Associate Professor, Nephrology
Responsibility Role
SPONSOR_INVESTIGATOR
Principal Investigators
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Adhish Agarwal, MD
Role: PRINCIPAL_INVESTIGATOR
University of Utah
Locations
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University of Utah
Salt Lake City, Utah, United States
Site Status
Countries
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United States
References
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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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
BACKGROUND
Other Identifiers
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IRB_00112270
Identifier Type: -
Identifier Source: org_study_id
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